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EDITORIAL BOARD
Professor Erik J. Sorensen

Department of Chemistry
Frick Laboratory
Princeton University
Washington Road
Princeton, NJ, USA
Professor Dirk Trauner

New York University
100 Washington Square East
New York, NY, USA
Professor Frederick G. West

University of Alberta
Gunning-Lemieux Chemistry Centre E3-43
Edmonton, Alberta
Canada
Professor Craig M. Williams

School of Chemistry and Molecular Biosciences
University of Queensland Brisbane
Queensland, Australia
Professor Pauline Chiu

The University of Hong Kong
Pokfulam Road, Hong Kong
Dr. Jean Suffert

Universite de Strasbourg
Faculte de Pharmacie
Laboratoire d’Innovation Therapeutique
Equipe SOMP
(UMR 7200 CNRS/UDS)
Illkirch Cedex, France
Strategies and Tactics
in Organic Synthesis
Volume 15
Edited by
Michael Harmata
University of Missouri,
Columbia, MO, United States
Elsevier
Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
Copyright © 2021 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by
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www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under
copyright by the Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this ﬁeld are constantly changing. As new research and
experience broaden our understanding, changes in research methods, professional
practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge
in evaluating and using any information, methods, compounds, or experiments
described herein. In using such information or methods they should be mindful of
their own safety and the safety of others, including parties for whom they have a
professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or
editors, assume any liability for any injury and/or damage to persons or property as a
matter of products liability, negligence or otherwise, or from any use or operation of
any methods, products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
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A catalogue record for this book is available from the British Library
ISBN: 978-0-12-822212-6
ISSN: 1874-6004
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Typeset by TNQ Technologies
Dedication
This volume is dedicated to the memory of

my collaborator and friend, Victor Snieckus,
August 1, 1937eDecember 18, 2020.
Contributors
Wen-Ju Bai, Amgen Research, One Amgen Center Drive, Thousand Oaks, CA, United
States
Korey Bedard, Brock University, St. Catharines, ON, Canada
Tanner W. Bingham, Department of Chemistry, University of Illinois, Urbana, IL,
United States
Gaëlle Blond, Université de Strasbourg, CNRS Strasbourg, France
Reinhard Brückner, Institut für Organische Chemie, Albert-Ludwigs-Universität,
Freiburg, Germany
Eric M. Ferreira, Department of Chemistry, University of Georgia, Athens, GA,
United States
Saswata Gupta, Department of Chemistry, University of Illinois at Chicago, Chicago,
IL, United States
Lucas W. Hernandez, Department of Chemistry, University of Illinois, Urbana, IL,
United States
Tomas Hudlicky, Brock University, St. Catharines, ON, Canada
Stephen K. Jackson, OmegaChem, Lévis, QC, Canada
Phil C. Knutson, Department of Chemistry, University of North Carolina at Chapel
Hill, Chapel Hill, NC, United States
Julia Kopp, Institut für Organische Chemie, Albert-Ludwigs-Universität, Freiburg,
Germany
Daesung Lee, Department of Chemistry, University of Illinois at Chicago, Chicago, IL,
United States
Christopher C. McAtee, Department of Chemistry, University of Michigan, Ann
Arbor, MI, United States
Ryan P. Murelli, Department of Chemistry, Brooklyn College, The City University of
New York, Brooklyn, NY, United States; PhD Program in Chemistry, The Graduate
Center, The City University of New York, New York, NY, United States; PhD
Program in Biochemistry, The Graduate Center, The City University of New York,
New York, NY, United States
Eric T. Newcomb, Pfizer Boulder Research and Development, Boulder, CO, United
States
Thomas R.R. Pettus, Department of Chemistry and Biochemistry, University of
California, Santa Barbara, CA, United States
xv
xvi Contributors
David Sarlah, Department of Chemistry, University of Illinois, Urbana, IL, United

States
Corinna S. Schindler, Department of Chemistry, University of Michigan, Ann Arbor,
MI, United States
Jean Suffert, Université de Strasbourg, CNRS Strasbourg, France
David R. Williams, Department of Chemistry, Indiana University, Bloomington, IN,
United States
Xu Zhu, Department of Chemistry, University of Michigan, Ann Arbor, MI, United
States; College of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China
Preface
How did he manage to retain his youth? Victor Snieckus appeared to be

eternally young and forever filled with enough energy to make many who were
younger be somewhat envious. He was old enough (barely) to be my dad, but
he often seemed like an older brother. He had a twinkle in his eye. Yet with all
that vim, vigor, and mischief, he was in many ways old school. He demanded
rigor in scientific thought and action, and he was very serious about organic
chemistry. One could not turn out bad trying to emulate him. It was a sad day
when I recently learned he had died. I felt it keenly as a personal loss; I wanted
more time to talk with him, learn more about him, and learn more about
chemistry from him. Vic, Kenneth Wärnmark, and I had a collaboration
involving Tröger’s base that continued nearly 15 years in total, with the latest
publication in our series appearing in mid-2020 in ARKIVOC. This was a
highlight of my professional life.
A little over a month before he died, Vic sent me and several others an
email with a link to a skit from Stephen Colbert’s show celebrating the defeat
of Trump. It was great. The cruelty, lies, and incompetence had been driven
from office, by a clear majority, yet far too few, of my fellow Americans. Still,
the deed was done, and Vic celebrated. So did I.
Vic did not live to see the tragedy of 1/6/21 in the United States, a day on
which many US citizens hoped to defeat the electoral process because of their
addiction to lies and their fear of true suffrage for all, and mostly their fear of
the loss of white supremacy. But in all fairness, the idea of superiority, caste,
class.whatever you wish to call it.is not unique to the United States. It is
everywhere, sometimes overt, always covert. Purging ourselves of this poison
is not a trivial task.
Vic also did not live to see a change in Senate leadership in the United
States. I have no doubt that he would have been pleased by this, a chance for
the United States to begin to redeem itself after 4 years of leadership which
treated lies as facts for the sake of power, and did everything in its power to
reject reason, whether in the form of science or just simple common sense.
Were I Canadian as was Vic, I would have been quite concerned about the
monsters living in my basement over the last 4 years. As it was, I was just
depressed to be in a country that had a sociopath as a leader with a huge
number of mindless zealots following him, many worshiping a Jesus Christ
xvii
xviii Preface
wrapped in a US flag, carrying an AR-15. Sick but dangerous people. Here’s to

creating a civil and just society for all. Vic would have wanted this, I believe.
Now, on to some science. In case it is not known, this is going to be my last
Strategies and Tactics in Organic Synthesis. Trying to get authors for the series
has been a serious challenge, a problem with which I no longer desire to be
afflicted. Hydrocortisone and sitz baths do not help. A perk arising from that
decision is that I got to fire the entire editorial board. Am I president yet? I
didn’t think so. In any case, it has been a pleasure to bear witness to volumes
of beautiful, stimulating chemistry over these many years.
I do want to thank all those who contributed to this volume. My hope to go
out on a bang with a record number of chapters was thwarted by SARS-CoV-2
and the havoc it has and is wreaking even at this writing, but some colleagues
got in under the wire and others battled, at least one, through a COVID
infection, to deliver some nice science. Synthesis survives. Let’s make sure it
lives on for a long time by ensuring that interest and funding in the area re-
mains vibrant. Experience has led me to think that synthetic chemists are their
own worst enemies with respect to the latter. Retain high standards, but take
good care in doing so. Our dedication to helping the community through
helpful, constructive reviewing is crucial.
I would like to thank Elsevier for their continued commitment to this se-
ries. I pushed Academic Press many years ago to reboot this series and suc-
ceeded. It was great while it lasted. I have had the opportunity to work with
some wonderful people at Elsevier. Susan Ikeda and Emily McCloskey have
been key to the success of the series. I am grateful for their help and support.
Finally, I want to mention the National Science Foundation of the United
States, without which I would not have had the pleasure of engaging in
research. Their support enabled me to take on projects like this and I am
thankful.
Michael Harmata
January, 2021
Chapter 1
Amaryllidaceae isocarbostyril
alkaloids
Tanner W. Bingham, Lucas W. Hernandez and David Sarlah*
Department of Chemistry, University of Illinois, Urbana, IL, United States
*Corresponding author at: sarlah@illinois.edu.
Chapter Outline
1. Introduction 1 4. Narciclasine and lycoricidine 33
2. Synthetic strategy 12 4.1 Optimization of Ni(II)
2.1 Retrosynthetic analysis 12 conditions 33
2.2 Development of the 4.2 Initial synthesis of
dearomative narciclasine 36
carboamination reaction 12 4.3 Scalable route to
2.3 Mechanistic hypothesis 17 (þ)-lycoricidine (3) and
2.4 Optimization of our new (þ)-narciclasine (4) 40
nickel-catalyzed 4.4 Synthesis and biological
conditions 19 evaluation of C-7 analogs 42
3. Pancratistatins 21 4.5 Metabolic studies 46
3.1 Initial investigations 21 5. Conclusion 46
3.2 Optimizing the route 24 Acknowledgments 49
3.3 Methods for lactam References 49
formation 27 Further reading 52
3.4 C-7 oxidation and final
route 31
1. Introduction
The anticancer properties of crude plant extracts from the Amaryllidaceae
family have been recorded in the literature since the time of the ancient Greeks,
with Hippocrates prescribing Narcissus oils for the treatment of uterine tumors.1
Recently, the therapeutic effects of these extracts have been attributed to the
isocarbostyril alkaloids (þ)-7-deoxypancratistatin (1), (þ)-pancratistatin (2),
(þ)-lycoricidine (3), and (þ)-narciclasine (4) (Fig. 1.1). The first of this family
Strategies and Tactics in Organic Synthesis. https://doi.org/10.1016/B978-0-12-822212-6.00004-7
Copyright © 2021 Elsevier Inc. All rights reserved. 1
2 Strategies and Tactics in Organic Synthesis
OH OH
2
HO OH OH
1 3
10
9 10a 4a 4 O
O OH O 10b OH
NH 6 NH 5
O NH
O O 8 6a
7
R O O R O
(+)-7-deoxypancratistatin (1, R=H) (+)-lycoricidine (3, R=H)
(+)-pancratistatin (2, R=OH) (+)-narciclasine (4, R=OH)
FIGURE 1.1 The Amaryllidaceae isocarbostyril alkaloids (þ)-deoxypancratistatin (1), pan-

cratistatin (2), (þ)-lycoricidine (3), and (þ)-narciclasine (4) and their numbering.
to be isolated, (þ)-narciclasine (4), was initially investigated for its growth

inhibitory effects in plants, as placing a cut daffodil in a vase with other flowers
significantly shortens their vase life.2 After exhibiting potent antimitotic activity
against mouse sarcoma 180 cells,2 (þ)-narciclasine’s structure (4) was
determined by chemical degradation studies3 and was eventually determined by
X-ray diffraction analysis of the corresponding tetraacetate.4 The promising
activity of (þ)-narciclasine (4) prompted much interest in the isolation of other
isocarbostyril alkaloids in its family; (þ)-7-deoxynarciclasine or (þ)-lycor-
icidine (3) was eventually isolated from various species, including Hymenocallis
littoralis, which contained another structurally similar isocarbostyril, (þ)-pan-
cratistatin (2).5 These alkaloids, along with another congener, (þ)-7-
deoxypancratistatin (1), have all shown similar growth-inhibitory properties to
that of (þ)-narciclasine (4).
These interesting findings prompted Pettit and coworkers to measure the
cytotoxicity of these compounds against the NCI’s panel of 60 human cancer
cell lines.6 Narciclasine (4) exhibited the most potent activity with a mean
GI50 of 0.016 mM. Pancratistatin (2) exhibited a 5-fold decrease in activity
compared with narciclasine with a GI50 of 0.091 mM, while lycoricidine (3)
displayed a 10-fold decrease in activity with a GI50 of 0.15 mM (Table 1.1).
Interestingly, 7-deoxypancratistatin (1) also exhibited a drastic decrease in
activity with respect to pancratistatin (2), suggesting that the C-7 phenol is
important for the potency of these natural products. Furthermore, the fivefold
drop in activity due to the presence of an alcohol at the C-1 position (2 vs. 4)
indicates that hydrophilic functionality at that position is disfavored. Impor-
tantly, these cytotoxic properties were noticeably reduced in noncancerous
cells, making these molecules appealing as potential chemotherapeutics.7e9
In addition to their in vitro activity, both (þ)-pancratistatin (2) and
(þ)-narciclasine (4) have shown promising in vivo activity. Pancratistatin (2)
demonstrated significant in vivo activity against murine M-5076 ovarian sar-
coma and murine P-388 lymphocytic leukemia,5 as well as reducing the
growth of subcutaneous colon HT-29 tumors.10,11 Similarly, narciclasine (4)
displayed considerable in vivo activity against murine P-388 lymphocytic
leukemia as well as MC-38 murine colon carcinoma, and it reduced the growth
TABLE 1.1 In vitro activity of the Amaryllidaceae isocarbostyril alkaloids.a
Amaryllidaceae isocarbostyril alkaloids Chapter j 1

Mean Leukemia Pancreas Breast CNS Lung-NSC Colon Prostate
GI50 P388 BXPC-3 MCF-7 SF268 NCIeH460 KM20L2 Du-145
7-Deoxypancratistatin NT 1.420 NT NT NT NT 0.710 NT
(1)
Pancratistatin (2) 0.091 0.052 0.061 0.071 0.043 0.098 0.077 0.046
Lycoricidine (3) 0.150 0.065 0.240 0.160 0.410 0.180 0.290 0.170
Narciclasine (4) 0.016 0.042 0.011 0.010 0.010 0.027 0.011 0.011
NT, not tested.

a
IC50 and GI50 values reported in mM.
3
of MX-1 breast carcinoma tumors,12 and invasive Hs683 and GL19 human
glioblastomas.13 Furthermore, narciclasine (4) inhibited mitosis in carcinoma,
glioma, and melanoma and was found to impair cancer cell migration.8 In
addition to their potent anticancer activity, 1e4 also showed significant anti-
viral activity against Japanese encephalitis, yellow fever, Rift Valley fever, and
dengue type 4 viruses,14 and narciclasine (4) has been found to attenuate diet-
induced obesity15 and possess antiinflammatory properties.16
Although these compounds have shown a myriad of promising activities,
their precise mode of action has yet to be uncovered. Studies suggest that
pancratistatin’s (2) anticancer activity proceeds through intrinsic apoptosis, as
evidenced by release of caspase-9 and caspase-3, exposure of phosphatidyl
serine, and destabilization of mitochondrial membrane potential.10,11,17
Interestingly, the cytotoxic activity of narciclasine (4) has been attributed to
extrinsic apoptosis as evidenced by the release of caspase-8 and the activation
of the Fas and death receptor 4 (DR4) or death-inducing signaling complex
(DISC).9 Yet, despite their structural homology, there have been no studies
directly comparing their mechanisms of action.9,18e22 Aside from its cytotoxic
activity, narciclasine has also displayed activity in various cytostatic pathways.
It has been shown to disrupt cytokinesis through two different pathways,
disruption of actin bundle formation through the binding of the translation
elongation factor eEF1A,25 and the formation of F-actin stress fibers through
the activation of GTPase RhoA.13 Additionally, narciclasine has been shown to
bind to the A-site of the 60S ribosome, thereby directly blocking peptide
synthesis.23,24 Notably, many of these promising activities of 4 have yet to be
shown for 2, thus necessitating further investigation and comparison of these
compounds and their structureeactivity relationships (SAR).
To fully elucidate their mechanism(s) of action and promote their pre-
clinical development, scalable access to isocarbostyrils 1e4 was needed.
Various isolation protocols for narciclasine (4) are reported in the literature,
mostly from the bulbs of the Narcissus plant, the yields of which can range
from 30 to 200 mg/kg depending on the species and time of year.19 When
harvested from the Hawaiian wilderness, Hymenocallis litoralis is the highest
yielding source of 2 (144 mg/kg) and 3 (222 mg/kg).5 However, when culti-
vated in fields and greenhouses in Arizona, the isolation yield dropped
significantly to 22 mg/kg for 2 and 15 mg/kg for 3 in the peak month of
October. This lack of availability has inhibited the investigations into their
bioactivities. Additionally, although the initial studies into these compounds
revealed their potential use as therapeutics, such as their notoriously low
aqueous solubility, there are drawbacks to overcome for these compounds to
become medicinally relevant.26
Owing to the lack of scalable access and the need for further biological
evaluations, as well as their structural complexity, 1e4 have attracted
considerable attention from the synthetic community. To date, there have been
11,27e38 13,30,39e50 14,27,38,51e62 and 843,57,62e67 syntheses of 1e4,
Amaryllidaceae isocarbostyril alkaloids Chapter j 1 5
respectively, as well as many formal, semi, epi-, and analog syntheses pub-
lished over the years.18e22 As such, there have been various strategies
developed for installing the correct stereocenters on the cyclitol core and
constructing the lactam ring. One notable approach, reported by the Hudlicky
group in 1992, involves the use of microbial arene oxidation to stereo-
selectively install the syn-diol present on the cyclitol core (Scheme 1.1),54
subjecting bromobenzene (5) to the bacterial dioxygenases of Pseudomonas
putida, followed by acetonide protection of the resulting diol-delivered diene
6. Subsequent stereoselective [4 þ 2] cycloaddition of diene 6 with an acyl
nitroso species provided bicycle 7a, which contains all the stereocenters
present in the cyclitol core of (þ)-lycoricidine (3). Reduction of the bromide
followed by cleavage of the NeO bond was accomplished with mercury
aluminum amalgam. Silyl protection followed by imide formation with
2-bromo-piperonyloyl chloride furnished key intermediate 9a. Closure of the
lactam was attempted with various methods including radical cyclization,
epoxide-opening, and the Pd-catalyzed Heck reaction. Ultimately, they found
that the modified Heck conditions, initially reported by Grigg and co-
workers,68 and optimized for a diastereomer of 9 by Chida and coworkers,53
were the only conditions that could provide the benzolactam. However, the
product was isolated as a mixture of fully protected, desilylated, and free
amide products. Fortunately, these could be isolated together and subjected to
global deprotection to furnish lycoricidine 3 in 9 steps and 25% yield overall.
Notably, 3 years later, Hudlicky was able to take advantage of this same
strategy of microbial arene oxidation for his synthesis of (þ)-pancratistatin.
Stereoselective aziridination followed by radical dehalogenation of diene 6
provided vinyl aziridine 7b. Installment of the necessary trans relationship
between the arene and amine then became possible by the nucleophilic ring
opening of the aziridine at the allylic position by cuprate 8b. Arylated inter-
mediate 9b was then further elaborated to yield (þ)-pancratistatin (1) in the
first asymmetric total synthesis in 14 steps and 2% overall yield. These
landmark total syntheses were the state-of-the-art before we started our work
on these molecules, and they demonstrated the power of dearomative pro-
cesses for the rapid introduction of complexity to feedstock petrochemical
starting materials.
Key steps in other notable approaches to this family of natural products are
shown in Fig. 1.2. In Trost’s 1995 synthesis of (þ)-pancratistatin, a desym-
metrization reaction was employed to define three existing stereocenters and
install a fourth in the product 12.41 In 1998, Magnus applied a beazidonation
strategy toward (þ)-pancratistatin, to yield allylic azide 14.42 Rigby reported
an interesting photocyclization approach in 2000.15 While the absolute ste-
reochemistry was dictated by the TBS protected alcohol in 15, the required
relative stereochemistry was imparted by the 6p-conrotatory photochemical
cyclization and subsequent suprafacial [1,5]-H shift to yield product 16. In
2009, Madsen utilized a Zn-mediated fragmentation to afford diene 19 that
OH O
O Bu4NIO4 Br 1. PhI=NTs, O 8b
O AlH2(Hg) Br O Cu(acac)2 BF3·Et2O O O
CbzNHOH O
THF CH2Cl2 2. Bu3SnH, O 75% NHTs
O TsN O
91% O 74% O AIBN CONMe2
NHCbz N 42% OTBS
8a Cbz 7a 6 7b 9b
1. P. putida 39/D1 Cu(CN)Li2

1. ClSiMe2i-Pr, im. 85% 2. 2,2-DMP O
CH2Cl2 2 1. s-BuLi
pTsOH
76% 2. n O (Boc)2O 56%
CONMe2
then, 2-bromo- Br 2. Na/anthracene
piperonyloyl chloride OTBS
8b
OSiMe2iPr OH 5 OH
O
O OH HO OH
1. Pd(OAc)2 7 steps
Br TlOAc, DIPHOS O O
O O O O OH
2. Pd/C, EtOH OH NHBoc
NCbz cyclohexene NH NH O CONMe2
O O O
OH
O 23% O OH O
9a (+)-lycoricidine (3) (+)-pancratistatin (1) 10
9 steps 10% overall yield 14 steps 2% overall yield
SCHEME 1.1 Hudlicky’s dearomative approach to (þ)-lycoricidine (3) and (þ)-pancratistatin (2).
Trost - 1995 Magnus- 1998
OTIPS OTIPS
OCO2Me OCO2Me PhIO
(pC3H7PdCl)2 (0.5 mol%)
O O TMSN3
(R,R)-DACH-phenyl (0.75 mol%) Ar Ar
95%
O TMSN3 O N3
O
82% 13 Ar = 14
OCO2Me N3 O
11 12 OMe
Madsen - 2009
Rigby - 2000 O OMe
O O
TBSO hn TBSO I
OH
Zn
30% O TESO OBn
17 THF, O OBn
O NPMB O NPMB O Br H2O, MeOH O
O

30%
O O O O O CO2Me
H 15 H 16 OBn O 19
18
OBn
OTBS OTBS OH
Yan - 2002 Keck - 1999 OH
O AcO O PhS O
O O
O O 1. SnCl4, CH2Cl2 O O O O O
O PhSH, hn
O NH 2. Ac2O, K2CO3 O NH O PhMe NOBn
O NOBn O
98% 90%
Et2N O Et2N O OMe O
20 21
O O 22 23
OMOM
Padwa - 2007 Banwell - 2007 OMOM
OH
MeO2C SnBu3 OH
O Br OMOM
16 MeO2C O
O IO O B NH2
27
CuCl/Pd(0) O O O OH
LiCl, DMSO 1. Pd(PPh3)4, K2CO3, mwave
O NPMB O NPMB O NH
O 2. BSBr O
82%
O O 30% over
24 25 MOMO OMe OH O ent-4
26 two steps
7
FIGURE 1.2 Selected approaches toward the Amaryllidaceae isocarbostyril alkaloids.
allowed for a ring-closing metathesis reaction to close the cyclitol ring.46

Lewis acidemediated opening of epoxide 20, reported by Yan and coworkers
in 2002, closed the tetracyclic core of the natural product.58 While this step
furnished 21 in high yield, opening of the epoxide led to cis ring fusion,
making this strategy only useful for the synthesis of 3 and 4. In 1999, Keck and
coworkers reported a preparation of (þ)-lycoricidine (3) that used the 6-exo-
trig cyclization of a vinyl radical with an oxime ether, subjecting alkyne 22 to
thiophenol and visible light furnished lactam 23 in high yield as a single
diastereomer.56,57 Unfortunately, when this strategy was applied to the total
synthesis of narciclasine (4), the lactam cyclization did not proceed sponta-
neously and required stoichiometric amounts of Me3Al to mediate the cycli-
zation. A racemic synthesis of lycoricidine (3) was reported in 2007 by Padwa
and coworkers that employed an elegant one-pot Stille coupling/DielseAlder
sequence to form the lactam and install the necessary functional handles
needed for the cyclitol core.59 In 2007, Banwell and coworkers employed a
convergent approach, using an intermolecular Suzuki coupling to bring frag-
ment 26 and 27 together to furnish ent-4.67
One strategy for closing the lactam ring that has been used in various
syntheses of these natural products is the modified BischlereNapieralski re-
action, first reported by Banwell and coworkers in 1994 during their synthesis
of pancratistatin analogs (Scheme 1.2).61 These modified conditions utilize
Tf2O as a Lewis acid to promote the conversion of a carbamate (28) to either
an isocyanate (29) or nitrilium ion (30), which can then undergo a Frie-
deleCrafts reaction to close the lactam or dihydroisoquinoline, respectively,
with further hydrolysis yielding lactam 31. In 1999, Hudlicky and coworkers
were able to use this strategy to synthesize narciclasine precursor 31 in just
one step from methyl carbamate 28.64 While this endgame strategy has been
used by many syntheses to conveniently close the lactam ring in a single
transformation,29,42,44,49,64 it requires the cyclitol core to be fully protected to
proceed, thus necessitating additional manipulations.
Despite many elegant approaches, the development of a sustainable route
with practical access to these natural products has remained elusive, as none of
the previously reported syntheses have been able to produce more than
milligram quantities of these compounds in a single pass. Nevertheless, these
impressive synthetic endeavors enabled basic SAR studies that identified the
pharmacophore and provided more potent and selective analogs that could not
be accessed through direct modification of the natural products.18e22
While developing more potent molecules is often the goal of derivatization,
coincidental discovery of inactive compounds during this process can provide
much information about the significance of each structural motif on the
compound of interest. This is evidenced by compounds 3269 and 33,70 which
show the importance of the 1,3-benzodioxole moiety on the aromatic ring
(Fig. 1.3). Compounds 34e3671e73 suggest that not only is the amide, but also
its cyclic structure, important for activity. The inactivity of cyclitol derivatives
OAc OAc OAc OAc

AcO OAc AcO OAc AcO OAc AcO OAc
O Tf2O O O HCl O
OAc OAc OAc OAc
O HN OR O N O N O NH
O
OPG O OPG OPG OPG O
OR
28
R=OMe, OEt, OtBu 29 or 30 31
SCHEME 1.2 The modified BischlereNapieralski reaction for lactam formation.
9
Arene derivatives Lactam derivatives

OH OH OH OH OH
OH OH OH OH HO OH
TMS O O O
OH OH OH OH OH
NH NH O O O NH O OH
TMS
O O O O OMe
32 33 34 35 36
Banwell - 200770 Hudlicky - 200671 Chapleur - 200472 Chapleur - 199373 Kornienko - 200674
inactive inactive inactive inactive inactive
Cyclitol derivatives Cyclitol skeleton derivatives
OH OH OH OH
OH HO HO OH
O OH O O OH O OH
O NH O NH O NH O NHBz
O O O
37 38 39 40
McNulty - 200575 Banwell - 200770 Kornienko - 200976 McNulty - 200877
inactive inactive inactive inactive
More potent derivatives
OH OBz OH OH OH
OH OH BzHN OH OH
O O O O N
OH OH OH OH
O NH O NH O NH O NH
OH O OH O OH O OH O
41 42 43 44
(+)-transdihydronarciclasine6 Hudlicky - 201278 Marion - 200979 Hudlicky - 201580
IC50 = 3.2 nM (P-388) IC50 = 50 nM (HCT116) IC50 = 4.7 nM (HCT116) IC50 = 193.7 nM (HCC1954)
FIGURE 1.3 Selected analogs of the Amaryllidaceae isocarbostyril alkaloids.

3774 and 3869 show the beneficial role of each of the alcohols on the core,
while structural derivates 3975 and 4076 showcase the need for the polyol to be
cyclic. Together, this information suggests that much of the core scaffold of
the natural product is necessary for the high activity. However, the increased
activity of (þ)-trans-dihydronarciclasine (41) (IC50 ¼ 3.2 nM in P388 leuke-
mia cells) over (þ)-pancratistatin (2) (IC50 ¼ 52 nM in P388 leukemia cells)
suggests that the C-1 hydroxyl in 1 is detrimental for its activity.6 This led
Hudlicky, and Marion, to synthesize analogs 4277 and 43,78 respectively, which
have increased activity when compared with 1e4. Since the C-1 position is
spatially close to the C-10 position, Hudlicky and coworkers wanted to explore
this region as well. This led to analog 44,79 which was slightly less active in
HCC1954 human T-cell leukemia cells (193.7 nM) when compared with its
natural counterpart, narciclasine (4) (173.2 nM). While this analog did not
show increased activity, this position has been understudied as no other ana-
logs of the C-10 position have been synthesized, and its proximity to the C-1
position suggests that hydrophobic groups may lead to increased activity.
Lastly, little effort has gone into derivatizing the C-7 position. As previously
stated, the presence of a free phenol at that position increases activity. Other
than protected phenols, few other analogs of this position have been produced
despite its importance in the activity of these compounds.18e22 All this in-
formation together points at three distinct positions of the pharmacophore that
are underexplored: C-1, C-7, and C-10 (Fig. 1.4). As most previously reported
strategies required a de novo synthesis to access each analog, and hampered
efficient SAR studies, the development of a more facile route toward these
natural products as well as a means of late-stage functionalization is highly
desirable. With this in mind, we set out to develop more concise and scalable
syntheses of these compounds that would also expedite the synthesis of
analogs.
Hydrophobic
Groups
C-10 C-1 OH
OH
O OH
O NH
O
C-7
Hydrophilic
Groups
FIGURE 1.4 Potential sites of diversification.
2. Synthetic strategy
2.1 Retrosynthetic analysis
In our retrosynthetic analysis of the Amaryllidaceae isocarbostyril alkaloids,
we were aware that the greatest synthetic challenge resided in the densely
functionalized cyclitol core encompassing six and four contiguous stereocenters.
As discussed, several methods were already in place for the installation of the
benzolactam, i.e., the BischlerNapieralski reaction. Furthermore, in many of
the previous total syntheses, significant effort was required for the installation of
the requisite functionalities for the annulation, that led to a dramatic increase in
sequential operations (protection, lactam formation, and deprotection). Based on
these observations, we knew there were safer methods to install the lactam,
giving us the freedom to initially focus on the cyclitol core; particularly the
rapid and controlled formation of six contiguous stereocenters, enabling rapid
downstream installment of the lactam ring of the natural products (Scheme 1.3).
With this in mind, our first simplifying disconnect was lactam formation,
tracing back to aminocyclitol 45 and epoxy acetonide 46. We realized that
installation of the oxygen functionalities would be most straightforward at this
point, but we were not sure what selectivity would be inherent to the system to
install the correct relative stereochemistry and were resigned to an empirical
approach. By design, both disconnects revealed a convergent intermediate,
diene 47, which we designated as the key motif that would enable our syn-
thesis, that being: concise, scalable, and highly modular for the synthesis of
analogs. However, this meant that our total syntheses would rely on the
scalable preparation of diene 47. Additionally, while not of immediate priority,
but of overall importance, the asymmetric synthesis of these natural products
was crucial to allow us to test their biological activity, as the enantiomers were
shown to be inactive.69 Based on these requirements, we believed deriving this
product from benzene through a dearomative carboamination reaction would
be the most straightforward approach.
2.2 Development of the dearomative carboamination reaction

At the time of the project’s conception, our use and understanding of
MTAD-mediated (50) dearomative transformations was still in its infancy as
we were in the process of developing the dearomative dihydroxylation reaction
(Scheme 1.4).80 Yet, we hypothesized that an expansion of this methodology
would involve the use of transition metals in an allylic substitution-type
mechanism, similar to those employed by Lautens and others.81e84 The ura-
zole moiety could be considered a doubly allylic leaving group perfectly suited
for either of the two mechanisms shown, i.e., carbometalation followed by
b-elimination, or SN20 oxidative addition with subsequent transmetalation and
reductive elimination to furnish the requisite dearomative carboamination
product. However, we knew the development of this transformation would be
OH OH
HO OH HO OH
lactam olefin
O formation functionalization
OH O OH
O MgBr
NH NH2 trans-dihydroxylation
O O cis-dihydroxylation
O
R O 48

7-deoxypancratistatin (R = H, 1) 45 +
pancratistatin (R = OH, 2)
dearomative
functionalization
O
NUR trans-carboamination benzene (49)
O
47 +
OH
O Me
OH O O N O
lactam olefin
O O functionalization N N
OH formation O
MTAD (50)
O NH O NUR epoxidation
Br cis-dihydroxylation
R O
lycoricidine (R = H, 3) 46
narciclasine (R = OH, 4)
SCHEME 1.3 Retrosynthetic analysis of the Amaryllidaceae isocarbostyril alkaloids.
13
R O
N
concurrent development [TM]
N NMe
O
HO O O R [M]
N N
HO OsO4 [TM]
N NMe N NMe dearomative carboamination R
O O NUR
R [M]
benzene-MTAD
cycloadduct (51)
N
N O
[TM]n+2
NMe
O
SCHEME 1.4 Conception of the dearomative carboamination.

fraught with challenges. For example, the selective induction of trans ste-
reochemistry as well as formation of the desired 1,2-product rather than the
1,4-product would be difficult. Furthermore, we knew that the benzene-MTAD
cycloadduct (51) was unstable to temperatures above 40 C. Unfortunately,
most conditions for allylic substitution with softer nucleophiles required
elevated temperatures.
With these concerns in mind, we chose to simplify our problem signifi-
cantly. Based on our limited studies at the time, we knew that the generation
and isolation of the naphthalene-MTAD cycloadduct (52) was possible in a
51% yield (Fig. 1.5A). Furthermore, we knew that 52 was stable at higher
temperatures (i.e., 0 C) for a short period of time and believed this would
allow us to greatly expand the number of screening experiments we could run
at a time. With 52 in hand, we immediately tested traditional conditions with
softer nucleophiles to no avail.81e84 We then turned to harder nucleophiles and
found a report from Pineschi and coworkers that described a copper-catalyzed
allylic substitution of diazabicyclic systems employing Grignard reagents.85
We were particularly attracted to these conditions as not only could they be run
cryogenically, but they also employed rac-BINAP as the ligand which gave
hope to our long-term desire for asymmetric induction.
To our delight, when we tested Pineschi’s conditions, albeit with a higher
catalyst loading, our desired dearomative trans-carboaminated product 53 was
afforded with exclusive selectivity in 60% isolated yield. After a short ligand
screen, we eventually found that dppf gave us the highest yield of 72%. Yet, a
model system will always be a model system. When we moved our conditions
to begin mirroring our actual desired transformation, i.e., in situ generation of
the cycloadduct, we found a significant decrease in yield of ca. 42%
(Fig. 1.5B). Despite this reduction in efficiency, we pushed forward and tested
our conditions with benzene (49) as the substrate to find that no reaction was
observed (Fig. 1.5C). While many hypotheses could be put forth to explain this
dearth in reactivity and potentially allow for optimization to a working system,
we knew we needed to consider alternative options. As is often the case when
working with a model system in total synthesis, we had excellent conditions
that failed to perform on the actual substrate.
Undeterred, we decided to go for the home-run approach and merely swap
the transition metal and keep the remaining conditions consistent (Fig. 1.5D).
While many of the metals we tested either underperformed or did not react, we
found that in the case of Ni(cod)2, there was an increase in yield when
naphthalene (54) was used as substrate from 42% to 66%. However, there was
still one more reaction that needed to succeed before our proof of concept
could be validated, and that was the dearomative carboamination of benzene
(49, Fig. 1.5E). We knew that if this transformation did not work with the
reaction conditions as developed, we would either need to redo the screen with
benzene (49) or reevaluate our approach toward the Amaryllidaceae iso-
carbostyril alkaloids. With much anticipation, we set up the transformation and
a) Me [Cu] (10 mol%)
O N O O
[4+2] N Ligand (20 mol%)
+

N N N NMe
visible light PMgBr, CH2Cl2
naphthalene (54) MTAD (50) NUR
51% O
naphthalene-MTAD cycloadduct (52) 53
isolable, allowing for rapid screening
PPh2
PPh2 Cu(OAc)2 Cu(OTf)2
O Fe
PPh2 dppb (n=4): 64% dppb (n=4): 64% PPh2
Ph2P PPh2 PPh2 PPh2
( )n
dpppent (n=5): 67% dpppent (n=5): 81%
DPEPhos: 57% dppf
dpphex (n=6): 57% dpphex (n=6): 65%
(rac)-BINAP
Cu(OAc)2: 19% Cu(OAc)2: 65%
Cu(OAc)2: 53%
Cu(OTf)2: 46% Cu(OTf)2: 72%
Cu(OTf)2: 60%
b) c)
Me visible light Me visible light
O N O O N O
+ then + then
N N Cu(OTf)2 (10 mol%) N N Cu(OTf)2 (10 mol%)
NUR NUR
naphthalene (54) MTAD (50) dppf (20 mol%) benzene (49) MTAD (50) dppf (20 mol%)
PhMgBr, CH2Cl2 53 PhMgBr, CH2Cl2 55
d) e)
Me visible light Me visible light
N O N O
O O then then
+ +
Ni(cod)2 (10 mol%) N N Ni(cod)2 (10 mol%)
N N NUR
dppf (20 mol%) NUR dppf (20 mol%)
naphthalene (54) MTAD (50) benzene (49) MTAD (50)
PhMgBr, CH2Cl2 53 PhMgBr, CH2Cl2 55
FIGURE 1.5 (A) Development of the copper-catalyzed dearomative carboamination. (B) Testing of the copper conditions on in situegenerated 52. (C) Testing of
the copper conditions with benzene as substrate. (D) Discovery of the nickel-catalyzed dearomative carboamination conditions. (E) Application of the nickel
conditions with benzene as substrate.
were delighted to find whether the reaction was now proceeding in a syn-
thetically useful 72% isolated yield of 55.
2.3 Mechanistic hypothesis

One thing that must be noted is that in this nickel-catalyzed transformation, as
in the case for copper, we observed only one constitutional isomer as well as
diastereoisomer. While not proven, the argument could perhaps be made in the
copper-catalyzed variant that a carbocupration event occurred followed by
b-elimination.86 This could easily explain the 1,2-selectivity in that case.
However, for the nickel-catalyzed reaction, this is no longer a valid
mechanism. Thus, we were left with exclusive 1,2-trans selectivity and no
explanation. After a careful search of the literature, we found many examples
of iron and chromium (as well as numerous other transition metals) stoi-
chiometric h5-complexes that, upon reaction with nucleophiles or electro-
philes, would also give exclusive 1,2-trans selectivity (Fig. 1.6).87 In our
system, this explained not only the selectivity but also increase in yield be-
tween naphthalene (53) and benzene (49) as substrates. For the case of 53, the
h5-complex would require nickel to bind the p-bond of the aromatic system,
whereas for 49, an h5-complex bound only to olefins would be formed thereby
increasing stability of the reactive species.
Interestingly, in the case of stoichiometric chromium complexes, a number
of methods were described to generate these 1,2-trans products asymmetri-
cally (Fig. 1.6A). One major drawback of this chemistry is that the stoichio-
metric use of chiral auxiliaries and ligands was necessary to afford
enantioinduction. On the other hand, while racemic, the generation of cyclo-
hexadienyl iron complexes can be achieved from a diene starting material 56
rather than arene (Fig. 1.6B). Hydride abstraction by a trityl cation then
generates the complex 57, which can undergo nucleophilic addition on the
opposite face to that of the iron. In each of these cases, the products with
exclusive 1,2-selectivity are formed, as the greatest localization of charge
resides at the termini of the cyclohexadienyl system. Fig. 1.6C describes some
of the transition metals that have been reported to form cyclohexadienyl
complexes and their typical nucleophiles. Based on this previous body of
literature, and our exclusive 1,2-trans selectivity, we have proposed in our
mechanism that nickel catalytically generates this cyclohexadienyl complex
(Fig. 1.6D). Upon generation of the benzene-MTAD cycloadduct (51), nickel
can coordinate to the two olefins (VI) allowing for oxidative addition to
generate cyclohexadienyl nickel complex VII. Upon transmetalation and
subsequent inner-sphere reductive elimination to form p-complexed nickel
species IX, the nickel is then regenerated, and product 55 is formed.
Furthermore, at this point, we were keenly aware that our overarching goal of
a) R* b) 1. Fe(CO)5 1. Nu
R'
2. Ph3C d+ 2. Oxidant
R

(CO)3Fe d+ Nu
Cr(CO)3 Cr(CO)3
56 57 58
I R'Li/R''X R'Li/R''X II
c)
Arene bound Planar chiral
R' transition metals capable of forming typical nucleophiles:
chiral auxiliary arene complexes
R'' cyclohexadienyl complexes: OH-, H-, OMe-, CN-, acac-, Me-, OAc-,
R* or R Fe, Os, Cr, Ru, Mn, V, Re [TM] R2Zn, R2NH
d)
R'Li/R''X V R'Li/L*/R''X Me
O N O O
R [4+2] N [Ni]n
+
N N N NMe
visible PhMgBr
benzene (49) MTAD (50)
light O NUR
Cr(CO)2L*
III IV Cr(CO)3 benzene-MTAD 55
Chromium coordinated Chiral nucleophile cycloadduct (51)
chiral ligand
p-decomplexation p-complexation
[Ni]0 [Ni]0
[Ni]0
Mg O
N N
N O N NMe
Ph NMe
O
IX VI O
plane of symmetry Ph
reductive NUR oxidative

elimination d+ 55 [Ni]2 addition
[Ni]2 Mg
N
N N O
N
Ph d+ O
VIII VII NMe
NMe transmetalation O
O PhMgBr
FIGURE 1.6 (A) Methods for enantioselective synthesis of 1,2-trans products utilizing stoichiometric chromium complexes. (B) Generation and reactivity of
stoichiometric iron cyclohexadienyl cation complexes. (C) Transition metals capable of forming cyclohexadienyl complexes and their typical nucleophiles. (D)
Proposed method for the nickel-catalyzed dearomative trans-carboamination proceeding through a cyclohexadienyl complex.
an enantioselective total synthesis was within reach, as intermediates VII and

VIII have a plane of symmetry and are amenable for desymmetrization.
2.4 Optimization of our new nickel-catalyzed conditions

With the proof of concept for enantioinduction, we immediately set out to
achieve this goal as it would not only enable an asymmetric synthesis but also
be (to the best of our knowledge) the first catalytic desymmetrization of
benzene reported.
While our end goal was the development of the enantioselective method,
we wanted to ensure we had optimal conditions for the racemic reaction in
case we were unsuccessful, as well as begin work on our synthesis (Fig. 1.7).
Starting with our dppf result, we screened other achiral ligands such as
xantphos, DPEphos, and alkyl bis-phosphines with the benzodioxole-
containing Grignard reagent 48. However, none of the other ligands we
tested were able to compete with dppf. Having verified that we had optimal
racemic conditions, we then set forth to make the reaction enantioselective.
The first chiral ligand we tested was (S,S)-BDPP, which gave us a 27% yield
and an astounding 90:10 er of desired carboaminated product 47. We were
greatly heartened by this result as it verified our hypothesis of asymmetric
induction and led us to believe we could improve the yield and enantiose-
lectivity further. However, this class of ligands leaves little room for variation
and optimization, so we decided to continue our ligand screen and test for
alternatives.
The PHOX class of ligands is well known for use in allylic substitution
reactions, giving high yields and enantioselectivities. Another attractive
feature of this scaffold is that it allows for the rapid diversification through the
installation of different amino alcohols. We were slightly disappointed to find
that with (S)-tBu-PHOX, the yield remained consistent, and the enantiose-
lectivity dropped appreciably. Yet, we came across a report from Uemura and
coworkers where they directly compared the use of PHOX ligands with a
similar class, Phosferrox, where the benzene ring was replaced with ferro-
cene.88 They found a remarkable improvement in enantioselectivity when
utilizing the Phosferrox ligands, and this led us to test these as our third
scaffold as it also contains the benefits previously described. We decided to
first synthesize and test their optimal ligand, the valine-derived iPr-Phosferrox
ligand, and were astounded to find that our yield improved to 75% and
enantioselectivity to 98:2. This was the first real breakthrough moment for the
project, as we had now an excellent method for the synthesis of our key diene
starting material with high enantioselectivity. Moreover, we also synthesized
and tested a series of other Phosferrox ligands, but none of them outcompeted
the initial result. Finally, to ensure we had the optimal ligand for the trans-
formation, we tested a series of traditional commercially available chiral li-
gands with no improvements.
Me visible light
N then O
O O
+ Ni(cod)2 (10 mol%)
N N O N O
ligand (20 mol%) HN
benzene (49) MTAD (50) MgBr
O NMe
O
O 48
47
CH2Cl2
achiral ligands
dppe (n=2): 55%
dppp (n=3): 24% PPh2
Ph2P PPh2 Fe
O O ( )n dppb (n=4): 14% PPh2
PPh2 PPh2 PPh2 PPh2 dpppent (n=5): 17%
dpphex (n=6): 45%
xantphos: 21% DPEPhos: 57% dppf: 74%
chiral ligands
PPh2
PPh2 PPh2 N
O R PPh2
R = Bn (59%, 95:5 er)
Me Me Ph2P N Fe O PPh2
R = iPr (75%, 98:2 er)
(S,S)-BDPP tBu R = tBu (26%, 85:15 er)
27% (90:10 er) (S)-tBu-PHOX
30% (66:34 er) (R,Rp)-Phosferrox-type ligands (S)-BINAP
O 11% (63:37 er)
H
O N
PPh2 MeO PPh2
O PPh2 P PPh2 PPh2
P H
O OMe
(S,S)-NORPHOS
(S)-SEGPHOS (S,S)-DIPAMP (S)-QUINAP
65% (68:32 er)
27% (62:38 er) no reaction no reaction
FIGURE 1.7 Ligand screen for the nickel-catalyzed dearomative carboamination reaction.
3. Pancratistatins
3.1 Initial investigations
With access to our key diene 47 from our retrosynthetic analysis, we were now
able to study the reactivity of the system (Scheme 1.5). While we had hy-
potheses as to how the olefins would react, we could still not be certain about
the stereo- and chemoselectivity. The urazole moiety is inductively with-
drawing, making the adjacent olefin more electron deficient. Therefore, we
believed that the distal olefin would be the first to undergo electrophilic attack.
Furthermore, the aryl ring is sterically demanding, so we believed that the
reagent would approach from the opposite face. Finally, FürstePlattner
analysis revealed that regardless of the diastereomer formed in the epoxidation
reaction, we could still access the correct relative stereochemistry of the
cyclitol core.
Based on this analysis, we subjected diene 47 to epoxidation conditions
with mCPBA and found an intriguing bicyclic product 59, which we verified
by X-ray crystallography. This outcome confirmed our hypothesis about the
urazole moiety: the hydrazyl proton was acidic enough to direct epoxidation
with mCPBA in a manner like that of an allylic amide NeH. We believed that
this product could have formed in one of two ways. After directed epoxidation,
the epoxide could either be opened by TsOH, followed by an SN2 reaction, or
the formation of the allyl cation and ring closure. Either way, we knew this
product would not lead to the desired natural product, and we opted to mask
this acidic proton with a methyl group.
Our conditions for methylation turned out to be crucial as the diene 47 was
unstable to basic conditions, and if our base was fully soluble, we only ob-
tained an undesired biaryl that resulted from elimination of the urazole. We
found that the use of CH2Cl2 in combination with potassium carbonate and
methyl iodide led to quantitative formation of methylated diene product 60. At
this time, we were confident that if we performed the halohydrin reaction on
the system, we could not only form the desired bromohydrin but also
brominate the aromatic ring. This would give us a key functional handle
further in the synthesis that we could exploit to form the lactam. Upon
exposure of 60 to traditional halohydrin conditions, we formed dibromide 61
in 90% yield. Interestingly, we found that the bromide in fact approached from
the top face of the diene, leading to the unexpected diastereomer.
We first attempted to close the epoxide from bromohydrin 61 but observed
no reaction. Using more forcing conditions led only to decomposition, and we
were left with no choice but to move forward and hope to close the epoxide
later. When bromohydrin 61 was subjected to traditional Upjohn dihydrox-
ylation conditions, we observed partial conversion to bromotriol 62 (Scheme
1.6). This was mainly due to the insolubility of 61 in the reaction conditions.
After some optimization, we found that with the addition of acetone for
O
O H
OH O O
mCPBA, pTSOH MeI, K2CO3
N CH2Cl2 O N O CH2Cl2 O N O
N O HN MeN
37% NMe quant. NMe
NMe
59 O 47 O 60 O
OTs
NBS
O 79%
OH THF, H2O
O N O
HN
OH
NMe
Br
O Br
O N
O O O MeN O
OH
O NMe
O N O O N O
HN HN O
NMe NMe 61
O O
SCHEME 1.5 First empirical investigation of diene reactivity involving the formation of 59 through directed epoxidation/ring opening. Then observation of the
facial selectivity in employment of traditional halohydrin reaction conditions.
OH OH OH
Br OsO4 (5 mol%), Br OH HO OH
Br Br Br
NBS citric acid, NMO NaOBz
OH OH
H2O, THF N O
H2O, tBuOH N O H2 N O
O MeN acetone O MeN O MeN
79% O O 45% O
NMe NMe NMe
91%

O O O
61 62 63
O N O
MeN
NMe
60 O
OH OH
O
HO HO OH
OsO4 (5 mol%),
mCPBA O NaOBz O NMO O OH
NaHCO3, CH2Cl2 O N O H2 O N H2O, tBuOH O N O
MeN MeN O MeN
68% NMe 93% 91% NMe
NMe
O O O
64 65 66
SCHEME 1.6 Divergent reactivity of diene 60 leading to cyclitols 63 and 66.
23
solubility and citric acid to accelerate the reaction,89 we could obtain 62 in

91% yield. Upon heating the bromotriol in the presence of sodium benzoate at
100 C for 1 week,40 we could obtain the cyclitol core of the natural product
63 in 45% yield, with the remainder of the mass balance being the interme-
diary epoxide. While these studies were under way, we also investigated the
other diastereomer of the epoxide. Exposure of diene 60 to mCPBA gave the
now empirically expected epoxide diastereomer 64 in 68% yield. The
remainder of the mass balance was ring-opening of the epoxide from the
benzoate by-product, which we wanted to address eventually. Upon heating the
vinyl epoxide in the presence of catalytic sodium benzoate, we obtained trans-
diol 65 in 93% yield. The diastereomer observed was expected as harder
nucleophiles, like oxygen-based benzoate, are known to attack at the allylic
position in these types of systems.90 In this case, Upjohn dihydroxylation
proceeded without issue to give the cyclitol 66 in 91% yield without modifi-
cation. As we were able to access significantly larger quantities of 66 over 63,
we decided to perform our further studies on 66 and return to 63 later.
We first began our investigation of the urazole cleavage in tetraol 66 by
subjecting the compound to multiple basic conditions (Scheme 1.7). Many
bases, solvents, temperatures, and even combinations of cleavage and further
functionalization came to no avail. We could synthesize semicarbazide 67
efficiently in most cases, but with more forcing conditions, we only observed
decomposition. Unfortunately, 67 proved to be resistant to reductive, oxidative,
basic, and acidic conditions alike, each time only providing recovered starting
material. We then decided to examine reductive conditions and found that in
most cases, we observed no reactivity or decomposition. Interestingly, upon
exposure to the combination of DIBAL and n-BuLi, a single bond was severed,
leading to formamide 69 (verified by X-ray, not shown). When we had employed
LiAlH4 before in more moderate equivalents (ca. 4.0 equiv), we observed no
reaction. However, we found that upon exposure to excess equivalents (20
equiv) and heating, we were able to form cyclic hydrazine hemiaminal 70 in
68% yield. Much to our chagrin, upon standing on the bench for a few hours, we
found that full autooxidation of the hemiaminal methylene occurred giving
carbamate 71. We knew at this point that if we were to further cleave the NeN
bond, we would need to perform this in a single pot. Intriguingly, when sub-
jecting bromotetraol 63 to the LiAlH4 conditions, we also observed the hemi-
aminal with concomitant cleavage of the AreBr bond giving the same 70.
3.2 Optimizing the route

When considering the epoxidation of diene 60, we believed the system was
perfectly set up for a one-pot trans-dihydroxylation as we were observing
opening of the resultant vinyl epoxide with the benzoate. Thus, we set out to
develop this reaction into a one-pot procedure, first beginning with Prévost
reaction conditions (Fig. 1.8A). However, we were disappointed to find that we
OH OH
HO OH HO OH
basic conditions O various conditons O
OH OH
>90% yield O N O O NH
in all cases MeHN MeHN
MeHN
67 68
OH

OH OH
HO OH
HO OH HO OH
LiAlH4 upon standing
O OH O O O O
THF
O N O
MeN 68% O HN O HN
N N O
NMe other hydrides led
O to no reaction or 70 LiAlH4, THF 71
66 decomposition
OH
OH
HO OH 71%
HO OH
Br
DIBAL, nBuLi O OH
OH
THF O N O
MeHN N O
60% O MeN
NMe O NMe
O O
69 63
SCHEME 1.7 Investigation of the urazole cleavage in tetraol 66, leading to the discovery of cyclic hydrazine hemiaminal 70.
25
a) OH OH
HO HO
AgOBz, I2 O mCPBA, TsOH
O O
O N O
O N MeN CH2Cl2, HFIP, H2O O N
MeN O MeN O
NMe 74%
NMe O NMe
O O
72 60 65
b) c)
H
O H
CF3 O
H H H
F3C O H O
O H O HO O
O O O
H O O H
R O HO O
H H H
H H O H
73 H O 74
H
FIGURE 1.8 (A) One-pot dihydroxylation attempt using Prévost reaction, followed by success with HFIP. (B) Explanation for HFIP-mediated rate acceleration
for olefin epoxidation. (C) Jamison’s explanation of how HFIP can stabilize hydrogen bonding interactions of water molecules with the substrate. HFIP,
1,1,1,3,3,3-hexafluoro-2-propanol.
observed no reaction. We then decided to optimize the reaction we were

already employing and see if we could open the epoxide with water instead of
benzoate. We eventually found that the solvent HFIP can play a key role in not
only epoxidation reactions, but also epoxide-opening. For example, in a
computational study by Berkessel and coworkers to explain the rate
enhancement of fluorinated solvents for olefin epoxidation with H2O2, it was
found that HFIP can activate the reagent similarly to the intramolecular
activation observed with peracids (Fig. 1.8B).91 Furthermore, Jamison and
coworkers described the dramatic rate acceleration of epoxides in water and
HFIP due to the preorganization of the substrate due to hydrogen bonding
networks (Fig. 1.8C).92 This led us to the conclusion that the inclusion of HFIP
would dramatically increase the epoxide formation and hydrolysis in our
transformation. To our delight, upon attempting this reaction under acidic
conditions with TsOH as a catalyst, we found that we could achieve the trans-
diol 65 in 74% yield in a single operation.
With the issue of autooxidation of cyclic hydrazine hemiaminal 70, we
knew we needed the subsequent cleavage to the amine to be a one-pot pro-
cedure (Scheme 1.8A). Our first roadblock came in the practical form of the
reaction quench. As we were planning to perform the subsequent reduction in
the same flask, we needed the solution to be tolerant of any catalyst or con-
ditions we were about to employ. Fortunately, we found that both the alkaline
and Rochelle salt quenches gave us free-stirring slurries that allowed for the
testing of subsequent chemistry. Unfortunately, Glauber’s salt did not give
satisfactory results as it often required significantly longer stir times to fully
quench the reaction, leading to the eventual autooxidation of the intermediate.
Furthermore, 1M HCl led to full decomposition when tested and was deemed
to be incompatible in this case. With two potential quenches for the first phase
of the reaction, we could now set forth to test reductive conditions to cleave
the hydrazine NeN bond. All but a single hydrogenolysis condition failed to
perform the desired cleavage. Adam’s catalyst as well as palladium and
several doped platinum catalysts failed in this reaction. With both quenches,
we found that Raney-Ni gave thick slurries that would not stir well and did not
lead to any product. However, we eventually found that its counterpart,
Raney-Co, could achieve this transformation when saturated aqueous
Rochelle salt was used as the quench for the LiAlH4 reaction giving amino-
tetraol 45 in 60% yield.93
3.3 Methods for lactam formation

Though at this point we were relieved as we knew we could achieve the
synthesis of the natural product 7-deoxypancratistatin (1) in just a few oper-
ations, we implemented the proven strategy involving protection with subse-
quent BischlereNapieralski reaction to close the lactam (Scheme 1.8B).
a) OH
OH
HO OH OH
HO OH Failed hydrogenolysis conditions:
HO OH
O LiAlH4 Raney Co, H2 - PtO2 - Pd/C - Pt(S)/C
OH O - Pt(V)/C - Raney Ni
THF O 60% O
O N OH
MeN O HN Failed reductive conditions:
quench with O N NH2
O - AlH3 - BH3 - Zn/AcOH
NMe sat. aq.
O - Ni(acac)2 - Co(acac)2
66 Rochelle salt 70 45
Other quenches tested:
- Na2SO4 2O HMTA,
- Alkaline quench - 1N HCl TFA, AcOH 95%
OH OH
Pinnick-Lindgren oxidation was HO OH HO OH
Failed formylation conditions:
irreproducible NaClO2, NaH2PO4 - Zn(CN)2/HCl - CH(OMe)3
O OH O OH
2-methyl-2-butene - Cl2CHOMe/ZnBr2
Other oxidation conditions tested: NH N - MeNO2/PPA
- KI/TBHP - H2O2 - MnO2 O THF, H2O O
- KHSO5 - AgNO3 - TEMPO O 57%
7-deoxypancratistatin (1) 76
b)
OH
OH OAc
HO OH
HO OH AcO OAc
Boc2O, Et3N Ph3P(O), Tf2O
O OH
O OH 1,4-dioxane, H2O; O OAc BF3 2O, CH2Cl2;
then Ac2O then NaOMe, MeOH O NH
O NH2 O NHBoc
76% 75% O
45 75 7-deoxypancratistatin (1)
SCHEME 1.8 (A) Completion of the first-generation synthesis of 7-deoxypancratistatin (1) through the use of the Duff formylation and the PinnickeLindgren
oxidation. (B) Fail-safe strategy involving the BischlereNapieralski reaction to close the lactam.
In practice, we could Boc protect the amine followed by acetylation of the

cyclitol core to give the fully protected carbamate 75 in 76% yield. We could
then employ Hendrickson’s reagent to perform the BischlereNapieralski
reaction which closed the desired lactam in 75% yield to provide, after
deprotection, 7-deoxypancratistatin (1).94
However, our goal in performing this total synthesis was not to employ the
tried and true methods previously reported in the literature. Instead, it was to
innovate new chemistry for the synthesis of these natural products to allow for
a concise and scalable approach. We knew the difficulty in closing this lactam
resided in the fact that the cyclitol core contained four free alcohols that would
preclude many methods for the synthesis of lactams (vide infra). We realized
that formylation of aromatic rings could be performed in protic solvents,
thereby making it possible for us to perform this transformation without
having to mask any functionalities. Many conditions were tested for the for-
mylation of the aromatic ring, but only Duff formylation conditions gave the
desired dihydroisoquinoline product 76 in an excellent 95% yield.
All that remained to achieve our goal was to oxidize the dihy-
droisoquinoline to the desired lactam. We were fortunate to find that just such
a method existed in the literature95 and found that in our case we obtained
7-deoxypancratistatin (1) in 57% yield by employing the PinnickeLindgren
oxidation. Unfortunately, we found that this oxidation was often irreproducible
and gave inconsistent yields. Furthermore, the reaction often required kicker
charges of base and oxidant, eventually leading to the use of 100 equivalents of
NaClO2. We then tested numerous methods for the oxidation of the dihy-
droisoquinoline, but to no avail. At this point, we knew that this would not be a
sustainable approach toward these natural products and elected to investigate
new methods for the formation of the lactam.
As we were reconsidering alternatives for closure of the lactam, we knew
we would be facing the same challenges as before. We needed to find a method
to close the lactam without having to protect the cyclitol core (Scheme 1.9).
While we were unable to retain the aryl bromide, we installed using the hal-
ohydrin reaction, and we found that the same bromide could be introduced by
employing Br2 in AcOH to furnish brominated amine 77. With this functional
handle in place, we could begin investigating different catalytic methods to
complete the natural product. As we hypothesized, and quickly verified, we
found that traditional carbonylative conditions employing palladium led to
either recovered starting material or the generation of complex mixtures of
oxidation byproducts of the cyclitol core. Aromatic cyanation, such as the
Rosenmundvon Braun reaction resulted in no reactivity observed. We
eventually found an interesting report by Caubere and coworkers that
described the use of cobalt carbonyl under phase transfer catalysis (PTC) with
UV irradiation to form lactams.96 In their report, they employed a biphasic
Pd/CO
Various oxidation
byproducts
expected reaction
OH OH
OH OH
HO OH HO OH
HO OH HO OH
Br2 Co2(CO)8, n-Bu4NBr CO2H
O OH
O AcOH O OH
OH OH 5N NaOH, PhH
O NH NH2
NH2 90% NH2 CO, hn (365 nm)
O O Br O
O
O
45 77 7-deoxypancratistatin (1) 78
25% 60%
NaCo(CO)4, n-Bu4NBr
dioxane:NaHCO3 (aq.)
CO, hn
80%
CuCN; Pd/Zn(CN)2
SCHEME 1.9 Development of alternative and more scalable conditions for lactam formation to provide 7-deoxypancratistatin (1).
reaction system with 5N NaOH and benzene as solvents. The role of the base
was to activate the cobalt carbonyl, as well as maintain alkaline conditions
during the reaction as HBr was the major by-product. Fortuitously for them,
they found that the lactam would form in the aqueous phase and, upon closure,
would be sequestered in the organic phase. When we employed these condi-
tions in our system, we were gratified to find we could isolate
7-deoxypancratistatin (1) in 25% yield. Interestingly, we found that the
remainder of the mass balance resided in the amino acid 78 which likely
resulted by hydrolysis of the lactam of the natural product.
When considering the issue of lactam hydrolysis, we knew the major factor
was the use of 5N NaOH. Furthermore, as our UV lamps became warm during
the reaction, we noticed that the solution would also heat from their proximity,
potentially increasing the rate of hydrolysis. Therefore, we knew we needed to
obviate the need for such strongly alkaline conditions. Based on Caubere’s
report, the main purpose of the base was to convert Co2(CO)8 to the active
catalyst NaCo(CO)4. We hypothesized that if we could prepare and employ
NaCo(CO)4, then perhaps we could remove the strong base and utilize sodium
bicarbonate instead, potentially reducing the amount of hydrolyzed lactam.
After some optimization, we found this to be the case and obtained
7-deoxypancratistatin (1) in 80% yield and did not observe the amino acid by-
product.
3.4 C-7 oxidation and final route

Upon finally achieving the total synthesis of 7-deoxypancratistatin (1) in a
concise and scalable fashion, we set our sights on the next goal: the
oxidation of the C-7 position to directly prepare pancratistatin (2). In the
decades of work that went into the previous total syntheses of the Amar-
yllidaceae isocarbostyril alkaloids, there had never been a direct oxidation at
the C-7 position. Instead, one would repeat the previous synthesis anew with
an aryl ether functionality preinstalled at the C-7 position and hope any
subsequent chemistry would not be inhibited by the new addition
(Fig. 1.9).56,57
We knew that we would be unable to perform any kind of metalation of the
C-7 position in the presence of the cyclitol core, despite our previous efforts to
close the lactam in just such a manner. We elected to install TMS protecting
groups in situ and perform the subsequent metalation/oxidation sequence with
an acidic workup to furnish pancratistatin (2). During our studies, the main
silylation reagent we employed was N,O-bis(trimethylsilyl)trifluoroacetamide
(BSTFA), as the by-products from the silylation reaction were reported to be
volatile.97 Thus, we believed such impurities could be azeotropically removed
and allow for the subsequent metalation to occur.
OH OH
HO OH HO OH Silylation reagents tested:
silylation; HMDS/I2, TMSCl, TMSCN, TMSN3,
O OH O OH
conditions N,O-bis(trimethylsilyl)acetamide (BSA)
O NH O NH N-methyl-N-trimethylsilylacetamide (MSA)
O OH O N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA)
N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA)
7-deoxypancratistatin (1) pancratistatin (2)
C-H borylation Directed ortho-lithiation Deprotonative metalation

1/2[Ir(OMe)(COD)]2 tBuLi, sBuLi, nBuLi Mg(TMP)2 Al(TMP)3 LiCl Mn(TMP)2 MgCl2 LiCl
[Ir(COD)Cl]2
B2Pin2, HBPin
B2Pin2, bpy then Fe(TMP)2 MgCl2 LiCl Zn(TMP)2 MgCl2 LiCl
N-N ligands
1/2[Ir(OMe)(COD)]2 B(O Pr)3, then [Ox.] Li(TMP)Al(iBu)3 Li(TMP)Zn(tBu)2 (TMP)2Cu(CN)Li2
B2Pin2, P(3,5-2F3C-C6H3)3
FIGURE 1.9 Conditions tested to metalate/oxidize the C-7 position of 7-deoxypancratistatin (1).
We tested numerous conditions for metalation of the C-7 position,

including CeH borylation, directed ortho-lithiation, and deprotonative met-
alation, but none were successful. Eventually, we found a report by Uchiyama
and coworkers in 2016 that described a new reagent (TMP)2Cu(CN)Li2 for
directed ortho-cupration.98 The resultant aryl cuprate could then be oxidized
by employing tert-butyl hydroperoxide (TBHP). We were delighted to find that
we could achieve partial conversion of 7-deoxypancratistatin (1) to pan-
cratistatin (2). To our dismay, this reaction turned out to be irreproducible and,
on many occasions, would not work for weeks, thereby consuming much
precious material. We then began a methodical investigation to determine
which reagent was preventing the reaction from occurring, but this did not
solve our reproducibility issues. With little success in this approach, we
eventually decided to look elsewhere and hypothesized that the BSTFA could
be at fault. Perhaps the volatile by-products of the silylation were not as
volatile as the literature led us to believe. After performing the silylation and
subsequent azeotrope, we observed by 19F NMR three species that we hy-
pothesized to be the bis-, mono-, and nonsilylated reagent. Having confirmed
our hypothesis, we then set out to identify a new silylation system that would
allow for the cupration/oxidation sequence to occur without issue. After
testing many reagents, we eventually found that HMDS/I2 was uniquely suited
to our task. The only by-products of the reaction were HMDS and ammonia,
which were both volatile enough to be removed by azeotropic distillation.
Gratifyingly, upon employing these conditions for silylation, we obtained
pancratistatin (2) in 62% yield after cupration/oxidation. Furthermore, we
found these conditions to be reproducible.
Putting all the pieces together, our final optimized synthesis of the pan-
cratistatins is depicted in Scheme 1.10. Our overall yields for
7-deoxypancratistatin (1) and pancratistatin (2) were 19% and 12%, respec-
tively. Throughout the course of our studies, we prepared >300 g of diene 60
and produced around 10 g of 7-deoxypancratistatin (1). While we were
delighted to have completed these natural products, we knew there were still
two in the class we had not achieved. We then set our sights on a scalable
synthesis of lycoricidine (3) and narciclasine (4).
4. Narciclasine and lycoricidine

4.1 Optimization of Ni(II) conditions
Upon completion of the synthesis of the pancratistatins, we knew that further
studies would be inhibited by the prohibitive cost of the Ni(cod)2 on scale, as
well as the high loadings of both nickel and ligand. Therefore, we opted to
readdress these conditions, and perhaps seek new Ni(II) sources as catalyst
Me
O N O
OH OH
N N HO
MTAD (50) HO OH
visible light mCPBA, TsOH OsO4, NMO
O O O OH
Ni(cod)2 (5 mol%) CH2Cl2:HFIP:H2O t-BuOH, H2O
O NUR O NUR NUR
benzene (49) (R,Rp)-iPr-phosferrox (10 mol%) O
74% 91%
60 65 66
quench with Me2SO4 O
65%, 98:2 er MgBr LiAlH4
N O
NUR = NMe ArMgBr = then 60%
53 mmol scale MeN
>10 g in a single batch O Raney Co, H2
O 48
>300 g produced
OH OH
HO OH HO OH OH
HMDS, I2 HO OH
1. Br2, AcOH
O OH then O OH
(TMP)2Cu(CN)Li2, t-BuOOH 2. NaCo(CO)4, nBu4NBr O OH
O NH O NH
62% CO, hn (365 nm) NH2
O
OH O 12% overall O 72% for two steps
(+)-pancratistatin (2) (+)-7-deoxypancratistatin (1) 19% overall 45
2g in a single pass
~10g produced
SCHEME 1.10 Final optimized synthesis of the pancratistatins.

precursors for the transformation as they would be inexpensive and easier to use
due to their air stability (Table 1.2).99 One of our first goals was to reduce the
ratio of nickel to ligand, as well as lower the catalyst loading (entries 1e3). We
found that lowering the nickel loading to 5.0 mol%, as well as the ligand to
TABLE 1.2 Optimization studies for Ni(II)-catalyzed carboamination.a
Me
O N O
N N
MTAD (50)
visible light
[Ni] (x mol%)
NUR
benzene (49) (R,Rp)-iPr-phosferrox (y mol%)
55
Entry Grignard [Ni] x (mol%) y (mol%) Yield %b erc

equiv.
1d 3.0 Ni(cod)2 10.0 20.0 70 95:5
2d 3.0 Ni(cod)2 5.00 10.0 67 95:5
3d 3.0 Ni(cod)2 5.00 7.00 67 94.5:5.5

4 3.0 Ni(cod)2 5.00 7.00 63 96.5:3.5
5 2.0 Ni(cod)2 5.00 7.00 67 94:6
6 1.5 Ni(cod)2 5.00 7.00 56 93:7
7 3.0 NiCl2 10.0 20.0 42 90:10
8 3.0 Ni(dmg)2 10.0 20.0 51 90:10
9 3.0 Ni(acac)2 10.0 20.0 59 93:7

10 3.0 NiBr2lglyme 10.0 20.0 55 93:7
11 3.0 NiCl2lglyme 10.0 20.0 55 91:9
12 3.0 Ni(acac)2 10.0 12.0 51 95:5
13 2.5 Ni(acac)2 5.00 7.00 65 95:5
14 2.5 Ni(acac)2 2.50 3.50 66 97:3
15 2.5 Ni(acac)2 1.50 2.00 70 97:3

16 2.5 Ni(acac)2 1.25 1.75 71 98:2
17 2.5 Ni(acac)2 1.00 1.40 68 96.5:3.5

a
Standard reaction conditions: MTAD (50, 0.5 mmol, 1.0 equiv), benzene (49, 5.0 mmol, 10 equiv),
CH2Cl2 (0.20 M), visible light, 78 C, 12 h; then PhMgBr (3 M in THF, 1.25 mmol, 2.5 equiv.), solution
of catalyst [Ni precursor (x mol %), (R,Rp)-i-Pr-Phosferrox (y mol %), CH2Cl2], 45 C to rt, 3 h.
b
Isolated yield of pure 55 after purification by flash chromatography.
c
Determined using HPLC analysis.
d
Reaction concentration (0.05 M).
7.0 mol%, had minimal impact on yield and enantiomeric ratio. We found that
concentrating the reaction (entry 4) gave a lower yield, but higher er. We then
tested to see if 3.0 equivalents of our Grignard reagent were necessary (entries
4e6). Interestingly, lowering the Grignard equivalents impacted the yield and
enantioselectivity, but we found this to still be in the acceptable range. We then
tested a series of Ni(II) sources (entries 7e11) and found that many sources
could be employed in this transformation. However, Ni(acac)2 (entry 9) gave us
the highest yield and enantioselectivity out of the series tested. We then began
to lower the nickel loading, as well as Ni:ligand ratio (entries 12e17). Notably,
we found that as we lowered the catalyst loading, as well as Ni:ligand, a marked
increase in yield and er was observed. We eventually decided on the conditions
in entry 15, which we found to be the most practical and reproducible.
4.2 Initial synthesis of narciclasine

With the synthesis of the pancratistatins completed, and the improved,
glovebox-free dearomative trans-1,2-carboamination conditions, our focus
turned toward the synthesis of the remaining congeners (þ)-lycoricidine (3)
and (þ)-narciclasine (4).100 Since these conditions could provide >20 g of
diene 60 in a single batch, we wanted our approach toward 3 and 4 to be highly
scalable and operationally simple. Seeing as how many of the hurdles we faced
during the synthesis of the pancratistatins centered around the formation of the
lactam, we wanted to approach its construction from a different angle. Before,
our strategy was to remove the urazole ring through exhaustive reduction and
then perform carbonylative coupling with the free amine and an aryl bromide;
however, the urazole ring itself contains a carbonyl group that could poten-
tially be utilized in the formation of the lactam. With this proposed strategy in
mind, 3 and 4 were retrosynthetically traced back to compound 46 (Scheme
1.3). The aryl bromide could be a viable handle for nucleophilic addition of the
aryl ring into the urazole, and the epoxide could undergo isomerization to
provide the corresponding allylic alcohol. We were particularly interested in
this intermediate, as it could be readily derived from diene 47 as observed in
our early investigations with this intermediate.
Wanting to initially synthesize the more potent natural product, we
commenced our studies toward (þ)-narciclasine (4) by using Grignard 79 in
our dearomative trans-1,2-carboamination reaction (Scheme 1.11). The use of
a more functionalized aryl nucleophile provided no issues and led to diene 80
in 66% yield and 97:3 er. Utilizing the halohydrin conditions discovered while
investigating the reactivity of the diene, we were able to furnish bromohydrin
81 in 85% yield. From here only, a few manipulations were required to furnish
the intermediate needed to test our new lactam closing strategy. Upjohn
dihydroxylation of bromohydrin 81 followed by basic workup (K2CO3),
served to install the remaining syn-diol and close the bromohydrin to form
epoxy diol 82. Similarly to 61, we found that closure of the bromohydrin in 81
Me
O N O
OH
N N Br
MTAD (50)
visible light O NBS, H2O OsO4, NMO;
O
Ni(cod)2 (1.5 mol%) 85% then K2CO3
O NUR O NUR
benzene (49) (R,Rp)-iPr-phosferrox (2 mol%) Br
ArMgBr (79 OMe OMe
quench with Me2SO4 81
80 O
66%, 97:3 er MgBr OH
[glovebox-free protocol] O
ArMgBr =
O OH
O
OMe O NUR
Br
79 OMe
OH OH 82
OH O
O O
O OH SmI2 O O t-BuLi O O TsOH, 2,2-DMP
NH quench with N 65% 77% for two steps
O O O NUR
HCl NMe Br
OH O 89% OMe O OMe
O NHMe
(+)-narciclasine (4) 85 83
SCHEME 1.11 Synthesis of (þ)-narciclasine (4).

37
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Canada. Thus, in the event of war breaking out, the King’s
magazines would be kept secure, the northern colonies would be
separated from the southern, and delay in transport Carleton’s policy:
and difficulty of communication, so dangerous, (1) adequate
defences and
especially in the early stages of a war, would be garrisons: (2)
averted. In the years which preceded the War of attachment of the
Canadians to the
American Independence, Carleton had constantly in British Crown
especially by giving
view the twofold contingency of war with France and them employment
war with the British colonies in America; and there under the
government.
were two cardinal points in his policy, which he never
ceased to impress upon the Home Government, on the one hand the
necessity for adequate military forces, and adequate forts in
America, on the other the necessity for taking such steps as would
attach the Canadians to the British Crown.
In November, 1767,[59] he wrote to Shelburne, ‘The town of
Quebec is the only post in this province that has the least claim to be
called a fortified place; for the flimsy wall about Montreal, was it not
falling to ruins, could only turn musketry.’ He went on to show how
the French officers who still remained in Canada, and the Canadian
seigniors who had served France, had lost their employment through
the conquest of Canada, and, not having been taken into the English
King’s service, had no motive to be ‘active in the defence of a people
that has deprived them of their honours, privileges, profits, and laws’;
and again he urged the importance of building a citadel, for which he
enclosed a plan, within the town of Quebec. ‘A work of this nature,’
he wrote, ‘is not only necessary as matters now stand, but supposing
the Canadians could be interested to take a part in the defence of
the King’s Government, a change not impossible to bring about, yet
time must bring forth events that will render it essentially necessary
for the British interests on this continent to secure this port of
communication with the mother country.’
In January, 1868,[60] he wrote again to Shelburne, and referring to
his previous letter and to the scheme for constructing a citadel at
Quebec, he said—‘Was this already constructed, and I could
suppose it impossible for any foreign enemy to shake the King’s
dominion over the province, still I shall think the interests of Great
Britain but half advanced, unless the Canadians are inspired with a
cordial attachment and zeal for the King’s Government.’ Once more
he urged that the Canadians had no motive of self-interest to attach
them to British rule. The laws and customs which affected their
property had been overturned. Justice was slow and expensive. The
different offices claimed ‘as their right, fees calculated for much
wealthier provinces’; and the leading Canadians were excluded from
all places of trust and profit. Give the people back their old laws and
customs in civil matters, let them feel thereby secure in their
property, take a few Canadians into the service of the Crown, enlist
in the King’s forces ‘a few companies of Canadian foot, judiciously
officered’, ‘hold up hopes to the gentlemen, that their children,
without being bred up in France, or in the French service, might
support their families in the service of the King their master,’ and, at
any rate, some proportion of the French Canadians would be found
loyally attached to the British Government.
Another letter, written to Lord Hillsborough in November, 1768,[61]
was in similar terms. It referred to rumours of French intrigues and of
a contemplated rising on the part of the Canadian gentry. Carleton
discredited the rumours, but added, ‘Notwithstanding this, and their
decent and respectful obedience to the King’s Government hitherto, I
have not the least doubt of their secret attachment to France, and
think this will continue, as long as they are excluded from all
employments under the British Government.’ He reflected ‘that
France naturally has the affections of all the people: that, to make no
mention of fees of office and of the vexations of the law, we have
done nothing to gain one man in the province, by making it his
private interest to remain the King’s subject’. He went on to point out
that ‘the King’s dominion here is maintained but by a few troops,
necessarily dispersed, without a place of security for their
magazines, for their arms, or for themselves, amidst a numerous
military people, the gentlemen all officers of experience, poor,
without hopes that they or their descendants will be admitted into the
service of their present Sovereign’, and he argued that, were a war
with France to coincide with a rising of the British colonies in North
America, the danger to the British power would be great. ‘Canada,
probably, will then become the principal scene, where the fate of
America may be determined.’ On the other hand he urged—‘How
greatly Canada might for ever support the British interests on this
continent, for it is not united in any common principle, interest, or
wish with the other provinces, in opposition to the supreme seat of
government, was the King’s dominion over it only strengthened by a
citadel, which a few national troops might secure, and the natives
attached by making it their interest to remain his subjects.’
In the second of these letters[62] from which Carleton’s
quotations have been made, Carleton said that he sympathy with the
French Canadians.
would endeavour to represent the true situation of the
province to the ministers at home, who were already engaged in
considering ‘the improvement of the civil constitution of Quebec’, lest
the King’s servants, with all their ability, should be at a disadvantage
in forming their conclusions ‘for want of having truly represented to
them objects at so great a distance, and in themselves so different
from what is to be found in any other of his dominions’. But it was not
merely a case of the man on the spot advising the men at a distance;
the value of Carleton’s advice was largely due to the fact of his being
a soldier. To this fact must be attributed, in great measure, the strong
sympathy which the soldier-governors felt with the French
Canadians, and on Carleton’s part more especially with the French
Canadian gentry. As Murray had pointed out,[63] the Canadians were
a people of soldiers; they were accustomed to The French
personal rule and attachment rather than to the rule of Canadians were a
people of soldiers
the law. To high minded English officers, themselves accustomed to
brought up in the King’s service, trained to discipline, personal rule.
to well ordered grades of obedience, the old Canadian system with
its feudal customs was congenial and attractive, and they resented
attempts to substitute for it the beginnings of undisciplined
democracy. Hence Carleton laid stress on taking Canadian
gentlemen into the government service, and on enlisting companies
of Canadian soldiers, in other words, on making the Canadians feel
that they were, as they had been in past times, the King’s men.
Hence, too, we find him in a letter to Shelburne of April, 1768,[64]
recommending full recognition and continuance of the old feudal
tenures of Canada, including ‘a formal requisition of all those
immediately holding of the King, to pay faith and homage to him at
his castle of St. Lewis’. If left to himself, he would have liked to
repeal entirely the Ordinance of September, 1764, which introduced
English laws into Canada, ‘and for the present leave the Canadian
laws almost entire;’[65] and, though he assented to the compromise
embodied in the Quebec Act, whereby the criminal law was to be
that of England, while in civil matters Canadian law and custom were
in the main to prevail, we find him in June, 1775,[66] after war had
begun, writing to Dartmouth, ‘For my part, since my return to this
province I have seen good cause to repent my ever having
recommended the Habeas Corpus Act and English criminal laws.’
It was due to Carleton that the Ordinance of 1770, to which
reference has already been made,[67] was passed, taking away from
the justices of the peace jurisdiction in matters of private property
which had been exercised to the detriment of the French Canadians.
It was due to him that in 1771 a new Royal Instruction was issued,
authorizing the governor to revert to the old French system of grants
of Crown lands ‘in Fief or Seigneurie’;[68] and his influence was all in
favour of the clauses in the Quebec Act which were favourable to the
‘new subjects’, the French Canadians, who, at the time when the
War of American Independence began, seem to have numbered
under 100,000.[69]
As has been told, Carleton came back from England Carleton returns
to Quebec in the middle of September, 1774, finding from England in
September, 1774,
the French Canadians in great good humour at the and sends two
passing of the Quebec Act. Twenty hours after his regiments
Boston.
to
arrival an express letter reached him from General

Gage, still Commander-in-Chief in North America, who was then at
Boston.[70] In it Gage asked his colleague to send at once to Boston,
if they could be spared, the 10th and 52nd Regiments, which formed
a large part of the scanty garrison of Canada. The transports which
brought the letter were to take back the troops. September, 1774,
was a critical month in the North American provinces. The first
continental Congress met at Philadelphia; and at Suffolk, near
Boston, on the 9th September, a public meeting passed resolutions,
[71] boldly advocating resistance to the recent Acts of Parliament.
Accordingly, in addition to his request for the two Proposals to raise

regiments, Gage wrote—‘As I must look forward to the Canadian and
Indian forces.
worst, from the apparent disposition of the people
here, I am to ask your opinion, whether a body of Canadians and
Indians might be collected and confided in, for the service in this
country, should matters come to extremities.’ Carleton promptly
replied: ‘Pilots are sent down the river, the 10th and 52nd shall be
ready to embark at a moment’s notice;’ and the regiments were sent
to Boston, as in later years Lord Lawrence, at the time of the Indian
Mutiny, denuded the Punjaub of soldiers, in order to strengthen the
force which was besieging Delhi. Carleton’s letter continued: ‘The
Canadians have testified to me the strongest marks of joy and
gratitude, and fidelity to the King, and to his Government, for the late
arrangements made at home in their favour: a Canadian regiment
would complete their happiness, which in time of need might be
augmented to two, three, or more battalions ... the Carleton strongly
savages of this province, I hear, are in very good favours raising a
Canadian regiment.
humour, a Canadian battalion would be a great motive
and go far to influence them, but you know what sort of people they
are.’ Here was the opportunity which Carleton desired, of taking the
Canadians into the King’s service. Following on the Quebec Act, he
looked to such a measure as likely to rivet Canadian loyalty to the
British Crown, and evidently took himself, and inspired the Home
Government with, too hopeful a view of the amount of support to be
expected from the Canadians, looking to and sympathizing with the
seigniors rather than the lower classes of the people of Canada. It
will be noted that both Gage and he contemplated employing
Indians, in the event of war between the mother country and the
North American colonies. Indians had been used on either side in
the wars with the French, but it seems strange that there is no hint or
suggestion in these letters of the danger and impolicy of employing
them against the British colonists.[72]
In November, 1774, writing to Dartmouth,[73] Carleton still spoke of
the gratitude and loyalty of the French Canadians, but there was a
warning note in his letter. While the respectable members of the
English community at Quebec supported the Government, there was
much disloyalty among the British residents at Montreal. The
resolutions of the Philadelphia Congress, and their address to the
people of Canada, had reached that place. Walker was much in
evidence, embittered by the outrage which he had suffered some
years before,[74] and, with others, was organizing meetings and
petitions both at Montreal and at Quebec. These proceedings,
Carleton wrote, were causing uneasiness to the Canadians, and he
concluded that ‘Government cannot guard too much, or too soon,
against the consequences of an infection, imported daily, warmly
recommended, and spread abroad by the colonists here, and indeed
by some from Europe, not less violent than the Americans’.
The year 1774 ended in anxiety and suspense, and the year 1775
opened, memorable and disastrous to Great Britain. On Christmas
Day, 1774, Gage had written again to Carleton on the subject of
Canadian and Indian levies, and on the 4th of February, 1775,
Carleton answered the letter.[75] Political matters relating to the
Indians, he said, he had always considered to be the Canadian feeling at
special charge of the late Sir William Johnson, and the beginning of
1775.
outside the sphere of his own authority, but his
intelligence was to the effect that the Indians would be ready for
service if called upon.[76] Of the Canadians Carleton wrote that they
had in general been made very happy by the passing of the Quebec
Act, but he reminded Gage that that Act did not come into force until
the 1st of May following, that the new commissions and instructions
expected in connexion with it had not yet arrived, and that the whole
machinery for carrying out the new system of government had still to
be created. ‘Had the present settlement taken place,’ he added,
‘when first recommended, it would not have aroused Carleton strongly
the jealousy of the other colonies, and had the urges employing
the Canadian
appearance of more disinterested favour to the gentry in the
Canadians.’ He pointed out that the gentry, ‘well regular army.
disposed and heartily desirous as they are, to serve the Crown, and
to serve it with zeal, when formed into regular corps, do not relish
commanding a bare militia.’ They had not been used to act as militia
officers under the French Government, and they were further
deterred from taking such employment by recollection of the sudden
disbandment of a Canadian regiment, which had been raised in
1764, and subsequently broken up, ‘without gratuity or recompense
to officers, who engaged in our service almost immediately after the
cession of the country, or taking any notice of them since, though
they all expected half pay.’[77] The habitants, again, had since the
introduction of civil government into Canada, and in consequence of
the little authority which had been exercised, ‘in a manner
emancipated themselves.’ Time and good management would be
necessary ‘to recall them to their ancient habits of obedience and
discipline’, and meanwhile they would be slow to allow themselves to
be suddenly and without preparation embodied into a militia.
Carleton accordingly deprecated attempting to raise a militia force in
Canada and recommended enlisting one or two regular battalions of
Canadian soldiers. ‘Such a measure might be of singular use, in
finding employment for, and consequently firmly attaching the gentry
to our interests, in restoring them to a significance they have lost,
and through their means obtaining a further influence upon the lower
class of people, a material service to the state, besides that of
effectually securing many nations of savages.’
From the above correspondence we can form some Summary of the
impression of the state of political feeling in Canada, political conditions
of Canada at the
when the great revolt of the American colonies began. beginning of the
We have the picture of a conquered people, War of American
Independence.
accustomed to a military system, to personal rule, and
to feudal laws and customs. This people had been brought by the
fortune of war under the same flag as covered very democratic
communities, which communities were their immediate neighbours
and had been their traditional rivals. The few years which had
passed since the conquest of Canada had, with the exception of the
Indian rising under Pontiac, been years of uncomfortable peace and
administrative weakness. The government of the country, which was
the mother country of the old colonies and the ruler of the new
possession, was anxious to curtail expenses as much as possible, in
view of the great expenditure which had been caused by the Seven
Years’ War; to maintain and, if possible, to emphasize its precarious
authority over the democratic communities of the Atlantic seaboard;
and, on the other hand, in a sense to relax its authority over Canada,
by modifying in the direction of English institutions the despotism
which had prevailed under the old French régime. The net result was
that on the American continent the Executive, having insufficient
force behind it and in the old colonies no popular goodwill, was
increasingly weak, and the people were more and more unsettled.
The democratic communities became more democratic, and from
those communities individuals brought themselves and their ideas
into the sphere of French conservatism, adding to the uncertainty
and confusion which attempts to introduce English laws and customs
had already produced in Canada. The Canadian gentry under British
rule found their occupation gone, their importance minimized, and no
outlet for their military instincts and aspirations. The peasantry found
old rules relaxed and unaccustomed freedom. Strength was nowhere
in evidence in Canada. The forts were falling into ruin; the English
soldiers were few; there was the King’s Government without the
backing of the King’s men; the old subjects were a small number of
men, of whom a large proportion were noisy, disloyal, adventurers;
the new subjects were not held in submission, but not admitted to
confidence. On the other hand, the French Canadians had recent
and undeniable evidence of the goodwill of the British Government in
the passing of the Quebec Act. Their governors, Murray and
Carleton, had transparently shown their sympathies with the French
Canadian race, its traditions, and even its prejudices. Amid many
inconveniences, and with some solid grounds for discontent, the
Canadians had none the less tasted British freedom since the
cession of Canada; and they had not yet imbibed it to such an extent
as to overcome their traditional animosity to, and their inveterate
suspicion of, the militant Protestants of the old colonies who were
rising against the King.
It is unnecessary for the purposes of this book to give a full
account of the War of American Independence, except so far as
Canada was immediately concerned. Here the Americans appeared
in the character of invaders, and the issue really depended upon the
attitude of the French Canadians. Would they rise against their
recent conquerors and join hands with the rebellious colonists, or
would their confidence in Carleton, coupled with their long standing
antipathy to the British settlers in America, keep them in allegiance
to the British Crown? For the moment all went well for the
Americans.
It was characteristic of the state of unrest which The Green
prevailed at this time in America that, while the Mountain rising.
colonies as a whole were quarrelling with the mother country, one
portion of a colony was declaring its independence of the state to
which it was supposed to belong. On the eastern side of Lake
Champlain were a number of settlers who had come in under grants
issued by the Governor of New Hampshire, but over whom the
government and legislature of New York claimed jurisdiction, the
New York claim having moreover been upheld by the Imperial
Government. These settlers were known at the time as the ‘Green
Mountain Boys’, and they were the nucleus of the present state of
Vermont. In April, 1775, they held a meeting to declare their
independence of New York, their leaders being Ethan Allen, who had
been proclaimed an outlaw by the Governor of New Ethan Allen.
York in the previous year, and Seth Warner. They had
already apparently in their minds the possibility of taking possession
of the forts on Lake Champlain. There were few men Capture of
at Ticonderoga and Crown Point, only about fifty at the Ticonderoga
Crown Point.
and
former and half a dozen or so at the latter, belonging

to the 26th Regiment, enough and no more than sufficient to guard
the guns and the stores. The garrison apprehended no attack and
had made no preparations for defence.
The news of Lexington suggested to the Green Mountain Boys to
commend themselves to Congress by at once securing these two
forts. If they had any instructions in planning their expedition, those
instructions seem to have come from Connecticut; and though,
before a start was made, Benedict Arnold was sent up by Congress
to take the matter in hand, the insurgents refused his leadership;
and, while he accompanied the expedition, it was Allen who mainly
carried out the enterprise. Under Allen’s command, on the night of
the 9th of May, a band of armed men, variously estimated at from
under 100 to over 200 in number, marched to the shore of the Lake
Champlain, where it narrows to little more than a river immediately
opposite Ticonderoga; and, crossing over in two parties, early on the
morning of the 10th were admitted to the fort on pretence of bringing
a message to the commandant, overpowered the guard, and
surprised the rest of the little garrison in their beds. Two days later
Crown Point was secured by Seth Warner; and shortly afterwards,
under the command of Arnold, part of the expedition made their way
in a captured schooner to the northern end of the lake, took
prisoners a dozen men who represented the garrison at the fort of
St. John’s, seized a vessel belonging to the Government which was
lying off the fort, and retreated up the lake on the approach of a
detachment from Montreal.[78]
Thus the old fighting route by the way of Lakes George and
Champlain, the scene of numberless raids and counter-raids, where
Robert Rogers, William Johnson, Montcalm, Abercromby, Amherst,
and many others had played their parts, passed into the hands of the
revolutionary party, and only the forts of St. John’s and Chambly,
beyond the outlet of Lake Champlain, barred the way to Montreal.
The British power in Canada seemed gone to nothingness, and at
the beginning of June, in reporting to Dartmouth what had taken
place, Carleton wrote: ‘We are equally unprepared for attack or
defence; not six hundred rank and file fit for duty upon the whole
extent of this great river,[79] not an armed vessel, no place of
strength; the ancient provincial force enervated and broke to pieces;
all subordination overset, and the minds of the people poisoned by
the same hypocrisy and lies practised with so much success in the
other provinces.’[80]
The gentry and clergy, he reported, had shown zeal and loyalty in
the King’s service, but they had lost much of their influence over the
people, and the Indians had been as backward as the peasantry in
rallying to the defence of Canada. The crisis had come, and
Carleton’s warnings of past years had been amply justified. Absence
of military preparations, and neglect to take measures to attach the
Canadians to the British Crown had resulted in a situation full of
danger, a province open to invasion, a government without material
for defence, and a confused and half-hearted people. Even
Carleton’s forecast had not been wholly accurate. He seems to have
over-rated the good effects of passing the Quebec Miscalculations as
Act, and not to have fully realized the strength of class to Canadian
feeling.
feeling in Canada, or the extent to which the
peasantry, under the influence of the disloyal British minority and of
emissaries from the revolting colonies, had emancipated themselves
from the control of the seigniors and the gentry. It was even
suggested that the lower orders in the province, instead of being
grateful for the Quebec Act, regarded it with suspicion and dislike, as
intended to restore a feudal authority which they had repudiated, and
such no doubt would have been the doctrine taught by the British
malcontents inside and outside the province. ‘What will be your
lordship’s astonishment,’ wrote Hey, the Chief Justice of Canada, to
the Lord Chancellor, towards the end of the following August,[81]
‘when I tell you that an Act passed for the express purpose of
gratifying the Canadians, and which was supposed to comprehend
all that they either wished or wanted, is become the first object of
their discontent and dislike. English officers to command them in
time of war, and English laws to govern them in time of peace, is the
general wish. The former they know to be impossible (at least at
present), and by the latter, if I understand them right, they mean no
laws and no government whatsoever. In the meantime, it may be
truly said that General Carleton has taken an ill measure of the
influence of the seigniors and clergy over the lower order of people.’
If Carleton had misjudged the feelings of the Canadians, the Chief
Justice frankly admitted that he himself had been fully as much
deceived.
The mischief was that the Government in England Mistakes of the
had imbibed the confident anticipations of Canadian Home Government.
loyalty which had been formed by the men on the spot immediately
after the passing of the Quebec Act; and, instead of sending
reinforcements to Canada, they expected Carleton to reinforce
Gage’s army in New England. On the 1st of July, Dartmouth wrote to
Carleton, instructing him to raise a body of 3,000 Canadians to co-
operate with Gage; on the 24th of July, having had further news from
America, he doubled the number and authorized a levy of 6,000
Canadians; and no hope was given of sending British troops to
Canada until the following spring. At the beginning of the American
war the greatest danger to the British Empire consisted in the utter
weakness of the position in Canada. It was some excuse, no doubt,
for the ministers at home that the Governor of Canada had latterly
over-estimated the loyalty of the Canadians; and it may well have
been too that the dispatch of troops to the St. Lawrence was delayed
in order not to alarm the American colonies, before they openly
revolted, and while there was still some faint hope of peace, by a
measure which might have been interpreted as a threat of war. But
those who were responsible for the safe keeping of British interests
in America stand condemned in the light of the repeated warnings
which Carleton had given in previous years. As a skilled soldier, he
had pointed out, and history confirmed, the vital importance of
Canada in the event of war in America, its commanding position for
military purposes in relation to the other[82] provinces. He had urged
the necessity of military strength in Canada, of strength which was
both actual and apparent; of forts strong enough to be defended and
of British soldiers numerous enough to defend them; moreover, of
forts strong enough and British soldiers numerous enough to at once
compel and attract the attachment of a military people. As a
statesman, he had recommended more than a Quebec Act, years
before the Quebec Act was passed. Political and financial exigencies
outside Canada may have made it impossible to take his guidance,
but had it been followed, the whole course of history might have
been changed.
On hearing of the capture of the forts on Lake Carleton moves
Champlain, Carleton took what measures he could. troops John’s.
to St.
He moved all his available troops, including some

Canadian volunteers,[83] to St. John’s, and strengthened its
defences. He went up himself from Quebec to Montreal, where he
arrived on the 26th of May. On the 9th of June he called out the
Canadian militia under the old French law, with little effect beyond
causing irritation and discontent, which American emissaries and
sympathizers turned to account; and on the 2nd of August he went
back to Quebec, to summon the first Legislative Council which was
constituted under the Quebec Act, that Act having now come into
operation. Meanwhile, after the battle of Bunker’s Hill, the American
Congress had resolved on invading Canada in force; General Philip
Schuyler was placed in charge of the expedition, but, his health
giving way, the command devolved upon Richard Montgomery, who
had served under Amherst throughout the campaign The Americans
which ended with the conquest of Canada, and had under Richard
Montgomery invade
subsequently settled in the state of New York and Canada.
married an American lady.
At the beginning of September, the American troops moved
northward down Lake Champlain, and took up a position at the Isle
aux Noix, twelve miles from the fort at St. John’s, preparatory to
besieging that fort. ‘The rebels are returned into this province in
great numbers, well provided with everything, and seemingly
resolved to make themselves masters of this province. Hardly a
Canadian will take arms to oppose them, and I doubt all we have to
trust to is about 500 men and two small forts at St. John’s.
Everything seems to be desperate,’ so wrote Chief Justice Hey from
Quebec to the Lord Chancellor on the 11th of September.[84] On the
17th he added, ‘The rebels have succeeded in making peace with
the savages who have all left the camp at St. John’s, many of the
Canadians in that neighbourhood are in arms against the King’s
troops, and not one hundred except in the towns of Montreal and
Quebec are with us. St. John’s and Montreal must soon fall into their
hands, and I doubt Quebec will follow too soon.’
There was skirmishing between scouts and outposts, and on the
night of the 24th of September, a party of about 150 Americans
under Ethan Allen crossed over into the island of Montreal and
penetrated to the suburbs of the town. Their daring attempt,
however, miscarried: they were driven out: Allen was taken prisoner
and sent in irons to England: and his failure gave for the moment
some encouragement to the Loyalists’ cause.
On hearing of Schuyler’s and Montgomery’s Carleton applies to
Gage for
advance Carleton at once hurried back from Quebec reinforcements.
to Montreal. There were two possibilities of saving the
town, and with it, perhaps, the whole of Canada. One was by
obtaining reinforcements from the British army at Boston, the other
by contriving, even without reinforcements, to hold the forts at St.
John’s and Chambly until winter drove the invaders back whence
they had come. Early in September Carleton applied to Boston for
two regiments, the same number that in the previous autumn he had
sent to Boston at Gage’s request; his message came to hand on the
10th of October, just as Gage was leaving for England, and Howe,
who took over the command of the troops, at once prepared to send
the men. But there was a blight on English sailors as on English
soldiers in America in these days. Admiral Graves, who commanded
the ships, refused to risk the dangers of the passage Admiral Graves
from Boston to Quebec at the season of the year, and refuses to move.
Carleton in his sore straits was left unaided. All, therefore, turned on
the defence of the forts.
St. John’s fort was manned by between 600 and The siege of St.
700 men, 120 of whom were Canadian volunteers, the John’s and
Chambly.
rest being regulars. Chambly was held by some 80
men of the line. A few men were stationed at Montreal, but Quebec
was almost emptied of its garrison. Major Preston,[85] of the 26th
Regiment, commanded at St. John’s, and Chambly was in charge of
Major Stopford. On the 18th of September Montgomery laid siege to
the former fort, cutting off communication between the defenders
and the outside world; but, notwithstanding, news reached Preston
of Allen’s unsuccessful attempt on Montreal, and he held out bravely,
helped by the fact that Montgomery had hardly any artillery, and
could only rely on starving out the garrison, while his own men were
suffering from exposure, privations, and want of ammunition. But in
the middle of October the outlook was changed, for, after less than
two days’ siege, the fort at Chambly, said to have been well
provisioned, and with ample means of defence, was The two forts taken.
on the 17th of that month surrendered,[86] providing
Montgomery with supplies, guns, and ammunition to be used against
the main fort. Preston’s condition was now desperate. An attempt
made by Carleton to cross from Montreal to his relief on the 30th of
October was beaten back, and on the 2nd of November, St. John’s
surrendered, after having held out for forty-five days.
The fall of St. John’s made the defence of Montreal Carleton leaves
impossible. Carleton dismissed such of the militia as Montreal,
were in arms to their homes, and with the few Imperial troops in the
town, rather over 100 in number, and any arms and supplies that he
could carry away, embarked on the afternoon of the 11th of
November to make the best of his way to Quebec. On the 13th,
Montgomery and his men entered Montreal. Already which is occupied
advanced parties of the Americans were heading by the Americans.
down the river banks. Colonel Maclean, who had come up from
Quebec as far as the Richelieu river with a small body of Canadians
and Scotchmen, to co-operate with Carleton for the relief of St.
John’s, had fallen back, Benedict Arnold was threatening Quebec
itself, and it became a question whether Carleton would ever reach
the city to take charge of its defence. His vessels and boats sailed
down the river to a point some miles above Sorel at the confluence
of the Richelieu river. There one of them grounded; the wind veered
round and blew up-stream; for three days the little Carleton narrowly
flotilla remained stationary; the enemy overtook them escapes capture
and reaches
on the land, raised batteries in front to bar their Quebec.
progress, and summoned them to surrender. On the
night of the 16th Carleton went on board a whale boat; silently, with
muffled oars, and at one point propelled only by the rowers’ hands,
she dropped down-stream, undetected by the watchers on the
banks. On the 17th Carleton reached Three Rivers, with the
American troops close behind him, and lower down he met an armed
British ship, which carried him in safety to Quebec. He entered the
city on the 19th. On the same day the vessels in which he had
started from Montreal surrendered with all on board, and, being
brought back to Montreal, were used to carry Montgomery and his
men down to Quebec.
Quebec was already threatened by a small force under Benedict
Arnold. In the year 1761, while General Murray was in military
command of the city and district, an engineer officer, acting under his
instructions, had marked out a trail along the route Arnold’s march
from the mouth of
from the Atlantic coast, at the mouth of the Kennebec the Kennebec to
Quebec.
river, to the confluence of the Chaudière with the St.
Lawrence over against Quebec. In 1775, when the American
colonists determined to invade Canada, Washington decided to send
an expedition by this route to co-operate with the main advance by
Lake Champlain and the St. Lawrence. The enterprise required a
daring, resourceful leader, and the command was given to Arnold. In
the middle of September, Arnold embarked with 1,100 men at
Newbury port at the mouth of the Merrimac, and sailed for the
Kennebec. In the latter days of September he began his march:
some 200 batteaux were taken up the Kennebec, carrying arms,
ammunition, and supplies; the troops were partly on board the boats,
partly kept pace with them on the banks. The expedition followed the
course of the Kennebec and its tributary, the Dead River, crossed the
height of land, reached the headwaters of the Chaudière in Lake
Megantic, and descended the Chaudière to the St. Lawrence. It was
a march of much danger and privation, no easy task for a skilled
backwoodsman to accomplish, and full of difficulty when it was a
case of transporting a small army. All through October and into
November the men toiled in the wilderness, boats were lost,
provisions were scarce, the sick and ailing were left behind, the
rearguard turned back, but eventually Arnold brought two-thirds of
his men through, and, with the goodwill and assistance of the
Canadians on the southern bank of the St. Lawrence, emerged at
Point Levis on the 8th of November, having achieved a memorable
exploit in the military history of America. On the 14th he crossed the
river by night, landed where Wolfe had landed before his last
memorable fight, and, after summoning the city to surrender without
effect, retreated to Pointe aux Trembles, nearly twenty miles up the
river, to await Montgomery’s arrival. Meanwhile, Carleton passed by
and entered Quebec.
On the 5th of December, Montgomery came upon Montgomery
the scene, having landed his guns at Cap Rouge, arrives before
Quebec.
about nine miles above the city.[87] A threatening letter
which he sent to Carleton on the day after his arrival summoning the
British general to surrender, received no answer, and he took up his
position and planted batteries within reach of the walls on the
western side—the side of Wolfe’s attack, while Arnold occupied the
suburb of St. Roch, on the north of the city, with the river St. Charles
behind him. So far the American advance had been little more than a
procession. Montreal had received Montgomery without fighting.
Three Rivers had given in its adhesion to the revolutionary cause,
without requiring the general’s presence, as he passed down the
river. Nearly all the British regulars were prisoners; and, with the help
of the disloyal element in the population, Montgomery had good
reason to expect that Quebec would forthwith pass into his hands
and the Imperial Government be deprived of its last foothold in
Canada. He was soon undeceived, however, and found the task
beyond his strength.
His whole force, when united to Arnold’s and The siege of
including some Canadians, seems not to have Quebec.
exceeded 2,000 men; his artillery was inadequate, and winter was
coming on. On the other hand, Carleton’s garrison was a nondescript
force of some 1,600 to 1,800 men. Nearly one-third of Number of the
the number were Canadians. About 400 were seamen garrison.
and marines from the ships in the harbour, including the Lizard ship
of war, which, with one convoy ship containing stores and arms,
represented all the aid that had come from England. There were less
than 300 regulars, including about 200 of a newly-raised corps under
Colonel Maclean’s command, Scotch veterans who were known as
the Royal Highland Emigrants; and there were about 300 militia of
British birth. But the city was well provisioned; the disloyal citizens
had been ejected; Carleton himself had been through the famous
winter siege of 1759-60; and the preparations which had been made
during his recent absence at Montreal, showed that he had capable
officers serving under him. The upper classes of Canada had from
the first sided with the British Government, and now that Quebec, the
hearth and home of Canada, was in deadly peril, some spirit of
Canadian citizenship was stirred in its defence.
PLAN OF QUEBEC IN 1775-6
Reduced from Plan in Colonial Office Library
To face p. 112
Montgomery’s army was too small in numbers, Montgomery plans

a night attack.
without the support of powerful artillery which he did
not possess, to justify a direct assault upon the town walls, and a
prolonged siege in the depth of winter meant severe strain on the
American resources with no sure hope of ultimate success.
Moreover, many of the men had enlisted only for a specified term,
which expired at the end of the year. Before the year closed,
therefore, the general determined to attempt a night surprise, and
laid his plans not to attack the city from the plateau, but to storm the
barricades which guarded the lower town by the water’s edge, and
thence to rush the heights above.
Before dawn on the morning of Sunday the 31st of The attack of
December,[88] 1775, between the hours of two and December
1775.
31,
seven, in darkness and driving snow, the attempt was

made. From Montgomery’s batteries on the Heights of Abraham the
guns opened fire on the town. At Arnold’s camp at St. Roch, troops
placed themselves in evidence under arms; and, while this
semblance of attack was made, the two leaders led two separate
columns from opposite directions, intended to converge in the centre
of the lower town, so that the combined parties might force the steep
ascent from the port to the city on the cliff.
About two in the morning Montgomery led his men, Repulse of
according to one account, 900 in number, down to the Montgomery
his death.
and
river side at Wolfe’s landing-place; and signalling with

rockets to Arnold to begin his march, started about four o’clock along
a rough pathway which skirted the river under Cape Diamond and
led to the lower town. Unnoticed, it would seem, by an outpost on
Cape Diamond, and by an advance picket, he came at the head of
his force within thirty yards of a barricade, which had been
constructed where the houses began at Prés de Ville. Up to this
point the defenders had given no sign, but now every gun, large and
small, blazed forth: the general fell dead with 12 of his following, and
the whole column beat a hasty retreat.
Meanwhile, on the other side, in the angle between Repulse of Arnold’s
the St. Charles and the St. Lawrence, Arnold led column.
forward 700 men, passing below Palace Gate, and fired at from the
walls where the garrison were all on the alert, for Carleton had for
some days past been warned of a coming attack. The Americans
crossed a small projecting point, known as the Sault au Matelot, and
reached one end of the narrow street which bore the same name.
Here there was a barricade, a second barricade having been erected
at the other end of the street. The first barrier was forced, but not
until Arnold himself had been disabled by a wound; and led by the
Virginian, Daniel Morgan, who was second in command, and who,
later in the war, won the fight at Cowpens, the assailants pressed
boldly on to take the second barricade and effect a junction with
Montgomery. But Montgomery was no more; the garrison grew
constantly stronger at the threatened point; the way of retreat was
blocked; and caught in a trap, under fire from the houses, the
attacking party surrendered to the number of 431, in addition to 30
killed, including those who fell with Montgomery. The day had hardly
broken when all was over, the result being an unqualified success for
the English, a crushing defeat for the American forces. Quebec was
saved, and with Quebec, as events proved, the whole of Canada.
The English, according to a letter from Carleton to Continuance of the
General Howe, written on the 12th of January, only siege.
lost 7 killed and 11 wounded on this memorable night; but,
notwithstanding, in view of the small numbers of the garrison, the
governor did not follow up his success by any general attack on the
American lines; he contented himself with bringing in five mortars
and a cannon from Arnold’s position, and settled down with his force
to wait for spring. The Americans, from time to time reinforced by
way of Montreal, continued the blockade, but it was somewhat
ineffective, as firewood and even provisions were at intervals
brought into the town. On the 25th of March a party of Canadians,
who attempted to relieve Quebec by surprising an American battery
at Point Levis, on the other side of the St. Lawrence, were
themselves surprised and suffered a reverse; on the 4th of April the
battery in question opened on the town with little effect: on the 3rd of
May a fire ship was directed against the port and Quebec relieved on
proved abortive. On the 6th of May English ships once May 6, 1776.
more came up the river with reinforcements, and the siege was at an
end. The Congress troops retreated in hot haste, as Levis’s men had
fled when Murray was relieved: artillery, ammunition, stores, were
left behind; and the retreat continued beyond Three Rivers, as far as
Sorel, at the mouth of the Richelieu.
‘After this town had been closely invested by the Carleton’s Report.
rebels for five months and had defeated all their
attempts, the Surprise frigate, Isis and sloop Martin came into the
Basin the 6th instant.... Thus ended our siege and blockade, during
which the mixed garrison of soldiers, sailors, British and Canadian
militia, with the artificers from Halifax and Newfoundland, showed
great zeal and patience under very severe duty and uncommon

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Strategies and Tactics in Organic

Synthesis 1st Edition Michael Harmata

Strategies and Tactics for the MBE (Strategies &

Organic Synthesis Using Biocatalysis 1st Edition

Firefighting Strategies and Tactics 3rd Edition – Ebook

Strategies & Tactics for the MBE (Bar Review)

Disaster Response and Recovery: Strategies and Tactics

Carbon Monoxide in Organic Synthesis - Carbonylation

Organic Corrosion Inhibitors: Synthesis,

Stereochemistry and Organic Reactions Conformation,

Professor Erik J. Sorensen

Professor Dirk Trauner

Professor Frederick G. West

Professor Craig M. Williams

Professor Pauline Chiu

Dr. Jean Suffert

British Library Cataloguing-in-Publication Data

For information on all Elsevier publications visit our website at

Publisher: Susan Dennis

This volume is dedicated to the memory of

David Sarlah, Department of Chemistry, University of Illinois, Urbana, IL, United

How did he manage to retain his youth? Victor Snieckus appeared to be

wrapped in a US flag, carrying an AR-15. Sick but dangerous people. Here’s to

FIGURE 1.1 The Amaryllidaceae isocarbostyril alkaloids (þ)-deoxypancratistatin (1), pan-

to be isolated, (þ)-narciclasine (4), was initially investigated for its growth

Amaryllidaceae isocarbostyril alkaloids Chapter j 1

NT, not tested.

1. P. putida 39/D1 Cu(CN)Li2

Amaryllidaceae isocarbostyril alkaloids Chapter j 1

allowed for a ring-closing metathesis reaction to close the cyclitol ring.46

Amaryllidaceae isocarbostyril alkaloids Chapter j 1

SCHEME 1.2 The modified BischlereNapieralski reaction for lactam formation.

10 Strategies and Tactics in Organic Synthesis

FIGURE 1.3 Selected analogs of the Amaryllidaceae isocarbostyril alkaloids.

2.2 Development of the dearomative carboamination reaction

Amaryllidaceae isocarbostyril alkaloids Chapter j 1

SCHEME 1.3 Retrosynthetic analysis of the Amaryllidaceae isocarbostyril alkaloids.

SCHEME 1.4 Conception of the dearomative carboamination.

16 Strategies and Tactics in Organic Synthesis

2.3 Mechanistic hypothesis

18 Strategies and Tactics in Organic Synthesis

reductive NUR oxidative

an enantioselective total synthesis was within reach, as intermediates VII and

2.4 Optimization of our new nickel-catalyzed conditions

Amaryllidaceae isocarbostyril alkaloids Chapter j 1

SCHEME 1.6 Divergent reactivity of diene 60 leading to cyclitols 63 and 66.

solubility and citric acid to accelerate the reaction,89 we could obtain 62 in

3.2 Optimizing the route

Amaryllidaceae isocarbostyril alkaloids Chapter j 1

observed no reaction. We then decided to optimize the reaction we were

3.3 Methods for lactam formation

In practice, we could Boc protect the amine followed by acetylation of the

3.4 C-7 oxidation and final route

C-H borylation Directed ortho-lithiation Deprotonative metalation

We tested numerous conditions for metalation of the C-7 position,

4. Narciclasine and lycoricidine

SCHEME 1.10 Final optimized synthesis of the pancratistatins.

TABLE 1.2 Optimization studies for Ni(II)-catalyzed carboamination.a

Entry Grignard [Ni] x (mol%) y (mol%) Yield %b erc

3d 3.0 Ni(cod)2 5.00 7.00 67 94.5:5.5

9 3.0 Ni(acac)2 10.0 20.0 59 93:7

15 2.5 Ni(acac)2 1.50 2.00 70 97:3

17 2.5 Ni(acac)2 1.00 1.40 68 96.5:3.5