Strategies and Tactics in Organic

Synthesis 1st Edition Michael Harmata

Visit to download the full and correct content document:
https://ebookmass.com/product/strategies-and-tactics-in-organic-synthesis-1st-edition
-michael-harmata/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...

Strategies and Tactics for the MBE (Strategies &

Tactics for the MBE Book 1) (Ebook PDF)

https://ebookmass.com/product/strategies-and-tactics-for-the-mbe-
strategies-tactics-for-the-mbe-book-1-ebook-pdf/

Organic Synthesis Using Biocatalysis 1st Edition

Goswami

https://ebookmass.com/product/organic-synthesis-using-
biocatalysis-1st-edition-goswami/

Firefighting Strategies and Tactics 3rd Edition – Ebook

PDF Version

https://ebookmass.com/product/firefighting-strategies-and-
tactics-3rd-edition-ebook-pdf-version/

Strategies & Tactics for the MBE (Bar Review)

https://ebookmass.com/product/strategies-tactics-for-the-mbe-bar-
review/
eTextbook 978-1305506381 Managerial Economics:
Applications, Strategies and Tactics

https://ebookmass.com/product/etextbook-978-1305506381-
managerial-economics-applications-strategies-and-tactics/

Disaster Response and Recovery: Strategies and Tactics

for Resilience 2nd Edition, (Ebook PDF)

https://ebookmass.com/product/disaster-response-and-recovery-
strategies-and-tactics-for-resilience-2nd-edition-ebook-pdf/

Carbon Monoxide in Organic Synthesis - Carbonylation

Chemistry Gabriele Bartolo. (Ed.)

https://ebookmass.com/product/carbon-monoxide-in-organic-
synthesis-carbonylation-chemistry-gabriele-bartolo-ed/

Organic Corrosion Inhibitors: Synthesis,

Characterization, Mechanism, and Applications
Chandrabhan Verma

https://ebookmass.com/product/organic-corrosion-inhibitors-
synthesis-characterization-mechanism-and-applications-
chandrabhan-verma/

Stereochemistry and Organic Reactions Conformation,

Configuration, Stereoelectronic Effects and Asymmetric
Synthesis 1st Edition Dipak Kumar Mandal

https://ebookmass.com/product/stereochemistry-and-organic-
reactions-conformation-configuration-stereoelectronic-effects-
and-asymmetric-synthesis-1st-edition-dipak-kumar-mandal/
 EDITORIAL BOARD

Professor Erik J. Sorensen

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

Professor Dirk Trauner

Department of Chemistry
New York University
100 Washington Square East
New York, NY, USA

Professor Frederick G. West

Department of Chemistry
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

Department of Chemistry
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
any means, electronic or mechanical, including photocopying, recording, or any
information storage and retrieval system, without permission in writing from the
publisher. Details on how to seek permission, further information about the Publisher’s
permissions policies and our arrangements with organizations such as the Copyright
Clearance Center and the Copyright Licensing Agency, can be found at our website:
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

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library
ISBN: 978-0-12-822212-6
ISSN: 1874-6004

For information on all Elsevier publications visit our website at

https://www.elsevier.com/books-and-journals

Publisher: Susan Dennis

Acquisitions Editor: Emily McCloskey
Editorial Project Manager: Susan Ikeda
Production Project Manager: Paul Prasad Chandramohan
Cover Designer: Alan Studholme
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
4 Strategies and Tactics in Organic Synthesis

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
 6 Strategies and Tactics in Organic Synthesis
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

Amaryllidaceae isocarbostyril alkaloids Chapter j 1

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.
8 Strategies and Tactics in Organic Synthesis

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

Amaryllidaceae isocarbostyril alkaloids Chapter j 1

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

10 Strategies and Tactics in Organic Synthesis

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.

 Amaryllidaceae isocarbostyril alkaloids Chapter j 1 11

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.
12 Strategies and Tactics in Organic Synthesis

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
Another random document with
no related content on Scribd:
 *** END OF THE PROJECT GUTENBERG EBOOK LE DÉMON
SECRET ***

Updated editions will replace the previous one—the old editions will
be renamed.

Creating the works from print editions not protected by U.S.

copyright law means that no one owns a United States copyright in
these works, so the Foundation (and you!) can copy and distribute it
in the United States without permission and without paying copyright
royalties. Special rules, set forth in the General Terms of Use part of
this license, apply to copying and distributing Project Gutenberg™
electronic works to protect the PROJECT GUTENBERG™ concept
and trademark. Project Gutenberg is a registered trademark, and
may not be used if you charge for an eBook, except by following the
terms of the trademark license, including paying royalties for use of
the Project Gutenberg trademark. If you do not charge anything for
copies of this eBook, complying with the trademark license is very
easy. You may use this eBook for nearly any purpose such as
creation of derivative works, reports, performances and research.
Project Gutenberg eBooks may be modified and printed and given
away—you may do practically ANYTHING in the United States with
eBooks not protected by U.S. copyright law. Redistribution is subject
to the trademark license, especially commercial redistribution.

START: FULL LICENSE

THE FULL PROJECT GUTENBERG LICENSE
 PLEASE READ THIS BEFORE YOU DISTRIBUTE OR USE THIS WORK

To protect the Project Gutenberg™ mission of promoting the free

distribution of electronic works, by using or distributing this work (or
any other work associated in any way with the phrase “Project
Gutenberg”), you agree to comply with all the terms of the Full
Project Gutenberg™ License available with this file or online at
www.gutenberg.org/license.

Section 1. General Terms of Use and

Redistributing Project Gutenberg™
electronic works
1.A. By reading or using any part of this Project Gutenberg™
electronic work, you indicate that you have read, understand, agree
to and accept all the terms of this license and intellectual property
(trademark/copyright) agreement. If you do not agree to abide by all
the terms of this agreement, you must cease using and return or
destroy all copies of Project Gutenberg™ electronic works in your
possession. If you paid a fee for obtaining a copy of or access to a
Project Gutenberg™ electronic work and you do not agree to be
bound by the terms of this agreement, you may obtain a refund from
the person or entity to whom you paid the fee as set forth in
paragraph 1.E.8.

1.B. “Project Gutenberg” is a registered trademark. It may only be

used on or associated in any way with an electronic work by people
who agree to be bound by the terms of this agreement. There are a
few things that you can do with most Project Gutenberg™ electronic
works even without complying with the full terms of this agreement.
See paragraph 1.C below. There are a lot of things you can do with
Project Gutenberg™ electronic works if you follow the terms of this
agreement and help preserve free future access to Project
Gutenberg™ electronic works. See paragraph 1.E below.
1.C. The Project Gutenberg Literary Archive Foundation (“the
Foundation” or PGLAF), owns a compilation copyright in the
collection of Project Gutenberg™ electronic works. Nearly all the
individual works in the collection are in the public domain in the
United States. If an individual work is unprotected by copyright law in
the United States and you are located in the United States, we do
not claim a right to prevent you from copying, distributing,
performing, displaying or creating derivative works based on the
work as long as all references to Project Gutenberg are removed. Of
course, we hope that you will support the Project Gutenberg™
mission of promoting free access to electronic works by freely
sharing Project Gutenberg™ works in compliance with the terms of
this agreement for keeping the Project Gutenberg™ name
associated with the work. You can easily comply with the terms of
this agreement by keeping this work in the same format with its
attached full Project Gutenberg™ License when you share it without
charge with others.

1.D. The copyright laws of the place where you are located also
govern what you can do with this work. Copyright laws in most
countries are in a constant state of change. If you are outside the
United States, check the laws of your country in addition to the terms
of this agreement before downloading, copying, displaying,
performing, distributing or creating derivative works based on this
work or any other Project Gutenberg™ work. The Foundation makes
no representations concerning the copyright status of any work in
any country other than the United States.

1.E. Unless you have removed all references to Project Gutenberg:

1.E.1. The following sentence, with active links to, or other

immediate access to, the full Project Gutenberg™ License must
appear prominently whenever any copy of a Project Gutenberg™
work (any work on which the phrase “Project Gutenberg” appears, or
with which the phrase “Project Gutenberg” is associated) is
accessed, displayed, performed, viewed, copied or distributed:
 This eBook is for the use of anyone anywhere in the United
States and most other parts of the world at no cost and with
almost no restrictions whatsoever. You may copy it, give it away
or re-use it under the terms of the Project Gutenberg License
included with this eBook or online at www.gutenberg.org. If you
are not located in the United States, you will have to check the
laws of the country where you are located before using this
eBook.

1.E.2. If an individual Project Gutenberg™ electronic work is derived

from texts not protected by U.S. copyright law (does not contain a
notice indicating that it is posted with permission of the copyright
holder), the work can be copied and distributed to anyone in the
United States without paying any fees or charges. If you are
redistributing or providing access to a work with the phrase “Project
Gutenberg” associated with or appearing on the work, you must
comply either with the requirements of paragraphs 1.E.1 through
1.E.7 or obtain permission for the use of the work and the Project
Gutenberg™ trademark as set forth in paragraphs 1.E.8 or 1.E.9.

1.E.3. If an individual Project Gutenberg™ electronic work is posted

with the permission of the copyright holder, your use and distribution
must comply with both paragraphs 1.E.1 through 1.E.7 and any
additional terms imposed by the copyright holder. Additional terms
will be linked to the Project Gutenberg™ License for all works posted
with the permission of the copyright holder found at the beginning of
this work.

1.E.4. Do not unlink or detach or remove the full Project

Gutenberg™ License terms from this work, or any files containing a
part of this work or any other work associated with Project
Gutenberg™.

1.E.5. Do not copy, display, perform, distribute or redistribute this

electronic work, or any part of this electronic work, without
prominently displaying the sentence set forth in paragraph 1.E.1 with
active links or immediate access to the full terms of the Project
Gutenberg™ License.
1.E.6. You may convert to and distribute this work in any binary,
compressed, marked up, nonproprietary or proprietary form,
including any word processing or hypertext form. However, if you
provide access to or distribute copies of a Project Gutenberg™ work
in a format other than “Plain Vanilla ASCII” or other format used in
the official version posted on the official Project Gutenberg™ website
(www.gutenberg.org), you must, at no additional cost, fee or expense
to the user, provide a copy, a means of exporting a copy, or a means
of obtaining a copy upon request, of the work in its original “Plain
Vanilla ASCII” or other form. Any alternate format must include the
full Project Gutenberg™ License as specified in paragraph 1.E.1.

1.E.7. Do not charge a fee for access to, viewing, displaying,

performing, copying or distributing any Project Gutenberg™ works
unless you comply with paragraph 1.E.8 or 1.E.9.

1.E.8. You may charge a reasonable fee for copies of or providing

access to or distributing Project Gutenberg™ electronic works
provided that:

• You pay a royalty fee of 20% of the gross profits you derive from
the use of Project Gutenberg™ works calculated using the
method you already use to calculate your applicable taxes. The
fee is owed to the owner of the Project Gutenberg™ trademark,
but he has agreed to donate royalties under this paragraph to
the Project Gutenberg Literary Archive Foundation. Royalty
payments must be paid within 60 days following each date on
which you prepare (or are legally required to prepare) your
periodic tax returns. Royalty payments should be clearly marked
as such and sent to the Project Gutenberg Literary Archive
Foundation at the address specified in Section 4, “Information
about donations to the Project Gutenberg Literary Archive
Foundation.”

• You provide a full refund of any money paid by a user who

notifies you in writing (or by e-mail) within 30 days of receipt that
s/he does not agree to the terms of the full Project Gutenberg™
License. You must require such a user to return or destroy all
 copies of the works possessed in a physical medium and
discontinue all use of and all access to other copies of Project
Gutenberg™ works.

• You provide, in accordance with paragraph 1.F.3, a full refund of

any money paid for a work or a replacement copy, if a defect in
the electronic work is discovered and reported to you within 90
days of receipt of the work.

• You comply with all other terms of this agreement for free
distribution of Project Gutenberg™ works.

1.E.9. If you wish to charge a fee or distribute a Project Gutenberg™

electronic work or group of works on different terms than are set
forth in this agreement, you must obtain permission in writing from
the Project Gutenberg Literary Archive Foundation, the manager of
the Project Gutenberg™ trademark. Contact the Foundation as set
forth in Section 3 below.

1.F.

1.F.1. Project Gutenberg volunteers and employees expend

considerable effort to identify, do copyright research on, transcribe
and proofread works not protected by U.S. copyright law in creating
the Project Gutenberg™ collection. Despite these efforts, Project
Gutenberg™ electronic works, and the medium on which they may
be stored, may contain “Defects,” such as, but not limited to,
incomplete, inaccurate or corrupt data, transcription errors, a
copyright or other intellectual property infringement, a defective or
damaged disk or other medium, a computer virus, or computer
codes that damage or cannot be read by your equipment.

1.F.2. LIMITED WARRANTY, DISCLAIMER OF DAMAGES - Except

for the “Right of Replacement or Refund” described in paragraph
1.F.3, the Project Gutenberg Literary Archive Foundation, the owner
of the Project Gutenberg™ trademark, and any other party
distributing a Project Gutenberg™ electronic work under this
agreement, disclaim all liability to you for damages, costs and
expenses, including legal fees. YOU AGREE THAT YOU HAVE NO
REMEDIES FOR NEGLIGENCE, STRICT LIABILITY, BREACH OF
WARRANTY OR BREACH OF CONTRACT EXCEPT THOSE
PROVIDED IN PARAGRAPH 1.F.3. YOU AGREE THAT THE
FOUNDATION, THE TRADEMARK OWNER, AND ANY
DISTRIBUTOR UNDER THIS AGREEMENT WILL NOT BE LIABLE
TO YOU FOR ACTUAL, DIRECT, INDIRECT, CONSEQUENTIAL,
PUNITIVE OR INCIDENTAL DAMAGES EVEN IF YOU GIVE
NOTICE OF THE POSSIBILITY OF SUCH DAMAGE.

1.F.3. LIMITED RIGHT OF REPLACEMENT OR REFUND - If you

discover a defect in this electronic work within 90 days of receiving it,
you can receive a refund of the money (if any) you paid for it by
sending a written explanation to the person you received the work
from. If you received the work on a physical medium, you must
return the medium with your written explanation. The person or entity
that provided you with the defective work may elect to provide a
replacement copy in lieu of a refund. If you received the work
electronically, the person or entity providing it to you may choose to
give you a second opportunity to receive the work electronically in
lieu of a refund. If the second copy is also defective, you may
demand a refund in writing without further opportunities to fix the
problem.

1.F.4. Except for the limited right of replacement or refund set forth in
paragraph 1.F.3, this work is provided to you ‘AS-IS’, WITH NO
OTHER WARRANTIES OF ANY KIND, EXPRESS OR IMPLIED,
INCLUDING BUT NOT LIMITED TO WARRANTIES OF
MERCHANTABILITY OR FITNESS FOR ANY PURPOSE.

1.F.5. Some states do not allow disclaimers of certain implied

warranties or the exclusion or limitation of certain types of damages.
If any disclaimer or limitation set forth in this agreement violates the
law of the state applicable to this agreement, the agreement shall be
interpreted to make the maximum disclaimer or limitation permitted
by the applicable state law. The invalidity or unenforceability of any
provision of this agreement shall not void the remaining provisions.
1.F.6. INDEMNITY - You agree to indemnify and hold the
Foundation, the trademark owner, any agent or employee of the
Foundation, anyone providing copies of Project Gutenberg™
electronic works in accordance with this agreement, and any
volunteers associated with the production, promotion and distribution
of Project Gutenberg™ electronic works, harmless from all liability,
costs and expenses, including legal fees, that arise directly or
indirectly from any of the following which you do or cause to occur:
(a) distribution of this or any Project Gutenberg™ work, (b)
alteration, modification, or additions or deletions to any Project
Gutenberg™ work, and (c) any Defect you cause.

Section 2. Information about the Mission of

Project Gutenberg™
Project Gutenberg™ is synonymous with the free distribution of
electronic works in formats readable by the widest variety of
computers including obsolete, old, middle-aged and new computers.
It exists because of the efforts of hundreds of volunteers and
donations from people in all walks of life.

Volunteers and financial support to provide volunteers with the

assistance they need are critical to reaching Project Gutenberg™’s
goals and ensuring that the Project Gutenberg™ collection will
remain freely available for generations to come. In 2001, the Project
Gutenberg Literary Archive Foundation was created to provide a
secure and permanent future for Project Gutenberg™ and future
generations. To learn more about the Project Gutenberg Literary
Archive Foundation and how your efforts and donations can help,
see Sections 3 and 4 and the Foundation information page at
www.gutenberg.org.

Section 3. Information about the Project

Gutenberg Literary Archive Foundation
The Project Gutenberg Literary Archive Foundation is a non-profit
501(c)(3) educational corporation organized under the laws of the
state of Mississippi and granted tax exempt status by the Internal
Revenue Service. The Foundation’s EIN or federal tax identification
number is 64-6221541. Contributions to the Project Gutenberg
Literary Archive Foundation are tax deductible to the full extent
permitted by U.S. federal laws and your state’s laws.

The Foundation’s business office is located at 809 North 1500 West,

Salt Lake City, UT 84116, (801) 596-1887. Email contact links and up
to date contact information can be found at the Foundation’s website
and official page at www.gutenberg.org/contact

Section 4. Information about Donations to

the Project Gutenberg Literary Archive
Foundation
Project Gutenberg™ depends upon and cannot survive without
widespread public support and donations to carry out its mission of
increasing the number of public domain and licensed works that can
be freely distributed in machine-readable form accessible by the
widest array of equipment including outdated equipment. Many small
donations ($1 to $5,000) are particularly important to maintaining tax
exempt status with the IRS.

The Foundation is committed to complying with the laws regulating

charities and charitable donations in all 50 states of the United
States. Compliance requirements are not uniform and it takes a
considerable effort, much paperwork and many fees to meet and
keep up with these requirements. We do not solicit donations in
locations where we have not received written confirmation of
compliance. To SEND DONATIONS or determine the status of
compliance for any particular state visit www.gutenberg.org/donate.

While we cannot and do not solicit contributions from states where

we have not met the solicitation requirements, we know of no
prohibition against accepting unsolicited donations from donors in
such states who approach us with offers to donate.

International donations are gratefully accepted, but we cannot make

any statements concerning tax treatment of donations received from
outside the United States. U.S. laws alone swamp our small staff.

Please check the Project Gutenberg web pages for current donation
methods and addresses. Donations are accepted in a number of
other ways including checks, online payments and credit card
donations. To donate, please visit: www.gutenberg.org/donate.

Section 5. General Information About Project

Gutenberg™ electronic works
Professor Michael S. Hart was the originator of the Project
Gutenberg™ concept of a library of electronic works that could be
freely shared with anyone. For forty years, he produced and
distributed Project Gutenberg™ eBooks with only a loose network of
volunteer support.

Project Gutenberg™ eBooks are often created from several printed

editions, all of which are confirmed as not protected by copyright in
the U.S. unless a copyright notice is included. Thus, we do not
necessarily keep eBooks in compliance with any particular paper
edition.

Most people start at our website which has the main PG search
facility: www.gutenberg.org.

This website includes information about Project Gutenberg™,

including how to make donations to the Project Gutenberg Literary
Archive Foundation, how to help produce our new eBooks, and how
to subscribe to our email newsletter to hear about new eBooks.