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Design and synthesis of novel heterocycles and peptidomimetics from organoboronic acids, amines and carbonyl compounds

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Design and synthesis of novel heterocycles and peptidomimetics from organoboronic acids, amines and carbonyl compounds

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Content DESIGN AND SYNTHESIS OF NOVEL HETEROCYCLES AND
PEPTIDOMIMETICS FROM ORGANOBORONIC ACIDS, AMINES
AND CARBONYL COMPOUNDS
Copyright 2002
by
Jeffrey C. Raber
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements of the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
August 2002
Jeffrey C. Raber
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UMI Number: 3094370
Copyright 2002 by
Raber, Jeffrey Charles
All rights reserved.
®
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UNIVERSITY OF SOUTHERN CALIFORNIA
The Graduate School
University Park
LOS ANGELES, CALIFORNIA 90089-1695
This dissertation, w ritten b y
Under th e direction o f hJ.L. D issertation
Com m ittee, an d approved b y a ll its m em bers,
has been p resen ted to an d accepted b y The
G raduate School, in p a rtia l fulfillm ent o f
requirem ents fo r th e degree o f
J ~ g f - P c e . ^ C . f t c d o f i r
DOCTOR OF PHILOSOPHY
Dean o f G raduate S tu d ies
D ate
A ugust 6 , 2002
DISSER TA TION COMMITTEE
Chairperson
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DEDICATION
This work is dedicated to my father.
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ACKNOW LEDGEMENTS
I would like to gratefully acknowledge Professor Nicos A. Petasis for his
support and guidance over the past five years. I appreciate his instruction and
encouragement, without which this work would not have been possible. I would
like to thank him for the numerous discussions on chemistry and life in general,
which have helped shape me into the chemist and person I am today.
I wish to thank my committee members, Professors G. K. S. Prakash,
William P. Weber, Robert Bau, and M. Michael Appleman for their time and effort
in the guidance of this dissertation. I would especially like to thank Professors
Prakash and Weber for their valuable advice and friendly interactions. I would also
like to thank the faculty and staff of the USC Chemistry Department and LHI for
all of their help and support.
I am eternally grateful for being able to work with such an enjoyable group
of colleagues in my lab. I would like to thank Dr. Valery V. Fokin, Dr. Ilia A.
Zavialov, Dr. Kourousch A. Tehrani, Dr. Marko Friedrich, Dr. Walter Keung, Dr.
Sougato Boral, Dr. Giovanni Bemasconi, Rong Yang, and Wei Fluang for their
support. I would especially like to thank Dr. Xin Yao, Raquel Keledjian, and Brad
Douglass for their support and incredible friendship.
I would especially like to thank Dr. Zubin D. Patel for his friendship and
for the immeasurable amount of fun we have had. I would also like to thank his
family, Penny, Kent, and Miranda for all of their love and support.
Finally, I would like to thank my family, specifically my father, for all of
their love, support and sacrifices they have offered while I have pursued my degree.
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TABLE OF CONTENTS
Dedication ii
Acknowledgements iii
List of Tables viii
List of Figures ix
List of Schemes x
Abstract xiv
Chapter 1. Heterocycles, Peptidomimetics, and Organoboronic Acids
in Organic Synthesis 1
1.1. Introduction 2
1.1.1. Heterocycles 2
1.1.2. Peptidomimetics 3
1.2. Organoboronic Acids in Organic Synthesis 4
1.2.1. Introduction to Organoboronic Acids 4
1.2.2. Preparations of Organoboronic Acids 5
1.2.3. The Suzuki-Miyaura Coupling Reaction 9
1.2.4. Reactions of Boronic Acids with Amines and Carbonyls 11
1.2.4.1. The Synthesis of Novel Amino Acids 14
1.2.4.2. The Synthesis of Novel Amines 15
1.2.4.3. The Synthesis of Novel Peptides and Peptidomimetics 18
1.2.4.4. The Stereoselective Synthesis of Amino Alcohols 19
1.3. Further Extensions of the Three Component Process 21
IV
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1.4. References
Chapter 2. Synthesis of Novel Benzodiazepines from Diamines and
Organoboronic Acids
2.1. Introduction
2.1.1. Biological Properties of Benzodiazepines
2.1.2. Synthesis of Tetrahydro-Benzodiazepines
2.2. Results and Discussion
2.2.1. Synthesis of Tetrahydro-l,4-Benzodiazepine-3-ones
2.2.2. Synthesis of Tetrahydro-l,4-Benzodiazepine-2-ones
2.3. Conclusion
2.4. Experimentals
2.4.1. General
2.4.2. Synthesis and Physical Properties of Diazepine-3-ones
2.4.3. Synthesis and Physical Properties of Diazepine-2-ones
2.5. References
Chapter 3. Condensation Products Generated from Amines, Glyoxals,
and Organoboronic Acids
3.1. Introduction
3.1.1. Biological Importance of a-Amino Ketones and
Their Synthetic Utility
3.1.2, Synthesis of a-Amino Ketones
3.2. Results and Discussion
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3.2.1. Synthesis of a-Amino Ketones 99
3.2.2. Synthesis of 1,2,3,4-Tetrahydropyrazines 105
3.2.3. Synthesis of 2-Hydroxymorpholines 110
3.3. Conclusion 119
3.4. Experimentals 120
3.4.1. General 120
3.4.2. Synthesis and Physical Properties of a-Amino Ketones 120
3.4.3. Synthesis and Physical Properties of 1,2,3,4-Tetrahydropyrazines 127
3.4.4. Synthesis and Physical Properties of 2-Hydroxymorpholines 128
3.5. References 133
Chapter 4. Synthesis of P-Amino Alcohols and Their Use as Building
Blocks Towards Valuable Products 135
4.1. Introduction 136
4.1.1. Importance of p-Amino Alcohols 136
4.2. Results and Discussion 137
4.2.1. Synthesis of P-Amino Alcohols 138
4.3. Conclusion 165
4.4. Experimentals 166
4.1.1. General 166
4.4.2. Synthesis and Physical Properties of Amino Polyols 167
4.5. References 190
vi
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Comprehensive Bibliography
Appendix. 'H and 1 3 C NMR Spectra
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List of Tables
Table 2.1. Synthesis of Tetrahydro-1,4-Benzodiazepin-3-ones 40
Table 2.2. Synthesis of Tetrahydro-1,4-Benzodiazepin-2-ones 50
Table 3.1. Synthesis of a-Amino Ketones 103
Table 3.2. Synthesis of Highly Functionalized a-Amino Ketones 105
Table 3.3. Synthesis of 2-Hydroxymorpholines 113
Table 3.4. Synthesis of Chiral 2-Hydroxymorpholines 118
Table 4.1. Synthesis of anh-p-Amino Alcohols 139
Table 4.2. Synthesis of N-Boc a«rt-p-Amino Alcohols 143
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List of Figures
Figure 1.1. Examples of Heterocycles 2
Figure 1.2. Examples of Organoboronic Acids 5
Figure 2.1. Known Benzodiazepine Drugs 28
Figure 2.2. Various Benzodiazepine Core Structures 29
Figure 2.3. Rationally Designed Benzodiazepine-3-one 31
Figure 2.4. Lotraflban 32
Figure 2.5. Benzodiazepine Core Structures Synthesized 35
Figure 2.6. ORTEP Diagram of Structure (2,50) 44
Figure 2.7. ORTEP Diagram of Structure (2.86) 57
Figure 3.1. Bupropion 89
Figure 3.2. Indinavir 107
Figure 4.1. Palinavir 145
Figure 4.2. Chiral HPLC Analysis 147
Figure 4.3. (-)-Cytoxazone 151
Figure 4.4. Toloxatone 154
Figure 4.5. HIV-1 Protease Inhibitor DMP-323 165
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List of Schemes
Scheme 1.1.
6
Scheme 1.2. 6
Scheme 1.3.
7
Scheme 1.4.
7
Scheme 1.5.
8
Scheme 1.6.
10
Scheme 1.7.
11
Scheme 1.8.
12
Scheme 1.9.
13
Scheme 1.10.
15
Scheme 1.11.
17
Scheme 1.12.
18
Scheme 1.13.
20
Scheme 1.14.
22
Scheme 2.1.
30
Scheme 2.2.
33
Scheme 2.3.
36
Scheme 2.4.
37
Scheme 2.5.
37
Scheme 2.6.
38
Scheme 2.7.
39
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Scheme 2.8. 39
Scheme 2.9. 40
Scheme 2.10. 42
Scheme 2.11. 42
Scheme 2.12. 45
Scheme 2.13. 46
Scheme 2.14. 46
Scheme 2.15. 47
Scheme 2.16. 47
Scheme 2.17. 48
Scheme 2.18. 49
Scheme 2.19. 50
Scheme 2.20. 52
Scheme 2.21. 53
Scheme 2.22. 53
Scheme 2.23. 54
Scheme 2.24. 55
Scheme 2.25. 56
Scheme 2.26. 57
Scheme 3.1. 90
Scheme 3.2. 91
Scheme 3.3. 92
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Scheme 3.4.
93
Scheme 3.5.
94
Scheme 3.6.
95
Scheme 3.7.
96
Scheme 3.8.
97
Scheme 3.9.
98
Scheme 3.10.
99
Scheme 3.11.
101
Scheme 3.12.
102
Scheme 3.13.
104
Scheme 3.14.
106
Scheme 3.15.
108
Scheme 3.16.
109
Scheme 3.17.
110
Scheme 3.18.
111
Scheme 3.19.
114
Scheme 3.20.
115
Scheme 3.21.
116
Scheme 4.1.
137
Scheme 4.2.
142
Scheme 4.3.
144
Scheme 4.4.
146
xii
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Scheme 4.5.
148
Scheme 4.6.
149
Scheme 4.7.
150
Scheme 4.8.
151
Scheme 4.9.
152
Scheme 4.10.
153
Scheme 4.11.
155
Scheme 4.12.
156
Scheme 4.13.
157
Scheme 4.14.
158
Scheme 4.15.
160
Scheme 4.16.
161
Scheme 4.17.
162
Scheme 4.18.
163
Scheme 4.19.
163
Scheme 4.20.
164
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ABSTRACT
This dissertation describes the development of new, practical and efficient
synthetic methodologies for the expedited synthesis of functionally diverse
heterocycles and peptidomimetics.
Chapter 1 offers a brief introduction to heterocycles and peptidomimetics,
and presents the foundation of our methodology, a three-component process
involving boronic acids. After an overview of boronic acids in synthesis, this
Chapter gives a number of examples of the three-component process and its use by
others.
Chapter 2 describes a novel approach to the construction of both
benzodiazepin-3-ones and benzodiazepin-2-ones. The methodologies presented are
fast, efficient, and experimentally convenient, while offering the ability to
introduce a large amount of structural diversity in this biologically important class
of compounds,
Chapter 3 presents a new extension of our three-component coupling
reaction, with the use of an oc-keto aldehyde as the carbonyl component. This
Chapter details our work with these substrates, and demonstrates its application to
the synthesis of structurally diverse a-amino ketones, 1,2,3,4-tetrahydropyrazines,
and 2 -hydroxymorpholines.
Chapter 4 details the facile synthesis and further manipulation of enantiopure
amino alcohols and amino polyols. These synthetically valuable intermediates
xiv
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were exploited for their utility in the synthesis of a wide range of products,
including a-amino aldehydes, oxazolidinones, and functionalized
pyrrolidines.
Benzodiazepin-3-ones Benzodiazepin-2-ones
HO'
NH
R — B(OH)2
O
R
n OH
2
OH
2 3
n OH
OH
■ d
a-Amino Ketones
OH
R - _ N N— R
R4 R1
R
R 1 N R 3
R2
T etrahydro- 2-Hydroxy-
pyrazines morpholines
R2 \ .R3 9 f
X h n A o r V V
r1 ii v - 7 H
0 R 1 HO' OH
Amino Oxazoli- Pyrrolidines
Aldehydes dinones
xv
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CHAPTER 1
Heterocycles, Peptidomimetics, and
Organoboronic Acids in Organic Synthesis
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1.1. INTRODUCTION
1.1.1. Heterocycles
Heterocycles are cyclic compounds possessing one or more atoms other
than carbon in their ring. The heteroatom is often nitrogen or oxygen, but can also
include sulphur, phosphorus, and other atoms. Various heterocycles have long
been recognized as key components of many medicinal agents, covering a wide
spectrum of biological activity. Heterocycles can be molecules as simple as
tetrahydrofuran ( 1.1), a common solvent, and morpholine ( 1.2), and can be as
complex as the Oxycodone (1.3), a prescription analgesic, or Ciprofloxacin (1.4),
which is Bayer’s antianthrax antibiotic (Figure 1).
H
(1.1) (1.2)
M eC
O
(1.3) (1.4)
Figure 1.1 Examples of Heterocycles
2
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One of the most recognized heterocyclic core structures is the benzodiazepine ring
system, which will be further discussed in Chapter 2. Various heterocycles will be
discussed throughout the dissertation in their respective chapters,
1.1.2. Peptidomimetics
Peptidomimetics are those molecules which are similar in structure to
peptides (a sequence of amino acids of varying length), yet are either
conformationally restricted, resist biological degradation, or possess both
properties. Since there are many rotatable bonds present in peptides, an almost
endless number of conformations can exist, yet typically only one conformation is
the biologically active one. Therefore, to probe the biologically active
conformation of molecules of these types, the design and synthesis of
conformationally restricted peptide-like molecules, or peptidomimetics, often
proves to be a powerful method for probing the active conformation of various
bioactive peptides and enzyme inhibitors.1 ,2
Certain peptides can be degradated, or cleaved at specific bonds, by certain
enzymes such as peptidases and proteases. Peptide bonds are also susceptible to
cleavage under strong acidic conditions. One such place that these conditions exist
is in the stomach. This limits the use of peptides as orally bioavailable medicinal
agents, and hence peptidomimetics, those molecules which resemble certain
peptides yet resist this degradation, are often used as the medicinally active
3
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2
components of many pharmaceuticals. As was mentioned above, the
benzodiazepines are a class of compounds which possess restricted conformations,
and are often used as the core for the construction of hydrolytically stable bioactive
peptidomimetics.4
1.2. ORGANOBORONIC ACIDS IN ORGANIC SYNTHESIS
1.2.1. Introduction to Organoboronic Acids
In recent years organoboronic acids have been frequently used as key
components in the synthesis of many complex molecules. Organoboronic acids are
often the choice reagents, over other organometallic species, due to their increasing
commercial availability, they are generally thermally stable, and are not sensitive to
air and water, which allows for their use with no special precautions, and the
byproduct of boric acid is environmentally benign.5 These favorable properties are
what continue to drive the use of organoboronic acids in the synthesis of many
complex molecules and pharmaceutical agents. Organoboron compounds are
highly electrophilic, and boron’s reactivity if often tunable making it possible to
increase the reactivity of the organic group attached to boron. For example,
boronic acids can be activated by the addition of a negatively charged base, as is
the case in the Suzuki reaction.5 The general structure of a boronic acid can be
seen in (1.5), and examples of an alkyl (1.6), alkenyl (1.7), aryl (1.8), and
heteroaryl (1.9) boronic acid can be seen in Figure 1.2.
4
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Figure 1.2 Examples of Organoboronic Acids
1.2.2. Preparations of Organoboronic Acids
1-Alkenylboronic acids or esters are often prepared from their
corresponding Grignard or lithium reagents by reaction with trialkyl borates,
followed by hydrolysis to yield the boronic acid. Triisopropyl borate is often the
choice boron source as it limits the formations of unwanted stereoisomers, or bis-
alkylation products, and is frequently used in the preparation of large quantities of
the desired organoboronic acid (Scheme 1.1).6
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1.) Mg
H 3C Br & H 3C' B (O H T
\ _ _ / 2.) B(OMe)3 '
H CH3 3.) H30 H CH3
(1.10) (1.11)
1.) B(OzPr)3
RLi 2 ) H 0 +— R—B(OH)2
(1.12) ' 3 (1.13)
R = alkyl, aryl, 1-alkenyl, and 1-alkynyl
Scheme 1.1
Although alkenyl boronic acids can be prepared according to Scheme 1.1, it is often
more experimentally convenient to prepare them by hydroboration of the
appropriate alkyne (1.14) with an appropriate borane, followed by hydrolysis to
yield the desired boronic acid (1.15) (Scheme 1.2).
R— E E E E —H --------------------------► B(OH)2
2.) Hydrolysis R
(1.14) H (1.15)
Scheme 1.2
This method is extremely convenient and provides the boronic acid in
geometrically pure form.7
6
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Haloboration of an alkyne (1.14) leads to formation of a P-halo-l-alkenylboronic
acid (1.16), which produces another point for the introduction of further diversity
by various coupling methods (Scheme 1.3).8
Arylboronic acids (1.18) can also be prepared from the corresponding lithium or
Grignard reagent as in Scheme 1.1, but this procedure limits the functional groups
that can be present on the aromatic ring. To overcome this limitation, highly
functionalized arylboronic acids are often prepared from their corresponding
arylhalide (1.17) by the palladium catalyzed cross coupling with an
(alkoxy)diboron compound, followed by hydrolysis of the boronic ester to produce
the desired boronic acid (1.18) (Scheme 1.4).9
^ B(OH)
2.) R'OH
3.) Hydrolysis
Br
Scheme 1.3
PdCl2(dppf),
-B(OR)2
KOAc,
(RO)2 B-B(OR)2,
(1.17) DMSO, 80°C (1.18)
Scheme 1.4
7
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Very recently, Miyaura and Hartwig’s research groups reported a joint paper in
which an iridium catalyst was used in the direct borylation of arenes with
bis(pinacolato)diboron (1.19) to produce pinacol arylboronate esters under mild
conditions at room temperature.1 0 The iridium catalyst activates the C-H bond of
various arenes to produce the desired boronate esters (1.20) in high yields (Scheme
1 .5 ).1 0
\ A) O - /
S B—B7
'O V
+ 2 A rH J r ^ p y c a ^
r.t to 80°C
2 A r-B ,
P '
(1.19)
V \
(1.20)
Arene Product Arene Product
o
(1.21)
H,C
H,C
(1.25)
— Bpin
(1.22) 95%
H3C
H3C— ^ \ — Bpin
(1.26) 83%
Cl Bpin
(1.23)
MeO
(1.24) 83%
MeO
— Bpin
H3C (1.27) H3C (1.28) 72%
MeO
MeO—^
(1.29)
MeO
MeO— — Bpin
(1.30) 86%
MeO
Br (1.31)
MeO
-Bpin
Br' (1.32) 73%
Scheme 1,5
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This reaction is significant as it allows for arylboron compounds to be formed from
readily available feedstocks, offering an economical and efficient process for the
generation of a wide range of functionalized arylboronic acids.
1.2.3. The Suzuki-Miyaura Coupling Reaction
One o f the most predominant reasons for boronic acids becoming
commercially available in recent years is due to their use in the Suzuki-Miyaura
coupling reaction. This process has been extensively used in industry for the
construction of functionalized biaryl compounds, and in the construction of varying
types of polyenes. Scheme 1.6 shows the general mechanism for this reaction5, and
Scheme 1.7 shows a few examples of its use. The reaction is extremely useful for
the generation of polyenes and ene-ynes, and compound (1.47) is prepared
according to this method on an industrial scale, as is a precursor to the potent
angiotensin II receptor antagonist Losartan.1 1 This reaction has been extensively
reviewed,5,1 2 and it will not be further discussed here.
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(1.37)
(1.41)
(1.36)
(1.34)
OR
(1.35)
[R2 B(OH)2(OR3 ) ] °
(1.39)
Scheme 1.6
10
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H
c / ^ / b (o h )2 Pd(PPh3)4,
(1.42)
B r— = — Ph
(1.43)
CPln
NaOMe-MeOH,
benzene, reflux,
93 % Yield
H,C
N—N
N.
B(OH) Pd(OAc)2 4 PPh3,
aq. Na2CQ3,______
THF/DME, reflux,
95 % yield
(1.44)
CPh
N —N
(1.47)
Scheme 1.7
1.2.4. Reactions of Boronic Acids with Amines and Carbonyls
In the early 1990’s our research group reported the first intermolecular
transfer of an alkenylboron derivative with an electrophilic iminium species,
initially called the Boronic Acid Mannich reaction, which has also been referred to
as the “Petasis Reaction” by a number of authors.
The first variation of this process involved the addition of an alkenyl
boronic acid (1.48) to a preformed adduct of an amine (1.49) with
paraformaldehyde (1.50) to produce geometrically pure allylamines (1.51) (Scheme
1.8).1 3 ,1 4
11
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R2
b(oh)2 R ^ - R '
R1 ^ (CH20 ) n Toluene,
R3 H
(1.48) (1.49) (1.50) 90 C, 30 mm.
(1.51)
Scheme 1.8
Subsequently, it was shown that a wide range of amines, carbonyls, and
boronic acids can be used in this process if this reaction is performed in a one-step
reaction of all three components.1 5 ,1 6 This novel multicomponent C-C bond
forming process is believed to proceed through initial formation of an amine (1.49)
and carbonyl (1.52) adduct, the aminol (1.53), which upon reaction with the
boronic acid (1.48) forms an iminium salt (1.54) and a nucleophilic boronate
species (1.55), which together form an ion pair that finally reacts to give the
product (1.56). All of these steps are in equilibrium until the final C-C bond
forming process occurs, which is irreversible, extruding boric acid and the desired
product (1.56) (Scheme 1.9).
12
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rV „ r5
N
I
H
O
' ^ VR7
(1.49) (1.52)
RV HR
N
X r'
R ^ R
(1.53)
OH
R
R 1
B(OH)2
R
(1.48)
- B(OH)3
rV©„R5
N
r6 / ^ r7
(1.54)
R'
r 2 HO
I^OH
Q OH
R3
(1.55)
Scheme 1.9
Based on this proposed mechanism, the three substrates used in the reaction
should have the following features: The carbonyl component should have R6 and
R7 that facilitate the formation of the aminol, and activate the iminium salt for
nucleophilic addition. The amines can possess alkyl or aryl substituents, those that
are electron withdrawing can render the reaction much slower due to difficulty in
forming the ion pair. The boronic acid can be alkenyl or aryl, and should possess a
good migratory aptitude. Electron-donating substituents generally seem to
facilitate the reaction. Based on these features, our research group has set forth in
recent years to expand the scope of this reaction, and to exploit its synthetic utility
in the synthesis of complex molecules and novel building blocks which are useful
13
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to the organic chemist. Since its inception, a large variety of the three components
in this process were successfully employed, and some of these will briefly be
summarized below.
1.2.4.1. The Synthesis of Novel Amino Acids
After the successful synthesis of allylamines, the ability of a-keto acids to
participate in the reaction as the carbonyl component was explored. It was shown
that glyoxylic acid (1.57) successfully participated in the reaction with a variety of
amines and boronic acids to generate non-natural a-amino acids (1.58). The
reaction was found to be experimentally convenient, as it could be performed in a
large variety of solvents, including methanol, toluene, dichloromethane, and even
water. Reactions performed in dichloromethane precipitate the product, allowing
for fast an easy purification of the final product. Scheme 1.10 shows a few
examples of this reaction. 16
14
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R
R'
B(OH)2
R
(1.48)
(1.49)
OH
■ O H
(1.57)
Ph'
O
N
OH
O
(1.59)
94%
HN Ph
(1.62)
71%
Ph
MeO
Ph'
Br HN Ph
„OH
O
(1.60)
87%
OMe
(1.61)
94%
HN Ph
OMe .OH
HN
•O H
(1.63)
8 8 %
Scheme 1.10
84%
I.2.4.2. The Synthesis of Novel Amines
To extend the diversity that could be produced via this multicomponent
reaction, a range of functionalized amines were formed by varying the carbonyl
15
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component used. For example, substituted salicylaldehydes (1.65) and pyridine-2-
carboxaldehyde (1.69) were also found to participate successfully in the reaction,
ultimately producing a variety of highly functionalized amines. Some products are
shown in Scheme 1.11. 17,18
16
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R
R'
RJ
(1.48)
B(OH)2 r V n .R 5
I
H
(1.49)
Ph
L .Me
N OH
(1.67)
79%
O OH
(1.66)
o
N OH
(1.68) N° 2
62%
R
R
R
(1.48)
B(OH)2 r4 \ n .R 5
I
H
(1.49)
R \ .R
(1.70)
MeO
Ph Ph
(1.71)
58 %
'N
.N.
(1.72)
49%
Scheme 1.11
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1.2.4.3. The Synthesis of Novel Peptides and Peptidomimetics
A recent discovery in our lab has been the successful utilization of
glyoxamides as the carbonyl component in the three-component process. This
reaction is an excellent way to create novel peptidomimetics, and has been applied
to the synthesis o f linear peptides in both solution, and on solid support. This
methodology is conceptually different from traditional peptide synthesis, and offers
the advantage of incorporating two different functionalities, the boronic acid and
the amine, into the peptide in one reaction. Scheme 1.12 offers an example of the
solid phase synthesis of a linear peptide created using this methodology. 19
Ph
0
Ph
Scheme 1.12
18
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I.2.4.4. The Stereoselective Synthesis of Amino Alcohols
One of the most useful extensions of this reaction has been the
incorporation of a-hydroxy aldehydes (1.77) as the carbonyl components,
ultimately producing diastereomerically pure anti-amino alcohols (1.78)1 5 ’ 20. These
amino alcohols have been used to create many valuable products, such as
y |
enantiopure amino acids (1.79) and amino sugars (1.80) (Scheme 1.13).“
19
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R 2 o
EV Ri K s *
R3 H OH
(1.48) (1.49) (1.77)
MeO'
R OH
NHBoc
OH
O
(1.79)
47 % overall
> 99 % e.e.
6 > 99 % d.e.
R > 99 % e.e.
HO
~OH
HON '' NHAc
OH
(1.80)
72 % overall
> 99 % d.e.
> 99 % e.e.
Scheme 1.13
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1.3. Further Extensions of the Three Component Process
The above examples offer a slight introduction to the extreme versatility
and synthetic utility of our key reaction. The use of three components, of varying
degrees of functionalities, allows for the generation of many novel compounds, in a
fast and efficient manner. Multicomponent reactions, such as this process, have
long been recognized as being extremely valuable for their simplicity and speed
with which they can provide a densely functionalized product, and have been
99
increasingly used in combinatorial chemistry.
The remainder of this thesis will present some of our efforts in expanding
the utility and scope of the three-component reaction in organic synthesis. Chapter
2 offers an extension of the amino acid synthesis, where the use o f a properly
tailored amine allowed for the synthesis of novel tetrahydrobenzodiazepine-3-ones.
Chapter 2 also details an extension of the use of glyoxamides, in an intramolecular
fashion, to provide tetrahydrobenzodiazepine-2-ones. Chapter 3 offers a novel
synthesis of a-amino ketones, as well as 1,2,3,4-tetrahydropyrazines and 2-
hydroxymorpholines, by the use of a new carbonyl component, glyoxals, in the
reaction. Finally, Chapter 4 presents our efforts in expanding the scope of the
synthesis of anti-amino alcohols, and presents a large variety of products that could
be generated from these valuable intermediates, including the novel synthesis of
functionalized pyrrolidines. A summary of these reactions can be seen in Scheme
1.14.
21
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Benzodiazepin-3-ones Benzodiazepin-2-ones
HO'
1h > k ,
n OH
a-Amino Ketones
( \
O R2
0 1 9 3
R \
N
r 4' ^ V ,N s r 3
r ' ^ N ^ V - O H
R 1
l 6 h
Amino Alcohols
R2—N N—R2
R-
OH
,0 R 3
R R'
r 1/ ^ n A r 3
^2
Tetrahydro- 2-Hydroxy-
pyrazmes morpholines
O
,A,
R2
I
! HN/ X 0 R1 * ^ / Nsy - R 1
o R‘ H(3 o h
Ammo Oxazoli- Pyrrolidines
Aldehydes dmones
Scheme 1.14
22
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1.4. REFERENCES
1. (a) Fredinger, R. M.; Veber, D. F.; Perlow, D. S.; Broods, J. R.; Saperstein, R.,
Science, 1980, 210, 656; (b) Aebi, J. D.; Guillaume, D.; Dunlap, B. E.; Rich, D.
H., J. Med. Chem., 1988, 31, 1805.
2. (a) Thaisrivongs, S.; Pals, D. T.; Turner, S. R.; Kroll, L. T. J. Med. Chem.,
1988, 31, 1369; (b) Shuman, R. T.; Rothenberger, R. B.; Campbell, C. S.;
Smith, G. F.; Gifford-Moore, D, S.; Gesellchen, P. D. J. Med. Chem., 1993, 36,
314.
3. Budavari, S. The Merck Index 12th Ed., Merck Research Laboratories: New
Jersey, 1996.
4. (a) Gante, L. Agnew. Chem. Int. Ed. E ngl, 1994, 33, 1699; (b) Kohl, N. E.;
Mosser, S. D.; deSolms, S. J.; Giuliani, E. A.; Pompilano, D. L.; Graham, S. L.;
Smith, R. L.; Scolnick, E. M.; Oliff, A.; Gibbs, J. B. Science, 1993, 260, 1934.
5. Suzuki, A.; Miyaura, N. Chem. Rev., 1995, 95, 2457.
6 . (a) Gerrard, W. The Chemistry o f Boron, Academic Press, New York, 1961; (b)
Muetterties, E. L. The Chemistry o f Boron and its Compounds, Wiley, New
York, 1967. (c)Matteson, D. S.; Liedtke, J. D. J. Am. Chem. Soc., 1965, 57,
1526. (d) Brown, H. C.; Cole, T. E. Organometallics, 1983, 2, 1316; (e)
Brown, H. C., Bhat, N. G., Srebnik, M. Tetrahedron Lett., 1988, 29, 2631; (f)
Brown, H, C., Rangaishenvi, M. V. Tetrahedron Lett., 1990, 49, 7113 and
7115.
23
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
7. (a) Brown, H. C. Organic Synthesis via Boranes\ John Wiley and Sons, New
York, 1975. (b) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc., 1972, 94, 4370.
(c) Matteson, D. S.; Soundararajan, R. J. Org. Chem., 1990, 55, 2274.
8 . Suzuki, A. Pure Appl. Chem., 1986, 58, 629.
9. Miyaura, N.; Ishiyama, T.; Murata, M. J. Org. Chem., 1995, 60, 7508.
10. Miyaura, N.; Ishida, K.; Takagi, J.; Ishiyama, T.; Hartwig, J. F.; Anastasi, N. R.
J. Am. Chem. Soc., 2002,124, 390.
11. Larson, R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster, B. S.; Roberts,
F. E.; Yang, C. Y.; Lieberman, D. R.; Reamer, R. A.; Tschaen, D. M.;
Verhoeven, T. R.; Amett, J. F. J. Org. Chem., 1994, 59, 6391.
12. Tsuji, J Palladium Reagents and Catalysts, Innovations in Organic Synthesis,
John Wiley and Sons, Chichester, 1995.
13. Akritopoulou-Zanze, I. Synthetic Studies on Allylamines, Alkenylsilanes, and
Lipoxins, Ph.D. Thesis, University of Southern California, 1994.
14. Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett., 1993, 34, 583.
15. Zavialov, I. New Reactions o f Organoboronic Acids and Their Derivatives,
Ph.D. Thesis, University of Southern California, 1998.
16. Petasis, N. A.; Zavialov, I. A. US Patent # 6,232,467, 2001.
17. (a) Boral, S. Synthesis o f Poly functional Molecules Using Organoboron
Compounds, Ph.D. Thesis, University o f Southern California, 2001, (b) Petasis,
N. A.; Boral, S. Tetrahedron Lett., 2001, 42, 539.
24
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
18. Petasis, N. A.; Huang, W. One-Step Three-Component Synthesis o f Substituted
Aminomethylpyridines, Abstracts of the 219th ACS National Meeting, 2000.
19. Y ao, X, Synthetic Studies and Novel Application o f the Reactions o f Boronic
Acids with Amines and Carbonyl Compounds., Ph.D. Thesis, University of
Southern California, 2002.
20. Petasis, N. A.; Zavialov, I. Z. J. Am. Chem. Soc., 1998,120, 11798.
21. Patel, Z. D. Synthesis o f Novel Compounds from Boronic Acids, Amines, and
Carbonyl Derivatives, Ph.D. Thesis, Universtiy of Southern California, 2002.
22. Ugi, I.; Domling, W. H. Endeavor, 1994,18, 115.
25
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CHAPTER 2
Synthesis of Novel Benzodiazepines from
Diamines and Organoboronic Acids
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2.1. INTRODUCTION
2.1.1. Biological Properties of Benzodiazepines
The benzodiazepine structure can be found in a large number of medicinal
agents and in molecules possessing biological activity. 1 1,4-benzodiazepines are
known to exhibit anti-anxiety, sedative, anti-convulsant, and tranquilising
properties.2 Along with being known antidepressants, benzodiazepines have also
been shown to be gamma amino butyric acid (GABA) agonists/antagonists, and
have been employed as anti-tumor agents. 1 The benzodiazepine core structure has
been deemed a “privileged” 3 structure for the construction of novel medicinal
agents, and has been increasingly used as hydrolytically stable bioactive
peptidomimetics.4
One of the most popular benzodiazepines is diazepam, commonly known as
Valium® (2.1) (Figure 2.1). Diazepam represents the class of diazepines known to
possess a 1,3-dihydro-l,4-benzodiazepine-2-one core structure, and is commonly
prescribed for the management of anxiety dissorders. 5 The 4,5,6,7-tetrahydro-5-
methylimidazo[4,5,l-yA][l,4]benzodiazepin-2(lH)-one core structure is commonly
referred to as TIBO, and this class of benzodiazepines are currently receiving much
attention due to their anti-HIV properties, of which compound (2.2) is known to be
one of the most potent non-nucleoside reverse transcriptase inhibitors, and has
recently entered clinical trials (Figure 2.1) . 6
27
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HN
(2.1) (2.2)
Figure 2.1 Known Benzodiazepine Drugs
Figure 2.2 presents a few examples of the various benzodiazepine core
structures which include, but are not limited to, 1,3-dihydro-1,4-benzodiazepin-2-
ones (2.3), 1,3,4,5 -tetrahydro-1,4-benzodiazepine-2-ones (2.4), 1,4-
benzodiazepine-2,5-diones (2.5), and l,2,4,5-tetrahydro-l,4-benzodiazepine-3-ones
(2.6).
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Figure 2.2 Various Benzodiazepine Core Structures
2.1.2. Synthesis of Tetrahydro-Benzodiazepines
Recently, Bhalay and co-workers have described the first solid phase
synthesis of l,3,4,5-tetrahydro-l,4-benzodiazepine-2-ones.7 A library of 120
compounds was produced according to the general methodology in Scheme 2.1,
and represents the synthesis of a diverse library of compounds which can serve as
n
potential leads in the drug discovery process.
29
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o
(2.7)
R-r ci
(2.8)
1.) NaHC03 (2 eq.)
THF, r.t., 6 hrs._____
2.) LiAlH4 (1 eq.),
THF, 0°C to r.t., 2 hrs.
R ,
OH
NH
(2.9) ^ R 2
O
o
C l
(2.9) (4 eq.),
O
O DCM, r.t., 10 hrs.
^ cr°
r1
N
O
(2.10) O H
1.) MsCl (5 eq.), Et3N (5 eq.),
DCM, 0°C to r.t., 4 hrs.
2.) R3NH2, DMF, r.t., 10 hrs.
R,
N
NaOMe (2 eq.),
N ^ C 0 2 M e THF/MeOH (4:1 v:v),
/ o
j 2 ) \ r.t., 1 0 hrs.
(2.12)
R,
(2.11) hn
Scheme 2.1
The synthesis of the amino alcohols was prepared from commercially available
anthranilic esters (2.7) by first reacting the aniline amine with acid chlorides (2.8),
followed by double reduction of the amide and ester using lithium aluminum
hydride to produce the desired amino alcohols (2.9). The amino alcohols were then
attached to Wang resin, which was first derivatized with fumaryl chloride, to yield
the tt,f-unsaturated amides (2 .1 0 ). The benzyl alcohol moiety was first converted
to the mesylate, and reacted with various primary amines to produce the advanced
30
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intermediates (2.11). The final tetrahydro-benzodiazepines were created via a
cleavage-conjugate addition protocol using sodium methoxide to produce
compounds (2.12) in excellent purity and good overall yields (>72%).
Recently, the first direct design of a highly potent nonpeptide 3-oxo-1,4-
benzodiazepine fibrinogen receptor antagonist (2.13) was described by Ku and co
workers at SmithKline Beecham (Figure 2.3) . 8 Starting with the constrained cyclic
peptide (2.14) ^ NMR, X-Ray crystallography and molecular modeling studies
were used to determine a “tum-extended-tum” conformation about the Arg-Gly-
Asp tripeptide.
COOH
'S—s'
HN
COOH
H
H N ^ N
(2-13) NH2 (2.14)
Figure 2.3 Rationally Designed Benzodiazepine-3one
Synthetic studies determined that the Arg and Asp side chains, or their equivalents,
where critical for the desired biological activity. Two particular conformational
features of the peptide backbone, the C7 turn at Asp and the extended Gly residue,
were deemed critical to the three-dimensional placement of the Arg and Asp side
31
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chains. The 1,4-benzodiazepine core system offered the potential to mimic these
orientations, and presents a rigid conformation for the nonpeptide molecule. All
together, it was deemed that the diazepine, the aromatic ring, and amide moiety of
(2.13) represented a small molecule template that properly mimics the Arg-Gly-
Asp backbone o f (2.14). Both high affinity for the GPIfb/IIIa receptor and potent
antiaggregatory activity were exhibited by (2.9).8 Subsequent studies on
derivatives of compound (2.13) lead to the development of (2.15) (Figure 2.4),
known as Lotrafiban, a potent antiaggregatory agent, which was orally active and
has recently entered into Phase III clinical trials for the protection of secondary
thrombotic events such as heart attack and stroke. 9-15
COOH
(2.15)
Figure 2.4 Lotrafiban
Recently, Ma and co-workers have described a facile synthesis of Lotrafiban by
utilizing a Cul-catalyzed coupling between an aryl halide and a P-amino acid as the
key step in construction of the diazepine core (Scheme 2.2) . 15
32
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COOH
(Boc)70/D M A P
t-BuOH, 89%
(2.16)
Fmoc-(S)-aspartic acid
P-methyl ester
------------------------------------j
DCC, HOBt, DCM, 75%
OH
C 02'Bu
1.) NBS,CC14>
2 .) aq. CH3NH 2
Me
93%
C02'Bu
(2.17) (2.18)
C02 Bu
C02 Bu
NHFmoc
NaOH, t-BuOH,
H2 0 , 98%
1.) Cul, K2C 0 3 ,
DMF, 90°C
2.) CH2N2, Et20
67%
(2.20)
1.) TFA, anisole, DCM
BocN^ Vf 11
EDCI, HOBt, DCM, 91%
1.) aq. NaOH, MeOH
2.) HCl/Dioxane, 79%
BocN,
COOMe
(2.21)
COOMe
(2.22)
Me
COOH
HN
(2.15)
HC1
Scheme 2.2
Compound (2.16) was first converted to the tert-butyl ester to yield (2.17), which
was then brominated with NBS and reacted with methylamine to yield (2.18).
33
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(2.18) was then coupled with Fmoc-fS')-aspartic acid (3-methyl ester to afford the
amide (2.19), which was then saponified to produce (2.20). Intermediate (2.20)
was subjected to the coupling conditions of 10 mol% Cul, in the presence of
potassium carbonate in DMF at 90°C to provide the desired cyclized product (2.21)
with no racemization detected. The tert-butyl protecting group was then removed
with trifluoroacetic acid, and the acid was coupled with the desired amine to yield
(2.22). Subsequent saponification, and Boc removal lead to the desired compound
(2.15) as the HC1 salt, in 30% overall yield.
34
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2.2. RESULTS AND DISCUSSION
Due to the wide range of pharmacological profiles that benzodiazepines
display, there is an ever-increasing demand for the synthesis of novel types of these
compounds, which possess this core stucture.7 Although many possible synthetic
routes exist towards substituted benzodiazepines, there is still a clear need for
efficient, environmentally benign, and convergent approaches, which allow for a
wide range o f structural variability.
Herein, we introduce the synthesis of substituted tetrahydro-1,4-
benzodiazepine-3-ones (2.23), as well as the synthesis of substituted tetrahydro-
l,4-benzodiazepine-2-ones (2.24) (Figure 2.5), using organoboronic acids and
substituted diamines to introduce diversity.
(2.24) (2.23)
— — II I ' I l i u m #
Figure 2.5 Benzodiazepine Core Structures Synthesized
35
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2.2.1. Synthesis of Tetrahydro-l,4-Benzodiazepine-3-ones
Previously in our group, it was established that a three component
condensation between an organoboronic acid (2.25), an amine (2.26), and an a-keto
acid (2.27) could be used to generate novel amino acids (2.28) (Scheme 2.3) . 16
R
(2.26)
B(OH)2
R 1
OH
OH
(2.25)
(2.28)
(2.27)
Scheme 2.3
This reaction was further extended by using substituted diamines (2.29) as the
amine component, and found to produce oxopiperazines (2.31) (Scheme 2.4) . 17
36
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R4— NH HN—R4
(2.29)
W
R
B(OH)2
o
V
OH
R
(2.25)
0
(2.31)
(2.30)
Scheme 2.4
We therefore sought to extend this methodology towards the synthesis of higher
homologs, specifically, tetrahydro-l,4-benzodiazepine-3-ones (2.23).
Initial attempts of using o-aminobenzylamine (2.32) as the amine
component in the condensation reaction proved unsuccessful, as no boronic acid
addition was observed. Therefore, we chose to selectively protect the benzyl amine
by converting it to the te/t-butoxycarbonyl derivative first. Reacting o-
aminobenzylamine with di-tert-butyl dicarbonate in dichloromethane or acetonitrile
proceeded smoothly, and in approximately 2 0 minutes provided the desired amine
(2.33), in nearly pure form and high yield (Scheme 2.5).
(Boc)2 0,
DCM or
NHBoc
(2.32) (2.33)
Scheme 2.5
37
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With this reaction being so efficient it was deemed experimentally
convenient to perform the protection in acetonitrile without isolation of the product,
as the subsequent condensation reaction with this amine could be carried out in
acetonitrile. Thus, it was observed that the condensation reaction between (2.33),
glyoxylic acid (2.30), and (£)-2-phenylvinylboronic acid (2.34) was complete in 4
hours in refluxing acetonitrile, as deemed by the disappearance of the boronic acid
on TLC, to afford the intermediate amino acid derivative (2.35) (Scheme 2.6).
NHBoc
O
OH
+ ¥ +
NH9 o
(2.33) (2.30)
B(OH), CH3CN,
reflux,
4 hrs.
(2.34)
Scheme 2.6
NHBoc
COOH
Initial attempts at deprotection and cyclization of intermediate (2.35) were
performed using 1M HC1 in acetic acid, and standard coupling protocols. Smooth
deprotection of the tert-butyl carbamate was performed using 1M HC1 in acetic
acid for 1 hour at room temperature, as observed by ]H NMR. However, all
attempts to directly cyclize this intermediate salt proved unsuccessful. Therefore,
an alternative deprotection method, which avoided the formation of salts, was
] 8
employed. Following previous literature reports a 3:1 mixture of 4M phenol in
dichloromethane, and 4M TMS-C1 in dichloromethane was premixed, and stirred at
38
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room temperature under Ar(g) for 20 minutes. It was found that this solution could
be directly added to the crude condensation reaction mixture and stirred at room
temperature under Ar(g) for 20 minutes to smoothly afford the desired intermediate
(2.36) (Scheme 2.7).
NH2 NHBoc
COOH COOH
3 eq. 4M Phenol in DCM
1 eq. 4M TMS-C1 in PCM
20 min, r.t., 98%
(2.36) (2.31)
Scheme 2.7
This intermediate could easily be isolated by trituration with diethylether. The
resulting precipitate was then transferred to a flask, dried under vacuum, and finally
dissolved in dry acetonitrile. To this solution was added EDCI and N,N-
diisopropylethylamine, which after work-up afforded the desired styryl substituted
tetrahydro-1,4-benzodiazepine-3-one (2.37) (Scheme 2.8).
NH-
COOH
(2.36)
EDCI, /PiyNEt, a
c h 3 c n ,
16 hrs., r.t.
55% overall
Scheme 2.8
39
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It should be noted that the use of other coupling agents, such as DCC, did afford
the product. However, purification from the urea side product was found to be
difficult. This prompted us to use EDCI, and to ultimately remove the water
soluble urea side-product with an extraction.
A series o f boronic acids were subjected to this procedure, without the
isolation of any intermediates, and alkenyl, aryl, and heteroaryl boronic acids were
all found to proceed well in this reaction (Table 2.1), to ultimately produce a
variety of substituted tetrahydro-l,4-benzodiazepine-3-ones in good overall yields.
The general four-step procedure is summarized in Scheme 2.9.
1.) (B oc)20 , CH3 CN,
1 0 min., r.t.
NHBoc
2.) HCOCOOH,
R-B(OH)2, c h 3 c n ,
3.) TMS-Cl/Phenql
DCM, 20 min.
reflux, 4 hr s. (2.38) O
4.) EDCI, (iPr)2NEt
— .........
CH3CN, 12-16 hrs.
H R
O
(2.39) O (2.40)
Scheme 2.9
40
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Table 2.1 Synthesis of tetrahydro-l,4-benzodiazepme-3-ones according to Scheme 2.9.
Product Yield Product Yield
H
H
H
A)
(2.37)
55 % overall
(2.42)
33 % overall
(2.44)
31 % overall
(2.46)
44 % overall
H
'OMe
H
(2.41)
48 % overall
(2.43)
34 % overall
(2.45)
39 % overall
(2.47)
41 % overall
41
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To explore the ability to introduce further diversity, and avoid the necessity of
protection-deprotection, the benzylamine was alkylated according to previous
reports19 using 9-BBN and benzylchloride to afford diamine (2.48) (Scheme 2.10).
1.) 9-BBN, THF, r.t.
G C 't S*—-CCs
l 2
n h 2 4.) Hydrolysis
(2.32) (2.48)
Scheme 2.10
Diamine (2.48) was reacted in a similar one-pot procedure, using furan-2-boronic
acid (2.49), to yield the desired product (2.50) (Scheme 2.11), whose absolute
structure was confirmed by X-Ray analysis.
NH-
n
(2.49)
(2.48)
■B(QH)2
1.) CTRCN, reflux, 4 hr s.
2.) EDCI, (zPr)2NEt,
CH3CN, 16 hrs., r.t.
46 % isolated yield
Scheme 2.11
42
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X-Ray analysis confirmed the higher reactivity of the aniline/primary amine over
the dibenzylamine in the three component condensation reaction to afford the
desired tetrahydro-l,4-benzodiazepine-3-one (2.50), an ORTEP diagram of this
product can be seen in Figure 2.6 . 20
43
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Figure 2.6 ORTEP Diagram of Structure (2.50)
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To further demonstrate the versatility that can be added to these tetrahydro-
l,4-benzodiazepine-3-one core systems, diazepine product (2.37) was reacted with
4-methoxyphenylboronic acid (2.51) and glyoxylic acid (2.30) to afford the desired
product (2.52) (Scheme 2.12).
-NH
OH
MeO'
(2.51) (2.30)
-NH
PCM , r.t., ^
24 hrs.
‘ COOH
MeO'
(2.52)
Scheme 2.12
2.2.2. Synthesis of Tetrahydro-1,4-Benzodiazepine-2-ones
Very recently, the use of glyoxamides (2.53) in place of the a-keto acid
(2.27) in our reaction was established, providing substituted a-amino amides (2.54)
(Scheme 2.13).2 1
45
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I
H
B(OH)2
(2.25)
Scheme 2.13
We envisioned that an extension of this methodology to an intramolecular reaction
with a properly tailored glyoxamide-amine (2.55) and a boronic acid (2.25) could
be used to generate novel, structurally diverse, tetrahydro-l,4-benzodiazepine-2-
ones (2.24) (Scheme 2.14).
(2.55)
R b ( o h )2
(2.25) (2.24)
Scheme 2.14
We already had easy access to selectively protected o-aminobenzylamine (2.33),
and therefore, this was chosen as our precursor for the amine source. Acylation of
the free aniline amine was accomplished by reacting (2.33) with 3,3-
46
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dimethylacrolylchloride (2.56) in the presence of pyridine in refluxing
dichloromethane for two hours to provide the desired product (2.57) in high yield
(Scheme 2.15).
NHBoc
(2.33) (2.56)
Pyridine,
DCM,
NHBo c
reflux, 2 hrs.
80% isolated
yield
(2.57)
Scheme 2.15
Although the crude product after extraction was nearly pure according to [H NMR,
this was recrystallized using ethyl acetate-hexanes to provide analytically pure
product, which was then smoothly deprotected using 1 M HC1 in acetic acid for two
hours at room temperature to provide the desired amine (2.58) (Scheme 2.16).
a
"'"'NHBoc
NH
(2.57)
1M HC1 in
Acetic Acid,
r.t., 2 hrs.
a
"v N H 2 HC1
NH
(2.58)
Scheme 2.16
47
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Subsequent attempts to take this salt directly to ozonolysis, to form the desired
amine (2.55) after neutralization, followed by reaction with the boronic acid proved
to be unsuccessful. Therefore, we decided to alkylate the benzyl amine via
reductive amination with benzaldehyde (2.59) to provide (2.60) (Scheme 2.17).
NH
(2.59)
(2.58)
1.) MeOH, r.t.,
30 mins.______
2.) NaBH4, 20 min.
95%
Scheme 2.17
NH
(2.60)
Compound (2.60) was then converted to the HC1 salt using excess 1M HC1 in ether,
and was subjected to ozonolysis in methanol. After removal of all of the volatiles
the resulting salt was suspended in ethyl acetate and neutralized with IN NaOH to
yield the intermediate (2.61). This intermediate was directly taken to the next
reaction without further purification, and found to successfully react with 4-
methoxyphenylboronic acid (2.51) to provide the desired product (2.62) in 73 %
yield (Scheme 2.18).
48
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HC1
(2.60)
1.) 0 3, -78°C,
MeOH, then ^
dimethylsulfide
2.) IN NaOH
OH
(2.61)
MeO
B(OH)2
(2.51)
CH3CN,
reflux,
4 hrs.,
73 % overall yield
•OMe
(2.62)
Scheme 2.18
Product (2.62) could easily be isolated as it precipitated from the reaction mixture.
Therefore, the solution was cooled to 0°C for 1 hour after the reaction, filtered,
washed with cold acetonitrile, and dried to provide the pure product. The general
procedure shown in Scheme 2.19 was then chosen to explore the reactivities of the
boronic acids used with this substrate and we found that a wide range of boronic
acids successfully participated.
49
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HC1
'NH
(2.60)
1.) 0 3, -78 C,
MeOH, then
' ]|pr
dimethylsulfide
2.) IN NaOH
R
R'
B(OH)2
R
(2.25)
CH3CN,
reflux,
4 hrs.,
73 % overall yield
(2.63)
Scheme 2.19
Table 2.2 summarizes the results, and presents how alkenyl (entries 1,2), heteroaryl
(entries 3,4), and aromatic; with both electron donating (entry 5) and electron
withdrawing groups (entry 6 ) present, all participated rather well in the reaction.
50
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Table 2.2 Synthesis of tetrahydro-l,4-benzodiazepme-2-ones according to scheme 2.19
Entry Boronic Acid Product Yield
B(OH)2
B(OH)2
(2.68)
o
B(OH)2
(2.49)
S
B(OH)2
(2.69)
(2.51)
Br
B(OH)2
(2.70)
•Ph
■ P h
(2.63)
-Ph
j-j O Br
(2.64)
Ph
N O-
N
H '0
(2.65)
/ — Ph
N S '
N
H 'O
(2.66)
63%
65%
77 %
64%
OMe
MeO'
73%
(2.62)
N
Ph
-Br
60%
N
H '0
(2.67)
51
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All of the reactions in the process, starting from o-aminobenzylamine (2.33), were
found to be highly efficient and along with the ease of isolation of the final product
results in a very efficient overall synthesis. To demonstrate this, along with
displaying the diversity that can be quickly introduced into these molecules with
this approach, product (2.71) was synthesized using 4-fluorobenzaldehyde (2.72)
and 2-Formylphenylboronic acid (2.73), without the isolation of any intermediates,
in 30 % overall yield (Scheme 2.20).
(2.33)
1.) Boc protection
2.) Acylation
3.) Deprotection
4.) Reductive Amination,
using (2.72)
5.) Ozonolysis
6 .) Neutralization
7.) (2.73) in refluxing CH3CN
30 % overall yield
Scheme 2.20
(2.71)
With this procedure being so successful, we decided to expand the diversity of the
products created by substitution at the benzyl (or 5) position of the core diazepine
structure. Since a large variety of 2-aminoacetophenones are commercially
available, we decided to use that as our starting amine source, and introduce the
second amine via reductive amination. Acylation of 2-aminoacetophenone was
performed as described earlier to afford (2.74), and the amine functionality was
52
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introduced via reductive amination with isopropylamine (2.75) according to the
literature22 to provide (2.76) (Scheme 2.21).
(2.74)
1.) 1 eq. | (2.75)
h 2n
2 eq. Ti(IV)isopropoxide,
EtOH, r.t., 16 hrs.
2.) NaBH4, 2 hrs.
83 % yield
Scheme 2.21
(2.76)
When (2.76) was subjected to the same procedure as before, and reacted with 1 -
Napthaleneboronic acid (2.77), compound (2.78) was produced in 57 % yield
(Scheme 2.22).
(2.76)
1.) 0 3, -78°C, MeOH,
then DMS
2.) IN NaOH
L -------------------------- ►
3.) CH3 CN, reflux, 4 hrs.
B(OH)2
(2.77)
57 % yield
Scheme 2.22
\ v ~
U H
)
H o £
J
(2.78)
53
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Unfortunately, this product did not precipitate from the reaction mixture, and was
instead isolated as a single diastereomer by flash column chromatography.
This synthetic process offers the ability to add functionalized amines to the
derivatized 2 -aminoacetophenone derivative, and thus it was envisioned that if
allylamine could be incorporated, the diene functionality could be exploited to
generate a more complex benzodiazepine. However, this amine would not survive
ozonolysis, and thus a slightly alternative approach was developed towards
9 1
formation of the glyoxamide. Previous reports in formation of the desired
glyoxamide were performed using periodic acid oxidation of a diol, and therefore
we sought to use this approach.
Compound (2.74) was successfully dihydroxylated according to the
literature23 to produce (2.79) in nearly quantitative yield. This was then subjected
to reductive amination with allylamine (2.80) to afford the desired (2.81), whose
yield was not optimized (Scheme 2.23).
1 .) 1 eq. / (2.80)
H2N
2 eq. Ti(IV)isopropoxide,
EtOH, r.t., 16 hrs.
■ O H 2.) NaBH4, 2 hrs.
•OH 29 % yield
(2.79) (2.81)
Scheme 2.23
54
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Compound (2.81) was then oxidized with periodic acid to generate the desired
glyoxamide, which, after work-up was directly treated with (£)-2 -
phenylvinylboronic acid (2.34) to provide (2.82) and the isomeric counterpart
(2.83) (Scheme 2.24).
NH
OH
■OH
(2.82)
(2.83)
1.) 2 eq. Periodic Acid,
MeOH, r.t., 2 hrs.
2.) CH3CN, reflux, 4 hrs.
r ^ r ^ / B ( O H )2
(2* 34)
^ 2 81 % combined yield
Scheme 2.24
’id NMR of the reaction mixture after extraction showed a ratio of 77:23 for
(2.82):(2.83). For fear of further isomerization of the desired (2.82) to (2.83) upon
isolation, we decided to take the crude reaction mixture and perform Grubb’s Ring-
Closing Metathesis on it using bis(tricyclohexylphosphine)benzylidine
ruthenium(IV) dichloride. Typically, these reactions are performed with 20 mol %
of the catalyst, but to avoid deactivation of the catalyst by (2.83) (which is 23% of
the mixture) we chose to use 50 mol % of the catalyst to produce a total of 27 mol
55
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% free catalyst, and allowed the reaction to proceed in dichloromethane at room
temperature for three days to ultimately yield (2.84) in 61 % isolated yield, based
on (2.82) (Scheme 2.25).
Ultimately, compound (2.84) represents the synthesis of a tricyclic tetrahydro-1,4-
benzodiazepine-2 -one, which was created by reacting the desired boronic acid with
a properly designed glyoxamide. Compounds (2.78) and (2.84) were isolated as
single diastereomers. The stereochemistry of the products was determined by X-
Ray crystallography of the 4-methoxyphenyl derived product (2.86) (scheme 2.26),
which showed an anti-configuration, as can be seen by the Ortep diagram in Figure
(2.83)
Scheme 2.25
56
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Me
NH
OH
•OH
(2.81)
1.) 2 eq. Periodic Acid,
MeOH, r.t., 2 hrs.
2.) CH3 CN, reflux, 4 hrs.
^ Y b(°h );
M e 0 ^ (2-5D
78% Yield
N / = N ^
V i u —
H O
(2.86)
Scheme 2.26
C A . v p
Figure 2.7 ORTEP Diagram of Structure (2.86)
57
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2.3. Conclusion
Overall, the synthesis o f both the tetrahydro-1,4-benzodiazepine-3 -ones and
2-ones proved to be highly efficient. The wide range of reactivity observed by the
boronic acids allows for the ability to introduce a large amount of structural
diversity into the core structure. Further diversity could be introduced based on the
design of the amine component, which when combined with the ease of the
synthetic steps, would serve well for combinatorial library design utilizing this
methodology. As the need for new, novel benzodiazepines to be used as
pharmaceutical lead compounds increases, this methodology represents a fast and
efficient access to a wide range of structurally diverse tetrahydro-1,4-
benzodiazepines.
58
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2.4. EXPERIMENTAL^
2.4.1. General
All starting materials, unless otherwise noted, were purchased from
commercial suppliers and used without further purification. Dry acetonitrile, ether,
and toluene were collected through an Anhydrous Engineering solvent system
according to the manufacturer’s specifications. Chloroform was distilled over
P 2 O 5 , dichloromethane was distilled over CaH, and tetrahydrofuran was distilled
over sodium/benzophenone prior to use. Pyridine was distilled over solid
potassium hydroxide prior to use. (£)-2-Phenylvinylboronic acid was either
prepared according to previous reports24 or commercial quantities were
recrystallized from hot water using decolorizing carbon prior to use. Thin layer
chromatography was performed on pre-coated TLC plates (Silica Gel 60 F254) and
flash column chromatography was performed using Silica Gel 60 (particle size
0.032-0.063 mm, 230-400 Mesh). NMR spectra were recorded on a Bruker
AMX-500 MHz, a Bruker AM-360 MHz, or a Bruker AC-250 MHz instrument.
High-Resolution mass spectra were obtained at the Southern California Mass
Spectrometry Facility, University of California, Riverside.
59
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2.4.2. Synthesis and Physical Properties of Diazepine-3-ones
2-Styryl-l,2,4,5-tetrahydro-benzo[e][l,4]diazepin-3-one (2.37).
NH
2-aminobenzylamine (245 mg, 2.0 mmol) was added to a 50 mL round
bottom flask and dissolved in dry acetonitrile (10 mL). To this flask a solution of
di-zm-butyl dicarbonate (436.5 mg, 2.0 mmol) in dry acetonitrile (5 mL) was
added dropwise at room temperature over a few minutes. The reaction was then
allowed to proceed until it was deemed complete by TLC (ethyl acetate:hexane 1 :1 ,
10 min.). To this solution was added glyoxylic acid monohydrate (200 mg, 2.16
mmol), followed by (£) -2 -Phenylvinylbo ronic acid (296 mg, 2.0 mmol). The
reaction vessel was then equipped with a reflux condenser and the mixture heated
to reflux. When the reaction was deemed complete by TLC (ethyl acetate:hexane
1:1) as observed by disappearance of the boronic acid (4 hrs) the reaction mixture
was allowed to cool to room temperature and the solvent removed under vacuum.
4M stock solutions of chlorotrimethylsilane and phenol were prepared initially, and
the Boc cleavage solution was prepared by mixing 1 mL of chlorotrimethylsilane
stock solution with 3 mL of phenol stock solution, and allowing them to stir for 20
minutes prior to addition to the reaction flask. This solution was then directly
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added to the Boc protected amino acid product, and allowed to stir for 20 minutes.
The solvent was then removed and the free amine product was isolated by
trituration with ether and collected by filtration. The precipitate was then placed in
a flask and dried under vacuum. To this flask was added dry acetonitrile ( 8 ml). 1 -
(3-Dimethylaminopropyl)-3-ethyldicarbodiimide hydrochloride (314 mg, 1.64
mmol) was placed in a separate flask and dry acetonitrile (2 mL) was added to this
vessel. To this resulting suspension was added N,N-diisopropylethylamine (212
mg, 1.64 m m ol). This mixture was stirred for 5 minutes and then added to the free
amino acid, being transferred with dry acetonitrile (2 mL). The reaction vessel was
then purged with nitrogen, sealed, and allowed to proceed at room temperature for
16 hrs. After this time, the volatiles were removed and the residue was re
dissolved in dichloromethane (30 mL) and transferred to a separatory funnel. The
organic layer was washed with a saturated NaHCCb solution (3x10 mL), and once
with brine (1 x 25 mL). The organic layer was then collected, dried over
magnesium sulfate, filtered and concentrated. The product was then isolated by
flash column chromatography using chloroform-ethyl acetate (4:1). Obtained 230
mg of a yellow crystalline solid (44 % overall yield). *H NMR (360 MHz, CDCI3)
6 7.44-7.39 (m, 2H), 7.35-7.22 (m, 3H), 7.11 (dt, 7=8.0 Hz, 7=1.4 Hz, 1H), 6.94
(dd, 7=7.3 Hz, 7=1.2 Hz, 1H), 6.74 (d, .7=16.2 Hz, 1H), 6.72 (dt, .7=7.3 Hz, .7=1.2
Hz, 1H), 6 . 6 6 (d, ,7=8,0 Hz, 1H), 6.55 (dd, 7=16.2 Hz, 7=6.5 Hz, 1H), 6.34 (bt,
7=6.2 Hz, 1H), 5.0 (d, 7=6.5 Hz, 1H), 4.61 (dd, 7=16.2 Hz, 7=6.2 Hz, 1 H), 4.22
(dd, 7=16.2 Hz, 7=6.2 Hz, 1H), 3.9 (bs, 1H). 1 3 C NMR (90 MHz, CDC13 ) 8 171.8,
61
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145.1, 136.1, 133.8, 129.1, 129.0, 128.6, 128.1, 126.7, 125.4, 122.0, 118.9, 117.8,
59.6, 44.9. HRMS-FAB/DEI calcd. for (M++ 1) 264.1263, obsd 264.1262.
2-(4-Methoxy-phenyl)-l,2,4,5-tetrahydro-benzo[e][l,4]diazepin-3-one (2.41).
OMe
NH
Prepared similarly to (2.37) (48 % overall yield). 'H NMR (250 MHz,
CDCla) 8 7.37 (d, J= 8 . 8 Hz, 2H), 7.11 (dt, .7=7.6 Hz, 7=1.7 Hz, 1 H), 6.93-6.85 (m,
3H), 6.76-6.65 (m, 2H), 6.38 (bt, 7=6.2 Hz, 1H), 5.23 (d 7=4.8 Hz, 1 H), 4.20 (d,
7=4.8 Hz, 1 H), 4.15 (d, 7=6.2 Hz, 2H), 3.79 (s, 3H). 1 3 C NMR (90 MHz, CDC13) (7
172.1, 159.5, 145.3, 130.8, 129.1, 129.0, 127.9, 122.6, 119.1, 117.9, 114.3, 62.8,
55.4, 44.8.
2-Furan-2-yl-l,2,4,5-tetrahydro-benzo[e] [ 1,4]diazepin-3-one (2.42).
NH
62
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Prepared similarly to (2.37) (33 % overall yield). 1H NMR (250 MHz,
CDCla) 6 7.41 (t, 7=1.3 Hz, 1H), 7.11 (dt, 7=7.7 Hz, .7=1.3 Hz, 1H), 6.97 (dd, 7=7.3
Hz, 7 = 1.3 Hz, 1H), 6.77 (dt, 7=7.3 Hz, 7=1.3 Hz, 1H), 6 . 6 8 (dd, 7=8 Hz, 7=1.0 Hz,
1H), 6.52 (bt, 7=6.1 Hz, 1H), 6.34 (d, 7=1.2 Hz, 2H), 5.40 (s, 1H), 4.46 (dd, 7=15.6
Hz, 7=6.1 Hz, 1H), 4.10 (dd, 7=15.6 Hz, 7=6.1 Hz, 1H). 1 3 C NMR (90 MHz,
CDCla) S 170.1, 151.0, 144.8, 142.5, 129.0, 128.8, 124.0, 120.1, 118.7, 110.5,
108.1,57.8, 44.9.
2-Thiophen-2-yl-l,2,4,5-tetrahydro-benzo[e][l,4]diazepin-3-one (2.43).
NH
Prepared similarly to (2.37) (34 % overall yield). 1H NMR (360 MHz,
CDCla) 8 7.32-7.28 (dd, 7=5.1 Hz, 1.3 Hz, 1H), 7.16-7.10 (m, 2H), 7.02-6.98 (m,
1H), 6.96 (d, 7=7.6 Hz, 1H), 6.77 (dt, 7=7.6 Hz, 1.2 Hz, 1H), 6 . 6 8 (d, 7=8.1 Hz,
1H), 6.26 (bt, 7=6.4 Hz, 1H), 5.58 (d, 7=4.6 Hz, 1H), 4.34 (dd, 7=15.9 Hz, 6.4 Hz,
1H), 4.25 (dd, 7=15.9 Hz, 6.4 Hz, 1H), 4.22 (bs, 1H). i3C NMR (90 MHz, CDCla)
8 170.67, 144.73, 141.67, 129.07, 128.81, 126.97, 125.95, 125.38, 123.37, 119.77,
118.33, 59.22, 44.84.
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2-Naphthalen-l-yl-l,2,4,5-tetrahydro-benzo[e][l,4]diazepin-3-one (2.44).
NH
Prepared similarly to (2.37) (31 % overall yield). ’H NMR (360 MHz,
DMSO-d6 ) 8 8.36-8.28 (m, 1H), 8.19 (t, 7=6.0 Hz, 1H), 8.00-7.93 (m, 1H), 7.89 (d,
7= 8 . 6 Hz, 1H), 7.66 (d, 7=7.0 Hz, 1H), 7.58-7.44 (m, 3H), 7.60 (t, 7=7.2 Hz, 1H),
6.93 (d, 7= 7.5 Hz, 1H), 6.87 (d, 7=7.6 Hz, 1H), 6.58 (t, 7=7.2 Hz, 1H), 6.51 (d,
7=4.9 Hz, 1H), 5.81 (d, 7=5.5 Hz, 1H), 4.19 (dd, 7=16.1 Hz, 7=6.0 Hz, 1H), 3.95
(dd, 7=16.1 Hz, 7=6.0 Hz, 1H). 1 3 C NMR (90 MHz, DMSO-d6 ) 8 180.2, 156.0,
145.2, 143.0, 139.7, 138.7, 138.0, 137.7, 135.8, 135.4, 134.8, 134.5, 133.5, 131.3,
126.8,126.6, 69.9, 52.9.
2-(4-Vinyl-pheny 1)-1,2,4,5-tetrahydro-benzo[e] [1,4]diazepin-3-one (2.45).
NH
Prepared similarly to (2.37) (39 % overall yield). %. !H NMR (360 MHz,
CDCla) 8 7.40 (bs, 4H), 7.12 (dt, 7=7.6 Hz, 1.6 Hz, 1H), 6.90 (d, 7=7.6 Hz, 1H),
64
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6.76-6.63 (m, 3H), 6.40 (bt, 7=5.7 Hz, 1H), 5.73 (d, 7=17.6 Hz, 1H), 5.27-5.21 (m,
2H), 4.29 (d, 7= 5.3 Hz, 1H), 4.15 (dd, 7=15.9 Hz, 5.7 Hz, 1H), 4.02 (dd, 7= 15.9
Hz, 6.7 Hz, 1 H). 1 3 C NMR (90 MHz, DMSO-cfe) 8 170.9, 145.9, 139.6, 136.3,
129.0,128.3, 126.4, 126.3, 121.0, 116.7, 116.6, 114.4, 61.8, 43.2.
2-(2-Methyl-propenyl)-l ,2,4,5-tetrahydro-benzo [e] [1,4]diazepin-3-one (2.46).
NH
Prepared similarly to (2.37) (44 % overall yield). 'H NMR (360 MHz,
CD3OD) 5 6.99 (t, 7=7.5 Hz, 1H), 6.91 (d, 7=7.5 Hz, 1H), 6.66-6.55 (m, 2H), 5.54-
5.48 (m, 1H), 5.12 (d, 7=8.3 Hz, 1H), 4.83 (d, 7=16.1 Hz, 1H), 4.04 (d, 7=16.1 Hz,
1H), 1.81 (s, 3H), 1.74 (s, 3H). 1 3 C NMR (90 MHz, CD3OD) 8 175.2, 147.5,
138.3, 129.9, 129.6, 122.8, 122.2, 118.9, 118.4, 55.3, 45.6, 26.0, 18.7.
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2-(2-Bromo-2-phenyl-vinyI)-l ,2,4,5-tetrahydro-benzo [e] [1,4] diazepin-3-one
(2.47).
NH
Br
Prepared similarly to (2.37) (41 % overall yield). 'H NMR (360 MHz,
DMSO-de) 5 8.24 (1, .7=6.0 Hz, 1H), 7.64-7.59 (m, 2H), 7.48-7.37 (m, 3H), 6.98 (t,
7=7.2 Hz, 1H), 6.91 (d, 7=7.7 Hz, 1H), 6.67-6.58 (m, 2H), 6.52 (t, 7=7.7 Hz, 1H),
5.99 (d, 7=4.0 Hz, 1H), 5,45-5.39 (m, 1H), 4.96 (dd, 7=16.0 Hz, 7=5.5 Hz, 1H),
3.80 (dd, 7=16.0 Hz, 7=5.5 Hz, 1H). 1 3 C NMR (62.5 MHz, CDC13 ) 8 170.8, 145.4,
138.6, 131.1, 130.6, 129.4, 129.1, 128.4, 127.8, 126.8, 122.6, 119.5, 118.2, 58.2,
45.2.
2-(Benzylamino-methyl)-phenylamine (2.48).
NH-
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Prepared according to the literature procedure19 ( 8 6 % yield). 1 H NMR
(250 MHz, CDCI3) 5 7.34-7.15 (m, 5 H), 7.08-6.92 (m, 2H), 6.66-6.56 (m, 2H),
4.37-4.25 (bs, 2H), 3.83-3.69 (m, 4H).
4-Benzyl-2-furan-2-yl-l,2,4,5-tetrahydro-benzo[el[l,4]diazepin-3-one (2.50).
2-(Benzylamino-methyl)-phenylamine (212 mg 1.0 mmol) was placed in a
25 mL round bottom flask and dry acetonitrile was added (7 mL), To this solution,
glyoxylic acid monohydrate ( 1 0 0 mg, 1.08 mmol) was then added, followed by
Furan-2-boronic acid (112 mg, 1.0 mmol). The reaction vessel was equipped with
a reflux condenser and the mixture heated to reflux. When the reaction was
deemed complete by TLC (ethyl acetate:hexane 1:1) as observed by disappearance
of the boronic acid (4 hrs) the reaction mixture was allowed to cool to room
temperature. The solvent was removed under vacuum and the crude mixture was
re-dissolved in dry acetonitrile (5 mL). l-(3-Dimethylaminopropyl)-3-
ethyldicarbodiimide hydrochloride (314 mg, 1.64 mmol) was placed in a separate
flask and dry acetonitrile (2 mL) was added to this vessel. To this resulting
67
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suspension was added N,N-diisopropylethylamine (212 mg, 1.64 mmol) . This
mixture was stirred for 5 minutes and then added to the free amino acid, being
transferred with dry acetonitrile (2 mL). The reaction vessel was then purged with
nitrogen, sealed, and allowed to proceed at room temperature for 16 hrs. After this
time, the volatiles were removed and the residue was re-dissolved in
dichloromethane (30 mL). This was washed with a saturated N aH C 0 3 solution (3
x 10 mL). The organic layer was then collected, dried over magnesium sulfate,
collected and concentrated. The product was then isolated by flash column
chromatography using ethyl acetate-hexanes (2:8). Obtained 146 mg of a colorless
solid (46 % yield). The absolute structure was determined by X-ray diffraction. 'H
NMR (360 MHz, CD3OD) 5 7.51 (bs, 1H), 7.29-7.16 (m, 5H), 7.05-6.98 (m, 1H),
6.90 (t, 7= 7.8 Hz, 2H), 6.52 (t, 7=7.4 Hz, 1H), 6.41-6.32 (m, 2H), 5.49 (s, 1H),
4.78 (d, 7=15.7 Hz, 1H), 4.58 (d, 7=15.7 Hz, 1H), 4.32-4.19 (m, 2H). 1 3 C NMR
(90 MHz, CD3OD) 5 170.9, 153.7, 146.6, 143.7, 138.2, 130.3, 129.9, 128.9, 128.4,
121.3, 119.0, 118.1, 111.6, 108.4, 59.3, 51.9, 51.2.
X-RAY Analysis for (2.50).
Crystals of (2.50) were obtained as thin colorless needles via
recrystallization from chloroform. A small sample of dimensions 0.30 x 0.05 x
0.05 mm was mounted on a glass fiber for X-ray data collection, which was carried
out at 100 K on a Bruker Smart/APEX CCD diffractometer with Mo radiation. The
68
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structure was solved by direct methods20 and refined to a final R factor of 5.26%
for 3565 reflections. Crystal details: space group P 2(l)2(l)2(l) (orthorhombic), a
= 7.134(1) A, b = 12.502(2) A, c = 17.452(3) A.
(4-Methoxy-phenyl)-(3-oxo-2-styryl-2,3,4,5-tetrahydro-benzo[e][l,4]diazepin-
l-yl)-acetic acid (2.52).
-NH
MeO'
COOH
Compound (2.37) (132 mg, 0.5 mmol) was dissolved in dichloromethane
and glyoxylic acid monohydrate (50 mg, 0.54 mmol) was added, followed by 4-
Methoxyphenylboronic acid (75 mg, 0.5 mmol). The reaction vessel was then
purged with nitrogen and stirred at room temperature for 24 hours. After this time,
the reaction vessel was then cooled to 0°C for 1 week. The product was then
collected by filtration and washed with a small amount of water to yield 118 mg of
a fine yellow-white powder (55% yield, mixture of diastereomers). !H NMR (360
MHz, CD3OD) 6 7.68-7.63 (m, 1H); 7.39-7.30 (m, 2H); 7.29-7.10 (m, 7H); 7.09-
6.92 (m, 2H); 6.82-6.66 (m, 1H); 6.56 (d, .7=15.8 Hz), 6.25 (d, 7=15.7 Hz), together
1H; 5.68 (dd, 7=15.8 Hz, 7=8.8 Hz), 5.56 (dd, 7=15.7 Hz, 7=9.1 Hz), together 1H;
5.19-5.40 (m, 2H); 4.59 (d, 7=8.8 Hz), 4.24 (d, 7=9.1 Hz), together 1H; 3.95 (bd,
69
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■7=13.5 Hz, 1H); 3.85 (s), 3.67 (s), together 3H. 1 3 C NMR (90 MHz, CD30D ) 8
174.9, 174.3, 162.0, 160.9, 148.4, 146.0, 137.6, 137.5, 137.2, 137.0, 136,6, 136.5,
131.5, 131.0, 129.7, 129,6, 129.2, 129.1, 128.9, 129.0, 129.3, 127.6, 127.5, 126.7,
125.8, 125.4, 124.0, 123.7, 123.0, 115.7, 114.8, 69.9, 68.5, 68.4, 6 6 .6 , 55.9, 55.6,
45.4, 45.3, 5 C’s overlapped in aromatic region.
2.4.3. Synthesis and Physical Properties of Diazepine-2-ones
N-(-tert-butoxycarbonyl)-2-aminobenzylamine (2.33).
NHBoc
'NH-
2-aminobenzylamine (2.440 g, 20.0 mmol) was added to a 100 mL round
bottom flask and dissolved in dry dichloromethane (30 mL). To this flask a
solution o f di-tert-butyl dicarbonate (4.360 g, 20.0 mmol) in dry dichloromethane
(12 mL) was added dropwise at room temperature over a few minutes. The
reaction was then allowed to proceed until it was deemed complete by TLC (ethyl
acetate.'hexane 1:1, 30 min.). The volatiles were removed and the resulting solid
was purified by flash column chromatography using ethyl acetate-hexanes (1.5:8 .5
to 3:7). Obtained 3.912 g of an off-white powder (8 8 %). ]H NMR (250 MHz,
CDC13 ) 8 7.10-6.90 (m, 2H), 6.70-6.61 (m, 2H), 4.76 (bs, 1H), 4.25-4.20 (d, .7=6,2
Hz, 2H), 1.43 (s, 9H). 1 3 C NMR (63 MHz, CDC13 ) 5 157.8, 145.5, 130.3, 129.0,
122.5, 117.9, 115.7, 79.8, 42.1,28.3.
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[2-(3-Methyl-but-2-enoylamino)-benzyl]-carbamic acid tert-butyl ester (2.57).
NHBoc
NH
Compound (2.33) (1.333g, 6.0 mmol) was placed in a 50 mL flame dried
round bottom flask, equipped with a condenser, and flushed with Ar(g). Dry
dichloromethane (20 mL) was then added. 3,3-Dimethylacrolyl chloride (0.67 mL,
6.06 mmol) was then added, followed by re-distilled pyridine (0.72 mL, 6.06
mmol). The mixture was then brought to reflux, and maintained at that temperature
for 2 hrs. After this time, the mixture was cooled to room temperature and diluted
with ethyl acetate (25 mL) and transferred to a separatory funnel with additional
ethyl acetate (10 mL). The organic layer was then washed with 2N HC1 (2x15
mL), and then carefully washed with saturated sodium bicarbonate (2 x 20 mL),
and finally washed with brine (2x15 mL). The organic solution was then dried
over magnesium sulfate, filtered and evaporated to dryness. The crude resulting
solid was then recrystallized using ethyl acetate-hexanes to yield 1.465g of a white
solid (80% yield). *H NMR (250 MHz, CDC13) 8 9.03 (brs, 1H), 8.24 (d, J =7.9
Hz, 1H), 7.32-6.88 (m, 3H), 5.88 (brs, 1H), 5.10-4.95 (m, 1H), 4.20 (d, 7=6.7 Hz,
2H), 2.18 (s, 3H), 1.85 (s, 3H), 1.38 (s, 9H). 1 3 C NMR (125 MHz, CDCfl) 8 165,7,
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157.1, 152.9, 137.3, 130.3, 128.8, 128.0, 123.5, 122.2, 119.2, 80.5, 41.8, 30.9, 28.3,
27.5, 19.9.
3-Methyl-but-2-enoic acid (2-aminomethyl-phenyl)-amide (2.58).
NH-
NH
Compound (2.57) (914 mg, 3.0 mmol) was placed in a 50 mL round bottom
flask and 15 mL of 1M HC1 in acetic acid was added. The mixture was allowed to
stir at room temperature for 2 hours. After this time 15 mL o f toluene was added
and the solvents were evaporated. An additional 20 mL of toluene was added and
evaporated, and this was repeated as necessary until a solid was recovered. This
solid was then suspended in 20 mL of ethyl acetate, 20 mL of IN NaOH was added
and the mixture was poured into a separatory funnel. The aqueous layer was
removed and the organic layer was washed further with IN NaOH (2x15 mL).
The organic layer was dried over magnesium sulfate, filtered, and the volatiles
removed to yield 612 mg of a yellow oil (quantitative yield). 'H NMR (360 MHz,
CD3OD) 8 7.66-7.13 (m, 4H), 6.00 (s, 1H), 4.01 (s, 2H), 2.21 (s, 3H), 1.96 (s, 3H);
1 3 C NMR (90 MHz, CD3OD) 8 169.4, 156.1, 137.6, 132.0, 131.3, 130.1, 128.4,
127.6, 118.6,41.1,27.6, 20.3.
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3-Methyl-but-2-enoic add [2-(benzylamino-methyl)-phenyl]-amide (2.59).
Compound (2.58) (612 mg, 3.0 mmol) was placed in a 25 mL round bottom
flask and dissolved in methanol (6 mL). To this solution was added benzaldehyde
(0.32 mL, 3.0 mmol) and the mixture was stirred at room temperature for 1 hr.
After this time sodium borohydride (170 mg, 4.5 mmol) was added slowly over 10
minutes, and the mixture was allowed to stir for an additional 20 minutes. 15 mL
of IN NaOH was then added to quench the reaction, and the mixture was
transferred to a separatory funnel with ethyl acetate. An additional 25 mL of ethyl
acetate was added and the organic layer was washed successively with IN NaOH
(3x15 mL), brine (1x15 mL), and then dried over magnesium sulfate, filtered,
and evaporated. The product was purified by flash column chromatography with
ethyl acetate-hexane (3:7 then 1:1) to yield 839 mg (95 % yield) of a yellow oil. *H
NMR (250 MHz, CDC13 ) 8 10.44 (s, 1H), 8.23 (d, J=S.O Hz, 1H), 7.39-6.84 (m,
8 H), 5.64-5.56 (m, 1H), 3.78 (s, 2H), 3.70 (s, 2H), 2.15 (s, 3H), 1.82 (s, 3H); 1 3 C
NMR (63 MHz, CDCI3) 8 165.0, 151.8, 139.2, 139.0, 129.4, 128.5, 128.2, 128.2,
127.3, 122.9, 121.0, 119.6, 53.0, 52.6,27.3, 19.8. The amine was then converted to
the HC1 salt with an excess of IN HC1 in ether to be used in further
transformations.
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4-Benzyl-3-(4-methoxy-phenyl)-l ,3,4,5-tetrahydro-benzo [e] [1,4] diazepin-2-one
(2.62).
Compound (2.59 HC1) (132 mg, 0,4 mmol) was placed in a dry ozonolysis
tube, and dissolved in an adequate amount of methanol. The tube was cooled to -
78°C and subjected to ozone until a blue color persisted. At this time, the tube was
flushed with oxygen, and then an excess of dimethylsulfide (1.0 mL) was added.
The solution was maintained at -78°C for 30 minutes, brought to 0°C and
maintained there for an additional 30 minutes, and finally brought to room
temperature and maintained there for an additional 1 hour. The volatiles were then
removed and the residue suspended in ethyl acetate. IN NaOH was added and
stirred until a clear solution persisted. The mixture was then transferred to a
separatory funnel with ethyl acetate, and the organic layer was washed with IN
NaOH (2x15 mL). The organic layer was dried with magnesium sulfate, filtered,
and evaporated to yield an off-white solid. This solid was then placed in a round
bottom flask, to which 5 mL of acetonitrile was added, followed by 4-
Methoxyphenylboronic acid (76 mg, 0.5mmol), the flask was equipped with a
reflux condenser, and the mixture was brought to reflux and held there for 4 hours.
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After this time, the mixture was cooled to 0°C, and the resulting solid was filtered
off, and washed with cold acetonitrile (10 mL) and vaccum dried to obtain 104 mg
(73 % yield) of a white fluffy solid. 'H NMR (360 MHz, CDCfi) 5 7.65-7.55 (bs,
1H), 7.42-7.23 (m, 8 H), 7.18-7.08 (m, 2H), 6.99 (d, 7=7.8 Hz, 1H), 6 . 8 6 (d, 7=8.6
Hz, 2H), 4.21 (s, 1H), 4.05 (d, 7=13.2 Hz, 1H), 3.77 (s, 3H), 3.67-3.58 (m, 2H),
3.36 (d, 7=13.2 Hz, 1H). 1 3 C NMR (63 MHz, CDC13 ) 8 172.3, 159.4, 130.7, 130.1,
128.9,128.7, 128.6, 128.4, 128.1,127.3, 125.1, 120.6, 113.6, 69.8, 56.2, 55.2, 51.2.
4-Benzyl-3-(4-bromo-phenyl)-l,3,4,5-tetrahydro-benzo[e][l,4]diazepin-2-one
(2.67).
Br
Prepared similarly to (2.62) (60 % yield). *H NMR (360 MHz, CDC13 ) 8
7.58-7.51 (bs, 1H), 7.46-7.41 (m, 2H), 7.38-7.22 (m, 7H), 7.20-7.10 (m, 3H), 6.98
(d, 7=8.0 Hz, 1H), 4.18 (s, 1H), 4.05 (d, 7=13.5 Hz, 1H), 3.64 (d, 7=14.5 Hz, 1H),
3.59 (d, 7=14.5 Hz, 1H), 3.39 (d, 7=13.5 Hz, 1H). 1 3 C NMR (90 MHz, CDC13 ) 8
171.3, 137.1, 131.3, 130.7, 130.6, 128.9, 128.8, 128.5, 128.2, 127.4, 125.4, 121.9,
120.8,69.8, 56.7, 51.5.
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4-Benzyl-3-(2-bromo-2-phenyl-vinyl)-l,3,4,5-tetrahydro-benzo[e][l,4]diazepin-
2-one (2.64).
Prepared similarly to (2.62) (65 % yield). lU NMR (360 MHz, CDC13 ) 8
7.63-7.56 (bs, 1H), 7.48-7.17 (m, 13H), 7.60 (d, 7=7.7 Hz, 1H), 6.53 (d, 7= 7.5 Hz,
1H), 4.21 (d, ,7=7.5 Hz, 1H), 3.92 (d, 7=14.4 Hz, 1H), 3.82 (d, .7=13.2 Hz, 1H), 3.64
(d, 7=14.4 Hz, 1H), 3.57 (d, 7=13.2 Hz, 1H). 1 3 C NMR (90 MHz, CDC13) 8 168.4,
137.3, 135.4, 130.8, 130.6, 129.1, 129.0, 128.7, 128.5, 128.2, 127.8, 127.4, 125.7,
121.1,67.0, 56.5, 52.4.
2- [4-(4-Fluoro-benzyl)-2-oxo-2,3,4,5-tetrahydro-l H-benzo[e] [1,4] diazepin-3-
yl]-benzaldehyde (2.71).
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Prepared similarly to (2.62) with reductive amination using 4-
Fluorobenzaldehyde, and the use of 2-Formylphenylboronic acid. Prepared in 34
% overall yield without isolation of intermediates starting from (2.33). 'H NMR
(500 MHz, DMSO-d6 ) 5 10.37 (s, 1H), 7.83-7.79 (m, 1H), 7.64-7.60 (m, 1H), 7.40-
7.34 (m, 2H), 7.29-7.19 (m, 3H), 7.70-6.95 (m, 5H), 6.32 (s, 1H), 5.09 (d, 7=15.4
Hz, 1H), 5.01 (d, 7=15.4 Hz, 1H), 4.56 (d, 7=15.3 Hz, 1H), 4.47 (d, 7=15.3 Hz,
1H)„ ,3C NMR (125 MHz, DMSO-d6 ) 5 195.2, 163.3, 162.6, 160.7, 139.9, 134.4,
133.0, 131.5, 129.84, 129.77, 129.32, 129.31, 127.9, 126.8, 126.4, 125.9, 125.6,
119.7, 118.3, 115.2, 115.0, 94.8, 52.2, 47.2.
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3-Methyl-but-2-enoic acid (2-acetyl-phenyI)-amide (2.74).
'NH
Prepared similarly to (2.57) (72 % yield). ’H NMR (250 MHz, CDC13 ) 8
8.87-8.77 (m, 1H), 7.89-7.79 (m, 1H), 7.56-7.43 (m, 1H), 7.10-6.98 (m, 1H), 5,82-
5.76 (m, 1H), 2.66-2.58 (m, 3H), 2.26-2.21 (m, 3H), 1.92 (s, 3H). 1 3 C NMR (63
MHz, CDCR) 8 202.3, 165.4, 153.6, 141.3, 134.6, 131.4, 121.5, 121.1, 120.1,
119.4,28.2, 27.1, 19.7.
3-Methyl-but-2-enoic acid [2-(l-isopropylamino-ethyl)-phenyl]-amide (2.76).
NH
Compound (2.74) (217 mg, 1.0 mmol) was placed in a flame dried 25 mL
round bottom flask, and flushed with Ar(g). The flask was charged with 8 mL of
absolute ethanol, followed by isopropylamine (85.2 pL, 1.0 mmol), followed by the
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addition of titanium(IV) isopropoxide (0.59 mL, 2.0 mmol). The reaction was
allowed to proceed at room temperature for 16 hours. After this time sodium
borohydride (60 mg, 1.5 mmol) was added slowly over 10 minutes, and the mixture
was allowed to stir for an additional 2 hours. The white precipitate was then
filtered off, and washed with dichloromethane (20 mL). The washings were then
collected, transferred to a separatory funnel, and washed successively with IN
NaOH (2x15 mL), and brine (1x15 mL). The organic layer was then dried over
magnesium sulfate, filtered and evaporated to yield a crude oil, which was purified
by column chromatography in ethyl acetate-hexane (3:7), to yield 216 mg of a
yellow oil (83 % yield). lH NMR (360 MHz, CDC13 ) 8 8.46-8.36 (m, 1H), 7.26-
7.17 (m, 1H), 7.07-7.00 (m, 1H), 6.99-6.90 (m, 1H), 5.70-5.66 (m, 1H), 4.08 (q,
7=6.5 Hz, 1H), 2.71 (sep., 7=6.5 Hz, 1H), 2.25 (d, ,7=0.8 Hz, 3H), 1.90 (d,7=1.2Hz,
3H), 1.38 (d, 7=6.5 Hz, 3H), 1.09 (d, 7=6.5 Hz, 3H), 1.05 (d, 7=6.5 Hz, 3H). I3C
NMR (90 MHz, CDC13 ) 8 164.9, 151.7, 138.5, 130.2, 128.5, 127.5, 122.8, 120.8,
119.7, 56.9, 46.0, 27.4, 23.7, 22.0, 21.9, 19.8.
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4-Isopropyl-5-methyl-3-naphthalen-l-yl-l,3,4,5-tetrahydro-
benzo[e] [1,4]diazepin-2-one (2.78).
Prepared similarly to (2.62) starting with (2.76) (57 % yield). 'H NMR
(360 MHz, CDCR) 8 8.48-8.43 (m, 1H), 7.82-7.78 (m, 1H), 7.72 (d, ,7=8.1 Hz, 1H),
7.64-7.59 (bs, 1H), 7.55 (d, 7= 7.2 Hz, 1H), 7.45-7.39 (m, 2H), 7.32 (t, .7=7.8 Hz,
1H), 7.18-7.12 (m, 2H), 7.05 (t, 7= 7.2 Hz, 1H), 6.73 (d, 7=7.9 Hz, 1H), 5.66 (s,
1H), 4.35 (q, 7=7.0 Hz, 1H), 2.92-2.79 (m, 1H), 1.49 (d, 7=7.0 Hz, 3H), 1.05 (d,
7=6.9 Hz, 3H), 0.97 (d, 7=6.9 Hz, 3H). 1 3 C NMR (90 MHz, CDCR) 8 175.1, 142.7,
136.5, 135.9, 134.0, 131.6, 128.7, 128.5, 127.5, 127.4, 126.0, 125.6, 125.2, 124.3,
124.0, 119.6, 66.2, 53.7, 49.8, 21.3, 19.2.
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N-(2-Acetyl-phenyl)-2,3-dihydroxy-3-metfayl-butyramide (2.79).
NH
OH
HO
9 - 3
Prepared according to the literature starting with (2.74), and purified by
flash column chromatography using ethyl acetate-hexane (1:1) (99 % yield). 'H
NMR (360 MHz, CDCI3) 8 8.69-8.61 (m, 1H), 7.85-7.77 (m, 1 H), 7.75-7.42 (m,
1H), 7.12-7.04 (m, 1H), 4.88 (d, .7=5.4 Hz, 1H), 4.10 (s, 1H), 4.07 (d, 7=5.4 Hz,
1H), 2.57 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H). 1 3 C NMR (90 MHz, CDCI3) 5 202.4,
172.8, 139.2, 134.8, 131.5, 122.9, 122.6, 120.8, 77.7, 72.7, 28.4, 25.6, 24.5.
N-[2-(l-Allylamino-ethyl)-phenyl]-2,3-dihydroxy-3-methyl-butyramide (2.81).
Me
NH
‘ OH
OH
Prepared analogously to (2.76) in 29 % isolated yield (mixture of
diastereomers), from flash column chromatography in ethyl acetate-hexane (3:2 to
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4:1). !H NMR (250 MHz, CDC13 ) 6 8.35-8.18 (m, 1H), 7.30-7.19 (m, 1H), 7.15-
6.98 (m, 2H), 5.99-5.77 (m, 1H), 5.23-5.03 (m, 2H), 4.06-3.91 (m, 2H), 3.13 (d,
J= 5.6 Hz, 2H), 1.42 (d, 7=6.7 Hz, 3H), 1.31 (s, 3H), 1.29 (d, J= 2.5 Hz, 3H). 1 3 C
NMR (63 MHz, CDCI3) 8 171.4, 171.3, 136.6, 136.4, 135.9, 135.9, 131.6, 131.4,
128.9, 128.8, 127.7, 124.2, 124.1, 121.7, 121.5, 116.2, 116.1, 77.7, 77.4, 72.9, 72.8,
58.6, 58.4, 49.9, 49.7, 26.2, 26.1, 24.5, 21.4, 21.3.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
4-Allyl-5-methyl-3-styryl-l,3,4,5-tetrahydro-benzo[e][l,4]diazepin-2-one
(2.82).
Me
Compound (2.81) (117 mg, 0.4 mmol) was placed in a 25 mL round bottom
flask and dissolved in methanol (2 mL) and water (1 mL). To this solution was
added periodic acid (192 mg, 0.84 mmol), and the mixture was allowed to stir at
room temperature for 2 hours. After this time, the solvent was then evaporated and
the resulting residue was taken up in ethyl acetate (20 mL) and transferred to a
separatory funnel. The organic layer was then washed with a saturated sodium
bicarbonate solution (5x15 mL) until the aqueous layer no longer turned pink in
color. The organic layer was then washed with brine (1 x 15 mL), dried over
magnesium sulfate, filtered and evaporated. This resulting aminol was then
dissolved in acetonitrile (4 mL) and to this solution was added {E)~2-
Phenylvinylboronic acid (75 mg, 0.5 mmol), and the solution was brought to reflux
for 4 hours. After this time, the reaction was diluted with ethyl acetate (40 mL),
and transferred to a separatory funnel. The organic layer was washed with IN
NaOH (3x15 mL), brine (1x15 mL), dried over magnesium sulfate, filtered, and
evaporated to yield the desired product, and an isomeric by-product in a combined
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yield of 81 %. !H NMR was used to estimate the ratio of product to by-product to
be approximately 77:23. This mixture was taken crude to the next transformation
to avoid further isomerization upon isolation. !H NMR (250 MHz, CDCI3, major
isomer) < 5 7.75 (bs, 1H), 7.43-7.37 (m, 2H), 7.33-7.15 (m, 6 H), 7.11-7.04 (m, 1H),
6.85-6.82 (m, 1H), 6.57 (dd, J-16.0 Hz, J=4.8 Hz, 1H), 5.92-5.69 (m, 1H), 5.18-
5.03 (m, 2H), 4.44-4.39 (m, 1H), 4.29 (q, J= 6 . 6 Hz, 1H), 3.27-3.16 (m, 1H), 2.92-
2.80 (m, 1H), 1.55 (d, J= 6 . 6 Hz, 3H).
5-Methyl-3,5,10,Ha-tetrahydro-benzo[e]pyrroIo[l,2-a][l,4]diazepin-ll-one
(2.84).
Me
Compound (2.z) (103 mg, 0.32 mmol) was first converted to the HC1 salt
with excess 1M HC1 in ether, and all of the volatiles were removed. The resulting
solid was then dissolved in dry dichloromethane (15 mL) and
Bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (132 mg, 0.16
mmol) was added, and the flask was flushed with Ar(g). The reaction was allowed
to proceed at room temperature for three days, after which time, the reaction was
diluted with an additional 10 mL of dichloromethane, and transferred to a
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separatory funnel. The organic layer was washed with a saturated solution of
sodium bicarbonate (3 x 15 mL), the aqueous layers were then combined and
extracted with dichloromethane (2 x 10 mL). The organic layers were then
combined, washed once with brine (15 mL), dried over magnesium sulfate, filtered
and evaporated to yield a crude residue which was purified by flash column
chromatography using ethyl acetate-hexane (3:1) to yield 32 mg (61 % yield) of a
dark oil. *H NMR (360 MHz, CDC13 ) 6 7.60 (bs, 1H), 7.42 (d, 7=7.6 Hz, 1H),
7.32-7.19 (m, 2H), 7.00-6.95 (m, 1H), 6.16-6.10 (m, 1H), 5.88-5.82 (m, 1H), 4.34
(bs, 1H), 3.96-3.81 (m, 2H), 3.55-3.46 (m, 1H), 1.58 (d, 7=6.5 Hz, 3H). ,3C NMR
(90 MHz, CDC13 ) 5 172.3, 136.6, 134.5, 131.1, 128.3, 127.1 (2 C ’s), 125.7, 121, i,
67.6, 57.5, 54.8, 17.9.
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2.5. REFERENCES
1. Grierson, D. S.; Fowler, F. W.; Adams, D. R.; Sisti, N. J.; Goulaouic-Dubois,
C. Tetrahedron Lett., 1998, 39, 4283.
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11. Keenan, R. M. et. al. J. Med. Chem., 1997, 40, 2289.
12. Miller, W. H. Tetrahedron Lett., 1995, 36, 9433.
13. Ku, T. W. et. al. Tetrahedron Lett., 1997, 38, 3131.
14. Keenan, R. M. et. al. J. Med. Chem., 1999, 42, 545.
15. Ma, D.; Xia, C. Organic Letters, 2001, 3, 2583.
86
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16. (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc., 1997, 119, 445; (b)
Petasis, N. A,; Goodman, A.; Zavialov, I. A. Tetrahedron, 1997, 53, 16463.
17. Petasis, N. A.; Patel, Z. D. Tetrahedron Lett., 2000, 41, 9607.
18. (a) Kaiser Sr., E.; Kubiak, T.; Tam, J. P.; Merrifield, R. B. Tetrahedron Lett.,
1988, 29, 303; (b) Kaiser Sr., E.; Picart, F.; Kubiak, T.; Tam, J. P.; Merrifield,
R. B. J. Org. Chem., 1993, 58, 5167.
19. Kol., M., Bar-Haim, G. Tetraheadron Lett., 1998, 39, 2643.
20. G.M. Sheldrick, SHELX system of crystallographic programs, 1997,
University of Gottingen.
21. Yao, X, Synthetic Studies and Novel Application o f the Reactions o f Boromc
Acids with Amines and Carbonyl Compounds., Ph.D. Thesis, University of
Southern California, 2002.
22. Neidigh, K. A.; Avery, M. A.; Williamson, J. S.; Bhattacharyya, S., J. Chem.
Soc., Perkin Trans. 1 ,1998, 2527.
23. VanRheenen, V.; Kelly, R.C.; Cha, D.Y. Tetrahedron Lett., 1976, 1973.
24. Zavialov, I. New Reactions o f Organoboronic Acids and Their Derivatives,
Ph.D. Thesis, University of Southern California, 1998.
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CHAPTER 3
Condensation Products Generated from
Amines, Glyoxals, and Organoboronic Acids
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
3.1. INTRODUCTION
3.1.1. Biological Importance of a-Amino Ketones and Their
Synthetic Utility
a-Amino ketones are among the most versatile functional groups in organic
chemistry, and are frequently used as intermediates towards natural products and
nitrogen-containing heterocycles.1 ’ 2 In addition to their synthetic utility aryl a-
amino ketones, such as Bupropion (3.1) (Figure 3.1), have been employed in the
clinical treatment of nicotine dependence, and are widely used as late life
antidepressants.3
(3.1)
Figure 3.1 Bupropion
An ample number o f examples utilizing a-amino ketones as key building
blocks towards the synthesis of a large variety of end products exist. For example,
Nyori and coworkers have shown the asymmetric reduction of an a-amino ketone
(3.2) can offer an efficient and convenient way of preparing (R)-denopamine (3.3),
a f5\-receptor agonist used to treat congestive heart failure (Scheme 3.1).4
89
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97 % e.e.
OH
H H C 1
HO 'OMe
(3.3)
OMe
Protecting group
m anipulation, and
recrystallization.
94 % yield
100 % e.e.
Scheme 3.1
Wills has demonstrated that another catalytic system could also successfully be
used for the asymmetric reduction of an a-amino ketone (3.4), and further
transformed the amino alcohol (3.5) into an aziridine (3.6) (Scheme 3.2).5
90
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(3-4)
0.5 mol % [Ru(cymene)Cl2 ] 2
TsHN Nii-
1.0 m o l %
NHBoc
Ph
H C 02 H, Et3N, r.t.
86 % yield,
99 % e.e.
Ph
OH
NHBoc
(3.5)
DEAD, PPh3,
THF
92 % yield
t 99 % e.e.
H
(3.6)
Scheme 3.2
Miller and co-workers used solid-supported a-amino ketones as precursors
towards carboxypyrrolinones.6 Various amino alcohols (3.7) were coupled to
Wang resin-bound malonic acid (3.8), to provide the amido-alcohols (3.9), which
were then oxidized to the corresponding ketones (3.10) using CrO?(OtBu)2 . These
substrates were then cyclized using a strong hindered base in the presence of a
Lewis Acid to proved the resin bound 3-carboxypyrrolinones, which were finally
cleaved using TFA to provide the desired end products (3.11) in good overall yields
(69 % to 94 %) (Scheme 3.3).6
91
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R
r 1 h n / ^ y ,R +
OH
(3.7)
o o
HQBT/
O ' ^ 'OH DIC
A A
(3.8)
O 0 Rz
A A \
R
(3.9)
R 1 OH
O
O
C r02(0tBu)2
HO
-R 1
R3 R2
1.) LDA, or
. LHMDS.
ZnCl2
2.) TFA
o 0 R
" O '
N
R 1 O
R
(3.11)
(3.10)
Scheme 3.3
Hamby reacted a-amino Weinreb amides (3.12) with methylmagnesium
bromide to generate the desired a-amino ketone (3.13). This amino ketone was
used as a key building block towards highly substituted pyrroles. This was
accomplished by first derivatizing the a-amino ketone (3.13) to the free amino
derivative (3.14), via HC1 cleavage of the Boc derivative, this product was then
subjected to one equivalent of sodium acetate and a three fold excess of
acetylacetone in acetic acid at 80°C to yield the Knorr condensation product (3.15)
in 79% yield (Scheme 3.4).7
92
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o
Ph" 'N'
,NH Me
,OMe
Boc"
(3.12)
Me,
Me
Ph
Me
(3 .1 5 )
MeMgBr,
ether, 5°C ,)
74 % yield
O
Ph Me
„NH
Boc"
(3.13)
HCl(g),
74 % yield
o o
X X
AcONa, AcOH
80°C, 74 % yield
Ph"
O
'Me
NH2 HC1
(3.14)
Scheme 3.4
Buchanan used an a-amino ketone as a key intermediate in the generation
of substituted thiazoles.8 The a-ketoamide (3.17) was prepared from the
corresponding Weinreb amide (3.16) by reaction with (benzyloxymethyl)lithium.
The a-ketoamide (3.17) was then subjected to Lawesson’s reagent in THF at 67°C
for 1.5 hr s. generating the desired thiazole derivative (3.18) (Scheme 3.5).8
93
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BocHN
Bu3SnCH2OBn, «-BuLi, 0
DME, -78°C, then (3.16), ^ BocHN
THF, -78°C, 2.5 hrs. i H
86 % yield q ^
Lawesson's Reagent,
THF, 67°C,
1.5 hrs., 78 % yield
OBn
BocHN
(3.18)
Scheme 3.5
3.1.2. Synthesis of a-Amino Ketones
A large number of synthetic routes exist towards the synthesis of a-amino
ketones. Previously, we have seen that the reaction of a Weinreb amide with a
Grignard or organolithium reagent can provide the desired a-amino ketone. This
method, however, suffers from the required purification of the amide, and often
requires a large excess of Grignard to be efficient. Ricci and co-workers used N,N-
carbonyldiimidazole (3.20) in THF at room temperature to generate the activated
94
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amino ester (3.21), and reacted the crude mixture with the desired Grignard reagent
in the presence of 6 mol% Cul to afford the desired a-amino ketone (3.22) in
satisfactory to good yields (Scheme 3.6).9
O
R1
OH
NHBoc
(3.19)
O
I m ^ I m
(3.20)
o
R1
THF, r.t.,
30 min.
90 - 98 % yield
Im
NHBoc
(3.21)
r 2 m ,
6 mol % Cul
................. it
THF, 0°C,
2 - 3 hrs.
R
O
R”
NHBoc
(3.22)
O OBn O
NHBoc
(3.23)
56 % yield
Ph
NHBoc
(3.24)
70 % yield
Scheme 3.6
o.
NHBoc O
(3.25)
73 % yield
More recently, Giacomelli has reported activation of the carboxylic acid (3.26) by
using 2-chloro-4,6-dimethoxy[ 1,3,5]triazine (CDMT) in the presence of N-
methylmorpholine to provide the desired ester (3.27) in quantitative yield. After
removal of the N-methylmorpholine salt by filtration, one equivalent o f Cul was
added, followed by the desired Grignard reagent to provide the a-amino ketone
(3.28). High yields were obtained for alkyl reagents, however vinyl organometallic
reagents provided only modest yields (48 %), and alkynyl organometallic reagents
95
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reacted extremely slowly and provided only trace amounts of the product (Scheme
3.7).1 0
O OMe
0 CDMT, Ri N /
X H M M .., R M SX’ CulV X
RlX V O H THF.r.t., ' P f 0°C, 2-3 hrs. R,X V R!
1 hr
OMe
(3.26) (3.27) (3.28)
BocHN
(3.29) (3.30) (3.31)
98 % yield 95 % yield 48 % yield
Scheme 3.7
In perhaps what is the most versatile method for the generation of novel, chiral, a-
amino ketones, Myers reported the asymmetric alkylation o f pseudoephedrine
glycinamide (3.32) to provide intermediate (3.33), which after N-protection and
subsequent reaction with an excess of organolithium or Grignard reagent provided
the desired a-amino ketone (3.34) in good yields and high e.e. (> 95 %) (Scheme
3.8) (yields reported are for the organometallic addition only).1 1
96
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Ph
CH3 O
'N
OH CH3
(3.32)
NH,
T F) A CH3 O
u c ’ A M ,
T V ; 2.) R M,
R X OH CH3 R1 t h f
(3.33)
o
NHBoc
(3.35)
93 % yield
NHBoc
(3.36)
85 % yield
Scheme 3.8
NHBoc
O
H3C
R1
(3.34)
NHBoc
(3.37)
74 % yield
Racemic a-amino ketones are most commonly prepared by amination of a-
halo ketones or a-hydroxy ketones, by ring opening of phenylsulfinyl- or alkoxy-
epoxides, or addition of aldehydes to iminium cations.1 2 ,1 3 However, most of these
reactions suffer serious drawbacks, such as limitations in the type of substrate used,
extensive side reactions resulting in low yields, or undesired crossover products.
Perhaps one o f the most attractive methods is the addition o f aldehydes to iminium
ions in a Mannich type reaction. However, this synthetic route suffers from the
limitation that aldehydes other than formaldehyde did not readily react with the
amines to form the alkyliminium salts. To overcome this limitation, Katritzky and
co-workers used N-(a-morpholinoalkyl)benzotrizoles (3.38) as the iminium salt
generators.1 3 When substrate (3.38) was reacted with an aldehyde (3.39), in the
97
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presence of thiazolium salt (3.40), the desired a-amino ketone (3.41) could be
produced in moderate yield (Scheme 3.9).1 3
n
N
R
Bt
H
R
O
2J
(3.38) (3.39)
(3.42)
44 % yield
CEUCN
(3.43)
30 % yield
Scheme 3.9
R1
(3.41)
(3.44)
55 % yield
However, this reaction also suffered from some limitations, mainly that
unsymmetrical a-amino ketones, where R1 and R2 are different, with one
exception, could not be readily formed; this will be discussed further in Scheme
3.11.
13
98
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3.2. RESULTS AND DISCUSSION
a-Amino ketones have long been used as key building blocks towards many
valuable synthetic and natural products.1 ,2 Above this, a-amino ketones have also
been shown to be potent therapeutic agents.3 Since such a large array of
possibilities exist for the use of a-amino ketones, there is still a clear need for the
expedient, and efficient synthesis of diverse, and novel a-amino ketones.
Herein, we introduce the novel synthesis of a-amino ketones (3.48) via a
one-step three component condensation between an organoboronic acid (3.45), an
amine (3.46), and an a-keto aldehyde (3.47) (Scheme 3.10).
(3.46)
(3.48)
R
(3.45)
Scheme 3.10
3.2.1. Synthesis of a-Amino Ketones
It has been previously recognized that the addition of a nucleophile to
iminium ions offers the ability to introduce a wide range of structural diversity into
99
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an a-amino ketone product. However, the previous reports of this approach
suffered from limited introduction of variability, in that only symmetrical products
1 ^
could be formed successfully. Katritzky found that when benzaldehyde (3.49)
was reacted with a-(p-chlorophenyl)-7V-a-morpholinobenzotriazole (3.50) in the
presence of thiazolium salt (3.43), four products (3.51-3.54) were fonned in
comparable amounts, presumably due to reversible formation of the iminium ion
with both aldehydes (Scheme 3.11).1 3
100
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n
0
J ♦
Ph'
(3.49)
N
Cl
Cl
Bt
(3.50)
'H
(3.40)
c h 3 c n
R
(3.41)
(3.51)
O
N
O
Bt
H
O
BtH
PhCHO
(3.49)
(3.50)
+ N
(3.56) H
(3.55) (3.57)
Scheme 3.11
'H
Bt
(3.58)
We therefore sought to use organoboronic acids (3.45) that offer a large
range of structural diversity, are environmentally benign, and would allow us to
overcome the limitation of forming only symmetrical products. We envisioned that
a one-step three component condensation between an organoboronic acid (3.45), an
101
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amine (3.46) and a-keto aldehyde (3.47) would produce the desired structurally
diverse a-amino ketone (3.48) (Scheme 3.10).
Indeed, we found that when phenylglyoxal hydrate (3.59) was reacted with
a secondary amine (3.46) and an organoboronic acid (3.45) in methanol at room
temperature, the expected a-amino ketone (3.60) was formed (Scheme 3.12).
O
.OH
OH
(3.59)
OH R4
N
,R
H
(3.46)
R
r i/ V B(OH)2 MeOH, r.t.
J 3 18-24hrs.
K .
(3.45)
Scheme 3.12
(3.60)
Table 3.1 summarizes the reactions of secondary amines with phenylglyoxal
hydrate (3.60) and boronic acids (according to Scheme 3.12). Heteroarylboronic
acids (entries 1-3), electron donated arylboronic acids (entry 4), and electron
withdrawn arylboronic acids (entry 5) were all found to work equally well with
varying secondary amines, providing the desired a-amino ketone in good isolated
yields (reactions not optimized).
102
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Table 3.1 Synthesis of amino ketones from phenylglyoxal hydrate, secondary
_________ amines, and organoboronic acids._____________________________
Entry Amine Boronic Acid Product Yield
"N"
H
(3.61)
Ph
Me^ y
N
H
(3.64)
I > -B (O H ) 2
O Me
XL .P h
A— B(OH)2
(3.65)
43 %
49%
(3.66)
c
Boc
N
N
H
(3.67)
N
H
(3.69)
N
H
(3.69)
NBoc
(3.62) (3.68)
O
(3.71)
OMe
B r’
B(O H )2
(3.72)
53 %
84%
(3.73)
40%
All reactions were run in methanol, at r.t. for 18-24 hours. Yields are isolated yields.
103
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With the successful use of the three-component condensation reaction, we
sought to expand the scope of the reaction by using primary amines. It was found
that aniline (3.74) performed well in the reaction, providing the desired product
(3.75) (Scheme 3.13), however other primary amines lead to complicated mixtures.
NH,
(3.60) (3.74)
~ 0
[ Q ^ - B ( O H ) 2
(3.65)
MeOH,
r.t., 24 hrs. ^
58 % yield
N.
'O
(3.75)
Scheme 3.13
To exemplify the diversity that could be employed utilizing this reaction,
we also sought to vary the a-keto aldehyde used. Table 3.2 summarizes these
results, and indeed, we found that substituted aryl (entry 1 ), heteroaryl (entry 2 ),
and alykl (entry 3) a-keto aldehydes could successfully be employed to generate
the desired a-amino ketone in comparable yields to phenylglyoxal hydrate (3.60).
104
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Table 3.2 Synthesis of highly functionalized amino ketones from gyloxals, secondary
_________ amines, and organoboronic acids.____________________________________
Entry Glyoxal Amine Boronic Acid Product Yield
(3.76)
M eO
(3.70) (3.69) (3.77)
O M e
O M e
O
M e J
C l X
(3.78) (3.64)
Ph
-O
O
3 J - L /OH
H3C
OH
(3.80)
/ / — B (O H)2
(3.65)
B (O H)2
N
(3.69) Me0 (3.70)
(3.79)
O
(3.81)
OM e
84%
44%
41 %
All reactions were run in methanol, at r.t. for 18-24 hours. Yields are isolated yields.
3.2.2. Synthesis of 1,2,3,4-Tetrahydropyrazines
Having successfully demonstrated the use of boronic acids (3.45) in the
three component condensation to generate a-amino ketones, we decided to perform
the reaction with a 1,2-diamine. When N,N-dibenzylethylenediamine (3.82) was
reacted with phenylglyoxal hydrate (3.60) and (£)-2-phenylvinylboronic acid
(3.83) in methanol at room temperature, after 24 hours, a yellow precipitate was
105
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observed. Upon isolation of the precipitate, *H and 1 3 C NMR analysis provided a
structure other than an a-amino ketone was formed, and suggested product (3.84), a
1,2,3,4-tetrahydropyrazine was formed (Scheme 3.14). Indeed, high resolution
mass spectroscopy confirmed that (3.84) was the product formed.
OH
Ph Ph
r ~ \
-NH HN
OH
MeOH,
r.t., 24 hrs. ^
51 % yield *
(3.60) (3.82) +
B(OH)2
(3.83)
(3.84)
Scheme 3.14
The 1,2,3,4-tetrahydropyrazine system has previously been used to explore
the oxidative properties of cytochrome P-450 monooxygenase, 14 as a synthon
towards higher functionalized piperazines, 15 and as a key building block in the
synthesis of the Merck HIV protease inhibitor Indinavir (3.85) (Figure 3.2) . 16
106
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Figure 3.2 Indinavir
Optically active substituted piperazines can be found incorporated into a variety of
pharmaceutical agents. 16 One potential route towards these compounds is the
asymmetric hydrogenation of tetrahydropiperazines. Ito and Kuwano have shown
that high enantioselectivities in the asymmetric hydrogenation of substituted
tetrahydropiperazines could be achieved with a chiral diphosphine-rhodium
complex (Scheme 3.15).1 6
107
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1 m ol % I n h 'Bu
NH Bu 1 /u k .
? T [Rh(NBD)2 ]SbF6 ^
Ph^nD ° 1 ,2 -dichloroethane P h ^ ^ x ) °
(3.86) 50°C, 85 % yield (3.87)
96 % e.e.
Scheme 3.15
Eisner and Williams also provided a surprising result upon the oxidation of (3.88)
with Jones reagent, and provided the unexpected diol (3.89), which they attributed
to the high electron density of the double bond in the tetrahydropiperazine system
(Scheme 3.16).1 5
108
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Scheme 3.16
We therefore sought to explore the possibility of making other substituted
1,2,3,4-tetrahydropyrazines by the use of various boronic acids in the condensation
with N,N-dibenzylethylenediamine (3.82) and phenylglyoxal hydrate (3.60).
Unfortunately, using some aryl boronic acids provided none o f the desired product.
However, heteroaryl boronic acid, 2-furanboronic acid (3.65) did prove to
participate in the reaction, and generated the desired (3.90) (Scheme 3.17).
109
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OH
Ph Ph
/ \
-NH HN-
OH
MeQH,
r.t., 24 hrs. ^
59 % yield
(3.60) (3.82)
+
(3.90)
(3.65)
Scheme 3.17
It should be noted that the furan moiety is known to be one o f the most versatile
functional groups in organic chemistry, and that new compounds generated which
incorporate this group are of great synthetic interest.
3.2.3. Synthesis of 2-Hydroxymorpholines
Simultaneous to our efforts using a-keto aldehydes (3.47) in the three-
component reaction to generate a-amino ketones, Carboni and coworkers reported
the three component condensation of secondary amino alcohols (3.91) with an a-
keto aldehyde (3.47) and a boronic acid (3.45), ultimately producing 2-
hydroxymorpholines (3.92) (Scheme 3.18).1 7
110
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B(OH)2
(3.47)
Scheme 3.18
HO
(3.92)
Previous reports of the generation of 2-hydroxymorpholines include the
condensation of 1 ,2 -amino alcohols with an a-haloketone, 18 an a-hydroxyketone, 19
or reaction of an a-amino ketone with an epoxide, or the reduction of morpholin-
2-ones.21 Non-racemic 2-hydroxymorpholines have successfully been prepared by
the addition of organolithium, organozinc, or allcylcopper reagents to N-
cyanomethyl-1,3-oxazolines22 or 2-hydroxy-3 -phenylthiomorpholines23 The 2-
hydroxymorpholine ring system has previously been identified as a key structural
component of a number of biologically active compounds.24,23 A series of potent
orally active neurokinine- 1 antagonists which are based on this core structure have
recently been disclosed.26
Carboni and coworkers reported primarily that N-benzylethanolamine
(3.93) could successfully be employed in the reaction with an a-keto aldehyde
111
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(3.47), and that aryl (entries 1-3), heteroaryl (entry 4), and alkenyl (entry 5) boronic
acids could all be used to generate the desired 2 -hydroxymorpholines in good
1 7
yields and good diastereomeric ratios (Table 3.3).
112
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Table 3.3 Synthesis of 2-Hydroxymorpholines using N-benzylethanolamine,
1 7
__________ a glyoxal, and an organoboronic acid.______________________________
Entry Glyoxal Boronic Acid Product Yield
O
OH
OH
(3.94)
(3.60)
O
HiC
OH
OH
(3.80)
O
H
OH
OH
(3.94)
O
H
OH
OH
(3.94)
B(OH)2
(3.94)
MeO
B(OH)2
* ^
(3.96)
(3.72)
Bu
B(OH)2
(3.99)
r ^ S
[ j ^ - B ( O H )2
(3.62)
(3.95)
OH
. 0 ,
N
L
OMe
(3.97)
OH
Ph
Br
,0.
N
(3.98)
HO. ^O
Ph
Bu'
N
L
(3.100)
HO O
CTl
(3.101)
Ph
Ph
70%
d.r. = 87/13
53%
d.r. =87/13
52%
d.r. = 76/24
6 6 %
d.r. = 55/45
56%
d.r. = 75/25
All reactions were run in ethanol, at r.t. for 24 hours. Yields are isolated yields.
Diastereomeric ratios were determined by 1 I INMR.
113
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The diastereomeric ratios were determined by 'H NMR, with the relative
stereochemistry being trans for the major diastereomers of products generated with
arylboronic acids.1'
The proposed mechanism for the three component reaction involves
addition of an activated boronic acid to an iminium salt, with the boronic acid being
activated by a neighboring hydroxy group (Scheme 3.19).
R
R ‘n ^ R J
N
H OH
(3.91)
+ O R5
R
R
B(OH)2
r7(3.45)
O
(3-47)
0 R4
H O ^ ,0
HO
R f
R -
R7 N 0 R2
Rs
1,0
R1
(3.103)
HO
r 6 HO
OH
'OH
(3.102)
/-
HO
(3.92)
Scheme 3.19
114
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Carboni and coworkers confirmed this course of action by preforming the iminium
salt by reaction of perhydro-4,8-dimethyl-4,8-diazal,5,9,10-tetraoxoanthracene
(3.104) with BF3-OEt2 to generate the intermediate iminium ion (3.105), which
when subjected to a boronic acid (3.94 and 3.106) provided the desired 2-
hydroxymorpholines (3.107 and 3.108) (Scheme 3.20) . 17
Ph
Ph
(3.104)
BR-OBf,
U © J
N
k
Ph
(3.105)
B(OH)2
(3.94)
o
OMe
(3.106)
HO. O HO
OMe
Ph
(3.107)
94 % yield
d.r. = 73/27
(3.108)
76 % yield
d.r. = 60/40
Scheme 3.20
115
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Previous reports have shown that chiral 1,2-amino alcohols can successfully
be employed in the three-component reaction to control the stereochemistry of the
newly formed chiral center 27 Therefore, we sought to extend our work, and that of
Carboni, by using chiral 1,2-amino alcohols to potentially generate chiral 2-
hydroxymorpholines.
We found that when 4-methoxyphenylboronic acid (3.70) was reacted with
(5)-N-benzylphenylglycinol28 (3.109) and phenylglyoxal hydrate (3.60) in
methanol at room temperature for 24 hours, a white precipitate appeared. Upon
being filtered, and dried, !H NMR analysis showed the presence of only one
compound, resulting in > 99 % d.e. and > 99 % e.e. for this product (3.110)
(Scheme 3.21).
Ph Ph
L
N
H
1 J
OH MeO
(3.109) + (3.70)
O
.OH
MeOH,
r.t, 24 hrs.
57 % yield
> 99 % d.e.
> 99 % e.e.
r
'
\ \ l OH
S r '"Ph
k
MeO Ph
(3.110)
Scheme 3.21
116
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Unfortunately, crystals suitable for X-Ray analysis were unobtainable, and the
absolute stereochemistry of the newly formed centers could not be confirmed.
However, this proved to be a special case where only one diastereomer selectively
precipitated. The reactions employed using other chiral amino alcohols can be seen
in Table 3.4.
117
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Table 3.4 Synthesis of 2-Hydroxymorpholines using chiral amines, phenylglyoxal
_________ hydrate, and an organoboronic acid._______________________________
Entry Amine Boronic Acid Product Yield
Ph Ph
k X
N
H
OH
(3.109)
Ph Ph
V
H
OH
(3.112)
Ph, CH,
HO HN—CH3
(3.114)
H
B(OH)2
(3.83)
^ ^ ^ ^ / B(0 H )2
(3.83)
B(OH)2
(3.83)
MeO
B(OH)2
(3.116) (3.70)
OH
,0„
Ph
(3.111)
Ph
OH
,0
(3.113)
Ph
OH
O x P h
N ^ C H 3
Ph
(3.115)
OH
MeO
(3.117)
70%
75%
71 %
73 %
All reactions were run in methanol, at r.t. for 24 hours. Yields are isolated yields.
All of the compounds were isolated as a mixture of only two diastereomers
(determined by 'H NMR of the crude reaction mixture), instead of the expected
118
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four products, which presumably means that the new carbon bond formed in the
reaction is fixed, and that the acetal is the chiral center, in equilibrium with its’
other diastereomer, which is not fixed in one particular orientation.
3.3. CONCLUSION
We have demonstrated that the condensation of a boronic acid (3.45), an
amine (3.46), and an a-keto aldehyde (3.47) can be used to generate a-amino
ketones, 1,2,3,4-tetrahydropyrazines, and 2-hydroxymorpholines. As the need for
new and novel compounds of these types, which present interesting biological and
synthetic uses increases, the use of this methodology presents a rapid and efficient
method for the generation of libraries of diverse compounds of all three types.
119
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3.4. EXPERIMENTALS
3.4.1 General
All starting materials, unless otherwise noted, were purchased from
commercial suppliers and used without further purification. Dry acetonitrile, ether,
and toluene were collected through an Anhydrous Engineering solvent system
according to the manufacturer’s specifications. Chloroform and dichloromethane
were distilled over P2O5 and tetrahydrofuran was distilled over
sodium/benzophenone prior to use. (A)-2-Phenylvinylboronic acid was either
27 •
prepared according to previous reports or commercial quantities were
recrystallized from hot water using decolorizing carbon prior to use. Thin layer
chromatography was performed on pre-coated TLC plates (Silica Gel 60 F25 4) and
flash column chromatography was performed using Silica Gel 60 (particle size
0.032-0.063 mm, 230-400 Mesh). NMR spectra were recorded on a Bruker
AMX-500 MHz, a Bruker AM-360 MHz, or a Bruker AC-250 MHz instrument. IR
spectra were recorded on a Nicolet 460 machine. High-Resolution mass spectra
were obtained at the Southern California Mass Spectrometry Facility, University of
California, Riverside.
3.4.2. Synthesis and Physical Properties of a-Amino Ketones
2-Diallylamino-l-phenyl-2-thiophen-2-yl-ethanone (3.63).
120
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To a mixture of phenylglyoxal hydrate (67 mg, 0.5 mmol) and diallylamine
(61.7 pL, 0.5 mmol) in methanol (5 mL) was added 2-thiopheneboronic acid (64
mg, 0.5 mmol) and the solution was stirred at room temperature while being
monitored by TLC (30% ethyl acetate in hexanes). After completion of the
reaction (24 h), the volatiles were then removed and the residue dissolved in 20 mL
ethyl acetate and transferred to a separatory funnel. The organic layer was washed
with 3N HC1 (3x8 mL). The aqueous layer was then cooled to 0°C and carefully
brought to pH 6 . 8 with 6 N NaOH, and then to pH 7.0 with 0.1N NaOH. The
aqueous layer was then extracted with ethyl acetate (3x10 mL). The organic layer
was then dried over magnesium sulfate, filtered, concentrated, and the product was
isolated by flash column chromatography using 2 0 % ethyl acetate in hexanes.
(For acid sensitive substrates, the crude reaction mixture was purified directly by
flash chromatography). Obtained 64 mg of a yellow oil (43 % yield). 5 H NMR
(360 MHz, CDCfi) 8 8.0-7.95 (m, 2H), 7.54-7.29 (m, 4H), 6.94-6.84 (m, 2H), 5.89-
5.76 (m, 3H), 5.19-5.09 (m, 4H), 3.38 (dd, 14.3 Hz, 6.1 Hz, 2H), 3.12 (dd, 14.3 Hz,
6.1 Hz, 2H). 1 3 C NMR (90 MHz, CDCfi) 8 198.3, 137.8, 136.6, 136.2, 133.1,
121
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128.6, 128.5, 128.1, 126.5, 126.3, 117.8, 62.8, 53.6. IR (CDC13 film) 8 1687 cm' 1
(C O ). HRMS-DCI/NH3 calcd. for (MH+ ) 298.1263 found 298.1266.
2-(Benzyl-methyl-amino)-2-furan-2-yl-l-phenyl-ethauone (3.66).
Me
Prepared similarly to (3.63) (49 % yield). 'H NMR (250 MHz, CDCI3) 5
7.96-7.89 (m, 2H), 7.55-7.18 (m, 10H), 6.41-6.33 (m, 1H), 5.37 (s, 1H), 3.78 (d,
J=15 Hz, 1H), 3.57 (d, J=15 Hz, 1H), 2.31 (s, 3H). 1 3 C NMR (62.5 MHz, CDC13 ) 5
196.2, 149.2, 138.9, 136.1, 133.0, 129.2, 128.8, 128.4, 128.3, 127.1, 111.1, 110.5,
65.7, 58.9, 39.2.
2-(4-Methoxy-phenyl)-l-phenyl-2-pyrrolidm-l-yl-ethanone (3.71).
OMe
122
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Prepared similarly to (3.63) (84 % yield). NMR (360 MHz, CDC13 ) 8
8.00-7.96 (m, 2H), 7.48-7.41 (m, 1H), 7.38-7.30 (m, 4H), 6.83-6.77 (m, 2H), 4.80
(s, 1H), 3.73 (s, 3H), 2.69-2.59 (m, 2H), 2.45-2.34 (m, 2H), 1.84-1.72 (m, 4H). °C
NMR (90 MHz, CDCI3) 8 197.3, 159.4, 136.3, 132.8, 130.3, 128.8, 128.7, 128.4,
114.1,75.4,55.2, 52.7, 23.2.
2-(4-Bromo-phenyl)-l-phenyl-2-pyrrolidin-l-yl-ethanone (3.73).
Prepared similarly to (3.63) (40 % yield). *H NMR (360 MHz, CDCI3) 8
7.98 (d, J= 7.5Hz, 2H), 7.52-7.27 (m, 7H), 4.85 (s, 1H), 2.68-2.60 (m, 2H), 2.49-
2.39 (m, 2H), 1.85-1.75 (m, 4H). 1 3 C NMR (90 MHz, CDC13 ) 8 196.9, 135.9,
133.2, 132.0, 130.7, 129.1, 128.8, 128.5, 122.3, 75.3, 52.7, 23.3. IR (CDC13 film) 8
1683 cm' 1 (C O ).
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4-(2-Oxo-2-phenyl-l-thiophen-2-yl-ethyl)-piperazine-l-carboxylic acid tert-
butyl ester (3.68).
Boc
Prepared similarly to (3.63) (53 % yield). !H NMR (500 MHz, CDC13 ) 8
8.08-8.04 (m, 2H), 7.53 (t, 7= 7.5 Hz, 1H), 7.44-7.39 (m, 2H), 7.30 (d, 7=5.1 Hz,
1H), 6.99-6.97 (m, 1H), 6.94-6.91 (m, 1H), 5.30 (s, 1H), 3.48-3.39 (m, 4H), 2.62-
2.55 (m, 2H), 2.50-2.43 (m, 2H), 1.41 (s, 9H). 1 3 C NMR (125 MHz, CDC13 ) 5
196.8, 154.8, 139.1, 136.7, 133.4, 128.9, 128.6, 128.5, 127.1, 126.7, 79.7, 69.8,
50.7, 50.5, 28.4.
l-Phenyl-2-phenylamino-2-thiophen-2-yl-ethanone (3.75).
N
'S
Prepared similarly to (3.63) (58 % yield). lH NMR (360 MHz, CDC13 ) 8
8.07-8.01 (m, 2H), 7.58-7.51 (m, 1H), 7.48-7.42 (m, 2H), 7.33-7.31 (m, 1H), 7.18-
7.12 (m, 2H), 6.74-6.66 (m, 3H), 6.29-6.27 (m, 1H), 6.26-6.23 (m, 1H), 6.11 (d,
124
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J-6 .9 Hz, 1H), 5.31 (d, J=6.9 Hz, 1H). ,3C NMR (62.5 MHz, CD3OD) 5 196.3,
152.2, 147.9, 144.0, 136.3, 134.7, 130.0, 129.9, 129.7, 119.2, 115.1, 111.7, 110.2,
57.9.
l-(4-Fluoro-phenyl)-2-(4-methoxy-phenyl)-2-pyrrolidin-l-yl~ethanone (3.77).
OMe
Prepared similarly to (3.63) (84 % yield). *H NM R (250 MHz, CDC13 ) 8
8.38-8.28 (m, 2H), 7.67-7.59 (m, 2H), 7.36-7.22 (m, 2H), 7.14-7.06 (m, 2H), 5.09
(s, 1H), 4.03 (s, 3H), 3.00-2.87 (m, 2H), 2.81-2.67 (m, 2H), 2.15-2.03 (m, 4H).
2-(Benzyl-methyl-amino)-2-furan-2-yl-l-thiophen-2-yl-ethanone (3.79).
Me
Prepared similarly to (3.63) (44 % yield). 'H NMR (500 MHz, CDC13) 8
7.80 (d, ,7=3.8 Hz, 1H), 7.60 (d, J=4.8 Hz, 1H), 7.45 (bs, 1H), 7.38-7.22 (m, 5H),
125
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7.06 (t, 7=4.8 Hz, 1H), 6.43 (d, 7=3.4 Hz, 1H), 6.39-6.36 (m, 1H), 5.10 (s, 1H),
3.76 (d, 7=13.5 Hz, 1H), 3.59 (d, 7=13.5 Hz, 1H), 2.31 (s, 3H). 1 3 C NMR (125
MHz, CD3OD) 6 189.1, 149.1, 142.8, 142.0, 138.5, 134.1, 133.4, 129.2, 128.2,
127.7,127.1, 111.1, 110.5, 67.9, 59.2, 39.4.
l-(4-Methoxy-phenyl)-l-pyrrolidm-l-yI-propan-2-one (3.81).
OMe
Prepared similarly to (3.63) (41 % yield). *H NMR (360 MHz, CDC13 ) 5
7.31 (d, 7=9.0 Hz, 2H), 6.85 (d, 7=9.0 Hz, 2H), 3.79 (s, 1H), 3.78 (s, 3H), 2.53-2.44
(m, 2H), 2.40-2.31 (m, 2H), 2.05 (s, 3H), 1.81-1.72 (m, 4H). IR (CDC13 film) 8
1687 cm' 1 (C=0).
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3.4.3. Synthesis and Physical Properties of 1,2,3,4-
T etrahydropyrazines
l,4-Dibenzyl-5-phenyl-6-styryl-l,2,3,4-tetrahydro-pyrazine (3.84).
Prepared similarly to (3.63), with the reaction mixture being cooled to 0°C
for 2 hours upon completion, then filtered and washed with cold methanol, the solid
was collected and vacuum dried to obtain a yellow solid (51 % yield). 'H NMR
(500 MHz, C6D6 ) 6 7.65-7.61 (bd, .7=7.1 Hz, 2H), 7.49-7.45 (bd, ,7=7.1 Hz, 2H),
7.27-6.88 (m, 18H), 3.99 (s, 2H), 3.71 (s, 2H), 2.73-2.69 (m, 2H), 2.60-2.56 (m,
2H). 1 3 C NMR (125 MHz, C6D6 ) § 139.6, 138.5, 138.5, 137.9, 135.0, 130.5, 127.6,
127.5 (2C’s), 127.3 (2C’s), 127.1 (2C’s), 127.0, 126.6, 126.4, 126.0, 125.5, 125.4,
123.2, 56.7, 56.4, 43.6, 41.9. HRMS-DCI/NH3 calcd. for (MH+ ) 443.2486 found
443.2487.
127
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1,4-Dibenzyl-5-furan-2-yl-6-phenyl-l ,2,3,4-tetrahydro-pyrazine (3.90).
Prepared similarly to (3.84) (59 % yield). *H NMR (500 MHz, C6De) 5
7.58 (d, 7=7.8 Hz, 2H), 7.40 (d, 7=5.7 Hz, 2H), 7.25-6.97 (m, 12H), 6.08 (d, 7=3.3
Hz, 1H), 6.01-5.99 (m, 1H), 3.69 (s, 2H), 3.65 (s, 2H), 2.63-2.55 (m, 4H). 1 3 C
NMR (125 MHz, C6D6 ) 5 141.54, 141.52, 140.2, 139.9, 139.8, 130.5, 129.3, 129.0,
128.90, 128.88, 128.7, 127.6, 127.5, 127.1, 111.5, 110.8,57.7, 57.1,44.4, 44.2.
3.4.4. Synthesis and Physical Properties of 2-Hydroxymorpholines
4-Benzyl-3-(4-methoxy-phenyl)-2-phenyl-5-(S)-phenyl-morpholin-2-ol (3.110).
HO
OMe
128
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Prepared similarly to (3.84) (57 % yield, >99% d.e.). [H NMR (360 MHz,
CDC13 ) 5 7.40-7.21 (m, 14 H), 7.10-7.02 (m, 3H), 6.73 (d, 7=8.8 Hz, 2H), 5.96 (s,
1H), 4.40 (t, 7=11.7 Hz, 1H), 4.19 (dd, 7=11.7 Hz, 7=4.3 Hz, 1H), 4.10 (dd, 7=11.7
Hz, 7=4.3 Hz, 1H), 3.87 (s, 1H), 3.74 (s, 3H), 3.55 (d, 7=14.1 Hz, 1H), 2.85 (d,
7=14.1 Hz, 1H). 1 3 C NMR (90 MHz, CDC13 ) 5 159.1, 140.6, 138.8, 138.0, 132.8,
128.9, 128.7, 128.3, 128.2, 127.6, 127.4, 127.2, 126.3, 124.5, 112.9, 96.8, 77.2,
66.5, 66.4, 59.0, 55.0, 52.8. JR (film CDC13 ): OH = 3394 cm'1 . HRMS-DCI/NH3
calcd. for (MH+ ) 452.2217 found 452.2226.
4-(4-Methoxy-phenyl)-3-phenyl-hexahydro-pyrrolo[2,l-c][l,4]oxazin-3-ol
(3.117).
HO
OMe
Prepared similarly to (3.84) with the product, a yellow oil, being isolated by
flash column chromatography using methanol-dichloromethane (1:19) (73 % yield,
14 % d.e.). JH NMR for major diastereomer (360 MHz, CD3OD) 8 7.96 (d, ,7=8.8
Hz, 2H), 7.24-7.09 (m, 5H), 6.90 (d, 7=8.8Hz, 2H), 5.48 (s, 1H), 4.40 (m, 1H),
3.76-3.69 (m, 5H), 2.91-2.80 (m, 1H), 2.17-2.07 (m, 2H), 1.91-1.71 (m, 4H). 1 3 C
129
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NMR (90 MHz, CD3OD) 5 161.7, 135.5, 132.7, 130.6, 129.8, 129.4, 129.1, 128.6,
114.7, 99.1, 79.0, 66.2, 65.7, 56.4, 54.2, 27.6, 21.9.
4-Benzyl-2-phenyl-5-(S)-phenyl-3-styryl-morpholin-2-ol (3.111).
HO
Prepared similarly to (3.84) (74 % yield, 41 % d.e.). *H NMR for major
diastereomer (360 MHz, CDCI3) S 7.56-7.10 (m, 19H), 6.82-6.77 (m, 1H), 6.55
(dd, .7=16.1 Hz, .7=10.3 Hz, 1H), 5.96 (d, ,7=16.1 Hz, 1H), 5.77 (s, 1H), 4.31 (d,
7=11.7 Hz); 4.28 (d, 7=11.7 Hz, together=lH), 3.99 (dd, 7=12.1 Hz, 7=4.2 Hz, 1H),
3.87 (d, 7=14.8 Hz, 1H), 3.67 (d, 7=13.5 Hz, 1H), 3.30 (m, 2H). ,3C NMR for both
diastereomers (90 MHz, CDC13 ) 6 140.8, 140.7, 138.7, 138.6, 138.5, 137.8, 137.4,
136.6, 134.6, 129.0, 128.8, 128.7, 128.6, 128.5, 128.49, 128.39, 128.2, 128.1,
128.0, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 126.5, 126.4, 126.3, 126.2, 121.4,
97.7, 96.7, 74.8, 66.5, 66.4, 66.2, 65.9, 60.0, 55.2, 53.2.
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4-Benzyl-2-phenyl-5-(S)-phenyl-3-styryl-morpholm-2-ol (3.113),
HO
Prepared similarly to (3.84) (75 % yield, 43 % d.e.). ]H NMR for major
diastereomer (500 MHz, CDC13 ) 5 7.53-7.11 (m, 18H), 7.05-7.01 (m, 2H), 5.82 (d,
7=16.0 Hz, 1H), 5.68 (dd, 7-16.0 Hz, 7-9.4 Hz, 1H), 4.80 (s, 1H), 4.21 (d, 7-12.3
Hz); 4.19 (d, 7-12.3 Hz, together=lH), 3.87 (d, 7-14.9 Hz, 1H), 3.86 (d, 7-7.1 Hz,
1H), 3.79 (dd, 7=12.3 Hz, 7=4.1 Hz, 1H), 3.56 (d, 7-14.9 Hz, 1H), 3.44 (d, 7=9.4
Hz, 1H).
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N-methyl-5-(R)-methyl-2-phenyl-6-(R)-phenyl-3-styryl-morpholin-2-oI (3.115).
Prepared similarly to (3.84) with the product, a colorless oil, being isolated
by flash column chromatography using ethyl acetate-hexane (1:3) (71 % yield, 56
% d.e.). NMR for major diastereomer (500 MHz, CD3 OD) 5 7.60-7.56 (m, 2H),
7.53-7.49 (m, 2H), 7.40-7.35 (m, 2H), 7.33-7.29 (m, 1H), 7.25-7.13 (m, 8 H), 6.17
(dd, .7=16.7 Hz, J= 8.9 Hz, 1H), 5.81 (d, .7=16.7 Hz, 1H), 5.00 (d, .7=8.9 Hz, 1H),
3.03 (d, ,7=9.0, 1H), 2.52 (m, 1H), 2.28 (s, 3H), 0.96 (d, .7=6.5 Hz, 3H) . 1 3 C NMR
for major diastereomer (125 MHz, CD3 OD) 8 144.7, 141.7, 138.2, 136.0, 129.5,
129.4, 129.3, 129.2, 128.8, 128.5, 128.2, 128.1, 127.2, 98.9, 78.5, 76.9, 64.6, 40.4,
15.2.
132
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3.5. REFERENCES
1. (a) Overhand, M.; Hect, S. M, J. Org. Chem., 1994, 59, 4721; (b) Angle, S.
R.; Boyle, J. P. Tetrahedron L ett, 1995, 36, 6185.
2. (a) Falomi, M.; Giacomelli, G.; Spanedda, A. M. Tetrahedron Asymmetry,
1998, 9, 3039; (b) De Luca, L.; Falomi, M.; Giacomelli, G.; Porcheddu, A.
Tetrahedron, 1999, 40, 8701.
3. Liguori, A. et. al. J. Org, Chem., 2001, 66, 7002.
4. Nyori, R.; Ohkuma, T.; Ishii, D.; Takeno, H. J. Am. Chem. Soc., 2000,122,
6510.
5. Kawamoto, A. M.; Wills, M. J. Chem. Soc., Perkin Trans. 1, 2001, 1916.
6 . Miller, P. C.; Owen, T. J.; Molyneaux, J. M.; Curtis, J. M.; Jones, C. R. J.
Comb. Chem., 1999,1, 223.
7. Hamby, J. M.; Hodges, J. C. Heterocycles, 1993, 35, 843.
8 . Buchanan, J. L.; Mani, U. N.; Plake, H. R.; Holt, D. A. Tetrahedron Lett.,
1999, 40, 3985.
9. Bonini, B. F.; Comes-Franshini, M.; Fochi, M.; Mazzanti, G.; Ricci, A.;
Varchi, G. Synlett, 1998, 1013.
10. Luca, L. D.; Giacomelli, G.; Porcheddu, A. Organic Letters, 2001, 3, 1519.
11. Myers, A.; Yoon, T. Tetrahedron Lett., 1995, 36, 9429.
12. Fisher, L. E,; Muchowski, J. M. Org. Prep. Proceed. Int., 1990, 22, 399.
13. Katritzky, A, R.; Cheng, D.; Musgrave, R. P. Heterocycles, 1996, 42, 273.
14. Adam, W.; Ahrweiler, M.; Vlcek, P. J. Am. Chem. Soc., 1995,117, 9690.
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15. Eisner, U.; Williams, A. J. J. Chem. Soc. Chem. Comm., 1979, 606.
16. Kuwano, R.; Ito, Y. J. Org. Chem., 1999, 64, 1232.
17. Berree, F.; Debache, A.; Marsac, Y.; Carboni, B. Tetrahedron Lett., 2001, 42,
3591.
18. (a) Cromwell, N. H.; Tsou, K. C. J. Am. Chem. Soc., 1949, 71, 993; (b) Lutz,
R. E.; Jordan, R. H. J. Am. Chem. Soc., 1949, 71, 996.
19. Griffin, C. E.; Lutz, R. E. J. Org. Chem., 1956, 21, 1131.
20. (a) Easton, N. R.; Cassady, D. R.; Dillard, R. D. J. Org. Chem., 1963, 28, 448.
(b) Stevens, C. L.; Matiarbo, J. J. Org. Chem., 1964, 29, 3146.
21. Shafer, C. M.; Molinski, T. F. J. Org. Chem., 1996, 61, 2044.
22. Marco, J. L.; Royer, J.; Flusson, H. Tetrahedron Lett., 1985, 26, 6345.
23. Agami, C.; Couty, F.; Prince, B.; Puchot, C. Tetrahedron, 1991, 47, 4343.
24. Rekka, E.; Kourounakis, P. J. Med. Chem., 1989, 24, 179.
25. Kelley, J. L.; Musso, D. L.; Boswell, G. E.; Soroko, F. E.; Cooper, B. R. J.
Med. Chem., 1996, 39, 347.
26. (a) Hale, J. J. et. al. J. Med. Chem., 1996, 39, 1760. (b) Hale, J. J. et. al. J.
Med. Chem., 1998, 41, 4607. (c) Dorn, C. P.; MacCoss, M.; Hale, J. J.; Mills, S.
G. US Patent #5,512,570, 1996; (d) Baker, R.; Elliott, J. M.; Stevenson, G. L;
Swwain, C. J. US Patent #5,985,896, 1999.
27. Zavialov, I. New Reactions o f Organoboronic Acids and Their Derivatives,
Ph.D. Thesis, University of Southern California, 1998.
28. Roussi, F. Synthesis, 2000, 8, 1170.
134
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CHAPTER 4
Synthesis of P-Amino Alcohols and Their
Use as Building Blocks Towards Valuable Products
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4.1. INTRODUCTION
4.1.1. Importance of P-Amino Alcohols
The synthesis of enaxitiopure P-amino alcohols remains to be a subject of
enormous interest due to the use of these products as building blocks for
pharmaceutical agents,1 ligands for asymmetric catalysis,2’ 3 and in their
applications as peptidomimetics 4 -6 Moreover, this highly versatile functionality is
often used as a precursor to amino acids7, amino aldehydes8, oxazolidinones9,
amino-sugar derivatives1 0 , and many other valuable products.
Common synthetic routes to this functional moiety involve the reduction of
amino acids1 1 or other carbonyl derivatives,1 2 amino hydroxylation of olefins,1 3 or
nucleophilic ring opening of various substrates, including epoxides1 4 , aziridines1 5 ,
and sulfates.1 6 However, these routes often suffer from the limited ability to
introduce a large range of functional diversity, require multiple synthetic steps, and
sometimes proceed with low stereoselectivity. More flexible approaches to the
functional moiety allow for the addition of further diversity into the desired
products. These are often accomplished by the organometallic addition to an
appropriate substrate, such as oc-amino aldehydes,8 or imine derivatives of a-alkoxy
17 IS IQ
aldehydes. ’ ’ However, these methods suffer from the use of highly reactive
organometallic species, which often require protection/deprotection strategies of
other sensitive functional groups, the starting derivatives are not readily available
136
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in all cases, and moreover, the stereoselectivity in some cases is either low and/or
often mixed due to chelated and non-chelated control of the addition of the
nucleophilic reactant.
4.2. RESULTS AND DISCUSSION
Our group has previously reported the practical, highly diastereoselective
synthesis of anti-(3 -amino alcohols (4.4) by the one-step three component coupling
of an organoboronic acid (4.1), an amine (4.2), and an a-hydroxy aldehyde (4.3)
(Scheme 4.1)20.
R —B
R V R j
(4%
OH 0
(4.1)
R4
OH
(4.3)
Scheme 4.1
R2 \ . r3
V 4 >99 % d.e.
r . / V R > 99 % e.e.
OH
(4.4)
The reaction was shown to work with a variety of a-hydroxy aldehydes including
glyceraldehyde and various sugars. We therefore wished to expand on the scope
and versatility of these reactants and products, and herein report our efforts in this
area.
137
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4.2.1. Synthesis of P-Amino Alcohols
To facilitate further manipulation we used diallylamine as the amine
component. Indeed the three-component coupling of an organoboronic acid (4.1),
diallylamine (4.6), and an a-hydroxy aldehyde (4.3) was found to proceed
smoothly in methanol at room temperature (or 50°C) to provide the desired anti-(3 -
amino alcohols (4.4) in good to moderate yields (yields not optimized), and high
diastereoselectivty and enantioselectivity (> 99% d,e. and > 99 % e.e.). Table 4.1
summarizes the reactions carried out to produce the range of diverse products
derived from these reactions. A variety of other secondary amines, were
successfully employed with alkenyl-, aryl-, and heteroarylboronic acids. Aniline
was also found to participate successfully in the reaction, and product (4.29) had
the adventitious property of precipitating directly from the reaction mixture. It is
important to note that most of the products could be isolated by a simple acid/base
extraction procedure and used in numerous further transformations without further
purification.
138
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Table 4.1 Synthesis of anti- P-Amino Alcohols
Entry Boronic Acid Amine
a-Hydroxy
Aldehyde
Product Yield
Ph
OH
OH
HO'"
N
H
’ OH Ph'
'OH
OH OH OH
O
(4.11)
■B(OH)2
86%
(4.7) (4.8) (4.5) (4.6)
OH
OH
HO""
OH
OH
(4.9)
OH OH
(4.10) (4.6) (4.5)
87%
OH
OH N
HO""
'N
H
'OH
'OH
OH
(4.7)
OH OH
(4.12)
32%
OH
OH
4
HO""
'OH N
H
‘ OH
OH
(4.7)
OH OH
(4.14) (4.13) (4.6)
OH
OH B(OH)2
HO""
OH
OH
(4.7) Me0'
'OH
'N
H
MeO‘
OH OH
(4.16) OM e (4.15)
45 %
40%
OMe
139
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Table 4.1 Continued
Entry Boronic Acid Amine
a-Hydroxy
Aldehyde
Product Yield
O
B (OH)2
(4.17)
B (O H)2
M e d
(4.19)
M e d
B (O H)2
(4.19)
y — B (O H)2
(4.24)
.O ^ .d H
N
H
HO'
(4.6)
OH
(4.7)
OH
OH
'OH
OH OH
(4.18)
71 %
N
H
(4.6)
’ N
OH
'OH
OH
(4.20)
OH
M e d
(4.21)
91 %
N
H
H O ""
O ^ ~OH
OH
N OH
I 1 30 %
OH
OH
(4.22) (4.7)
M eO
OH OH
(4.23)
OH
OH
H O ""
’ OH
OH
H
(4.22)
OH
(4.7)
OH OH
(4.25)
41 %
10 />— B (O H)2
(4.26)
^ Ph
I ^ ^OH
H O ""
OH
(4.6)
OH
(4.7)
N OH
70%
-S OH OH
(4.27)
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Table 4.1 Continued
Entry Boronic Acid Amine
a-Hydroxy
Aldehyde
Product Yield
11 ^ ^ B(OH)2
Ph
(4.5)
12 ^ ^ B(OH)2
Ph ~ ~
(4.5)
13
MeO
B(OH)2
n h 2
(4.28)
Ph
OH
N H OH
H O '"'
'OH
‘ OH
OH OH OH
87%
(4.7)
X>,^~OH
N ' H O "
H
(4.30)
V-
OH
(4.9)
'OH Ph"
(4.29)
Ph
k. ,Me
N OH
OH OH
(4.31)
Ph
85 %
Ph
Me
N
H
(4.19) (4.30)
„M e
'OH
‘ OH
OH
(4.20)
OH
M eO'
(4.32)
85 %
To further manipulate the products we used an amine cleavable by hydrogenation,
with in-situ Boc protection to provide the N-Boc derivatives directly (Scheme 4.2).
141
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(4.1) (4.34)
O
OH
(4.3)
1.) MeOH, r.t.,
16-24hrs. a
2.) H2, Pd/C
B oc20 , NEt3,
MeOH, r.t, 24hrs.
Scheme 4.2
Boc-
R
NH 2 > 99 % d.e.
A / R > 99 % e.e.
OH
(4.4)
Indeed, aminodiphenylmethane (4.34) was found to proceed smoothly in the
reaction and these products were easily converted to the N-Boc derivatives by
hydrogenation of the crude reaction mixtures in the presence of Boc20 and NEt3,
followed by flash column chromatography to provide the desired N-protected
amino alcohol products in good overall yields (Table 4.2).
142
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Table 4.2 Synthesis of j V-Boc a«/(-p-Amino Alcohols.
Entry Boronic Acid Amine
a-Hydroxy
Aldehyde
Product Yield
b(OH)2 ph ph
(4.33)
n h 2
(4.34)
-O Ph^ ^ Ph
n B(OH)2
(4.17)
NH2
(4.34)
B(OH)2 P h. ,Ph
Ph
(4.5)
NH2
(4.34)
P h ^ / B(0H)2 phy Ph
N H ,
(4.5) (4.34)
Cl
HO"
OH
(4.7)
O . ^O H B o c,
NH OH
OH
48%
OH
OH OH
(4.35)
O
Boc.
NH
OH
OH
(4.20)
8 6 %
W
OH
-O OH
(4.36)
o
Boc.
OH
OH
(4.20)
AN .OH Boc
NH
OH
(4.37)
63 %
rr
HO"’ ''OH Pi1
OH
(4.38)
NH OH
54%
OH OH
(4.39)
Diallylamine derived products can easily be deallylated according to literature
reports2 1 and subsequently Boc protected to provide the desired N-Boc amino
alcohol derivatives as is shown in Scheme 4.3.
143
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MeO
N
OH
(4.21)
OH
OH
OH OH
(4.14)
1.) Pd(dba)2, DPPB,
thiosalicylic acid,
0H THF, 60°C, lhr.
2.) B oc20 , NEt3,
MeOH, 1 hr.
1.) Pd(dba)2, DPPB,
thiosalicylic acid,
THF, 60°C, lhr.
2.) B oc20 , HEt3,
MeOH, 1 hr.
Boc.
NH
MeO
OH
Boc.
OH
(4.40)
71 % Yield
NH OH
OH OH
(4.41)
53 % Yield
Schem e 4.3
Having established a fast and efficient access to N-Boc protected amino alcohols,
we sought to use these highly versatile substrates as building blocks towards a
range of products.
The first set of products we sought to explore were the a-amino aldehydes.
N-protected a-amino aldehydes are widely used synthetic building blocks,4’ 5 and
have been employed as a key synthon in the construction of Palinavir (4.42)
(Figure 4.1), a potent HIV protease inhibitor.2 2 ,2 3
144
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OH
(4.42)
Figure 4.1 Palinavir
Previous reports on the oxidation of diols with sodium periodate had shown
that the use of silica gel supported periodate was efficient, and experimentally
convenient.2 4 Since we were targeting a sensitive substrate we sought to use this
procedure and take advantage of the ease in isolation of the product, which would
be filtration of the silica gel followed by evaporation of the solvent. Indeed, we
found that when (4.37) was added to a rapidly stirring solution of silica gel
supported sodium periodate in dichloromethane, oxidation of the diol was complete
in 25 minutes, and provided a-amino aldehyde (4.43) in 97 % crude yield (Scheme
4.4). Polyhydroxylated substrates, such as (4.39) were also shown to successfully
participate in the reaction, and provided the desired aldehyde in 70 % yield.
(Scheme 4.4).
145
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Boc,
NH
Boc.
"NH OH
N aI04,
Silica gel,
PCM,
25 min.
97 % yield
N aI04,
Silica gel,
OH DCM,
OH OH
(4.39)
25 min.
70 % yield
Scheme 4.4
> 99 % e.e.
The enantiomeric purity of these products was determined by reduction of the
aldehyde to the alcohol (4.45), using sodium borohydride in methanol, and chiral
HPLC analysis of the resulting amino alcohol. Chiral HPLC was performed on a
Chiracel OD column using 7 % 2-propanol in hexanes as the elutant, and the
enantiomeric excess was determined by comparison with a prepared racemic
standard (4.44), derived from (D,L)-glyceraldehyde. The enantiopurity of the
resulting amino alcohols was deemed > 99 %, as shown by the comparative data
traces shown in Figure 4.2
146
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Boc
NH
Ph'
(4.44) 0H
2
(
(4.44) and (4.45)
\ A
) \ J
Figure 4.2 Chiral HPLC Analysis
Since this reaction process proved to be efficient and experimentally convenient,
we envisioned using this in conjunction with a reaction on the resulting aldehyde to
generate another class of compounds that can easily be derived from our amino
alcohol substrates. We chose the Wittig reaction using
(carbethoxymethylene)triphenylphosphorane (4.46) to create vinylogous amino
acid esters, such as (4.47), which represent building blocks towards higher amino
acid derivatives. Oxidation of (4.40) with silica supported sodium periodate again
147
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proved to be fast and efficient, and this crude reaction mixture was then passed
through a pipet plugged with glass wool, as the filtration system, and washed
directly into the next flask, to which the Wittig reagent was added. Isolation of the
product (4.47) by flash column chromatography provided an 88 % overall yield,
demonstrating the efficiency of this overall process. (Scheme 4,5).
Boc.
NH
MeO
OH
(4.40)
1.) N aI04,
Silica gel,
PCM , 25 min.
OH 2.)
O
PhqP.
(4.46)
'OEt
16 hrs., r.t.
MeO
Boc.
NH
OEt
(4.47) O
88 % yield
94 : 6
E : Z
Scheme 4.5
Having determined that periodate oxidation of our amino alcohols was fast and
efficient, we sought to demonstrate the versatility of our three component reaction
by generating a novel a-amino aldehyde. We chose (4.27) as our substrate, due to
j ^
the large incorporation of the piperazine moiety in many pharmaceutical agents.
However, this substrate was not soluble in dichloromethane and another oxidation
procedure had to be employed. Therefore, substrate (4.27) was placed in a solution
148
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of methanol and water, and sodium periodate was added. Oxidation was shown to
be as fast and efficient as the silica supported method, and extraction o f the product
from the reaction mixture provided the desired a-amino aldehyde (4.48) in 80 %
crude yield (Scheme 4.6).
N OH
-S OH OH
(4.27)
4 eq. N aI04,
MeOH:H?Q, >
25 min.
80 % yield
> 99 % e.e.
Scheme 4.6
It should be noted that a-amino aldehydes are often converted to their
corresponding a-amino epoxides, which are used as key components in the
construction of novel amino alcohols, and often incorporated in the synthesis of
pharmaceutical agents.2 2 ,2 3 One possible synthetic route to a-amino epoxides can
be derived from the corresponding amino diols. When amino diol (4.40) was
subjected to Mitsunobu conditions, the desired a«h-a-am ino epoxide (4.49) was
generated in 76 % yield in > 99 % d.e. and > 99 % e.e. (Scheme 4.7).
149
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Boc.
"NH
MeO
OH
OH
PPh3, DEAD,
CHC13, reflux
76% yield
(4.40)
Scheme 4.7
We now had access to a-amino aldehydes, and their corresponding alcohols by our
previous methods, and we sought to perform these steps in one pot, to provide fast
access to these important substrates. We found that oxidation of the corresponding
amino polyol (4.27) in methanol could be directly subjected to reduction of the
aldehyde with sodium borohydride, which after work-up and isolation of the
product by flash column chromatography provided the desired amino alcohol (4.50)
in 76 % isolated yield (Scheme 4.8).
150
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N OH
OH
-S OH OH
(4.27)
1.) 4 eq. N aI04,
MeOH:H20 ,
25 min.
2.) NaBH4
76 % yield
> 99 % e.e.
Scheme 4.8
Amino alcohols are often converted to the corresponding oxazolidinone,
which represent an extremely versatile class of compounds. Oxazolidinones have
been employed as chiral auxilaries26, and have recently started receiving attention
due to the pharmacological activities. One particularly interesting oxazolidinone is
(-)-Cytoxazone (4.51) (Figure 4.3).
HN
MeO
(4.51)
Figure 4.3 (-)-Cytoxazone
151
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(-)-Cytoxazone (4.51) was first discovered in 1998 from the culture broth of
-in
Streptomyces RK95-31, which was isolated from a soil sample m Hiroshima/
This new potent chemotherapeutic agent inhibits cytokine modulation and is
currently the subject of biological and synthetic studies due to its
immunostimulating activity.2 7 '3 1 Having already established a fast and efficient
process to (4.40), one synthetic transformation remained to produce (+)-
Cytoxazone (4.51), and that was oxazolidinone formation. This was achieved by
reacting (4.40) with 2 equivalents of potassium fert-butoxide in THF to generate
(+)-Cytoxazone (4.51) in 97 % yield (Scheme 4.9). It should be noted that the
overall synthetic process to (+)-Cytoxazone (4.51), using this methodology, is 3
synthetic steps and 80% overall yield from readily available starting materials.
Boc
NH HN
2 eq. KOtBu
OH THF, r.t.____
97 % yield
OH
OH
MeO
(4.40) (4.51)
MeO
Scheme 4.9
152
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Oxazolidinones that are used as chiral auxilaries are most commonly prepared from
chiral (3-amino alcohols, which are prepared by reduction of the corresponding a-
amino acid. Although a number o f syntheses exist for the preparation of novel
oxazolidinones, many of the routes employed for their preparation are limited in
generality and scope.9 Since the most effective oxazolidinones possess sterically
demanding side chains, we chose to convert amino polyol (4.41) to the
corresponding oxazolidinone in a rapid, one pot manner. Indeed, it was found that
periodate oxidation o f (4.41) followed by in-situ reduction o f the aldehyde to
generate the intermediate amino alcohol (4.52), which after extraction could be
directly subjected to potassium tert-butoxide in THF, generated the desired
oxazolidinone (4.53) in 92 % overall yield (Scheme 4.10).
B oc.
NH OH
B oc.
B oc.
OH OH
(4.41)
"n h
OH 1.) N aI04,
MeQH:H?0
2.) NaBH4
3.) KOfBu,
THF
Scheme 4.10
NH
92 % yield
153
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Recently, substituted 3-aryl-2-oxazolidinones have received much attention
due to their pharmacological activity, and more specifically, Toloxatone (4.54)
(Figure 4.4) is used as an antidepressant.3 2 ’ 3 3 ’ 3 4
H,C
(4.54)
Figure 4.4 Toloxatone
We therefore sought to use compound (4.29) as a model building block towards
substituted oxazolidinones of this type. Previous reports of oxazolidinone
formation from amino diols was performed using sodium methoxide in the
presence of a large excess of diethylcarbonate (Scheme 4.11).3 5
154
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OH
Toluene,
Diethylcarbonate,
cat. NaOMe
O
H
.N
R '
105°C
OH
(4.55) (4.56)
Scheme 4.11
However, when we used the same procedures, we isolated large amounts of starting
material and a small amount of unidentified side products. This is presumably due
to the low solubility of substrate (4.29) in many solvents, which lead us to chose
DMF as our solvent. When (4.29) was dissolved in DMF in the presence of a
catalytic amount o f potassium fe/t-butoxide (15 mol %) and a large excess of
diethylcarbonate the starting material was completely converted to the product in
30 minutes. However, subsequent oxidation o f the remaining diols with periodate,
and reduction of the aldehyde to an alcohol (which would provide the desired
compounds similar to Toloxatone (4.54)) provided a compound with an extra
1 T
carbon atom (4.58), according to C NMR, and the carbonyl carbon was no longer
present. This result led us to examine more closely the oxazolidinone formation
with (4.29), and we discovered that we did not form the desired oxazolidinone, we
had in fact selectively formed a carbonate with the 3- and 4-hydroxy groups to
provide (4.57) in 96 % crude yield after extraction (Scheme 4.12).
155
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NH OH
OH
OH OH
KOfBu, (15 mol %)
EtgCQ^ (excess)
0H DMF, r.t., 30 min.
(4.29)
96 % yield
QH 1.) N aI04,
OH MeQH:H?Q
2.) NaBH4
3.) 1 N N aO H
(4.57)
Scheme 4.12
NH OH
OH
OH
(4.58)
77 % yield
We sought to extend this methodology towards our diallylamine derived products,
and indeed, we found that (4.8) successfully participated to provide the desired
carbonate (4.59) in 88 % isolated yield (Scheme 4.12). The polyol derived from D-
Ribose (4.10) was also subjected to the carbonate forming conditions, however, the
un-desired (4.60) was formed, which was deduced by no further reaction with
sodium periodate (Scheme 4.13).
156
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N OH
OH OH
(4.8)
N OH
KOfBu, (15 mol %)
Et?CO^ (excess)
DMF, r.t., 30 min.
88 % yield
KOiBu, (15 mol %)
Et2CQ3 (excess)
''OH DMF, r.t., 30 min.
OH OH 57 % yield
(4.10)
N O O
Scheme 4.13
We realized that carbonate formation with (4.18) would produce (4.61),
which after oxidation of the diol, reduction to the alcohol, and removal of the
carbonate in the work-up, would generate (4.62), an attractive alternative to using
the expensive Threose as the a-hydroxy aldehyde component (Scheme 4.14).
157
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KOfBu, (15 mol %)
Et2CQ 3 (excess)
OH DMF, r.t., 30 min.
-O OH OH
(4.18)
° °
O
(4.61)
72 % vield
OH
•OH
(4.61) O
1.) N aI04,
MeOH:H?Q
2.) NaBH4
3.) 1 NNaOH
Scheme 4.14
76 % yield
Having successfully demonstrated that carbonates derived from the
Arabinose products could be selectively formed, we sought to extend this
methodology by generating the a-hydroxy aldehyde of these compounds, and using
these components in our three component condensation. This would allow us to
further extend the use of these valuable amino alcohols as building blocks, and
provide us access to highly functionalized novel products. We first sought to use
carbonate (4.57), since we had easy access to clean product, and we subjected this
compound to a one-pot procedure of oxidation o f the diol to the aldehyde using
158
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sodium periodate in an aqueous solution of methanol, followed by removal of the
carbonate by making the reaction mixture a IN NaOH solution, and stirring this for
5 minutes. After this time, the reaction mixture was extracted with ethyl acetate
and further washed with IN NaOH. The organic layer was then dried, collected,
and the volatiles removed. This crude residue was re-dissolved in methanol and the
desired boronic acid was added and the mixture allowed to stir at room temperature
for 16 hours. Indeed, this one pot procedure lead us to produce novel N-aryl
pyrrolidines (4.63 and 4.64), related to azasugars, in good overall yields (Scheme
4.15). It should be noted that the intramolecular addition of the boronic acid also
proceeds with complete sterecontrol as in the intermolecular reaction, however
addition of the boronic acid comes from the same side as the hydroxy group, as was
deduced by the presence of 4 aliphatic carbons in (4.63), and is in conjunction with
previous studies of similar reactions.3 6
159
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(4.57) Y
O
C X .0
(4.57) Y
O
O H
1.) N aI04,
M e0H:H20
2.) I N NaOH a
3.) MeOH, r.t., 16 hrs.
,B(OH)2
(4.5)
1.) NaIQ4,
M e0H:H20
O H 2.) I N NaOH ,
3.) MeOH, r.t., 16 hrs.
O
Y ~B (O H )2
(4.17)
71 % Yield
73 % Yield
Scheme 4.15
Polyhydroxylated nitrogen azasugars are considered to be mimics of natural
sugars, in which the ring oxygen has been substituted for a nitrogen atom.3'
Moreover, the potent inhibitory activity of these types of molecules has lead to
38 39
investigations for their use as potential treatments for cancer, diabetes,
tuberculosis,4 0 and many other diseases. Along with their potential therapeutic
uses, azasugar transition state analogs have proved to be invaluable tools in the
study of the mechanism of action of carbohydrate-processing enzymes.4 1 ,4 2 Seeing
that we could successfully generate substituted analogs of these compounds, and
that there is an extremely large interest in compounds of this type and a demand for
160
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novel compounds that possess this structure, we set forth to develop methodology
towards a variety o f analogs of this type.
We had already established easy access to N-aryl derivatives of these
azasugars, and decided to establish a route towards cleavable amines, such as the
N-allyl derivatives. Indeed, we found that mono-deallylation of the corresponding
carbonate (4.59) and subjection to our previously determined method provided the
N-allyl azasugar derivatives in good yields over 4 steps, without isolation of any
intermediates (Scheme 4.16).
°Y °
(4.59) &
Y
(4.59) fi
1.) Pd(dba)2, DPPB,
Thiosal. acid (1 eq)
2.) N aI04,
MeOH:H?Q
3.) 1 N NaOH
4.) MeOH, r.t., 16 hrs.
,B (O H )2
(4.5)
1.) Pd(dba)2, DPPB,
Thiosal. acid (1 eq)
2.) NaIG4,
MeOH:H?Q
3.) 1 N NaOH
4.) MeOH, r.t, 16 hrs.
Q h - B (° H )2
(4.17)
Scheme 4.16
68 % Yield
55 % Yield
161
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To exemplify the synthetic diversity that could be incorporated to these azasugar
derivatives, carbonate (4.67) was subjected to these reaction conditions and reacted
with l-(tert-Butoxycarbonyl)pyrrole-2-boronic acid (4.68) to produce the highly
substituted azasugar (4.69) in 49 % yield from the carbonate (Scheme 4,17).
MeO'
Y
OMe 5 < 4 -67>
1.) Pd(dba)2, DPPB,
Thiosal. acid (1 eq)
2.) NaI04,
MeOHdfrO
3.) 1 N NaOH ”
4.) MeOH, r.t., 16 hrs.
Boc
/
r"N
B(O H )2
(4.68)
Scheme 4.17
Boc
M eO"
HO OH
(4.69)
49 % Yield
The free amino analogs could also successfully be prepared using similar
methodology by first performing a double de-allylation, and directly taking this
HC1 salt through the previously described procedure, which when reacted with (£)-
phenylvinylboronic acid (4.5) produced compound (4.70) in 45 % yield over 4
steps (Scheme 4.18).
162
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OH
OH
(4.59)
1.) Pd(dba)2, DPPB,
Thiosal. acid (2 eq)
2.) NaIG4,
MeOH:H20
3.) 1 N NaOH
4.) MeOH, r.t., 16 hrs.
,B(OH)2
Scheme 4.18
HO
(4.70)
45 % Yield
OH
Higher homologs of these azasugars could be produced by simple mono-
deallylation of (4.8) followed by subjection to Mitsunobu conditions, as was
previously reported,4 3 to provide (4.71) in 83 % yield (Scheme 4,19).
OH
1.) Pd(dba)2, DPPB,
Thiosal. acid (1 eq^
2.) PPh3, zPr2 NEt,
CC14, DMF, r.t.
83 % yield
Scheme 4.19
HO' 'OH
OH
(4.71)
For further discussions on the use of substrates similar to (4.71) towards the
synthesis of higher natural products see reference 36.
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Since we have successfully demonstrated the effectiveness of the carbonate
methodology, we sought to use this as the a-hydroxy aldehyde component in our
three component condensation with another amine and boronic acid. Indeed, we
found that subjecting (4.59) to the oxidation and carbonate cleavage conditions,
followed by the addition of one equivalent of diallylamine (4.6), and (E)-
phenylvinylboronic acid (4.5), provided compound (4.72) in 35 % yield (Scheme
4.20).
1.) NaI04,
MeOH:H2 0
2.) 1 N NaOH
3.) MeOH, r.t., 16 hrs.
°Y °
(4.59) JJ
B(OH)2
Scheme 4.20
OH
35 % Yield
Compound (4.72) represents analogous synthetic precursors to molecules similar to
DMP-323 (4.73) (Figure 4.5).
164
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o
HQ
OH
Ph
t)H HO
(4.73)
Figure 4.5 HIV-1 Protease Inhibitor DMP-323
DMP-323 and analogs similar to this structure are know to be potent HIV-1
protease inhibitors developed at the DuPont Merck Laboratories.4 4 ,4 5 ,4 6
4.3. CONCLUSION
We have demonstrated that our three component condensation of an
organoboronic acid (4.1), an amine (4.2), and an a-hydroxy aldehyde (4.3) can
successfully be used to generate a large range of structurally diverse enantiopure
amino alcohol derivatives. We have also demonstrated how these compounds can
efficiently be used to make a plethora of valuable products which are important as
novel building blocks and can also be used as potential chemotherapeutic agents.
165
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4.4. EXPERIMENTALS
4.4.1 General
All starting materials, unless otherwise noted, were purchased from
commercial suppliers and used without further purification. Dry acetonitrile, ether,
and toluene were collected through an Anhydrous Engineering solvent system
according to the manufacturer’s specifications. Chloroform was distilled over
P 2O5 , dichloromethane was distilled over CaH, and tetrahydrofuran was distilled
over sodium/benzophenone prior to use. (A)-2-Phenylvinylboronic acid was either
prepared according to previous reports4 7 or commercial quantities were
recrystallized from hot water using decolorizing carbon prior to use. Thin layer
chromatography was performed on pre-coated TLC plates (Silica Gel 60 F2 5 4) and
flash column chromatography was performed using Silica Gel 60 (particle size
0.032-0.063 mm, 230-400 Mesh). NMR spectra were recorded on a Bruker
AMX-500 MHz, a Bruker AM-360 MHz, or a Bruker AC-250 MHz instrument. IR
spectra were recorded on a Nicolet 460 machine. High-Resolution mass spectra
were obtained at the Southern California Mass Spectrometry Facility, University of
California, Riverside.
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4.4.2. Synthesis and Physical Properties of Amino Polyols
(£)-(2if,35,4/?,5i?)-5-Diallylamino-7-phenyl-hept-6-ene-l,2,3,4-tetraol (4.8).
OH
OH
OH OH
D-Arabinose (1.210 g, 8.0 mmol) and (E)-2-phenylvinyl boronic
acid (1.200 g, 8.0 mmol) were dissolved in methanol (20 mL) and to this solution
was added diallylamine (988 pL, 8.0 mmol). The reaction flask was flushed with
nitrogen, sealed with a plastic stopper, and stirred for 24 hours at ambient
temperature. The volatiles were then removed under vacuum and the residue was
heated with 6 N HC1 (20 mL) at 60°C for 2.5 hours. Upon cooling to r.t., the
mixture was diluted with water (10 mL), transferred to a separatory funnel and the
aqueous layer was washed with dichloromethane (3x15 mL). The aqueous layer
was then cooled in an ice bath and made basic (pH 9-10) with 6 N NaOH resulting
in a white suspension. This suspension was then transferred to a separatory funnel
and the aqueous layer was extracted with ethyl acetate (3 x 25 mL), the organic
layers were then combined, dried over sodium sulfate, filtered, and concentrated
under vacuum. This crude solid was then passed through a silica column using 1:1
dichloromethane:methanol, until the UV active spot stopped eluting. Obtained
167
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2.10g of a white crystalline solid. (79 % yield, > 99 % d.e., > 99 % e.e.). *H NMR
(360 MHz, CD3OD) 6 7.44-7.38 (m, 2H), 7.33-7.26 (m, 2H), 7.23-7.17 (m, 1H),
6.48 (d, 7=16.0 Hz, 1H), 6.26 (dd, 7=16.0 Hz, 7=9.5 Hz, 1H) 5.94-5.80 (m, 2H),
5.21 (bs, 1H), 5.16 (bs, 1H), 5.13 (bs, 1H) 5.10 (bs, 1H), 4.05 (dd, 7=9.4 Hz, 7=1.7
Hz, 1H) 3.95 (dd, 7=8.3 Hz, 7=1.7 Hz, 1H), 3.83 (dd, 7=11.1 Hz, 7=3.4 Hz, 1H),
3.77-3.70 (m, 1H) 3.67-3.61 (m, 1H) 3.54 (t, 7=9.5 Hz, 1H) 3.42-3.38 (m, 1H),
3.38-3.34 (m, 1H), 2.92 (dd, 7=14.2 Hz, 7=8.3 Hz, 2H). ,3C NMR (90 MHz,
CD 3OD) 8 138.5, 138.2, 136.4, 129.5, 128.4, 127.3, 126.8, 117.6, 73.5, 71.8, 71.4,
65.3, 64.3, 54.8.
(2i?,3‘ S'?4i?,5i?)-5-Diallylamiiio-5-(3,4-dimethoxyphenyl)-pentane-l,2,3,4-tetraol
(4.16).
OH
•O H
OH OH
MeO'
OMe
Prepared similarly to (4.8) (40 % crude yield after acid/base work-up; > 99
% d.e., > 99 % e.e.). *H NMR (360 MHz, CD3OD) 8 6.96-6.81 (m, 3H), 5.93-5.77
(m, 2H), 5.18 (bs, 1H), 5.12 (bs, 2H), 5.09 (m, 1H), 4.46 (d, 7=10.3 Hz, 1H), 4.09
(d, 7=5.6 Hz, 1H), 3.98 (d, 7=10.3 Hz, 1H), 3.88-3.79 (m, 7H), 3.79-3.72 (m, 2H),
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3.69-3.61 (m, 1H), 3.36-3.33 (m, 1H), 2.56 (d, 7=8.3 Hz, 1H), 2.53 (d, 7=8.4 Hz,
1H). 1 3 C NMR (90 MHz, CD 3 OD) 6 149.8, 149.6, 138.6, 129.8, 123.6, 117.4,
115.1, 112.3, 73.4, 71.5, 69.8, 65.3, 64.6, 56.5, 56.4, 54.6.
(2i?,35,4if,5if)-5-(4-Methoxyphenyl)-5-pyrrolidin-l-yl-pentane-l,2,3,4-tetraol
(4.23).
OH
'OH
OH OH
MeO'
Prepared similarly to (4.8), with the aqueous layer being saturated with
NaCl after basification (30 % yield after acid/base work-up; > 99 % d.e., > 99 %
e.e.). *H NMR (360 MHz, CD 3OD) 5 7.25 (d, 7= 8.7 Hz, 2H), 6 . 8 8 (d, 7= 8.7 Hz,
2H), 4.29 (dd, 7= 7.5 Hz, .7=2.4 Hz, 1H), 3.81-3.74 (m, 4H), 3.71-3.65 (m, 3H),
3.63-3.55 (m, 1H), 2.57-2.48 (m, 2H), 2.46-2.39 (m, 2H), 1.68-1.61 (m, 4H). 1 3 C
NMR (90 MHz, CD 3OD) 5 160.5, 132.1, 130.1, 114.1, 73.3, 72.9, 71.1, 69.9, 65.0,
55.6,51.2, 23.7.
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(2i?,3^4i?,5i?)-5-Benzofuran-2-yl-5-pyrrolidin-l-yl-pentane-l,2,3,4-tetraol
(4.25).
OH
OH
OH OH
Prepared similarly to (4.8), purified by flash column chromatography with
8 % methanol in dichloromethane (41 % yield; > 99 % d.e., > 99 % e.e.). ’H NMR
(360 MHz, CD 3OD) 5 7.55-7.52 (m, 1H), 7.45-7.41 (m, 1H), 7.24-7.13 (m, 2H),
6 . 6 6 (s, 1H), 4.47 (dd, > 9.6 Hz, >=1.6 Hz, 1H), 4.16 (d, > 9 .6 Hz, 1H), 3.92 (dd,
> 9 .5 Hz, > 1 .7 Hz, 1H), 3.84 (dd, > 1 1 .2 Hz, > 3 .0 Hz, 1H), 3.76-3.70 (m, 1H),
3.68-3.62 (m, 1H), 2.69-2.59 (m, 4H), 1.66-1.61 (m, 4H). ,3C NMR (90 MHz,
CD 3OD) 5 156.8, 156.1, 129.7, 124.6, 123.6, 121.7, 111.9, 107.4, 73.0, 70.3, 65.3,
62.1, 50.3,24.1.
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(2R, 3S,4R, 5i?)-5-(4-Benzyl-piperaziii-l-yl)-5-thiophen-2-yl-pentane-l, 2,3,4-
tetraol (4.27).
OH
‘ OH
OH OH
Prepared similarly to (4.8), purified by flash column chromatography with
8 % methanol in dichloromethane (70 % yield; > 99 % d.e., > 99 % e.e.). 1 H NMR
(360 MHz, CD3OD) 5 7.32-7.20 (m, 6 H), 7.04-7.00 (m, 1H), 6.95-6.92 (m, 1H),
4.31 (d, > 1 0 .2 Hz, 1H), 4.03 (d, > 9 .9 Hz, 1H), 3.99 (d, > 9 .9 Hz), 3.84 (dd,
> 1 1 .1 Hz, > 2 .9 Hz, 1H), 3.74-3.68 (m, 1H), 3.66-2.61 (m, 1H), 3.45 (bs, 2H),
2.58-2.38 (m, 8 H). 1 3 C NMR (90 MHz, CD 3OD) § 139.8, 138.0, 130.9, 129.3,
128.4, 128.2, 127.3, 125.1, 72.9, 71.4, 70.9, 66.0, 65.4, 64.0, 54.31, 54.30.
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(25,3iS)-3-Diallylamino-3-(4-methoxyphenyl)-propane-l,2-diol (4.21).
OH
OH
MeO'
Prepared similarly to (4.8) (91 % crude yield after acid/base work-up; > 99
% d.e., > 99 % e.e.), was used in the next step without further purification. 'H
NMR (360 MHz, CDC13 ) £7.19-7.13 (m, 2H), 6.93-6.88 (m, 2H), 5.85-5.71 (m,
2H), 5.21-5.11 (m, 4H), 4.29-4.20 (m, 1H), 3.86 (d, .7=9.5 Hz, 1H), 3.80 (s, 3H),
3.78-3.69 (m, 2H), 3.36-3.28 (m, 2H), 2.55 (dd, J=14.0 Hz, 8.7 Hz, 2H). 1 3 C NMR
(90 MHz, CDCI3) S 159.29, 135.60, 130.84, 125.62, 118.40, 113.88, 68.28, 67.09,
67.06,55.21,53.31.
(2£,3£)-3-(7V-Boc-amino)-3-(4-methoxyphenyl)-propane-l,2-diol (4.40).
Boc
NH
OH
OH
MeO'
Pd(dba) 2 (253 mg, 0.44 mmol, 5 mol %) and 1,4-bis(diphenylphosphino)-
butane (DPPB, 187.6 mg, 0.44 mmol, 5 mol %) were added to a dry 25 mL round
bottom flask, which was then evacuated and flushed with argon. To this flask 2 mL
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of dry THF was added, and the solution stirred at room temperature for 10 minutes.
After this time a solution of (4.21) (2.440 g, 8.80 mmol) and thiosalicylic acid
(2.992 g, 19.4 mmol) in 5 mL of dry THF was injected into the flask, and the
mixture was heated at 60°C for 1 hour under an argon atmosphere. Di-tert-butyl
dicarbonate (1.964 g, 9.0 mol) was added and the reaction was kept at 60°C for an
additional hour. After removal of all volatiles under vacuum, the residue was
dissolved in ethyl acetate (50 mL) and washed with 2x10 mL o f 2N NaOH. The
aqueous layer was back extracted with ethyl acetate (3 x 20 mL), the organic layers
were then combined, dried over magnesium sulfate, filtered, and evaporated. The
residue was purified using 5 % methanol in dichloromethane to provide 1.806 g of
a white solid (69% yield, >99% de, >99% ee). *H NMR (360 MHz, CD3 OD) 8
7.27-7.22 (m, 2H), 6.89-6.83 (m, 2H), 4.61 (d, .7=6.1 Hz, 1H), 3.83-3.73 (m, 1H),
3.76 (s, 3H), 3.48 (dd, 7=11.3 Hz, 4.1 Hz, 1H), 3.40 (dd, 7=11.3 Hz, 5.8 Hz, 1H),
1.41 (s, 9H). 1 3 C NMR (90 MHz, CD3OD) 8 160.34, 157.75, 133.21, 129.90,
114.53, 80.30, 75.15, 64.40, 57.62, 55.66, 28.74.
(2iS')-2-(/V-Boc-ammo)-4-phenyl-butyraldehyde (4.43).
Boc
NH
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To a room temperature stirred solution containing 1.0 g of NaIC>4 supported
on silica2 4 (which could also be prepared in-situ4 8 ) was added 0.5 mmol o f (26, 36)-
3-(N-Boc-amino)-5-phenyl-pentane-l,2-diol4 9 in a solution of dichloromethane
containing a few drops of methanol which were added until the solution was clear,
and the reaction mixture was stirred for 30 minutes. The silica gel was then
removed by filtration and washed with dichloromethane (3x5 mL), the organics
pooled, and volatiles removed to provide 0.127g of a yellow oil (97 % crude yield).
This compound was also prepared by the use of 3.5 equivalents of NalCL on silica
gel in dichloromethane and adding a solution of (2R, 3R, 46, 56)-5-(7V-Boc-amino)-
7-phenyl-heptane-1,2,3,4-tetraol4 9 in dichloromethane (70 % yield). 1 1 1 NMR (250
MHz, CDC13 ) § 9.53 (bs, 1H), 7.32-7.14 (m, 5 H), 5.08 (bs, 1H), 4.30-4.17 (m,
1H), 2.28-2.13 (m, 2H), 1.98-1.78 (m, 2H), 1.45 (s, 9H). 1 3 C NMR (62.5 MHz,
CDCI3) 5 199.5, 156.7, 141.7, 128.6, 128.4, 126.3, 80.1, 59.5, 31.4, 30.9, 28.3.
(25)-2-(Ar -Boc-amino)-4-phenyl-butan-l-ol (4.45).
Boc
NH
.OH
The crude (4.43) recovered after removal of the volatiles was dissolved in
methanol at room temperature, and to this stirring solution was slowly added
NaBH4 (37.8 mg, 1.0 mmol) and the mixture stirred until TLC indicated complete
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disappearance o f the starting (4.43). The reaction was then quenched by the
addition of IN NaOH (15 mL), the mixture transferred to a separatory funnel using
ethyl acetate, and the aqueous layer was extracted with ethyl acetate (3x10 mL).
The organics were combined, dried over magnesium sulfate, filtered and
evaporated to dryness. 2 mL of heptanes was then added to the flask, and the
vessel was stored overnight in the refrigerator. After 20 hours, the solid was
filtered and washed with cold hexanes, and vacuum dried to provide 0.108 mg of a
white fluffy solid (82 % yield over 2 steps). (> 99 % e.e. as determined by HPLC
analysis using a Chiracel OD column and 7 % 2-propanol in hexane; ret. time =
12.03 min.). lH NMR (360 MHz, CDC13 ) 8 7.29-7.23 (m, 2H), 7.19-7.14 (m, 3H),
4.79-4.63 (m, 1H), 3.70-3.49 (m, 3H), 2.75-2.59 (m, 2H), 2.47 (bs, 1H), 1.88-1.74
(m, 2H), 1.43 (s, 9H). 1 3 C NMR (90 MHz, CDC13 ) 8 156.5, 141.4, 128.5, 128.3,
126.0, 79.7, 65.9, 52.5, 33.3, 32.4, 28.4.
3-(Ar -Boc-amino)-5-phenyl-pentane-l,2-diol (4.72)
Boc
NH
'OH
OH
To a stirred solution of aminodiphenylmethane (192 mg, 1.0 mmol) and
D,L-glyceraldehyde (90.5 mg, 1.0 mmol) in 7 mL o f ethanol was added (E)-2-
phenylvinylboronic acid (150 mg, 1.01 mmol), and the solution was stirred at
175
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ambient temperature for 24 hours. Pd/C (5 wt. %, 85 mg), triethylamine (1 mL),
and di-tert-butyl dicarbonate (340 mg, 1.5 mmol) were added and the flask was
evacuated and fitted with a hydrogen balloon. The flask was flushed with
hydrogen several times, and then allowed to stir at ambient temperature for 16
hours. The mixture was filtered through a thin pad of Celite, washed with
methanol, the filtrate was then collected and evaporated. Flash column
chromatography using 8 % methanol in dichloromethane provided 273 mg of a
white fluffy solid (92 % overall yield and > 99 % d.e.). 'H NMR (250 MHz,
CD 3OD) 5 7.28-7.08 (m, 5H), 6.62 (d, J=9.2 Hz, 1H), 3.60-3.39 (m, 4H), 2.80-2.65
(m, 1H), 2.63-2.48 (m, 1H), 2.09-1.93 (m, 1H), 1.75-1.53 (m, 1H), 1.46 (s, 9H).
2-(A/-Boc-am ino)-4-phenyl-butan-l-ol (4.45).
Boc
NH
.OH
Prepared similarly to (4.45) using (4.72). Analytically pure sample was
obtained by recrsytallization from ethyl acetate:hexanes. Chiracel OD retention
times in 7 % 2-propanol in hexanes is 10.47 and 12.03 min.
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(S)-(4-Benzyl-piperazm-l-yI)-thiophen-2-yl-acetaldehyde (4.48).
137 mg, 0.35 mmol of (4.27) was placed in a 25 mL round bottom flask
equipped with a stir bar, and 8.0 mL of an 30 % aqueous methanol solution was
added, followed by an additional 6 mL of methanol. To this stirring solution was
added 278 mg, 1.3 mmol of NalCL and the solution was stirred for 25 minutes at
room temperature. Water (10 mL) was then added to the solution and transferred to
a separatory funnel. The aqueous layer was then extracted with dichloromethane (3
x 15 mL), the organic layers were combined, dried over magnesium sulfate, filtered
and the volatiles removed to provide 84 mg of a yellow oil (80 % crude yield). 'H
NMR (360 MHz, CDCL) 8 9.51 (d, .7=3.4 Hz, 1H), 7.33-6.79 (m, 8 H), 4.09 (d,
.7=3.4 Hz, 1H), 3.49 (bs, 2H), 2.59-2.38 (m, 8 H).
I
I I 7
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(1 S)-2-(4-Benzyl-piperazin-l-yl)-2-thiophen-2-yl-ethanol (4.50).
c
.N.
)
'N
OH
Prepared similarly to (4.48) (0.425 mmol scale) with the direct addition of 5
equivalents (2.1 mmol) of NaBhh to the reaction mixture after the required 25
minutes of stirring. The solution was then quenched with IN NaOH (10 mL), and
the rest of the work-up was done according to (4.45). Flash column
chromatography provided 98 mg (76 % yield over 2 steps). 'H NMR (360 MHz,
CD3OD) 5 7.32-7.19 (m, 6 H), 7.01-6.97 (m, 1H), 6.96-6.94 (m, 1H), 3.95-3.86 (m,
2H), 3.80-3.72 (m, 1H), 3.49 (s, 2H), 2.64-2.42 (m, 8 H). 1 3 C NMR (90 MHz,
CD3OD) 5 141.2, 138.1, 130.8, 129.3, 128.4, 127.51, 127.46, 125.8, 67.0, 63.9,
63.7, 54.1,50.3.
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(i?)-4-(4-MethoxyphenyI)-4-(Af -Boc-amino)-but-2-enoic acid ethyl ester (4.47).
Boc
NH
MeO'
To a room temperature stirred solution containing 1.0 g o f NalCL supported
on silica2 4 was added 0.5 mmol of (4.40) in a solution o f dichloromethane
containing a few drops of methanol which were added until the solution was clear,
and the reaction mixture was stirred for 30 minutes. The silica gel was then
removed by passing the solution through a pipet, which had been plugged with a
small amount of glass wool. This was filtered directly into another 25 mL round
bottom flask equipped with a stir bar, and the pipet was flushed with an additional
5 mL of dichloromethane. To the resulting solution was added 174.2 mg, 0.5 mmol
of (carbethoxymethylene)triphenylphosphorane, the flask was flushed with
nitrogen, sealed with a plastic cap, and stirred for 16 hours at room temperature.
After this time, the volatiles were removed, and the residue was subjected to flash
column chromatography using ethyl acetate-hexanes (1:3) to provide 147 mg of a
white solid ( 8 8 % yield, 94:6 E:Z). *H NMR for major isomer (360 MHz, CD 3OD)
8 7.32 (bs, 1H), 7.19 (d, J= 9.0 Hz, 2H), 6.98 (dd, J=15.8Hz, <7=4.7 Hz, 1H), 6.89
(d, .7=9.0 Hz, 2H), 5.90 (d, .7=15.8 Hz, 1H), 5.30 (bs, 1H), 4.16 (q, .7=6.9 Hz, 2H),
3.77 (s, 3H), 1.43 (s, 9H), 1.25 (t, .7=6.9 Hz, 3H). 1 3 C NMR (90 MHz, CD 3OD) 5
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167.9, 160.8, 157.5, 149.3, 133.2, 129.4, 121.7, 115.1, 80.6, 61.6, 56.3, 55.6, 28.6,
14.5. HRMS-FAB/MeOH/NBA/PEG calcd for (M+ + 1) 336.1795, found 336.1811.
(2S,35)-3-(A'-Boc-amino)-4-(4-methoxyphenyl)-l,2-epoxypropane. (4.49).
Boc
NH
MeO'
Prepared according to previous reports4 7 starting from (4.40) purified by
flash column chromatography using 35 % ethyl acetate in hexanes (76 % yield). 'H
NMR (360 MHz, CD3OD) 5 7.28-7.23 (m, 2H), 6.90-6.85 (m, 2H), 4.88 (s, 1H),
4.54-4.46 (m, 1H), 3.77 (s, 3H), 3.17-3.12 (m, 1H), 2.76-2.72 (m, 1H), 2.60-2.56
(m, 1H), 1.42 (s, 9H). 1 3 C NMR (90 MHz, CD3OD) 8 160.9, 157.8, 133.5, 129.5,
114.8, 80.3, 62.5, 55.6, 54.9, 45.8, 28.7.
(i?)-4-Naphthalen-l-yl-oxazolidin-2-one (4.53).
HN
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The corresponding alcohol was prepared similarly to (4.50) using (2R, 35,
4R, 5R)-5-(MBoc-amino)-5-napthalen-l-yl-l,2,3,4-tetraol49. The resulting crude
alcohol (0.196 mmol) was dissolved in dry THF (2 mL), and KOtBu (20.0 mg,
0 . 2 0 mmol) was added, the reaction flask was flushed with argon, and stirred at
room temperature for 2 hours. The reaction was then diluted with ethyl acetate (10
mL) and transferred to a separatory funnel. The organic layer was washed 3x15
mL with saturated ammonium chloride, the organic layer was then dried over
magnesium sulfate, filtered, and the volatiles removed. The resulting residue was
purified by flash column chromatography using 30 % ethyl acetate-hexanes to
provide 38 mg of a white solid (92 % overall yield from the polyol). 'H NMR (360
MHz, CD 3OD) § 7.95-7.83 (m, 3H), 7.62-7.48 (m, 4H), 5.80 (dd, 7=9.1 Hz, 7=6.1
Hz, 1H), 5.06 (t, 7=8.4 Hz, 1H), 4.09 (dd, 7=8.3 Hz, 7=5.9 Hz, 1H). I3C NMR (90
MHz, CD 3OD) 5 162.6, 137.5, 135.5, 131.5, 130.1, 129.7, 127.8, 127.2, 126.5,
123.4,122.9, 73.4, 54.2. HRMS-EI calcd for (M+ + 1) 213.0796, found 213.0790.
(£0-(2i?,3^»4i?,5if)-l-Allyl-2-styryl-piperidme-3,4,5-triol (4,71).
'OH
OH
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Prepared according to previous literature reports48 starting with 54.3 mg
(0.18 mmol) of (E)-{2R,3S,4i?,5R)-5-Allylamino-7-phenyl-hept-6-ene-l,2,3,4-
tetraol, which was prepared by mono-deallylation of (4.8). The product was
purified by flash column chromatography using 1 0 % methanol in
dichloromethane, to provide 41 mg of a fine white solid (83 % yield). NMR
(360 MHz, CD 3OD) 5 7.46-7.41 (m, 2H), 7.33-7.26 (m, 2H), 7.25-7.18 (m, 1H),
6.60 (d, J=16.0Hz, 1H), 6.10 (dd, JM 6.0 Hz, J=8.3Hz, 1H), 5.94-5.80 (m, 1H),
5.19-5.12 (m, 2H), 3.93-3.89 (m, 1H), 3.58 (t, > 2.7H z, 1H), 3.48-3.41 (m, 1H),
3.36 (dd, J=9.3Hz, J=3.1Hz, 1H), 3.07 (dd, J=12.4Hz, J=3.7Hz, 1H), 2.84 (dd,
13.6Hz, /= 8 .6 Hz, 1H), 2.66 (t, J=9.2Hz, 1H), 2.30-2.24 (m, 1H). 1 3 C NMR (90
MHz, CD 3OD) 6 138.3, 136.2, 135.5, 129.8, 129.6, 128.7, 127.5, 118.9, 75.9, 72.5,
72.1,69.2,58.8, 56.6.
(£)-(2J?,3iS',4i?,5i?)-7-Pheiiyl-5-phenylammo-hept-6-ene-l,2,3,4-tetraol (4,29).
NH OH
'OH
OH OH
Prepared similarly to (4.8) with the reaction mixture being cooled in the
freezer for 1 hour before isolating the product by filtration, and washing with cold
methanol to provide a white solid (85 % yield). 'H NMR (360 MHz, DMSO-c4) 5
182
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
7.36-7.24 (m, 4H ), 7.21-7.15 (m, 1H), 7.05-6.99 (m, 2H), 6.62-6.57 (m, 2H), 6.52-
6.53 (m, 2H), 6.34 (dd, J= 16.1Hz, /=6.2Hz, 1H), 5.58 (d, J=8.7Hz, 1H), 4.56 (d,
4.15 (q, J=7.8Hz, 1H), 3.79 (t, y=7.2Hz, 1H), 3.63-3.45 (m, 3H), 3.44-3.36 (m,
1 H). 1 3 C NMR (90 MHz, DMSO-<4) 5 148.3, 137.1, 130.9, 129.5, 128.8, 128.5,
127.0, 126.1, 115.4, 112.7, 71.6, 71.4, 70.2, 63.6, 56.9.
(£)-(4R,5R)-4-(lR,2-Dihydroxy-ethyl)-5-(3-phenyl-lR-phenylamino-al!yl)-
[ 1,3]dioxoIan-2-one (4.57).
Compound (4.29) (791 mg, 2.4 mmol) was placed in a dry 25 mL round
bottom flask and DMF (15 mL) was added. To this solution potassium tert-
butoxide (44 mg, 15 mol %) and 0.5 mL diethylcarbonate was added and the
mixture was stirred at room temperature until all starting material had disappeared
by TLC. The solution was then diluted with ethyl acetate (50 mL) and transferred
to a separatory funnel. The organic layer was then washed with saturated
ammonium chloride (2 x 10 mL), water (5x15 mL), and finally brine (2 x 10 mL).
The organic layer was then dried over sodium sulfate, filtered, and evaporated to
O
183
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
provide an opaque film (819 mg, 96 % crude yield) which was used in further
transformations as is. *H NMR (360 MHz, CD 3OD) 5 7.39-7.34 (m, 2H), 7.30-7.24
(m, 2H), 7.23-7.19 (m, 1H), 7.14-7.08 (m, 2H), 6.78-6.72 (m, 3H), 6.67-6.61 (m,
1H), 6.20 (dd, J=16.2Hz, J= 7.0Hz, 1H), 4.98 (t, J=4.6Hz, 1H), 4.72 (t, J=4.1Hz,
1H), 4.41-4.36 (m, 1H), 3.88 (q, J=4.6Hz, 1H), 3.63-3.61 (m, 2H). 1 3 C NMR (90
MHz, CDjOD) 5 156.9, 148.5, 137.9, 135.4, 130.1, 129.6, 128.9, 127.6, 125.5,
118.9, 115.0, 80.7, 80.4, 72.3, 63.3, 59.1.
(£)-(2J?,3i?,4R)-6-Phenyl-4-phenylamino-hex-5-ene-l,2,3-triol (4.58).
NH OH
.OH
OH
Prepared similarly to (4.50) with the product being isolated by flash column
chromatography using ethyl acetate:hexanes (3:1) (77 % yield). ’H NMR (360
MHz, CD3OD) 8 7.37-7.32 (m, 2H), 7.28-7.21 (m, 2H), 7.18-7.13 (m, 1H), 7.10-
7.04 (m, 2H), 6.70-6.66 (m, 2H), 6.63-6.54 (m, 2H), 6.32 (dd, J=16.1Hz, /=6.7Hz,
1H), 4.28-4.23 (m, 1H), 3.88-3.83 (m, 1H), 3.74-3.59 (m, 3H). I3C NMR (90 MHz,
CD 3 OD) 5 149.3, 138.6, 132.8, 130.00, 129.97, 129.5, 128.3, 127.4, 117.9, 114.8,
74.1,72.6, 64.8, 59.1.
184
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
(25,3J?,4i?,5i?)-l-Phenyl-2,5-distyryl-pyrrolidine-3,4-diol (4.63).
OH
Compound (4.57) (144 mg, 0.405 mmol) was placed in a 25 mL round
bottom flask, and dissolved in 1.25 mL methanol and 1.25 mL water. To this
solution was added sodium periodate (128 mg, 0 . 6 mmol), and the resulting
solution was stirred for 20 minutes at room temperature. After this time, 0.5 mL of
6 N NaOH was added, and the solution was allowed to stir for an additional 5
minutes. After this time, the reaction mixture was transferred to a separatory
funnel and diluted with ethyl acetate (30 mL). The organic layer was washed with
saturated sodium bicarbonate (3 x 10 mL), saturated ammonium chloride (1 x 20
mL), collected and dried over sodium sulfate, filtered and evaporated. The
resulting residue was dissolved in methanol, and (£)-2 -phenylvinylboronic acid (75
mg, 0.5 mmol) was added, the flask was flushed with nitrogen, and allowed to stir
at room temperature for 16 hours. After this time, the volatiles were removed, the
residue was then transferred to a separatory funnel and diluted with ethyl acetate
(30 mL). The organic layer was washed with IN NaOH (1 x 15 mL), and then
brine (2 x 10 mL), the organic layer was then collected and dried over sodium
sulfate, filtered, and evaporated. The residue was purified by flash column
185
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
chromatography using 5 % methanol in dichloromethane to provide a light yellow
solid (110 mg, 71 % yield). *H NMR (360 MHz, DMSO-76 ) 5 7.49-7.45 (m, 4H),
7.36-7.29 (m, 4H), 7.25-7.19 (m, 2H), 7.12-7.05 (m, 2H), 6.75-6.63 (m, 4H), 6.61-
6.55 (m, 1H), 6.46-6.36 (m, 2H), 5.46 (d, 7=5.2Hz, 1H), 5.33 (d, 7=5.1 Hz, 1H),
4.34 (t, 7=6.8 Hz, 1H), 4.05 (q, 7=6.1Hz, 1H), 3.98 (t, 7=6.4Hz, 1H), 3.86 (q,
7=5.4Hz, 1H). 1 3 C NMR (90 MHz, DMSO-76) 6 148.3, 136.9, 136.7, 132.1, 130.2,
130.1, 129.6, 128.60, 128.59, 128.55, 127.3, 127.2, 126.35, 126.27, 116.2, 112.6,
79.3, 76.5,68.1,64.8.
(2R,3i?,4if,5if)-2-Furan-2-yl-l-phenyl-5-styryI-pyrrolidine-3,4-diol (4.64).
OH HO
Prepared similarly to (4.63) (73 % yield). ]H NMR (360 MHz, DMSO-76 )
8 7.62 (bs, 1H), 7.48-7.42 (m, 2H), 7.36-7.28 (m, 3H), 7.26-7.19 (m, 2H), 7.10-
7.02 (m, 2H), 6.73 (d, 7=16.9Hz, 1H), 6.61-6.55 (m, 2H), 6.44-6.34 (m, 2H), 5.53
(d, 7=5.4Hz, 1H), 5.28 (d, 7=4.3Hz, 1H), 4.77 (d, 7=6.6Hz, 1H), 4.17-4.08 (m, 1H),
4.06-3.95 (m, 2H). 1 3 C NMR (90 MHz, DMSO-76 ) 8 153.7, 147.7, 142.1, 136.6,
131.7, 130.5, 128.60, 128.58, 127.4, 126.2, 116.4, 112.5, 110.4, 108.0, 79.2, 75.3,
67.2, 60.9.
186
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(25,3i?,4if,5i?’ )-l-Allyl-2,5-(iistyryI-pyrrolidine-3,4-diol (4.65).
OH HO'
(4R,5f?)4-(lR-Diallylamino-3-phenyl-allyl)-5-(lf?,2-dihydroxy-ethyl)-
[l,3]dioxolan-2-one4 9 (180 mg, 0.5 mmol) was first subjected to mono-deallyation
similarly to (4.40) using one equivalent o f thiosalicylic acid and allowing the
reaction to proceed at room temperature for 30 minutes. The desired HC1 salt of
the resulting product was collected by diluting the reaction mixture with ethyl
acetate (40 mL), and extracting the organic layer with 1 N HC1 (3x15 mL). The
aqueous layers were collected and the water evaporated to provide the desired HC1
salt. This salt was then subjected to the procedure for the preparation of (4.61).
The product was isolated by flash column chromatography using 3 % methanol in
dichloromethane to provide 118mg of a light yellow solid ( 6 8 % yield). 1 H NMR
(360 MHz, CD 3OD) 6 7.46-7.40 (m, 4H), 7.33-7.27 (m, 4H), 7.24-7.18 (m, 2H),
6.61 (d, 7=16.0Hz, 1H), 6.60 (d, 7=16.0Hz, 1H), 6.30 (dd, 7=16.0Hz, 7=8.8Hz,
1H), 6.21 (dd, 7=16.0Hz, 7=8.8 Hz, 1H), 6.01-5.89 (m, 1H), 5.19-5.08 (m, 2H), 3.96
(dd, 7=6.0Hz, /-3.2H z, 1H), 3.85 (dd, 7=6.0Hz, 7=3.2Hz, 1H), 3.55 (dd, 7=6.0Hz,
7 -8 . 8 Hz, 7=6.0Hz, 1H), 3.28-3.24 (m, 2H), 3.17 (dd, 7=8.8 Hz, 7=5.9Hz, 1H). 1 3 C
187
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
NMR (90 MHz, CD3OD) 5 138.5, 138.4, 135.0, 134.6, 134.1, 130.9, 129.60,
129.57, 128.6, 128.42, 128.41, 127.5, 127.4, 119.2, 83.6, 80.4, 73.0, 69.2, 53.6.
(4R,5/?)-4iN[DiaHyIamino-(3,4-dimethoxy-phenyl)-methyl]-5-(17?,2-dihydroxy-
ethyl)-[l,3]dioxolan-2-one (4.67).
OH
.OH
MeO'
OMe
Prepared similarly to (4.57) using crude (4.16) with the product being
isolated by flash column chromatography using 60 % ethyl acetate in hexanes to
provide a white fluffy solid (194 mg, 28 % yield). 'H NMR (360 MHz, CD3 OD) 5
6.99-6.94 (m, 2H), 6.90-6.82 (m, 1H), 5.93-5.80 (m ,2H), 5.38-5.34 (m, 1H), 5.24-
5.15 (m, 4H), 4.55 (t, J= 3.7Hz, 1H), 3.87-3.78 (m, 8 H), 3.61 (d, J=6.0Hz, 2H),
3.42-3.39 (m, 1H), 3.39-3.35 (m, 1H), 2.86 (dd, /=14.1Hz, J= 7.8Hz, 2H). 1 3 C
NMR (90 MHz, CD3OD) 6 156.7, 150.5, 136.7, 128.1, 124.1, 118.7, 114.3, 112.5,
81.6, 77.4, 72.4, 6 6 .6 , 63.1, 56.5, 56.4, 54.3.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
(2S,3i?,4i?,5f?)-l-Allyl-5-(3,4-dimethoxy-phenyl)-2,3,4,5-tetrahydro-lH,l'H-
[2,2']bipyrrolyl-3,4-diol (4.69).
Boc
MeO'
OH HO'
Prepared similarly to (4.65) using (4.67) and 1 -{tert-
Butoxycarbonyl)pyrrole-2-boronic acid. Flash column chromatography using 2 %
methanol in dichloromethane provided 100 mg of a light yellow solid (49 % yield).
’H NMR (360 MHz, CD3OD) 5 7.24-7.21 (m, 1H), 7.16-7.14 (m, 1H), 7.05-6.86
(m, 2H), 6.50-6.46 (m, 1H), 6.18-6.15 (m, 1H), 5.87-5.70 (m, 1H), 4.99-4.94 (m,
1H), 4.86-4.79 (m, 1H), 4.17 (dd, /=8.1Hz, J=5.5Hz, 1H), 3.87-3.72 (m, 8 H), 3.48
(d, Jr =7.8Hz, 1H), 3.16 (dd, JM 4.7Hz, /=6.4Hz, 1H), 3.02 (dd, J=14.7Hz, J=6.7Hz,
1H), 1.61 (s, 9H). 1 3 C NMR (90 MHz, CD3OD) § 160.7, 150.6, 149.9, 135.4,
135.1, 134.6, 122.5, 121.9, 118.3, 114.9, 112.8, 112.6, 111.2, 85.1, 84.7, 82.0, 78.5,
71.8, 62.8, 56.3,54.4, 28.2.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
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APPENDIX
C u & 1 3 C NMR Spectra)
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
H NM R CDC1:
1 3 C NMR CDCI3
JL
200 150 100 50 P P m
203
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
'II NMR DMSO- d 6
•NH
r T f...>
8 p p m
,3C NMR DMSO-rf6
200 150 1 0 0 50 0 ppm
204
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
lH NMR CD3OD
JX JU
U
> p
ppm
13
C NMR CD3OD
200 1 5 0 100
Jl/L.
50 ppm
205
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
'H NM R CDCI3
'OMe
_yw
' i i
13
C NMR CDCI3
y u i
7 ..r
7
7.0 6.8 [ip
ppm
200 150 100 50 Oppm
206
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
*H NMR DMS0-<4
" t '
4
C
8 10 9 7 6 5
1 3 C NMR DMSO-rfe
H H H i
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
M l NMR CDCI3
Me
7.4 7.2 7.0 6.8 G.6 6.4 6.2 6.0 j> p
13
C NMR CDCI3
ppm
l l l l l m .L i.J || i
50 ppm
208
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
*H NMR CDCI3
T 'T
ppm
13
C NMR CDCI3
200 150 100 50 ppm
209
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
’H NM R CD3OD
_ J U
8.0
J L
7.5 7.0 6.5 6.0 5.5 5.0 ppm
13
C NMR CD3OD
) 0 ppm 200
210
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
'H NMR CDCI3
Me
7.4 7.2 6 .6 6.4pp 7.6 7.0
8 7 6 5 4 3 2 ppm
1 3 C NMR CDCI3
200 150 100 r~ 50 " ppm
211
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
*H NMR C6D 6
7.6 7.4 7.2 7.0 pp
ppm
13
C NM R C 6 D6
200 150 100 50
212
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
'H NMR CDCI3
i l j W l
H
j'O L * .
4.4 4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 pp-
HO,
OMe
iL Jik U L ji
ppm
13
C NMR CDCI3
50 200 150 100 ppm
213
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission
'H NMR CD3OD
OH
‘ OH
OH OH
4.4
PP
T"
2 ppm
13
C NMR CD3OD
200 150 100
M tftM ,
50 ppm
214
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
'H NMR CD3OD
OH
OH
OH OH
4.3 4.2 4.1 4.0 3.9 3.8 3.7 3.6 3.5 pp-
- 1 T
8 7 6 5 4 3 ppm
l3C NM R CD3OD
200 150 100 50 ppm
215
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
*H NMR CD3OD
Boc
N'H
MeO
6.4 6.2 7.2 7.0 6.0 6.6
13
C NMR CD3OD
200 150 100 50
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
lH NM R CD3OD
HN
5.0 4.5
pp
r T "
ppm
13
C NMR CD3OD
200 150 100 50 ppm
217
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
NMR CD3OD
OH NH
•OH
5.0 4.6 4.4 4.2 4.0
V__
T
1 3 C NM R CD3OD
200 150 100 50 ppm
218
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
'H NMR DMSO-rftf
HO OH
6.5 7.0 6.0 5.5 7.5
I I } A/ll /
4 2 ppm
13
C NMR DMSO-rfg
5 0 150 100 0 ppm 200
219
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
'H N M R CD3OD
C NMR CD3OD
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

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Asset Metadata

Creator Raber, Jeffrey Charles (author)

Core Title Design and synthesis of novel heterocycles and peptidomimetics from organoboronic acids, amines and carbonyl compounds

School Graduate School

Degree Doctor of Philosophy

Degree Program Chemistry

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag chemistry, organic,OAI-PMH Harvest

Language English

Contributor Digitized by ProQuest (provenance)

Advisor Petasis, Nicos (committee chair), Appleman, Michael (committee member), Bau, Robert (committee member), Prakash, G.K. Surya (committee member), Weber, William P. (committee member)

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c16-543974

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Legacy Identifier 3094370.pdf

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Document Type Dissertation

Rights Raber, Jeffrey Charles

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the au...

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