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a-TERTIARY AMINES EN ROUTE
TO NATURAL PRODUCTS
This page intentionally left blank
VISUAL GUIDES TO NATURAL PRODUCT
SYNTHESIS SERIES

a-TERTIARY
AMINES EN
ROUTE TO
NATURAL
PRODUCTS
ABDUL HAMEED
MARIYA AL-RASHIDA
MUHAMMAD RAZA SHAH
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
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permission, further information about the Publisher’s permissions policies and our arrange-
ments 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
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A catalogue record for this book is available from the British Library
ISBN: 978-0-12-822262-1

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 Contents

Preface xi

1. Natural products with a-tertiary amine 1

1.1 Abstract 1
References 3

2. Altemicidin 5
2.1 Abstract 5
2.2 Kende’s first total (
)-altemicidin synthesis 6
2.3 Kan’s approach toward altemicidin Bicyclo[3.3.0]
framework (2008) 7
2.4 Kan’s total synthesis of SB-203207: an altemicidin’s
analogue (2014) 8
2.5 Hayakawa’s studies toward altemicidin’s analogue (SB-203207) 9
References 10

3. Amathaspiramides AeF 11
3.1 Abstract 11
3.2 Trauner’s first total synthesis of (
)-amathaspiramide F (2002) 11
3.3 Ohfune’s (
)-total synthesis of (
)-amathaspiramide F (2008) 13
3.4 Fukuyama’s total syntheses of (
)-amathaspiramides (2012) 13
3.5 Tambar’s formal synthesis of ()-amathaspiramide F (2013) 13
3.6 Lee’s synthesis of amathaspiramide C (2015) 15
3.7 Sun’s synthesis of amathaspiramides B, D, and F (2016) 15
3.8 Kim’s synthesis of (
)-amathaspiramide F (2018) 15
References 18

4. Cephalotaxine 19
4.1 Abstract 19
4.2 Biosynthesis 20
4.3 Weinreb’s first total ()-cephalotaxine synthesis (1975) 20
4.4 Semmelhack’s total synthesis of cephalotaxine (1975) 20
4.5 Hanaoka’s first-generation ()-total synthesis (1986) 21
4.6 Hanaoka’s second-generation formal synthesis (1988) 22
4.7 Kuehne’s total synthesis (1988) 22
4.8 Fuchs’s total synthesis of ()-cephalotaxine (1988) 23

v
vi Contents

4.9 Ikeda’s total racemic synthesis (1990/1993) 23

4.10 Mori’s asymmetric (
)-cephalotaxine synthesis (1995) 23
4.11 Mariano’s synthesis via two interrelated strategies (1996) 24
4.12 Nagasaka’s synthesis of (
)-cephalotaxine (1997) 25
4.13 El Bialy’s formal synthesis (1998) 25
4.14 Ikeda’s formal synthesis (1999) 25
4.15 Tietze’s synthetic approach (1999) 26
4.16 Nagasaka’s synthesis (2002) 27
4.17 Yoshida’s formal synthesis (2002) 27
4.18 Li’s synthesis (2003) 27
4.19 Royer’s synthesis via semipinacolic
rearrangement (2004) 28
4.20 Li’s second-generation formal synthesis (2005) 28
4.21 Li’s synthesis of DolbyeWeinreb enamine 29
4.22 Mariano’s formal synthesis via photocyclization
reaction (2006) 29
4.23 Gin’s synthetic studies (2006) 30
4.24 Li’s formal synthesis (2007) 30
4.25 Stoltz’s formal synthesis via Pd-catalyzed aerobic oxidative
heterocyclization chemistry (2007) 31
4.26 Ishibashi’s total synthesis (2008) 31
4.27 Hayes’s first formal synthesis (2008) 31
4.28 Hayes’s second formal synthesis via 1,5-CH insertion
reaction (2008) 32
4.29 Bubnov’s approach toward cephalotaxine (2008) 32
4.30 Liu’s formal synthesis (2009) 33
4.31 Zhang synthesis (2009) 33
4.32 Li’s total synthesis (2011) 33
4.33 Tu’s (
)-formal synthesis (2012) 34
4.34 Renaud’s (
)-formal synthesis (2012) 34
4.35 Zhang-Liu’s formal synthesis (2012) 34
4.36 Jiang’s formal synthesis (2013) 35
4.37 Huang’s formal synthesis (2013) 36
4.38 Huang’s formal synthesis (2015) 36
4.39 Hong’s formal synthesis (2015) 37
4.40 Chandrasekhar’s formal total synthesis (2016) 38
4.41 Fan’s total synthesis (2017) 39
4.42 Beaudry’s (
)-total synthesis via furan oxidationetransannular
Mannich cyclization (2019) 41
4.43 Kim’s formal (
)-total synthesis (2019) 41
References 63

5. Kaitocephalin 67
5.1 Abstract 67
5.2 Kitahara’s total synthesis (2002) 68
5.3 Kitahara’s total synthesis (2002) 68
5.4 Ohfune’s total enantioselective synthesis (2005) 68
 Contents vii

5.5 Chamberlin’s total synthesis (2008) 68

5.6 Ohfune’s total enantioselective synthesis (2009) 69
5.7 Ma’s reinvestigation of kaitocephalin (2011) 69
5.8 Hatakeyama’s total synthesis (2012) 69
5.9 Kang’s kaitocephalin total synthesis (2013) 72
5.10 Garner’s synthesis via [C þ NC þ C] coupling (2014) 76
5.11 Dhavale’s formal synthesis (2014) 77
5.12 Lee’s total synthesis (2019) 78
References 79

6. Lactacystin 81
6.1 Abstract 81
6.2 Biosynthesis of lactacystin 82
6.3 Corey’s first total synthesis of (þ)-lactacystin (1992) 83
6.4 Corey’s revised synthesis (1998) 83
6.5 Corey’s second-generation synthesis (1998) 83
6.6 Corey’s synthesis of a-methylomuralide (2003) 83
6.7 Smith-Õmura’s (þ)-total synthesis (1993/1996) 83
6.8 Baldwin’s (þ)-total synthesis (1994) 84
6.9 Chida’s (þ)-total synthesis (1997) 84
6.10 Kang’s formal synthesis (1998) 85
6.11 Adams clasto-lactacystin synthesis (1999) 85
6.12 Panek Total Synthesis (1999) 85
6.13 Ohfune synthesis (2000) 86
6.14 Pattenden’s formal synthesis (2003) 86
6.15 Hatakeyama’s total synthesis (2004) 87
6.16 Donohoe’s racemic synthesis (2004) 87
6.17 Wardrop’s formal synthesis (2005) 87
6.18 Jacobsen’s total synthesis (2006) 87
6.19 Shibasaki’s total synthesis (2006) 88
6.20 Hayes’s total synthesis via 1,5-CH insertion (2008) 88
6.21 Hayes’s formal synthesis (2010) 89
6.22 Silverman’s total synthesis (2011) 89
6.23 Inoue’s total synthesis (2015) 89
6.24 Chandrasekhar’s formal synthesis (2019) 90
6.25 Page’s formal synthesis (2019) 90
6.26 Poisson’s (
)-omuralide synthesis (2019) 90
References 102

7. Salinosporamide A 105
7.1 Abstract 105
7.2 Corey’s first total synthesis of salinosporamide A (2004) 106
7.3 Second-generation improved synthesis (2005) 107
7.4 Danishefsky enantioselective synthesis (2005) 108
7.5 Pattenden racemic synthesis (2006) 109
7.6 Lam’s formal synthesis (2008) 109
viii Contents

7.7 Romo’s asymmetric total synthesis (2011) 110

7.8 Ling’s formal synthesis (2010) 111
7.9 Fukuyama’s total synthesis (2011) 112
7.10 Chida’s total synthesis (2011) 113
7.11 Lannou’s approach (2012) 114
7.12 Burton’s (
)-formal synthesis (2014) 114
7.13 Gonda’s approach (2016) 115
7.14 Burton’s total synthesis (2018) 116
References 117

8. Manzacidins 119
8.1 Ohfune’s total synthesis of manzacidin
A and C (2000) 120
8.2 Du Bois’ enantioselective manzacidins
A and C syntheses (2002) 121
8.3 Mackay’s ()-manzacidin D synthesis (2004) 122
8.4 Lanter’s manzacidin C synthesis (2005) 122
8.5 Maruoka’s manzacidins A synthesis (2005) 123
8.6 Deng’s formal synthesis of manzacidin A via tandem conjugate
additioneprotonation (2006) 124
8.7 Sibi’s manzacidin A synthesis (2007) 125
8.8 Ohfune’s synthesis of manzacidin B (2007) 125
8.9 Leighton’s manzacidin C synthesis (2008) 127
8.10 Ohfune’s manzacidins A and C synthesis (2008) 128
8.11 Mohapatra’s synthesis of manzacidin B (2012) 129
8.12 Ohfune’s synthesis of manzacidin B (2012) 130
8.13 Kawabata’s manzacidin A synthesis (2013) 131
8.14 Ichikawa’s manzacidins A and C synthesis (2012) 132
8.15 Inoue’s manzacidin A synthesis (2015) 133
8.16 Sakakura’s synthesis of mazacidins A and C (2017) 134
8.17 Ukaji’s formal synthesis of manzacidin (2017) 135
8.18 Renata’s formal synthesis of manzacidin C (2018) 136
References 136

9. Neooxazolomycin 139
9.1 Kende’s first enantioselective total neooxazolomycin
synthesis (1990) 140
9.2 Hatakeyama‘s total neooxazolomycin synthesis (2007) 141
9.3 Hatakeyama‘s total oxazolomycin synthesis (2011) 142
9.4 Pattenden’s approach toward oxazolomycin A and
neooxazolomycin synthesis (2007) 143
9.5 Moloney’s approach toward oxazolomycin (2002) 144
9.6 Taylor’s formal synthesis of (þ)-neooxazolomycin (2011) 145
9.7 Mohapatra‘s approach toward oxazolomycin (2006) 146
9.8 Donohoe‘s approach toward pyrrolidinone core of
oxazolomycin A (2012) 147
References 148
 Contents ix

10. Sphingofungins 149

10.1 Abstract 149
10.2 Kobayashi’s asymmetric synthesis of sphingofungin F (1998) 150
10.3 Trost’s total synthesis of sphingofungin F (1998) 151
10.4 Trost’s total synthesis of sphingofungin F (2001) 152
10.5 Trost’s total synthesis of sphingofungin E (2001) 153
10.6 Lin’s total synthesis of sphingofungin F (2000) 154
10.7 Shiozaki’s total synthesis of sphingofungin E (2001) 155
10.8 Lin’s total synthesis of sphingofungin E (2001) 156
10.9 Chida’s total synthesis of sphingofungin E (2002) 157
10.10 Chida’s total synthesis of sphingofungin E (2002) 158
10.11 Ham’s total synthesis of sphingofungin F (2002) 159
10.12 Hayes’s approach toward sphingofungin E (2006) 160
10.13 Xu’s total synthesis of sphingofungin F (2010) 161
10.14 Martinková’s total synthesis of sphingofungin E (2010) 162
10.15 Kan’s total synthesis of sphingofungin E (2013) 163
10.16 Chida’s total synthesis of sphingofungin F (2015) 164
10.17 Yakura’s total synthesis of sphingofungin E (2017) 165
References 165

11. (
)-FR901483 and TAN1251 (A-D) 167

11.1 Abstract 167
11.2 Proposed biosynthesis of FR901483 and TAN1251 168
11.3 Sinder’s total synthesis of (
)-FR901483 (1999) 168
11.4 Sorensen’s synthesis via oxidative cyclization (2000) 171
11.5 Ciufolini’s synthesis via oxidative cyclization (2001) 172
11.6 Funk’s total synthesis (2001) 173
11.7 Wardrop’s formal synthesis of ()-desmethylamino FR901483 (2001) 174
11.8 Fukuyama’s total synthesis (2004) 175
11.9 Brummond’s formal synthesis (2005) 176
11.10 Kerr’s total synthesis via ring-opening/annulation reaction (2009) 177
11.11 Fukuyama’s intermediate synthesis of FR901483 (2010) 178
11.12 Bonjoch’s tricyclic skeleton of FR901483 (2003) 179
11.13 Weinreb’s studies toward total synthesis (2006) 180
11.14 Reissig’s approach toward azaspirane core of FR901483 (2006) 180
11.15 Huang’s formal enantioselective synthesis of (
)-FR901483 (2012) 181
11.16 Huang’s enantioselective total syntheses of (
)-FR901483 and
(þ)-8-epi-FR901483 (2013) 182
11.17 Gaunt’s syntheses of (
)-FR901483 and (þ)-TAN1251C (2019) 184
References 185

12. Synthetic approach to the TAN1251 alkaloids 187

12.1 Kawahara’s total synthesis of TAN1251A (2002) 187
12.2 Kawahara’s total synthesis of (
)-TAN1251A (2002) 188
12.3 Wardrop’s formal synthesis of (
)-TAN1251A (2001) 189
12.4 Snider’s biomimetic total syntheses of TAN1251AeD (2000) 190
12.5 Ciufolini’s approach via oxidative cyclization (2001) 192
x Contents

12.6 Honda’s formal synthesis (
)-TAN1251A (2002) 193

12.7 Honda’s enantiospecific total synthesis of TAN1251C
and D (2002) 194
12.8 Hayes’s enantioselective total synthesis of (
)-TAN1251A (2000) 195
12.9 Peiqiang’s enantioselective synthesis key core of TAN1251C 196
12.10 Kan’s total synthesis of TAN1251C (2017) 197
References 198

13. (1S,3R)-1-Aminocyclopentane-1,3-diarboxylic acid (ACPD) 199

13.1 Abstract 199
13.2 Ma’s total synthesis of (1S,3R)-1-aminocyclopentane-1,3-diarboxylic
acid (1997) 200
13.3 Hodgson’s total (1S,3R)-1-aminocyclopentane-1,3-diarboxylic
acid synthesis via hydroboration 200
13.4 Hayes’s total (1S,3R)-1-aminocyclopentane-1,3-diarboxylic
acid synthesis via 1,5-CH insertion 201
References 201

14. Tetrodotoxin 203

14.1 Abstract 203
14.2 Du Bois’s stereoselective synthesis of (
)-tetrodotoxin (2003) 203
14.3 Isobe’s first asymmetric total synthesis (2003) 204
14.4 Isobe’s efficient total synthesis of tetrodotoxin (2004) 204
14.5 Sato’s stereocontrolled synthesis of ()-tetrodotoxin (2005) 206
14.6 Ohfune’s synthesis of (
)-5,6,11-trideoxytetrodotoxin and
its 4-epimer (2006) 206
14.7 Sato’s stereoselective synthesis of tetrodotoxin (2007) 206
14.8 Nishikawa’s synthesis of (
)-5,11-dideoxytetrodotoxin (2013) 208
14.9 Ciufolin’s formal synthesis of ()-tetrodotoxin (2015) 219
14.10 Fukuyama’s total synthesis of (
)-tetrodotoxin (2017) 220
References 221

Index 223
 Preface

To date, Nature continues to be the greatest reservoir of astonishingly

diverse array of structural diversity observed in chemical space; interest-
ingly a lot of this chemical space is speculated to be yet unexplored.
All living organisms including the microbes synthesize a plethora of
biologically active compounds de novo in their cells and tissues. These
active molecules are vital for sustenance of life and associated delicate
ecosystems. Since the beginning, it has been the deepest desire of man to
harness this power of nature for therapeutic intervention and prevention
of diseases. A significant chunk of modern medicinal and pharmaceutical
chemistry is based on either pure natural products or synthetic compounds
having scaffolds inspired and derived from the natural products. Hence,
natural products, by virtue of their vast structural diversity, continue to
hold the fascination of synthetic chemists.
Herein, we propose a book series that will cover the area of total syn-
thesis of natural products. The multistep syntheses of natural products
will be presented in easy-to-grasp schemes, highlighting the key steps
involved in synthetic layout. This visual guide will provide a quick and
easy way to read and to understand the new/novel synthetic strategies
to construct the whole structural framework of natural products. The
visual guide on natural products synthesis will deliver express access to
read and understand the synthetic strategies. Volume I will cover the class
of natural products bearing a-tertiary amine motif. Some of the examples
of such natural products include altemicidin, amathaspiramide (AeF),
kaitocephalin, lactacystin, salinosporamide, manzacidins, neooxazolomy-
cin, sphingofungins, (1S,3R)-1-aminocyclopentane-1,3-diarboxylic acid
(ACPD), and tetrodotoxin. These molecules have gained much popularity
among synthetic chemists. A large number of synthetic approaches and
total syntheses of these molecules have been published. Thus, the
collection of natural product syntheses in this book will provide a quick
and an easy access to the readers to get the gist of synthetic route toward
the targeted natural products.

xi
This page intentionally left blank
 C H A P T E R

1
Natural products with a-tertiary
amine

1.1 Abstract

Natural products isolated from various sources such as plants, marine

life forms, fungus, algae, and bacteria have been the greatest source of
design inspiration for synthesis of biologically active molecules and drugs
targeting various diseases. These natural products provide an almost
unlimited source of biologically active unique molecules and novel
scaffolds. These molecules are constantly being synthesized de novo,
inside the living cells, and serve various purposes from simple survival to
growth and defense. Such molecules serve as a design template for
synthetic chemists and medicinal chemists for the synthesis of molecules
with specific biological activities. Most of the drugs available in the
market are based on natural products. Alkaloids are a unique class of
natural products that have been vital in the development of drugs against
various diseases (Fig. 1.1).
It has long been the quest of synthetic organic chemistry to come up
with the design and experiments for in-lab synthesis of naturally occur-
ring molecules and their derivatives. Although the staggering structural
complexity and multiple stereocenters in alkaloids have proved to be a
challenge from synthetic chemistry point of view, this structural diversity
is responsible for the activity of these molecules against various biological
targets, hence their potential to treat different diseases.
On the basis of structural diversity, alkaloids have been classified into
different groups, among which the natural products bearing a-tertiary
amine moiety have attracted considerable attention from the synthetic
community. Among the pool of natural products having N-quaternary
center, we have selected the most popular natural products such as

a-Tertiary Amines en Route to Natural Products

https://doi.org/10.1016/B978-0-12-822262-1.00001-9 1 © 2021 Elsevier Inc. All rights reserved.
2 1. Natural products with a-tertiary amine

O
O
SO2NH2
HHN CO H O
Me 2 N R A B
C N
N N D
OH H O
OH H E
H O
Br HO
O NH2 OMe
Br Amathaspiramides Cephalotaxine
Altemicidin

Cl Cl
HO OH O
H CO2H O
N OH O N
Cl NH2 O H OH
H N N S NHAc
O CO2H H H H
HO CO2H O
CO2H
Kaitocephalin Lactacystin
Salinosporamide A

Br O
HN N
H2N CO2H HO
O 5 H OO
N 4 CO2H HO2C H2N N
H OH
O OH ACPD N
Manzacidin B H HO
OH
Tetrodotoxin OH

O
N

O
OH OH O
O
OH OH
O O
OH NH2 R
N
R = Me, CH2OH HO N
H HO
OH O
Sphingofungins Neooxazolomycin

OMe

N
HO NHMe N
N O
R
H
O O
HCl
(HO)2P O R = H, TAN1251A
(–)-FR901483 R = OH, TAN1251B

FIGURE 1.1 Structures of different natural products containing a-tert-alkylamino carbon

center.
 References 3

altemicidin, amathaspiramides, cephalotaxine, kaitocephalin, lactacystin,

salinosporamide, manzacidines, tetradoxtin, neooxazolomycin, sphingo-
fungins, ACPD, TAN1251A & B, and ( )-FR901483 with diverse enantio-
and diaseteroselective methodologies to construct tetra-substituted carbon
center surrounded by three carbons and one nitrogen atom, i.e., a-tert-
alkylamino carbon center1 or in case of bearing acid moiety, termed as a,a-
disubstituted-a-amino acid.2

References
1. (a) Mailyan, A. K.; Eickhoff, J. A.; Minakova, A. S.; Gu, Z.; Lu, P.; Zakarian, A. Cutting-
Edge and Time-Honored Strategies for Stereoselective Construction of CeN Bonds in
Total Synthesis. Chem. Rev. 2016, 116, 4441e4557.
(b) Kang, S. H.; Kang, S. Y.; Lee, H.-S.; Buglass, A. J. Total Synthesis of Natural Tert-Alky-
lamino Hydroxy Carboxylic Acids. Chem. Rev. 2005, 105, 4537e4558.
2. Ohfune, Y.; Shinada, T. Enantio and Diastereoselective Construction of a, a-disubstituted
a-amino Acids for the Synthesis of Biologically Active Compounds. Eur. J. Org Chem.
2005, 2005, 5127e5143.
This page intentionally left blank
 C H A P T E R

2
Altemicidin

2.1 Abstract

( )-Altemicidin is an interesting naturally occurring 6-azainden

monoterpene sulfonamide alkaloid that exhibits strong inhibition
against tumor cells and has potent acaricidal activity. ( )-Altemicidin 1
was isolated by Takahashi research group in 1989 from the actinomycete
strain Streptomyces sioyaensis.1 The acylated structure of the altemicidin
showed strong inhibitory activity against isoleucyl, leucyl, and valyl
tRNA synthetase.2 The interesting biological properties and complex
structural features of ( )-altemicidin make it an attractive target for
synthetic organic chemists (Fig. 2).
The structural features of altemicidin include a core 6-azainden ring,
b-hydroxy group at C-2 position, and key a,a-dialkyl-a-amino acid
moiety at C-1 position. So far, only three synthetic approaches toward this
alkaloid have been reported. The first enantioselective total synthesis of
altemicidin was carried out by Kende’s group via DielseAlder reaction to
construct C-1 N-bearing quaternary center and PotierePolonovski rear-
rangement in the synthetic sequence. Later, Kan’s group built the ster-
eocontrolled core framework of altemicidin as an advanced intermediate.
Further, the Kan’s group competed the total synthesis of altemicidin
derivative SB-203202 via desymmetrical C H insertion reaction and
Curtius rearrangement in an enantioselective way. The schematic outlook
of all approaches has been presented in the coming section.

FIGURE 2 Structure of altemicidin.

a-Tertiary Amines en Route to Natural Products

https://doi.org/10.1016/B978-0-12-822262-1.00002-0 5 © 2021 Elsevier Inc. All rights reserved.
6 2. Altemicidin

2.2 Kende’s first total (L)-altemicidin synthesis

See (Scheme 1).

SCHEME 1 Total synthesis of ( )-altemicidin via PotierePolonovski rearrangement.3

 2.3 Kan’s approach toward altemicidin Bicyclo[3.3.0] framework (2008) 7

2.3 Kan’s approach toward altemicidin Bicyclo[3.3.0]

framework (2008)
See (Scheme 2).

SCHEME 2 Stereocontrolled construction of altemicidin core framework.4

8 2. Altemicidin

2.4 Kan’s total synthesis of SB-203207: an

altemicidin’s analogue (2014)
See (Scheme 3).

SCHEME 3 Total synthesis of altemicidin’s analog (of SB-203207).5

 2.5 Hayakawa’s studies toward altemicidin’s analogue (SB-203207) 9

2.5 Hayakawa’s studies toward altemicidin’s

analogue (SB-203207)
See (Scheme 4).

SCHEME 4 Altemicidin’s analog: formation of four contiguous nitrogen-containing

stereogenic centers.6
10 2. Altemicidin

References
1. Takahashi, A.; Kurasawa, S.; Ikeda, D.; Okami, Y.; Takeuchi, T. Altemicidin, a New Acar-
icidal and Antitumor Substance. J. Antibiot. 1989, 42, 1556e1561.
2. (a) Banwell, M. G.; Crasto, C. F.; Easton, C. J.; Forrest, A. K.; Karoli, T.; March, D. R.;
Mensah, L.; Nairn, M. R.; O’Hanlon, P. J.; Oldham, M. D. Analogues of SB-203207 as
Inhibitors of tRNA Synthetases. Bioorg. Med. Chem. Lett 2000, 10, 2263e2266.
(b) Houge-Frydrych, C. S. V.; Gilpin, M. L.; Skett, P. W.; Tyler, J. W. SB-203207 and
SB-203208, Two Novel Isoleucyl tRNA Synthetase Inhibitors from a Streptomyces Sp.
J. Antibiot. 2000, 53, 364e372.
3. (a) Kende, A. S.; Liu, K.; Jos Brands, K. Total Synthesis of (-)-Altemicidin: A Novel
Exploitation of the Potier-Polonovski Rearrangement. J. Am. Chem. Soc. 1995, 117,
10597e10598. and references therein.
(b) Kende, A. S.; Brands, K.; Blass, B. A Novel Dyatropic Rearrangement of g-N,N-diben-
zylamino a,b-dehydro N-Formylamino Acid Esters. Tetrahedron Lett. 1993, 34, 579e582.
4. Kan, T.; Kawamoto, Y.; Asakawa, T.; Furuta, T.; Fukuyama, T. Synthetic Studies on
Altemicidin: Stereocontrolled Construction of the Core Framework. Org. Lett. 2008, 10,
169e171. and references therein.
(i) Kan, T.; Inoue, T.; Kawamoto, Y.; Yonehara, M.; Fukuyama, T. A Novel Synthesis of
Bicyclo [3.3.0] Octane Ring System via a Desymmetric CH Insertion Reaction. Synlett
2006, 1583e1585, 2006.
5. Hirooka, Y.; Ikeuchi, K.; Kawamoto, Y.; Akao, Y.; Furuta, T.; Asakawa, T.; Inai, M.;
Wakimoto, T.; Fukuyama, T.; Kan, T. Enantioselective Synthesis of SB-203207. Org. Lett.
2014, 16, 1646e1649.
6. Hayakawa, I.; Nagayasu, A.; Sakakura, A. Toward the Synthesis of SB-203207: Construc-
tion of Four Contiguous Nitrogen-Containing Stereogenic Centers. J. Org. Chem. 2019, 84,
15614e15623.
 C H A P T E R

3
Amathaspiramides AeF

3.1 Abstract

The amathaspiramides AeF are a class of marine alkaloids that have

been isolated from a New Zealand collection of the bryozoan Amathia
wilsoni by Prinsep and Morris.1 The core of these alkaloids is a highly
functionalized aza-spirobicyclic structural framework possessing a-tert-
alkylamino carbon center and a hemiaminal center. The amathaspiramides
have exhibited excellent bioactivities as antiviral and antimicrobial agents,
albeit with moderate cytotoxicity. This family of structurally complex
natural products has attracted significant attention from the synthetic
chemists. There are many different synthetic methodologies reported for
total synthesis of different members of amathaspiramides AeF. Trauner
and Ohfune completed the total synthesis of amathaspiramide F, whereas
Fukuyama completed the total synthesis of AeF in a stereoselective way.
The Tambar’s group reported synthesis of amathaspiramide F, whereas
Lee et al. completed total synthesis of amathaspiramide C; formal synthesis
of AeF was reported via Fukuyama’s route. Recently, Sun’s group
reported the synthesis of amathaspiramides B, D, and F in an asymmetric
way (Fig. 3).

3.2 Trauner’s first total synthesis of

(L)-amathaspiramide F (2002)

See (Scheme 5).

a-Tertiary Amines en Route to Natural Products

https://doi.org/10.1016/B978-0-12-822262-1.00003-2 11 © 2021 Elsevier Inc. All rights reserved.
12 3. Amathaspiramides AeF

FIGURE 3 Structures of amathaspiramides AeF.

SCHEME 5 Total synthesis of (
)-amathaspiramide F via Micheal addition.2

 3.5 Tambar’s formal synthesis of ()-amathaspiramide F (2013) 13

3.3 Ohfune’s (L)-total synthesis of (L)-amathaspiramide

F (2008)
See (Scheme 6).

3.4 Fukuyama’s total syntheses of (L)-amathaspiramides

(2012)

See (Scheme 7).

3.5 Tambar’s formal synthesis of (±)-amathaspiramide F (2013)

See (Scheme 8).

I
OMOM a) PhSNH-tBu
OH
OH OH NCS; b) (+)-DIP-Cl
-40 °C, 70% (2 steps) TBS
TBS TBS
PdCl2(PPh3)2
CuI, 73%
MOMO
MOMO

a) PdCl2(PPh3)2, nBu3SnH
BCl
b) AcOH, MeOH
(+)-DIP-Cl = c) Boc-homoallylglycine
2 EDCI, DMAP,
59% (3 steps)
a) OsO4, NMO
O
b) NaIO4; c) NaBH3CN
d) p-TsOH; e) TFAA MeO2C NHBoc i) LDA (4 equiv)
O
f) Ozonlysis ZnCl2 (1.2 equiv)
g) MeN(TMS)2 THF, -78 °C to RT NH
Boc
20% (7 steps) TBS ii) then CH2N2, 88%
TBS
O CF3 MOMO Claisen rearrangement OMOM
erythro/threo (dr = 7:1)
O N

Me N a) nBu4NBrCl2
b) MeI, K2CO3
HO c) LiBH4,
HO 53% (3 steps)
(-)-Amathaspiramide F

Total synthesis of (-)-Amathaspiramide F with overall yield 1.3% in 17 steps

[ α]D24 –39.0 (c 0.30, MeOH)

SCHEME 6 Total synthesis via Claisen rearrangement.3

14 3. Amathaspiramides AeF

SCHEME 7 Total syntheses of (
)-amathaspiramides via Micheal addition.4

 3.8 Kim’s synthesis of (
)-amathaspiramide F (2018) 15

SCHEME 8 Formal synthesis of ()-amathaspiramide F via [2,3]-Stevens rearrangement.5

3.6 Lee’s synthesis of amathaspiramide C (2015)

See (Scheme 9).

3.7 Sun’s synthesis of amathaspiramides B, D, and F (2016)

See (Scheme 10).

3.8 Kim’s synthesis of (L)-amathaspiramide F (2018)

See (Scheme 11).

16 3. Amathaspiramides AeF

Path I OTBS
Br Br
MeO2C
MeO MeO
Br
MeO a) LDA, MePh2SiCl
b) LDA, Aldehyde, Br Br
MeO2C Li TMS MeO2C
Br
TMS
-78 oC; HCl; c) TsCl N2 -78 oC
Aldehyde O N N
[3+2] Cycloaddition
OTs
Path II
d) TsOH; e) HCO2H
Br Br
f) PPh3, DIAD
MeO MeO
g) DIBAL, -78 oC
13% (7 steps)
Br Br
MeO2C Li TMS O Total Amathaspiramide C
-78 oC Steps = 7
N2 N N
H Overall Yield = 13%
O Me
CO2Et Amathaspiramide C

[3+2] Cycloaddition Br
a) p-TsOH, 95%
Br Br b) HOOH, 66% MeO
MeO MeO c) MeOH, DBAD,
PS-PPh3, Br
sonication, 58%.
Br Br O
MeO2C MeO2C
SiMe3 N N
SiMe3 Steps H
N N N N Fukuyama's route (2012) O Me
Li O Amathaspiramide A-F
OEt
O

SCHEME 9 Amathaspiramide C via [3 þ 2]-cycloaddition.6

 3.8 Kim’s synthesis of (
)-amathaspiramide F (2018) 17

SCHEME 10 Amathaspiramides B, D, and F via aza-Barbier Allylation.

Another random document with
no related content on Scribd:
 2. THE COMPATIBILITY OF THE
ARITHMETICAL AXIOMS.
When we are engaged in investigating the foundations of a
science, we must set up a system of axioms which contains an exact
and complete description of the relations subsisting between the
elementary ideas of that science. The axioms so set up are at the
same time the definitions of those elementary ideas; and no
statement within the realm of the science whose foundation we are
testing is held to be correct unless it can be derived from those
axioms by means of a finite number of logical steps. Upon closer
consideration the question arises: Whether, in any way, certain
statements of single axioms depend upon one another, and whether
the axioms may not therefore contain certain parts in common, which
must be isolated if one wishes to arrive at a system of axioms that
shall be altogether independent of one another.
But above all I wish to designate the following as the most
important among the numerous questions which can be asked with
regard to the axioms: To prove that they are not contradictory, that is,
that a finite number of logical steps based upon them can never lead
to contradictory results.
In geometry, the proof of the compatibility of the axioms can be
effected by constructing a suitable field of numbers, such that
analogous relations between the numbers of this field correspond to
the geometrical axioms. Any contradiction in the deductions from the
geometrical axioms must thereupon be recognizable in the arithmetic
of this field of numbers. In this way the desired proof for the
compatibility of the geometrical axioms is made to depend upon the
theorem of the compatibility of the arithmetical axioms.
On the other hand a direct method is needed for the proof of the
compatibility of the arithmetical axioms. The axioms of arithmetic are
essentially nothing else than the known rules of calculation, with the
addition of the axiom of continuity. I recently collected them[4] and in
so doing replaced the axiom of continuity by two simpler axioms,
namely, the well-known axiom of Archimedes, and a new axiom
essentially as follows: that numbers form a system of things which is
capable of no further extension, as long as all the other axioms hold
(axiom of completeness). I am convinced that it must be possible to
find a direct proof for the compatibility of the arithmetical axioms, by
means of a careful study and suitable modification of the known
methods of reasoning in the theory of irrational numbers.
To show the significance of the problem from another point of
view, I add the following observation: If contradictory attributes be
assigned to a concept, I say, that mathematically the concept does
not exist. So, for example, a real number whose square is does
not exist mathematically. But if it can be proved that the attributes
assigned to the concept can never lead to a contradiction by the
application of a finite number of logical processes, I say that the
mathematical existence of the concept (for example, of a number or
a function which satisfies certain conditions) is thereby proved. In the
case before us, where we are concerned with the axioms of real
numbers in arithmetic, the proof of the compatibility of the axioms is
at the same time the proof of the mathematical existence of the
complete system of real numbers or of the continuum. Indeed, when
the proof for the compatibility of the axioms shall be fully
accomplished, the doubts which have been expressed occasionally
as to the existence of the complete system of real numbers will
become totally groundless. The totality of real numbers, i. e., the
continuum according to the point of view just indicated, is not the
totality of all possible series in decimal fractions, or of all possible
laws according to which the elements of a fundamental sequence
may proceed. It is rather a system of things whose mutual relations
are governed by the axioms set up and for which all propositions,
and only those, are true which can be derived from the axioms by a
finite number of logical processes. In my opinion, the concept of the
continuum is strictly logically tenable in this sense only. It seems to
me, indeed, that this corresponds best also to what experience and
intuition tell us. The concept of the continuum or even that of the
system of all functions exists, then, in exactly the same sense as the
system of integral, rational numbers, for example, or as Cantor's
higher classes of numbers and cardinal numbers. For I am
convinced that the existence of the latter, just as that of the
continuum, can be proved in the sense I have described; unlike the
system of all cardinal numbers or of all Cantor's alephs, for which, as
may be shown, a system of axioms, compatible in my sense, cannot
be set up. Either of these systems is, therefore, according to my
terminology, mathematically non-existent.
From the field of the foundations of geometry I should like to
mention the following problem:
[4] Jahresbericht der Deutchen Mathematiker-Vereinigung, vol. 8
(1900), p. 180.
 3. THE EQUALITY OF THE VOLUMES
OF TWO TETRAHEDRA OF EQUAL
BASES AND EQUAL ALTITUDES.
In two letters to Gerling, Gauss[5] expresses his regret that
certain theorems of solid geometry depend upon the method of
exhaustion, i. e. in modern phraseology, upon the axiom of continuity
(or upon the axiom of Archimedes). Gauss mentions in particular the
theorem of Euclid, that triangular pyramids of equal altitudes are to
each other as their bases. Now the analogous problem in the plane
has been solved.[6] Gerling also succeeded in proving the equality of
volume of symmetrical polyhedra by dividing them into congruent
parts. Nevertheless, it seems to me probable that a general proof of
this kind for the theorem of Euclid just mentioned is impossible, and
it should be our task to give a rigorous proof of its impossibility. This
would be obtained, as soon as we succeeded in specifying two
tetrahedra of equal bases and equal altitudes which can in no way
be split up into congruent tetrahedra, and which cannot be combined
with congruent tetrahedra to form two polyhedra which themselves
could be split up into congruent tetrahedra.[7]
[5] Werke, vol. 8, pp. 241 and 244.
[6] Cf., beside earlier literature, Hilbert, Grundlagen der
Geometric, Leipzig, 1899, ch. 4. [Translation by Townsend,
Chicago, 1902.]
[7] Since this was written Herr Dehn has succeeded in proving
this impossibility. See his note: "Ueber raumgleiche Polyeder," in
Nachrichten d. K. Gesellsch. d. Wiss. zu Göttingen, 1900, and a
paper soon to appear in the Math. Annalen [vol. 55, pp. 405-478].
4. PROBLEM OF THE STRAIGHT LINE
AS THE SHORTEST DISTANCE
BETWEEN TWO POINTS.
Another problem relating to the foundations of geometry is this:
If from among the axioms necessary to establish ordinary euclidean
geometry, we exclude the axiom of parallels, or assume it as not
satisfied, but retain all other axioms, we obtain, as is well known, the
geometry of Lobachevsky (hyperbolic geometry). We may therefore
say that this is a geometry standing next to euclidean geometry. If
we require further that that axiom be not satisfied whereby, of three
points of a straight line, one and only one lies between the other two,
we obtain Riemann's (elliptic) geometry, so that this geometry
appears to be the next after Lobachevsky's. If we wish to carry out a
similar investigation with respect to the axiom of Archimedes, we
must look upon this as not satisfied, and we arrive thereby at the
non-archimedean geometries which have been investigated by
Veronese and myself. The more general question now arises:
Whether from other suggestive standpoints geometries may not be
devised which, with equal right, stand next to euclidean geometry.
Here I should like to direct your attention to a theorem which has,
indeed, been employed by many authors as a definition of a straight
line, viz., that the straight line is the shortest distance between two
points. The essential content of this statement reduces to the
theorem of Euclid that in a triangle the sum of two sides is always
greater than the third side—a theorem which, as is easily seen,
deals solely with elementary concepts, i. e., with such as are derived
directly from the axioms, and is therefore more accessible to logical
investigation. Euclid proved this theorem, with the help of the
theorem of the exterior angle, on the basis of the congruence
theorems. Now it is readily shown that this theorem of Euclid cannot
be proved solely on the basis of those congruence theorems which
relate to the application of segments and angles, but that one of the
theorems on the congruence of triangles is necessary. We are
asking, then, for a geometry in which all the axioms of ordinary
euclidean geometry hold, and in particular all the congruence axioms
except the one of the congruence of triangles (or all except the
theorem of the equality of the base angles in the isosceles triangle),
and in which, besides, the proposition that in every triangle the sum
of two sides is greater than the third is assumed as a particular
axiom.
One finds that such a geometry really exists and is no other than
that which Minkowski constructed in his book, Geometric der Zahlen,
[8] and made the basis of his arithmetical investigations. Minkowski's
is therefore also a geometry standing next to the ordinary euclidean
geometry; it is essentially characterized by the following stipulations:
1. The points which are at equal distances from a fixed point
lie on a convex closed surface of the ordinary euclidean space with
as a center.
2. Two segments are said to be equal when one can be carried
into the other by a translation of the ordinary euclidean space.
In Minkowski's geometry the axiom of parallels also holds. By
studying the theorem of the straight line as the shortest distance
between two points, I arrived[9] at a geometry in which the parallel
axiom does not hold, while all other axioms of Minkowski's geometry
are satisfied. The theorem of the straight line as the shortest
distance between two points and the essentially equivalent theorem
of Euclid about the sides of a triangle, play an important part not only
in number theory but also in the theory of surfaces and in the
calculus of variations. For this reason, and because I believe that the
thorough investigation of the conditions for the validity of this
theorem will throw a new light upon the idea of distance, as well as
upon other elementary ideas, e. g., upon the idea of the plane, and
the possibility of its definition by means of the idea of the straight
line, the construction and systematic treatment of the geometries
here possible seem to me desirable.
[8] Leipzig, 1896.
[9] Math. Annalen, vol. 46, p. 91.
 5. LIE'S CONCEPT OF A CONTINUOUS
GROUP OF TRANSFORMATIONS
WITHOUT THE ASSUMPTION OF THE
DIFFERENTIABILITY OF THE
FUNCTIONS DEFINING THE GROUP.
It is well known that Lie, with the aid of the concept of continuous
groups of transformations, has set up a system of geometrical axioms
and, from the standpoint of his theory of groups, has proved that this
system of axioms suffices for geometry. But since Lie assumes, in the
very foundation of his theory, that the functions defining his group can be
differentiated, it remains undecided in Lie's development, whether the
assumption of the differentiability in connection with the question as to the
axioms of geometry is actually unavoidable, or whether it may not appear
rather as a consequence of the group concept and the other geometrical
axioms. This consideration, as well as certain other problems in
connection with the arithmetical axioms, brings before us the more
general question: How far Lie's concept of continuous groups of
transformations is approachable in our investigations without the
assumption of the differentiability of the functions.
Lie defines a finite continuous group of transformations as a system
of transformations

having the property that any two arbitrarily chosen transformations of the
system, as
applied successively result in a transformation which also belongs to the
system, and which is therefore expressible in the form

where are certain functions of and . The

group property thus finds its full expression in a system of functional
equations and of itself imposes no additional restrictions upon the
functions . Yet Lie's further treatment of these
functional equations, viz., the derivation of the well-known fundamental
differential equations, assumes necessarily the continuity and
differentiability of the functions defining the group.
As regards continuity: this postulate will certainly be retained for the
present—if only with a view to the geometrical and arithmetical
applications, in which the continuity of the functions in question appears
as a consequence of the axiom of continuity. On the other hand the
differentiability of the functions defining the group contains a postulate
which, in the geometrical axioms, can be expressed only in a rather forced
and complicated manner. Hence there arises the question whether,
through the introduction of suitable new variables and parameters, the
group can always be transformed into one whose defining functions are
differentiable; or whether, at least with the help of certain simple
assumptions, a transformation is possible into groups admitting Lie's
methods. A reduction to analytic groups is, according to a theorem
announced by Lie[10] but first proved by Schur,[11] always possible when
the group is transitive and the existence of the first and certain second
derivatives of the functions defining the group is assumed.
For infinite groups the investigation of the corresponding question is, I
believe, also of interest. Moreover we are thus led to the wide and
interesting field of functional equations which have been heretofore
investigated usually only under the assumption of the differentiability of
the functions involved. In particular the functional equations treated by
Abel[12] with so much ingenuity, the difference equations, and other
equations occurring in the literature of mathematics, do not directly involve
anything which necessitates the requirement of the differentiability of the
accompanying functions. In the search for certain existence proofs in the
calculus of variations I came directly upon the problem: To prove the
differentiability of the function under consideration from the existence of a
difference equation. In all these cases, then, the problem arises: In how
far are the assertions which we can make in the case of differentiable
functions true under proper modifications without this assumption?
It may be further remarked that H. Minkowski in his above-mentioned
Geometrieder Zahlen starts with the functional equation

and from this actually succeeds in proving the existence of certain

differential quotients for the function in question.
On the other hand I wish to emphasize the fact that there certainly
exist analytical functional equations whose sole solutions are non-
differentiable functions. For example a uniform continuous non-
differentiable function can be constructed which represents the only
solution of the two functional equations

where and are two real numbers, and denotes, for all the real
values of , a regular analytic uniform function. Such functions are
obtained in the simplest manner by means of trigonometrical series by a
process similar to that used by Borel (according to a recent
announcement of Picard)[13] for the construction of a doubly periodic, non-
analytic solution of a certain analytic partial differential equation.
[10] Lie-Engel, Theorie der Transformationsgruppen, vol. 3, Leipzig,
1893, §§ 82, 144.
[11] "Ueber den analytischen Charakter der eine endliche
Kontinuierliche Transformationsgruppen darstellenden Funktionen,"
Math. Annalen, vol. 41.
[12] Werke, vol. 1, pp. 1, 61, 389.
[13] "Quelques théories fondamentales dans l'analyse mathématique,"
Conférences faites à Clark University, Revue générale des Sciences,
1900, p. 22.
 6. MATHEMATICAL TREATMENT OF
THE AXIOMS OF PHYSICS.
The investigations on the foundations of geometry suggest the
problem: To treat in the tame manner, by means of axioms, those
physical sciences in which mathematics plays an important part; in
the first rank are the theory of probabilities and mechanics.
As to the axioms of the theory of probabilities,[14] it seems to me
desirable that their logical investigation should be accompanied by a
rigorous and satisfactory development of the method of mean values
in mathematical physics, and in particular in the kinetic theory of
gases.
Important investigations by physicists on the foundations of
mechanics are at hand; I refer to the writings of Mach,[15] Hertz,[16]
Boltzmann[17] and Volkmann.[18] It is therefore very desirable that
the discussion of the foundations of mechanics be taken up by
mathematicians also. Thus Boltzmann's work on the principles of
mechanics suggests the problem of developing mathematically the
limiting processes, there merely indicated, which lead from the
atomistic view to the laws of motion of continua. Conversely one
might try to derive the laws of the motion of rigid bodies by a limiting
process from a system of axioms depending upon the idea of
continuously varying conditions of a material filling all space
continuously, these conditions being defined by parameters. For the
question as to the equivalence of different systems of axioms is
always of great theoretical interest.
If geometry is to serve as a model for the treatment of physical
axioms, we shall try first by a small number of axioms to include as
large a class as possible of physical phenomena, and then by
adjoining new axioms to arrive gradually at the more special
theories. At the same time Lie's a principle of subdivision can
perhaps be derived from profound theory of infinite transformation
groups. The mathematician will have also to take account not only of
those theories coming near to reality, but also, as in geometry, of all
logically possible theories. He must be always alert to obtain a
complete survey of all conclusions derivable from the system of
axioms assumed.
Further, the mathematician has the duty to test exactly in each
instance whether the new axioms are compatible with the previous
ones. The physicist, as his theories develop, often finds himself
forced by the results of his experiments to make new hypotheses,
while he depends, with respect to the compatibility of the new
hypotheses with the old axioms, solely upon these experiments or
upon a certain physical intuition, a practice which in the rigorously
logical building up of a theory is not admissible. The desired proof of
the compatibility of all assumptions seems to me also of importance,
because the effort to obtain such proof always forces us most
effectually to an exact formulation of the axioms.

So far we have considered only questions concerning the

foundations of the mathematical sciences. Indeed, the study of the
foundations of a science is always particularly attractive, and the
testing of these foundations will always be among the foremost
problems of the investigator. Weierstrass once said, "The final object
always to be kept in mind is to arrive at a correct understanding of
the foundations of the science.[19] But to make any progress in the
sciences the study of particular problems is, of course,
indispensable." In fact, a thorough understanding of its special
theories is necessary to the successful treatment of the foundations
of the science. Only that architect is in the position to lay a sure
foundation for a structure who knows its purpose thoroughly and in
detail. So we turn now to the special problems of the separate
branches of mathematics and consider first arithmetic and algebra.
[14] Cf. Bohlmann, "Ueber Versicherungsmathematik", from the
collection: Klein and Kiecke, Ueber angewandte Mathematik und
Physik, Leipzig, 1900.
[15] Die Mechanik in ihrer Entwickelung, Leipzig, 4th edition,
1901.
[16] Die Prinzipien der Mechanik, Leipzig, 1894.
[17] Vorlesungen über die Principe der Mechanik, Leipzig, 1897.
[18] Einführung in das Studium der theoretischen Physik, Leipzig,
1900.
[19] Math. Annalen, vol. 22, 1883.
 7. IRRATIONALITY AND
TRANSCENDENCE OF CERTAIN
NUMBERS.
Hermite's arithmetical theorems on the exponential function and
their extension by Lindemann are certain of the admiration of all
generations of mathematicians. Thus the task at once presents itself
to penetrate further along the path here entered, as A. Hurwitz has
already done in two interesting papers,[20] "Ueber arithmetische
Eigenschaften gewisser transzendenter Funktionen." I should like,
therefore, to sketch a class of problems which, in my opinion, should
be attacked as here next in order. That certain special
transcendental functions, important in analysis, take algebraic values
for certain algebraic arguments, seems to us particularly remarkable
and worthy of thorough investigation. Indeed, we expect
transcendental functions to assume, in general, transcendental
values for even algebraic arguments; and, although it is well known
that there exist integral transcendental functions which even have
rational values for all algebraic arguments, we shall still consider it
highly probable that the exponential function , for example, which
evidently has algebraic values for all rational arguments , will on the
other hand always take transcendental values for irrational algebraic
values of the argument . We can also give this statement a
geometrical form, as follows:
If, in an isosceles triangle, the ratio of the base angle to the
angle at the vertex be algebraic but not rational, the ratio between
base and side is always transcendental.
In spite of the simplicity of this statement and of its similarity to
the problems solved by Hermite and Lindemann, I consider the proof
of this theorem very difficult; as also the proof that
 The expression , for an algebraic base and an irrational
algebraic exponent , e. g., the number or , always
represents a transcendental or at least an irrational number.
It is certain that the solution of these and similar problems must
lead us to entirely new methods and to a new insight into the nature
of special irrational and transcendental numbers.
[20] Math. Annalen, vol. 32, 1888.
 8. PROBLEMS OF PRIME NUMBERS.
Essential progress in the theory of the distribution of prime
numbers has lately been made by Hadamard, de la Vallée-Poussin,
Von Mangoldt and others. For the complete solution, however, of the
problems set us by Riemann's paper "Ueber die Anzahl der
Primzahlen unter einer gegebenen Grösse," it still remains to prove
the correctness of an exceedingly important statement of Riemann,
viz., that the zero points of the function defined by the series

all have the real part , except the well-known negative integral real
zeros. As soon as this proof has been successfully established, the
next problem would consist in testing more exactly Riemann's infinite
series for the number of primes below a given number and,
especially, to decide whether the difference between the number of
primes below a number and the integral logarithm of does in fact
become infinite of an order not greater than in .[21] Further, we
should determine whether the occasional condensation of prime
numbers which has been noticed in counting primes is really one to
those terms of Riemann's formula which depend upon the first
complex zeros of the function .
After an exhaustive discussion of Riemann's prime number
formula, perhaps we may sometime be in a position to attempt the
rigorous solution of Goldbach's problem,[22] viz., whether every
integer is expressible as the sum of two positive prime numbers; and
further to attack the well-known question, whether there are an
infinite number of pairs of prime numbers with the difference , or
even the more general problem, whether the linear diophantine
equation

(with given integral coefficients each prime to the others) is always

solvable in prime numbers and .
But the following problem seems to me of no less interest and
perhaps of still wider range: To apply the results obtained for the
distribution of rational prime numbers to the theory of the distribution
of ideal primes in a given number-field —a problem which looks
toward the study of the function belonging to the field and
defined by the series

where the sum extends over all ideals of the given realm and
denotes the norm of the ideal .
I may mention three more special problems in number theory:
one on the laws of reciprocity, one on diophantine equations, and a
third from the realm of quadratic forms.
[21] Cf. an article by H. von Koch, which is soon to appear in the
Math. Annalen [Vol. 55, p. 441].
[22] Cf. P. Stäckel: "Über Goldbach's empirisches Theorem,"
Nachrichten d. K. Ges. d. Wiss. zu Göttingen, 1896, and Landau,
ibid., 1900.
 9. PROOF OF THE MOST GENERAL
LAW OF RECIPROCITY IN ANY
NUMBER FIELD.
For any field of numbers the law of reciprocity is to be proved for
the residues of the th power, when denotes an odd prime, and
further when is a power of or a power of an odd prime.
The law, as well as the means essential to its proof, will, I
believe, result by suitably generalizing the theory of the field of the
th roots of unity,[23] developed by me, and my theory of relative
quadratic fields.[24]
[23] Jahresber. d. Deutschen Math.-Vereinigung, "Ueber die
Theorie der algebraischen Zahlkörper," vol. 4 (1897), Part V.
[24] Math. Annalen, vol. 51 and Nachrichten d. K. Ges. d. Wiss.
zu Göttingen, 1898.
 10. DETERMINATION OF THE
SOLVABILITY OF A DIOPHANTINE
EQUATION.
Given a diophantine equation with any number of unknown
quantities and with rational integral numerical coefficients: To devise
a process according to which it can be determined by a finite number
of operations whether the equation is solvable in rational integers.
 11. QUADRATIC FORMS WITH ANY
ALGEBRAIC NUMERICAL
COEFFICIENTS.
Our present knowledge of the theory of quadratic number
fields[25] puts us in a position to attack successfully the theory of
quadratic forms with any number of variables and with any algebraic
numerical coefficients. This leads in particular to the interesting
problem: to solve a given quadratic equation with algebraic
numerical coefficients in any number of variables by integral or
fractional numbers belonging to the algebraic realm of rationality
determined by the coefficients.
The following important problem may form a transition to
algebra and the theory of functions:
[25] Hilbert, "Ueber den Dirichlet'schen biquadratischen
Zahlenkörper," Math. Annalen, vol. 45; "Ueber die Theorie der
relativquadratischen Zahlenkörper," Jahresber. d. Deutschen
Mathematiker-Vereinigung, 1897, and Math. Annalen, vol. 51;
"Ueber die Theorie der relativ-Abelschen Körper," Nachrichten d.
K. Ges. d. Wiss. zu Göttingen, 1898; Grundlagen der Geometrie,
Leipzig, 1899, Chap. VIII, § 83 [Translation by Townsend,
Chicago, 1902]. Cf. also the dissertation of G. Rückle, Göttingen,
1901.