Belmar Dissertation Dec 2012

The Pennsylvania State University
The Graduate School

Eberly College of Science
TOTAL SYNTHESES OF ()-ISOPHELLIBILINE AND ()-COMMUNESIN F,
AND DESIGN, SYNTHESIS AND PHARMACOLOGICAL EVALUATION
OF DIHYDRO-!-ERYTHROIDINE (DH!E) ANALOGS
A Dissertation in

Chemistry

by

Johannes Belmar
" 2012 Johannes Belmar
Submitted in Partial Fulfillment
of the Requirements
for the Degree of
Doctor of Philosophy

December 2012
The dissertation of Johannes Belmar was reviewed and approved* by the
following:

Raymond L. Funk
Professor of Chemistry
Dissertation Advisor
Chair of Committee

Kenneth S. Feldman
Professor of Chemistry

Scott T. Phillips
Assistant Professor of Chemistry

Robert Rioux
Friedrich G. Helfferich Assistant Professor of Chemical Engineering

Barbara J. Garrison
Shapiro Professor of Chemistry
Head of the Chemistry Department

*Signatures are on file in the Graduate School

iii
ABSTRACT
The intramolecular cycloaddition reactions of 2-amidoacroleins are
discussed in Part I. Application of this methodology in natural product synthesis
resulted in the first total synthesis of a member of the nonaromatic
homoerythrinan class of natural products, ()-isophellibiline. The synthesis was
completed in 16 linear steps from 2,2-dimethyl-1,3-dioxan-5-one in an overall
yield of 2.3%. In addition, the design, synthesis and pharmacological evaluation
of analogs of the nicotinic acetylcholine receptor (nAChR) antagonist dihydro-!-
erythroidine (DH!E) are described.
In Part II efforts towards the total synthesis of the marine natural product
()-communesin F are discussed. First, we describe the reactions of aza-ortho-
xylylenes generated via the Lewis acid catalyzed retrocycloaddition reaction of
3,1-benzoxazin-2-ones. Although, the total synthesis of communesin F was not
realized through application of this methodology, it resulted in the preparation
of an advanced intermediate towards communesin F.
Next, we explore the DielsAlder cycloaddition reactions of indol-2-one
and detail the successfully applied this methodology in a concise total synthesis
of ()-communesin F. The synthesis was completed in 15 linear steps from 4-
bromotryptophol in an overall yield of 6.7%.

iv
TABLE OF CONTENTS
LIST OF SCHEMES ................................................................................................... vi
LIST OF FIGURES ..................................................................................................... x
LIST OF TABLES ....................................................................................................... xi
ACKNOWLEDGEMENTS ....................................................................................... xii
Part I: Total Synthesis of ()-Isophellibiline and Design, Synthesis and
Pharmacological Evaluation of Dihydro-!-Erythroidine (DH!E)
Analogs ................................................................................................................ 1
Chapter 1. Introduction and Background ...................................................... 2
1.1. The Erythrina alkaloids ...................................................................... 2
1.2. Pharmacology of the Erythrina alkaloids ........................................ 2
1.3. Biosynthesis of the Erythrina alkaloids ............................................ 5
1.4. Previous synthetic efforts towards the Erythrina alkaloids ........... 8
1.4.1. Padwas strategy for the synthesis of erythrinan and
homoerythrinan alkaloids ........................................................... 9
1.4.2. Tus strategy for the synthesis of erythrinan and
homoerythrinan alkaloids ........................................................... 10
1.4.3. Tsudas syntheses of erythrinan and homoerythrinan
alkaloids via a unified synthetic strategy ................................. 11
1.5. Studies towards the erythrinan and homoerythrinan alkaloids
in the Funk laboratory: A 2-Amidoacrolein Cycloaddition
Route ..................................................................................................... 12
1.5.1. 2-Amidoacroleins ...................................................................... 12
1.5.2. Previous synthetic effort directed toward the Erythrina
alkaloids in the Funk laboratory ................................................ 15
Chapter 2. Total Synthesis of ()-Isophellibiline ........................................... 18
2.1. Retrosynthetic analysis of isophellibiline ........................................ 18
2.2. Total synthesis of ()-isophellibiline ................................................. 19
2.3. Concluding remarks ............................................................................ 26
Chapter 3. Preparation of Dihydro-!-Erythroidine (DH!E) Analogs ........ 27
3.1. Background and significance ............................................................. 27
3.1.1. Nicotinic acetylcholine receptors (nAChRs) ......................... 27
3.1.2. Pharmacophore models for nAChR ligands ......................... 29
3.1.3. Dihydro-!-erythroidine (DH!E) ............................................. 32
3.2. Synthesis of DH!E analogs ................................................................ 39
3.3. Results and discussion ........................................................................ 42
Chapter 4. Experimental ................................................................................... 44
4.1. Materials and Methods ....................................................................... 44

v
4.2. Preparative Procedures ....................................................................... 45
Spectra of Isophellibiline (Authentic and Synthetic) .................................... 72
References ........................................................................................................... 77
Part II: Total Synthesis of ()-Communesin F ....................................................... 81
Chapter 5. Introduction and Background ...................................................... 82
5.1. Isolation and structural characterization of the communesins
and perophoramidine ......................................................................... 82
5.2. Pharmacology of the communesins and perophoramidine .......... 84
5.3. Biosynthesis of the communesins and perophoramidine ............. 84
5.4. Previous synthetic approaches to the communesins ...................... 88
5.4.1. Stoltzs approach to the communesin ring system ............... 88
5.4.2. Adlingtons approach to the communesin ring system ....... 89
5.4.3. Qins total synthesis of ()-communesin F ............................ 90
5.4.4. Weinrebs total synthesis of ()-communesin F .................... 92
5.4.5. Mas total synthesis of (-)-communesin F .............................. 93
5.4.6. Mas total synthesis of communesins A and B ...................... 94
Chapter 6. Studies Towards the Communesins in the Funk
Laboratory: An Aza-ortho-xylylene Route .............................................. 97
6.1. Introduction .......................................................................................... 97
6.2. Previous synthesis efforts directed towards the communesins
in the Funk laboratory ........................................................................ 100
Chapter 7. An Approach to the Synthesis of Communesin F: An Aza-
ortho-xylylene Route ................................................................................... 103
7.1. Retrosynthetic analysis of communesin F ........................................ 103
7.2. Synthesis of an advanced intermediate towards the synthesis
of communesin F ................................................................................. 104
Chapter 8. Studies Towards the Communesins in the Funk
Laboratory: An Indol-2-one Route ........................................................... 111
8.1. Introduction .......................................................................................... 111
8.2. Prior work in the Funk laboratory .................................................... 113
Chapter 9. Total Synthesis of ()-Communesin F via a Cycloaddition
with Indol-2-one ......................................................................................... 118
9.1. Retrosynthetic analysis of communesin F ........................................ 118
9.2. Total synthesis of ()-communesin F ................................................ 119
Chapter 10. Experimental ................................................................................. 137
10.1. Materials and Methods ..................................................................... 137
10.2. Preparative Procedures ..................................................................... 138
Spectra of 1-Deoxocommunesin F and Communesin F ............................. 171
References ........................................................................................................... 176

vi
LIST OF SCHEMES
Scheme 1.3.1. Bartons proposed biosynthesis of the Erythrina alkaloids ........ 6
Scheme 1.3.2. Zenks proposed biosynthesis of the Erythrina alkaloids ........... 7
Scheme 1.4.1. Synthetic strategies for the construction of the erythtinan
and homoerythrinan ring system .................................................................... 8
Scheme 1.4.2. Padwas approach to the erythrinan and homoerythrinan
ring systems ........................................................................................................ 10
Scheme 1.4.3. Tus approach to the erythrinan and homoerythrinan ring
systems ................................................................................................................ 10
Scheme 1.4.4. Tsudas total syntheses of erysotrine and 3-epi-
schelhammeridine .............................................................................................. 11
Scheme 1.5.1. Katos synthesis of 2-amidoacroleins ............................................ 13
Scheme 1.5.2. Hons synthesis of 2-amidoacroleins ............................................ 13
Scheme 1.5.3. Funks synthesis of 2-amidoacroleins ........................................... 13
Scheme 1.5.4. Funks total syntheses featuring cycloaddition reactions of
2-amidoacroleins ................................................................................................ 14
Scheme 1.5.5. Ishiharas enantioselective cycloaddition reaction of a 2-
imidoacrolein ...................................................................................................... 15
Scheme 1.5.6. He and Funks total syntheses of ()-!-erythroidine and ()-
8-oxo-!-erythroidine .......................................................................................... 16
Scheme 2.1.1. Retrosynthetic analysis of isophellibiline ..................................... 19
Scheme 2.2.1. Preparation of dioxin 1-89 .............................................................. 19
Scheme 2.2.2. Intramolecular amidoacrolein cycloaddition .............................. 20
Scheme 2.2.3. Preparation of Z-enoate 1-84 .......................................................... 21
Scheme 2.2.4. Preparation of vinyl iodide 1-92 .................................................... 22
Scheme 2.2.5. Introduction of the tetrahydroazepine ring ................................. 22
Scheme 2.2.6. Preparation of diene 1-94 ................................................................ 23

vii
Scheme 2.2.7. Introduction of the C(3) hydroxyl substituent ............................ 23
Scheme 2.2.8. Protection of the C(3) hydroxyl group .......................................... 24
Scheme 2.2.9. Attempted reintroduction of the C(6)C(7) unsaturation .......... 24
Scheme 2.2.10. Reintroduction of the C(6)C(7) unsaturation ........................... 25
Scheme 2.2.11. Completion of the total synthesis of ()-isophellibiline ........... 25
Scheme 2.2.12. Attempted conversion of isophellibiline to phellibiline .......... 26
Scheme 3.2.1. Preparation of Type I deslactone-DH!E analogs .......................... 40
Scheme 3.2.2. Preparation of Type II deslactone-DH!E analogs ......................... 41
Scheme 5.3.1. Mantles biosynthetic pathway to communesin B ...................... 85
Scheme 5.3.2. Biosynthesis of perophoramidine ................................................. 86
Scheme 5.3.3. Stoltzs biosynthetic pathway to communesin B ........................ 86
Scheme 5.3.4. Funks biosynthetic pathway to communesin B ......................... 87
Scheme 5.4.1. Stoltzs approach to the communesin ring system ..................... 88
Scheme 5.4.2. Adlingtons initial approach to the communesin ring system .. 89
Scheme 5.4.3. Adlingtons modified approach to the communesin ring
system .................................................................................................................. 90
Scheme 5.4.4. Qins total synthesis of ()-communesin F ................................... 91
Scheme 5.4.5. Weinrebs total synthesis of ()-communesin F .......................... 92
Scheme 5.4.6. Mas total synthesis of (-)-communesin F .................................... 94
Scheme 5.4.7. Mas total synthesis of communesins A and B ............................ 95
Scheme 6.1.1. Thermal decarboxylation of 3,1-benzoxazin-2-ones ................... 98
Scheme 6.1.2. Competitive [1,5]-sigmatropic hydrogen shift ............................ 98
Scheme 6.1.3. Palladium catalyzed decarboxylation of 4-vinyl-3,1-
benzoxazin-2-ones ............................................................................................. 98

viii
Scheme 6.1.4. Base-mediated elimination of HCl from o-
chloromethylanilines ......................................................................................... 99
Scheme 6.1.5. Acid-catalyzed dehydration of 2-aminobenzyl alcohols ........... 99
Scheme 6.2.1. Crawley and Funks first-generation synthetic plan .................. 100
Scheme 6.2.2. Crawley and Funks second-generation synthetic plan ............. 101
Scheme 6.2.3. Crawley and Funks third-generation synthetic plan ................ 102
Scheme 7.1.1. Retrosynthetic analysis for communesin F .................................. 103
Scheme 7.2.1. Preparation of allenyl indole 2-110 ............................................... 105
Scheme 7.2.2. Preparation of N-acyl-4-acyl-3,1-benzoxazin-2-one 2-114 ......... 105
Scheme 7.2.3. Synthesis of aminal 2-103 ............................................................... 106
Scheme 7.2.4. Alkylation of lactam 2-103 .............................................................. 107
Scheme 7.2.5. Attempted transamidation reaction .............................................. 108
Scheme 7.2.6. Crawleys inadvertent transamidation reaction .......................... 108
Scheme 7.2.7. Crawleys transamidation reaction of tosylimide 2-120 ............. 109
Scheme 7.2.8. Attempted preparation of a more reactive imide ....................... 110
Scheme 8.1.1. Remote addition of a nucleophile to an indol-2-one
intermediate ........................................................................................................ 112
Scheme 8.1.2. Cycloaddition reaction of an indol-2-one intermediate ............. 112
Scheme 8.2.1. Fuchs and Funks total synthesis of ()-perophoramidine ........ 114
Scheme 8.2.2. Crawley and Funks intramolecular indol-2-one
cycloaddition approach towards the communesins ..................................... 115
Scheme 8.2.3. Crawley and Funks planned intermolecular indol-2-one
cycloaddition approach towards the communesins ..................................... 116
Scheme 8.2.4. Intermolecular indol-2-one cycloaddition and determination
of the stereochemical outcome ......................................................................... 117
Scheme 9.1.1. Retrosynthetic analysis for communesin F .................................. 118
Scheme 9.2.1. Reaction of 3-bromoindol-2-one with 3-methylindole ............... 120

ix
Scheme 9.2.2. Preparation of indolenine 2-157 ..................................................... 120
Scheme 9.2.3. Construction of aminal 2-167 ......................................................... 121
Scheme 9.2.4. Preparation of amide 2-169 ............................................................. 122
Scheme 9.2.5. Attempted Heck reaction ................................................................ 123
Scheme 9.2.6. Deprotection of tosylamide 2-169 .................................................. 123
Scheme 9.2.7. Preparation of bis-Boc allylic alcohol 2-173 ................................. 124
Scheme 9.2.8. Attempted benzazepine formation ............................................... 124
Scheme 9.2.9. Preparation of allylic alcohol 2-177 ............................................... 125
Scheme 9.2.10. Allylic amination with mercuric triflate ..................................... 126
Scheme 9.2.11. Introduction of the benzazepine ring ......................................... 126
Scheme 9.2.12. Possible pathway for the mercuric triflate catalyzed
cyclization ........................................................................................................... 127
Scheme 9.2.13. Preparation of bridgehead lactam 2-185 ..................................... 128
Scheme 9.2.14. Attempted alkylation of bridgehead lactam 2-186 ................... 129
Scheme 9.2.15. Preparation of bridgehead lactam 2-188 ..................................... 130
Scheme 9.2.16. Alkylation of bridgehead lactam 2-188 ....................................... 131
Scheme 9.2.17. Synthesis of 1-deoxocommunesin F .......................................... 132
Scheme 9.2.18. N-Ethylation of indolines with acyloxyborohydrides .............. 133
Scheme 9.2.19. A proposed synthetic pathway to 1-deoxocommunesin F .... 134
Scheme 9.2.20. Completion of the total synthesis of ()-communesin F .......... 135
Scheme 9.3.1. Total synthesis of ()-communesin F ............................................ 136

x
LIST OF FIGURES
Figure 1.1.1. The Erythrina alkaloids ...................................................................... 3
Figure 1.2.1. Biologically active erythrinan and homoerythrinan alkaloids .... 4
Figure 3.1.1. Structures of acetylcholine and nicotine ......................................... 27
Figure 3.1.2. (1) BeersReich pharmacophore, (2) as applied to nicotine ......... 30
Figure 3.1.3. (1) Sheridan pharmacophore, (2) as applied to nicotine .............. 30
Figure 3.1.4. Abbott four-point pharmacophore as applied to nicotine ....... 31
Figure 3.1.5. (1) Novo Nordisk pharmacophore, (2) as applied to nicotine ..... 32
Figure 3.1.6. Structures of lead compounds and synthetic analogues .............. 34
Figure 3.1.7. Pharmacophoric elements in !-E as determined by Beers and
Reich, and DH!E and strychnine as determined by Sheridan .................... 35
Figure 3.1.8. Conformations of DH!E, protonated-cis and -trans ...................... 36
Figure 3.1.9. Type I and Type II analogs of deslactone-DH!E ............................. 39
Figure 5.1.1. The communesins and perophoramidine ....................................... 83
Figure 9.2.1. X-ray crystal structure of aminal 2-167 ........................................... 121
Figure 9.2.2. Comparison of cyclization precursor conformations.................... 125
Figure 9.2.3. X-ray crystal structure of benzazepine 2-180 ................................. 126

xi
LIST OF TABLES
Table 3.1.1. Structure and binding results for Funk and Hes DH!E
analogs ................................................................................................................. 37
Table 3.1.2. Structure and binding results for Wildeboers !-E analogs .......... 38
Table 3.3.1. Binding results for Type I and II analogs ......................................... 43
Table 8.2.1. Comparison of
1
H NMR and
13
C NMR data for synthetic ()-
communesin F and natural communesin F
5
in CDCl
3
.................................. 170

xii
ACKNOWLEDGEMENTS
Though one name appears on the cover, a dissertation is a far more collaborative
project than that. I owe a debt of gratitude to Professor Raymond Funk, who not
only offered me a place in his lab even though my background was in biology,
but also gave me the guidance and support necessary to get this thing done. I am
also indebted to the members of the Funk laboratory, individually and
collectively, for their willingness to answer my questions and give me
experimental advice. Thanks too to all my friends for the many years of good
company and friendship while in State College. Deep expressions of gratitude,
along with love, are due to my family for a lifetime of support of every kind.

Part I: Total Synthesis of ()-Isophellibiline and Design,
Synthesis and Pharmacological Evaluation of Dihydro-!-
Erythroidine (DH!E) Analogs

2
Chapter 1. Introduction and Background
1.1. The Erythrina alkaloids
The Erythrina alkaloids,
1
which have attracted significant attention due to
their biological activity and their unique structure, are a large class of natural
products isolated from the genus Erythrina. The Erythrina alkaloids can be
categorized into two groups based on their structural features: the erythrinans
which posses a 6-5-6-n tetracyclic core (A-B-C-D) and the homoerythrinans
which posses a 6-5-7-n tetracyclic core (Figure 1.1.1). These groups can be further
subdivided depending on whether the D-ring is aromatic or nonaromatic. To
date, well over 110 erythrinan alkaloids and over 70 homoerythrinan alkaloids
have been isolated.
1a,2

1.2. Pharmacology of the Erythrina alkaloids
The Erythrina genus consists of about 110 species that are distributed
throughout tropical and subtropical regions worldwide. Many Erythrina species
have played important roles in indigenous medicines.
1b,1c,3
For example, E.
americana was used by Aztec Indians as a purgative, diuretic, sudorific, and
hypnotic.
4
The Huastec of Mexico used the aqueous extract of the leaves of E.
americana in the treatment of insomnia and restless anxiety.
5
The bark of E. fusca
and E. indica have been used to treat fever, malaria, rheumatism, toothache, and
boils.
6

3

Figure 1.1.1. The Erythrina alkaloids
In the late 1870s, Altimirano and Dominguez reported that extracts of the
seeds of E. americana produced a curare-like action (i.e., causes paralysis of
smooth muscle).
7
However, it was not until 1937 that Folkers and Major
8
isolated
a physiologically active crystalline alkaloid, named erythroidine, from the seeds
of E. americana and demonstrated that it caused a curare-like action. Subsequent
analysis showed that the substance isolated was a mixture of two isomeric
alkaloids designated #-erythroidine (1-9, Figure 1.2.1) and !-erythroidine (1-6,
Figure 1.1.1), the latter being the more active isomer.
9
!-Erythroidine (1-6) and its
N
O
HO
O
1-8
isophellibiline
N
O
O
O
N
O
O
O
N
O
O
O
N
O
O
O
N
O
O
O
1-4
3-epi-schelhammericine
1-3
comosine
1-6
!-erythroidine
1-7
cocculolidine
1-1
erythraline
N
O
O
1-5
selaginoidine
N
O
O
1-2
8-oxo-erymelanthine
N
MeO
2
C
N
A B
C
D
3
1
6
8
5
( )
n
n = 1 erythrinan alkaloids
n = 2 homoerythrinan alkaloids
(aromatic erythrinan) (heteroaromatic erythrinan)
(aromatic homoerythrinan) (heteroaromatic homoerythrinan)
(nonaromatic erythrinan) (nonaromatic homoerythrinan)
2
7

4

Figure 1.2.1. Biologically active erythrinan and homoerythrinan alkaloids
more potent dihydro derivative, 2,7-dihydro-!-erythroidine (DH!E, 1-10), are
antagonists of nicotinic acetylcholine receptors (nAChRs). DH!E is widely used
in functional assays as a nonselective, competitive antagonist for nAChRs.
In contrast to the erythrinan alkaloids, there are few reports on the
pharmacological effects of the homoerythrinan alkaloids. Wilsonine (1-11) has
been found to be a weak antileukemic agent in mice.
10
3-epi-12-
hydroxyschelhammericine (1-12) has been found to possess cardioactivity in rat
atrial preparations.
11
3-epi-Schelhammericine (1-4, Figure 1.1.1) and
dyshomoerythrine (1-13) have been shown to exhibit potent molluscicidal
activity.
12
Dyshomoerythrine has also demonstrated activity against a number of
agricultural pests, including the Australian sheep blowfly L. cuprina.
13

N
O
O
O
1-9
!-erythroidine
N
O
O
O
1-11
wilsonine
O
O
N
O
O
1-10
2,7-dihydro-"-erythroidine
(DH"E)
N
O
O
O
1-12
3-epi-12-hydroxyschelhammericine
N
O
O
O
1-13
dyshomoerythrine
O
OH

5
1.3. Biosynthesis of the Erythrina alkaloids
In 1957, Barton and coworkers proposed the first broadly accepted
biosynthetic pathway for the biosynthesis of the Erythrina alkaloids (Scheme
1.3.1).
14
This proposal was supported by feeding studies with young E. crista-galli
plants wherein they observed that the benzylisoquinoline (S)-
norprotsoinomenine (1-14) was incorporated to the extent of 0.25% into the
erythrinan alkaloid erythraline (1-1).
15
Thus, it was proposed that (S)-
norprotsoinomenine undergoes cyclization by para-para phenol oxidative
coupling to give dienone 1-15. Ring opening of dienone 1-15 and subsequent
reduction of the imine functionality of 1-16 gives the symmetric bisphenol 1-17.
Oxidation of bisphenol 1-17 provides the bisquinone 1-18. A subsequent
intramolecular conjugate addition reaction completes the erythrinan tetracyclic
ring system to afford erysodienone (1-19), which is transformed into erythraline
(1-1).
However, Zenks observation that Bartons proposed pathway would
have constituted a biosynthetic exception to the multitude of isoquinoline
alkaloids, including the aporphines, pavines, and morphinanes, that are derived
from (S)-reticuline (1-20: N-CH
3
instead of N-H, Scheme 1.3.2), and the low
incorporation rate (0.25%) of (S)-norprotsoinomenine (1-14) prompted a
reinvestigation by Zenk and coworkers.
16
Thus, following
3
H and
13
C labeling
studies, it was shown that (S)-[1-
13
C]norreticuline (1-20) was incorporated at a
rate of 7.9% into erythraline (1-1) with exclusive incorporation of
13
C at the C(10)
position, thereby excluding the possibility of a symmetric intermediate such as

6
Scheme 1.3.1. Bartons proposed biosynthesis of the Erythrina alkaloids

1-17. A new biosynthetic pathway and mechanism for Erythrina alkaloid
biosynthesis was required in light of these findings (Scheme 1.3.2).
The revised route commences with a para-para phenol coupling of (S)-
norreticuline (1-20) to give, according to model reactions performed by Franck
and Teetz,
17
a morphindienone derivative, such as norisosalutaridine (1-21).
Subsequent formation of the methylenedioxy group provides noramurine (1-22),
which after rearrangement and reduction gives asymmetric dibenzazonine 1-25.
The free phenolic ring of dibenzazonine 1-25 is then oxidized in a two-electron
process to the diallylic cation 1-27, which reacts with the nitrogen atom to
produce erythratinone (1-28). Finally, erythratinone (1-28) is transformed into
erythraline (1-1) according to the steps previously proposed by Barton.
14

NH
HO
O
O
OH
H
NH
O
O
O
OH
H
OH
O
O
OH
N
OH
O
O
OH
NH
O
O
O
O
NH
N
O
O
HO
O
[H]
[O]
1-14
(S)-norprotosinomenine
1-19
erysodienone
1-15 1-16
1-17 1-18
N
O
O
O
1-1
erythraline

7
Scheme 1.3.2. Zenks proposed biosynthesis of the Erythrina alkaloids

The biosynthetic pathway proposed for the homoerythrinan alkaloids
based on Bartons proposal starting from the homolog of (S)-norprotsoinomenine
(1-14)
18
would likely require revision in light of the work of Zenk and coworkers.
NH
OH
O
O
OH
NH
OH
O
O
O
NH
O
O
O
O
NH
O
OH
O
O
O
OH
O
O
NH
O
OH
O
O
NH
O
O
O
O
NH
O
O
O
O
NH
N
O
O
1-28
erythratinone
O
O
- e
-
- e
-
1-20
(S)-[1-
13
C]norreticuline
1-21
norisosalutaridine
1-22
noramurine
1-23
1-24 1-25
1-26
1-27
N
O
O
O
1-1
erythraline
10
1

8
1.4. Previous synthetic efforts towards the Erythrina alkaloids
The Erythrina alkaloids have attracted considerable attention from the
synthesis community due to their biological activity and unique tetracyclic core.
In many cases, new synthetic methods have been developed and tested in the
course of this synthesis work. The most common strategies for construction of
the erythrinan and homoerythrinan core can be classified into three general
routes based on the last ring formed in the synthetic sequence: (I) formation of
the A-ring by introduction of a four-carbon unit onto the tricyclic B-C-D skeleton,
(II) formation of the B-ring by elaboration of the C(5) spirocyclic ring system,
and, the most prevalent strategy, (III) formation of the C-ring and simultaneous
construction of the C(5) quaternary center (Scheme 1.4.1).
1a
The aromatic
erythrinans have been the target of the majority of synthetic efforts, resulting in
many successful total syntheses.
1
The nonaromatic erythrinans have posed a
greater challenge,
19
and accordingly, only three members of this subclass have
Scheme 1.4.1. Synthetic strategies for the construction of the erythtinan and
homoerythrinan ring system

N
A B
C
D
3
1
6
8
5
( )
n
n = 1 erythrinan alkaloids
n = 2 homoerythrinan alkaloids
2
7
N
A B
D
5
( )
n
NH
A
C
D
5
( )
n
N
B
C
D
6
5
( )
n
I
II
III

9
been synthesized: ()-cocculolidine (1-7),
19d
!-erythroidine (1-6),
19e,19f
and ()-8-
oxo-!-erythroidine.
19f
The homoerythrinans, in comparison to the erythrinans,
have received little attention and all work has been limited to the aromatic
homoerythrinans.
2,20

Surprisingly, in light of the small structural difference between the
erythrinan and homoerythrinan alkaloids, the development of a concise, unified
strategy for the preparation of both groups of natural products has proven
elusive.
20e-h,20m
Strategies aimed at overcoming this difficult problem have thus far
focused on the synthesis of the aromatic erythrinan and homoerythrinan
alkaloids. The most notable of these efforts are described below.
1.4.1. Padwas strategy for the synthesis of erythrinan and homoerythrinan
alkaloids
Padwas strategy for constructing the core of the aromatic erythrinan and
homoerythrinan alkaloids employed a tandem reaction to construct the B and C
rings in a single operation (a combination of strategies II and III).
20k
The reaction
proceeds via an initial acid catalyzed Pummer reactions of sulfoxides 1-29 and 1-
30, and subsequent $-cyclization of the thionium ion (Scheme 1.4.2). The newly
generated N-acyliminium ions 1-31 and 1-32 then undergo a PictetSpengler
reaction to furnish the core ring system of the erythrinan and homoerythrinan
alkaloids, 1-33 and 1-34, respectively. The authors have yet to report on the
application of this strategy in the context of total syntheses of members of the
erythrinan and homoerythrinan alkaloids.

10
Scheme 1.4.2. Padwas approach to the erythrinan and homoerythrinan ring
systems

1.4.2. Tus strategy for the synthesis of erythrinan and homoerythrinan alkaloids
Tu utilized a similar disconnection to construct the C ring in their
synthesis of the aromatic erythrinan and homoerythrinan alkaloid core ring
systems (strategy III).
20i
In this case, the B ring was constructed via an initial
alkylation of 1-35 with either 1-36 or 1-37, which was followed by a subsequent
intramolecular cyclization (Scheme 1.4.3). Upon treatment with TFA, lactams 1-
38 and 1-39 underwent a PictetSpengler reaction to give the respective
tetracycles, 1-42 and 1-43.
Scheme 1.4.3. Tus approach to the erythrinan and homoerythrinan ring systems

N
CO
2
Et
O
SEt
O
R
n N
O
O
R
EtO
2
C
SEt
n
1-29 n = 1, R = H
1-30 n = 2, R = Et
1-33 n = 1, R = H (76%)
1-34 n = 2, R = Et (40%)
N
O
O
R
EtO
2
C
SEt
n
1-31 n = 1, R = H
1-32 n = 2, R = Et
O
TFAA, TFA,
CH
2
Cl
2
, rt,
2 h
O
O
O
O
O
N
O
HO
O
R
n
O
O
N
O
O
R
n
N
O
O
R
n
O
TFA,
CH
2
Cl
2
,
rt, 24 h
O
n
R
NH
O
I
LDA, THF, -78 C;
1-36 n = 1, R = H
1-37 n = 2, R = Me
1-38 n = 1, R = H (84%)
1-39 n = 2, R = Me (86%)
1-42 n = 1, R = H (75%)
1-43 n = 2, R = Me (83%)
1-40 n = 1, R = H
1-41 n = 2, R = Me
1-35
H

11
1.4.3. Tsudas syntheses of erythrinan and homoerythrinan alkaloids via a
unified synthetic strategy
To date, the Tsuda group has reported the only total synthesis of members
of the aromatic homoerythrinan alkaloids. They have reported the total syntheses
of six members of the aromatic homoerythrinan alkaloids, including comosine (1-
3, Figure 1.1.1), 3-epi-schelhammericine (1-4, Figure 1.1.1) and 3-epi-
schelhammeridine (1-51, Scheme 1.4.4).
20a-d
While lengthy (2226 steps), these
syntheses employed a strategy (strategy I) similar to that employed in the
synthesis of the aromatic erythrinan alkaloid erysotrine (1-51).
21

Thus, the [2 + 2] photocycloaddition of Danishefskys diene and
dioxopyrroloisoquinolines 1-44 and 1-45 provided the respective cyclobutane
adducts 1-46 and 1-47 (Scheme 1.4.4). Reduction of the ketone in 1-46 and 1-47
was followed by a 1,3-anionic rearrangement to complete the construction of the
Scheme 1.4.4. Tsudas total syntheses of erysotrine and 3-epi-schelhammeridine

O
OTMS
N
O
O
EtO
2
C
TMSO
O
RO
R
1
O
N
O
O
EtO
2
C
RO
R
1
O
N
O
OH EtO
2
C
RO
R
1
O
O
300 W Hg lamp,
0 C, 1 h
N
RO
R
1
O
O
erysotrine (1-50)
n = 1, R = R
1
= Me
3-epi-schelhammeridine (1-51)
n = 2, R = R
1
= -CH
2
-
n
n n
n
1-48 n = 1, R = R
1
= Me (60%)
1-49 n = 2, R = R
1
= -CH
2
- (89%)
1-44 n = 1, R = R
1
= Me
1-45 n = 2, R = R
1
= -CH
2
-
1-46 n = 1, R = R
1
= Me (64%)
1-47 n = 2, R = R
1
= -CH
2
- (80%)
1. NaBH
4
, MeOH,
0 C, 0.3 h
2. TBAF, THF,
-30 C, 1.25 h

12
A ring in 1-48 and 1-49. Further manipulation of 1-48 and 1-49 led to the total
syntheses of erysotrine (1-50) and 3-epi-schelhammeridine (1-51), respectively,
via a unified synthetic strategy.
Although these syntheses of aromatic Erythrina alkaloids are noteworthy,
it is evident that there certainly remains a need for the further development of
concise, unified routes towards the erythrina and homoerythrina alkaloids. In
particular, approaches that can accommodate the construction of the
nonaromatic erythrina and homoerythrina alkaloids are completely lacking.
1.5. Studies towards the erythrinan and homoerythrinan alkaloids in the Funk
laboratory: A 2-Amidoacrolein Cycloaddition Route
1.5.1. 2-Amidoacroleins
A survey of the literature for known methods to access 2-amidoacroleins
uncovered few possibilities, some representative examples of which are
described below. Kato and coworkers have described the oxidation of 2-amido-
1,3-diols to give 2-amidoacroleins (Scheme 1.5.1).
22
In their report, they disclosed
that oxidation of diol 1-52 under Swern conditions gives an initial !-hydroxy
aldehyde which was dehydrated under the reaction conditions to give
amidoacrolein 1-53.

13
Scheme 1.5.1. Katos synthesis of 2-amidoacroleins

Additionally, Hon and coworkers have prepared amidoacroleins 1-56 via
methlenylation of the ozonide 1-55 prepared by ozonolysis of allylamide 1-54
(Scheme 1.5.2).
23

Scheme 1.5.2. Hons synthesis of 2-amidoacroleins

The Funk laboratory has developed a versatile method for the preparation
of 2-amidoacroleins 1-59.
24
In practice, condensation of dioxanone 1-57 with an
amine generates the corresponding imine, which following acylation with an
acid chloride gives amidodioxin 1-58 (Scheme 1.5.3). The thermal or Lewis acid
catalyzed retrocycloaddition of amidodioxins 1-58 yields the 2-amidoacrolein 1-
59.
The Funk laboratory has demonstrated the synthetic utility of
amidoacroleins in cycloaddition
19f,24b,25
and electrophilic aromatic substitution
26

Scheme 1.5.3. Funks synthesis of 2-amidoacroleins

N
H
OH
O
N
H
H
O
O OH
(COCl)
2
, DMSO,
Et
3
N, -70
o
C
65%
1-52 1-53
N
H
O
N
H
O
O
O
O
N
H
O
H
O
O
3
,
CH
2
Cl
2
,
-78
o
C
CH
2
Br
2
,
Et
2
NH,
55
o
C, 1.5 h
42%
1-54 1-55 1-56
O O
O
O O
N
R
R'
O
O
N
H
R
R'
O
Cl
O
R'
R
NH
2
! or LA
1-57 1-58 1-59
+
O
1.
2.
PhNEt
2

14
reactions by completing the total syntheses of a number of natural products. The
key cycloaddition reactions of a few representative total syntheses are shown in
Scheme 1.5.4. In the synthesis of FR901483 (1-62), the amidoacrolein, generated
from amidodioxin 1-60, participated in a cycloaddition reaction to give the 1-
alkyl-1-aminocyclohexene 1-61 (eq. 1, Scheme 1.5.4).
24b
In the key cycloaddition
reaction in the synthesis of fasicularin (1-66), amidoacrolein 1-64 reacted with
diene 1-63 under high-pressure reaction conditions to give 1-alkyl-1-
aminocyclohexene 1-65 (eq. 2, Scheme 1.5.4).
25a
The synthesis of !-erythroidine (1-
6) featured the intramolecular cycloaddition of an amidoacrolein to prepare
Scheme 1.5.4. Funks total syntheses featuring cycloaddition reactions of 2-
amidoacroleins

O O
N
O
OMe
OMe
TIPSO
TIPSO
N
O
OMe
MeO
N
O
H
N
H
O
O
P
O
HO
HO
benzonitrile,
120
o
C
64%
1-60 1-61 1-62
FR901483
O
H
O
H
H
O
O
N
Tf
Ph
N
H
Tf
Ph
O
H
O
O N
H
H
H
SCN
12 kbar,
CH
2
Cl
2
93%
1-64 1-65 1-66
fasicularin
O O
N
O
Br
N
O
O
H
H
Br
1-67 1-68
O
N
O
O
1-6
!"erythroidine
(eq. 1)
(eq. 2)
(eq. 3)
toluene,
110
o
C
66% exo
(+ 11% endo)
1-63

15
lactam 1-68 (eq. 3, Scheme 1.5.4).
19f
Thus, 2-amidoacroleins are competent
dienophiles in intramolecular and intermolecular cycloaddition reactions under
both thermal and high-pressure reaction conditions.
More recently, Ishihara and coworkers have described the enantioselective
cycloaddition reaction of 2-imidoacrolein 1-69 (Scheme 1.5.5).
27
They report that
2-imidoacrolein 1-69 undergoes cycloaddition with diene 1-70 in the presence of
the organocatalyst 1-71 to give the 1-alkyl-1-aminocyclohexene 1-72 with 96% ee
in 82% yield.
Scheme 1.5.5. Ishiharas enantioselective cycloaddition reaction of a 2-
imidoacrolein

1.5.2. Previous synthetic effort directed toward the Erythrina alkaloids in the
Funk laboratory
To date, work in the Funk laboratory has resulted in the total synthesis of
()-!-erythroidine (1-6) and ()-8-oxo-!-erythroidine (1-79), both members of the
nonaromatic erythrinan subclass of natural products (Scheme 1.5.6).
19f
The
syntheses of the natural products commenced with the retrocycloaddition of
dioxin 1-67 and concomitant intramolecular cycloaddition of the intermediate
amidoacrolein to afford exo-cycloadduct 1-68 as the major product. Aldehyde 1-
H
O
N
O
O
+ PhthN
O
H
NH N
NH
2
Bn
iBu
C
6
F
5
SO
3
H
82% (96% ee)
1-69 1-70
1-71
1-72

16
68 was transformed under the StillGennari protocol to the Z-enoate 1-73. Heck
cyclization of vinyl bromide 1-73 afforded the E-dienoate, which was hydrolyzed
to give acid 1-74. Upon heating, acid 1-74 underwent a 6$-electrocyclic closure to
the corresponding lactone. The lactone was protected as ortho ester 1-75. The
C(6)C(7) unsaturation was introduced by selenylation/oxidative deselenylation
to give the diene lactam which was deconjugated to diene 1-76. A
diastereoselective cycloaddition of diene 1-76 with singlet oxygen from the less
hindered face and a reductive workup gave diol 1-77. Subsequent treatment of
diol 1-77 with potassium hydroxide and methyl iodide in the presence of a phase
Scheme 1.5.6. He and Funks total syntheses of ()-!-erythroidine and ()-8-oxo-
!-erythroidine

O
N
O
O
N
O
O
O
O
N
O
O
H
N
O
H
O
O
Br
O O
N
O
Br
N
O
O
H
H
Br
O
N
O
O
O
O
N
O
O
O
O
OH
HO
toluene,
110
o
C
66% exo
(+ 11% endo)
(F
3
CH
2
CO)
2
P
O
OMe
OK
18-Crown-6,
95%
1. Pd(OAc)
2
,
PPh
3
, K
2
CO
3
90%
2. LiOH
95%
HO
N
O
O
O
O 1. toluene,
110
o
C
89%
2. CH(OMe)
3
,
HOCH
2
CH
2
OH
95%
1. LDA, PhSeSePh;
H
2
O
2
, pyridine
86%
2. KHMDS, HMPA;
AcOH
91%
1
O
2
, h!,
rose bengal;
NH
2
CSNH
2

73%
KOH, MeI,
Et
4
NBr
88%
1. AlH
3
NEt(Me)
2
80%
2. H
3
O
+
95%
H
3
O
+
96%
1-79
8-oxo-"-erythroidine
1-67 1-68 1-73
1-74 1-75 1-76
1-77 1-78 1-6
"#erythroidine
6
7
3
6

17
transfer catalyst allowed for simultaneous methylation of the C(3) hydroxyl and
for elimination of the C(6) hydroxyl to provide lactam 1-78. Hydrolysis of the
ortho ester of 1-78 furnished ()-8-oxo-!-erythroidine (1-79). Reduction of lactam
1-78 with alaneethyldimethyamine complex, followed by hydrolysis of the
ortho ester functionality completed the total synthesis of ()-!-erythroidine (1-6).

18
Chapter 2. Total Synthesis of ()-Isophellibiline
2.1. Retrosynthetic analysis of isophellibiline
Following He and Funks successful total syntheses of two nonaromatic
erythrinan alkaloids, we aimed to demonstrate the versatility of this strategy by
completing the total synthesis of a nonaromatic homoerythrinan alkaloid,
isophellibiline (1-8).
28
Isophellibiline was isolated from Phelline billiardieri
(Iliacaces) and its structure was determined from chemical and spectral data. Our
retrosynthetic approach to the synthesis of isophellibiline is illustrated in Scheme
2.1.1. It was proposed that isophellibiline could be prepared by seemingly
straightforward extension of He and Funks !-erythroidine synthesis. However,
it was expected that the seven-membered ring, the C(1)C(6) alkene, and the C(3)
hydroxyl group would make the synthesis of this natural product more
challenging. Thus, 1,6-reduction of diene amide 1-80, reduction of the lactam,
and unmasking of the lactone would give isophellibiline (1-8). Oxidation of the
deconjugated diene derived from diene 1-81 would install the C(3) hydroxyl
substituent in diene amide 1-80. Diene 1-81 would in turn arise from lactam 1-82
following protection of the lactone functionality, and introduction of the diene
functionality. Lactone 1-82 would derive from dieneoate 1-83 via a 6$-
electrocyclic ring closure. Acid 1-83 could arise from an intramolecular Heck
reaction of ester 1-84. Finally, the intramolecular cycloaddition of amidoacrolein

19
Scheme 2.1.1. Retrosynthetic analysis of isophellibiline

1-85 which possesses the necessary additional carbon within the amide alkenyl
side chain would be followed by StillGennari olefination to furnish ester 1-84.
2.2. Total synthesis of ()-isophellibiline
The total synthesis of isophellibiline commenced with the condensation of
2,2-dimethyl-1,3-dioxan-5-one (1-57) with 4-bromopent-4-ene-1-amine (1-86)
29
in
the presence of sodium sulfate to give imine 1-87 (Scheme 2.2.1.). Acylation of
imine 1-87 with hexa-3,5-dienoyl chloride

(1-88), prepared in two steps from
sorbic acid,
30
gave amidodioxin 1-89.
Scheme 2.2.1. Preparation of dioxin 1-89

N
O
O Br H
HO
N
O
O
N
O
O
O
O
N
O
O
H
O
N
O
H
HO
O
N
O
H
O
O
Br
1-8
isophellibiline
1-80 1-81 1-82
1-83 1-84
N
O
O
O
O
HO
1-85
3
1
6
7
1-89 1-57
1-86
1-88
1-87
O O
N Cl
O
Br
H
2
N
Br
O O
Na
2
SO
4
,
benzene,
rt, 8 h;
PhNEt
2
, THF,
rt, 12 h
63% (2 steps)
O
O
O O
N
Br

20
Scheme 2.2.2. Intramolecular amidoacrolein cycloaddition

Upon heating, amidodioxin 1-89 underwent a retrocycloaddition and
concomitant cycloaddition to give a 4.5:1 mixture of exo-cycloadduct 1-91 and
endo-cycloadduct 1-90, respectively (Scheme 2.2.2). Presumably, this ratio reflects
the strain energy difference between the cis-cycloadduct 1-91 and the trans-
cycloadduct 1-90 (~3 kcal/mol, PCMODEL, MMX) that is, to some extent, also
present in the respective exo-1-85 and endo-1-85 transition states, thus overriding
any putative stabilization incurred through secondary orbital interactions in
endo-1-85.
At this stage, we attempted to rectify a shortcoming in Funk and Hes !-
erythroidine (1-6) synthesis, namely, the lack of an enantioselective approach.
However, our attempt to address this issue through a classical substrate
controlled approach employing an #-silyloxy substituent on C(2) of the hexa-3,5-
dienoyl moiety was unsuccessful. Moreover, all attempts to catalyze the
O O
N
Br
N
O
H
H
N
O
O
H
H
Br
Br
N
O
O
H
H
N
O
O
H
Br
H
Br
exo-1-85 endo-1-85
13% 59%
O
O
1-89
1-90 1-91
toluene,
110 C,
6.5 h

21
intramolecular cycloaddition of amidoacrolein 1-85 with chiral catalysts such as
Carmonas rhodium catalyst,
31
Kndigs ruthenium catalyst,
32
, Nishidas
ytterbium(III) BINAMIDE complex,
33
and Ishihara
34
or Yamamotos
35
chiral
Brnstead acid catalysts, among others also proved unsuccessful.
With racemic cycloadduct 1-91 in hand, we turned our attention towards
the introduction of the key tetrahydroazepine ring. Thus, StillGennari
olefination
36
of neopentyl aldehyde 1-91 gave Z-enoate 1-84 (Scheme 2.2.3).
However, initial attempts to effect the Heck cyclization of vinyl bromide 1-84
using the conditions (Pd(OAc)
2
, PPh
3
, K
2
CO
3
) employed in the course of He and
Funks !-erythroidine synthesis, as well as several other protocols (e.g.,
Pd(OAc)
2
, P(o-tol)
3
, K
2
CO
3
; Pd(OAc)
2
, AsPh
3
, iPrNEt
2
; Pd(OAc)
2
, dppp, Et
3
N;
Pd(PPh
3
)
4
, NaOAc), provided the desired E-dienoate in very low yield (<5%)
along with significant decomposition of the starting material, usually the result
of debromination. Similarly, Heck cyclization of vinyl iodide 1-92, prepared from
the from vinyl bromide 1-84 via halogen exchange (Scheme 2.2.4),
37
led mainly to
the deiodination product. Padwa and coworkers noted similar difficulties in
effecting a Heck cyclization to form a tetrahydroazepine ring in their approach
ambiguine
38
synthesis gave the desired E-dienoate with clean inversion of
Scheme 2.2.3. Preparation of Z-enoate 1-84

(F
3
CH
2
CO)
2
P
O
OMe
OK
N
O
O
H
Br
H
N
O
H
O
O
Br
18-Crown-6, THF,
-78 C, 1 h
66%
1-91 1-84

22
Scheme 2.2.4. Preparation of vinyl iodide 1-92

stereochemistry (Scheme 2.2.5).
39
The resulting methyl ester was immediately
saponified with LiOH to give dienoic acid 1-83. As noted by Baran and
coworkers, the slow addition of Herrmanns catalyst
40
was necessary to achieve a
consistent yield in the Heck reaction. Interestingly, the reduced product was not
observed. Thus, it can be concluded that even in the highly reducing
environment (excess sodium formate), interception of the intermediate alkyl-
palladium species by hydride ion is slower than the competing !-hydride
elimination.
The next task in the total synthesis involved introduction of the lactone D-
ring (Scheme 2.2.6) and installation of the C(3) hydroxyl substituent. With these
goals in mind, heating dienoic acid 1-83 in refluxing toluene promoted a clean
6$-electrocyclic closure to lactone 1-82. Lactone 1-82 was then protected with 1,2-
ethanediol in the presence trimethyl orthoformate and catalytic acid to give ortho
Scheme 2.2.5. Introduction of the tetrahydroazepine ring

N
O
H
O
O
Br
1-84
N
O
H
O
O
I
1-92
H
N
N
H
CuI, KI, dioxane,
115 C, 96 h
95%
Pd
P
Ar
Ar
Ar = o-CH
3
C
6
H
4
O
O
Pd
O
O
P
Ar
Ar
1.

NaOCOH, Bu
4
NBr, Et
3
N,
MeCN, 85
C, 24 h
2. LiOH, THF, MeOH, H
2
O,
rt, 3 h, 65% (2 steps)
N
O
H
O
O
Br
N
O
H
HO
O
1-84 1-83

23
Scheme 2.2.6. Preparation of diene 1-94

ester 1-93. The C(6)C(7) unsaturation present in 1-81 was introduced via a
selenylation/deselenylation sequence. Treatment of diene amide 1-81 with LDA,
followed by a kinetic quench with acetic acid at low temperature (78 C),
yielded the deconjugated diene lactam 1-94.

With diene 1-94 in hand, the C(3) hydroxyl substituent could be installed.
Thus, a stereoselective cycloaddition with singlet oxygen, from the face opposite
to the bulky ortho ester, gave endoperoxide 1-95 (Scheme 2.2.7). Reduction of the
crude endoperoxide with thiourea proceeded smoothly, affording the cis-1,4-diol
1-96 in good yield.
Scheme 2.2.7. Introduction of the C(3) hydroxyl substituent

N
O
O
O
O
N
O
O
O
O
1. nBuLi, THF,
-78 C, 0.75 h;
PhSeSePh, 1 h
2. H
2
O
2
, pyridine,
CH
2
Cl
2
, 0 C, 1 h
81% (2 steps)
1-81 1-94
N
O
H
HO
O
N
O
H
O
O
N
O
H
O
O
O
1-83 1-82 1-93
toluene,
110 C,
12 h
80%
CH(OMe)
3
, CSA
HOCH
2
CH
2
OH,
CH
2
Cl
2
, rt, 12 h
78%
LDA, HMPA,
THF, -78 C,
2.5 h; AcOH

96%
6
7
1-94 1-95 1-96
N
O
O
O
O
N
O
O
O
O
OH
HO
N
O
O
O
O
O O
1
O
2
, h!,
rose bengal,
acetone,
0
o
C, 2 h;
H
2
N NH
2
S
MeOH, rt,
12h, 70%

24
Since isophellibiline (1-8) possesses a C(3) hydroxyl substituent instead of
the C(3) methoxy substituent present in !-erythroidine (1-6), we could not
employ the strategy previously utilized to reintroduce the C(6)C(7)
unsaturation (1-77!1-78, Scheme 1.5.6). Therefore, after extensive
experimentation, the C(3) hydroxyl of diol 1-96 was protected selectively as its
silyl ether (1-97) with N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide
(Scheme 2.2.8).
41

Scheme 2.2.8. Protection of the C(3) hydroxyl group

An attempt to implement the aforementioned methylation/elimination
sequence (KOH, MeI, Et
4
NBr) to install the C(6)C(7) unsaturation was
hampered by a competitive silyl transfer, resulting in the C(6) silyl ether and
subsequent methylation of the hydroxyl group at C(3) (Scheme 2.2.9). Efforts to
dehydrate 1-97 using either Martins sulfurane or the Burgess reagent also were
unsuccessful.
Scheme 2.2.9. Attempted reintroduction of the C(6)C(7) unsaturation

N
O
O
O
O
OH
TBSO
1-97
N
O
O
O
O
OH
HO
1-96
F
3
C
O
N
TBS
MeCN,
rt, 12 h
65%
3
6
N
O
O
O
O
OH
TBSO
N
O
O
O
O
OTBS
O KOH, MeI,
Et
4
NBr, THF,
DMSO, rt, 12 h
98%
1-97 1-98

25
Ultimately, a two-step sequence involving acetylation of the tertiary C(6)
hydroxyl group and subsequent elimination of the acetate with DBU
reintroduced the C(6)C(7) unsaturation present in lactam 1-99 (Scheme 2.2.10).
Scheme 2.2.10. Reintroduction of the C(6)C(7) unsaturation

All that remained to complete the total synthesis of isophellibiline was 1,6-
reduction of the diene 1-99, reduction of the lactam, and global deprotection. To
that end, selective 1,6-reduction of diene lactam 1-99 with L-Selectride gave
lactam 1-100 as the only reduction product (Scheme 2.2.11). Reduction of
lactam1-100 with alaneethyldimethylamine complex gave the corresponding
amine. Finally, hydrolysis of the ortho ester and concomitant cleavage of the silyl
ether under mildly acidic conditions furnished ()-isophellibiline (1-8) whose
spectroscopic properties were identical to those previously reported and
authentic spectra provided by Dr. Nicole Langlois.
28,42
Attempts to convert
isophellibiline (1-8) to phellibiline (1-101) under the conditions (per passage sur
Scheme 2.2.11. Completion of the total synthesis of ()-isophellibiline

N
O
O
O
O
TBSO
1-99
N
O
O
O
O
OH
TBSO
1-97
1. Ac
2
O, Et
3
N,
DMAP, CH
2
Cl
2
,
rt, 36 h, 97%
2. DBU, benzene,
80 C, 24 h
82%
6
7
N
O
O
O
O
TBSO
N
O
O
O
O
TBSO
N
O
HO
O
1. AlH
3
NEt(Me)
2
,
THF, 0 C, 0.75 h
70%
2. HCl, H
2
O, THF,
rt, 1.75 h
90%
1-99 1-100 1-8
isophellibiline
L-Selectride,
THF, -78 C,
3 h; 0 C, 2 h;
AcOH, -78 C
83%

26
une colonne dalumine; basic, neutral and acidic alumina were tested) disclosed
in the isolation paper
28
were unsuccessful (Scheme 2.2.12).
Scheme 2.2.12. Attempted conversion of isophellibiline to phellibiline

2.3. Concluding remarks
In conclusion, the first and only total synthesis of a member of the
nonaromatic homoerythrinan class of natural products, ()-isophellibiline,
43
was
completed in 16 linear steps from 2,2-dimethyl-1,3-dioxan-5-one (1-57) in an
overall yield of 2.3%. Not unexpectedly, the seven-membered ring present in the
homoerythrinan class represented an additional challenge. Finally, we have
demonstrated the versatility of the Funk laboratorys strategy for the preparation
of members of the nonaromatic erythrinan and homoerythrinan subclass of
natural products.
N
O
HO
O
1-8
isophellibiline
N
O
HO
O
1-101
phellibiline
"alumina"

27
Chapter 3. Preparation of Dihydro-!-Erythroidine (DH!E) Analogs
3.1. Background and significance
3.1.1. Nicotinic acetylcholine receptors (nAChRs)
Nicotinic acetylcholine receptors (nAChRs) are members of the ligand-
gated ion channels family.
44
The nicotinic acetylcholine receptors are the most
extensively studied of the ligand-gated ion channels. Opening of the channel
pore is triggered by the endogenous neurotransmitter acetylcholine (1-102) or
exogenous agonists, such as nicotine (1-103) (Figure 3.1.1).
45
nAChRs can be
divided into two groups: muscular and neuronal. Muscular nAChRs are located
at neuromuscular junctions where they mediate neuromuscular transmission.
Neuronal nAChRs are pentameric ion channels composed of # and ! subunits
and are critical in signal transmission in the mammalian peripheral and central
nervous system (CNS).
46
To date, eight # (#2#7, #9, and #10) and three ! (!2
!4) subunits have been identified in the mammalian nervous system.
47
The
neuronal nAChRs can be further subdivided into two subtypes: (1) the

Figure 3.1.1. Structures of acetylcholine and nicotine
1-103
nicotine
N
N
N
O
O
1-102
acetylcholine

28
homomeric nAChRs composed of an association of #7#9 subunits that binds #-
bungarotoxin (#-Bgtx), and (2) the heteromeric nAChRs composed of a
combination of # and ! subunits that are #-Bgtx insensitive.
48
Different
combinations of subunits result in receptors with distinct pharmacological and
physiological properties. The most abundant nAChRs in the CNS, and the most
interesting from a drug discovery perspective, are the #4!2 heteromeric
receptors and the #7 monomeric receptors.
45,48a
The former constitutes the high-
affinity binding site in the mammalian CNS for nicotine.
46,49
#4!2 nAChRs are
therapeutic targets for the treatment of pain, neurodegenerative diseases, such as
Alzheimers and Parkinsons diseases, and psychiatric disorders, such as
schizophrenia, attention deficit hyperactivity disorder (ADHD), anxiety and
depression, drug addiction, and nicotine addiction.
50
The development of novel
therapeutic agents that selectively interact with nAChRs has traditionally
focused on full or partial agonists, and more recently, allosteric activators.
47,50b

Full agonists are ligands that elicit a maximal response following binding and
anything producing a lower response after binding is a partial agonist. In
contrast, little effort has been directed towards the development of competitive
nAChR antagonists.
46
Competitive antagonists are ligands that reversibly bind to
the active site without eliciting a response.

29
3.1.2. Pharmacophore models for nAChR ligands
A pharmacophore model is a 3D ensemble of the minimal structural
features, such as aromatic rings, hydrophobic centroids, hydrogen bond
acceptors or donors, cations and anions, necessary to permit binding to the active
site and elicit a biological response.
46,51
Pharmacophore models can be used in the
identification of novel ligands, through drug design or database searching, that
bind to the same receptor. Given the difficulties associated with the
determination of the structure of membrane bound proteins via X-ray
crystallography or NMR studies, the structurs of nAChRs have only recently
begun to emerge.
52
Consequently, ligand-based pharmacophore models for
nACh receptors have been defined, and optimized, based on structure activity
relationships (SAR) and the binding data of a diverse set of ligands.
Beers and Reich
53
proposed the first useful pharmacophore model for the
nAChR. They suggested that a ligand required two structural elements: (1) an
onium group (N
+
) that engages in a coulombic interaction with the receptor, and
(2) a heteroatom (N or O) capable of acting as a hydrogen bond acceptor with the
receptor (Figure 3.1.2). The optimal distance between the van der Waals (vdW)
surface of the hydrogen bond acceptor (X) and the center of the onium group
was found to be 5.9 A.

30

Figure 3.1.2. (1) BeersReich pharmacophore, (2) as applied to nicotine
Sheridan and coworkers
54
utilized an ensemble distance geometry
approach to develop the BeersReich pharmacophore further. They proposed a
triangular relationship between three pharmacophore components: (1) an onium
group, (2) a hydrogen bond acceptor, and (3) a dummy site (C) representing
the centroid of an aryl ring or the carbon of a carbonyl group (Figure 3.1.3).
Sheridans model dictated that the pharmacophoric elements of a ligand meet the
following parameters: (1) a distance of 4.8 A belveen lhe hydrogen bond
acceptor (X) and lhe onium grou (N
+
), (2) a dislance of 1.2 A belveen lhe
hydrogen bond accelor and lhe dummy sile (C), and (3) a dislance of 4.0 A
belveen lhe onium grou and lhe dummy sile.

Figure 3.1.3. (1) Sheridan pharmacophore, (2) as applied to nicotine
N
+
5.9
onium group
hydrogen bond
acceptor
X
N
N
H
H
(1) (2)
vdW surface
H
3
C
N
+
4.0
4.8
1.2
aryl centroid
or carbonyl C
onium group
hydrogen bond
acceptor
X
N
N
H
C
(1) (2)

31
A key limitation with both the BeersReich and Sheridan pharmacophores
is their inherent two-dimensionality. For instance, neither model is capable of
explaining the higher binding affinity of (S)-nicotine compared to (R)-nicotine.
Additional components are required within the pharmacophore model to
provide three-dimensionality.
This deficiency was, in part, addressed by the Abbott four-point
model,
49,55
which, when compared to previous models, placed less emphasis on
the N-X (onium-hydrogen bond acceptor) distance. Rather the Abbott model
emphasized the directionality of the vectors between the onium group (1), the
hydrogen bond acceptor (2), and their respective protein counterparts (3) and (4)
(Figure 3.1.4).
Researchers at Novo Nordisk
56
have proposed a more developed vector
model, which, not unlike the Abbott model, emphasizes the importance of
receptor-related features over the N-X distance. The Novo Nordisk model maps
key interatomic distances and angles (Figure 3.1.5). The three key site points of
the model are: (1) site point a, the receptor feature related to the onium group, (2)
site point b, the receptor feature correlated to the hydrogen bond acceptor, and
(3) site point C which represents the centroid of the aryl ring or the carbon of a
carbonyl group. Site points a and b are located at the end of vectors 2.9 A in

Figure 3.1.4. Abbott four-point pharmacophore as applied to nicotine
3
4
2
1
N
H
N

32

Figure 3.1.5. (1) Novo Nordisk pharmacophore, (2) as applied to nicotine
Ienglh originaling from lhe onium grou and lhe hydrogen bond accelor. The
aramelers defining lhe harmacohore modeI are lhe dislances from ! lo C and
! lo ", and lhe angIe belveen lhese inleralomic dislance veclors. The modeI
suggesls lhal lhe key faclor for Iigand aclivily are lhe veclors lo sile oinls ! and
". Thus, lhe veclor modeI can accommodale Iigands vilh bolh shorl and
Iong N-X dislances.
It should be noted that acetylcholine (1-102, Figure 3.1.1) only possesses
two pharmacophoric features, an onium group and a hydrogen bond acceptor,
and is extremely flexible. Therefore it cannot be assumed that ligands must
conform to three-point pharmacophore models.
57

3.1.3. Dihydro-!-erythroidine (DH!E)
A compound that has been found to interact with the receptor of interest
can be an attractive starting point (lead) for drug discovery and as a biological
N
+
X C
2.9
7.3 - 8.0
2.9
6.5 - 7.4
a
b
30 - 35
onium group
aryl centroid
or carbonyl C
hydrogen bond
acceptor
site point b
site point a
N C
N H
a
b
(1) (2)

33
tool for the investigation of receptor function and mechanism. The diverse
biological activities found in Nature have resulted in natural products that
possess a high degree of molecular diversity, thus making them invaluable
sources for drugs as well as lead compounds. A number of natural products that
target nAChRs have served as leads in the development of potential drugs.
47,50a

For example, anabaseine (1-104), a toxin isolated from a marine worm, was found
to stimulate all nAChR subtypes (Figure 3.1.6).
58
However, a synthetic derivative,
3-(2,4-dimethoxybenzylidene)-anabaseine (DMXBA, 1-105) is a selective #7
nAChR partial agonist.
59
DMXBA is in clinical trials for cognition enhancement in
patients with schizophrenia, AD and ADHD.
59b
Similarly, nicotine (1-103, Figure
3.1.1), epibatidine (1-110), lobeline (1-106), anatoxin A (1-107) and others have
served as leads towards the development of novel therapeutics. To date,
varenicline (Chantix
, 1-109), a partial agonist of #4!2 nAChRs derived from

cytisine (1-108), represents the only nAChR-based therapeutic approved for use
in nicotine replacement therapy that was derived from a rational medicinal
chemistry effort.
The Funk laboratory was intrigued by the notion of examining 2,7-
dihydro-!-erythroidine (DH!E) (1-10, Figure 3.1.6) as a lead compound and to
create structure activity relationships (SAR) that may be useful in designing
subtype-selective nAChR antagonists.
2,7-Dihydro-!-erythroidine (DH!E) (1-10, Figure 3.1.6) is a semi-synthetic
compound that was first prepared by Merck researchers in the 1940s by partial
hydrogenation of !-erythroidine (!-E) (1-6, Figure 1.1.1).
9
While DH!E was

34

Figure 3.1.6. Structures of lead compounds and synthetic analogues
found to be an extremely potent curarizing agent, undesirable side-effects
limited its use in clinical practice. However, forty years after its discovery,
Williams and Robinson
60
determined that DH!E binds with high-affinity (2 nM)
to neuronal receptors in rat brain and that its distribution of binding was similar
to that of [
3
H]-nicotine and [
3
H]-acetylcholine. DH!E has since become widely
used in functional assays as a nonselective, competitive antagonist for nAChRs.
DH!E exhibits high-affinity (low nanomolar K
i
values) competitive antagonism
for #4!2 nAChRs.
61
Decker and coworkers found that DH!E had a 114-fold
greater selectivity for rat #4!2 than rat #7 receptor.
61a
Furthermore,
electrophysiological measurements on oocytes expressing human #4!2 receptor
O
N
O
O
1-10
2,7-dihydro-!-erythroidine
(DH!E)
H
N
N
Cl
1-110
epibatidine
N
O OH
H
N
O
1-107
anatoxin A
1-106
lobeline
N N
N N
OMe
OMe
1-104
anabaseine
1-105
DMXBA
N
NH
O
N
N
HN
1-108
cytisine
1-109
varenicline
(Chantix")
2
7

35
indicated that DH!E was approximately fifteen-fold less potent of an inhibitor of
the #3!2 subtype.
61c

In order to develop analogues of DH!E that displayed antagonist activity
at the #4!2 receptor, an understanding of the interaction with the receptor was
required. Specifically, it was necessary to determine which structural features of
DH!E confer affinity. In Beers and Reichs
53
examination of !-erythroidine as
compared to acetylcholine, they concluded that the oxygen atoms of the methoxy
group on the A-ring and of the lactone D-ring could both form hydrogen bonds
whose van der Waals surface measured 5.9 A from lhe onium sile (!"#, Iigure
3.1.7). In their analysis of DH!E (1-10), Sheridan and covorkers
54
also noted that
two potential hydrogen bond acceptors, which fit within the pharmacophore
constraints existed. Sheridan and coworkers favored the oxygen of the lactone D-
ring as the hydrogen bond acceptor on the basis of structural analogy to
strychnine (1-111). However, as noted previously, a shortcoming of the Beers
Reich and Sheridan pharmacophores are their inherent two-dimensionality.
Indeed, application by Funk of the more restrictive Abbott four-point model to

Figure 3.1.7. Pharmacophoric elements in !-E as determined by Beers and Reich,
and DH!E and strychnine as determined by Sheridan
O
N
O
O
1-10
(DH!E)
O
N
O
O
1-6
!-erythroidine
(!"E)
N
O
N
O
H
H
H
H H
H
1-111
strychnine
C
C

36
the analysis of DH!E led to a different conclusion. Funk concluded that a higher
energy diastereomeric trans-BC bicyclic ammonium salt (1-10b) must be invoked
in order to achieve the correct directionality vectors for the onium site and the
hydrogen bond acceptor if the lactone ring lone pair is to function as the
hydrogen bond acceptor (Figure 3.1.8). Thus, Funk proposed that the methoxy
lone pair served as the hydrogen bond acceptor.

Figure 3.1.8. Conformations of DH!E, protonated-cis and -trans
To test this hypothesis, two 2,7-dihydro-!-erythroidine (DH!E) analogs
desmethoxy-DH!E (1-112) and deslactone-DH!E (1-113)were synthesized by
Funk and He, and preliminary [
3
H]-nicotine binding assays were performed by
Prof. Peter Crooks of the University of Kentucky (Table 3.1.1). The Crooks group
found that the analog lacking the methoxy group (desmethoxy-DH!E) exhibited
an 84-fold decrease in affinity relative to DH!E, whereas the analog lacking the
lactone ring (deslactone-DH!E) exhibited only a 2.6-fold decrease in affinity
relative to DH!E. These results are in keeping with the conjecture that the
methoxy lone pair, as opposed to the lactone lone pair, functions as the hydrogen
bond acceptor.
N
O
O O
H
cis
1-10a
DH!E
(protonated-cis)
N
O
O
O
H
trans
1-10b
DH!E
(protonated-trans)
O
N
O
O
2
1
6
7
1-10
(DH!E)
"S.E. =
7.8 kcal/mol
B
C

37
Table 3.1.1. Structure and binding results for Funk and Hes DH!E analogs
Compound
K
i
(nM)
Human
[
3
H]-nicotine (#4!2)

1-10 25

1-112 2090

1-113 66

Further evidence to support this hypothesis could be found in the
structure activity relationship (SAR) studies performed by Wildeboer.
62

Wildeboer prepared two !-erythroidine (1-6) analogsdesmethoxy-!E (1-114) and
!E-diol (1-115)and performed rat and human [
3
H]-cytisine binding assays
(Table 3.1.2). In this case, it was found that the analog lacking the methoxy group
(desmethoxy-!E) had no measurable binding to rat #4!2 receptors at
concentrations up to 20 000 nM. However, the reduction in affinity may also be
due to the addition of the third carbon-carbon double bond, not the absence of
the methoxy group; this observation may be an extension of the trend observed
in the affinities of !-E versus DH!E. The analog lacking the lactone ring (!E-diol)
had an affinity that was 3.5-fold greater than that of !-E. The increase in affinity
O
N
O
O
DH!E
N
O
O
desmethoxy-DH!E
O
N
deslactone-DH!E

38
Table 3.1.2. Structure and binding results for Wildeboers !-E analogs
Compound
K
i
(nM)
Rat
[
3
H]-cytisine(#4!2)
Human
[
3
H]-cytisine(#4!2)

1-6 1 100840 Not determined

1-10
14018 620170

1-114 >20 000 Not determined

1-115
310120 24015

observed for this analog may be due to the absence of the lactone moiety, or
perhaps due to additional hydrogen bonding opportunities afforded by the diol
moiety.
We believed that these results warranted further investigation to
understand the interactions of these compounds with nAChRs. Specifically,
through the preparation of structurally simplified DH!E analogs and subsequent
binding assays, we aimed to determine structure-activity relationships that
O
N
O
O
!"E
O
N
O
O
DH!E
N
O
O
desmethoxy-!E
O
N
HO
HO
!E-diol

39
would aid in further structural manipulation of these compounds. We initiated
our investigation with the preparation of two groups of novel analogous of
deslactone-DH!E (1-113): Type I analogs that lack the piperidine ring, and Type II
analogs that lack the piperidine and pyrrolidine rings (Figure 3.1.9).

Figure 3.1.9. Type I and Type II analogs of deslactone-DH!E
3.2. Synthesis of DH!E analogs
The synthesis of the deslactone-DH!E analogs lacking the piperidine ring
(Type I) began with the known ester 1-118, prepared from either (R)- or (S)-
tyrosine (1-116) via the protocol developed by Wipf
63
(Scheme 3.2.1). The methyl
ester 1-118 was saponified to the corresponding acid, which upon treatment with
ethyl chloroformate provided lactone 1-119. Reductive cleavage of the lactone
with activated zinc and acetic acid gave acid 1-120 with concomitant
deconjugative isomerization of the olefin bond. Barton decarboxylation of acid 1-
120 furnished pyrrolidine 1-121. Reduction of the ketone 1-121 with sodium
borohydride gave alcohol 1-122 as a single diastereomer, which presumably
arose from the expected axial hydride delivery. The stereoselectivity of the
reduction was confirmed through NMR studies (COSY, NOSY) of a downstream
product (1-127). Deprotection of the Boc-carbamate 1-122 with trifluoroacetic
N
O
R
H
R
N
O
R
R
R
Type I analogs
R = H, Me
Type II analogs
R = H, Me

40
Scheme 3.2.1. Preparation of Type I deslactone-DH!E analogs

acid (TFA) afforded the parent analog 1-123. Reduction of the Boc-
carbamate 1-122 with lithium aluminum hydride provided the N-methyl analog
1-124. The alkoxide derivative of alcohol 1-122 was methylated with methyl
iodide to give methyl ether 1-125. As before, treatment of the Boc-carbamate 1-
125 with TFA gave the O-methyl analog 1-126. Finally, reduction of the Boc-
carbamate 1-125 furnished the bismethyl analog 1-127.
Preparation of the deslactone-DH!E analogs lacking both the piperidine
and pyrrolidine rings (Type II) began with the known mixture of trans-
dibromides 1-128, prepared in two steps from benzoic acid via Birch reduction,
in situ methylation,
64
followed by bromination (Scheme 3.2.2).
65
Upon treatment
NH
2
CO
2
H
HO
O
NHBoc
O
O
1-116
(R)-tyrosine
(or (S)-tyrosine)
N
O
OH
Boc
H
CO
2
Me
Na
2
CO
3
,
MeOH
90%
N
O
O
Boc
H
O
1-117 1-118
1-119
Zn, TMSCl,
BrCH
2
CH
2
Br,
AcOH
60%
N
O
Boc
H
CO
2
H
N
O
Boc
H
N
O
SH
, DCC,
DMAP;
Bu
3
SnH, AIBN
60%
NaBH
4
90%
1. LiOH
95%
2. Et
3
N;
ClCO
2
Et
96%
N
HO
Boc
H
N
O
Boc
H
NaH;
MeI 80%
1-120
1. Boc
2
O,
NaOH
77%
2. PhI(OAc)
2
,
27%
1-121
1-122
1-125
N
H
HO
H
N
HO
H
N
H
O
H
1-126
N
O
H
1-127
1-123 1-124
TFA;
K
2
CO
3

40%
TFA;
K
2
CO
3
50%
LiAlH
4
60%
LiAlH
4
65%

41
of the mixture with sodium bicarbonate, the major dibromocarboxylate
underwent an intramolecular cyclization to give bromolactone 1-129 as the only
neutral product.
66
The stereochemistry of the product (1-129) was assigned based
on the work of Ikota and Ganem,
66a
who prepared the des-methyl derivative of 1-
129. Radical debromination of bromolactone 1-129 gave the reduced lactone 1-
130. After significant experimentation with lactone 1-130 and the corresponding
methyl ester prepared via methanolysis of the lactone, it was found that lactone
1-130 could be converted into amide 1-131 in a slow reaction with ammonia gas
at elevated pressure and temperature. Treatment of amide 1-131 with lead
tetraacetate induces a rearrangement to an intermediate isocyanate, which was
trapped by the transannular hydroxyl group to give the cyclic urethane 1-132.
67

Hydrolysis of the urethane gave the primary amine 1-133. Reduction of the
Scheme 3.2.2. Preparation of Type II deslactone-DH!E analogs

Br
O
OH
O
O
O
O
HO
NH
2
O
NaHCO
3
54%
Bu
3
SnH,
AIBN
95%
NH
3
(100psi)
89%
Pb(OAc)
4
63%
O NH
O
O N
O
HO
NH
2
HO
HN
HO
N
KOH
57%
LiAlH
4
71%
LiAlH
4
56%
NaH;
MeI 78%
1-128 1-129 1-130 1-131
1-132 1-133 1-134
1-135 1-136
Br
Br

42
urethane with lithium aluminum hydride provided the N-methyl analog 1-134.
Methylation of carbamate 1-132 with methyl iodide gave the tertiary amide 1-135
that was subsequently reduced to deliver the N,N-dimethyl analog 1-136.
3.3. Results and discussion
These compounds were evaluated for their affinity in human #4!2,
human #6/#3!2!3, and human CHO #7 receptors under the supervision of
Daniel Yohannes, Senior Director for Drug Discovery at Targacept Inc. (Table
3.3.1). While all of the compounds showed excellent selectivity for the #4!2
receptor, most of the compounds, with the exception of compound (S)-1-123,
failed to bind below a micromolar concentration at the targeted receptors.
Furthermore, analysis of the data failed to reveal any trends that may have aided
in making structural refinements of our compounds in an attempt to increase
their binding affinities. Accordingly, functionality assays (antagonist/agonist)
were not pursued.

43
Table 3.3.1. Binding results for Type I and II analogs
Compound
K
i
(nM)
Human #4!2 Human #6/#3!2!3 Human CHO #7

(R)-1-123 5 400 100 000 79 000

(R)-1-127 5 500 100 000 100 000

(R)-1-124 5 600 100 000 47 000

(R)-1-127 7 900 100 000 68 000

(S)-1-123 990 37 000 100 000

(S)-1-126 1 800 100 000 4 700

(S)-1-124 6 000 45 000 78 000

(S)-1-127 65 000 100 000 28 000

1-133 11 000 100 000 100 000

1-135 18 000 75 000 43 000

1-136 5 600 90 000 100 000
N
H
HO
H
N
H
O
H
N
HO
H
N
O
H
N
H
HO
H
N
H
O
H
N
HO
H
N
O
H
HO
NH
2
HO
HN
HO
N

44
Chapter 4. Experimental
4.1. Materials and Methods
Unless otherwise stated, all reactions were performed in flame-dried
round-bottomed flasks. The flasks were fitted with rubber septa and reactions
were conducted under a positive pressure of nitrogen. Syringes or cannulae were
used to transfer air- and moisture sensitive liquids. Organic solutions were
concentrated on rotary evaporators at ~10 Torr at 30 C. Anhydrous acetonitrile
(CH
3
CN), benzene (PhH), tetrahydrofuran (THF), dichloromethane (CH
2
Cl
2
),
diethyl ether (Et
2
O), toluene, triethylamine (Et
3
N), methanol (MeOH) and
dimethylformamide (DMF) were obtained by passing commercially available
pre-dried, oxygen-free formulations through activated alumina columns. All
other commercial reagents and solvents were used as received without further
purification, unless otherwise noted. Analytical thinlayer chromatography
(TLC) was performed using Al plates (Merck 60F-254) visualized by exposure to
ultraviolet light and an aqueous solution of ceric ammonium molybdate (CAM).
Flash column chromatography was performed as described by Still et al. using
silica gel (SiO
2
) (60- pore size, 3263 m, standard grade, Dynamic
Adsorbents).
68
Silica gel was deactivated by washing, in order, with Et
3
N, EtOAc,
and then hexanes. NMR spectra were recorded on Bruker 300, 360 or 400 MHz
spectrometers and referenced from the residual undeuterated solvent in the

45
NMR solvent (CHCl
3
: % 7.26, d
6
-DMSO: % 2.50). Data is reported as follows:
chemical shift [multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet),
coupling constant(s) in Hertz, integration]. Carbon-13 NMR spectra were
recorded on Bruker 300, 360 or 400 MHz spectrometers and referenced from the
carbon resonances of the solvent (CDCl
3
: % 77.00, d
6
-DMSO: % 39.51). Data is
reported as follows: chemical shift. Infrared data (IR) were obtained with a
Perkin-Elmer 1600 IR, and are reported as follows: frequency of absorption (cm
1
). Melting points were obtained on a Thomas Hoover melting point apparatus
and are uncorrected.
4.2. Preparative Procedures

Amidodioxin 1-89: A solution of 4-bromopent-4-ene-1-amine
29
(1-86, 10.1 g, 60.8
mmol) in benzene (20 mL) was added via cannula to a suspension of 2,2-
dimethyl-1,3-dioxan-5-one (1-57, 7.26 mL, 60.8 mmol) and Na
2
SO
4
(30 g) in
benzene (200 mL) at 0 C. The suspension was warmed to rt. After 8 h, the
reaction mixture was passed through a plug of celite and the clear solution was
concentrated to provide 16.8 g (100%) of the crude imine 1-87 as colorless oil,
which was used without further purification.
O O
N
Cl
O
Br
H
2
N
Br
O O
Na
2
SO
4
,
benzene,
rt, 8 h;
PhNEt
2
, THF,
rt, 12 h
63%
O
O
O O
N
Br

46
1
H NMR (400 MHz, CDCl
3
): " 5.57 (s, 1H), 5.41 (s, 1H), 4.33 (s, 2H), 4.20 (s, 2H),
3.19 (t, J = 6.5 Hz, 1H), 2.49 (t, J = 7.2 Hz, 1H), 1.90 (p, J = 7.0, 7.1 Hz, 1H), 1.40 (s,
6H).
13
C NMR (75 MHz, CDCl
3
): " 169.3, 133.9, 116.9, 100.2, 66.8, 64.7, 60.0, 48.1,
38.9, 28.9, 23.7.
To a solution of the crude imine 1-87 (16.8 g, 60.8 mmol) in THF at -30 C was
added hexa-3,5-dienoyl chloride
30
(1-88, 7.64 mL, 61.5 mmol). After 10 minutes at
-30 C, PhNEt
2
(12.6 mL, 79.1 mmol) was added to the mixture. The mixture was
warmed to rt. After 12 h, the solvent was removed in vacuo. The residue was
taken up in Et
2
O, filtered and concentrated in vacuo. The orange oil was purified
by flash column chromatography (20% EtOAc/Hex) to give 14.4 g (64%) of
amidodioxin 1-89 as yellow oil.
1
3
): " 6.48 (s, 1H), 6.29 (ddd, J = 17.0, 10.2, 10.1 Hz, 1H),
6.07 (dd, J = 15.1, 10.9 Hz, 1H), 5.78 (ddd, J = 15.2, 7.4, 6.8 Hz, 1H), 5.57 (s, 1H),
5.36 (s, 1H), 5.10 (d, J = 16.9 Hz, 1H), 4.99 (d, J = 10.0 Hz, 1H), 4.10 (s, 2H), 3.36
(br. s, 2H), 3.14 (d, J = 6.6 Hz, 2H), 2.39 (t, J = 7.2 Hz, 1H), 1.73 (dt, J = 14.8, 7.4 Hz,
2H), 1.48 (s, 6H).
13
C NMR (75 MHz, CDCl
3
): " 171.6, 142.0, 136.3, 133.6, 133.2,
127.3, 117.1, 116.5, 114.6, 99.2, 59.4, 45.7, 38.4, 37.1, 26.3, 24.2. IR (thin film): 2994,
2941, 1662 cm
-1
. HRMS (ES) calc. for C
17
H
25
NO
3
Br [M+H]
+
: 370.1018. Found:
370.1020

47

Endo-cycloadduct 1-90 and exo-cycloadduct 1-91: To a solution of amidodioxin
1-89 (14.4 g, 38.9 mmol) in toluene (778 mL) was added butylated
hydroxytoluene (~ 100 mg). The solution was sparged with argon for 10 minutes.
The flask was fitted with a reflux condenser and heated to reflux. After 6.5 h, the
solvent was removed in vacuo. The resulting brown oil was purified by flash
column chromatography (25!66% EtOAc/Hex) to give 1.58 g (13%) of endo-
cycloadduct 1-90 as yellow oil and 7.17 g (59%) of exo-cycloadduct 1-91 as yellow
oil in the order of elution.
Endo-1-90:
1
3
): " 9.54 (s, 1H), 5.84 (d, J = 9.8 Hz, 1H), 5.61
(s, 1H), 5.53 (d, J = 9.9 Hz, 1H), 5.41 (s, 1H), 3.28 (ddd, J = 14.6, 9.2, 7.0 Hz, 1H),
3.08 (ddd, J = 14.5, 9.3, 6.4 Hz, 1H), 2.84 (br. s, 1H), 2.66 (dd, J = 16.8, 9.2 Hz, 1H),
2.45 (app. t, J = 6.6 Hz, 2H), 2.21-2.08 (m, 3H), 2.03 (m, 1H), 1.87 (m, 1H), 1.76 (m,
2H).
13
C NMR (75 MHz, CDCl
3
): " 199.5, 175.2, 133.0, 127.3, 126.2, 117.5, 70.5, 39.6,
38.8, 36.4, 32.6, 27.4, 22.6, 20.0. IR (thin film): 2928, 1731, 1693 cm
-1
. HRMS (ES)
calc. for C
14
H
19
NO
2
Br [M+H]
+
: 312.0599. Found: 312.0604.
Exo-1-91:
1
3
): " 9.51 (s, 1H), 5.80 (d, J = 9.2 Hz, 1H), 5.58
(s, 1H), 5.49 (d, J = 9.8 Hz, 1H), 5.37 (s, 1H), 3.26 (ddd, J = 14.7, 8.9, 6.2 Hz, 1H),
3.04 (ddd, J = 14.6, 8.0, 5.6 Hz, 1H), 2.81 (br. s, 1H), 2.62 (dd, J = 16.8, 9.1 Hz, 1H),
2.41 (app. t, J = 6.6 Hz, 2H), 2.18-2.03 (m, 3H), 2.02-1.91 (m, 1H), 1.90-1.78 (m, 1H),
O O
N
Br
N
O
O
H
H
N
O
O
H
Br
H
Br
endo
13%
toluene,
110
C,
6.5 h
O
+
exo
59%

48
1.77-1.63 (m, 2H).
13
C NMR (75 MHz, CDCl
3
): " 199.4, 175.1, 132.9, 127.1, 126.1,
117.4, 70.4, 39.4, 38.7, 36.3, 32.5, 27.2, 22.4, 19.8. IR (thin film): 2929, 1732, 1694 cm
-
1
14
H
19
NO
2
Br [M+H]
+
: 312.0599. Found: 312.0588.

Z-Enoate 1-84: To a solution of 18-crown-6 (3.2 g, 12.0 mmol) in THF (18 mL) at
78 C was added (CF
3
CH
2
O)
2
POCH
2
CO
2
CH
3
(0.764 mL, 3.60 mmol), followed by
dropwise addition of a solution of KHMDS (0.5 Min toluene, 7.2 mL, 3.60 mmol).
After 0.3 h, a solution of the aldehyde 1-91 (750 mg, 2.40 mmol) in THF (9.6 mL)
was added dropwise via cannula. After one hour, excess anion was quenched at
78 C by the addition of a half-saturated NH
4
Cl solution (10 mL). The reaction
mixture was then warmed to room temperature. All volatile organics were
removed in vacuo. The aqueous residue was extracted twice with EtOAc (20 mL).
The combined organic extracts were washed once with water (20 mL), once with
brine (20 mL), dried (MgSO
4
), filtered and concentrated in vacuo. Purification by
flash column chromatography (50% EtOAc/Hex) provided 703 mg (80%) of Z-
enoate 1-84 as yellow oil.
1
3
): " 6.12 (br. d, J = 12.9 Hz, 1H), 5.90 (br. d, J = 12.9 Hz,
1H), 5.77 (m, 1H), 5.59 (d, J = 0.96 Hz, 1H), 5.55, (m, 1H), 5.37 (d, J = 1.59 Hz, 1H),
3.69 (s, 3H), 3.16 (m, 2H), 3.02 (ddd, J = 14.0, 10.5, 5.3 Hz, 1H), 2.63 (dd, J = 16.6,
9.2 Hz, 1H), 2.42 (dd, J = 7.3, 7.3 Hz, 2H), 2.08 (dd, J = 16.6, 5.7 Hz, 2H), 2.02 (m,
2H), 1.87 (m, 1H), 1.76 (m, 1H).
13
C NMR (75 MHz, CDCl
3
): " 175.1, 165.5, 149.0,
N
O
O
H
Br
H
N
O
H
O
O
Br
(F
3
CH
2
CO)
2
P
O
OMe
OK
18-Crown-6, THF,
-78 C, 1 h
66%

49
133.2, 127.9, 125.8, 122.4, 117.2, 65.4, 51.9, 39.6, 39.1, 39.0, 37.1, 28.3, 27.1, 20.9. IR
(thin film): 3025, 2927, 1726, 1688 cm
-1
17
H
23
NO
3
Br [M+H]
+
:
368.0861. Found: 368.0872.

E-Dienoate S1-1: To vinyl bromide 1-84 (6.70 g, 18.2 mmol) was added sodium
formate (1.48 g, 21.8 mmol) and tetrabutylammonium bromide (11.7 g, 36.4
mmol). The flask was evacuated and backfilled with argon, twice. To this was
added MeCN (182 mL) followed by TEA (5.6 mL, 40.0 mmol, 2.2 equiv.). The
mixture was degassed by three freeze-pump-thaw iterations. The mixture was
heated to 85 C. A suspension of Hermanns catalyst (1.71 g, 1.82 mmol) in
MeCN (180 mL, degassed by three freeze-pump-thaw iterations) was added over
8 h via syringe pump to the reaction mixture. After 16 h, the reaction mixture
was cooled to rt. The mixture was diluted with EtOAc (500 mL), filtered through
a plug of silica gel, concentrated in vacuo to give E-dienoate S1-1, which was used
without further purification.
1
3
): " 5.82 (s, 1H), 5.78 (m, 1H), 5.46 (br. d, J = 10.0 Hz,
1H), 4.95 (d, J = 0.97 Hz, 1H), 4.79 (d, J = 1.3 Hz, 1H), 4.05 (ddd, J = 14.1, 5.1, 5.1
Hz, 1H), 3.64 (s, 3H), 2.85 (m, 1H), 2.77 (ddd, J = 13.7, 9.4, 3.8 Hz, 1H), 2.60 (dd, J
= 16.4, 8.8 Hz, 1H), 2.54 (m, 1H), 2.25 (ddd, J = 14.1, 9.8, 4.0 Hz, 1H), 2.1-1.75 (m,
7H).
13
C NMR (75 MHz, CDCl
3
): " 174.4, 166.8, 147.7, 128.3, 126.4, 117.1, 114.2,
Pd
P
Ar
Ar
Ar = o-CH
3
C
6
H
4
O
O
Pd
O
O
P
Ar
Ar
NaOCOH, Bu
4
NBr, Et
3
N,
MeCN, 85
C, 24 h
N
O
H
O
O
Br
N
O
H
O
O

50
67.0, 51.3, 41.1, 39.4, 37.3, 33.9, 29.9, 26.7, 20.9. IR (thin film): 2936, 1727, 1691 cm
-1
.
HRMS (ES) calc. for C
17
H
22
NO
3
[M+H]
+
: 288.1600. Found: 288.1603.

E-Dienoic acid 1-83: To a solution of the crude ester S1-1 (18.2 mmol) in
THF/MeOH/H
2
O (180 mL, 1:1:1) at 0 C was added LiOH (3.82 g, 90.9 mmol).
The mixture was warmed to rt. After 3 h at rt, the volatiles were removed in
vacuo. The aqueous residue was extracted three times with CH
2
Cl
2
(50 mL). The
aqueous layer was acidified to pH 2 (2 MHCl) and extracted three times with
EtOAc (100 mL). The combined organic extracts were dried (MgSO
4
), filtered and
concentrated in vacuo to give 3.23 g (65% over two steps) of acid 1-83.
1
H NMR (300 MHz, d
6
-DMSO): " 12.2 (s, 1H), 5.88 (s, 1H), 5.75 (br. d, J = 9.6 Hz,
1H), 5.44 (br. d, J = 9.9 Hz, 1H), 4.82 (s, 1H), 4.77 (d, J = 1.7 Hz, 1H), 3.76 (app. t, J
= 18.2, 4.6 Hz, 1H), 2.81 (m, 2H), 2.38 (m, 2H), 2.13 (m, 2H), 1.90 (m, 2H), 1.79 (d, J
= 16.2 Hz, 2H), 1.63 (m, 2H).
13
C NMR (75 MHz, d
6
-DMSO): " 173.3, 167.6, 163.4,
148.4, 129.0, 126.0, 118.8, 113.6, 66.2, 41.4, 36.7, 33.7, 29.3, 26.9, 20.5. IR (thin film):
2936, 1731, 1681 cm
-1
16
H
20
NO
3
[M+H]
+
: 274.1443. Found:
274.1421.

N
O
H
HO
O
N
O
H
O
O
LiOH, THF, MeOH,
H
2
O, rt, 3 h

65% (2 Steps)

51

Tetracyclic lactone 1-82: A solution of acid 1-83 (3.07 g, 11.2 mmol) in toluene
(750 mL) was heated at reflux for 12 h and then concentrated in vacuo.
Purification of the crude oil by flash column chromatography (100% EtOAc)
provided 2.46 g (80%) of lactone 1-82.
1
3
): " 5.81 (dd, J = 9.7, 5.8 Hz, 1H), 5.45 (br. d, J = 10.2 Hz,
Hz, 1H), 3.06 (d, J = 18.0 Hz, 1H), 2.97-2.92 (m, 2H), 2.8 (d, J = 8.3 Hz, 1H), 2.58
(dd, J = 16.6, 8.5 Hz, 1H), 2.31 (t, J = 14.9 Hz, 1H), 2.1-1.7 (m, 7H).
13
C NMR (75
MHz, CDCl
3
): " 174.7, 170.1, 133.6, 131.7, 127.7, 126.8, 72.1, 67.7, 36.8, 36.3, 35.4,
33.3, 27.3, 26.8, 26.6, 20.2. IR (thin film): 2932, 1744, 1682 cm
-1
. HRMS (ES) calc. for
C
16
H
20
NO
3
[M+H]
+
: 274.1443. Found: 274.1434.

Orthoester 1-93: To a solution of lactone 1-82 (1.00 g, 3.66 mmol) in CH
2
Cl
2
(36
mL) at 0 C was added ethylene glycol (21 mL, 366 mmol), CH(CH
3
)
3
(4.22 mL,
36.6 mmol) and 10-camphorsulfonic acid (850 mg, 3.66 mmol). The mixture was
warmed to rt. After 12 h, Et
3
N (1 mL, 7.17 mmol) was added, and the CH
2
Cl
2

removed in vacuo. The residue was taken up in EtOAc (100 mL) and washed
three times with H
2
O (100 mL), once with brine (100 mL), dried (MgSO
4
), filtered
N
O
H
HO
O
N
O
H
O
O
toluene,
110 C,
12 h
80%
N
O
H
O
O
N
O
H
O
O
O
CH(OMe)
3
, CSA
HOCH
2
CH
2
OH,
rt, 12 h
78%

52
and concentrated in vacuo. Purification by trituration (Et
2
O) gave 902 mg (78%) of
the orthoester 1-93.
1
3
): " 5.77 (dd, J = 10.6, 4.1 Hz, 1H), 5.41 (d, J = 10.2 Hz,
1H), 4.25-3.98 (m, 7H), 2.94 (ddd, J = 13.9, 7.6, 2.2 Hz, 1H), 2.87 (d, J = 8.1 Hz, 1H),
2.64 (dd, J = 16.3, 8.3 Hz, 1H), 2.55 (app. dq, J = 16.2, 2.4 Hz, 1H), 2.31 (app. dq, J
= 16.2, 1.5 Hz, 1H), 2.11-1.90 (m, 7H), 1.78 (m, 1H), 1.61 (dd, J = 16.1, 6.2 Hz, 1H).
13
C NMR (75 MHz, CDCl
3
): " 174.9, 131.8, 129.3, 128.1, 126.7, 118.3, 68.3, 64.4, 64.2,
37.3, 36.5, 35.1, 32.9, 26.8, 26.7, 25.4, 20.7. IR (thin film): 2927, 1686 cm
-1
. HRMS
(ES) calc. for C
18
H
24
NO
4
[M+H]
+
: 318.1705. Found: 318.1699.

Conjugated diene 1-81: To a solution of lactam 1-93 (300 mg, 0.945 mmol) in THF
(19 mL) at 78 C was added n-BuLi (2.5 Min hexanes, 1.5 mL, 3.78 mmol)
dropwise. The mixture was stirred for an additional 0.75 h at 78 C, then a
solution of (PhSe)
2
(885 mg, 2.84 mmol) in THF (9.5 mL) was added rapidly.
After one hour at 78 C, AcOH (0.227 mL, 3.67 mmol) was added to the mixture.
After warming to rt the reaction mixture was diluted with CH
2
Cl
2
(100 mL) and
washed with KHPO
4
(100 mL), H
2
O (100 mL), brine (100 mL), dried (MgSO
4
),
filtered and concentrated in vacuo. The crude selenide was used without further
purification.
1
3
): " 7.73 (dd, J = 5.8, 1.9 Hz, 2H), 7.28 (m, 3H), 5.78 (br.
d, J = 9.9 Hz, 1H), 5.40 (br. d, J = 10.0 Hz, 1H), 7.33-4.02 (m, 7H), 3.50 ( s, 1H), 3.13
N
O
O
O
O
N
O
H
O
O
O
1. nBuLi, THF,
-78 C, 0.75 h;
PhSeSePh, 1 h
2. H
2
O
2
, pyridine,
CH
2
Cl
2
, 0 C, 1 h
81% (2 steps)

53
(br. s, 1H), 2.96 (dd, J = 13.9, 7.5 Hz, 1H), 2.77 (dd, J = 16.0, 2.2 Hz, 1H), 2.27 (m,
2H), 2.07-1.80 (m, 6H), 1.63 (dd, J = 15.6, 5.5 Hz, 1H).
13
C NMR (75 MHz, CDCl
3
):
" 174.6, 133.3, 133.0, 131.5, 131.3, 129.2, 129.1, 127.5, 126.8, 118.3, 68.4, 67.4, 64.5,
64.1, 46.2, 43.8, 37.4, 32.9, 27.3, 27.0, 25.1, 20.6. IR (thin film): 2913, 1685 cm
-1
.
HRMS (ES) calc. for C
24
H
28
NO
4
Se

[M+H]
+
: 474.1184. Found: 474.1182.
To a solution of the crude selenide (0.945 mmol) in CH
2
Cl
2
(9 mL) at 0 C was
added sequentially, pyridine (0.322 mL, 3.96 mmol) and H
2
O
2
(50%, 0.316 mL,
5.48 mmol). Stirring was continued for one hour at 0 C. The mixture was then
poured into saturated NaHCO
3
(50 mL) and extracted three times with CH
2
Cl
2

(50 mL). The combined organic layers were dried (Na
2
SO
4
), filtered and
concentrated in vacuo. Purification by flash column chromatography (50!100%
EtOAc/Hex) provided 240 mg (81% over two steps) of diene 1-81.
1
3
): " 6.57 (dd, J = 10.0, 2.0 Hz, 1H), 6.11 (m, 1H), 5.80 (s,
1H), 4.46 (dt, J = 10.6, 3.5 Hz, 1H), 4.17-3.97 (m, 6H), 3.20 (ddd, J = 14.5, 12.1, 2.5
Hz, 1H), 2.87 (m, 1H), 2.74 (app. dq, J = 17.2, 2.8 Hz, 1H), 2.61 (t, J = 14.5 Hz, 1H),
2.40 (m, 2H), 2.17 (dd, J = 17.2, 2.2 Hz, 1H), 1.85 (dd, J = 15.3, 5.9 Hz, 1H), 1.74 (m,
1H), 1.7-1.5 (m, 2H).
13
C NMR (75 MHz, CDCl
3
): " 169.4, 158.1, 135.6, 132.2, 127.3,
118.6, 117.8, 68.7, 67.8, 64.2, 40.6, 36.5, 33.0, 28.4, 25.3, 24.2. IR (thin film): 2920,
1674 cm
-1
18
H
22
NO
4
[M+H]
+
: 316.1549. Found: 316.1544.

54

Deconjugated diene 1-94: To a solution of DIPA (0.126 mL, 0.906 mmol) in THF
(4.5 mL) at 78 C was added dropwise n-BuLi (2.5 Min hexanes, 0.346 mL, 0.865
mmol). After stirring for 0.5 h at 78 C, HMPA (0.717 mL, 4.12 mmol) was
added dropwise and stirring was continued for one hour at that temperature. To
this mixture was added dropwise a solution of diene 1-81 (130 mg, 0.412 mmol)
in THF (4.1 mL). After 2.5 h at 78 C, glacial acetic acid (0.236 mL, 4.12 mmol)
was added followed by a half saturated NH
4
Cl solution (10 mL). After warming
to rt the reaction mixture was extracted three times with EtOAc (15 mL), dried
(MgSO
4
), filtered and concentrated in vacuo. Purification by flash column
chromatography (60!80% EtOAc/Hex) provided 125 mg (96%) of the
deconjugated diene 1-94.
1
3
): " 5.95 (m, 1H), 5.91 (m, 1H), 5.84 (m, 1H), 4.29 (dt, J =
14.0, 6.9 Hz, 1H), 4.09 (m, 2H), 4.05 (s, 2H), 3.98 (m, 2H), 3.14 (d, J = 19.9 Hz, 1H),
2.93 (m, 2H), 2.83 (dd, J = 16.8, 6.3 Hz, 1H), 2.64 (d, J = 9.3 Hz, 1H), 2.56 (m, 2H),
2.06 (m, 1H), 1.97 (m, 1H), 1.77 (m, 1H).
13
C NMR (75 MHz, CDCl
3
): " 172.5, 132.8,
130.8, 124.4, 124.3, 118.3, 118.2, 67.8, 65.7, 64.1, 64.0, 38.6, 36.8, 35.8, 33.5, 33.2, 27.4,
26.1. IR (thin film): 2920, 1693, 1672 cm
-1
18
H
22
NO
4
[M+H]
+
:
316.1549. Found: 316.1545.
N
O
O
O
O
N
O
O
O
O
LDA, HMPA,
THF, -78 C,
2.5 h; AcOH

96%

55

Diol 1-96: A solution of deconjugated diene 1-94 (161 mg, 0.511 mmol) and rose
bengal (10 mg, 0.01 mmol) in a Pyrex reaction vessel was cooled to 0 C. An
oxygen sparge was established and the solution irradiated with a GE 275 Watt
sun lamp for 2 h. After warming to rt the reaction mixture was concentrated in
vacuo. The crude endoperoxide 1-95 was used without further purification.
1
3
): " 6.79 (m, 2H), 4.81 (dt, J = 5.1, 2.5 Hz, 1H), 4.33
(ddd, J = 13.9, 10.7, 6.5 Hz, 1H), 4.15 (m, 1H), 4.08-3.97 (m, 5H), 3.16 (ddd, J =
13.7, 5.9, 2.1 Hz, 1H), 2.76 (d, J = 16.4 Hz, 1H), 2.62 (dd, J = 14.4, 3.1 Hz, 1H), 2.36
(d, J = 16.4 Hz, 1H), 2.25 (dd, J = 16.9, 2.7 Hz, 1H), 2.17 (d, J = 16.9 Hz, 1H), 2.05
(m, 1H), 1.92-1.77 (m, 3H), 1.65 (m, 1H).
13
C NMR (75 MHz, CDCl
3
): " 172.5, 134.8,
131.7, 130.7, 129.6, 117.4, 82.1, 69.9, 67.9, 67.4, 64.4, 63.9, 38.8, 31.1, 26.9, 25.6. IR
(thin film): 2933, 1693 cm
-1
18
H
22
NO
6
[M+H]
+
: 348.1447.
Found: 348.1432.
To a solution of the crude endoperoxide 1-95 in MeOH (5 mL) was added
thiourea (58.0 mg, 0.767 mmol). The mixture was stirred at rt for 12 h.
Concentration of the reaction mixture and purification by flash column
chromatography (100% EtOAc) gave 126 mg (70%) of diol 1-96.
1
3
): " 6.32 (d, J = 9.7 Hz, 1H), 5.89 (d, J = 9.5 Hz, 1H), 4.29
(m, 2H), 4.16-3.93 (m, 6H), 3.10 (br. s, 1H), 2.67 (d, J = 15.3 Hz, 1H), 2.51 (m, 2H),
2.35 (m, 2H), 2.06 (d, J = 13.6 Hz, 1H), 1.83 (dd, J = 15.0, 4.2, 1H), 1.65 (m, 1H),
N
O
O
O
O
N
O
O
O
O
OH
HO
N
O
O
O
O
O O
1
O
2
, h!,
rose bengal,
acetone,
0
o
C, 2 h;
H
2
N NH
2
S
MeOH, rt,
12h, 70%

56
1.51 (m, 1H).
13
C NMR (75 MHz, CDCl
3
): " 173.8, 135.1, 134.3, 130.9, 129.1, 117.4,
74.1, 72.4, 68.6, 66.2, 64.5, 63.9, 41.7, 41.0, 40.0, 34.3, 28.9, 24.8. IR (thin film): 3405,
2917, 1665 cm
-1
18
H
24
NO
6
[M+H]
+
: 350.1604. Found:
350.1615.

Silyl ether 1-97: To a solution of diol 1-96 (40.0 mg, 0.114 mmol) in MeCN (4.6
mL) was added N-t-butyldimethylsilyl-N-methyltrifuoroacetamide (0.531 mL,
2.28 mmol). The mixture was stirred at rt for 12 h. Concentration of the reaction
mixture and purification by flash column chromatography (100% EtOAc) gave 37
mg (70%) of the silyl ether 1-97.
1
3
): " 6.32 (d, J = 9.7 Hz, 1H), 5.77 (d, J = 9.7 Hz, 1H),
4.37-4.26 (m, 2H), 4.12-3.90 (m, 6H), 2.97 (dd, J = 11.4, 11.4 Hz, 1H), 2.72 (dd, J =
11.3, 6.3 Hz, 1H), 2.64 (d, J = 15.3 Hz, 1H), 2.58-2.41 (m, 2H), 2.40-2.30 (m, 2H),
2.21 (s, 1H), 2.09 (d, J = 16.5 Hz, 1H), 1.82 (d, J = 15.2 Hz, 1H), 1.62 (m, 1H), 1.51
(m, 1H), 0.88 (s, 9H), 0.08 (s, 6H).
13
C NMR (75 MHz, CDCl
3
): " 172.8, 135.5, 134.0,
131.2, 129.4, 117.4, 74.0, 71.8, 68.6, 67.0, 64.4, 63.9, 41.4, 40.7, 39.6, 34.8, 28.9, 25.7,
24.6, 18.1, -4.65, -4.69. IR (thin film): 3392, 2929, 1682 cm
-1
. HRMS (ES) calc. for
C
24
H
38
NO
6
Si

[M+H]
+
: 464.2468. Found: 464.2459.
N
O
O
O
O
OH
HO
N
O
O
O
O
OH
TBSO
F
3
C
O
N
TBS
MeCN,
rt, 12 h
65%

57

Acetate S1-2: To a solution of silyl ether 1-97 (8.0 mg, 0.017 mmol) in CH
2
Cl
2

(0.345 mL) at 0 C was added sequentially Et
3
N (0.048 mL, 0.35 mmol), DMAP
(11.0 mg, 0.086 mmol) and Ac
2
O (0.016 mL, 0.17 mmol). The mixture was
warmed to rt. After 36 h, CH
2
Cl
2
(3 mL) was added to the mixture. The combined
organic extracts were washed five times with H
2
O (3 mL), once with brine (3
mL), dried (Na
2
SO
4
), filtered and concentrated in vacuo. Purification by flash
column chromatography (75% EtOAc/Hex) provided 8.5 mg (97%) of the acetate
S1-2.
1
3
): " 6.59 (dd, J = 10.8, 1.8 Hz, 1H), 5.73 (dd, J = 9.9, 2.8
Hz, 1H), 4.31 (m, 2H), 4.11 (m, 3H), 3.98 (m, 3H), 3.03 (d, J = 11.7 Hz, 1H), 2.96 (d,
J = 16.6 Hz, 1H), 2.73 (m, 2H), 2.54 (m, 2H), 2.44 (dd, J = 11.2, 9.0 Hz, 1H), 2.05 (d,
J = 16.3 Hz, 1H), 1.95 (s, 3H), 1.85 (dd, J = 15.6, 5.0 Hz, 1H), 1.67 (br. d, J = 10.8
Hz, 1H), 1.6-1.5 (m, 2H), 0.89 (s, 9H), 0.08 (s, 6H).
13
C NMR (75 MHz, CDCl
3
): "
171.7, 169.4, 135.3, 134.4, 130.6, 127.0, 117.3, 82.7, 72.1, 68.7, 66.8, 64.6, 64.0, 40.7,
40.1, 39.0, 34.4, 29.0, 25.8, 24.6, 22.1, 18.0, -4.4, -4.5. IR (thin film): 2930, 2856, 1737,
1700 cm
1
26
H
40
NO
7
Si

[M+H]
+
: 506.2574. Found: 506.2584.

N
O
O
O
O
OH
TBSO
N
O
O
O
O
OAc
TBSO
Ac
2
O, Et
3
N,
DMAP, CH
2
Cl
2
,
rt, 36 h
97%

58

Diene lactam 1-99: To a solution of acetate S1-2 (8.0 mg, 0.016 mmol) in PhH
(0.317 mL) was added DBU (0.003 mL, 0.02 mmol), the reaction mixture was
heated to 80 C. After 24 h, the reaction was cooled to rt and concentrated in
vacuo. Purification by flash column chromatography (100% EtOAc!5%
MeOH/EtOAc) provided 5.8 mg (82%) of diene lactam 1-99.
1
3
): " 6.53 (dd, J = 10.0, 2.1 Hz, 1H), 6.00 (d, J = 10.0 Hz,
1H), 5.89 (s, 1H), 4.54 (m, 1H), 4.45 (br. d, J = 14.1 Hz, 1H), 4.1-3.9 (m, 6H), 3.4-
3.15 (m, 2H), 3.11 (dd, J = 11.2, 4.63 Hz, 1H), 2.08 (m, 2H), 1.94-1.7 (m, 2H), 1.1
(ddd, J = 19.1, 7.1, 7.1 Hz, 1H), 0.89 (s, 9H), 0.09 (s, 6H).
13
C NMR (75 MHz,
CDCl
3
): " 169.1, 157.4, 140.1, 132.9, 127.0, 122.8, 119.6, 117.7, 69.8, 67.8, 67.0, 64.2,
64.1, 43.9, 40.7, 36.0, 28.3, 25.7, 25.2, 18.1, -4.7, -4.8. IR (thin film): 2929, 2856, 1682
cm
1
24
H
36
NO
5
Si

[M+H]
+
: 446.2363. Found: 446.2347.

Lactam 1-100: To a solution of diene 1-99 (73.0 mg, 0.164 mmol) in THF (3.3 mL)
at 78 C was added L-Selectride (1 Min THF, 0.328 L, 0.328 mmol). After 3
hours at that temperature, the reaction mixture was warmed to 0 C and stirred
for 2 hours. The mixture was then cooled to 78 C, AcOH (0.047 mL, 0.82 mmol)
was added, and warmed to rt. The reaction mixture was diluted with EtOAc (10
N
O
O
O
O
TBSO
N
O
O
O
O
OAc
TBSO
DBU, benzene,
80 C, 24 h

82%
N
O
O
O
O
TBSO
N
O
O
O
O
TBSO
L-Selectride,
THF, -78
o
C
to 0
o
C, 5 h;
AcOH, rt
83%

59
mL) and washed with NaHCO
3
(5 mL), H
2
O (5 mL), dried (MgSO
4
), filtered and
concentrated in vacuo. Purification by flash column chromatography (80%
EtOAc/Hex) provided 61 mg (83%) of lactam 1-100.
1
3
): " 5.59 (br. s, 1H), 4.37 (m, 1H), 4.17-3.93 (m, 7H),
3.09-2.92 (m, 2H), 2.79 (d, J = 18.6 Hz, 1H), 2.66 (dd, J = 10.6, 3.2 Hz, 1H), 2.55-2.38
(m, 2H), 2.33 (br. s, 2H), 2.11-1.98 (m, 1H), 1.87 (dd, J = 15.1, 5.2 Hz, 1H), 1.74 (br.
d, J = 14.0 Hz, 1H), 1.58 (dd, J = 11.5, 11.5 Hz, 2H), 0.88 (s, 9H), 0.05 (s, 6H).
13
C
NMR (75 MHz, CDCl
3
): " 171.4, 133.2, 132.5,131.2, 121.6, 118.0, 68.3, 68.1, 64.9,
64.4, 63.9, 41.5, 40.5, 36.7, 36.1, 35.5, 28.4, 25.8, 25.7, 18.2, -5.0, -5.1. IR (thin film):
2928, 1707, 1688 cm
1
24
H
38
NO
5
Si

[M+H]
+
: 448.2519. Found:
448.2501.

Amine S1-3: To a solution of lactam 1-100 (40.0 mg, 0.089 mmol) in THF (1.8 mL)
at 0 C was added AlH
3
EtNMe
2
(0.5 M in toluene, 0.232 mL, 0.116 mmol). After
45 minutes at 0 C, H
2
O/THF/Et
3
N (1:1:0.25, mL) were added to quench the
reaction. The reaction mixture was diluted with EtOAc (10 mL), and the resulting
layers were separated. The organic layer was dried (MgSO
4
), filtered and
concentrated in vacuo. Purification by flash column chromatography (40%
EtOAc/Hex) provided 27 mg (70%) of the amine S1-3.
1
3
): " 5.37 (br. s, 1H), 4.2-3.9 (m, 7H), 3.41 (dd, J = 14.2,
14.1 Hz, 1H), 3.18 (br. d, J = 23.3 Hz, 1H), 3.10 (app. dt, J = 8.4, 7.8 Hz, 1H), 2.79
N
O
O
O
O
TBSO
N
O
O
O
TBSO
AlH
3
NEt(Me)
2
,
THF,0 C, 0.75 h

70%

60
(dd, J = 8.5, 7.9 Hz, 1H), 2.60 (dd, J = 10.8, 2.8 Hz, 1H), 2.55-2.2 (m, 6H), 2.1-1.98
(m, 1H), 1.87-1.68 (m, 3H), 1.51 (dd, J = 11.4, 11.4 Hz, 1H), 1.4-1.25 (m, 2H), 0.88
(s, 9H), 0.05 (s, 6H).
13
C NMR (75 MHz, CDCl
3
): " 141.0, 131.7, 130.5, 118.4, 117.4,
68.2, 66.0, 64.3, 63.8, 49.7, 47.0, 43.1, 36.9, 35.9, 29.7, 29.3, 28.3, 25.9, 20.7, 18.2, -4.9,
-5.1. IR (thin film): 2925, 2854, 1708, 1688 cm
1
24
H
40
NO
4
Si

[M+H]
+
: 434.2727. Found: 434.2711.

Isophellibiline (1-8): To a solution of amine S1-3 (27.0 mg, 0.062 mmol) in THF
(0.900 mL) was added aqueous HCl (1 Min water, 0.250 mL, 0.249 mmol). After
1.75 h at rt, EtOAc (3 mL) was added to the mixture. The resulting layers were
separated and the aqueous layer was extracted two times with EtOAc (3 mL),
washed once with NaHCO
3
(5 mL), dried (MgSO
4
), filtered and concentrated in
vacuo. Purification by flash column chromatography (0!10% MeOH/CH
2
Cl
2
)
provided 15.0 mg (90%) of isophellibiline (1-8).
1
3
): " 5.49 (s, 1H), 4.78 (d, J = 15.5 Hz, 1H), 4.62 (d, J =
15.5 Hz, 1H), 3.89 (m, 1H), 3.40 (app. t, J = 12.8 Hz, 1H) 3.20 (d, J = 15.0 Hz, 1H),
3.00 (m, 2H), 2.83 (m, 2H), 2.64-2.43 (br. m, 5H), 2.22 (m, 2H), 2.05 (dd, J = 11.8,
3.8 Hz, 2H), 1.82 (app. dt, J = 13.5, 12.6 Hz, 1H), 1.65 (app. t, J = 11.6 Hz, 1H), 1.43
(d, J = 12.7 Hz, 1H).
13
C NMR (75 MHz, CDCl
3
): " 170.4, 140.6, 132.1, 132.0, 117.6,
72.6, 67.9, 65.4, 48.9, 46.5, 42.1, 35.7, 35.2, 30.8, 27.7, 20.6. IR (thin film): 3401, 2922,
N
O
O
O
TBSO
N
O
HO
O
isophellibiline
HCl, H
2
O,
THF, rt,
1.75 h
90%

61
2852, 1738 cm
1
16
H
22
NO
3
[M+H]
+
: 276.1600. Found:
276.1580.

Acid S1-4: To a solution of ester 1-118
63
(353 mg, 1.13 mmol) in
THF/MeOH/H
2
O (1:1:1, 11.3 mL) was added LiOH-H
2
O (238 mg, 5.67 mmol).
After 2 hours at rt, a 10% KHSO
4
solution (10 mL) and EtOAc (20 mL) were
added sequentially to the mixture. The resulting layers were separated, and the
aqueous layer was extracted twice with EtOAc (10 mL). The combined organic
extracts were dried (MgSO
4
), filtered and concentrated in vacuo to give 303 mg
(95%) of S1-4 as a brown foamy solid.
1
3
): " 6.84 (d, J = 10.3 Hz, 1H), 6.03 (d, J = 10.5 Hz, 1H),
4.60 (dd, J = 5.8, 2.5 Hz, 1H), 4.46 (dd, J = 11.7, 7.1 Hz, 1H), 3.12 (dd, J = 16.7, 6.4
Hz, 1H), 2.55 (m, 2H), 2.22 (m, 1H), 1.49 (s, 9H).

Lactone 1-119: To a solution of acid S1-4 (10.0 g, 34.8 mmol) in THF (140 mL) at 0
C was added Et
3
N (5.34 mL, 38.3 mmol). After 0.5 hours at 0 C, ethyl
chloroformate (3.66 mL, 38.3 mmol) was added to the mixture. The mixture was
warmed slowly to rt. After 12 hours, EtOAc (300 mL) was added to the mixture.
The combined organic extracts were washed once with a saturated NaHCO
3

solution (100 mL), once with water (100 mL), once with brine (100 mL), dried
N
O
OH
Boc
H
CO
2
Me
LiOH, H
2
O,
MeOH, THF
rt, 2 h
95%
N
O
OH
Boc
H
CO
2
H
N
O
OH
Boc
H
CO
2
H
N
O
O
Boc
H
O
Et
3
N, THF, 0
o
C,
1 h; ClCO
2
Et,
rt, 12 h
96%

62
(MgSO
4
), filtered and concentrated in vacuo. The brown residue was triturated
thrice with Et
2
O to yield 9.33 g (96%) of 1-119 as a white solid.
1
3
): " 6.99 (d, J = 10.4 Hz, 1H), 6.22 (d, J = 10.4 Hz, 1H),
4.69 (br. s, 1H), 4.03 (br. s, 1H), 3.36 (br. d, J = 9.3 Hz, 1H), 2.39 (m, 2H), 2.28 (dd, J
= 11.0, 1.0 Hz, 1H), 1.48 (s, 9H).

Acid 1-120: To a suspension of zinc (3.00 g, 46.1 mmol) in THF (6.6 mL) was
added dibromo ethane (0.060 mL, 0.692 mmol). The mixture was heated to reflux
for one minute. After cooling the mixture to rt, TMSCl (0.070 mL, 0.553 mmol)
was added to the mixture. After 0.25 h at rt, a solution of lactone 1-119 (1.30 g,
4.61 mmol) in THF/AcOH (1:1, 62 mL) was added slowly. After 24 h at rt, the
mixture was filtered (cotton plug), and diluted with EtOAc (300 mL). The
combined organic extracts were washed five times with water (100 mL), once
with brine (100 mL), dried (MgSO
4
), filtered and concentrated in vacuo. The crude
oil was purified by flash column chromatography (25% EtOAc/Hex) to give 779
mg (60%) of 1-120.
1
3
): " 5.77 (br. s, 1H), 4.524.45 (m, 2H), 3.56 (dd, J = 15.7,
4.7 Hz, 0.5H), 3.33 (dd, J = 15.7, 4.8 Hz, 0.5H), 3.02 (m, 1H), 2.852.73 (m, 2H), 2.24
(m, 1H), 1.48 (s, 5H), 1.42 (s, 4H).

Zn, BrCH
2
CH
2
Br,
TMSCl, AcOH,
THF, rt, 16 h
60%
N
O
Boc
H
CO
2
H
N
O
O
Boc
H
O

63

N-Boc amine 1-121: To a solution of acid 1-120 (795 mg, 2.83 mmol) in benzene
(57 mL) was added 2-mercaptopyridine N-oxide (431 mg, 3.39 mmol), N,N-
dicyclohexylcarbodiimide (875 mg, 4.24 mmol), and DMAP (518 mg, 4.24 mmol).
The mixture was heated to reflux for 2 hours. To the refluxing mixture was
added a mixture of AIBN (93 mg, 0.565 mmol) and freshly distilled tributyltin
hydride (2.28 mL, 8.48 mmol) in benzene (28 mL). After 3 hours at reflux, the
mixture was cooled to rt, and Et
2
O (100 mL) was added to the mixture. The
mixture was filtered (cotton plug) and concentrated in vacuo. The crude oil was
purified by flash column chromatography (100% Hex!10% EtOAc/Hex) to give
401 mg (60%) of 1-121.
1
3
): " 5.74 (m 1H), 4.33 (br. s, 1H), 3.86 (br. s, 1H), 3.27
(dd, J = 17.7, 6.9 Hz, 1H), 3.21 (br. s, 1H), 2.982.75 (m, 2H), 2.692.55 (m, 1H),
2.552.45 (m, 1H), 2.21 (t, J = 9.1 Hz, 1H), 1.47 (s, 9H). IR (thin film): 2974, 2929,
1700, 1697 cm
1
.

Alcohol 1-122: To a solution of ketone 1-121 (799 mg, 3.37 mmol) in MeOH (34
mL) at 0 C was added NaBH
4
(128 mg, 3.37 mmol). After 1.5 h at 0 C, water (50
mL) and EtOAc (100 mL) were added sequentially to the mixture. The resulting
N
O
Boc
H
N
O
SH
, DCC,
DMAP, PhH,
80
o
C, 2 h;
Bu
3
SnH, AIBN,
80
o
C, 3 h
60%
N
O
Boc
H
CO
2
H
N
HO
Boc
H
NaBH
3
, MeOH,
rt, 30 min
90%
N
O
Boc
H

64
layers were separated, and the aqueous layer was extracted twice with EtOAc (50
mL). The combined organic extracts were washed once with brine (50 mL), dried
(MgSO
4
), filtered and concentrated in vacuo to give 725 mg (90%) of 1-122.
1
3
): " 5.51 (m, 1H), 4.00 (br. s, 2H), 3.71 (br. s, 1H), 3.15
(ddd, J = 17.6, 10.9, 7.1 Hz, 1H), 2.952.61 (br. s, 1H), 2.512.28 (m, 3H), 1.99 (m,
1H), 1.48 (s, 9H), 1.25 (dd, J = 9.3, 7.2 Hz, 1H). IR (thin film): 3400, 2928, 1670 cm
1
.

Amine 1-123: To a solution of carbamate 1-122 (55.0 mg, 0.230 mmol) in CH
2
Cl
2

(2.3 mL) at 0 C was added TFA (0.460 mL) dropwise. After 1 hour at 0 C, the
mixture was concentrated in vacuo. The crude TFA salt was dissolved in a K
2
CO
3

solution (2 Min water, 2 mL). The aqueous layer was extracted three times with
EtOAc (5 mL). The combined organic extracts were dried (MgSO
4
), filtered and
concentrated in vacuo to give 25.0 mg (78%) of 1-123.
1
3
): " 5.49 (s, 1H), 3.98 (br. s, 1H), 3.88 (br. s, 2H), 3.47 (br.
s, 1H), 3.22 (m, 1H), 3.04 (m, 1H), 2.522.30 (m, 4H), 2.03 (m, 1H), 1.42 (dt, J =
22.0, 11.0 Hz, 1H).

N-Methyl amine 1-124: To a solution of carbamate 1-122 (41.0 mg, 171 mmol) in
Et
2
O (1.7 mL) at 0 C was added LiAlH
4
(39.0 mg, 1.03 mmol). After warming
slowly to rt, the mixture was heated to reflux. After 15 h at reflux, the mixture
TFA, DCM,
0
o
C, 1h;
K
2
CO
3
(aq)
78%
N
HO
H
H
N
HO
Boc
H
N
HO
Me
H
LAH, Et
2
O,
35
o
C, 15 h
60%
N
HO
Boc
H

65
was cooled to 0 C. To the cooled mixture was added sequentially: (1) water
(0.040 mL), (2) NaOH (4 Min water, 0.080 mL), and (3) water (0.120 mL). The
resulting suspension was filtered and concentrated in vacuo to give 16.0 mg (60%)
of 1-124 as a white solid.
1
3
): " 5.36 (s, 1H), 3.97 (m, 1H), 3.13 (t, J = 3.1 Hz, 1H),
2.47 (m, 2H), 2.38 (m, 2H), 2.33 (s, 3H), 2.322.14 (m, 2H), 2.051.83 (m, 2H), 1.32
(dd, J = 21.3, 11.1 Hz, 1H).

Methyl ether 1-125: To a solution of alcohol 1-122 (440 mg, 1.84 mmol) in DMF
(18 mL) at 0 C was added NaH (60% in mineral oil, 368 mg, 9.20 mmol). After 15
minutes at 0 C, MeI (0.286 mL, 4.60 mmol) was added to the mixture. After 1 h,
water (20 mL) and Et
2
O (80 mL) were added sequentially to the mixture. The
resulting layers were separated, and the combined organic extracts were washed
four times with water (20 mL), once with brine (20 mL), dried (MgSO
4
), filtered
and concentrated in vacuo. The crude oil was purified by flash column
chromatography (10% EtOAc/Hex) to give 373 mg (80%) of 1-125.
1
3
): " 5.51 (s, 1H), 3.96 (br. s, 1H), 3.71 (br. s, 1H), 3.52 (m,
1H), 3.39 (s, 3H), 3.15 (ddd, J = 17.5, 10.8, 6.7 Hz, 1H), 2.602.32 (m, 2H), 2.31 (dd,
J = 13.6, 6.5 Hz, 1H), 1.98 (m, 1H), 1.49 (s, 9H), 1.13 (m, 1H).

NaH, DMF,
0
o
C, 15 min;
MeI, 0
o
C, 1 h
80%
N
O
Boc
H
N
HO
Boc
H

66

Amine 1-126: To a solution of carbamate 1-125 (33.0 mg, 0.130 mmol) in CH
2
Cl
2

(2.6 mL) at 0 C was added trifluoroacetic acid (TFA) (0.261 mL) dropwise. After
1 hour at 0 C, the mixture was concentrated in vacuo. The crude TFA salt was
dissolved in a K
2
CO
3
solution (2 Min water, 2 mL). The aqueous layer was
extracted three times with EtOAc (5 mL). The combined organic extracts were
dried (MgSO
4
), filtered and concentrated in vacuo to give 10.0 mg (50%) of 1-126.
1
3
): " 5.53 (s, 1H), 3.53 (br. s, 2H), 3.38 (s, 3H), 3.27 (br. s,
1H), 3.12 (br. s, 1H), 2.50 (m, 4h), 2.02 (m, 1H), 1.36 (dd, J = 22.2, 11.1 Hz, 1H).

N-Methyl amine 1-127: To a solution of carbamate 1-125 (20.0 mg, 0.079 mmol) in
Et
2
O (1.6 mL) at 0 C was added LiAlH
4
(30.0 mg, 0.789 mmol). After warming
slowly to rt, the mixture was heated to reflux. After 15 h at reflux, the mixture
was cooled to 0 C. To the cooled mixture was added sequentially: (1) water
(0.030 mL), (2) NaOH (4 Min water, 0.060 mL), and (3) water (0.090 mL). The
resulting suspension was filtered and concentrated in vacuo to give 8.6 mg (65%)
of 1-127.
1
3
): " 5.37 (s, 1H), 3.51 (m, 1H), 3.39 (s, 1H), 2.36 (m, 1H),
2.522.28 (m, 8H), 2.18 (m, 2H), 1.91 (m, 1H), 1.18 (dd, J = 22.0, 10.4 Hz, 1H).
N
O
H
H
TFA, DCM,
0
o
C, 1h;
K
2
CO
3
(aq)
50%
N
O
Boc
H
N
O
Me
H
N
O
Boc
H
LAH, Et
2
O,
35
o
C, 15 h
65%

67

Bromolactone 1-129: To a mixture of trans-dibromides 1-128
65
(1.65 g, 5.54 mmol)
in THF (2.2 mL) and water (28 mL) was added NaHCO
3
(2.33 g, 27.7 mmol).
After 16 h at rt, Et
2
O (50 mL) was added to the mixture. The resulting layers were
separated, and the aqueous layer was extracted twice with Et
2
O (30 mL). The
combined organic extracts were washed once with brine (50 mL), dried (MgSO
4
),
filtered and concentrated in vacuo. This gave 649 mg (54%) of 1-129 that was
taken on without further purification.
1
3
): " 5.78 (br. d, J = 9.1 Hz, 1H), 5.65 (d, J = 9.2 Hz, 1H),
4.84 (br.s, 1H), 4.38 (s, 1H), 2.65 (ddd, J = 19.1, 2.5, 2.5 Hz, 1H), 2.53 (br. s, J = 19.1
Hz, 1H), 1.41 (s, 3H).
13
C NMR (75 MHz, CDCl
3
): " 175.9, 130.7, 127.2, 80.5, 77.4,
58.0, 47.5, 32.7, 17.5. IR (thin film): 3004, 1785 cm
1
.

Lactone 1-130: To a solution of bromide 1-129 (394 mg, 1.82 mmol) in benzene (9
mL) was added Bu
3
SnH (0.610 mL, 2.27 mmol) and AIBN (15.0 mg, 0.091 mmol).
The mixture was warmed to 85 C. After 3 h at 85 C, the mixture was
concentrated in vacuo. The crude oil was purified by flash column
chromatography (100% Hex ! 25% Et
2
O/Hex) to give 239 mg (95%) of 1-130.
1
3
): " 5.73 (app. t, J = 10.7 Hz, 2H), 4.82 (s, 1H), 2.45 (s,
2H), 2.25 (dd, J = 10.9, 5.9 Hz, 1H), 1.96 (d, J = 11.0 Hz, 1H), 1.36 (s, 3H).
13
C NMR
Br
O
O
O
OH
Br
Br
NaHCO
3
,
H
2
O, THF,
rt, 16 h

54%
Br
O
O
O
O
Bu
3
SnH,
AIBN, PhH
85
o
C, 3 h
95%

68
(75 MHz, CDCl
3
): " 179.0, 132.9, 126.2, 74.1, 41.0, 39.7, 31.3, 18.2. IR (thin film):
2973, 1774 cm
1
.

Amide 1-131: A Parr reactor containing solution of lactone 1-130 (408 mg, 2.95
mmol) in iPrOH (29 mL) was charged with NH
3
(g) (100 psi). After 5 days at rt,
the mixture was concentrated in vacuo to give 407 mg (89%) of 1-131 that was
1
3
): " 6.2-6.0 (br. d, 0.74H), 5.73 (m, 1H), 5.61 (d, J = 10.1
Hz, 1H), 4.00 (s, 1H), 2.96 (s, 2H), 2.25 (d, J = 17.9 Hz, 1H), 2.12 (dd, J = 13.4, 7.2
Hz, 1H), 2.02 (d, J = 17.8 Hz, 1H), 1.65 (d, J = 13.3 Hz, 1H), 1.21 (s, 3H).
13
C NMR
(75 MHz, CDCl
3
): " 180.9, 129.9, 126.5, 63.9, 42.8, 40.4, 33.0, 26.4. IR (thin film):
3346, 2947, 1643 cm
1
.

Carbamate 1-132: To a solution of amide 1-131 (1.00 g, 6.44 mmol) in DMF (130
mL) was added Pb(OAc)
4
(4.29 g, 9.67 mmol). The mixture was warmed to 90 C.
After 2 h at 90 C, the mixture was diluted with EtOAc (250 mL). The combined
organic extracts were washed five times with water (100 mL), once with brine
(100 mL), dried (MgSO
4
), filtered and concentrated in vacuo. The crude oil was
purified by flash column chromatography (70% EtOAc/Hex!100% EtOAc) to
give 621 mg (63%) of 1-132.
O
O
HO
NH
2
O
NH
3
(100psi),
iPrOH, rt, 6 d
89%
HO
NH
2
O
Pb(OAc)
4
,
DMF,
90
o
C, 2 h
63%
O NH
O

69
1
3
): " 7.21 (br. s, 1H), 5.73 (d, J = 9.7 Hz, 1H), 5.60 (d, J =
9.7 Hz, 1H), 4.87 (s, 1H), 2.50 (d, J = 19.1 Hz, 1H), 2.30 (dd, J = 19.1, 2.4 Hz, 1H),
2.00 (dd, J = 12.6, 3.4 Hz, 1H), 1.82 (d, J = 12.8 Hz, 1H), 1.29 (s, 3H).
13
C NMR (75
MHz, CDCl
3
): " 155.4, 134.5, 123.7, 72.6, 46.8, 34.5, 33.3, 25.8. IR (thin film): 3228,
2968, 1714 cm
1
.

Amine 1-133: Carbamate 1-132 (44.0 mg, 0.287 mmol) was taken up in a solution
of potassium hydroxide in water (3M, 4.8 mL, 14.4 mmol). The mixture was
heated to reflux. After 36 h at reflux, the mixture was cooled to rt. The aqueous
layer was extracted three times with 10% iPrOH/CH
2
Cl
2
(10 mL). The combined
organic extracts were dried (Na
2
SO
4
), filtered and concentrated in vacuo to give
21.0 mg (57%) of 1-133.
1
3
): " 5.64 (ddd, J = 10.0, 3.6, 3.6 Hz, 1H), 5.53 (d, J = 10.8
Hz, 1H), 3.10 (br. s, 1H), 2.20 (s, 2H), 1.84 (dd, J = 13.4, 5.5 Hz, 1H), 1.66 (dd, J =
13.4, 2.0 Hz, 1H), 1.21 (s, 3H).
13
C NMR (75 MHz, CDCl
3
): " 133.7, 124.7, 65.4, 49.1,
42.0, 34.1, 33.1. IR (thin film): 3340, 3274, 2920 cm
1
.

N-Methyl amine 1-134: To a suspension of carbamate 1-132 (35.0 mg, 0.229
mmol) in Et
2
O (4.6 mL) was added LiAlH
4
(87.0 mg, 2.29 mmol). The mixture
O NH
O
HO
NH
2
KOH, H
2
O,
100
o
C, 36 h
57%
O NH
O
HO
HN
LAH, Et
2
O,
35
o
C, 22 h
56%

70
was heated to reflux. After 22 h at reflux, the mixture was cooled to 0 C. To the
cooled mixture was added sequentially: (1) water (0.090 mL), (2) 10% NaOH(aq.)
(0.180 mL), and (3) water (0.270 mL). The resulting suspension was filtered
through celite (EtOAc) and concentrated in vacuo. The crude oil was purified by
flash column chromatography (10% MeOH/CH
2
Cl
2
, 1% NH
4
OH) to give 18.0 mg
(56%) of 1-134.
1
3
): " 5.71 (m, 1H), 5.56 (dd, J = 10.1, 1.5 Hz, 1H), 4.1 (s,
1H), 3.9-2.7 (br. s, 3H), 3.21 (s, 3H), 2.23 (m, 2H), 1.98 (dd, J = 13.6, 5.0 Hz, 1H),
1.47 (dd, J = 13.6, 2.2 Hz, 1H), 1.15 (s, 3H).
13
C NMR (75 MHz, CDCl
3
): " 132.0,
126.1, 65.4, 52.2, 38.5, 34.6, 28.2, 26.5. IR (thin film): 3283, 2925 cm
1
.

N-Methyl carbamate 1-135: To a solution of carbamate 1-132 (50.0 mg, 0.326
mmol) in DMF (3.3 mL) at 0 C was added NaH (60% in oil, 26.0 mg, 0.653
mmol). After 2 h at 0 C, methyl iodide (0.102 mL, 1.63 mmol) was added to the
mixture. The mixture was warmed slowly to rt. After 16 h at rt, a saturated
NH
4
Cl solution (5 mL) and EtOAc (10 mL) were added sequentially to the
mixture. The resulting layers were separated, and the aqueous layer was
extracted twice with EtOAc (10 mL). The combined organic extracts were washed
five times with water (5 mL), once with brine (5 mL), dried (MgSO
4
), filtered and
chromatography (2.5% MeOH/CH
2
Cl
2
) to give 42.0 mg (78%) of 1-135.
O NH
O
O N
O
NaH, DMF,
0
o
C, 2 h;
MeI, 16 h
78%

71
1
3
): " 5.94 (ddd, J = 7.6, 2.2, 1.8 Hz, 1H), 5.72 (dddd, J =
9.8, 3.8, 2.8, 0.9 Hz, 1H), 4.78 (t, J = 3.7 Hz, 1H), 2.93 (s, 3H), 2.55 (m, 1H), 2.34 (m,
1H), 2.21 (m, 1H), 1.84 (dd, J = 13.0, 1.2 Hz, 1H), 1.41 (s, 3H).
13
C NMR (75 MHz,
CDCl
3
): " 154.8, 132.1, 125.7, 70.5, 50.1, 35.7, 33.7, 29.9, 25.5. IR (thin film): 2955,
1694 cm
1
. M.P.: 75-77 C.

N-Dimethyl amine 1-136: To a solution of methyl carbamate 1-135 (22.0 mg,
0.132 mmol) in Et
2
O (2.6 mL) was added LiAlH
4
(50.0 mg, 1.32 mmol). The
mixture was heated to reflux. After 16 h at reflux, the mixture was cooled to 0 C.
To the cooled mixture was added sequentially: (1) water (0.050 mL), (2) 10%
NaOH(aq.) (0.100 mL), and (3) water (0.150 mL). The resulting suspension was
filtered through celite (EtOAc) and concentrated in vacuo. The crude oil was
purified by flash column chromatography (3.5% MeOH/CH
2
Cl
2
, 1% NH
4
OH) to
give 15.0 mg (71%) of 1-136.
1
3
): " 5.68 (m, 1H), 5.60 (dd, J = 10.3, 1.5 Hz, 1H), 4.08 (s,
1H), 2.24 (m, 8H), 1.28 (d, J = 15.5 Hz, 1H), 1.00 (s, 3H).
13
C NMR (75 MHz,
CDCl
3
): " 132.8, 125.5, 65.5, 55.5, 38.1, 35.3, 35.1, 18.9. IR (thin film): 3345, 2933 cm
1
.

O N
O
HO
N
LAH, Et
2
O,
35
o
C, 16 h
71%

72
Spectra of Isophellibiline (Authentic and Synthetic)

73

74

75

76

77
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58. Kem, W. R.; Mahnir, V. M.; Papke, R. L.; Lingle, C. J. J. Pharmacol. Exp.
Ther. 1997, 283, 979.

80
59. (a) Kem, W. R. Behav. Brain Res. 2000, 113, 169; (b) Kem, W.; Soti, F.;
Wildeboer, K.; LeFrancois, S.; MacDougall, K.; Wei, D. Q.; Chou, K. C.;
Arias, H. R. Mar. Drugs 2006, 4, 255.
60. Williams, M.; Robinson, J. J. Neurosci. 1984, 4, 2906.
61. (a) Decker, M. W.; Anderson, D. J.; Brioni, J. D.; Donnelly-Roberts, D. L.;
Kang, C. H.; O'Neill, A. B.; Piattoni-Kaplan, M.; Swanson, S.; Sullivan, J. P.
Eur. J. Pharmacol. 1995, 280, 79; (b) Harvey, S. C.; Maddox, F. N.; Luetje, C.
W. J. Neurochem. 1996, 67, 1953; (c) Chavez-Noriega, L. E.; Crona, J. H.;
Washburn, M. S.; Urrutia, A.; Elliott, K. J.; Johnson, E. C. J. Pharmacol. Exp.
Ther. 1997, 280, 346.
62. Wildeboer, K. M., University of Florida, 2005.
63. Wipf, P.; Kim, Y. T. Tetrahedron Lett. 1992, 33, 5477.
64. Binmore, G.; Cardellini, L.; Walton, J. C. J. Chem. Soc. Perkin Trans. 2 1997,
757.
65. Mah, T.; Sirat, H. M.; Thomas, E. J. J. Chem. Res., Synop . 1979, 392.
66. (a) Ikota, N.; Ganem, B. J. Am. Chem. Soc. 1978, 100, 351; (b) Ganem, B.;
Holbert, G. W.; Weiss, L. B.; Ishizumi, K. J. Am. Chem. Soc. 1978, 100, 6483.
67. (a) Acott, B.; Beckwith, A. L. J.; Hassanali, A.; Redmond, J. W. Tetrahedron
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Chem. 1975, 40, 3554.
68. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

81
Part II: Total Synthesis of ()-Communesin F

82
Chapter 5. Introduction and Background
5.1. Isolation and structural characterization of the communesins and
perophoramidine
Over the last half-century marine organisms have been found to be a rich
source of natural products possessing an enormous range of biological activity
and structural complexity.
1
In particular, the somewhat related communesins
and perophoramidine are marine natural products that have proven to be
significant challenges for synthetic chemists. Communesins A (2-1) and B (2-5)
were isolated in 1993 by Numata and coworkers from the mycelium of a strain of
Penecillium sp. stuck on the marine alga Entermorpha intestinalis (Figure 5.1.1).
2

The structures of communesins A and B were assigned via extensive NMR
experiments. Numata and coworkers also determined the relative
stereochemistry of all stereocenters, aside from the center at C(21), utilizing nOe
correlations. Subsequent studies by Hemscheidt and coworkers determined the
configuration at C(21) of communesin B (which they mistakenly assigned as the
natural product nomofungin (2-10) that bears an N,O acetal instead of the
additional aminal), and its absolute configuration (6R, 7R, 8R, 9S, 11R, 21R).
3

These findings have since been confirmed by the total synthesis of communesins
A and B (vide infra). Several other members of the communesin family have also
been identified, including: communesins C (2-6),
4
D (2-7),
4
E (2-2),
5
F (2-8),
5
G (2-
3),
6
and H (2-4).
6
The communesins all possess: (1) a tryptophan derived
heptacyclic skeleton, (2) two bicyclic aminals, and (3) four contiguous

83

Figure 5.1.1. The communesins and perophoramidine
stereocenters, including two vicinal quaternary centers at C(7) and C(8)
possessing a cis-relationship of the tryptamine derived (vide infra) aminoethyl
moieties. The communesins are differentiated by: (1) their substituents at N(15)
and N(16), and (2) the oxidation state of C(21) and C(22). Communesin F (2-8) is
the only member to not bear an epoxide functionality.
The structurally related natural product perophoramidine (2-9) was
isolated by Ireland and coworkers in 2002 from the colonial ascidian Perophora
nomei (Figure 5.1.1).
7
The structure of perophoramidine was elucidated by NMR
experiments. While structurally similar to the communesins, perophoramidine,
in contrast, possesses: (1) a hexacyclic skeleton lacking the azepine ring found in
the communesins, (2) two bicyclic amidines, (3) a trans-relationship of the
aminoethyl moietys at C(7) and C(8), and (4) halogenated aromatic rings. The
absolute configuration has been established via total synthesis.
8

N
R
N
H
N
N
O
H
H
H
N
R
N
H
N
N
O
H
H
H
N N
H
N
N
H
H
O O O R'
6
7
8
9
15
16
21
22
2-1 communesin A, R = R' = CH
3
2-2 communesin E, R = H, R' = CH
3
2-3 communesin G, R = CH
3
, R' = Et
2-4 communesin H, R = CH
3
, R' = Pr
2-5 communesin B, R = CH
3
2-6 communesin C, R = H
2-7 communesin D, R = CHO
2-8 communesin F
N
H
N
N N
Cl
Cl
Br
2-9 perophoramidine
N O
N
N
O
H
H
H
O
2-10 "nomofungin"

84
5.2. Pharmacology of the communesins and perophoramidine
Members of the communesin family and perophoramidine have been
shown to possess a variety of biological activities. Communesins A and B inhibit
proliferation of mouse leukemia cells P-388 (ED
50
= 3.5 and 0.45 g/mL,
respectively).
2
Communesin B also demonstrated moderate cytotoxicity against
KB and LoVo cells (MIC = 4.5 g/mL and 2 g/mL, respectively) by disruption
of the microfilament network in mammalian cells.
3
Communesins B, C, and D
exhibited moderate antiproliferation activity when tested on a series of human
leukemia cell lines.
4
Communesins A, B, D, E, and F also demonstrate insecticidal
activity against the third instar larvae of silkworms by oral administration.
5

Communesins G and H were found inactive in antimicrobial, antiviral, and
anticancer assays.
6
Perophoramidine demonstrates cytotoxicity towards HCT116
colon carcinoma cell line (IC
50
= 60 M) and induces apoptosis via
poly(adenosine-5-diphosphate ribose) polymerase (PARP) cleavage within 24
hours.
7

5.3. Biosynthesis of the communesins and perophoramidine
On the basis of biosynthetic labeling studies and the widely accepted
biosynthetic origins of the calycanthaceous alkaloids,
9
Mantle and coworkers
10

proposed a biosynthetic pathway predicated on an oxidative dimerization of
tryptamine (2-12, Scheme 5.3.1). Thus, oxidation/dimerization of two tryptamine
(2-12) subunits, derived via the decarboxylation of tryptophan (2-11), gives the

85
C
2
-symmetric bis-indolenine 2-13. Hydrolysis of the bis-indolenine gives rise to
the tetraaminodialdehyde 2-14, which, following cyclization and methylation,
would give the bis-aminal 2-15. The pathway from the bis-aminal to the
communesins remains unclear.
In response to alternate biosynthetic proposals (vide infra), Mantle and
coworkers
11
have since acknowledged that aurantioclavine (2-19, Scheme 5.3.3),
or 4-(dimethylallyl)tryptophan could be key intermediates in the biosynthesis of
the communensins.
Scheme 5.3.1. Mantles biosynthetic pathway to communesin B

A related biosynthetic pathway has been proposed for perophoramidine
(Scheme 5.3.2).
9
In this case, oxidative dimerization of tryptamine (2-12) gives
rise to the meso isomer 2-16 and subsequently bis-aminal 2-17. Oxidation and
halogenation would yield perophoramidine (2-9).
N
H
NH
2
N
H
NH
2
CO
2
H
N
NH
2
N
H
2
N
2-13
C
2
-symmetric isomer
N N
H
H
N
H
N
H
H
2-15
N N
H
N
N
O
H
H
H
O
2-5
communesin B
2-11
tryptophan
2-12
tryptamine
tryptophan
decarboxylase dimerase
methylase acylation?
prenylation?
mevalonate
[O]?
NH
2
NH
2
H
2
N
H
2
N
O
O
2-14
hydrolysis

86
Scheme 5.3.2. Biosynthesis of perophoramidine

Stoltz and coworkers have advanced an alternate biosynthetic pathway to
the communesins (Scheme 5.3.3).
12
Thus, tryptophan (2-11) or tryptamine (2-12) is
oxidized to the indol-2-one 2-20, which can then react with aurantioclavine (2-19)
in a cycloaddition reaction proceeding through an exo transition state to generate
the strained bridgehead lactam 2-21. An intramolecular ring opening of the
Scheme 5.3.3. Stoltzs biosynthetic pathway to communesin B

N
H
NH
2
N
H
N
N N
Cl
Cl
Br
2-9
perophoramidine
N
NH
2
N
H
2
N
N
H
N
H
H
N
H
N
H
H
[O]
2-16
meso isomer
2-17 2-12
tryptamine
N N
H
N
N
O
H
H
H
O
2-5
communesin B
N
H
N
N
H
N
H
N
H
N
H
N
H
O
O
H
2
N NH
2
CO
2
H
NH
2
N
H
2
N
O
H
H
N
O H
2
N
2-20
2-18 2-11
tryptophan
2-12
tryptamine
N
H
N
NH
H
H
O
NH
2
2-21
N
H
N
H
NH
H
N
H
H
O
2-22
2-19
aurantioclavine
+
[O] [O]

87
lactam by the pendant amine would give spirocyclic lactam 2-22. Further
functionalization would provide communesin B.
Funk and Fuchs proposed a related communesin biosynthesis within a
report of their biomimetic synthesis of perophoramidine (Scheme 5.3.4).
13

Thus, the cycloaddition reaction of 4-(dimethylallyl)tryptamine (2-23) with indol-
2-one 2-20 proceeding through an exo transition state would give rise to the
strained bridgehead lactam 2-24. A transamidation reaction with one of the
amines would provide spirocyclic lactam 2-25. Reduction of the lactam and
subsequent cyclizations with the remaining amine would give the communesin
ring system 2-25, which could provide communesin B itself upon further
functionalization.
Scheme 5.3.4. Funks biosynthetic pathway to communesin B

N N
H
N
N
O
H
H
H
O
2-5
communesin B
N
H
NH
2
N
H
NH
2
N
H
2
N
O
N
O H
2
N
2-20
N
H
N
H
2
N
H
O
NH
2
2-24
N
H
N
H
H
2
N
H
N
H
O
2-25
+
2-23
4-(dimethylallyl)tryptamine

88
5.4. Previous synthetic approaches to the communesins
Numerous groups have initiated programs towards the total syntheses of
the communesins due to their unique and fascinating structure, as well as their
potentially useful biological activity. Studies towards the syntheses of the
communesins by the groups of Stoltz and Adlington, as well as the completed
total syntheses of members of the communesins family by the groups of Qin,
Weinreb, and Ma, are summarized in the sections below.
5.4.1. Stoltzs approach to the communesin ring system
Stoltz prepared the core aminal ring structure of the communesins via an
intermolecular aza-ortho-xylylene cycloaddition reaction. The aza-ortho-xylylene
2-28, generated in situ from chloroaniline 2-27 (Scheme 5.4.1),
14
underwent a [4 +
2] cycloaddition reaction with aurantioclavine derivative 2-26 to give the
pentacyclic ring system 2-29 as a 1:1 mixture of diastereomers
12a
(this product
distribution was reported as a 2:1 mixture in a later publication
12b
). It was argued
that the poor stereoselectivity was due to the Boc group residing on the face
opposite of the olefin substituent.
Scheme 5.4.1. Stoltzs approach to the communesin ring system

N
N
Boc
N
Cl
Ts
H
N N
Ts
Boc
N
H
+
Cs
2
CO
3
,
CH
2
Cl
2
,
-78 C, 4 h
89%
2-26 2-27 2-28 2-29
N
N
H
O
OtBu
N
Ts
+

89
5.4.2. Adlingtons approach to the communesin ring system
Adlington and coworkers reported a synthesis strategy for the
communesin ring system via an intramolecular hetero DielsAlder reaction that
aimed to construct the vicinal quaternary centers in a single step (Scheme 5.4.2).
15

To investigate this idea, aniline 2-31 was prepared in two straightforward steps
from the tryptamine derivative 2-30. Treatment of alcohol 2-31 with
carbonyldiimidazole (CDI) gave 3,1-benzoxazin-2-one 2-32. However, much to
their chagrin, Adlington and coworkers found that heating 3,1-benzoxazin-2-one
2-32 up to 220 C failed to generate the anticipated aza-ortho-xylylene 2-33
intermediate, and instead returned the starting material unchanged.
Scheme 5.4.2. Adlingtons initial approach to the communesin ring system

Adlington and coworkers did however find that treatment of allylic
alcohol 2-35, prepared in an analogous manner to 2-31, with CDI gave
pentacyclic aminal 2-36, along with allylic imidazole 2-37 and dihydroquinoline
2-38 (Scheme 5.4.3). However, the relative stereochemistry of the vicinal
quaternary centers generated in the cycloaddition reaction is opposite to that
N
NHBn
N
Bn
N O
HO
BocHN
1. N-Boc-isatin,
THF, rt, 18 h
81%
2. allyl MgBr,
THF, rt, 2 h
73%
2-30 2-31 2-32
N
Bn
N O
O
N
Boc
O
CDI, THF,
60 C, 2 h

83%
2-33
N
Bn
N O
N
Boc
N N
Boc
Bn
N
H
O
2-34

90
Scheme 5.4.3. Adlingtons modified approach to the communesin ring system

required for the synthesis of the communesins, but would be suitable for the
synthesis of perophoramidine.
5.4.3. Qins total synthesis of ()-communesin F
In 2007, Qin and coworkers reported the first total synthesis of a member
of the communesin family, communesin F (2-8).
16
Towards this end, diazoester 2-
40, prepared in six steps from the known 4-bromotryptophol (2-39), underwent a
Cu-catalyzed intramolecular cylcopropanation reaction to yield the stable
cyclopropane 2-41 (Scheme 5.4.4). Staudinger reduction of the azide and
subsequent closure of the resulting amine on the indolenium formed during the
cyclopropane ring opening gave aminal 2-42 as a single diastereomer. After
protection of the aminal, lactone 2-43 was prepared via O-allylation followed by
a stereoselective Claisen rearrangement. The remaining two nitrogen atoms were
then introduced in a 9-step sequence to afford the spirolactam 2-44. A Heck
reaction with 2-methyl-3-buten-1-ol was followed by an acid catalyzed allylic
N
NHBn
N
Bn
N O
HO
BocHN
N N
Boc
Bn
N
H
O
2-30 2-35
2-36 (36%)
1. N-Boc-isatin,
THF, rt, 18 h
81%
2. vinyl MgBr,
THF, rt, 1 h
89%
CDI, THF,
40 C, 48 h
N
Bn
N O
HN
2-37 (42%)
N
Bn
N O
N
Boc
2-38 (10%)
Boc
N
N
+ +

91
substitution reaction to give benzazepine 2-45 along with the diene resulting
from dehydration of the allylic alcohol. Bicyclic amidine 2-46 was prepared from
lactam 2-45 utilizing a strategy pioneered in Fuchs and Funks synthesis of
perophoramidine (vide infra). Thus, imidate formation, removal of the Boc
protecting group and a silica gel (SiO
2
) catalyzed cyclization gave the strained
bridgehead amidine 2-46. To complete the synthesis of ()-communesin F (2-8),
the methyl carbamate was hydrolyzed and the amidine was reduced in the
presence of excess acetic anhydride to install the acetamide. The total synthesis
was competed in 23 linear steps from 4-bromotryptophol (2-39) in an overall
yield of 1.4%.
Scheme 5.4.4. Qins total synthesis of ()-communesin F

N
H
Br
OH
N
Br
O O
N
2
N
3
N
Br
O O
N
3
N
Br
O O
N
H H
H
N
Br
O
N
CO
2
Me H
O
N
Br
N
CO
2
Me H
H
N O
BocHN
N N
CO
2
Me H
H
N O
Boc
N
H
N N
CO
2
Me H
N N
H
N N
H H
N N
H
O
6 steps
CuOTf,
CH
2
Cl
2
,
rt, 1 h
88%
PBu
3
,
aq. THF,
0 C, 0.5 h
83%
9 steps
1. Et
3
OBF
4
,
iPrNEt
2
,
CH
2
Cl
2
2. TFA, CH
2
Cl
2
3. SiO
2
, MeOH
CH
2
Cl
2
77% (3 steps)
1. KOH, H
2
O,
MeOH
65%

2. NaBH
4
, Ac
2
O
AcOH
73%
2-8
communesin F
1. ClCO
2
Me,
DMAP, CHCl
3
93%
2. NaH, DMF,
0 C, 1 h;
allyl bromide,
65 C, 4 h
84%
1.
Pd(OAc)
2
,
P(o-Tol)
3
,
100 C, !,
2 h, 68%
2. PPTS, CHCl
3
66% (+ 26%
diene)
HO
2-40 2-41
2-42 2-43 2-44
2-45 2-46
2-39

92
5.4.4. Weinrebs total synthesis of ()-communesin F
Weinreb and coworkers
17
followed Qin and coworkers in 2010 with their
synthesis of communesin F using a spirooxindole-forming Heck reaction
pioneered by Overman.
18
Thus, aryl iodide 2-48, prepared in five steps from the
known enol triflate 2-47, underwent an intramolecular Heck reaction to give
spirooxindole 2-49 (Scheme 5.4.5). The nitroarene was converted to the
corresponding Boc-aniline derivative, which cyclized under reductive conditions
to give aminal 2-50. Enamine 2-50 was treated with cyanogen azide to give
lactam 2-51, which was then converted to aldehyde 2-52 over several steps.
Aldehyde 2-52 was subjected to an aldol condensation with acetone and the
lactam was activated for the subsequent transamidation as the imide 2-53.
Scheme 5.4.5. Weinrebs total synthesis of ()-communesin F

NBn
OTf
EtO
O
NCO
2
Et
N
O NO
2
I
OBOM
N O
BOMO
CO
2
Et
N
NO
2
N N
Boc
BOMO
CO
2
Et
N
N N
Boc
BOMO
Boc
N
H
H
O
N N
Boc
O
H
N
H
O
N
3
N N
H H
N N
H
O
5 steps
Pd(OAc)
2
, PPh
3
,
DMA, K
2
CO
3
,
nBu
4
NBr
150 C, 0.5 h

90%
1. Pt/C, H
2
,
toluene, rt
2. Boc
2
O, K
2
CO
3
,
THF, H
2
O,
87% (2 steps)
3. AlH
3
Me
2
NEt,
THF, 0 C
74%
1. KOH, EtOH
2. NCN
3
, MeCN
93% (2 steps)
3. KOH, EtOH
4. Boc
2
O, THF
LiHMDS
57% (2 steps)
8 steps
1. Me
2
CO,
NaOH, H
2
O
60 C, 93%
2. Boc
2
O, THF
LiHMDS
81%
1. PMe
3
, THF,
H
2
O, 70 C
88%
2. MeLi, THF
73%
2-8
communesin F
H
2-47 2-48 2-49
2-50 2-51 2-52
2-53 2-54
5 steps
N N
Boc H
H
N O
BocHN
HO
N N
Boc
Boc
N
H
O
N
3
O

93
Treatment of imide 2-53 with trimethyl phosphine afforded the transamidation
product, and addition of methyl lithium to the enone moiety gave the allylic
alcohol 2-54. The synthesis of communesin F (2-8) was completed, from this point
forward based on the precedent set by Qin and coworkers (vide supra). The total
synthesis was competed in 30 linear steps in an overall yield of 0.9%.
5.4.5. Mas total synthesis of (-)-communesin F
In 2010, Ma and coworkers reported the first asymmetric synthesis of
communesin F.
19
Thus, indole 2-55, prepared in three steps from 4-
bromotryptophol (2-39), underwent an oxidative cyclization to form
spiroindolenine 2-56 as a mixture of diastereomers (Scheme 5.4.6). Upon
reduction of the nitro group, the indolenine underwent spontaneous cyclization
to a pentacyclic intermediate which was regioselectively methylated to give
aminal 2-57. In addition a diastereomer that was epimeric at all stereogenic
centers except the acyclic one (3.1:1) was isolated. Thus, an acceptable level of
asymmetric induction was imparted by the chiral auxillary. Proceeding with
optically pure material now, protection of aminal 2-57 as the Boc-carbamate was
followed by stereoselective allylation of the corresponding lactam enolate to give
lactam 2-58. Deprotection of the lactam and straightforward transformation of
the vinyl moiety afforded alcohol 2-59. A Heck reaction installed the allyl alcohol
group in 2-60. Treatment of bis-alcohol 2-60 with mesyl chloride presumably
generated a bis-mesylate that spontaneously cyclized to the benzazepine. The
primary mesylate was subsequently converted to azide 2-61. Reduction of the

94
Scheme 5.4.6. Mas total synthesis of (-)-communesin F

azide under anhydrous Staudinger reaction conditions provided the amidine,
which was readily converted to (-)-communesin F (2-8). The total synthesis was
completed in 19 linear steps from 4-bromotryptophol (2-39) in an overall yield of
4.7%.
5.4.6. Mas total synthesis of communesins A and B
In 2011, Ma and coworkers followed up their synthesis of communesin F
with the first total syntheses of communesins A and B.
20
Ma and coworkers
found it necessary to redesign their previous route after attempts to prepare
communesins A and B directly from communesin F, or one of its synthetic
intermediates, failed. They speculated that the problem with a direct conversion
N
H
Br
OH
N
H
Br
N O
O
2
N
3 steps
Ph
TBSO
N
Br
N O
O
2
N
Ph
TBSO
N
Br
N O
N
H
Ph
TBSO
H
H
N
Br
N O
N
Boc
Ph
HO
H
N
Br
H
N O
N
Boc H
N N
Boc H
O N
H
N N
H H
N N
H
O
2-8
(!)-communesin F
OH
N
3
LiHMDS, THF
-78 C, 0.5 h;
I
2
, -78 C, 2 h
1. Fe, NH
4
Cl,
tBuOH, H
2
O
reux, 18 h
2. KOtBu, THF,
0 C; MeI
50% major
isomer (3 steps)
1. KHMDS, THF;
Boc
2
O, 0 C
89%
2. KOtBu, Et
2
O;
allyl bromide, rt
3. TBAF, THF
92% (2 steps)
1. MsCl, Et
3
N,
CH
2
Cl
2
2. NaN
3
, DMF,
nBuN
4
Br
49% (2 steps)
1. P(nBu)
3
,
toluene
2. NaBH
4
,
Ac
2
O,
AcOH
3. TFA,
CH
2
Cl
2
47% (3 steps)
2-55 2-56
2-57 2-58 2-59
2-61
4 steps
Pd(OAc)
2
, P(o-Tol)
3
,
nBu
4
NBr, DMF,
140 C, ", 0.3 h
67%
HO
N
H
N O
N
Boc H
OH
2-60
HO
2-39

95
was the sensitivity of the southern aminal to oxidants. This observation is in
accord with the observations made during previous syntheses of
perophoramidine, wherein the southern amidine functionality was installed by a
facile oxidation of an aminal with MnO
2
.
8,13,21
Therefore, the aurantioclavine
derivative 2-62 was prepared enantioselectively using a Sharpless asymmetric
dihydroxylation in a fourteen step sequence from 4-bromotryptophol (2-39,
Scheme 5.4.7). The indole 2-62 was converted to bridgehead lactam 2-63 utilizing
the oxidative cyclization/reductive cyclization featured in their aforementioned
synthesis of communesin F. Nitrile 2-64 was prepared by methylation of the
Scheme 5.4.7. Mas total synthesis of communesins A and B

N
H
Br
OH
14 steps
N
H
N
O
O
H
O
O
2
N
N
H
N
H H
N
H
O
H
O
O
N N
H H
N
H
O
O
O
CN
N N
H H
N
H
O
O
O
OH
N N
H H
N
H
H
N
O
O
N N
H H
N
H
N
O
O
H
1. LiHMDS, THF,
-78 C to rt;
I
2
, 0.25 h
66%
2. Raney-Ni, H
2
,
THF, MeOH
70%
1. KHMDS,
THF; MeI
90%
2. KHMDS,
THF, -78C;
ICH
2
CN
67%
LAH, THF
reux, 0.6 h
NH
4
OAc,
NaBH(OAc)
3
,
MeOH, rt, 45 h
92% (2 steps)
N N
H H
N
H
N
O
O
H
2-62 2-63
2-64 2-65 2-66
2-66
2-5
communesin B
2-1
communesin A
4 steps 4 steps
2-39

96
aminal, and alkylation of the lactam enolate within hexacycle 2-63. Nitrile 2-64
was then reduced to the corresponding lactol 2-65, which was converted to
aminal 2-66 by reductive amination with ammonium acetate. At this stage,
communesin A (2-1) and B (2-5) were each prepared in four steps from aminal 2-
66.

97
Chapter 6. Studies Towards the Communesins in the Funk Laboratory:
An Aza-ortho-xylylene Route
6.1. Introduction
Aza-ortho-xylylenes, also known as ortho-aza-xylylenes or ortho-quinone
methide imines, are extremely versatile and reactive intermediates that undergo
a wide range of reactions.
22
Specifically, they undergo: electrocyclization
reactions to give dihydroquinolines,
23
cycloadditions with electrophilic
23a,23b,24
and
nucleophilic
14,25
$-bonds, attack by nucleophiles,
23b,26
and dimerization reactions
to produce macrocycles.
23a,23b
A variety of methods for generating these reactive,
non-isolable intermediates have been reported, including but not limited to
photogeneration,
26-27
retrocheletropic extrusion of various species (CO, SO
2
),
22,26,28

[4 + 2] retrocycloaddition of 3,1-benzoxazin-2-ones,
29
or by the 1,4-elimination of
various species (H
2
O, NR
3
, HF, HCl) from 2-aminobenzyl derivatives.
14,30
Some of
the more efficient strategies for generating these intermediates and their
subsequent reactions, with a bias towards examples which undergo a subsequent
cycloaddition, are discussed below.
Ferraccioli
29b
reported the intramolecular cycloaddition reaction of aza-
ortho-xylylene 2-68, generated from benzoxazin-2-one 2-67 by a
retrocycloaddition with loss of carbon dioxide, to give sultam 2-69 (Scheme
6.1.1). Additionally, they reported the thermolysis reaction of the benzoxazin-2-
one 2-64 bearing an alkyl substituent at C(4) (Scheme 6.1.2). In this case, the

98
Scheme 6.1.1. Thermal decarboxylation of 3,1-benzoxazin-2-ones

reaction gave ortho-vinylaniline 2-72 as the only product. This result is due to a
competitive [1,5]-sigmatropic hydrogen shift in the Z-isomer of the aza-ortho-
xylylene intermediate 2-71.
Scheme 6.1.2. Competitive [1,5]-sigmatropic hydrogen shift

Tunge and coworkers
23a,23b
reported the palladium-induced
decarboxylation of vinyl benzoxazinone 2-73 to generate aza-ortho-xylylene
synthon 2-74 which readily undergoes a cycloaddition reaction with benzylidene
malononitrile (2-75) to give dihydroquinoline 2-76 with good diastereoselectivity
(Scheme 6.1.3). The palladium-induced decarboxylation occurs at room
temperature and is significantly milder than the conditions required for the
thermal decarboxylation of benzoxazinones (cf. Scheme 6.1.1).
Scheme 6.1.3. Palladium catalyzed decarboxylation of 4-vinyl-3,1-benzoxazin-2-
ones

N
O
N O
O
2
S
O
2
S
N
O
2
S
215 C
1,2,4-trichloro-
benzene
-CO
2
34%
2-67 2-68 2-69
H
N
O
O
Ts
N
Ts
H
N
Ts
[1,5]H
75%
2-70 2-71 2-72
215 C
1,2,4-trichloro-
benzene
-CO
2
N
Ts
O
N N
Ts
O
Ts
CN
CN
Ph
Ph
NC CN
PdL
2
5 mol%
Pd(PPh
3
)
4
,
CH
2
Cl
2
,
rt, 5 h
+
99%
8.9 : 1 dr
2-73 2-74 2-75 2-76

99
Corey and Steinhagen
14,25
have developed a simple, efficient method for
generating aza-ortho-xylylenes via base-induced elimination of hydrogen
chloride from the carbamate and sulfonamide derivatives of ortho-
chloromethylaniline 2-77 (Scheme 6.1.4). The generated N-acyl- and N-sulfonyl-
aza-ortho-xylylenes 2-78 undergo inverse-demand DielsAlder reactions with a
variety of electron rich olefins including enol ethers, ketene acetals, and 2,3-
dihydrofurans.
Scheme 6.1.4. Base-mediated elimination of HCl from o-chloromethylanilines

Wu and coworkers
30a
have reported the cycloaddition reaction between a
variety of indoles and a variety of aza-ortho-xylylenes 2-81 generated from the
respective 2-aminobenzyl alcohols 2-80 via acid-catalyzed dehydration (Scheme
6.1.5). A noteworthy feature of this methodology is that neither protection of the
aniline nitrogen or conversion of the alcohol to a suitable leaving group is
unnecessary.
Scheme 6.1.5. Acid-catalyzed dehydration of 2-aminobenzyl alcohols

N
R
N
R
NH
R
Cl
OEt OEt
+
2-77
R = Boc
R = Ts
2-79
R = Boc, 83%
R = Ts, 78%
2-78
Cs
2
CO
3
,
CH
2
Cl
2
,
rt, 4 h
N
H
N
NH
2 N NH
2
OH
H
+
30 mol% TFA,
ClCH
2
CH
2
Cl,
40 C, 16 h
2-82
R R R
2-80
R = H, Cl, Me
2-81
R = H, Cl, Me
2-83
R = H, Cl, Me

100
6.2. Previous synthesis efforts directed towards the communesins in the Funk
laboratory
Funk and Crawley initiated a synthesis program towards the
communesins following their realization that the natural products nomofungin
(10) and communesin B (5) were in fact the same compound.
12a,31
Funk and
Crawleys initial report described the intramolecular endo-cycloaddition reaction
of aza-ortho-xylylene 2-85 to give the advanced communesin ring system 2-86
that lacked only the pyrrolidine ring and the benzylic substituent on the
benzazepine ring found in the communesins (Scheme 6.2.1).
31
The aza-ortho-
xylylene intermediate 2-85 was generated via thermolysis of the phenyl
carbonate 2-84. However, all attempts to functionalize the tertiary benzylic
position (CAN, DDQ, NBS) in order to have a handle to install the vicinal
quaternary centers and the northern aminal proved unsuccessful.
32

Scheme 6.2.1. Crawley and Funks first-generation synthetic plan

In light of these difficulties, Funk and Crawley investigated an alternate
route wherein functionality for the elaboration of the pyrrolidine ring was
introduced at an earlier stage.
33
Thus, aziridine 2-89 was prepared from
tryptamine derivative 2-87 and dibromide 2-88 (Scheme 6.2.2). Treatment of the
Teoc-carbamate 2-89 with TBAF gave endo-cycloadduct 2-91, presumably
N
N
N N
CO
2
Et H
2-84 2-85 2-86
N
N
N
H
CO
2
Et
N
H
OCO
2
Ph
NHCO
2
Et
160
C
dichloro-
benzene
6 h
70%

101
proceeding via the aza-ortho-xylylene 2-90 generated by a decarboxylative ring
opening of the aziridine. Alkyne 2-91 was directly subjected to a gold(I)
catalyzed 7-exo-dig cyclization to give bridgehead enamine 2-92. Unfortunately,
as before, all attempts to functionalize the tertiary benzylic carbon primarily
through intramolecular carbene insertion chemistry failed.
32

Scheme 6.2.2. Crawley and Funks second-generation synthetic plan

The difficulties associated with the installation of the pyrrolidine ring in
their previous strategies forced Funk and Crawley to develop a third-generation
synthetic plan. This approach entailed the introduction of a lactam moiety as a
handle for the installation of the second quaternary center via enolate alkylation.
The success of this approach rested upon the ability to generate an
unprecedented and presumably more reactive acyl-aza-ortho-xylylene
intermediate such as 2-97 (Scheme 6.2.3). To that end, the 4-acyl-3,1-benzoxazin-
2-one 2-96 (prepared from the tryptamine derivative 2-93 and acid chloride 2-94)
underwent a retrocycloaddition/cycloaddition sequence in the presence of
N
NH
2
Br
Br
O
O
HN
O O
TMS
N
N
HN
O O
TMS
O
O
H
H
+
N N
H
H
N
H
O
O
H
N N
H
N
H
O
O
H
N
H
NH
NH
O
O
H
H
AuCl(PPh
3
),
AgOTf, CH
2
Cl
2
,
40 C, 12 h
89%
2-87 2-88 2-89
2-90 2-91 2-92
Cs
2
CO
3
,
CH
3
CN,
rt, 18h
65%
TBAF,
THF,
rt, 4h

102
ytterbium triflate to give cycloadduct 2-98 as a 2:1 mixture favoring the endo
adduct. The aza-ortho-xylylene intermediate is presumably generated via Lewis
acid mediated decarboxylation of the 4-acyl-3,1-benzoxazin-2-one 2-96 as
significantly elevated temperatures (180 C, trichlorobenzene) are required in the
absence of a lanthanide triflate catalyst.
32
Gratifyingly, the mixture of epimers
could be stereoselectively alkylated from the convex face to afford the desired
allylated lactam 2-99. With the vicinal quaternary carbons problem solved, it was
hoped, the total syntheses of the communesins were now within reach.
Scheme 6.2.3. Crawley and Funks third-generation synthetic plan

N
N O
O
N
CO
2
Et
O
N N
CO
2
Et
N O
H
H
N N
CO
2
Et
N O
H
DMB
DMB DMB
KOtBu,
THF, 0 C;
allyl iodide
90%
2-96
2-98 2-99
N
N O
N
DMB
2-97
N
N O
O
N
H
O
DMB
2-95
O
O
N
H
O
N
NH
DMB
Cl
CO
2
Et
H
Yb(OTf)
3
,
toluene,
CH
2
Cl
2
,
50 C, 12 h
50%
NaH, DMF,
50 C, 0.5 h;
ClC
2
Et, 0 C
50%
+
DIPEA,
CH
2
Cl
2
,
rt, 12 h
66%
2-94 2-93

103
Chapter 7. An Approach to the Synthesis of Communesin F: An Aza-
ortho-xylylene Route
7.1. Retrosynthetic analysis of communesin F
We were in a position to complete the total synthesis of communesin F on
the basis of Funk and Crawleys successful model study. Our retrosynthetic
approach to the synthesis of communesin F (2-8) is illustrated in Scheme 7.1.1.
Thus, the natural product could be prepared from azepine 2-100 by taking
advantage of Qins pioneering endgame (cf. Scheme 5.4.4) that featured addition
of the benzazepine to the corresponding cyclic imidate obtained by O-
methylation of the spirolactam. The benzazepine ring would be introduced via
the intramolecular hydroamination of allene 2-101, in turn available from azide
2-102 via a reduction/transamidation sequence. The ethyl azide would be
Scheme 7.1.1. Retrosynthetic analysis for communesin F

N N
CO
2
Et
H
DMB
N O
N
3
N N
CO
2
Et
H
DMB
N O
H
N N
CO
2
Et
DMB
N O
O
O
N N
H H
N N
H
O
2-8
communesin F
N N
CO
2
Et H
H
N O
Boc
N
H
N N
CO
2
Et H
H
N O
DMBHN
2-100 2-101
2-102 2-103 2-104

104
installed by the alkylation of lactam 2-103, in turn available from the benzoxazin-
2-one 2-104 through Lewis acid catalyzed retrocycloaddition/endo-cycloaddition
as previously observed in the Funk laboratory (2-96!2-98, Scheme 6.2.3).
7.2. Synthesis of an advanced intermediate towards the synthesis of
communesin F
In the forward sense, access to the key 4-acyl-3,1-benzoxazin-2-one 2-104
(Scheme 7.1.1) began with the preparation of the protected 4-allenyl tryptamine
2-106 from the known aldehyde 2-105
34
(Scheme 7.2.1). Thus, addition of
ethynylmagnesium bromide to aldehyde 2-105 gave propargyl alcohol 2-106. The
alcohol was then acetylated to give the corresponding propargyl acetate. The
propargyl acetate could also be prepared in a single step from aldehyde 2-105 by
trapping the alkoxide generated after addition of ethynylmagnesium bromide
with acetic anhydride. However, the two-step procedure was found to deliver
consistently higher yields. The propargyl acetate was then converted into allene
2-107 by the copper mediated addition of methylmagnesium bromide.
35

Displacement of the quaternary ammonium salt, generated by treatment of
amine 2-107 with an excess of MeI, with potassium cyanide was accompanied by
desilylation to provide nitrile 2-108. Methylation of indole 2-108 under standard
conditions was followed by reduction of the nitrile functionality to afford
tryptamine 2-109. Finally, amine 2-109 was protected as the 2,4-dimethoxybenzyl
(DMB) amine employing reductive amination conditions to supply the desired
tryptamine derivative 2-110.

105
Scheme 7.2.1. Preparation of allenyl indole 2-110

We next turned our attention towards the preparation of benzoxazin-2-
one 2-114 (Scheme 7.2.2). The known nitromandelic acid (2-111)
36
was
hydrogenated to give the corresponding aniline which was directly treated with
phosgene to give benzoxazinone 2-112. The benzyl ester of acid 2-112 was
converted into the corresponding imide derivative 2-113. After reductive
cleavage of the benzyl ester, the resulting acid was cleanly converted to acid
chloride 2-114.
We could prepare the benzoxazinone derivative 2-104 necessary for the
cycloaddition reaction with allenyl indole 2-110 and benzoxazinone 2-114 in
hand (Scheme 7.2.3). To that end, the tryptophol derivative 2-110 was acylated
with acid chloride 2-114 in the presence of Hunigs base to provide amide 2-104.
Scheme 7.2.2. Preparation of N-acyl-4-acyl-3,1-benzoxazin-2-one 2-114

N
TIPS
O
N
TIPS
OH
N
TIPS
N N N
N
H
NC
N
NHDMB NH
2
CH
3
CCMgBr,
THF, -78 C
to rt, 1 h
95%
1. Et
3
N, DMAP,
Ac
2
O, CH
2
Cl
2
,
rt, 14 h, 84%
2. MeMgBr, CuI,
LiBr, THF, 0 C
91%
1. MeI, PhH, rt, 8 h
2. KCN, H
2
O, DMF,
80 C, 6 h
60% (2 steps)
1. NaH, 0 C;
MeI, 1 h
98%
2. LiAlH
4
, Et
2
O
0 C, 1 h
78%
O O
O
MeOH, rt, 16 h;
NaBH
4
, rt, 1 h
86%
2-105 2-106 2-107
2-108 2-109 2-110
OH
O OH
NO
2
N
H
O
O OH
O N
CO
2
Et
O
O OBn
O N
CO
2
Et
O
O Cl
O
1. H
2
, Pd/C,
K
2
CO
3
, MeOH
rt, 16 h, 95%
2. COCl
2
, Na
2
CO
3
,
H
2
O, toluene,
rt, 12 h, 89%
1. BnBr, DMF,
Cs
2
CO
3
,
50 C, 5 h
72%
2. BuLi, THF,
-78 C, 1 h;
ClCO
2
Et, rt,
15 h, 87%
1. H
2
, Pd/C,
EtOAc, rt,
24 h, 95%
2. NaH, PhH,
rt; (COCl)
2
,
rt, 5 h, 95%
2-111 2-112 2-113 2-114

106
Scheme 7.2.3. Synthesis of aminal 2-103

Gratifyingly, benzoxazinone 2-104 in the presence of yttrium triflate underwent a
smooth retrocycloaddition/cycloaddition sequence to give the endo cycloadduct
2-103, presumably via aza-ortho-xylyene 2-115, in good yield as a single
diastereomer. A number of other lanthanide triflates [Eu(OTf)
3
, La(OTf)
3
,
Sc(OTf)
3
, Yb(OTf)
3
] also effected the desired retrocycloaddition/cycloaddition
reaction. However, Y(OTf)
3
was found to give the highest product yield and the
cleanest reaction profile. The stereoselectivity of the cycloaddition was confirmed
through
1
H NMR studies. Key nOe correlations were observed between the C(8)
alpha proton and the C(6) aminal proton, and the alpha proton and the C(19)
proton (2-103a, Scheme 7.2.3). These nOe correlations are consistent with the endo
adduct. On the other hand, the exo adduct would certainly not exhibit the nOe
correlation observed between the C(8) and C(6) protons.
The next task in the synthesis involved introduction of the remaining
quaternary center (Scheme 7.2.4). We hoped to avoid the step intensive
elaboration of the commonly installed allyl functionality to the desired
N N
CO
2
Et
DMB
N O
O
O
N N
CO
2
Et
H
DMB
N O
H
iPr
2
NEt,
CH
2
Cl
2
,
rt, 16 h
78%
N
NHDMB
2-110 2-104
2-103
N
CO
2
Et
O
O Cl
O
2-114
+
N
N
N
O
EtO
2
C
H
H
H
DMB
H
H
nOe
nOe
nOe
N
N
N
H
O
CO
2
Et
DMB
2-103a
1
6
19
8
11
2-115
10 mol%
Y(OTf)
3
,
ClCH
2
CH
2
Cl,
90 C, 8 h
73%

107
Scheme 7.2.4. Alkylation of lactam 2-103

aminoethyl functionality by alkylating directly with 1-azido-2-iodoethane. After
extensive experimentation, we found that treatment of lactam 2-103 with n-BuLi,
followed by HMPA and 1-azido-2-iodoethane provided the desired alkylation
product 2-102 in moderate yield. With azide 2-102 in hand, the stereochemical
relationship of the alkyl side chains was confirmed through NMR studies. Key
nOe correlations were observed between the C(18) proton and the C(6) aminal
proton, and the C(18) proton and the C(19) proton (2-102a, Scheme 7.2.4). These
results suggest a cis relationship between the alkyl substituents. Furthermore, an
nOe correlation between the C(11) allenyl proton and the C(1) aromatic proton,
and the absence of nOe correlations between the C(18) protons and the C(11) and
C(1) protons supports this conclusion. The alkylation, therefore, proceeds
through alkylation of the enolate generated via the less hindered convex face.
With azide 2-102 in hand, we investigated the preparation of the
transamidation product 2-101. Reduction of the azide 2-102 functionality to the
corresponding amine 2-116 under Staudinger conditions proceeded uneventfully
(Scheme 7.2.5). However, the proposed transamidation reaction failed to deliver
the desired lactam 2-101 under a variety of conditions. The direct preparation of
lactam 2-101 from azide 2-102 under anhydrous Staudinger reaction conditions
similarly failed. The problematic nature of this conversion presumably arises
N N
CO
2
Et
H
DMB
N O
H
N N
CO
2
Et
H
DMB
N O
N
3
nBuLi, THF,
-40 C, 1 h;
ICH
2
CH
2
N
3
,
HMPA, 1 h
45%
2-103 2-102
N
N
N
O
EtO
2
C
H
H
DMB
H
H
N
3
H
H
nOe
nOe
nOe
11
1
6
19
18
2-102a

108
Scheme 7.2.5. Attempted transamidation reaction

conditions result
200 C (&)
HCl, MeOH, 65 C, 24 h
NaOMe, MeOH, 65 C, 24 h
NR
NR
NR
NaN3, Et3N, DMF, 80 C, 20 h
37
NR
KHMDS, THF, 66 C, 16 h
38
NR
KHMDS, toluene, 110 C, 24 h NR
LiHMDS, HMDS, 100 C, 24 h NR
AlH3Net(Me)2, THF, rt, 1 h
32
decomposition

from the low reactivity of the lactam carbonyl. The problem does not appear to
be thermodynamic in origin since molecular modeling (PCMODEL, MMX) of
compounds analogous to 2-116 and 2-101 bearing vinyl and methyl substituents
in place of the dimethylallenyl and DMB groups, respectively, suggests that 2-
101 is favored by 2.9 kcal/mol. In fact, Crawley
32
inadvertently was able to effect
a relatedtransamidation reaction while attempting to prepare aminal 2-119 via
the corresponding hemiaminal of lactam 2-117 (Scheme 7.2.6). Surprisingly,
Crawley found that treatment of lactam 2-117 with alaneethyldimethylamine
complex gave spirolactam 2-118.
Scheme 7.2.6. Crawleys inadvertent transamidation reaction

N N
CO
2
Et
H
DMB
N O
N
3
2-102
N N
CO
2
Et
H
DMB
N O
NH
2
PPh
3
;
H
2
O
72%
2-116 2-101
N N
CO
2
Et H
H
N O
DMBHN
conditions
N N
CO
2
Et
H
N O
NHBn
N N
CO
2
Et H
Bn
N O
HN
2-117 2-118
AlH
3
NEt(Me)
2
,
THF, rt, 1 h
80%
N N
CO
2
Et
H
N
Bn
N
2-119

109
Scheme 7.2.7. Crawleys transamidation reaction of tosylimide 2-120

We reasoned that replacing the 2,4-dimethoxybenzyl group with an
electron-withdrawing group, such as an alkoxycarbonyl residue to give the
respective imide, should lead to a more efficient transamidation reaction. Indeed,
Weinreb effected a similar transamidation reaction in his communesin F total
synthesis (2-53!2.54, Scheme 5.4.4) and Crawley
32
had also effected the
transamidation of tosylimide 2-120 to spirolactam 2-121 (Scheme 7.2.7). To that
end, we attempted to prepare the corresponding Boc-imide 2-123 (Scheme 7.2.8).
Unfortunately, we were unable to remove the DMB group to furnish lactam 2-
122. The N-benzyl and N-cumyl lactam derivatives of 2-102, prepared in
analogous fashion, proved to be equally recalcitrant to deprotection. The
difficulties experienced can likely be attributed to the dimethylallenyl
functionality, as Crawley successfully deprotected (TFA, anisol, 88%) the
compound analogous to 2-102 lacking the dimethylallenyl functionality.

N N
CO
2
Et
H
Ts
N O
N
3
N N
CO
2
Et H
H
N O
TsHN
2-120 2-121
PMe
3
,
THF
80%

110
Scheme 7.2.8. Attempted preparation of a more reactive imide

conditions result
TFA, DCE, 90 C decomposition
TFA, anisol, 80 C decomposition
TFA, thioanisol, DCE, 90 C decomposition
TFA, iPr3SH, 110 C
39
decomposition
TFA, iPr3SH, H2O, 100 C
40

MsOH, DCE, 60 C
41

decomposition
decomposition
HCO2H, H2O, 100 C
42
NR
CAN, H2O, THF, rt
43
decomposition
CAN, H2O, MeCN, rt
44
decomposition
K2HPO4, K2S2O8, H2O, MeCN
45
NR
tBuLi, THF; O2 78 C
46
decomposition
DDQ, H2O, CHCl3
47
decomposition
Na, liq. NH3, 78 C
15
decomposition
In conclusion, we have synthesized an advanced intermediate in the
synthesis of communesin F, which possesses five of the seven rings found in the
target, the vicinal quaternary centers, and all the necessary atoms for
construction of the northern aminal and the two remaining rings. Unfortunately,
all attempts to complete the synthesis of communesin F from this intermediate
were met with failure and thus further efforts were abandoned in view of a more
viable approach.
N N
CO
2
Et
H
DMB
N O
N
3
2-102
N N
CO
2
Et
H
H
N O
N
3
2-122
conditions
N N
CO
2
Et
H
Boc
N O
N
3
2-123

111
Chapter 8. Studies Towards the Communesins in the Funk Laboratory:
An Indol-2-one Route
8.1. Introduction
The existence of transient indol-2-one intermediates, essentially cyclic aza-
ortho-xylylenes, was first proposed by Stoltz,
12a
and Funk
13
in their respective
biosynthetic routes to the communesins and perophoramidine (cf. section 5.3).
Funk and Fuchss communication also described their total synthesis of ()-
perophoramidine via the base-promoted reaction of a 3-bromoindol-2-one
derivative and a tryptamine derivative, which was believed to proceed through
an indol-2-one intermediate (vide infra). Further studies by Funk and Fuchs
48

provided evidence in support of the hypothesis that indol-2-ones are generated
in the base-promoted reactions of 3-bromoindol-2-ones. The most compelling
evidence for the generation of indol-2-one intermediates and their reactivity is
summarized briefly below.
Funk and Fuchs found that treatment of 3-bromoindol-2-one 2-124 with
cesium carbonate provided indolinone 2-126 as the major product (Scheme 8.1.1).
The reaction presumably proceeds via intramolecular attack upon the indol-2-
one intermediate 2-125 and subsequent rearomatization. The calculated LUMO
coefficients for the indol-2-one intermediate are consistent with the observed

112
Scheme 8.1.1. Remote addition of a nucleophile to an indol-2-one intermediate

preference for cyclization at the C(6) position. Possible steric interactions with the
methyl substituent, which also enforce the observed regioselectivity, cannot be
ruled out. An alternative mechanistic pathway wherein the triflamide anion adds
directly to the aromatic ring would seem unlikely.
Additionally, treatment of 3-bromoindol-2-one 2-127 with cesium
carbonate provided quinoline 2-130 (Scheme 8.1.2). It would seem difficult to
arrive at a reasonable mechanism that does not invoke an indol-2-one
intermediate. Thus, the indol-2-one intermediate 2-128 undergoes an
intramolecular cycloaddition with the tethered alkyne to give the bridgehead
lactam 2-129, which extrudes carbon monoxide to give quinoline 2-130, via a
retrocheletropic reaction.
Scheme 8.1.2. Cycloaddition reaction of an indol-2-one intermediate

Methods that have been utilized for generating the reactive indol-2-one
intermediates are similar to those developed by Corey,
14,25
and Wu
30a
for
generating aza-ortho-xylylenes (cf. section 6.1). This reactive intermediate is

N
H
N
H Tf
Br
O
N
N
Tf
O
N
H
N
O
Tf
4
6
(-0.27)
(0.28)
(0.46)
(0.35)
45%
2-124 2-125
(LUMO coefcients)
2-126
Cs
2
CO
3
,
CH
2
Cl
2
rt, 24h
N
H
O
Br
N
O
N
O
N
-CO
59%
2-127 2-128 2-129 2-130
Cs
2
CO
3
,
CH
2
Cl
2
rt, 24h

113
commonly prepared by acid-catalyzed dehydration of 3-hydroxyindol-2-ones,
49

acid-catalyzed elimination of 3-amino- and 3-oxoindol-2-ones,
50
and base-
induced elimination of HX from 3-chloroindol-2-ones
51
and 3-bromoindol-2-
ones.
13,48,52

8.2. Prior work in the Funk laboratory
The synthetic utility of an indol-2-one cycloaddition was demonstrated by
Funk and Fuchs in their total synthesis of the cytotoxin ()-perophoramidine (2-
9).
13
Their synthesis utilized a highly stereoselective indol-2-one cycloaddition
reaction to establish the trans-stereochemistry of the aminoethyl groups on the
vicinal quaternary centers present in the natural product. Thus, treatment of
indole 2-131 with 3-bromoindolin-2-one 2-132 gave indolinine 2-134 in excellent
diastereoselectivity (> 20:1, Scheme 8.2.1). In light of the excellent
diastereoselectivity observed, the reaction is thought to proceed through an
asynchronous endo [4+2] cycloaddition pathway with a high degree of bond
formation between the C(3) positions of both the indole and the indol-2-one 2-
133. Indolenine 2-134 was then converted to the corresponding N-Boc imide,
which, upon reduction of the azide functionality, underwent a cascade reaction
involving transamidation and closure of the Boc-anilide anion upon the
indolenine functionality to give aminal 2-135. Treatment of aminal 2-135 with N-
chlorosuccinimide in acetic acid provided the fully halogenated ring system 2-
136, which was converted to lactam 2-137 over several steps. Lactam 2-137 was
converted with Meerweins reagent to the corresponding cyclic imidate 2-138.

114
Scheme 8.2.1. Fuchs and Funks total synthesis of ()-perophoramidine

Deprotection of nosylamide 2-138 was accompanied by formation of the northern
amidine via the cyclization of the liberated secondary amine onto the imidate.
Oxidation of the southern aminal to the corresponding amidine with MnO
2

furnished perophoramidine (2-9).
Funk and Crawley proposed using an intramolecular indol-2-one
cycloaddition in the synthesis of the related natural product communesin B
based upon the successful application of the indol-2-one cycloaddition in the
total synthesis of perophoramidine, (2-5, Scheme 8.2.2).
32
It was proposed that an
indol-2-one intermediate generated from oxindole 2-142 could undergo an endo-
selective intramolecular cycloaddition to yield cycloadduct 2-143, a species that
would ring open to the indolenine/spirooxindole 2-144. Conversion of lactam 2-
N
H
OTIPS
N
H
Br
O
Br
N
3
N
N
H
O
Br
N
3
OTIPS
N
NH
O
N
3
TIPSO
Br
N
H
N
Boc H
H
N O
TIPSO
Br N
H
N
Boc H
H
N O
TIPSO
Br
Cl
Cl
N
H
N
Boc H
H
N
Br
Cl
Cl
NNs
O
N
H
N
H H
N
Br
Cl
Cl
NNs
O
N
H
N
N N
Br
Cl
Cl
+
1. NaH, THF;
Boc
2
O, rt
92%
2. PPh
3
, THF,
H
2
O, 50 C
89%
NCS, AcOH,
THF, rt
86%
1. Cs
2
CO
3
,
PhSH, DMF,
45 C, 24 h
70%
2. MnO
2
,
CH
2
Cl
2
65%
5 steps
2-131 2-132
2-135 2-136
2-137 2-138 2-9
perophoramidine
2-134 2-133
(endo cycloaddition)
Cs
2
CO
3
,
CH
2
Cl
2
,
rt, 48 h
89%
Me
3
OBF
4
,
DIPEA,
CH
2
Cl
2
,
rt, 48 h
68%

115
144 to the corresponding tosylimide and subsequent methanolysis would give
aminal 2-145.
Initial progress towards the cyclization precursor 2-142 proceeded
smoothly with the Mannich reaction of amine 2-139, 3-hydroxyindole (2-140),
and formaldehyde to give alcohol 2-141. However, at this point, it proved
difficult to convert the alcohol functionality to a suitable leaving group for the
base-induced elimination that was required to generate the desired indol-2-one
intermediate.
Scheme 8.2.2. Crawley and Funks intramolecular indol-2-one cycloaddition
approach towards the communesins

Funk and Crawley turned their attention towards an intermolecular indol-
2-one cycloaddition approach analogous to that used in the successful synthesis
of perophoramidine, having encountered difficulties in their intramolecular
indol-2-one cycloaddition approach towards the communesins.
32
As noted
previously (Section 5.1), a fundamental difference between these related natural
N
H
HN
N
H
O
HO
N
H
N
NH
O
HO
HCHO,
AcOH,
H
2
O
60%
+
2-139
2-140
2-141
N
N
NH
O
N
Ts
N
H
N O
O
N
H
N
NH
O
X
2-142
2-145 2-144
N N
H H
N N
H
2-5
communesin B
O
9
9
O
H
N
N
H
O
N
2-143

116
products is the trans-relationship of the aminoethyl C(7) and C(8) substituents
present in perophoramidine versus the cis-relationship of the aminoethyl C(7)
and C(8) substituents found in the communesins. To establish this relationship,
the key indol-2-one cycloaddition must proceed through an exo transition state
rather than the endo transition state that was shown to be favored in the
perophoramidine synthesis. It was conceivable that the C(4) substituent of indole
2-146 might help to disfavor the endo transition state (Scheme 8.2.3). Thus, an exo
cycloaddition between indole 2-146 and indol-2-one 2-148 would give indolenine
2-149, which possesses the required C(7)C(8) relationship for the syntheses of
the communesins and therefore merited investigation.
Scheme 8.2.3. Crawley and Funks planned intermolecular indol-2-one
cycloaddition approach towards the communesins

To this end, azide 2-147 was reacted with indole 2-146 in the presence of
cesium carbonate to provide indolenine 2-150 (Scheme 8.2.4). The lactam was
converted to the corresponding Boc-imide, which, upon reduction of the azide,
underwent a ring opening/cyclization cascade to give aminal 2-151. To aid in the
determination of the stereochemical outcome of the cycloaddition reaction,
lactam 2-151 was converted to the conformationally rigid lactone 2-152. With
lactone 2-152 in hand, the stereochemical relationship of the side chains was
confirmed through
1
H NMR studies. Unfortunately, the stereochemistry
N
H
OTIPS
N
O N
3
N
H
OTIPS
N
H
O
Br
N
3
+
Cs
2
CO
3
2-146 2-147
N
NH
O
N
3
TIPSO
2-149 2-148
exo cycloaddition
4
7
8

117
established in the indol-2-one cycloaddition was found to be trans, not the cis
relationship necessary for the syntheses of the communesins. Therefore, it can be
concluded that a C(4) substituent on the indole does not alter the stereoselectivity
of the cycloaddition reaction.
Scheme 8.2.4. Intermolecular indol-2-one cycloaddition and determination of the
stereochemical outcome

We believed that this methodology could still be utilized in the
preparation of the communesins despite the fact that the cycloaddition failed to
provide the necessary stereochemical relationship for the syntheses of the
communesins. Specifically, we believed that an indol-2-one cycloaddition
strategy wherein the C(8) quaternary center was introduced late in the synthesis,
as had been done in our aza-ortho-xylylene approach, would provide access to
the communesins.
N
H
OTIPS
N
H
O
Br
N
3
+
2-146 2-147
N
NH
O
N
3
TIPSO
2-150
N
H
N
Boc H
H
N O
TIPSO
1. NaH;
Boc
2
O
70%
2. PPh
3
,
H
2
O
78%
2-151
N
H
N
Boc H
O
NH
O
Ns
N
H
N
Boc H
O
NH
O
Ns
1. NaHMDS;
NsCl
85%
2. TBAF, THF
60%
2-152
(endo adduct)
2-153
(exo adduct)
7
8
7
8
Cs
2
CO
3
,
CH
2
Cl
2
,
rt, 24 h
65%

118
Chapter 9. Total Synthesis of ()-Communesin F via a Cycloaddition
with Indol-2-one
9.1. Retrosynthetic analysis of communesin F
The following retrosynthesis of communesin F was devised bearing in
mind the aforementioned limitations of the indol-2-one cycloaddition reaction
(Scheme 9.1.1). Thus, the natural product could be prepared from bridgehead
lactam 2-154 through stereoselective alkylation of the lactam enolate with 1-
azido-2-iodoethane, reduction of the azide to an amino group, reductive
amination with the reactive bridgehead lactam carbonyl, and acetylation. The
bridgehead lactam 2-154 could arise from an intramolecular lactamization of the
azepine derivative of amine 2-155, in turn prepared via an intramolecular allylic
Scheme 9.1.1. Retrosynthetic analysis for communesin F

N N
H H
N N
H
O
2-8
communesin F
N N
Boc H
O N
H
N N
Boc H
O O
HO
H
2
N
H
H
N
H
N
3
N
O
+
Br
N
NH
O
H
N
3
Br
2-157
N
Boc
N
H
Br
H
N
3 O O
H
2-156
2-154 2-155
2-159
2-160
8
8
N
N
H
O
N
3
Br
2-158
H

119
substitution reaction with the primary amine. Allylic alcohol 2-155 could be
derived from bromide 2-156 via a Heck reaction. Aminal 2-156 would be formed
via methanolysis of the Boc-imide derivative of lactam 2-157. Indolenine 2-157
should be available by ring opening of the endo cycloadduct 2-158 derived from
the cycloaddition of indole 2-159 and indol-2-one (2-160). Indole 2-159 could in
turn be prepared in a short sequence from 4-bromotryptophol (2-39). It should be
noted that the stereochemical outcome of the key cycloaddition is in fact
inconsequential; the final stereochemistry at C(8) is set during the alkylation of
lactam 2-154 which should, based on prior experience (2.117!2.102, Scheme
8.2.4), occur on the convex face to set the correct stereochemistry at C(8).
However, the stereochemistry of the cycloadduct does bear on the facility of
generating the enolate of lactam 2-154. Inspection of molecular models suggests
that the proton of the C(8) epimer of 2-154 is more accessible.
9.2. Total synthesis of ()-communesin F
Our retrosynthesis, therefore, hinged upon our ability to generate the
parent indol-2-one 2-160 that was not possible using the conditions (Cs
2
CO
3
,
CH
2
Cl
2
) reported in the initial Fuchs and Funk investigation. After examining a
number of base/solvent combinations, we discovered that treatment of 3-
bromoindol-2-one (2-161) with 3-methylindole (2-162) in the presence of silver
carbonate (Ag
2
CO
3
) in acetonitrile provided the desired indolenine 2-164 after
ring opening of the intermediate bridgehead lactam 2-163 (Scheme 9.2.1). In
contrast, treatment of 3-bromoindol-2-one with 3-methylindole with alternative

120
Scheme 9.2.1. Reaction of 3-bromoindol-2-one with 3-methylindole

base equiv solvent yield
(unoptimized)
Cs2CO3 2.5 CH2Cl2 NR
Ag2CO3 2.5 CH2Cl2 < 10%
DBU
52a
3 THF decomposition
Ag2CO3 2.5 acetone ~30%
Ag2CO3 2.5 CH3CN 47%
Cs2CO3 2.5 acetone NR
Cs2CO3 2.5 CH3CN NR

base/solvent combinations resulted in no reaction or complex mixtures of
products and/or decomposition of the 3-bromoindol-2-one (2-161).
We embarked on the synthesis of communesin F having established
conditions for the generation of the requisite indol-2-one intermediate. To this
end, indole 2-159, prepared in two steps form 4-bromotryptophol (2-39), was
treated with freshly recrystallized 3-bromoindol-2-one
53
(2-161, 1.6 equiv) and
silver carbonate (0.8 equiv) in acetonitrile to give indolenine 2-157 as a single
diastereomer in good yield (Scheme 9.2.2). The relative stereochemistry was
tentatively assigned as shown based upon an endo transition state and was
confirmed by the X-ray crystallographic derived structure of a downstream
product (2-167, vide infra).
Scheme 9.2.2. Preparation of indolenine 2-157

N
H
Br
O
N
NH
O
H
2-164 2-160 2-162 2-161
base,
solvent
N
H
N
H
O
N
H
N
H
O
H
2-163
N
H
Br
OH
1. I
2
, PPh
3
,
imidazole
CH
3
CN, Et
2
O,
rt, 4 h, 88%

2. NaN
3
, DMF,
50 C, 5 h
95%
N
H
Br
N
3
N
H
O
Br
Ag
2
CO
3
(0.8 equiv),
MeCN, rt
16 h,
70%
N
NH
O
H
N
3
Br
+
2-39 2-159 2-161 2-157

121
Drawing from Funk and Fuchss synthesis of perophoramidine, we
attempted to convert indolenine 2-157 to the corresponding Boc-imide. However,
the only product isolated under a variety of conditions was the corresponding O-
acylated oxindole. Thus, indolenine 2-157 was converted to tosylimide 2-165 with
sodium hydride and tosyl chloride (Scheme 9.2.3). Treatment of the reaction
mixture with methanol resulted in direct formation of aminal 2-167, the structure
and stereochemistry of which was confirmed by X-ray crystallography (Figure
9.2.1). Presumably the formation of aminal 2-167 occurs via an initial ring
Scheme 9.2.3. Construction of aminal 2-167

Figure 9.2.1. X-ray crystal structure of aminal 2-167
N
NH
O
H
N
3
Br
N
Ts
N
H
Br
H
N
3 O O
H
TsCl (1.02 equiv),
NaH (2.1 equiv),
THF, 0
o
C, 0.5 h
then MeOH,
rt, 16 h
N
NTs
O
H
N
3
Br
2-157 2-165
2-167
N
N
Br
N
3
O
O
H
2-166
Ts
61%

122
opening of imide 2-165 with methoxide and subsequent cyclization of the tosyl-
anilide anion intermediate 2-166 into the indolenine functionality to give the
aminal.
We next turned our attention towards the methylation of the differentially
protected aminal. After an exhaustive screening of traditional methylating
reagents and procedures (NaH, MeI; KOtBu, MeI; Cs
2
CO
3
, MeI; HCHO,
NaBH
3
CN; (HCHO)
n
, Ti(OiPr)
4
, NaBH
3
CN; MeOTf), we discovered that we could
effect the desired transformation with Meerweins reagent and cesium carbonate.
Thus, aminal 2-167 was cleanly converted to its N-methyl derivative (Scheme
9.2.4). The resulting azide 2-168 was then reduced in the presence of excess tert-
butyl pyrocarbonate to provide the Boc-carbamate 2-169.
Scheme 9.2.4. Preparation of amide 2-169

The next task in the synthesis involved elaboration of the aryl bromide to
the allylic alcohol and subsequent closure to the benzazepine ring. Thus,
bromide 2-169 was subjected to conditions employed in Qin, and Mas respective
syntheses of communesin F (Scheme 9.2.5). In this case, however, the bromide
proved unreactive and none of the desired allylic alcohol 2-170 was observed.
N
Ts
N
Br
H
N
3 O O
H
N
Ts
N
H
Br
H
N
3 O O
H
Me
3
OBF
4
, Cs
2
CO
3
,
CH
2
Cl
2
, rt, 24 h

80%
N
Ts
N
Br
H
BocHN
O O
H
Boc
2
O, PtO
2
, H
2
,
EtOAc, rt, 16 h

88%
2-167 2-168 2-169

123
Scheme 9.2.5. Attempted Heck reaction

catalyst ligand base solvent temperature
Pd(OAc)2 P(o-tol)3 Et3N neat 100 C (&)
Pd(OAc)2 P(o-tol)3 PMP DMF 140 C (&)
Pd(OAc)2 K2CO3 DMF/H2O 90 C

Reasoning that the tosyl amide was in some way attenuating the reactivity
of bromide 2-169 in the Heck reaction, tosyl amide 2-169 was treated with
magnesium in methanol to give aminal 2-171 (Scheme 9.2.6).
54
Interestingly, the
addition of ammonium chloride
12a
accelerated this reaction but also led to a large
amount of the debrominated product.
Scheme 9.2.6. Deprotection of tosylamide 2-169

We again turned our attention towards elaborating the aryl bromide with
aminal 2-171 in hand. To that end, the aminal 2-171 was converted to Boc-aminal
2-172 (Scheme 9.2.7). The resulting bromide 2-172 was then coupled with 2-
methyl-3-buten-1-ol to afford allylic alcohol 2-173 in moderate yield.
55

With the allylic alcohol 2-173 in hand, we could investigate the closure to
the benzazepine functionality (Scheme 9.2.8). Attempted cyclization under
conditions utilized in previous syntheses of communesin F by Qin, Weinreb, and
N
Ts
N
Br
H
BocHN
O O
H
N
Ts
N
HO
H
BocHN
O O
H
OH
2-169 2-170
conditions
N
H
N
Br
H
BocHN
O O
H
N
Ts
N
Br
H
BocHN
O O
H
Mg, MeOH,
rt, 18 h
87%
2-169 2-171

124
Scheme 9.2.7. Preparation of bis-Boc allylic alcohol 2-173

Ma afforded none of the desired benzazepine 2-175 and instead led to exclusive
formation of diene 2-174. The diene resulting from dehydration of the starting
allylic alcohol was observed by Qin and Weinreb as substantial byproducts (24-
26%) under acidic conditions in their respective syntheses. Subtle conformational
effects may be at play here. Qin and Weinreb had the spirolactam in place that
favors the planar conformation 2-176 (Figure 9.2.2). The preferred conformation
for our carbamate is cup shaped (2-173), which, in principle, is capable of
cyclization since Mas cyclization proceeded through this conformer, albeit,
using a conformationally rigidified lactam (2-60).
Scheme 9.2.8. Attempted benzazepine formation

Concurrent with this work, we discovered that the Heck reaction with the
unprotected aminal 2-171 furnished allylic alcohol 2-177 in a much-improved
yield (93% v. 53%, Scheme 9.2.9). In light of this finding and the difficulties
N
H
N
Br
H
BocHN
O O
H
N
Boc
N
HO
H
BocHN
O O
H
N
Boc
N
Br
H
BocHN
O O
H
OH
2-171 2-172 2-173
Boc
2
O, KHMDS,
THF, rt, 1.25 h
97%
Pd(OAc)
2
,
K
2
CO
3
, H
2
O,
DMF, 90 C, 5h
53%
N
Boc
N
HO
H
BocHN
O O
H
N
Boc
N
H
Boc
N
O O
H
H
H
+
or
MsCl,
Et
3
N
2-173
N
Boc
N
H
BocHN
O O
H
2-174 2-175
not observed

125

Figure 9.2.2. Comparison of cyclization precursor conformations
encountered in forming the benzazepine with the protected aminal, we
proceeded with the unprotected aminal 2-177 with the expectation that
protection of the aminal might be mandated at a later stage.
Subjection of allylic alcohol 2-177 to the aforementioned cyclization
conditions (cf. Scheme 9.2.8) again gave the respective diene as the only product.
However, a thorough review of the literature uncovered a 2010 paper describing
the mercuric triflate catalyzed enantioselective cyclization of anilino sulfonamide
with allylic alcohols.
56
In this report, Yamamoto and coworkers disclosed as part
of their optimization studies the asymmetric cyclization of tert-butyl carbamate
2-178 in the presence of mercuric triflate and a chiral auxiliary to give 2-vinyl
indoline 2-179 (Scheme 9.2.10).
Scheme 9.2.9. Preparation of allylic alcohol 2-177

N
H
N
N
O
Boc
H
HO
OH
N
NHBoc
H
N
Boc
H
HO
O
O
N
NHBoc
N
O
R
H
HO
NH
2-173 2-60 2-176
R = CO
2
Me, CO
2
tBu
N
H
N
Br
H
BocHN
O O
H
N
H
N
HO
H
BocHN
O O
H
Pd(OAc)
2
,
K
2
CO
3
, H
2
O,
DMF, 90 C, 5 h

93%
OH
2-171 2-177

126
Scheme 9.2.10. Allylic amination with mercuric triflate

We were delighted to discover that treatment of allylic alcohol 2-177 with
2.5 mol% mercuric triflate initiated a stereoselective 7-exo-trig cyclization to give
benzazepine 2-180 (Scheme 9.2.11). The structure and stereochemistry of which
was confirmed by X-ray crystallography (Figure 9.2.3). The corresponding diene
resulting from the dehydration of alcohol 2-177 was not observed.
A possible rationale for the excellent stereoselectivity observed in the
mercuric triflate catalyzed cyclization is illustrated in Scheme 9.2.12. The reaction
Scheme 9.2.11. Introduction of the benzazepine ring

Figure 9.2.3. X-ray crystal structure of benzazepine 2-180
NH OH
Boc
N
Boc
(R)-BINAPHANE (1 mol %),
Hg(OTf)
2
(1 mol %),
mesitylene, rt, 6 h
72% (41% ee)
2-178 2-179
N
H
N
HO
H
BocHN
O O
H
N
H
N
H
Boc
N
O O
H
H
Hg(OTf)
2
,
CH
2
Cl
2
,
rt, 20 h
86%
2-177 2-180

127
is likely initiated by $-complexation,
57
or possibly a mercurinium ion, of alkene 2-
177 with mercuric triflate from the face opposite the bulky Boc-carbamate (2-181).
Intramolecular nucleophilic attack by the carbamate nitrogen onto the $-complex
gives the organomercuric intermediate 2-182 and triflic acid. Protonation of the
hydroxyl moiety with the in situ-generated triflic acid and subsequent
demercuration affords the benzazepine 2-180 and regenerates the mercuric
triflate catalyst. The possibility of a triflic acid catalyzed pathway can likely be
discounted in light of the absence of any of the diene resulting from the
dehydration of alcohol 2-177. Finally, it should be noted that the planar
conformations for 2-177 and the corresponding intermediates are more accessible
without the N-Boc-aminal group due to the absence of A
1,3
strain.
Scheme 9.2.12. Possible pathway for the mercuric triflate catalyzed cyclization

N
HN
N
O
H
H
HO
H
O
N
N
N
O
H
H
H
H
O
O
O
N
NH
N
O
H
H
HO
H
O
O
O
(TfO)
2
Hg
N
N
N
O
H
H
HO
H
H
O
TfOHg
N
N
N
O
H
H
H
2
O
H
H
O
TfOHg
TfO
O O
O O O O
H
Hg(OTf)
2
TfOH
Hg(OTf)
2
2-177 2-181 2-182
2-183 2-180
TfOH

128
We turned our attention to the construction of the critical bridgehead
lactam with the requisite benzazepine 2-180 in hand. With the anticipated
alkylation of the bridgehead lactam in mind, aminal 2-180 was protected as its
methyl carbamate (Scheme 9.2.13). The Boc-carbamate was then deprotected via
the Ohfune protocol
58
to give amine 2-184. Saponification of methyl ester 2-184
with lithium hydroxide provided the corresponding acid. Treatment of the acid
with carbonyldiimidazole (CDI) led directly to the bridgehead lactam 2-185 with
concomitant epimerization of the C(8) proton. The low basicity of imidazole
effectively rules out a pathway wherein the epimer of 2-185 is epimerized. Thus,
the epimerization observed under the reaction conditions might proceed through
a ketene intermediate rather than an acyl imidazole intermediate. Subsequent
protonation of the ketene aminal intermediate from the concave face then yields
the epimerized product. Although epimerization during the course of the
saponification reaction could not be completely ruled out, our inability to effect
C(8) epimerization (NaOMe, MeOH, rt to 65 C) of methyl ester 2-184 provides
evidence to support our conjecture.
Scheme 9.2.13. Preparation of bridgehead lactam 2-185

N
H
N
H
Boc
N
O O
H
H
N
CO
2
Me
N
H
H
N
O O
H
H
N N
CO
2
Me H
O N
H
H
1. (CH
3
OCO)
2
O,
KHMDS, THF
90%
2. 2,6-lutidine,
TMSOTf,
CH
2
Cl
2
,
97%
2-180 2-184 2-185
1. LiOH, THF,
MeOH, H
2
O,
50 C, 20 h,
80%
2. CDI, THF, rt,
15 h, 89%
8

129
Scheme 9.2.14. Attempted alkylation of bridgehead lactam 2-186

base additive solvent electrophile
KHMDS THF ICH2CH2N3
LDA HMPA THF ICH2CH2N3
nBuLi THF ICH2CH2N3
nBuLi HMPA THF ICH2CH2N3
NaH DMF ICH2CH2N3
KHMDS THF ICH2CN
LiHMDS THF ICH2CN
LDA THF ICH2CN

The next task in the synthesis was the installation of the remaining
quaternary center. However, treatment of twisted amide 2-185 with 1-azido-2-
iodoethane under a variety of conditions, including those successfully utilized
during our previous synthesis effort (cf. Scheme 7.2.4), failed to generate
thedesired alkylated product 2-186 (Scheme 9.2.14). Moreover, the conditions
employed (KHMDS; ICH
2
CN) by Ma and Zuo to alkylate a similar bridgehead
lactam, notably lacking the methoxy carbonyl, in the course of their syntheses of
communesins A and B (cf. 2-63!2-64, Scheme 5.4.7) also failed to provide the
corresponding alkylated lactam.
20

We turned to preparing the bridgehead lactam lacking the methoxy
carbonyl moiety drawing upon our previous observation on the influence of
remote substituents on reactivity, and based upon the precedent established by
Ma and Zuo. To this end, Boc-carbamate 2-180 was deprotected to give amine 2-
187. In this case, removal of the Boc protecting group required initial conversion
to the TBS carbamate followed by fluoride treatment. To our dismay, treatment
N N
CO
2
Me H
O N
H
H
N N
CO
2
Me H
O N
H
R
conditions
2-185 2-186

130
of ester 2-187 under the previously established conditions (1. LiOH, 2. CDI, 2-
184!2-185, Scheme 9.2.13) failed to yield any of the desired bridgehead lactam 2-
188 (or 2-189) and resulted only in decomposition. However, treatment of ester 2-
187 with trimethylaluminum for 30 minutes at 0 C cleanly provided the
bridgehead lactam 2-188 (Scheme 9.2.15).
59
The stereochemistry of lactam 2-188
was confirmed through
1
H NMR studies. While a very small nOe correlation was
observed between the C(8) alpha proton and the C(11) allylic proton, it was the
absence of a strong nOe correlation between the C(8) alpha proton and the C(6)
aminal proton that proved most informative (2-188a, Scheme 9.2.15). This
observation suggests a trans relationship between the C(8) alpha proton and the
C(6) aminal proton as a strong correlation between the C(8) and C(6) protons
would be expected in the cis epimer 2-188. To the best of our knowledge, this
represents the first example of the construction of a twisted, bridged lactam
using this valuable protocol for the preparation of amides. However, the
construction of a pyrimidalized, fused lactam from an amino ester using
Scheme 9.2.15. Preparation of bridgehead lactam 2-188

N
H
N
H
Boc
N
O O
H
H
N
H
N
H
H
N
O O
H
H
N N
H H
O N
H
H
2-180 2-187 2-188
N
N
N
O
H
H
TBSOTf,
lutidine,
CH
2
Cl
2
, rt,
3 h;
KF, MeOH,
rt, 1 h, 94%
AlMe
3
,
CH
2
Cl
2
,
0 C, 1 h
87%
H
H
8
2-188a
6
19
nOe
11

131
triisobutylaluminum as reported by Woodward
60
as part of his classic synthesis
of cephalosporin C served as useful precedent.
We again set upon installing the remaining quaternary center with
bridgehead lactam 2-188 in hand. Attempts to alkylate the bridgehead lactam
with 1-azido-2-iodoethane under the conditions previously cited (Scheme 9.2.14)
proved unsuccessful. However, treatment of the bridgehead lactam 2-188 with
potassium hexamethyldisilazide (KHMDS) followed by iodoacetonitrile
provided nitrile 2-189 as a single diastereomer. The stereochemistry of the
alkylation reaction was confirmed through
1
H NMR studies. Key nOe
correlations were observed between the C(18) proton and the C(6) aminal proton,
and between the C(18) proton and the C(19) proton (2-189a, Scheme 9.2.16).
These results confirm the desired cis relationship of the eventual aminoethyl
groups.
Scheme 9.2.16. Alkylation of bridgehead lactam 2-188

With nitrile 2-189 in hand, we planned to continue with the endgame
employed by Ma and Zuo
20
in their syntheses of communesins A and B for the
preparation of the northern aminal (cf. 2-64!2-66, Scheme 5.4.7). Thus, nitrile 2-
189 was reduced with LiAlH
4
to give lactol 2-190 (Scheme 9.2.17). We were
surprised, however, to discover that subjecting lactol 2-190 to the reported
reductive amination/cyclization conditions (NH
4
OAc, NaBH(OAc)
3
, MeOH, rt,
N N
H H
O N
H
H
N N
H H
O N
H
2-188 2-189
CN
N
N
N
O
H
H
H
H
H
H
CN
nOe
nOe
2-189a
H
6
19
18
KHMDS, THF,
-78
o
C, 0.5 h;
ICH
2
CN, THF,
-78
o
C, 0.5 h
77%

132
Scheme 9.2.17. Synthesis of 1-deoxocommunesin F

48 h) cleanly provided 1-deoxocommunesin F (2-191), not the expected N-H
aminal 2-192.
While surprising, this result is not without precedent. In fact, it was the
observation that reduction of indoles with NaBH
4
AcOH gave rise to N-ethyl
indolines (eq. 1, Scheme 9.2.18)
61
that led to the discovery of sodium
triacetoxyborohydride (eq. 2, Scheme 9.2.18).
62
Abdel-Magid and coworkers have
extended the utility of sodium triacetoxyborohydride as an outstanding reducing
reagent in reductive amination reactions.
63
It has been observed that in the case of
many slow reductive amination reactions (>24 h) performed utilizing sodium
triacetoxyborohydride, the formation of up to 5% N-ethyl derivatives as side
products is not uncommon.
63
Whereas the pathway leading to N-ethylation is not
well defined, it does not appear to proceed through reduction of an acetamide.
Rather the triacetoxyborohydride in the presence of excess acetic acid is believed
to undergo a self-reduction to generate acetaldehyde, which then participates in
a typical reductive amination sequence with the amine.
61,64

N N
H H
O N
H
2-189
CN
N N
H H
N N
H
2-191
1"-deoxocommunesin F
H
H
1"
1. LiAlH
4
, THF,
60
C, 1.5 h
N N
H H
O N
H
OH
2-190
2. NH
4
OAc,
NaBH(OAc)
3
,
MeOH, rt, 48 h
70% (2 steps)
N N
H H
H
N N
H
2-192
not observed

133
Scheme 9.2.18. N-Ethylation of indolines with acyloxyborohydrides

A possible reaction pathway for the formation of 1-deoxocommunesin F (2-191)
from lactol 2-190 is outlined in Scheme 9.2.19. Thus, aldehyde 2-193 undergoes
an initial reductive amination reaction with ammonia to afford the primary
amine 2-194 that could undergo a second reductive amination reaction with in
situ generated acetaldehyde to give N-ethylamine 2-195. Collapse of the
hemiaminal 2-195 is followed by condensation of the N-ethylamine side chain
with the newly formed aldehyde 2-196 to give hemiaminal 2-197. Dehydration of
hemiaminal 2-197 generates an iminium ion intermediate 2-198 that is attacked
by the benzazepine nitrogen to give 1-deoxocommunesin F. Two key alternative
pathways exist which warrant consideration: (1) the dehydration of hemiaminal
2-194 or 2-195 to give a bridgehead iminium ion which then undergoes
cyclization to afford an aminal, and (2) the late-stage reductive amination of
aminal 2-192 (Scheme 9.2.17) to install the ethyl group. The poor orbital overlap
and the highly strained nature of the bridgehead iminium ion formed by a direct
dehydration of hemiaminal 2-194 or 2-195 makes this pathway seem highly
unlikely. Lastly, the relative rates for the reductive amination of the primary
amine with acetaldehyde (fast) versus the ring opening/ring closing reaction
sequence to form the aminal (slow) should favor a pathway featuring an early-
stage reductive amination.
N
H
N
H
N
Et
NaBH
4
,
AcOH
NaBH
4
+ 3AcOH NaBH(OAc)
3
+ 3H
2
(eq. 1)
(eq. 2)

134
Scheme 9.2.19. A proposed synthetic pathway to 1-deoxocommunesin F

After extensive screening of mild reducing reagents, amine sources, and a
variety of reaction conditionspH, temperature, and reaction timewe were
able to establish conditions that permitted the conversion of nitrile 2-189 to
communesin F (2-8, Scheme 9.2.20). Thus, nitrile 2-189 was reduced to give the
lactol derivative, which was treated with ammonium chloride in a saturated
methanolic ammonia solution for five hours at room temperature prior to
treatment with sodium cyanoborohydride for 72 hours. These conditions
preclude the generation of any acetaldehyde. Finally, the resulting crude aminal
was directly acetylated to give ()-communesin F (2-8) whose spectroscopic
properties were identical to those previously reported.
5

N N
H H
N N
H
2-191
1"-deoxocommunesin F
H
H
1"
N N
H H
O N
H
OH
NH
4
OAc,
NaBH(OAc)
3
2-190
N N
H H
NH
2
N
H
OH
N N
H H
NH N
H
OH
H
O
NaBH(OAc)
3
2-194
2-195
N N
H H
O
N
H
OH
2-193
N N
H H
NH
H
N
H
O
2-196
N N
H H
N
H
N
H
HO
N N
H H
N N
H
H
2-198 2-197
-H
2
O

135
Scheme 9.2.20. Completion of the total synthesis of ()-communesin F

In conclusion, we identified conditions where indol-2-one itself can be
generated and trapped in DielsAlder cycloadditions. We have successfully
applied this methodology in a concise total synthesis of the marine natural
product ()-communesin F. The synthesis, which was completed in 15 linear
steps from 4-bromotryptophol (2-39) in an overall yield of 6.7%, is outlined
below (Scheme 9.3.1). To date this represents the shortest, highest yielding total
synthesis of ()-communesin F (cf. Section 5.4). Highlights of this synthesis
include: (1) the stereoselective cycloaddition with the parent indol-2-one, (2) an
intramolecular mercuric triflate catalyzed cyclization of a carbamate with an
allylic alcohol, (3) the first preparation of a twisted bridgehead lactam from an
amino ester using trimethylaluminum and (4) the nuances (frustrations) of
N N
H H
O N
H
CN
LiAlH
4
, THF,
60
o
C, 1.5 h
N N
H H
N N
H
O
2-189
2-8
communesin F
N N
H H
O N
H
OH
2-190
N N
H H
H
N N
H
2-192
NH
3
, NH
4
Cl,
MeOH, rt, 1 h;
NaBH
3
CN, 72 h
Ac
2
O, Et
3
N,
DMAP, CH
2
Cl
2
rt, 0.5 h
51% (3 steps)

136
natural product synthesis that are frequently encountered, in this case the
unexpected preparation of 1-deoxocommunesin F.
Scheme 9.3.1. Total synthesis of ()-communesin F

N
H
Br
I
N
H
Br
OH
I
2
, PPh
3
, imid.,
CH
3
CN, Et
2
O,
rt, 4 h
88% N
H
Br
N
3
NaN
3
, DMF,
50
o
C, 5 h
95% N
H
O
Br
N
Br
NH
N
3
O
Ag
2
CO
3
,
MeCN, rt
16 h,
70%
H
+
N
Ts
N
H
Br
H
N
3 O O
H
TsCl, NaH,
THF, 0
o
C
0.5 h;
MeOH, rt
16 h, 61% N
Ts
N
Br
H
N
3 O O
H Me
3
OBF
4
, Cs
2
CO
3
,
CH
2
Cl
2
, rt, 24 h,

80%
N
Ts
N
Br
H
BocHN
O O
H Boc
2
O, PtO
2
, H
2
,
EtOAc, rt, 16 h,
88%
N
H
N
Br
H
BocHN
O O
H
Mg, MeOH,
rt, 18 h,
87%
N
H
N
HO
H
BocHN
O O
H
Pd(OAc)
2
,
K
2
CO
3
, H
2
O,
DMF, 90
o
C,
5 h, 93%
OH
N
H
N
H
Boc
N
O O
H
H
Hg(OTf)
2
,
CH
2
Cl
2
, rt,
20 h,
86%
N
H
N
H
H
N
O O
H
H
TBSOTf,
lutidine,
CH
2
Cl
2
, rt,
3 h;
KF, MeOH,
rt, 1 h, 94%
AlMe
3
,
CH
2
Cl
2
,
0
o
C, 1 h,
87%
N N
H H
O N
H
H
KHMDS, THF,
-78
o
C, 0.5 h;
ICH
2
CN, THF,
-78
o
C, 0.5 h
77%
N N
H H
O N
H
CN
LiAlH
4
, THF,
60
o
C, 1.5 h
N N
H H
N N
H
O
2-39
4-bromotryptophol
2-199 2-159 2-161
2-157 2-167 2-168
2-169 2-171 2-177
2-180 2-187 2-188
2-189
2-8
communesin F
N N
H H
O N
H
OH
2-190
N N
H H
H
N N
H
2-192
NH
3
, NH
4
Cl,
MeOH, rt, 1 h;
NaBH
3
CN, 72 h
Ac
2
O, Et
3
N,
DMAP, CH
2
Cl
2
rt, 0.5 h
51% (3 steps)

137
Chapter 10. Experimental
10.1. Materials and Methods
Unless otherwise stated, all reactions were performed in flame-dried
round-bottomed flasks. The flasks were fitted with rubber septa and reactions
were conducted under a positive pressure of nitrogen. Syringes or cannulae were
used to transfer air- and moisture sensitive liquids. Organic solutions were
concentrated on rotary evaporators at ~10 Torr at 30 C. Anhydrous acetonitrile
(CH
3
CN), benzene (PhH), tetrahydrofuran (THF), dichloromethane (CH
2
Cl
2
),
diethyl ether (Et
2
O), toluene, triethylamine (Et
3
N), methanol (MeOH) and
dimethylformamide (DMF) were obtained by passing commercially available
pre-dried, oxygen-free formulations through activated alumina columns. All
other commercial reagents and solvents were used as received without further
purification, unless otherwise noted. Analytical thinlayer chromatography
(TLC) was performed using Al plates (Merck 60F-254) visualized by exposure to
ultraviolet light and an aqueous solution of ceric ammonium molybdate (CAM).
Flash column chromatography was performed as described by Still et al. using
silica gel (SiO
2
) (60- pore size, 3263 m, standard grade, Dynamic
Adsorbents).
65
Silica gel was deactivated by washing, in order, with Et
3
N, EtOAc,
and then hexanes. NMR spectra were recorded on Bruker 300, 360 or 400 MHz
spectrometers and referenced from the residual undeuterated solvent in the
NMR solvent (CHCl
3
: % 7.26, C
6
D
6
: 7.16, d
6
-acetone: 2.05). Data is reported as

138
follows: chemical shift [multiplicity (s = singlet, d = doublet, t = triplet, m =
multiplet), coupling constant(s) in Hertz, integration]. Carbon-13 NMR spectra
were recorded on Bruker 300, 360 or 400 MHz spectrometers and referenced
from the carbon resonances of the solvent (CDCl
3
: % 77.00, C
6
D
6
: 128.39, d
6
-
acetone: 29.90). Data is reported as follows: chemical shift. Infrared data (IR)
were obtained with a Perkin-Elmer 1600 IR, and are reported as follows:
frequency of absorption (cm
1
). Melting points were obtained on a Thomas
Hoover melting point apparatus and are uncorrected.
10.2. Preparative Procedures

Propargyl alcohol 2-106: To a solution of aldehyde

2-105
34
(22.5 g, 62.6 mmol) in
THF (300 mL) at 78 C was added ethynylmagnesium bromide (0.5 Min THF,
138 mL, 68.9 mmol) dropwise. The mixture warmed to rt. After 1 h at rt, a
saturated NH
4
Cl solution (250 mL) and EtOAc (400 mL) were added sequentially
to the mixture. The resulting layers were separated, and the aqueous layer was
extracted two times with EtOAc (200 mL). The combined organic extracts were
washed once with brine (250 mL), dried (MgSO
4
vacuo to give 23.7 g (95%) of 2-106 as yellow oil that was taken on without further
purification.

139
1
3
): " 7.44 (d, J = 8.3 Hz, 1H), 7.27 (m, 1H), 7.09 (m, 2H),
5.72 (s, 1H), 4.14 (d, J = 9.5, 1H), 3.56 (d, J = 11.0, 1H), 2.25 (s, 6H), 1.93 (s, 3H),
1.69 (p, J = 7.5, 3H), 1.14 (s, 9H), 1.12 (s, 9H).
13
C NMR (75 MHz, CDCl
3
): " 143.4,
135.5, 132.4, 126.2, 121.6, 120.1, 114.4, 114.0, 81.7, 81.4, 64.3, 57.3, 44.0, 18.0, 12.8,
3.9. IR (thin film): 2948, 2867, 2233, 1555 cm
1
. HRMS (ESI): calc. for C
24
H
39
N
2
OSi
[M+H]
+
: 399.2832, Found: 399.2836.

Propargyl acetate S2-1: To a solution of alcohol 2-106 (12.8 g, 32.1 mmol) in
CH
2
Cl
2
(130 mL) at 0 C was added Et
3
N (22.4 mL, 161 mmol), 4-
(dimethylamino)pyridine (0.980 g, 8.03 mmol), and acetic anhydride (7.59 mL,
80.3 mmol). The mixture was warmed to rt. After 12 h, water (250 mL) and
CH
2
Cl
2
(250 mL) were added sequentially to the mixture. The resulting layers
were separated, and the aqueous layer was extracted one time with CH
2
Cl
2
(100
mL). The combined organic extracts were dried (MgSO
4
), filtered and
chromatography (25% EtOAc/Hex) to give 11.9 g (84%) of S2-1 as pale yellow
oil.
1
3
): " 7.59 (d, J = 7.4 Hz, 1H), 7.56 (m, 1H), 7.48 (d, J = 8.2
Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.11 (s, 1H), 3.50 (d, J = 12.9 Hz, 1H), 3.45 (d, J =
12.9 Hz, 1H), 2.21 (s, 6H), 2.11 (s, 3H), 1.91 (d, J = 2.1 Hz, 3H), 1.69 (p, J = 7.4 Hz,
3H), 1.15 (s, 9H), 1.13 (s, 9H).
13
C NMR (75 MHz, CDCl
3
): " 170.0, 142.6, 132.4,

140
129.7, 128.1, 121.4, 119.6, 115.8, 114.5, 83.1, 65.0, 56.4, 44.9, 21.4, 18.1, 12.8, 4.0. IR
(thin film): 2947, 2868, 2765, 1740 cm
1
26
H
41
N
2
O
2
Si
[M+H]
+
: 441.2937, Found: 441.2940.

Allene 2-107: To a suspension of CuI (17.9 g, 94.2 mmol) and LiBr (8.20 g, 94.2
mmol) in THF (300 mL) at 0 C was added methylmagnesium bromide (3 M in
Et
2
O, 63.0 mL, 188 mmol) dropwise. After 0.5 h, a solution of acetate S2-1 (8.30 g,
18.8 mmol) in THF (95 mL) was added dropwise via cannula. The mixture was
slowly warmed to rt. After 12 h, a saturated NH
4
Cl solution (250 mL) and EtOAc
(400 mL) were added sequentially to the mixture. The resulting layers were
separated, and the aqueous layer was extracted three times with EtOAc (250 mL).
The combined organic extracts were washed four times with NH
4
OH (3M, 250
mL), water (250 mL), and brine (250 mL), dried (MgSO
4
), filtered and
chromatography (20% EtOAc/Hex) to give 6.79 g (91%) of 2-107 as pale yellow
oil.
1
3
): " 7.31 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 7.3 Hz, 1H), 7.14
(m, 1H), 7.09 (m, 2H), 3.60 (s, 2H), 2.28 (s, 6H), 1.85 (s, 6H), 1.70 (p, J = 7.5 Hz,
3H), 1.16 (s, 9H), 1.14 (s, 9H).
13
C NMR (75 MHz, CDCl
3
): " 203.9, 142.7, 131.8,
128.9, 128.2, 121.6, 118.8, 116.1, 111.9, 97.0, 90.8, 56.8, 45.1, 20.4, 20.4, 18.1, 12.8. IR

141
(thin film): 2946, 2868, 2762, 1950, 1557 cm
1
25
H
41
N
2
Si
[M+H]
+
: 397.3039, Found: 397.3060.

Nitrile 2-108: To a solution of amine 2-107 (7.32 g, 18.5 mmol) in PhH (62 mL) at
5 C was added MeI (8.55 mL, 92.3 mmol). The mixture was warmed to rt. After 8
h at rt, the mixture was concentrated in vacuo. The crude semi-solid was
suspended in Et
2
O (100 mL) and collected by filtration to give the crude
ammonium salt. To a solution of the salt in DMF (37 mL) was added a solution of
potassium cyanide (1.3 Min H
2
O, 57.0 mL, 73.8 mmol). The mixture was warmed
to 80 C. After 6 h, the mixture was diluted with Et
2
O (200 mL). The resulting
layers were separated, and the aqueous layer was extracted one time with Et
2
O
(50 mL). The combined combined organic extracts were washed three times with
water (50 mL), dried (MgSO
4
) and concentrated in vacuo. The crude solid was
purified by flash column chromatography (15% EtOAc/Hex) to give 2.46 g (60%)
of 2-108 as a white solid.
1
H NMR (400 MHz, C
6
D
6
): " 7.40 (d, J = 7.4 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 6.82
(d, J = 8.1 Hz, 1H), 6.58 (broad s, 1H), 6.39 (p, J = 2.8 Hz, 1H), 3.21 (s, 2H), 1.69 (s,
3H), 1.68 (s, 3H).
13
C NMR (75 MHz, CDCl
3
): " 204.2, 137.3, 128.4, 123.8, 123.1,
122.8, 119.4, 118.6, 109.8, 104.6, 98.4, 89.5, 20.2, 17.0. IR (thin film): 3411, 2910,
2251, 1953 cm
1
15
H
15
N
2
[M+H]
+
: 223.1235, Found:
223.1214. M.P. (EtOAc/Hex): 98101 C.

142

N-methyl indole S2-2: To a solution of indole 2-108 (1.76 g, 7.93 mmol) in THF
(27 mL) at 0 C was added NaH (60% in oil, 380 mg, 9.51 mmol) portion-wise
over 0.1 h. After 0.5 h, MeI (0.543 mL, 8.72 mmol) was added dropwise. After 1 h,
a saturated NH
4
Cl solution (50 mL) and Et
2
O (100 mL) were added sequentially
to the mixture. The resulting layers were separated, and the aqueous layer was
extracted two times with Et
2
O (50 mL). The combines combined organic extracts
were dried (MgSO
4
), filtered concentrated in vacuo. The crude solid was purified
by flash column chromatography (10% EtOAc/Hex) to give 1.84 g (98%) of S2-2
as a white solid.
1
3
): " 7.21 (dd, J = 9.0, 6.2 Hz, 1H), 7.15 (m, 2H), 7.11 (s,
1H), 6.49 (p, J = 2.7 Hz, 1H), 4.05 (s, 2H), 3.75 (s, 3H), 1.86 (s, 3H), 1.85 (s, 3H).
13
C
NMR (75 MHz, CDCl
3
): " 204.2, 138.1, 128.5, 128.2, 123.5, 122.4, 119.0, 118.5, 107.8,
103.1, 98.3, 89.5, 32.8, 20.2, 16.9. IR (thin film): 2910, 2248, 1951, 1607 cm
1
. HRMS
(ESI): calc. for C
16
H
17
N
2
[M+H]
+
: 237.1392, Found: 237.1378. M.P. (EtOAc/Hex):
109110 C.

Tryptamine 2-109: To solution of nitrile S2-2 (3.25 g, 13.8 mmol) in Et
2
O (70 mL)
at 0 C was added LiAlH
4
(2.09 g, 55.0 mmol) portion-wise over 0.3 h. After 1 h at

143
0 C, the mixture was carefully quenched with water (5 mL). The thick slurry was
diluted with Et
2
O (150 mL). The resulting suspension was filtered and the filter
cake washed with Et
2
O (150 mL). The combined organic extracts were dried
(MgSO
4
) and concentrated in vacuo. The crude oil was purified by flash column
chromatography (5% MeOH/CH
2
Cl
2
/0.05% NH
4
OH) to give 2.45 g (74%) of 2-
109 as yellow oil.
1
3
): " 7.16-7.10 (m, 3H), 6.86 (s, 1H), 6.68 (sept, J = 2.8 Hz,
1H), 3.72 (s, 3H), 3.05 (app. s, 4H), 1.85 (s, 3H), 1.84 (s, 3H).
13
C NMR (75 MHz,
CDCl
3
): " 203.8, 138.1, 128.9, 127.9, 124.7, 121.6, 118.0, 112.2, 107.3, 97.9, 90.2, 42.9,
32.9, 31.7, 20.3. IR (thin film): 2932, 1950 cm
1
16
H
21
N
2

[M+H]
+
: 241.1705, Found: 241.1693.

Amine 2-110: To a solution of amine 2-109 (520 mg, 2.16 mmol) in MeOH (11 mL)
was added 2,4-dimethoxybenzaldehyde (378 mg, 2.27 mmol). After 16 h at rt,
NaBH
4
(82.0 mg, 2.16 mmol) was added to the mixture. After 1h, a saturated
solution of NaHCO
3
(10 mL) was added to the mixture. The biphasic mixture
was concentrated in vacuo to remove volatile organics. The aqueous layer was
extracted three times with EtOAc (10 mL). The combined organic extracts were
dried (MgSO
4
), filtered and concentrated in vacuo. The crude oil was purified by
flash column chromatography (5% MeOH/CH
2
Cl
2
/0.05% NH
4
OH) to give 0.725
g (86%) of 2-110 as pale yellow oil.

144
1
3
): " 7.15-7.08 (m, 4H), 6.82 (s, 1H), 6.67 (sept, J = 2.8 Hz,
1H), 6.42-6.40 (m, 2H), 3.79 (s, 3H), 3.77 (s, 2H), 3.69 (s, 3H), 6.68 (s, 3H), 3.12 (t, J
= 7.1 Hz, 2H), 2.96 (t, J = 7.1, Hz, 2H), 1.84 (s, 3H), 1.83 (s, 3H).
13
C NMR (75 MHz,
CDCl
3
): " 203.8, 159.9, 158.4, 138.0, 130.2, 128.9, 127.6, 124.8, 121.5, 120.8, 117.9,
112.7, 107.2, 103.5, 98.3, 97.7, 90.2, 55.2, 55.0, 49.8, 48.9, 32.5, 28.0, 20.3. IR (thin
film): 2934, 2834, 1950, 1613, 1588 cm
1
25
H
31
N
2
O
2
[M+H]
+
:
391.2386, Found: 391.2395.

Benzoaxazinone 2-112: To a Parr reactor containing a solution of 2-nitromandelic
acid (2-111, 20.0 g, 101 mmol)
36
in MeOH (338 mL) was added K
2
CO
3
(35.0 g, 254
mmol) and Pd/C (5 wt. % Pd on activated carbon, 2.00 g). The reactor was
flushed with N
2
gas, and then sealed. The reactor was cooled to 0 C, then
purged (pressurized to 100 psi, then vented) three times with H
2
gas before being
charged to 400 psi. After 24 h, the reactor was carefully vented. The mixture was
filtered through a short pad of celite (EtOAc) and concentrated in vacuo. This
gave 19.8 g (95%) of the crude potassium salt, which was used immediately
To a solution of the crude aniline (19.8 g, 96.5 mmol) in toluene (500 mL) and
water (500 mL) was added Na
2
CO
3
(11.8 g, 112 mmol) followed by phosgene
(20% in toluene, 58.5 mL, 112 mmol) dropwise. The biphasic mixture was stirred
vigorously. After 12 h, tthe resulting layers were separated. The aqueous layer

145
was acidified using a 2 M HCl solution. Upon standing a precipitate formed. The
precipitate was collected by filtration to give 16.6 g (89%) of 2-112 as an off-white
solid that was taken on without further purification. A portion was triturated
with Et
2
O to give a spectroscopically pure sample for characterization.
1
H NMR (400 MHz, d
6
-acetone): " 9.20 (s, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.31 (t, J =
7.7 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 5.94 (s, 1H).
13
C NMR
(75 MHz, d
6
-acetone): " 169.8, 150.9, 136.8, 130.6, 127.0, 123.6, 117.3, 114.9, 77.0. IR
(thin film): 3270, 1732 cm
1
. M.P.: 186 C (decomposition).

Benzyl ester S2-3: To a solution of acid 2-112 (12.7 g, 65.8 mmol) in DMF (270
mL) was added benzyl bromide (8.60 mL, 72.4 mmol) followed by Cs
2
CO
3
(24.7
g, 75.7 mmol). The mixture was warmed to 50 C. After 5 h, the mixture was
cooled to rt and diluted with EtOAc (1.25 L). The combined organic extracts were
washed five times with water (500 mL) and one time with brine (250 mL), dried
(MgSO
4
), filtered and concentrated in vacuo. The crude solid was triturated with
Et
2
O to give 13.5 g (72%) of S2-3 as an off-white solid.
1
3
): " 8.99 (s, 1H), 7.30-7.28 (m, 5H), 7.26-7.24 (m, 2H),
7.06 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 5.84 (s, 1H), 5.24 (d, J = 12.3 Hz,
1H), 5.15 (d, J = 12.3 Hz, 1H).
13
C NMR (75 MHz, CDCl
3
): " 167.7, 151.6, 134.8,
134.6, 130.2, 128.6, 128.5, 128.0, 125.8, 123.6, 115.2, 114.8, 67.8. IR (thin film):1743,
1739 cm
1
16
H
14
NO
4
[M+H]
+
: 284.0923, Found: 284.0905.
M.P.: 163165 C.

146

Imide 2-113: To a solution of oxazinone S2-3 (3.00 g, 10.6 mmol) in THF (70 mL)
at 78 C was added n-BuLi (2.5 M in hexanes, 4.45 mL, 11.1 mmol) dropwise.
After 1 h, ethyl chloroformate (1.10 mL, 11.7 mmol) was added dropwise. The
mixture was warmed to rt. After 12 h at rt, a saturated NH
4
Cl solution (100 mL)
and Et
2
O (300 mL) were added sequentially to the mixture. The resulting layers
were separated, and the aqueous layer was extracted twice with Et
2
O (50 mL).
The combined organic extracts were washed once with brine (50 mL), dried
(MgSO
4
), filtered and concentrated in vacuo. The crude oil was purified by flash
column chromatography (25% EtOAc/Hex) to give 3.27 g (87%) of 2-113 as
colorless oil.
1
3
): " 7.65 (d, J = 8.2 Hz, 1H), 7.42 (t, J = 7.0 Hz, 1H), 7.36-
7.31 (m, 4H), 7.26-7.24 (m, 3H), 5.66 (s, 1H), 5.27 (d, J = 12.2 Hz, 1H), 5.11 (d, J =
12.2 Hz, 1H), 4.36 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H).
13
C NMR (75 MHz, CDCl
3
): "
166.8 151.6, 148.0, 134.4, 134.2, 129.8, 128.6, 128.6, 128.1, 125.9, 122.3, 121.5, 76.3,
68.1, 64.4, 13.9. IR (thin film): 1770, 1602 cm
1
19
H
18
NO
6

[M+H]
+
: 356.1134, Found: 356.1131.

Acid S2-4: To a Parr reactor containing a solution of ester 2-113 (3.27 g, 9.21
mmol) in EtOAc (92 mL) was added Pd/C (5 wt. % Pd on activated carbon, 0.327

147
g). The reactor was flushed with N
2
gas, and then sealed. The reactor was purged
(pressurized to 100 psi, then vented) three times with H
2
gas before being
charged to 400 psi. After 24 h, the reactor was carefully vented. The mixture was
filtered through a pad of celite (EtOAc) and concentrated in vacuo. This gave 2.33
g (95%) of S2-4 as thick, yellow oil that was taken on without further
purification.
1
H NMR (400 MHz, acetone-d
6
): " 7.59 (d, J = 8.2 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H),
7.46 (t, J = 7.8 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 5.98 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H),
1.32 (t, J = 7.1 Hz, 3H).
13
C NMR (75 MHz, acetone-d
6
): " 168.8, 152.3, 148.6, 135.3,
130.3, 127.3, 126.5, 124.2, 121.7, 76.6, 64.7, 14.2. IR (thin film): 1794, 1752 cm
1
.
HRMS (ESI): calc. for C
12
H
12
NO
6
[M+H]
+
: 266.0665, Found: 266.0647.

Amide 2-104: To a suspension of NaH (95%, 366 mg, 14.5 mmol) in PhH (2 mL)
was added acid S2-4 (385 mg, 1.45 mmol) in PhH (7 mL) via cannula over 0.5 h.
After 1 h, oxalyl chloride (0.635 mL, 7.25 mmol) was added to the mixture. After
5 h, the mixture was diluted with Et
2
O (10 mL). The resulting suspension was
filtered and the filter cake washed with Et
2
O (5 mL). The combined organic
extracts were concentrated in vacuo. This gave 390 mg (95%) of acid chloride 2-
114 as thick, yellow oil that was used immediately without further purification.
To a solution of amine 2-110 (490 mg, 1.25 mmol) in CH
2
Cl
2
(13 mL) was added
iPr
2
NEt (0.635 mL, 3.75 mmol) dropwise. The mixture was cooled to 0 C and a
N N
CO
2
Et
DMB
N O
O
O
N
CO
2
Et
O
O Cl
O
N
NHDMB
iPr
2
NEt, CH
2
Cl
2
,
rt, 16 h
78%

148
solution of acid chloride 2-114 (390 mg, 1.38 mmol) in CH
2
Cl
2
(7 mL) was added
dropwise. The mixture was warmed to rt and after 16 h, water (20 mL) and
CH
2
Cl
2
(20 mL) were added sequentially to the mixture. The resulting layers
were separated, and the aqueous layer was extracted two times with CH
2
Cl
2
(10
4
), filtered and
chromatography (30% EtOAc/Hex) to give 622 mg (78%) of 2-104 as yellow oil.
1
3
): (mixture of rotamers and diastereomers) " 7.69 (d, J
= 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 1H), 7.45 (ddd, J = 8.6, 6.1, 3.0 Hz, 1H), 7.29 (d, J
= 7.7 Hz, 1H), 7.20-7.18 (m, 4H), 7.15-7.13 (m, 6.5H), 7.07-7.03 (m, 3.8H), 6.77 (m,
1.8H), 6.66 (s, 1H), 6.64 (s, 1H), 6.58 (m, 1H), 6.54 (m, 1H), 6.42 (d, J = 2.2 Hz, 1H),
6.40 (s, 1H), 6.38 (d, J = 2.3 Hz, 1H), 6.35 (m, 4H), 6.28 (s, 2H), 5.26 (s, 0.8H), 4.87
(d, J = 15.6 Hz, 0.9H), 4.5-4.3 (m, 8.5H), 3.79 (m, 6H), 3.78 (m, 9.8 H), 3.75 (m,
3.8H), 3.67 (m, 3.2H), 3.56 (s, 1H), 3.52 (s, 1H), 3.50 (s, 5.8H), 3.35 (m, 2H), 3.22-
2.93 (m, 6H), 1.83-1.78 (m, 17H), 1.45 (t, J = 7.1 Hz, 6H), 1.38 (t, J = 7.1 Hz, 3H).
13
C
NMR (75 MHz, CDCl
3
): " 204.0, 203.9, 166.1, 165.5, 161.0, 160.4, 158.6, 158.5, 152.2,
151.8, 138.3, 138.1, 135.4, 135.0, 131.0, 130.6, 129.0, 128.9, 128.8, 128.5, 128.1, 125.6,
125.5, 125.3, 124.6, 124.4, 122.4, 122.1, 121.5, 118.6, 117.9, 117.0, 115.5, 110.9, 109.9,
108.0, 107.4, 104.1, 104.0, 98.6, 98.4, 98.2, 98.0, 90.0, 89.6, 75.8, 74.7, 64.2, 64.0, 55.4,
55.3, 55.1, 48.0, 47.4, 46.6, 43.0, 32.8, 32.6, 26.3, 24.6, 20.4, 20.3, 14.2, 14.0. IR (thin
film): 2938, 1806, 1770, 1738 cm
1
.

149

Pentacycle 2-103: To a solution of amide 2-104 (155 mg, 0.243 mmol) in
dichloroethane (5 mL) was added Y(OTf)
3
(13.0 mg, 0.024 mmol). The mixture
was heated to reflux and stirred for 8 h. The mixture was then filtered through a
plug of SiO
2
and rinsed with DCM (24 mL). The solution was concentrated in
vacuo. The crude oil was purified by flash column chromatography (25%
EtOAc/Hex) to give 105 mg (73%) of 2-103 as colorless oil.
1
3
): " 7.97 (m, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.05-6.93 (m,
3H), 7.58 (t, J = 7.8 Hz, 1H), 6.49 (m, 2H), 7.11 (d, J = 7.7 Hz, 1H), 6.74 (d, J = 7.7
Hz, 1H), 5.91 (sept., J = 2.7 Hz, 1H), 5.75 (br. s, 1H), 5.17 (d, J = 14.4 Hz, 1H), 4.27
(d, J = 14.5 Hz, 1H), 4.21 (m, 1H), 4.10 (br. s, 1H), 3.86 (s, 1H), 3.81 (m, 7H), 3.57
(ddd, J = 12.7, 12.7, 3.7 Hz, 1H), 3.40 (ddd, J = 12.9, 4.6, 2.9 Hz, 1H), 2.93 (s, 3H),
2.33 (ddd, J = 13.1, 13.1, 5.2 Hz, 1H), 2.16 (m, 6H), 1.22 (m, 3H).
13
C NMR (75
MHz, CDCl
3
): " 204.1, 168.1, 160.3, 158.7, 151.7, 138.4, 132.5, 131.5, 131.3, 128.2,
126.1, 126.0, 125.7, 125.1, 118.2, 117.3, 104.3, 103.8, 98.3, 97.6, 90.1, 85.9, 62.0, 55.6,
55.3, 44.5, 44.3, 44.0, 34.7, 30.9, 20.4, 19.9, 14.3. IR (thin film): 2937, 1697, 1639,
1612, 1585 cm
1
36
H
40
N
3
O
5
[M+H]
+
: 594.2968, Found:
594.2966.

N N
CO
2
Et
DMB
N O
O
O N N
CO
2
Et
H
DMB
N O
H
10 mol%
Y(OTf)
3
,
ClCH
2
CH
2
Cl,
90 C, 8 h
73%

150

Azide 2-102: To a solution of amide 2-103 (135 mg, 0.227 mmol) in THF (3.8 mL)
at 40 C was added nBuLi (2.5 M in hexanes, 0.227 mL, 0.569 mmol) dropwise.
After 1 h, freshly distilled HMPA (0.115 mL) was added to the mixture. After 0.5
h, azido iodoethane was added dropwise. After 0.5 h at 40 C, a saturated NH
4-
Cl solution (5 mL) and Et
2
O (10 mL) were added sequentially to the mixture. The
resulting layers were separated, and the aqueous layer was extrtacted one time
with Et
2
O (10 mL). The combined combined organic extracts were washed with
brine (5 mL), dried (MgSO
4
), filtered and concentrated in vacuo. The crude oil
was purified by flash column chromatography (15% EtOAc/Hex) to give 68.0 mg
(45%) of 2-102 as white foam.
1
3
): " 8.38 (d, J = 6.4 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.97
(m, 3H), 6.86 (t, J = 7.7 Hz, 1H), 6.48 (m, 2H) 6.37 (d, J = 7.6 Hz, 1H), 6.15 (d, J =
7.6 Hz, 1H), 5.96 (m, 1H), 5.62 (s, 1H), 5.46 (d, J = 14.4 Hz, 1H), 4.24 (m, 2H), 3.82
(s, 3H), 3.81 (s, 3H), 3.72 (d, J = 14.5 Hz, 1H), 3.61 (m, 1H), 3.31 (s, 3H), 2.87 (m,
1H), 2.42 (ddd, J = 13.1, 13.1, 6.6 Hz, 1H), 2.28 (m, 2H), 1.95 (d, J = 13.1 Hz, 1H),
1.80 (m, 6H), .1.26 (m, 3H).
13
C NMR (75 MHz, CDCl
3
): " 204.0, 171.2, 160.5, 158.9,
151.0, 138.1, 132.9, 132.4, 130.8, 128.3, 127.7, 127.1, 126.8, 126.6, 125.9, 119.9, 117.4,
104.8, 104.3, 98.6, 97.1, 90.9, 83.3, 62,4, 59.0, 55.4, 55.3, 49.1, 47.2, 44.4, 44.0, 35.3,
31.2, 29.6, 21.0, 20.1, 14.4. IR (thin film): 2938, 2097, 1698, 1634 cm
1
. HRMS (ESI):
calc. for C
38
H
43
N
6
O
5
[M+H]
+
: 663.3295, Found: 663.3269.

151

Amine 2-116: To a solution of azide 2-102 (30.0 mg, 0.045 mmol) in THF (0.9 mL)
was added PPh
3
(18.0 mg, 0.068 mmol). After 1 h at rt, water (16 L, 0.91 mmol)
was added to the mixture. After 16 h at rt, the mixture was concentrated in vacuo.
The crude residue was purified by flash column chromatography (5%
MeOH/CH
2
Cl
2
) to give 21.0 mg (72%) of 2-116 as a colorless film.
1
3
): " 8.43 (m, 1H), 7.24 (m, 1H), 6.96 (s, 3H), 6.84 (t, J =
7.7 Hz, 1H), 6.47 ( m, 2H), 6.36 (d, J = 7.7 Hz, 1H), 6.13 (d, J = 7.7 Hz, 1H), 5.96 (s,
1H), 5.61 (s, 1H), 5.40 (d, J = 14.6 Hz, 1H), 4.21 (br. s, 2H), 3.80 (m, 7H), 3.31 (m,
2H), 2.95 (s, 3H), 2.92 (m, 1H), 2.46 (m, 2H), 2.17 (m, 2H), 2.01 (s, 2H), 1.94 (d, J =
14.7 Hz, 1H), 1.79 (m, 6H), 1.15 (br. s, 3H).
13
C NMR (75 MHz, CDCl
3
): " 204.0,
172.1, 160.2, 158.8, 151.0, 138.0, 133.6, 132.9, 130.6, 128.1, 128.0, 127.0, 126.2, 124.8,
119.8, 117.6, 104.2, 104.2, 98.4, 96.9, 91.0, 83.4, 62.1, 59.2, 55.4, 55.3, 47.7, 44.3, 39.5,
31.2, 29.5, 22.6, 20.8, 20.1, 14.6. IR (thin film): 2938, 1695, 1932 cm
-1
. HRMS (ESI):
calc. for C
38
H
45
N
4
O
5
[M+H]
+
: 637.3390, Found: 637.3376.

4-bromo-3-(2-iodoethyl)-1H-indole (2-200): To a solution of 4-bromotryptophol
(2-39) (4.99 g, 20.7 mmol) in CH
3
CN (140 mL) and Et
2
O (140 mL) was added
imidazole (1.97 g, 29.0 mmol), triphenyl phosphine (7.06 g, 26.9 mmol) and
N
H
Br
I
N
H
Br
OH
I
2
, PPh
3
, imid.,
CH
3
CN, Et
2
O,
rt, 4 h
88%

152
iodine (7.35 g, 29.0 mmol). After 4 h, a 10% Na
2
S
2
O
3
solution (100 mL) was added
to the mixture. The mixture was stirred vigorously for 0.25 h. The resulting layers
were separated, and the aqueous layer was extracted three times with Et
2
O (150
4
), filtered and
chromatography (15% EtOAc/Hex) to give 6.39 g (88%) of 2-200 as yellow oil.
1
3
): " 8.09 (br. s, 1H), 7.31 (d, J = 7.7 Hz, 2H), 7.11 (d, J =
7.9 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 3.51 (m, 4H).
13
C NMR (75 MHz, CDCl
3
): "
137.4, 124.9, 124.1, 124.0, 123.0, 116.0, 113.8, 110.6, 30.7, 8.5. IR (thin film): 3423
cm
-1
10
H
9
NBr [M-I]
-
: 221.9918, Found: 221.9903.

3-(2-azidoethyl)-4-bromo-1H-indole (2-159): To a solution of iodide 2-200 (7.05 g,
20.1 mmol) in DMF (50 mL) was added NaN
3
(2.61 g, 40.2 mmol). The mixture
was warmed to 50 C. After 5 h, water (200 mL) was added to the mixture. The
mixture was extracted three times with Et
2
extracts were washed with five times with water (50 mL), dried (MgSO
4
), filtered
and concentrated in vacuo. This gave 5.08 g (95%) of 2-159 as yellow oil that was
1
3
): " 8.13 (br. s, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.29 (d, J =
6.5 Hz, 1H), 7.12 (s, 1H), 7.03 (t, J = 7.9 Hz, 1H), 3.62 (t, J = 7.1 Hz, 2H), 3.31 (t, J =
7.1 Hz, 2H).
13
C NMR (90 MHz, CDCl
3
): " 137.5, 125.1, 124.4, 124.0, 123.0, 114.0,
N
H
Br
N
3
N
H
Br
I
NaN
3
, DMF,
50
o
C, 5 h
95%

153
113.0, 110.6, 52.7, 25.8. IR (thin film): 3423, 2929, 2100 cm
-1
. HRMS (ESI): calc. for
C
10
H
10
N
4
Br [M+H]
+
: 265.0089, Found: 265.0103.

Cycloadduct 2-157: To a solution of indole 2-159 (4.93 g, 18.5 mmol) in CH
3
CN
(60 mL) in a foil covered flask was added 3-bromooxindole (2-161, 6.29 g, 29.7
mmol)
53
followed by Ag
2
CO
3
(4.09 g, 14.8 mmol). After 16 h, the mixture was
filtered through a short pad of celite (acetone) and concentrated in vacuo. The
crude solid was purified by flash column chromatography (5% acetone/CH
2
Cl
2
)
to give 5.14 g (70%) of 2-157 as a pale yellow solid.
1
3
): " 8.45 (s, 1H), 7.93 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H),
7.53 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 6.78 (d, J =
7.7 Hz, 1H), 6.54 (t, J = 7.6 Hz, 1H), 5.70 (d, J = 7.6 Hz, 1H), 4.50 (s, 1H), 3.45 (ddd,
J = 15.0, 7.9, 7.9 Hz, 1H), 3.10 (ddd, J = 12.7, 7.3, 7.1 Hz, 1H), 2.95 (ddd, J = 12.5,
7.3, 7.0 Hz, 1H), 2.67 (ddd, J = 12.4, 7.5, 7.5 Hz, 1H).
13
C NMR (90 MHz, CDCl
3
): "
177.4, 174.4, 158.1, 140.9, 136.6, 131.1, 130.4, 128.8, 124.1, 123.9, 122.1, 118.4, 109.8,
64.7, 47.0, 46.2, 28.1. IR (thin film): 3028, 2101, 1703 cm
-1
C
18
H
15
N
3
OBr [M-N
2
+H]
+
: 368.0398, Found: 368.0394.

N
H
Br
N
3
N
H
O
Br
N
Br
NH
N
3
O
Ag
2
CO
3
,
MeCN, rt
16 h,
70%
H
+

154

Tosyl aminal 2-167: To a solution of oxindole 2-157 (1.26 g, 3.18 mmol) in THF
(65 mL) at 0 C were added tosyl chloride (0.618 g, 3.24 mmol) followed by NaH
(60% in oil, 0.267 g, 6.68 mmol) portion-wise over 0.25 h. After 1 h, MeOH (12.9
mL, 318 mmol) was added dropwise. After 12 h at rt, a saturated NH
4
Cl solution
(50 mL) and EtOAc (100 mL) were added sequentially to the mixture. The
resulting layers were separated, and the aqueous layer was extracted three times
with EtOAc (30 mL). The combined organic extracts were washed with water (50
mL) and brine (50 mL). The combined organic extracts were dried (MgSO
4
),
filtered and concentrated in vacuo. The crude solid was purified by flash column
chromatography (10% EtOAc/Hex) to give 1.13 g (61%) of 2-167 as a colorless
solid.
1
3
): " 7.74 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.22
(m, 3H), 7.07 (td, J = 8.1, 1.0 Hz, 1H), 6.95 (td, J = 7.5, 0.7 Hz, 1H), 6.72 (t, J = 7.9
Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.41 (d, J = 7.4 Hz, 1H), 6.12 (s, 1H), 5.04 (s, 1H),
4.86 (s, 1H), 3.39 (ddd, J = 12.4, 9.4, 5.8 Hz, 1H), 3.29 (s, 3H), 3.03 (ddd, J = 12.4,
9.1, 6.5 Hz, 1H), 2.62 (ddd, J = 14.0, 9.1, 5.8 Hz, 1H), 2.45 (ddd, J = 14.0, 9.4, 6.5
Hz, 1H), 2.36 (s, 3H).
13
C NMR (75 MHz, CDCl
3
): " 169.5, 150.6, 143.8, 136.2, 130.2,
129.3, 129.2, 128.6, 128.4, 127.8, 125.6, 125.2, 123.6, 122.5, 118.3, 107.8, 78.9, 56.7,
51.8, 47.8, 47.5, 34.2, 21.5. IR (thin film): 3402, 2952, 2099, 1733 cm
-1
. HRMS (ESI):
calc. for C
26
H
25
N
5
O
4
SBr [M+H]
+
: 582.0811, Found: 582.0800. M.P.: 133-136 C.
N
Ts
N
H
Br
H
N
3 O O
H
N
Br
NH
N
3
O
TsCl, NaH,
THF, 0
o
C
0.5 h;
MeOH, rt
16 h, 61%
H

155

Methyl aminal 2-168: To a solution of aminal 2-167 (1.66 g, 2.85 mmol) in CH
2
Cl
2

(55 mL) was added Me
3
OBF
4
(0.842 g, 5.70 mmol). After 0.5 h, Cs
2
CO
3
(1.02 g,
3.13 mmol) was added to the mixture. After 24 h, a saturated NaHCO
3
solution
(30 mL) and CH
2
Cl
2
(50 mL) were added sequentially to the mixture. The
resulting layers were separated, and the aqueous layer was extracted two times
with CH
2
Cl
2
(30 mL). The combined organic extracts were dried (MgSO
4
), filtered
and concentrated in vacuo. The crude oil was purified by flash column
chromatography (10% EtOAc/Hex) to give 1.35 g (80%) of 2-168 as white foam.
1
3
): " 7.78 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 8.3 Hz, 2H),
7.16-7.09 (m, 4H), 6.96 (t, J = 7.5 Hz, 1H), 6.74 (t, J = 7.9 Hz, 1H), 6.54 (d, J = 8.0
Hz, 1H), 6.20 (s, 1H), 6.14 (d, J = 7.9 Hz, 1H), 5.00 (s, 1H), 3.19 (ddd, J = 12.3, 9.4,
6.3 Hz, 1H), 3.13 (s, 3H), 3.05 (s, 3H), 2.98 (ddd, J = 12.3, 9.1, 5.9 Hz, 1H), 2.82
(ddd, J = 13.6, 9.1, 6.2 Hz, 1H), 2.46 (ddd, J = 13.7, 9.3, 5.9 Hz, 1H), 2.32 (s, 3H).
13
C
NMR (75 MHz, CDCl
3
): " 169.0, 152.3, 143.4, 136.3, 135.3, 131.3, 130.3, 129.3, 128.7,
128.5, 128.4, 126.3, 125.8, 124.2, 122.0, 117.9, 104.1, 83.7, 56.9, 51.7, 48.1, 47.7, 33.7,
30.5, 21.4. IR (thin film): 2952, 2099, 1738 cm
-1
C
27
H
27
N
5
O
4
BrS [M+H]
+
: 596.0967, Found: 596.0955.

N
Ts
N
Br
H
N
3 O O
H
N
Ts
N
H
Br
H
N
3 O O
H Me
3
OBF
4
, Cs
2
CO
3
,
CH
2
Cl
2
, rt, 24 h,

80%

156

Carbamate 2-169: To a solution of azide 2-168 (1.35 g, 2.27 mmol) in EtOAc (45
mL) was added Boc
2
O (1.48 g, 6.90 mmol) followed by PtO
2
(135 mg). The
mixture was stirred vigorously under an atmosphere of hydrogen (1 atm,
balloon). After 16 h, the mixture was sparged with nitrogen gas, filtered through
a plug of celite (EtOAc) and concentrated in vacuo. The crude oil was purified by
flash column chromatography (15% EtOAc/Hex) to give 1.34 g (88%) of 2-169 as
colorless gummy solid.
1
3
): " 7.77 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.8 Hz, 2H),
7.13-7.05 (m, 4H), 6.93 (t, J = 7.5 Hz, 1H), 6.69 (t, J = 7.9 Hz, 1H), 6.51 (d, J = 8.0
Hz, 1H), 6.16 (s, 1H), 6.09 (d, J = 7.8 Hz, 1H), 4.95 (s, 1H), 4.35 (br. s, 1H), 3.10 (s,
3H), 3.02 (m, 4H), 2.82-2.71 (m, 2H), 2.36 (m, 1H), 2.29 (s, 3H), 1.40 (s, 9H).
13
C
NMR (75 MHz, CDCl
3
): " 168.9, 155.5, 152.1, 143.2, 136.4, 135.3, 131.4, 130.3, 129.2,
128.6, 128.4, 128.3, 126.3, 126.2, 124.1, 122.0, 117.9, 104.0, 83.9, 78.6, 57.1, 51.5, 48.4,
36.7, 34.6, 30.3, 28.3, 21.3. IR (thin film): 3410, 2977, 2251, 1732, 1713, 1694 cm
-1
.
HRMS (ESI): calc. for C
32
H
37
N
3
O
6
SBr [M+H]
+
: 670.1586, Found: 670.1605.

Aminal 2-171: To a solution of tosyl amide 2-169 (1.69 g, 2.53 mmol) in MeOH
(130 mL) at 0 C was added Mg (0.614 g, 25.3 mmol) portion-wise over 1 h. The
N
Ts
N
Br
H
BocHN
O O
H
N
Ts
N
Br
H
N
3 O O
H Boc
2
O, PtO
2
, H
2
,
EtOAc, rt, 16 h,
88%
N
H
N
Br
H
BocHN
O O
H
N
Ts
N
Br
H
BocHN
O O
H Mg, MeOH,
rt, 18 h,
87%

157
mixture was warmed to rt. After 18 h at rt, a saturated NH
4
Cl solution (100 mL)
and EtOAc (200 mL) were added sequentially to the mixture. The mixture was
stirred vigorously for 0.5 h. The resulting layers were separated, and the aqueous
layer was extracted two times with EtOAc (100 mL). The combined organic
extracts were washed with brine (50 mL), dried (MgSO
4
), filtered and
concentrated in vacuo. The crude yellow oil was purified by flash column
chromatography (25% EtOAc/Hex) to give 1.14 g (87%) of 2-171 as yellow oil.
1
3
): " 7.04-6.99 (m, 2H), 6.85 (t, J = 7.9 Hz, 1H), 6.70 (d, J =
8.0 Hz, 1H), 6.66 (t, J = 7.6 Hz, 1H), 6.55 (d, J = 7.7 Hz, 1H), 6.27 (d, J = 7.7 Hz,
1H), 4.78 (s, 1H), 4.66 (s, 1H), 4.52 (s, 1H), 4.46 (br. s, 1H), 3.70 (s, 3H), 3.20 (m,
1H), 2.93 (m, 1H), 2.53 (m, 1H), 2.08 (m, 1H), 1.39 (s, 9H).
13
C NMR (75 MHz,
CDCl
3
): " 171.9, 155.6, 152.1, 141.8, 129.8, 128.4, 128.2, 128.1, 122.7, 120.5, 118.8,
118.7, 114.6, 105.9, 79.5, 78.9, 52.2, 49.8, 48.2, 36.9, 32.0, 30.5, 29.6, 28.3. IR (thin
film): 3392, 2977, 1732, 1694 cm
-1
25
H
31
N
3
O
4
Br [M+H]
+
:
516.1498, Found: 516.1506.

Boc-aminal 2-172: To a mixture of aminal 2-171 (50.0 mg, 0.097 mmol) and Boc
2
O
(106 mg, 0.482 mmol) in THF (1.9 mL) at 0 C was added a solution of KHMDS
(0.5 Min toluene, 0.581 mL, 0.291 mmol). After 1 h at 0 C, a saturated NH
4
Cl
solution (2 mL) and EtOAc (5 mL) were added sequentially to the mixture. The
resulting layers were separated, and the aqueous layer was extracted twice with
EtOAc (5 mL). The combined organic extracts were washed once with brine (5
N
H
N
Br
H
BocHN
O O
H
N
Boc
N
Br
H
BocHN
O O
H
Boc
2
O,
KHMDS,
rt, 1.25 h
97%

158
mL), dried (MgSO
4
), filtered and concentrated in vacuo. The crude oil was
purified by flash column chromatography (15% EtOAc/Hex) to give 58 mg (97%)
of 2-172 as colorless oil.
1
3
): " 7.17 (d, J = 7.4 Hz, 1H), 7.06 (br. s, 1H), 6.94 (m, 1H),
6.70 (t, J = 7.9 Hz, 1H), 6.51 (d, J = 7.8 Hz, 1H), 6.16 (s, 1H), 6.02 (d, J = 7.8 Hz, 1H),
5.18-5.01 (m, 1H), 3.71-3.45 (m, 4H), 3.18 (m, 1H), 2.86 (s, 3H), 2.51 (m, 2H), 1.49 (s,
18H).

Alcohol 2-173: To a solution of bromide 2-172 (58.0 mg, 0.094 mmol) in DMF
(0.940 mL) and H
2
O (0.940 mL) was added Pd(OAc)
2
(5.0 mg, 0.02 mmol), K
2
CO
3

(26.0 mg, 0.187 mmol) and 2-methyl-3-buten-2-ol (0.440 mL, 4.21 mmol). The
mixture was warmed to 90 C. After 5 h, water (3 mL) and Et
2
O (5 mL) were
added sequentially to the mixture. The resulting layers were separated, and the
aqueous layer was extracted one time with Et
2
extracts were washed five times with water (5 mL), once with brine (10 mL),
dried (MgSO
4
), filtered and concentrated in vacuo. The crude brown oil was
purified by flash column chromatography (20% EtOAc/Hex) to give 31 mg (53%)
of 2-173 as colorless oil.
1
3
): " 7.09 (br. s, 2H), 6.97 (d, J = 15.8 Hz, 1H), 6.89 (m, 2H),
6.84 (t, J = 7.8 Hz, 1H), 6.51 (d, J = 7.7 Hz, 1H), 6.20 (d, J = 15.7 Hz, 1H), 6.12 (s, 1H),
N
Boc
N
HO
H
BocHN
O O
H
N
Boc
N
Br
H
BocHN
O O
H
Pd(OAc)
2
,
K
2
CO
3
, H
2
O,
DMF, 90 C,
5h, 53%
OH

159
5.97 (d, J = 7.7 Hz, 1H), 4.32 (s, 1H), 3.61 (s, 3H), 3.51 (br. s, 1H), 3.17 (m, 1H), 2.84 (s,
3H), 2.46 (t, J = 8.3 Hz, 2H), 1.71 (s, 6H), 1.47 (s, 18H).

Alcohol 2-177: To a solution of bromide 2-171 (978 mg, 1.89 mmol) in DMF (19
mL) and H
2
O (19 mL) was added Pd(OAc)
2
(85.0 mg, 0.379 mmol), K
2
CO
3
(524
mg, 3.79 mmol) and 2-methyl-3-buten-2-ol (8.90 mL, 85.2 mmol). The mixture
was warmed to 90 C. After 5 h, water (40 mL) and Et
2
O (50 mL) were added
sequentially to the mixture. The resulting layers were separated, and the aqueous
layer was extracted one time with Et
2
O (30 mL). The combined organic extracts
were washed five times with water (20 mL), once with brine (20 mL), dried
(MgSO
4
), filtered and concentrated in vacuo. The crude brown oil was purified by
flash column chromatography (25% EtOAc/Hex) to give 0.916 g (93%) of 2-177 as
colorless oil.
1
3
): " 7.11 (t, J = 7.8 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.98-
6.91 (m, 2H), 6.83 (d, J = 15.8 Hz, 1H), 6.69 (t, J = 7.5 Hz, 1H), 6.60 (d, J = 7.9 Hz,
1H), 6.42 (d, J = 7.7 Hz, 1H), 6.33 (d, J = 15.7 Hz, 1H), 4.88 (s, 1H), 4.69 (t, J = 5.9
Hz, 1H), 4.28 (s, 1H), 4.02 (s, 1H), 3.69 (m, 4H), 3.29 (m, 1H), 2.81 (m, 1H), 2.70 (m,
4H), 1.45 (s, 3H), 1.42 (s, 3H), 1.35 (s, 9H).
13
C NMR (75 MHz, CDCl
3
): " 173.1,
155.7, 149.6, 140.4, 134.4, 128.4, 127.2, 122.8, 118.2, 117.9, 116.5, 113.5, 107.2, 79.4,
78.8, 76.6, 70.4, 52.1, 48.3, 44.5, 37.1, 31.8, 30.0, 29.3, 28.8, 28.3. IR (thin film): 3402,
N
H
N
HO
H
BocHN
O O
H
N
H
N
Br
H
BocHN
O O
H
Pd(OAc)
2
,
K
2
CO
3
, H
2
O,
DMF, 90
o
C,
5 h, 93%
OH

160
2974, 1732, 1694 cm
-1
30
H
40
N
3
O
5
[M+H]+: 522.2968, Found:
522.3004.

Benzazepine 2-180: To a solution of allyl alcohol 2-177 (550 mg, 1.05 mmol) in
CH
2
Cl
2
(21 mL) was added a solution of mercuric triflate (0.01 Min MeCN, 2.60
mL, 0.026 mmol). After 16 h at rt, Et
3
N (0.037 mL, 0.26 mmol) was added to the
mixture. After 30 min, the mixture was filtered through short pad of silica gel
(CH
2
Cl
2
). The combined organic extracts were concentrated in vacuo. The crude
solid was purified by flash column chromatography (15% EtOAc/Hex) to give
456 mg (86%) of 2-180 as a white solid.
1
3
): " 7.14-6.94 (m, 3H), 6.68 (br. m, 1H), 6.61 (d, J = 7.7
Hz, 1H), 6.50 (br. s, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.90 (br. s, 043H), 5.71 (br. s,
0.57H), 5.24 (br. s, 1H), 4.71 (s, 1H), 4.3-3.75 (m, 3H), 3.71 (s, 3H), 3.11 (t, J = 11.6
Hz, 1H), 2.74 (s, 3H), 2.64 (t, J = 11.1 Hz, 1H), 2.00-1.70 (m, 6H), 1.51 (s, 9H).
13
C
NMR (75 MHz, CDCl
3
): " 172.3, 154.7, 150.1, 141.5, 137.9, 137.2, 133.7, 132.6, 129.5,
128.9, 128.5, 128.0, 127.7, 124.2, 120.2, 118.4, 117.9, 113.9, 106.5, 84.1, 79.8, 57.9,
57.2, 52.1, 51.7, 48.8, 46.8, 45.8, 41.5, 31.4, 30.4, 28.5, 25.6, 18.6. IR (thin film): 3357,
2978, 1738, 1682 cm
-1
30
H
38
N
3
O
4
[M+H]+: 504.2862, Found:
504.2874. M.P.: 224 C (decomposition).

N
H
N
HO
H
BocHN
O O
H
N
H
N
H
Boc
N
O O
H
H
Hg(OTf)
2
,
CH
2
Cl
2
, rt,
20 h,
86%

161

Carbamate S2-6: To a mixture of aminal 2-180 (30.0 mg, 0.060 mmol) and methyl
pyrocarbonate (0.031 mL, 0.298 mmol) in THF (1.2 mL) at 0 C was added a
solution of KHMDS (0.5 Min toluene, 0.357 mL, 0.179 mmol). After 0.25 h at 0 C,
a saturated NH
4
Cl solution (2 mL) and EtOAc (5 mL) were added sequentially to
the mixture. The resulting layers were separated, and the aqueous layer was
extracted twice with EtOAc (5 mL). The combined organic extracts were washed
once with brine (5 mL), dried (MgSO
4
), filtered and concentrated in vacuo. The
crude oil was purified by flash column chromatography (20% EtOAc/Hex) to
give 30 mg (90%) of S2-6 as colorless oil.
1
3
): " 7.13 (s, 1H), 7.09 (d, J = 6.7 Hz, 1H), 6.82 (t, J = 7.8
Hz, 1H), 6.22 (m, 1H), 6.10 (s, 1H), 6.00 (t, J = 6.8 Hz, 1H), 5.76 (m, 1H), 5.06 (m, 1H),
4.33 (s, 0.5H), 4.24 (s, 0.5H), 3.90 (m, 1H), 3.73 (br. s, 3H), 3.54 (app. d, 3h), 3.11 (m,
0.6H), 2.83 (m, 4.4H), 1.98-1.71 (m, 6H), 1.45 (m, 9H).

Amine 2-184: To a solution of Boc-carbamate S2-6 (43.0 mg, 0.085 mmol) in
CH
2
Cl
2
(3 mL) at 0 C was added 2,6-lutidine (0.050 mL, 0.427 mmol) and
TMSOTf (0.062 mL, 0.342 mmol). After 1 h at 0 C, a saturated NH
4
Cl solution (3
mL) and CH
2
Cl
2
(5 mL) were added sequentially to the mixture. The resulting
N
H
N
H
Boc
N
O O
H
H
N
CO
2
Me
N
H
Boc
N
O O
H
H
(CH
3
OCO)
2
O,
KHMDS, THF
0 C, 0.25 h
90%
N
CO
2
Me
N
H
H
N
O O
H
H
N
CO
2
Me
N
H
Boc
N
O O
H
H
2,6-lutidine,
TMSOTf,
CH
2
Cl
2
,
0 C, 2.5 h

97%

162
layers were separated, and the aqueous layer was extracted three times with
CH
2
Cl
2
(5 mL). The combined organic extracts were dried (MgSO
4
), filtered and
chromatography (5% MeOH/CH
2
Cl
2
) to give 38 mg (97%) of 2-184 as colorless
oil.
1
3
): " 7.22 (d, J = 6.0 Hz, 1H), 7.02 (m, 2H), 6.83 (t, J = 7.5
Hz, 1H), 6.43 (d, J = 7.7 Hz, 1H), 5.98 (d, J = 7.5 Hz, 2H), 5.31 (m, 2H), 4.90 (d, J = 8.2
Hz, 1H), 4.55 (s, 1H), 3.81 (br. s, 3H), 3.63 (s, 3H), 3.41-3.24 (m, 2H), 2.70 (s, 3H), 2.56
(d, J = 12.6 Hz, 1H), 1.95 (t, J = 11.6 Hz, 1H), 1.86 (s, 3H), 1.71 (s, 3H).

Lactam 2-185: To a mixture of methyl ester 2-184 (31.0 mg, 0.067 mmol) in THF
(0.335 mL) and MeOH (0.335 mL) was added a solution of lithium hydroxide (1
Min H
2
O, 0.335 mL). The mixture was warmed to 50 C. After 20 h, the mixture
was acidified to pH 2 (1 MHCl). The resulting layers were separated, and the
aqueous layer was extracted three times with CH
2
Cl
2
organic extracts were dried (MgSO
4
), filtered and concentrated in vacuo. The solid
was washed twice with Et
2
O to give 24 mg (80%) of the acid, which was used
To a solution of the acid (20.0 mg, 0.045 mmol) in THF (1.5 mL) was added a
solution of carbonyldiimidazole (0.1 MTHF, 1.3 mL, 0.134 mmol). After 15 h at rt,
the mixture was concentrated in vacuo. The crude solid was purified by flash
N
CO
2
Me
N
H
H
N
O O
H
H
N N
CO
2
Me H
O N
H
H
1. LiOH, THF,
MeOH, H
2
O,
50 C, 20 h,
80%
2. CDI, THF, rt,
15 h, 89%

163
column chromatography (20% EtOAc/Hex) to give 17 mg (89%) of 2-185 as
colorless oil.
1
H NMR (400 MHz, d
6
-acetone): " 8.55 (d, J = 7.5 Hz, 1H), 7.35 (s, 1H), 7.20 (t, J =
7.4 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.88 (t, J = 7.7 Hz, 1H), 6.21 (d, J = 7.6 Hz, 1H),
6.11 (s, 1H), 6.02 (t, J = 8.2 Hz, 2H), 5.26 (d, J = 7.7 Hz, 1H), 3.78 (s, 3H), 3.58 (m, 1H),
3.47 (m, 1H), 2.65 (s, 3H), 2.40 (t, J = 9.8 Hz, 1H), 2.24 (t, J = 9.3 Hz, 1H), 1.89 (s, 3H),
1.85 (s, 3H).

Amine 2-187: To a solution of Boc-carbamate 2-180 (172 mg, 0.342 mmol) in
CH
2
Cl
2
(7 mL) was added 2,6-lutidine (0.200 mL, 1.71 mmol) and TBSOTf (0.314
mL, 1.37 mmol). After 3 h at rt, a saturated NH
4
Cl solution (5 mL) and CH
2
Cl
2
(10
mL) were added sequentially to the mixture. The resulting layers were separated,
and the aqueous layer was extracted three times with CH
2
Cl
2
(5 mL). The
combined organic extracts were dried (MgSO
4
vacuo. The crude oil was used without further purification.
To a solution of the crude TBS-carbamate in MeOH (7 mL) was added potassium
fluoride (99.0 mg, 1.71 mmol). After one hour at rt, water (5 mL) and CH
2
Cl
2
(20
mL) were added sequentially to the mixture. The resulting layers were separated,
and the aqueous layer was extracted twice with CH
2
Cl
2
(10 mL). The resulting
layers were separated, dried (Na
2
SO
4
N
H
N
H
Boc
N
O O
H
H
N
H
N
H
H
N
O O
H
H
TBSOTf,
lutidine,
CH
2
Cl
2
, rt,
3 h;
KF, MeOH,
rt, 1 h, 94%

164
crude oil was taken up in MeCN (15 mL) and washed five times with hexanes (10
mL) to give 129 mg (94%) of 2-187 as dark yellow oil.
1
3
): " 7.08 (m, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.73 (t, J = 7.4
Hz, 1H), 6.65 (d, J = 7.3 Hz, 2H), 6.43 (d, J = 7.8 Hz, 1H), 5.40 (d, J = 8.5 Hz, 1H),
4.87 (d, J = 8.6 Hz, 1H), 4.80 (br. s, 1H), 4.22 (s, 1H), 4.12 (s, 1H), 3.68 (s, 3H), 3.14
(m, 1H), 3.08 (m, 1H), 2.69 (s, 3H), 2.53 (dd, J = 13.2, 5.4 Hz, 1H), 1.85 (s, 3H), 1.76
(s, 3H), 1.47 (ddd, J = 14.6, 9.4, 2.8 Hz, 1H).
13
C NMR (75 MHz, CDCl
3
): " 174.2,
150.6, 141.9, 139.8, 134.4, 131.5, 128.8, 128.5, 128.3, 125.7, 120.5, 119.0, 116.8, 114.7,
107.7, 85.2, 55.8, 52.2, 48.1, 47.6, 44.9, 32.4, 26.3, 19.1. IR (thin film): 3401, 2952,
1732, 1595 cm
-1
25
H
30
N
3
O
2
[M+H]
+
: 404.2338, Found:
404.2330.

Lactam 2-188: To a solution of amine 2-187 (55.0 mg, 0.136 mmol) in CH
2
Cl
2
(4.5
mL) at 0 C was added a solution of AlMe
3
(2 Min hexanes, 0.072 mL, 0.143
mmol). After one hour at 0 C, a saturated Rochelles salt solution (4 mL) was
added to the mixture. After 0.25 h, tthe resulting layers were separated, and the
aqueous layer was extracted three times with CH
2
Cl
2
organic extracts were dried (MgSO
4
crude oil was purified by flash column chromatography (20% EtOAc/Hex on
deactivated SiO
2
) to give 44 mg (87%) of 2-188 as a colorless solid.
N
H
N
H
H
N
O O
H
H
AlMe
3
,
CH
2
Cl
2
,
0
o
C, 1 h,
87%
N N
H H
O N
H
H

165
1
H NMR (400 MHz, d
6
-acetone): " 7.10 (t, J = 7.7 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H),
6.96 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.72 (t, J = 7.4 Hz, 1H), 6.36 (d, J =
7.3 Hz, 1H), 6.34 (d, J = 7.3 Hz, 1H), 6.30 (d, J = 5.1 Hz, 1H), 5.80 (d, J = 8.4 Hz,
1H), 5.33 (d, J = 8.4 Hz, 1H), 4.60 (d, J = 5.4 Hz, 1H), 3.58 (s, 1H), 3.40 (dd, J = 15.3,
9.7 Hz, 1H), 2.92 (ddd, J = 15.3, 9.2, 9.2 Hz, 1H), 2.81 (s, 3H), 1.91 (s, 3H), 1.85-1.77
(m, 4H), 1.39 (dd, J = 12.8, 8.7 Hz, 1H).
13
C NMR (75 MHz, d
6
-acetone): " 187.0,
149.7, 144.3, 140.5, 140.1, 133.0, 129.5, 128.3, 125.4, 122.2, 118.8, 118.5, 117.7, 114.9,
105.6, 81.6, 66.7, 53.9, 43.2, 36.3, 32.3, 31.1, 25.6, 18.2. IR (thin film): 3353, 2928,
1694, 1594 cm
-1
24
H
26
N
3
O [M+H]
+
: 372.2076, Found:
372.2072. M.P.: 178 C (decomposition).

Nitrile 2-189: To a solution of lactam 2-188 (60.0 mg, 0.162 mmol) in THF (3.2
mL) at 78 C was added a solution of KHMDS (0.5 Min toluene, 0.630 mL, 0.315
mmol). After 0.5 h at 78 C, a solution of iodoacetonitrile (1 Min THF, 0.323 mL,
0.323 mmol) was added slowly down the inside wall of the reaction vessel. After
0.5 h, a saturated NH
4
Cl solution (3 mL) and EtOAc (5 mL) were added
sequentially to the mixture. The resulting layers were separated, and the aqueous
layer was extracted twice with EtOAc (5 mL). The combined organic extracts
were washed once with brine (5 mL), dried (MgSO
4
vacuo. The crude oil was purified by flash column chromatography (25%
EtOAc/Hex) to give 51 mg (77%) of 2-189 as colorless oil.
KHMDS, THF,
-78
o
C, 0.5 h;
ICH
2
CN, THF,
-78
o
C, 0.5 h
77%
N N
H H
O N
H
H
N N
H H
O N
H
CN

166
1
H NMR (400 MHz, d
6
-acetone): " 8.69 (d, J = 7.9 Hz, 1H), 7.04 (td, J = 6.5 Hz, 1H),
6.88 (d, J = 6.9 Hz, 1H), 6.83 (t, J = 7.8 Hz, 1H), 6.75 (td, J = 8.3, 1.1 Hz, 1H), 6.08
(d, J = 7.8 Hz, 1H), 6.05 (br. s, 1H), 5.95 (app. t, J = 7.3 Hz, 2H), 5.25 (d, J = 7.7 Hz,
Hz, 1H), 3.54 (d, J = 17.1 Hz, 1H), 3.53 (m, 1H), 2.79 (s, 3H), 2.44 (ddd, J = 13.1,
9.4, 2.4 Hz, 1H), 2.24 (ddd, J = 13.0, 10.9, 7.5 Hz, 1H), 1.91 (s, 3H), 1.84(s, 3H).
13
C
NMR (75 MHz, d
6
-acetone): " 184.6, 152.8, 144.6, 142.9, 140.9, 131.5, 130.6, 130.2,
129.6, 128.6, 123.2, 121.0, 118.3, 117.4, 115.5, 103.0, 82.44, 82.36, 67.9, 54.1, 51.6,
37.7, 36.7, 25.8, 21.9, 18.5. IR (thin film): 3352, 2933, 2250, 1694 cm
-1
. HRMS (ESI):
calc. for C
26
H
27
N
4
O [M+H]
+
: 411.2185, Found: 411.2167.

1"-Deoxocommunesin F (2-191): To a solution of nitrile 2-189 (40.0 mg, 0.097
mmol) in THF (3.5 mL) at 0 C was added a solution of LiAlH
4
(1 Min THF, 0.585
mL, 0.585 mmol). The solution was warmed to 60 C. After 1.5 h at 60 C, the
mixture was cooled to 0 C. To the cooled mixture was slowly added a 10%
water/THF solution (2 mL). The mixture was diluted with Et
2
O (10 mL) and
filtered through a short pad of celite (Et
2
O). The combined organic extracts were
dried (MgSO
4
), filtered and concentrated in vacuo. The crude oil was used
1. LiAlH
4
, THF,
60
o
C, 1.5 h
2. NH
4
OAc,
NaBH(OAc)
3
,
MeOH, rt, 48 h
70% (2 steps)
N N
H H
O N
H
CN
N N
H H
N N
H
H
H
1"

167
To a solution of the crude lactol in MeOH (3.9 mL) was added NH
4
OAc (75.0 mg,
0.974 mmol) and NaBH(OAc)
3
(206 mg, 0.974 mmol). After 40 h at rt, EtOAc (10
mL) was added to the mixture. The combined organic extracts were washed once
with a saturated NaHCO
3
solution, once with brine (3 mL), dried (MgSO
4
),
filtered and concentrated in vacuo. The crude oil was purified by flash column
chromatography (33% EtOAc/Hex) to give 29 mg (70%) of 2-191 as colorless oil.
1
3
): " 6.97 (d, J = 7.5 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.78
(t, J = 7.7 Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 6.07 (d, J = 7.7
Hz, 1H), 5.91 (d, J = 7.6 Hz, 1H), 5.31 (d, J = 8.1 Hz, 1H), 4.81 (d, J = 8.3 Hz, 1H),
4.60 (s, 1H), 4.48 (br. s, 1H), 4.30 (s, 1H), 3.46 (m, 1H), 3.17-2.99 (m, 3H), 2.85 (s,
3H), 2.70 (m, 2H), 2.33 (ddd, J = 9.0, 9.0, 3.9 Hz, 1H), 2.20 (m, 1H), 2.07 (m, 1H),
1.83 (s, 3H), 1.77-1.74 (m, 4H).
13
C NMR (75 MHz, CDCl
3
): " 149.7, 143.8, 140.6,
134.8, 132.3, 127.7, 126.6, 126.4, 123.9, 119.0, 115.9, 115.5, 101.4, 85.2, 81.7, 63.7,
51.5, 51.3, 48.6, 46.9, 35.5, 34.0, 33.2, 29.7, 25.9, 18.5, 13.9. LRMS (ESI): calc. for
C
28
H
35
N
4
[M+H]
+
: 427.3, Found: 427.4.

Communesin F (2-8): To a solution of nitrile 2-189 (20.0 mg, 0.049 mmol) in THF
(1.6 mL) at 0 C was added a solution of LiAlH
4
(1 M in THF, 0.292 mL, 0.292
mmol). The solution was warmed to 60 C. After 1.5 h at 60 C, the mixture was
cooled to 0 C. To the cooled mixture was slowly added a 10% water/THF
1. LiAlH
4
, THF,
60
o
C, 1.5 h
2. NH
3
, NH
4
Cl,
MeOH, rt, 1 h;
NaBH
3
CN, 72 h

3. Ac
2
O, Et
3
N,
DMAP, CH
2
Cl
2
rt, 0.5 h
51% (3 steps)
N N
H H
N N
H
O
N N
H H
O N
H
CN

168
solution (1 mL). The mixture was diluted with Et
2
O (5 mL) and filtered through a
short pad of celite (Et
2
O). The combined organic extracts were dried (MgSO
4
),
filtered and concentrated in vacuo. The crude oil was used without further
purification.
To a solution of the crude lactol in MeOH (2.4 mL) was added NH
4
Cl (26.0 mg,
0.487 mmol). The mixture was cooled to 0 C and sparged with ammonia gas for
0.5 h. After 5 h at 0 C, NaBH
3
CN (31.0 mg, 0.487 mmol) was added and the flask
sealed with a glass stopper. The mixture was warmed to rt. After 72 h, all
volatiles were removed under a heavy stream of nitrogen. The crude residue was
taken up in EtOAc (5 mL). The combined organic extracts were washed once
with a saturated NaHCO
3
solution, once with brine (3 mL), dried (MgSO
4
),
filtered and concentrated in vacuo. The crude solid was used without further
purification.
To a solution of the crude amine in CH
2
Cl
2
(2.4 mL) at 0 C was added acetic
anhydride (0.025 mL, 0.268 mmol), Et
3
N (0.037 mL, 0.268 mmol) and DMAP (~0.5
mg). The mixture was warmed to rt. After 0.5 h, a saturated NaHCO
3
solution (3
mL) and CH
2
Cl
2
(3 mL) were added sequentially to the mixture. The resulting
layers were separated, and the aqueous layer was extracted twice with CH
2
Cl
2
(3
mL). The combined organic extracts were washed once with brine (5 mL), dried
(MgSO
4
), filtered and concentrated in vacuo. The crude oil was purified by flash
column chromatography (20% acetone/Hex) to give 11 mg (51%) of communesin
F (2-8) as colorless oil.

169
Major rotamer:
1
3
): " 7.00 (t, J = 7.2 Hz, 1H), 6.82 (t, J =
7.7 Hz, 1H), 6.73-6.65 (m, 3H), 6.08 (d, J = 7.7 Hz, 1H), 5.86 (d, J = 7.4 Hz, 1H), 5.23
(d, J = 8.7 Hz, 1H), 5.11 (s, 3H), 5.05 (d, J = 8.8 Hz, 1H), 4.67 (s, 1H), 4.57 (br.s, 1H),
3.85 (dd, J = 11.5, 9.1 Hz, 1H), 3.34 (dd, J = 15.7, 9.4 Hz, 1H), 3.15 (m, 1H), 3.03 (td,
J = 11.5, 7.5 Hz, 1H), 2.82 (s, 3H), 2.78-2.70 (m, 1H), 2.40 (s, 3H), 2.32-2.19 (m, 2H),
1.99-1.94 (m, 1H), 1.85 (s, 3H), 1.77 (s, 3H).
13
C NMR (75 MHz, CDCl
3
): " 171.6,
150.1, 142.7, 140.6, 136.1, 132.7, 131.3, 128.4, 127.3, 124.6, 123.2, 120.6, 117.0, 114.7,
100.7, 82.6, 79.6, 64.4, 51.8, 51.2, 44.2, 37.8, 36.2, 30.8, 29.7, 26.0, 22.6, 18.5. IR (thin
film): 3321, 2927, 1634, 1606 cm
-1
28
H
33
N
4
O [M+H]
+
:
441.2654, Found: 441.2640.

170

Table 8.2.1. Comparison of
1
H NMR and
13
C NMR data for synthetic ()-
communesin F and natural communesin F
5
in CDCl
3

Position
1
H natural
1
H synthetic
13
C natural
13
C synthetic
1 6.68 (dd, 7.3, 1.5) 6.73-6.65 (m, overlapped) 123.2 123.2
2 6.70 (td, 7.3, 1.5) 6.73-6.65 (m, overlapped) 120.6 120.6
3 7.00 (td, 7.3, 1.5) 7.00 (t, 7.2) 127.3 127.3
4 6.68 (dd, 7.3, 1.5) 6.73-6.65 (m, overlapped) 117.0 117.0
4a 142.7 142.7
6 4.66 (s) 4.67 (s) 82.7 82.6
7 51.2 51.2
7a 131.2 131.3
8 51.8 51.8
8a 132.7 132.7
9 5.11 (s) 5.11 (s) 79.6 79.6
11 5.05 (d, 8.8) 5.05 (d, 8.8) 64.4 64.4
11a 140.7 140.6
12 6.08 (d, 7.6) 6.08 (d, 7.7) 114.7 114.7
13 6.82 (t, 7.6) 6.82 (t, 7.7) 128.4 128.4
14 5.86 (d, 7.6) 5.86 (d, 7.4) 100.7 100.7
14a 150.1 150.1
17 3.03 (td, 11.6, 7.6) 3.03 (td, 11.5, 7.5) 44.2 44.2
3.85 (dd, 11.6, 8.8) 3.85 (dd, 11.5, 9.1)
18 1.96 (dd, 12.8, 7.6) 1.99-1.94 (m) 30.8 30.8

2.74 (ddd, 12.8, 11.6,
8.8)
2.78-2.70 (m)
19 2.22 (dt, 12.2, 9.1) 2.32-2.19 (m, overlapped) 37.8 37.8
2.29 (dd, 12.2, 8.5) 2.32-2.19 (m, overlapped)
20
3.14 (ddd, 15.5, 12.2,
8.5)
3.15 (m) 36.3 36.2

3.34 (ddd, 15.5, 12.2,
8.5)
3.34 (dd, 15.7, 9.4)
21 5.22 (br. d, 8.8) 5.23 (d, 8.7) 124.6 124.6
22 136.1 136.1
23 1.79 (d, 0.6) 1.77 (s) 26.0 26.0
24 1.85 (d, 0.6) 1.85 (s) 18.5 18.5
1' 2.82 (s) 2.82 (s) 29.7 29.7
1'' 171.6 171.6
2'' 2.41 (s) 2.40 (s) 22.6 22.6
5-NH 4.60 (br. s) 4.57 (br. s)
()-communesin F
N N
H H
N N
H
O
1"
2"
1'
12
13
14
24
23
22
21
11
11a
7a
14a
19 20
5
6
7
1
2
3
4
4a
8
8a
9 17
18

171
Spectra of 1-Deoxocommunesin F and Communesin F

172

173

174

175

176
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VITA
Johannes Belmar
Johannes was born in Vienna, Austria and raised elsewhere. He graduated
with a B.S. in Biology from The State University of New York College of
Environmental Science and Forestry in 2004. Johannes then moved to State
College, PA to pursue a Ph.D. in chemistry at the Pennsylvania State University
under the guidance of Professor Raymond Funk.

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, 1-109), a partial agonist of #4!2 nAChRs derived from

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