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1'HESIS

ICHI

It”?! I!

3 1

W

 

 

 

 

 

 

 

 

3 ltllllll

This is to certify that the

dissertation entitled
A Temporary Tethering Strategy for Stereocontrol

in the Pictet-Spengler Reaction

presented by

Stephen Herman Steffke

has been accepted towards fulfillment
of the requirements for

Ph.D. degree in ChemlStY‘y

mm

Major professor

 

tyne August 14, 1997

 

MSU is (m Al/irmutiw' Action/liquid ()plmrtum'ty Institution 0-12771

 

 

LIBRARY
Michigan State
University

 

 

 

PLACE IN RETURN BOX
to remove this checkout from your record.
TO AVOID FINES return on or before date due.

 

DATE DUE DATE DUE DATE DUE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1/98 chlRC/Dateouepss-nu

 

A TEMPORARY TETHERING STRATEGY FOR STEREOCONTROL IN THE
PICTET—SPENGLER REACTION

By
Stephen Herman Steffke

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry
1997

ABSTRACT

A TEMPORARY TETHERING STRATEGY FOR STEREOCONTROL IN THE
PICTET- SPENGLER REACTION

By
Stephen Herman Stefflte

Recently, much attention has been directed toward the development of asymmetric
versions of the Pictet-Spengler reaction, with the aim of gaining stereocontrolled entry into
the C-l-substituted tetrahydroisoquinoline and tetrahydro-B-carboline ring systems. These
substructures are widely distributed in natural products possessing important physiological
properties. Described here is the application of a temporary tethering strategy for
stereocontrol in the Pictet-Spengler reaction, that results in the asymmetric formation of
1,3-cis-disubstituted or 1,1,3-trisubstituted tetrahydro-B-carbolines from tryptophan. The
carboxyl group of the aromatic amino acid functions as a tethering site, allowing the
carbonyl component to be temporarily connected through an ester bond. The amino group
is protected during ester formation, and its deprotection later allows the Pictet-Spengler
condensation to commence. The stereocontrolled formation of a [3.3.1] bridged 8-lactone,
which bears a new asymmetric center at O], is followed by cleavage of the lactone to give
the di- or tri-substituted tetrahydro-B—carboline, that bears reactive functionality at both the
C—1 and C-3 appendages that may be exploited in the synthesis of more complex alkaloids.
In an effort to prepare tetrahydroisoquinolines by this method, tyrosine was also
investigated as the B—arylethylamine component. Finally, an attempt to deaminate the

tosylate of the bridged Pictet-Spengler product is described.

To my parents, who taught me life's most important lessons.

And to my loving wife, Beth.

ACKNOWLEDGMENTS

I am deeply grateful to Professor William Reusch for all of the guidance, insightful
discussion, and encouragement that made the completion of this project possible. Thanks
for believing in me when things looked bleak Thanks also to my committee members, Dr.
Jackson, Dr. Watson, Dr. McCracken and Dr. Nocera for the helpful feedback they
provided to me. To the Organic faculty, thank you for opening your doors and offering
your expertise freely. And thank you, Michigan State University, for giving me this
opportunity.

It has been a pleasure to work and learn with my fellow Reusch group members. A
special thanks to labmates Ed Bryant and Petr Benovsky for making my work easier and
more enjoyable. To the many graduate students and others who provided friendship,
advice, and diversion, thanks for making this long journey a happy one. I will carry many
fond memories of my time here. Thanks to Kermit Johnson and Long Le for NMR
assistance, and to Rui Huang and Bev Chamberlin for help in obtaining mass spectra. The
excellent and kind secretarial staff, especially Lisa Dillingham, Diane Frost, Nancy Lavrik,
and Beth Thomas, was of great help in getting things done. And thanks to St. John's
Student Parish for providing me with a spiritual anchor.

Mom and Dad, the getaways up north were of great relief and helped me through
the hard times. To my entire family, thanks for the love and support.

I want to thank my wife, Beth, for helping in so many ways, and for patiently
standing by me. I couldn't imagine getting through this without you. And little Emily,

thanks for bringing so much happiness into our lives.

iv

 

 

TABLE OF CONTENTS

LIST OF TABLES ........................................... iv
LIST OF FIGURES .......................................... v
LIST OF ABBREVIATIONS .................................... xi
INTRODUCTION ........................................... 1
RESULTS AND DISCUSSION .................................. 18
Plan of the Study ....................................... 18

Fsterification of Protected Amino Acids: Formation of the Tethering Bond . 19
Synthesis of a THBC Bearing an Asymmetric Quaternary Center at C-1 . . . 23

Synthesis of a THBC Bearing an Asymmetric Tertiary Center at C-1 ..... 41
Studies Employing Tyrosine as the B-arylethylamine Component ....... 57
Attempted Deamination of Tetracycle 77a ....................... 59
CONCLUSION ............................................. 66
ADDENDUM ............................................... 68
EXPERIMENTAL ........................................... 70
General Methods ....................................... 70
Preparation of N-Cbz Protected Ester 73 ....................... 71
Preparation of Imine 75 ................................... 72
Pictet-Spengler Cyclization of Imine 75 ........................ 72
Preparation of N-B oc Protected Ester 96 ....................... 73
One-Step Deprotection and Pictet-Spengler Cyclization of 96 .......... 74
Preparation of Amide 100 ................................. 74
Preparation of N-Cbz Protected Allyl Ester 103 ................... 75
Preparation of Diol 104 ................................... 76
Preparation of Aldehyde 101 ............................... 77
Preparation of N-Cbz Protected Methyl Acetal 109 ................. 77
Deprotection of Methyl Acetal 109 ........................... 78
Preparation of N—Cbz Protected Ethyl Acetal 110 .................. 79
Deprotection of Ethyl Acetal 110 ............................. 79
Preparation of 123a from Aldehyde 101 ....................... 80
Preparation of N-Cbz Protected Ester 132 ...................... 81
Preparation of Schiff Base 134 .............................. 82
Preparation of Tosylate 92 ................................. 83
Reaction of 92 with DBU ................................. 84
v

 

 

APPENDIX: SPECTRA ....................................... 85

BIBLIOGRAPHY ............................................ 159

LIST OF TABLES

Table 1 — Esterification of Protected Amino Acids ....................... 20
Table 2 - Leaving Group Comparisons .............................. 59
vii

 

 

 

LIST OF FIGURES

Figure l - Retrosynthetic Analysis of Et 729 .......................... 2
Figure 2 - Temporary Tethering Strategy ............................. 4
Figure 3 - Retrosynthetic Analysis of Fragment 5 ....................... 5
Figure 4 - Retrosynthetic Analysis of Fragment 3 ....................... 5
Figure 5 - Synthesis of Ajmaline .................................. 6
Figure 6 - Woodward's Reserpine Synthesis .......................... 7
Figure 7 - Methods for the Asymmetric Synthesis of THIQ's and THBC's ...... 9
Figure 8 - Alkaloids Synthesized from THIQ Precursors .................. 10
Figure 9 - Alkaloids Synthesized from THBC Precursors .................. 11
Figure 10 - Original Pictet-Spengler Reaction ......................... 12
Figure 11 - Possible Pictet-Spengler Cyclization Pathways ................. 13
Figure 12 - Pictet-Spengler Reaction of Tryptophan Derivatives ............. 14
Figure 13 - Tautomerization of the Schiff Base ......................... 15
Figure 14 - Epimerization of THBC's ............................... 16
Figure 15 - Epimerization of THIQ's ............................... 16
Figure 16 - General Strategy ..................................... 17
Figure 17 - Application of Traditional DCC Esterification .................. 19
Figure 18 - Role of Acid Catalyst in DCC Esterification ................... 22
Figure 19 - Preparation of Acyl Ester 73 ............................. 23
Figure 20 - Hydrogenolysis of Tethered Ketone Precursor 73 .............. 24

 

 

Figure 21 - Attempted Cyclization in Aprotic Medium .................... 26

Figure 22 - Effect of Imine Electrophilicity in the Pictet-Spengler Reaction ...... 28
Figure 23 - 1H NMR Spectrum in CDC13 of Reaction Product .............. 30
Figure 24 - 1H NMR Spectrum in Acetone-d6 of Reaction Product ........... 31
Figure 25 - Cyclization with Racemization ............................ 33
Figure 26 - Woodward's Push-Pull Approach ......................... 34
Figure 27 - Treatment of Schiff Base 75 with TsCl ...................... 35
Figure 28 - Stereospecific Cyclization ............................... 36
Figure 29 - Binary Solute-Solute Associations of Enantiomers .............. 37
Figure 30 - Proposed Dimeric Structures ............................. 38
Figure 31 - One Step Deprotection/Cyclization ......................... 39
Figure 32 - Yamada‘s Reductive Decyanization Sequence .................. 40
Figure 33 - Tether Cleavage via Ammonolysis ......................... 41
Figure 34 - Anticipated Behavior of Tethered Aldehyde 101 ................ 41
Figure 35 - Preparation of Tethered Aldehyde Precursor 101 ............... 42
Figure 36 - Catalytic Hydrogenation of Pretreated 101 ................... 45
Figure 37 - Alternative Route via Acetal ............................. 46
Figure 38 - Treatment of Methyl Acetal 111 with TFA ................... 46
Figure 39 - Oxonium Ion Intermediate .............................. 47
Figure 40 - Intramolecular Cyclization by Valls et aL ..................... 48
Figure 41 - van Maarseveen's In Situ Hydrolysis Method ................. 49
Figure 42 - Effect of Electron-Withdrawin g Groups on Acetal Hydrolysis ....... 50
Figure 43 - Hydrogenolysis of 73 with Formic Acid as Hydrogen Donor ....... 51
Figure 44 - Possible Outcome of Formic Acid Hydrogenolysis of 101 ......... 51
Figure 45 - Methanolysis Product ................................. 52
ix

 

 

Figure 46 — Possible Pathways for the Formation of 123 .................. 54

Figure 47 - Pertinent NOE Enhancement Precedents ..................... 55
Figure 48 - NOE for 123 ....................................... 56
Figure 49 - Destabilizing Effect of Hydroxyl on Epimerization Intermediate ...... 57
Figure 50 - Esterification of N-Cbz-L-Tyrosine ........................ 58
Figure 51 - Formation and Treatment of Schiff Base 134 .................. 59
Figure 52 - Deaminations Driven by Activation of the Alkyl Appendage ........ 60
Figure 53 - Possible Deamination Pathways for 92 ...................... 61
Figure 54 - Reaction of N-Tosylate 92 with DBU ....................... 63
Figure 55 - Examples of Nucleophilic Behavior of DBU .................. 64
Figure 56 - Corey's Synthesis of Et 743 ............................. 69
Figure 57 - IR Spectrum of 73 ................................... 86
Figure 58 - 1H NMR Spectrum of 73 ............................... 87
Figure 59 - 13C NMR Spectrum of 73 .............................. 88
Figure 60 - Mass Spectrum of 73 ................................. 89
Figure 61 - IR Spectrum of 75 ................................... 90
Figure 62 - 1H NMR Spectrum of 75 ............................... 91
Figure 63 - 13C NMR Spectrum of 75 .............................. 92
Figure 64 - Mass Spectrum of 75 ................................. 93
Figure 65 - IR Spectrum of 77a .................................. 94
Figure 66 - 1H NMR Spectrum of 77a in CDCl3 ....................... 95
Figure 67 - 1H NMR Spectrum of 77a in Acetone-d6 .................... 96
Figure 68 - 13C NMR Spectrum of 77a ............................. 97
Figure 69 - Mass Spectrum of 77a ................................. 98
Figure 70 - IR Spectrum of 92 ................................... 99
x

 

Figure 71 - 1H NMR Spectrum of 92 ............................... 100

Figure 72 - 13C NMR Spectrum of 92 .............................. 101
Figure 73 - Mass Spectrum of 92 ................................. 102
Figure 74 - IR Spectrum of 96 ................................... 103
Figure 75 - 1H NMR Spectrum of 96 ............................... 104
Figure 76 - 13C NMR Spectrum of 96 .............................. 105
Figure 77 - Mass Spectrum of 96 ................................. 106
Figure 78 - 1R Spectrum of 100 .................................. 107
Figure 79 - 1H NMR Spectrum of 100 .............................. 108
Figure 80 - 13C NMR Spectrum of 100 ............................. 109
Figure 81 - Mass Spectrum of 100 ................................ 110
Figure 82 - IR Spectrum of 101 .................................. 111
Figure 83 - 1H NMR Spectrum of 101 .............................. 112
Figure 84 - 13C NMR Spectrum of 101 ............................. 113
Figure 85 - Mass Spectrum of 101 ................................ 114
Figure 86 - IR Spectrum of 103 .................................. 115
Figure 87 - 1H NMR Spectrum of 103 .............................. 116
Figure 88 - 13C NMR Spectrum of 103 ............................. 117
Figure 89 - Mass Spectrum of 103 ................................ 118
Figure 90 - IR Spectrum of 104 .................................. 119
Figure 91 - 1H NMR Spectrum of 104 .............................. 120
Figure 92 - 13C NMR Spectrum of 104 ............................. 121
Figure 93 - Mass Spectrum of 104 ................................ 122
Figure 94 - IR Spectrum of 109 .................................. 123
Figure 95 - 1H NMR Spectrum of 109 .............................. 124
xi

 

 

Figure 121 - 13C NMR Spectrum of 133 ............................ 150

Figure 122 - Mass Spectrum of 133 ................................ 151
Figure 123 - 1H NMR Spectrum of 134 ............................. 152
Figure 124 - 13C NMR Spectrum of 134 ............................ 153
Figure 125 - IR Spectrum of 145 ................................. 154
Figure 126 - 1H NMR Spectrum of 145 ............................. 155
Figure 127 - 13C NMR Spectrum of 145 ............................ 156
Figure 128 - DEPT Spectrum of 145 ............................... 157
Figure 129 - Mass Spectrum of 145 ................................ 158

AcOH

DMAP
DMSO

Et 729

MCPI

NOE
Ph

TABLE OF ABBREVIATIONS

xiv

Acetyl

Acetic acid

Aryl

Benzyl

t-Butoxycarbonyl

Butyl

Benzoyl

Concentration

Carbobenzoxy

Correlated spectroscopy
1,8-Diazabicyclo[5.4.0]undec-7-ene
1,3—Dicyclohexylcarbodiimide
1,3-Dicyclohexylurea

Distortionless enhancement by
polarization transfer

4-Dimethylaminopyridine
Dirnethylsulfoxide

Ethyl

Ecteinascidin 729

Methyl
2-Chloro-l-methylpyridinium iodide
Nuclear Overhauser Effect

Phenyl

 

 

Phe

P)’r

TFA
TH pc
THIQ

Trp
Ts
TsCl
TsOH

XV

Phenylalanine

Pyridine

Triethylamine

Trifluoroacetic acid

1 ,2,3 ,4-Tetrahydro- B-carboline
1 ,2,3 ,4-Tetrahydroisoquinoline
'Ihin layer chromatography
Tryptophan

p-Toluenesulfonyl
p-Toluenesulfonyl chloride
p-Toluenesulfonic acid

Tyrosine

INTRODUCTION

The impressive structural diversity of alkaloids reflects their equally impressive
range of biological properties; and the medicinal and cultural application of naturally
derived alkaloids spans centuries, as well as far reaching geographical and societal
boundaries.1 Modern pharmacology continues to benefit from the exploration of traditional
or folk medicine as well as from the systematic practice of isolation, characterization, and
testing of newly discovered alkaloids.2

Given their prominent utility, the laboratory synthesis of alkaloids is frequently
pursued as a source of these valuable compounds. However, it is often an intriguing
structure that attracts the attention of the synthetic chemist, and the analysis of complex
synthetic problems frequently inspires the creation of new methodologies, which may be
broadly applicable.

The ecteinascidins (Et's) are a family of alkaloids, possessing potent antitumor
activity, isolated from the Caribbean tunicate Ecteinascidia turbinata3 The most active
ecteinascidin, Et 7 29 (1), comprises only 0.000l6% of the wet weight of the tunicate.
Because it is highly biologically active, scarce, and has an unusual and interesting
structure, Et 729 is an attractive synthetic target. Contributing to the complexity of Et 729
are the seven stereocenters, the moderately complex topology including a spiro fusion and
two bridges, the high degree of functionalization, and the sheer size of the molecule.

Contemplation of Et 729 led to a highly convergent retrosynthetic strategy based
mainly on topological and stereochemical concerns, and employing several hetero-keyed
bond disconnections (Figure 1). The task was simplified by the identification of L-tyrosine

and L-cysteine (or its synthetic equivalent L-serine) as inexpensive, chiral starting materials,

 

0 0H 2 COOH
Figure 1 - Retrosynthetic Analysis of Et 729

 

3

which allowed for what Corey4 refers to as a bidirectional search.

Pondering the execution of this scheme made it clear that the key difficulty is the
introduction of the asymmetric centers in the l,2,3,4-tetrahydroisoquinoline (THIQ)
fragments 3 and 5. The synthesis of THIQ alkaloids containing an asymmetric center at C-
1 has been the subject of extensive investigation, since such alkaloids are widespread in
nature and have important pharmacological properties.5 Various approaches to the
enantioselective introduction of an appendage at the 1-position of THIQ's have given
satisfactory and sometimes excellent results. However, only three routes to the analogous
1-(hydroxymethy1)TI-IIQ's have been reported. The first of these relies on the resolution
of a racemic mixture to obtain the enantiomerically pure product7 The second is a
stereoselective process that relies on the separation of a 9:1 mixture of diastereomers which
after several steps yields the desired enantiomer.8 The length of this sequence, however,
results in an overall yield that is lower than that of the former process. Also, the immediate
precursor of the alcohol is a 1-fonnyltetrahydroisoquinoline derivative, that must be used
immediately upon isolation, as it is prone to racemization (75% of optical activity is lost
upon chromatography on silica gel and 25% is lost during storage for 12 h in the cold).
The third approach is actually a formal route based on the second, as it involves an
essentially stereospecific approach to the aldehyde precursor described above.9 While this
approach could conceivably provide the enantiomerically pure THIQ fragments 3 and 5, it
is clear that a satisfactory solution has yet to be developed.

Unsatisfied with the current methodology available, we sought to devise a new
procedure capable of delivering maximum stereocontrol in an efficient manner.
Stereocontrol may result from steric bias, mechanistic requirements, stereoelectronic
effects, or chelation control.10 Intramolecular reactions may benefit from a powerful
additional mode of control; conformational restriction. By temporarily connecting two
reactants by means of a short tether, a previously intermolecular reaction can enjoy the

advantages of intramolecularity. The power of this strategy is exemplified by Stork's

 

4
technology, which employs a temporary silyl tether to control the regiochemistry and

stereochemistry of a variety of reactions, en route to a diverse assortment of natural
products.11

To successfully execute any temporary tethering strategy (Figure 2), several
requirements must be met. First, the reactants must contain appropriately placed functional
groups that are capable of participating in tether bond formation. Second, the new
connection must withstand the reaction conditions under which the intramolecular reaction
occurs. Third, the system must be flexible enough to allow the reaction to proceed, yet
sufficiently rigid that conformational restriction results in stereoselective bond formation.

Finally, cleavage of the tether must be accomplished without affecting the remainder of the

molecule.

KY
A-B
q: tether intramolecular

X——> formation reaction
X-Y
8+ Conformationally

rigid system
A tether

Q: cleavage
Ym
X’ B

Figure 2 - Temporary Tethering Strategy

An examination of target fragment 5 suggests that these criteria can be met by the
synthesis of 5-lactone 9 (Figure 3), via an intramolecular Pictet-Spengler reaction of 10, in
which the aldehyde is tethered via an ester linkage to the carboxyl group of the tyrosine
derivative. Conformational restriction should be absolute, as a 1,3-diaxial relationship
about the developing single atom bridge is mandatory. Likewise, one could envision the
sulfur-containing target fragment 3 arising from an analogous route, generating the crucial

asymmetric quaternary center with complete stereocontrol (Figure 4).

 

 

 

OAc 0 OAc
CH
30 0H 0 0
NH :» NH
0L 0L. 0
o
O OH
5 / 9
OAc 0
CH3 0
O NH H
o 2 K0’
\.—o o
10

Figure 3 - Retrosynthetic Analysis of Fragment 5

OH

0“\\ \

H300 NH<|)\
=> M,\\ O

HO

 

/ 11
HO
HO l ""ln’o
O

12
Figure 4 - Retrosynthetic Analysis of Fragment 3

6
A similar Pictet-Spengler reaction in which the tether is permanent has been

employed by Masamune12 in the construction of the [3.3.1] skeleton of 14 from 13 in the
synthesis of ajmaline (Figure 5), suggesting that our scheme is workable. Also,
Woodward” has demonstrated the adequacy of a bridged 1,3-diaxial lactone to temporarily
create a rigid system in his classic reserpine synthesis (Figure 6). Sodium borohydride
reduction of the quaternary salt 16 from the less hindered side gave 17, with the undesired
stereochemistry at position 3. Hydrolysis of both esters, followed by lactone formation,
gave 18, which is sterically congested since the 1,3-diaxia1 requirement of the bridged
lactone rigidly fixes the cis-decalin framework, such that in the chair conformation the
indole ring at C-3 must adopt an axial orientation. Acid-catalyzed epirnerization at C—3 gave
the more stable epimer 19, in which the indole ring is equatorial. Cleavage of the lactone

and execution of the final coupling gave reserpine 20.

 

Ajmaline

Figure 5 - Synthesis of Ajmaline

 

 

 

MeO

 

 

 

 

o 1)NaOME
\ NH MeacCOZH EN 2) ArCOCI
H > __ >
N .—
H H
18 \ / 19
OMe

MeO

 

Reserpine

Figure 6 - Woodward‘s Reserpine Synthesis

 

8
Our temporary tethering strategy may be broadly applicable in the asymmetric

synthesis of numerous alkaloids containing the THIQ or the 1,2,3,4-tetrahydro-B-carboline
(THBC) framework. As pointed out by Seebach,6b all possible methods of synthesizing
enantiomerically pure compounds have been applied in this vein. As shown in Figure 7,
these broad categories are: a) resolution, b) catalytic and c) stoichiometric enantioselective
reactions and d) e) f) the incorporation of components from the pool of chiral building
blocks. Many of these methods, as well as our own, rely upon the transfer of asymmetry
from O3 to C-1, resulting in the initial formation of a 1,3-disubstituted derivative. These
derivatives may themselves be desirable targets but more often function as stepping stones
leading to C-1 substituted products through decarboxylation. Both classes of compounds
may provide a springboard to more complex alkaloid skeletons, as illustrated in Figure 8

(THIQ's) and Figure 9 (THBC'S).

/ I
R/ \
\ N R
/ I
R/\ NH2
CHO
+ I,

 

 

R / |
b) R/\ N
y l .
R
BuLi/R‘X
BuLi/R‘X

V\COZ
0 / . COOH
“mm/Q

O

Chirality denoted by asterisk.

Adapted from: Huber, I. M. P.; Seebach, D., Helv. Chim. Acta 1987, 70, 194-4.
Figure 7 - Methods for the Asymmetric Synthesis of THIQ's and THBC'S

10

 

W“
CH30 O COzEt CH30
NH
CH 30 CH30
CH3
21 (+)-O-methylcorytenchirine 22

 

 

(:t) 25 OCH3 (i)-Morphine 26

Figure 8 - Alkaloids Synthesized from THIQ Precursors

 

11

 

 

Mass/'0?"

M902C

(—)-Ajmalicine 32

 

33 (+)-Macroline 34
Figure 9 - Alkaloids Synthesized from THBC Precursors

 

    

 

 

12
For over eighty years the Pictet-Spengler reaction,22 illustrated in Figure 10, has

played a prominent role in alkaloid synthesis. A reaction of the Mannich type, it involves
the condensation of a B-arylamine and a reactive carbonyl compound. The formation of an
intermediate Schiff base, followed by cyclization, yields a THIQ or tetrahydro-B—carboline

(THBC). The cyclization is usually acid-catalyzed.

O CHscHO ‘11—.
NH2 HCI, A

37H CH3
H JLCH3

 

35 36

Figure 10 - Original Pictet-Spengler Reaction

When the B—arylamine component is an indole derivative, there are two conceivable
pathways by which the cyclization could proceed (Figure 11).2?-°’23b Attack of the
intermediate iminium ion may take place directly at the C-2 position of the indole to give
carbonium ion 42 (path A), or at the C-3 position to give the spiroindolenine 41, which
then rearranges to give 42 (path B). While path B is generally believed to be the operative
pathway, the reaction may proceed by direct attack when the irninium ion is very

electrophilic.

 

 

 

 

I
38 H H H—o—R‘
39 OH
-H20
NH2 B I |
'69/ 1 @NR2
N R u I
41 H 40 R1
A
-H“
H H R, H R,
42 43

Figure 11 - Possible Pictet-Spengler Cyclization Pathways

If either the amine or carbonyl component is chiral, asymmetric induction is possible.
Since aromatic amino acid derivatives provide a convenient and inexpensive source of
chiral B-arylamines, their utility has been investigated with vigor.

The diastereomeric ratio obtained in the condensation of tryptophan derivatives with
aldehydes (Figure 12) has been studied extensively, and has been found to be dependent
upon the steric and electronic nature of the system as well as the reaction conditionszzcv23
Early attempts to achieve stereocontrol typically gave mixtures of the cis and trans isomers
with a few exceptions. As the factors governing the stereoselectivity of the reaction became
better understood, the ratios improved, culminating with the attainment of 100% trans
stereoselectivity in the reaction of Nb—diphenylmethyl substituted tryptophan esters with

various aldehydes, yielding 1,3-disubstituted THBC's, as reported by Cook et 31.24

14

Unfortunately, the stereochemistry of most naturally occurring THBC's is opposite that of
the trans product obtained from the naturally occurring L-tryptophan. A general method for
the specific production of 1,3-cis isomers has been elusive, although Massiot25 has
reported an instance of success in the condensation of L-tryptophanamide with 4—formyl-
2,2-bis(phenylthio)butyrate. Similar reactions reported by Overrnan,26 however, gave

diastereomeric mixtures.

 

o o o
ln/\')LX R‘CHO 3' l X Cl I
2 2 + 2
NHR N NR N : NR
H R, H -,
44 45 Q3 46 11225

Figure 12 - Pictet-Spengler Reaction of Tryptophan Derivatives

Contrasting the many reports regarding tryptophan derivatives, only a handful of
reports about the diastereomeric ratio obtained in the Pictet-Spengler condensation of
phenylalanine derivatives have appeared. This may be due to the simple fact that the
aromatic ring of phenylalanine does not readily undergo Pictet-Spengler cyclization, and
therefore requires prior activation,22b via substitution with electron-donating groups,
making tryptophan a more convenient choice for study. Asymmetric condensations
involving L-DOPA [3-(3,4-dihydroxyphenyl)-L-alanine] or its alkylated derivatives
reported by Brossi27 and Yamada‘Sfi’28 gave diastereomeric mixtures, with the 1,3-cis
isomer predominating. Apparently, there have been no investigations of asymmetric Pictet-
Spengler reactions involving N-substituted derivatives of the phenylalanine family.
However, epirnerization studies6'3v29 have shown that N-substituted THIQ's equilibrate to
favor the 1,3-trans geometry to a much greater extent than do their unsubstituted
counterparts, in accordance with the much studied asymmetric formation and epirnerization

of the THBC system.

 

 

15
In both systems racemization and epirnerization of products is a concern.

Racemization is believed to occur through tautomerization of the Schiff base intermediate

47 with the irnine 48 before product formation (Figure 13).23b’30

o o
t1 O H
Ar/VKILOR Ar/YLOR Ar/YLOR
'P.‘ — N — i”.
,0. 4x ,0.
H R H H R H R
47 48 49

Figure 13 - Tautomerization of the Schiff Base

Epimerization may occur under a variety of conditions and has been advantageously
employed in certain alkaloid synthesesfievnvzzc Acid-catalyzed epirnerization of THBC's
occurs at C-1 and is believed to arise from expulsion of the protonated Nb nitrogen to form

the stabilized cationic intermediate 52, followed by re-formation of the ring to give

epimerized product (Figure 14).22c,23,31
Similarly, properly SUbStituted phenolic THIQ's have been observed to epirnerize at

C-1, presumably through the quinone methide intermediate 56 (Figure 15).”,31 Acid-
catalyzed epirnerizations of either system generally require elevated temperatures, and the
substitution pattern of the benzene ring largely determines the ease of the process”:31

Base catalyzed epimerizations may occur at GB in both systems through enolate

formation, followed by re-protonationfie’30

 

 

 

Figure 15 - Epimerization of THIQ's

17
Our tether mediated strategy may expand the usefulness of the asymmetric Pictet-

Spengler reaction in several ways: 1) Conformational restriction should result in the
exclusive formation of 1,3-cis disubstituted THIQ's and THBC's, which at C-1 leads to the
stereochemistry usually found in nature, if the naturally occurring L-amino acid is
employed. 2) By lowering the energy of activation, tethering the amine and carbonyl
components may extend the range of practical substrates to include those displaying poor
intermolecular reactivity. The enhanced reactivity is expected to arise from a favorable
entropy effect, attributed to the intramolecular nature of the condensation, and a favorable
enthalpy effect, attributed to the inductive effect of the tethering ester linkage, which should
render the carbonyl, as well as the resulting Schiff base, more electrophilic. 3) The
introduction of asymmetric quaternary centers at the crucial C-l site may be possible.
Though compounds containing such a structure are extremely rare in nature, such a
technology could provide unnatural analogs having altered or enhanced physiological
effects, that are presently unattainable. 4) Cleavage of the bridged lactone function of the
cyclization product would provide reactive functionality at both the C-1 and C-3
appendages that may be exploited in the synthesis of more complex alkaloids. 5) The
[3.3.1] bridged system should resist epirnerization. If enolate formation at C-3 or acid-
catalyzed elimination of the bridgehead nitrogen at C-1 were to occur, the remaining
stereocenter would provide "memory" upon recyclization due to the same conformational
restriction that directed the original ring closure.

This study aims to validate the feasibility of employing our tether mediated strategy
to gain stereocontrolled entry into the TI-HQ and THBC ring systems, by the synthesis of

the apprOpriate model compounds.

RESULTS AND DISCUSSION

Plan of the Study

Our temporary tethering strategy for stereocontrol in the Pictet-Spengler reaction is
schematized below (Figure 16). The carboxyl group of the aromatic amino acid would
function as a tethering site allowing the carbonyl component to be temporarily connected
through an ester bond. The amino group would require protection during ester formation,
and its deprotection would later allow the Pictet-Spengler condensation to commence. The
stereocontrolled formation of 8-1actone 59, which bears a new asymmetric center at C-1,
would be followed by nucleophilic or reductive cleavage to give the di- or tri-substituted

product 60.

O

D NH2 OH __> 2mg? ____,

57

   

59 so 0”

Figure 16 - General Strategy

We devised our model systems to facilitate the assessment of our scheme, and to
cultivate methodological practicality. We explored the use of tryptophan, phenylalanine,

and tyrosine as starting materials, but focused mainly on the use of tryptophan, due to the

18

19
demonstrated ability of the electron-rich indole nucleus to participate in Pictet-Spengler

cyclization without prior modification. Numerous protective groups are available for the
amino function.32 We chose to feature two of the most versatile and widely used, the

carbobenzoxy (Cbz) group and the t-butoxycarbonyl (Boc) group. We investigated both
aldehyde and ketone carbonyl components, to demonstrate the generation of both tertiary

and quaternary asymmetric centers, respectively, at the C-1 position.

Esterification of Protected Amino Acids: Formation of the Tethering Bond
For each of the model systems we investigated, the esterification of an N-protected
amino acid with a functionalized alcohol played a key role. Since simple acid-catalyzed
esterification gave poor results, we explored several other methods in pursuit of efficiency.
The results are summarized in Table 1. We first examined the use of the coupling reagent
2-chloro-1-methy1pyridinium iodide (MCPI), due to its reported effectiveness when acid
sensitivity or steric bulkiness is a concem,33 but the result was disappointing (entry a).
Next, we tried the widely used l,3-dicyclohexylcarbodiimide (DCC) as a coupling reagent,
but found that the standard procedure34 gave only moderate yields of the desired ester
(entries b, d, e, h), along with a significant amount of a solid impurity, identified as the N-

acylurea derivative of the protected amino acid (see product 63 in Figure 17).

O
O/\n/\
NHCbz O
62
OH 2) o + .
NHCbz Hk/ o
N H
61 OH >—N
63 . 2:3,.

Figure 17 - Application of Traditional DCC Esterification

0 1) DCC, DMAP

 

V

20
Table 1 - Esterification of Protected Amino Acids

 

 

 

 

 

 

 

 

 

 

 

 

 

 

entry amino acid alcohol reagent(s) solvent yield ref.
a L-Trp-Z ”OW MCPI/TEA CH2C12 27 33
b L-Trp-Z ”A DCC/DMAP CH2C12 47 34
c L-Trp-Z ”A TsCl pyridine 87 , 36
d L-Trp-Z HOQCL/ DCC/DMAP CH2C12 26 ' 34
e L-Trp-Z Ho\/fi\/ DCC/DMAP CH3CN 39 34
f L-Trp-Z HOJCL/ TsCl pyridine 85 36
g D-Trp-Z Hei/ TsCl pyridine 81 36
h L-Phe-Z HO\/fi\/ DCC/DMAP CHzClz 33 34
i L-Phe-Z HOJK/ DCC/TsOH pyridine 86 35
j L-Phe—Z HOJK/ TsCl pyridine 94 36
k L-Tyr-Z HOdCL/ DCC/TsOH pyridine 67 35
l L-Trp-Boc HOVEL/ TsCl pyridine 6O 36

 

 

 

 

 

 

 

 

21
This side-product has been encountered often in DCC-mediated esterifications. Holrnberg

and Hansen35 have reported that the addition of a catalytic amount of para-toluenesulfonic
acid and the use of pyridine as the solvent greatly increases the yield of ester, while the N-
acylurea formation is diminished. Their explanation of the role of the acid catalyst is
illustrated in Figure 18. Employing this modification in the reaction of N-Cbz-L-
phenylalanine with l-hydroxy-Z-butanone increased the yield of ester 62 to 86% (entry i),
compared to 33% with the standard procedure (entry h). Simultaneously, we also
investigated the classic ester preparation from mixed sulfonate anhydrides.36 This method
proved even more efficient than the acid-catalyzed DCC coupling procedure, providing the

ester (entry j) 62 in 94% yield.

22
R‘COOH + H11C6-N=C=N-CGH11

 

 

64 65
9
<3 a-R‘
9 H1106 —u—C-N-CGH11
Q'C'R‘ 68
H11C6 ‘fi‘c=N'CeH11 RZOH
55 ‘R-e-o—R2 + ocu
H+ 67
_ ll _
911* .
Q—C"R1 R OH > 68 + DCU
H11C6 'fl'CzN‘CeHn a

 

 

= ‘R-c—
H11C6 -n-C=|N-|-C6H11 71

u 69
<3 b N _> O _
o-c-R‘ ‘ / " 6,21; /> + ocu

 

 

7o RZOH

Figure 18 - Role of Acid Catalyst in DCC Esterification

23
Synthesis of a THBC Bearing an Asymmetric Quaternary Center at C-1

We felt that the tethered ketone precursor necessary for this synthesis could be
prepared by direct coupling of the protected amino acid with an or-hydroxyketone, and
were pleased to find that 1-hydroxy-2-butanone is commercially available. N-Cbz-L-
tryptophan was prepared from the amino acid by a modified Schotten-Baumann
procedure,37 or obtained directly from a commercial supplier. The coupling of these
components was best achieved by reaction of the alcohol with the mixed para-
toluenesulfonate anhydride of the protected amino acid, as described above, to give acyl

ester 73 in 85% yield (Figure 19).

O O

1)TsCl,pyr
H = 0
C' I O 0 CI I A"A
NHCbz 2) NHCbz o
N N
H (UV H
72 73

OH
Figure 19 - Preparation of Acyl Ester 73

 

Expecting that amino deprotection would occur without complication by way of
standard hydrogenolysis, an ethanolic solution of 73 was stirred at room temperature
under an atmosphere of hydrogen, in the presence of 10% palladium on carbon (Figure
20). Carbobenzoxy cleavage initiated the spontaneous intramolecular condensation of the
amino group with the tethered ketone of 74 (not isolated) to give the cyclic Schiff base 75,
but in a disappointing 42% yield. The major side product was tryptophan (76), apparently
generated by the hydrogenolysis of the acyl ester. The possible side reaction intermediate
72 was not isolated. While benzyl, ally] and vinyl esters are known to be susceptible to
catalytic hydrogenolysis, we were surprised to find that the acyl group weakened the

carbon-oxygen bond sufficiently to promote cleavage. Only one other such example was

24

O O
| | OH L. | | OH
N NHCbz N NH2
72 H x H 76
H2
H
o ,2 o
H
ln/WJLQ/\n/\ 4W0/fib
NHCbz o N NH2 0
73 H 74
+H20 -H20
0
| | N O
N \
H

Figure 20 - Hydrogenolysis of Tethered Ketone Precursor 73

 

 

25
found in the literature, and in this case the acyl group was substituted with a 2-benzofuran

ring, making it more electron-deficient than normal.38 Similarly, the enhanced reactivity of
73 may be due to the electron-withdrawing effect of the N-Cbz group on the ester function.
Performing the reaction at 0 °C suppressed the undesired acyl ester cleavage, raising the
yield of the cyclic imine 75 to 92%.

The reaction of aliphatic ketones with amines to form imines is reputed to require
elevated temperatures and the removal of water from the reaction mixture to shift the
equilibrium in favor of the product, and acid catalysis is often employed.39 The formation
of imine 75 without these aids can be attributed to intramolecularity and perhaps the
electron-withdrawing effect of the ester substitution on the or-carbon. It is likely that
hydrogenolysis of the acyl ester bond of 73 does not occur once the imine is formed, since
the carbon-nitrogen double bond is less polar than the carbonyl bond. This prompted us to
speculate that the removal of water from the reaction mixture would prevent equilibration of
the Schiff base with the tethered amino ketone 74, mitigating the reductive cleavage of the
acyl ester. However, the addition of water (11 equivalents) to the reaction reduced the
yield only slightly to 81%, compared to a range of 85 - 92% for the anhydrous reaction.
Also, the use of molecular sieves (3 A) hampered the hydrogenation, resulting in
incomplete deprotection over a comparable reaction time. Given the excellent results
obtained without the sieves, and the modest effect of added water, their use was deemed
unworthy of further investigation.

Changing the catalyst to palladium hydroxide (moist), known to be highly effective
for the hydrogenolysis of benzyl groups,40 gave a modest 78% yield of the imine.
Catalytic transfer hydrogenolysis, with ammonium forrnate41 as the transfer agent, gave the
imine in only 69% yield. Other known methods of deprotection32 were investigated but
found comparatively ineffective. These include treatment with trimethylsilyl iodide,

methanesulfonic acid/anisole, HBr/acetic acid and BF3 etherate.

 

 

26
A molecular ion peak at m/z 256 in the mass spectrum of the isolated product

provided evidence that the condensation did occur. The basis for the identification of the
product as the Schiff base 75, as opposed to the isomeric Pictet—Spengler cyclization
product, is the existence of a carbon-nitrogen double bond stretch at 1696 cm'1 in the IR
spectrum, as well the proton NMR. The coupling relationships in the aliphatic region of
the two possible products were expected to be similar, and the absolute chemical shifts
were difficult to anticipate. However, the presence of five aromatic hydrogens in the Schiff
base, as opposed to four in the Pictet-Spengler product, was easily determined by
integration ratios.

The Pictet-Spengler reaction traditionally has been carried out in one step from the
amine and carbonyl components in protic solvents, in the presence of an acid catalyst.22
However, Cook et al. reported42 that in the neutral, aprotic medium of refluxing benzene,
tryptophan methyl ester derivatives and aldehydes reacted to give higher yields of THBC's
than in aqueous, acidic media. We found this encouraging, due to concerns that cleavage
of the tethering bond might occur under traditional reaction conditions.

With this is mind, Schiff base 75 was refluxed in dry benzene. Unfortunately,
analysis of the reaction by thin layer chromatography (TLC) revealed that only starting

material was present after 12 hours.

 

75
Figure 21 - Attempted Cyclization in Aprotic Medium

Ail...

27
The failure of 75 to cyclize under Cook's conditions may be due to ring strain in

the bridged, tetracyclic framework of 773, or in the spiroindolenine intermediate that
precedes it, raising the energy of the transition state relative to non-tethered carbonyls.
Alternatively, the imine may be less reactive than those studied by Cook, resulting in no
cyclization. Compared to imines derived from aldehydes, those derived from ketones are
more sterically crowded, and are less electrOphilic due to the electron-releasing property of
the additional alkyl group. In the case of imine 75 this is probably not true, since the
additional alkyl group is substituted with an electron-withdrawing ester function. Cook et
al. have demonstrated42 that modest structural changes can affect the electrophilicity of the
imine, and hence the outcome of the reaction (Figure 22). When refluxed in benzene in the
presence of benzaldehyde, tryptamine yielded only imine 80, while the less basic amine,
tryptophan methyl ester, yielded the Pieter-Spengler product 82. Likewise, salicylaldehyde
reacted with tryptamine under the same conditions to yield only imine 84 (eq. 2a), while

acetylsalicylaldehyde gave the rearranged Pictet-Spengler product 86 (eq. 2b).

73 pKa=10.2 80

 

Figure 22 - Effect of Imine Electrophilicity in the Pictet-Spengler Reaction

29
The addition of an acid catalyst was next examined in an effort to cyclize Schiff

base 75. To the previously refluxed solution of 75 in benzene, an anhydrous solution of
p-toluenesulfonic acid (0.11 equivalents in benzene) was added, and refluxing was
resumed. TLC revealed the slow but steady emergence of a single new product spot. The
conversion was complete after 11 days. Purification by flash chromatography yielded a
white crystalline solid.

To evaluate the enantiomeric purity of the product, we planned to use 1H NMR
chiral lanthanide shift reagents.43 First, it was necessary to obtain a normal spectrum of
the product. Because chiral lanthanide shift reagents are effective only in non-complexing
NMR solvents, deuterated chloroform was employed, even though the product was only
sparingly soluble in chloroform at room temperature. Heating was required to accomplish
dissolution. Surprisingly, the resulting spectrum indicated the presence of two distinct
species, in a ratio of 3:1 (Figure 23).

We speculated that perhaps heating the sample in deuterated chloroform resulted in
the formation of the second species, and therefore decided to obtain a spectrum in
deuterated acetone, a solvent in which dissolution is easily achieved at room temperature.
The resulting spectrum indicated the presence of only a single species, supporting our
suspicion (Figure 24).

We were not convinced, however, since TLC of the sample prepared in deuterated
chloroform for NMR still revealed only a single product spot To determine if a solvent
effect was responsible for the disparity of the two spectra obtained, the solvent was
removed in vacuo from the deuterated chloroform sample, and the residue redissolved
deuterated acetone. The result was dramatic; only a single magnetic resonance signature
was present, identical to the spectrum obtained previously by direct dissolution in

deuterated acetone.

 

 

30

335.5 5:28: e «58 e 5.58% «22 E . mu 2:5

am: can m.mmu.«m.m o. h 0.5: “.mma o.mm h vvmd

_..LIJ 1.J .ltl-l—lg) 1P _.|II>I|J 1|._|:1.J Linn:
0 zan— « m m v m w n G
Ll. _Ir.:_ .-._LL1—LLL.L!_-.. LLL -_L.L,.rLL hirer. _LLI...rLLlFLLLL-_LLLL-:_L.FFLLLL1.1..-_.-r. _ . . . _ _ _ _ . . _ .L .-._-._.rLl.rLL.LLl

 

b
14 J

DIlll r

-411 l l l

 

 

 

 

 

 

 

31

335.5 .3323“ we «6.2.893. 5 523an E2 m: . an 95me

9:. «.«N oKN m.mm o www.mm m.o~«.wv m.mv 0.0V add
.LJ 1.. 1f 1r. 1ft. 1r} _LJ .IIJ 11]
c zaa « m m v m m n m m o“

__.__p...bL—...p....._..___.____p-_._.-_PP....—_..._.hL_—....—.._._p...—___.___.F_._.f_...._..-__...__.E..o

- <1

 

 

 

 

 

 

 

 

 

 

32
Proton NMR spectra were then obtained in deuterated chloroform in the presence of

the chiral shift reagent Resolve-AlTM [europium tris (6,6,7,7,8,8,8-heptafluoro-2,2-
dimethyl-3,5-octanedionate), Sievers's Reagent]. No additional signals were observed,
which would have indicated the presence of a third or fourth species -- the enantiomeric
partners of the original species. However, the reagent did effect the separation of several
overlapping signals, making the spectrum easier to interpret.

The mass spectrum gave a parent ion at m/e 256, identical with that of the Schiff
base precursor, suggesting only a rearrangement of atoms had occurred, as would be true
of the Pictet-Spengler product 773. In addition, the base peak at m/e 197 indicates the
presence of l-ethylcarbolinium cation, that could be generated from 773 by cleavage of the
bridged lactone and aromatization. All aspects of the 1H NMR spectrum obtained in
deuterated acetone were also consistent with 77a, key indicators being the loss of one
aromatic proton, relative to the Schiff base, and a new high field signal consistent with an
N-H proton. The spectra obtained in deuterated chloroform in the presence of Resolve-
A1TM allowed us to evaluate the identity of both components. The signals corresponding
to both the major and minor components were consistent with 77a, and we postulated that
the product consists of a 3:1 ratio of enantiomers 77a and 77b (Figure 25). The apparent
enantiomeric differentiation observed when the spectrum was taken in deuterated
chloroform was reasoned to arise from unusually strong solute-solute hydrogen bonding
interactions, resulting in an equilibrating series of dimeric complexes. Since these
interactions are diminished in the strongly complexing deuterated acetone, enantiomeric
differentiation is not observed. However, our initial literature search failed to reveal a

precedent for this behavior.

33

o C6H6. TsOH

 

N\ A

IZ

75

 

Figure 25 - Cyclization with Racemization

While we were disappointed that the product was partially racemized, we were
excited at the prospect of uncovering a new NMR phenomenon. To test our hypothesis, it
was necessary to achieve our original goal of synthesizing 77a in enantiomerically pure
form.

Racemization, via tautomerization of the Schiff base (Figure 13), is expected to be
hastened by heating and acid catalysis.23v31 A method that avoids both would be ideal.
Woodward's push-pull approach44 to the spiroindolenine 88, employed en route to
strychnine (Figure 26, eq. 1), fits these criteria. Electrophilic attack by tosyl chloride on
the imine nitrogen and deprotonation of the indolic N-H bond by pyridine resulted in
cyclization to give sulfonamide 88, a more stable product than the analogous indolenium
salt that failed to form when 87 was treated with acid. However, Woodward notes that
this reaction may be a special case, since the carbon-nitrogen double bond of the product is
conjugated with the veratryl group. This suspicion was supported by the observation45
that spiroindolenine 90 was not formed when 2-methylbenzylidene tryptamine (89) was
subjected to these conditions (Figure 26, eq. 2). However, the benzylidene derivative of

tryptamine reacted under these conditions to give the THBC 91 (Figure 26, eq. 3).

 

34

9')
SOZC7H7

room
tem p

 

   

CEO 7:.”

CH3 C’H
TsCl, pyr
89
CHO
N NH2 —>
H

78

 

Figure 26 - Woodward's Push-Pull Approach

35
Unfortunately, no useful results were attained by treating imine 75 under these

conditions. Substituting a stronger base, triethylamine in methylene chloride, gave no

reaction at room temperature (Figure 27).

Ts-Cl, pyr

||N\O X

N or
H Ts-Cl, Et3N,
75 CH2Cl2

Figure 27 - Treatment of Schiff Base 75 with TsCl

 

 

 

Further literature review revealed an alternative set of Pictet-Spengler reaction
conditions -- methylene chloride/trifluoroacetic acid —- in which THBC's are formed at
room temperature.25v46 In addition, these reaction conditions are reported to effectively
mitigate the racemization problem.23’47

This was our experience also. Schiff base 75 was treated according to the method
of Ottenheijm.45 As when treated in refluxing benzene/1‘ sOH, a single product spot was
evident by TLC, and a white crystalline product was isolated. However, the 1H NMR
spectrum obtained in deuterated chloroform indicated the presence of only one species,
consistent with 77a. The addition of Resolve AlTM gave no indication that the antipode of
77a was present. The spectrum in deuterated acetone was identical to that obtained earlier.
The product was also found to be optically active, ruling out the possibility that complete
racemization had occurred.

In order to confirm that the 1H NMR of the original sample was indeed exhibiting
enantiomeric differentiation, we repeated the synthetic sequence beginning with D-
tryptophan. The end product displayed a 1H NMR spectrum identical to that derived from
L-tryptophan, and an inverted optical rotation. A spectrum was then obtained for a 4:1

mixture of the D- and L—derived products in deuterated chloroform. Again, the presence of

36
two distinct species was indicated, establishing at once two important facts; the synthesis of

77a had been achieved enantiospecifically (Figure 28), and enantiomeric differentiation is

observed in the 1H NMR for non-racemic mixtures of the enantiomers.

 

 

Figure 28 - Stereospecific Cyclization

We soon learned that this unusual NMR phenomenon had been previously
observed, and while rare, had been thoroughly studied and well documented.48 Known as
self-induced nonequivalence, it is rationalized by considering the average environment of
each enantiomer generated through binary solute-solute associations (Figure 29). For
example, when the L-enantiomer is the predominant isomer, the D—forrn is associated
mainly as the heterochiral dimer (equation 2), and the L-form mainly as the homochiral
dimer (equation 3). Since each enantiomer exists in a different average environment,
different NMR signals are observed for each. If the association constants are weak, the
enantiomers exist mainly in their unassociated states and give identical NMR signals,
accounting for the rarity of self-induced nonequivalence. A strongly complexing solvent
will compete for binding sites, diminishing the association constant and resulting in the
appearance of only one NMR signal. This is what we observed when changing the NMR
solvent from deuterated chloroform to deuterated acetone. In the case of a racemic sample,
the average environment of each enantiomer is identical, resulting in one NMR signal,

although the chemical shifts may deviate from those of an optically pure sample.

37

 

 

 

 

 

1) D+D DD
2) D+L D-L
3) L+L L-L

 

Figure 29 - Binary Solute-Solute Associations of Enantiomers

A common trait of the small group of compounds reported to display self-induced
nonequivalence is the ability to form particularly strong hydrogen bonding interactions, and
in most cases a cyclic dimeric complex has been invoked to explain the tendency to
associate.48b We propose the bidentate, hydrogen bonded dimers 93 and 94, modeled in

Figure 30, to account for the NMR behavior of 77.

38

H
o o----H—N N
1 O
3
3
o 1 (1S,3R)
u N—H----o 0
(13,313)

Homochiral Dimer (L- L) 93

 

120

(1 S,3R)
Heterochiral Dimer (L- D) 94

Figure 30 - Proposed Dimeric Structures

39
The large number of protective groups available for the amino function provide

many options for variation of our strategy. The prospect of performing the deprotection
and Pictet-Spengler reaction in one step prompted us to investigate the use of the t-
butoxycarbonyl (Boc) protecting group, since a commonly used combination of reagents
for the cleavage of the Boc group is methylene chloride/trifluoroacetic acid, the same
reagents that we found to be effective in the stereospecific cyclization of 75 to 77a.
Na-(t-butoxycarbonyl)-L-tryptophan 95 was prepared from the amino acid and di-
t-butyl dicarbonate, according to the method of Keller et al.,49 or purchased directly from a
commercial supplier. The coupling of the Boc-protected amino acid and 1-hydroxy-2-
butanone was achieved by the reaction of the alcohol with the mixed para-toluenesulfonate

anhydride of the protected amino acid, providing acyl ester 96 in a 60% yield (Figure 31).

O O

 

1)TsCl,pyr
OH = O
0 . 2 o 0 . 61“
NHBoc ) NHBoc o
N N
H KUV H
95 96

OH

 

Figure 31 - One Step Deprotection/Cyclization

Our major concern in employing the Boc protecting group was that the indole ring
may be alkylated by the cations generated during deprotection, or undergo general oxidative

degradation, two types of side reactions often encountered in peptide synthesis.50 Cation

40
scavengers, usually thiols or thioethers, are commonly used to combat these problems.

Treatment of the N-Boc protected tethered ketone 96 with a 2% solution of trifluoroacetic
acid in methylene chloride, in the presence of one equivalent of dirnethyl sulfide, gave the
desired Pictet-Spengler product 773 in a yield of 60%.

Having successfully achieved the crucial stereospecific synthesis of bridged lactone
77a from both Boc- and Cbz-protected tryptophan, we turned our attention to the cleavage
of the tethering bond. We chose to effect this cleavage through ammonolysis, since the
generation of an amide functionality at C-3 sets the stage for the eventual removal of the
carboxyl carbon, if desired, through Yamada's procedure51 for the reductive decyanization

of (It-amino nitriles (Figure 32).

o
I I ”“2 3L8“- I I CN
N N“ 2) Pool3 N N3”
97 H CH3 98 H CH3
1)NaBH4
2) Pd/C, H2
I u I NH
99 CH3

Figure 32 - Yamada's Reductive Decyanization Sequence

NH2

   

77a 100

Figure 33 - Tether Cleavage via Ammonolysis

To this end, treatment of lactone 77 a with a cold, saturated solution of methanolic
ammonia proceeded smoothly, giving a quantitative yield of the hydroxy amide 100

(Figure 33).

Synthesis of a THBC Bearing an Asymmetric Tertiary Center at C-1

This synthesis requires the preparation of tethered aldehyde derivatives. We chose
to investigate the behavior of forrnylmethylester 101, which upon cyclization and cleavage
would give a THBC bearing a hydroxymethyl substitution at the newly created asymmetric
center (Figure 34), analogous to the proposed fragment 5 in our retrosynthetic analysis of
Ft 729 (see Figures 1 and 3). The direct coupling approach to aldehyde 101 was ruled out
due to the instability of glycolaldehyde52 and the expense of the corresponding acetals.

Our indirect approach utilizes allyl alcohol as an inexpensive, stable synthetic equivalent of

 

      

glycolaldehyde.
O 1. Deprotection o
2. Cyclization
I | O H 3. Tether Cleavage X
N NHCbz O .
H H H‘
101 102 0”

Figure 34 - Anticipated Behavior of Tethered Aldehyde 101

 

  

0304(cat.),
OH 1)TsCI pyr o/\/ K3Fe(CN)6’ e

 

 

N NHCbz 2) Hofim NHCbZ féfigfielaztgm
72 H 103
C) C)
In O/\I/\OH NalO4, H20: CI I O/\n/H
NHCbz OH acetone N NHCbz O
104 H 101

Figure 35 - Preparation of Tethered Aldehyde Precursor 101

Allyl ester 103 was formed in 87% yield by treating the mixed sulfonate anhydride
of the protected amino acid with ally alcohol. The next task was to effect the oxidative
cleavage of the olefin, while avoiding oxidation of the indole moiety. Ozonolysis was
ruled out since ozone has been reported to oxidize the 2,3-bond of indole derivatives.53
Likewise, periodate ion is known to oxidize the indole ring,54 making the application of
one-step methods55 that employ a catalytic amount of glycolating agent in the presence of
periodate seem unattractive. However, periodate has been used to selectively cleave pre-
formed 1,2-diols of compounds containing an indole function without oxidizing the indole
ring.12’56 Conversion of the olefin to the diol 104 was accomplished in a yield of 66%,
using a catalytic amount of osmium tetroxide, with potassium ferricyanide/potassium
carbonate as the cooxidant, a practice introduced by Minato et al. 57 and popularized by
Sharpless,58 as a feature of his asymmetric dihydroxylation procedure. Tertiary amines are
known to accelerate the catalysis. Therefore, 1,4-diazabicyclo[2.2.2]octane (DabcoTM)
was added to the reaction mixture.57 The dihydroxylation of the olefin results in the
creation of an additional chiral center. Proton NMR analysis revealed the preponderance of
one of the diastereomers in the purified product mixture. Since the new stereocenter is

removed in the next step, no attempt was made to separate the diastereomers. Treatment of

 

43
this isomeric mixture of diols with sodium metaperiodate, according to the method of van

Tarnelen,56~’1l gave the desired aldehyde 101 in a yield of 79%, along with 11% of
recovered starting material. Though the reaction seemed to progress smoothly, it
stubbornly resisted going to completion, even with the addition of more periodate.

With the tethered aldehyde 101 in hand, we were confident that deprotection and
cyclization could be easily accomplished using the methodology developed for the
preparation of 77. Contrary to our expectations, this objective was achieved only after
extensive study.

Treatment of 101 with hydrogen in the presence of 10% palladium on carbon, in
ethanol at 0 °C -- reaction conditions which successfully led to deprotection and imine
formation with tethered ketone 73 -- failed to remove the blocking group. Performing the
reaction at room temperature again led to the recovery of starring material, as did changing
the solvent to benzene. Likewise, changing the catalyst to palladium on calcium carbonate
also failed to effect hydrogenolysis. When the hydrogenation was attempted in the
presence of hydrochloric acid in methanol, a pink oil was obtained, an outcome associated
with the degradation of indole-containing molecules.5011

These surprising results caused us to re-evaluate the structural assignment of 101.
An area of concern in the proton NMR was that the resonance assigned to the aldehyde
proton at 8 9.35 ppm appeared as a sharp singlet, instead of the expected apparent triplet or
doublet of doublets resulting from coupling of the vicinal methylene group, which typically
ranges from 1 to 3 Hz.59 A spectrum was thus obtained on a high field (500 MHz)
instrument, but also failed to reveal any splitting of this resonance. If the coupling in this
case is unusually small, the resonance should still experience broadening which can be
determined by a decoupling experiment. When the vicinal methylene (5 4.6 ppm) was
irradiated, the line width at half height of the resonance at 5 9.35 ppm was reduced to 2.35

Hz from the original width of 2.67 Hz, supporting our structural assignment.

44
Some insight into the inability to effect this seemingly routine deprotection was

provided by Freifelder,6O who observed that hydrogenolysis may be retarded by the
presence of catalyst poisoning impurities in the substrate. Freifelder suggests pretreating
the unreactive substrate with Raney nickel (10 - 15% by weight) and/or activated carbon to
remove the impurities. Therefore, 101 was pretreated with Raney nickel and activated
charcoal and subjected to hydrogenation in the presence of 10% palladium on carbon in
ethanol at 0 °C (Figure 36). After 4 hours TLC showed that most of the starting material
was still present The reaction was then allowed to proceed at room temperature, and after
an additional 13 hours the reaction was halted, as only a small amount of starting material
was evident by TLC. Unfortunately, the main reaction product isolated was tryptophan
(60% yield), resulting from cleavage of the acyl ester linkage as well as the protecting
group. None of the expected cyclic imine 107 was isolated; however, we were able to
isolate a small amount of the hydrogenated product 108 (10% yield). These results raised
serious concern that standard hydrogenolysis of 101 to yield 107 was not a viable option,
since undesired hydrogenolysis of the acyl ester linkage of tethered aldehyde 101 appeared
to be much more facile than in the previously discussed case of tethered ketone 73, and
because the cyclic imine was susceptible to hydrogenation of the carbon nitrogen double
bond, with the possibility that any imine which escaped hydrogenation decomposed upon

workup and isolation.

45

 

o o
I I 0” ”2 I I 0”
NHCbz N NH,
H 72 76 H
H
H2 0 12 O
H H
o
I I O ._> | | /\H/
NHCbz o H, N NH2 0
H 101 H 105
0
W0“?
HN
N
H H H
108 107

Figure 36 - Catalytic Hydrogenation of Pretreated 101

Thus, an alternative route was devised to avoid these pitfalls (Figure 37). By
converting the aldehyde 103 to its corresponding acetal, the linkage should become stable
to hydrogenolysis. In addition, we suspected that the catalyst poisoning problem would be
eliminated with removal of the aldehyde function, since the only difference between the
successfully deprotected ketone 73 and problematic aldehyde 101 is the nature of the
tethered carbonyl. The relative difficulty experienced in purifying 101 bolstered this
suspicion. Deprotected acetal could then be subjected to Pictet-Spengler cyclization. The

successful use of acetals as aldehyde equivalents in this reaction is well documented.61

46

  

 

   

O
l H OR
3' I C’/\n’ _. ONOR
NHCbz o NHCbz H
N N
H 101 H 199 Ft=Me
110 R=Et
OR
OR >
H
111 R=Me
112R=Et

Figure 37 - Alternative Route via Acetal

Aldehyde 101 was converted to its methyl acetal 109 by treatment with trimethyl
orthoforrnate and catalytic p—toluenesulfonic acid in methanol in a yield of 76%. The
hydrogenolysis of the carbobenzoxy protecting group then proceeded smoothly to give
111 (H2, Pd/C, EtOH, 97% yield).

The deprotected acetal was then treated with trifluoroacetic acid (1.3 eq) in
methylene chloride at room temperature, but only starting material was recovered after 3
days. Increasing the amount of trifluoroacetic acid (13.7 eq) also gave no reaction (Figure

38).

O M e
TFA, H Cl ,
OM e C 2 2: No Reaction

H

 

1 1 1
Figure 38 - Treatment of Methyl Acetal 111 with TFA

This was surprising, since similar reactions have proven successful.61 In addition, since

the formation of acetals from simple alcohols is known to be a reversible process with the

 

47
equilibrium constant favoring the aldehyde,62 we felt that switching the nucleophile from

water to an intramolecular amino group on a flexible tether would create an even more
favorable equilibrium for the in situ formation of the imine. This led us to speculate that
perhaps the activation energy for the formation of the oxonium ion intermediate 114 was
prohibitive in the trifluoroacetic acid/methylene chloride medium. Furthermore, because
the same oxonium intermediate was involved in the formation of the acetal, it must be

stabilized sufficiently under the conditions of formation.

 

G)
OMe OMe
o o
I I NH H9 I I NH “If
N 2 N 2
H 114 H

Figure 39 - Oxonium Ion Intermediate

The ability of methanol to solvate cations was reasoned to account for this divergent
behavior. Thus, we decided to attempt cyclization of 111 under conditions similar to those
used in the acetal formation -- refluxing methanol and catalytic p—toluenesulfonic acid
(0.026 eq). A reaction ensued, but the only product recovered was tryptophan methyl
ester. When the reaction was run at room temperature with trifluoroacetic acid (2.0 eq),
mainly starting material was recovered along with a small amount of tryptophan methyl
ester. Reasoning that a non-nucleophilic but polar solvent would stabilize the oxonium ion
but not result in trans-esterification, we switched the solvent to acetonitrile. After 30 hours
no reaction was observed, so 5 A molecular sieves were added to trap any methanol that
might reform the acetal, but this had no effect. Heating the mixture to reflux also failed to
produce a reaction. Valls et al.6121 successfully promoted the conversion of 115 to 116
using p-toluenesulfonic acid in benzene at room temperature (Figure 40), but these

conditions returned only starting material in our case.

48

 

   

   
 

N N
H H H
N
116a
N N o +
H H CGHS
Eto7/\N
EtO N O
o N
115 H H H

“Sb
0

Figure 40 - Intramolecular Cyclization by Valls et al.

The in situ hydrolysis of diethyl acetals to aldehydes was employed by van
Maarseveen et (11.63 to effect Pictet-Spengler cyclization, leading to the Eudistomin
framework (Figure 41). The application of these conditions to 111 was also unsuccessful.
These workers pointed out that the diethyl acetals are much easier to hydrolyze than the
corresponding dimethyl acetals. Therefore, we synthesized the corresponding diethyl
acetal 112 in the same manner as described for methyl acetal 111. Again, however,
treatment with chloroform/trifluoroacetic acid/water mixture was unsuccessful, yielding a
complex mixture of products. When treated with trichloroacetic acid (1.0 eq) in methylene
chloride the diethyl acetal 112 behaved no differently than the methyl acetal 111, giving no

reaction even after 2 weeks at room temperature.

 

TFA/H20
I I N
N \O CHCI3
H )
(EtO)ZCH s

 

117 R H 118a 118b

Figure 41 - van Maarseveen's In Situ Hydrolysis Method

The failure to achieve the Pictet-Spengler condensation of acetals 111 and 112
under conditions known to be effective suggests that a structural feature unique to these
species is responsible for this anomalous behavior. The electron-withdrawing ability of the
ester function results in a partial positive charge on the carbon at to the acetal, destabilizing
alkoxonium ion 114 relative to those generated from ordinary acetals, which could account
for the lack of reactivity. The field of carbohydrate chemistry provides numerous examples
of acetal reactivity being reduced by the inductive effect of nearby heteroatoms.64
Silverman and Ding65 have shown that even when the electron-withdrawing group is three
bonds removed from an acetal center, the rate of hydrolysis is significantly reduced. Most
pertinent to our study was their finding that the relative rate of hydrolysis for 'y-lactone

acetal 120 was only 1.3 x 10‘4 that of the saturated analog 119 (Figure 42).

50

OEt OEt
E OEt
o o W O
o
o
"9 krel=1-O 120 k,,.,,=1.3x10'4
OEt
OEt /\I/‘\0Et
MeO-.—N MeO—.—N)r
o
121 k,e,=6x1o'3 122 k,a,= 4.2 x10'6

Figure 42 - Effect of Electron-Withdrawing Groups on Acetal Hydrolysis

Finding the acetal route to be unworkable, we focused our attention once again on
finding a suitable means for the deprotection of aldehyde 101, and chose to investigate
catalytic transfer hydrogenation66 for this purpose. Compared with reduction systems
using a catalyst and molecular hydrogen, catalytic transfer hydrogenation offers an
additional variable -- the hydrogen donor -- which may affect the rate and specificity of the
reduction, both of which were problematic when molecular hydrogen was employed in the
attempted deprotection of 101.

Early indications regarding the use of formic acid as the hydrogen donor67 were
encouraging. The N-Cbz protected amino aldehyde 101 was treated with 4.4% formic
acid in methanol in the presence of 10% Pd/C at room temperature. 'Ihin layer
chromatography revealed that all starting material was consumed after only five minutes,
with the appearance of a single product spot. However, this product could not be,isolated.
Filtration gave a clear, colorless solution, but removal of the volatile materials in vacuo
gave a yellow resinous material. TLC analysis revealed that the original product was no

longer present, with the sample clinging to the baseline. For comparison, tethered ketone

 

51
73 was treated under these conditions, giving imine 75 in good yield, the same product

obtained previously with molecular hydrogen.

0 formic acid,

 

NCbz o Pd/C, MeOH Nx

I2
I2

73 75

Figure 43 - Hydrogenolysis of 73 with Formic Acid as Hydrogen Donor

We suspect that hydrogenolysis of the carbobenzoxy group of 10] led to the rapid
formation of imine 107, in line with the behavior of tethered ketone 73 upon amino
deprotection (Figure 44). Decomposition of the Schiff base is believed to have
subsequently occurred upon isolation, giving the yellow tar. A review of the literature
revealed that the stability of imines varies greatly with their structure.39 Those formed

from primary aldehydes are prone to polymerization through an aldol-like process, and are

extremely difficult to isolate.

O

H formic acid,

 

o
I N I NHCbz O Pd/C, MeOH
H 101

 

concentration

polymer tar ,

Figure 44 - Possible Outcome of Formic Acid Hydrogenolysis of 101

To circumvent the polymerization problem, the two-step reaction was attempted

without isolation of the Schiff base intermediate, even though this meant sacrificing the

52
preferred cyclization solvent (methylene chloride), for one with dramatically different

properties (methanol). During the deprotection stage the reaction vessel was immersed in
an ice bath to further reduce polymerization. After the starting material had been consumed
the trifluoroacetic acid catalyst (11.4 eq) was added and the reaction allowed to continue at
room temperature.

The product isolated from this reaction exhibits spectral properties that are
inconsistent with the expected tetracyclic bridged lactone 113. An additional signal is
present in the 13C NMR spectrum. The proton NMR spectrum (DMSO) displays a three-
hydrogen singlet (8 3.72 ppm) and a one-hydrogen triplet (8 5.00 ppm), which are clearly
incompatible with structure 113. The one—hydrogen triplet coalesces over time with
residual water to give a broad singlet along with the concomitant simplification of one-
hydrogen multiplets centered at 8 3.65 and 8 3.75, to the less complex doublet of doublets
splitting pattern, suggesting it is an exchangeable hydrogen adjacent to an AB methylene
group. This data along with a parent ion at m/z 260 in the mass spectrum strongly suggests
that methanolysis of the tethering bond has occurred to give 123 (Figure 45). The first
order coupling relationships, as determined by a lH COSY NMR experiment, are

consistent with this structure.

0
H
i l OCH3
NH
N
H H
OH
123

Figure 45 - Methanolysis Product

53
While the crude yields of this product were quite good (66 — 98%), the purified yield after

chromatography on silica gel was a disappointing 29%, lower than expected based on an
examination of the crude proton NMR spectra. This raises the possibility that 123 may be
susceptible to decomposition on silica gel.

The timing of the tethering bond cleavage is crucial to the stereochemical outcome
of the reaction. Only if the cleavage occurs after the Pictet—Spengler cyclization will
conformational restriction be maintained, and the product will be the cis-1,3-disubstituted
THBC (Figure 46). If cleavage occurs before cyclization this element of stereocontrol is
lost and either diastereomer can form, with a mixture being expected, based on the

numerous reports of the reaction of tryptophan esters with aldehydeszzcv23

54
O O

H HCOOH H
'n O/\li/ —> In 0%
NHCbz 0 WC NH2 105 o

101

o
OCHa CH30H

N TFA
path a

 
   

H H“

 

OH

123b 123a
Figure 46 - Possible Pathways for the Formation of 123

55
Only one product was isolated by column chromatography. Precedent indicated

that the stereochemistry of this product could be determined by nuclear Overhauser effect
(NOE) difference spectroscopy. This technique was employed by Nicolaou68 to determine
similar stereochemical relationships in the structures of compounds 125 and 126.
Irradiation of the C-4 methyl signal of compound 125 caused a 30 % NOE enhancement of
the C—10 proton signal, confirming their syn relationship. Likewise, an NOE enhancement
of 14% was invoked to assign the syn relationship between Ha and Hb of compound 126,
which was later confirmed by the X-ray crystal structure of a derivative of compound 126.
NOE techniques were also used by Cook69 to determine the stereochemistry of the six-

membered nitrogen heterocycles 127, 128, and 129.

30%(‘M e,
L4 o

 

Figure 47 - Pertinent NOE Enhancement Precedents

56
Application of the N OE experiment to product 123 revealed that it was the cis

isomer (Figure 48). Irradiation of C-1 proton resulted in an 8.7% enhancement of the C-3
proton signal, which was revealed as a clean doublet of doublets in the difference
spectrum, after subtraction of the overlapping methyl ester singlet in the normal spectrum.
Likewise, irradiation of the C-3 proton resulted in a 1.9% enhancement of the C-1 proton
signal, and no enhancement of the C-1 methylene signals. Irradiation of the C-1 methylene

signals gave no enhancement of the C-3 proton signal.

8.7%

 

Figure 48 - NOE for 123

The isolation of only the cis diastereomer agrees with expectations for a scenario in
which methanolysis occurs after formation of the tetracyclic bridged lactone 113. The
relief of ring strain in the bridged lactone framework is believed to be the driving force for
the methanolysis. It is possible, however, that methanolysis occurred before the Pictet-
Spengler reaction and still gave stereospecific formation of the cis isomer for reasons
peculiar to this substrate, or that small amounts of the trans isomer were formed but not
isolated. There is also the question of whether 123 is susceptible to epirnerization at C-1
under the reaction conditions employed (methanol, formic acid, Pd-C, trifluoroacetic acid,
room temperature, 4 days). As described in the introduction, the mechanism of ,
epirnerization has been determined to involve protonation of the Nb nitrogen, followed by
cleavage of the C- l/Nb bond to give a resonance stabilized cationic intermediate, followed
by reformation of this bond. 'Such epirnerizations have been carried out on 1,3-

disubstituted THBC’s in refluxing methanolic hydrogen chloride.23 We are unaware of

 

57
any reported epirnerizations that have been carried out at room temperature in methanol.

Also, it is likely that 123 is more resistant to epirnerization than C-l alkyl substituted

THBC’s, because the cationic intermediate species 130 is destabilized by the inductive

effect of the hydroxyl function.

 

130 5-

Figure 49 - Destabilizing Effect of Hydroxyl on Epimerization Intermediate

Separate from the epirnerization concern, is the question of racemization (Figure
13). The solubility of 123a in only polar, complexing solvents precluded the use of NMR
chiral shift reagents for the determination of enantiomeric purity. However, a strong optical

rotation ([00]) = -118°, MeOH, c = 0.1 1 g/ 100 mL) indicates the maintenance of at least a

degree of enantiomeric integrity.

Studies Employing Tyrosine as the B-arylethylamine Component

The formation of THIQ’s through the Pictet-Spengler reaction usually requires an
electron-rich benzene ring, or more specifically the presence of an electron-donating group
para to the point of ring closure.22 Despite this, we decided to test L-tyrosine as the 8
arylethylamine component in an attempt to demonstrate our temporary tethering strategy
could also be applied to the synthesis of the THIQ ring system. We wondered if the small
activating effect of the hydroxyl substituent of L-tyrosine, although meta to the point of
ring closure, in combination with the increased electrophilicity of the tethered imine
intermediate, would be sufficient to prompt the reaction. The alternative, ring activation
through placement of an electron-donating group in the 3-position of L-tyrosine, would

require a multi-step sequence. Therefore, the risk was deemed worth taking.

 

58
The coupling of N-Cbz-L-tyrosine and l-hydroxy-Z-butanone was accomplished

through a variation of Holmberg and Hansen's procedure” using DCC in pyridine in the
presence of catalytic p-toluenesulfonic acid. Excess alcohol used was increased to 4.4
equivalents to help reduce the formation of by-product 133, which results through the
competitive esterification by the phenolic hydroxyl of tyrosine. The tethered ketone 132

was obtained in 67% yield, along with a 15% yield of 133.

 

O
O 0“
NHCbz
“0 131
DCC, TsOH, pyr.
(CIL/
v OH
O
NHCbz o 67%
H0
132
+ O

O 0%

NHCbz 015%
O 0
HO NHCbz

133
Figure 50 - Esterification of N-Cbz-L-Tyrosine

l

The cyclic Schiff base 136 was obtained in only 16% yield on hydrogenation of 132
(Figure 51). The reaction was complicated by competing hydrogenolysis of the acyl ester

bond, as well as hydrogenation of the carbon-nitrogen double bond, which made

 

59
purification difficult. Unfortunately, treatment of 134 with trifluoroacetic acid in

methylene chloride failed to induce Pictet-Spengler cyclization.

 

O 0
H2, Pd/C, EtOH
O O
HO NHCbz 0 3A sieves, 0°C HO N\
133 1 34
TFA

methylene chloride

No Reaction

Figure 51 - Formation and Treatment of Schiff Base 134

Attempted Deamination of Tetracycle 77a

Amines are known to be very poor leaving groups. A high degree of activation is
required to convert them into suitable substrates for substitution or elimination reactions.7O
While N,N-diarylsulfonimides are commonly employed substrates, N-arylsulfonamides
only rarely give carbon-nitrogen cleavage. This is in sharp contrast to the behavior of

alcohols, whose sulfonates are routinely employed as leaving groups (Table 2).

Table 2 - Leaving Group Comparisons

substrate structure substrate classification

 

60
The ease with which deamination occurs is also dependent upon the nature of the

alkyl appendage of the amine.71 For example, N-2-(phenylethyl)-p—toluenesulfonamide
has been pyrolyzed with KOH to give good yields of styrene (Figure 52, eq. 1), and
Mannich bases are known to undergo reverse Michael addition reactions (Figure 52, eq. 2).

The driving force for these reactions is believed to be the formation of conjugated products.

KOH \
1
) mHTs A 0A so -70%
135 136

 

 

o o

NaOH
2) R/U\/\NR2 RM + RZNH
137 or?“ 138 139

Figure 52 - Deaminations Driven by Activation of the Alkyl Appendage

Structural features unique to the tetracyclic Pictet-Spengler product 77a prompted
us to speculate that it might be induced to eliminate the previously tosylated bridging
nitrogen (Figure 53). The new double bond would be conjugated with the indole ring, as
well as the lactone carbonyl. The relief of ring strain in the bicyclic framework of 92
would provide an additional driving force.

Several reaction pathways exist for anionic intermediate 140, all leading to
interesting and highly functionalized products. Simple protonation would give the eight
membered macrocycle 141. Alternatively, addition of the nitrogen at the carbonyl,
followed by elimination of oxygen would give a similar eight membered macrocycle 142,
while the Michael addition pathway would yield the rearranged tetracycles 143a and
1 43b.

61

 

 

  

O
l IHNTs o
N ,.
H s
l 141
BH+
50 0
IN I NTs
j base
92 \
1,2 addition 1, 4 addition
N
143b H I

Figure 53 - Possible Deamination Pathways for 92

 

62
Computer based molecular modeling (Spartan® version 3.1, AMl, semiempirical

geometry optimization, Silicon Graphics® workstation) was carried out to determine if 92
meets the stereoelectronic requirements for E2 elimination. The dihedral angle between the
departing nitrogen and proton Hi3 was calculated to be 167°, close enough to the ideal trans
periplanar arrangement to ensure that there would be sufficient orbital overlap of the
developing p-orbitals of the new pi bond.

We felt that a non-nucleophilic, yet strong base should be used, to prevent attack of
the strained bridged lactone. These properties have made l,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) a popular choice for elirninations involving sensitive molecules.72 Thus, we
decided to employ it here.

The treatment of 773 with p-toluenesulfonyl chloride in pyridine gave p-
toluenesulfonamide 92 in a yield of 93%. When the tosylate was treated with DBU (55
eq.) in tetrahydrofuran at reflux, product 145 was isolated in a yield of 69% (Figure 54).
The formation of 145 results from nucleophilic attack by DBU at the lactone carbonyl to
give betaine 144, which is hydrolyzed to 145 on aqueous workup. Reducing the amount
of DBU (5.5 eq) gave the same product in lower yield. Key spectral evidence to support
this assignment is the presence of two irnide carbonyl bands in the IR spectrum (1646,
1622 cm'l), and in the mass spectrum a parent molecular ion peak at 580 m/z, which
indicates that the product is an adduct of the tosylate, DBU and water. No elimination

products were isolated.

 

 

 

 

A O

N N\
H

6' NJ NTs |\/l

H '8. OH
145
Figure 54 - Reaction of N-Tosylate 92 with DBU

Additional molecular modeling suggests that the rigid framework of 92 limits the
degree of activation toward elimination that can be gained from conjugation of the departing
groups with the indole ring or the carbonyl. In the most stable conformation of the starting
material, the dihedral angle of Hp with the indole ring was calculated to be 132° (optimum
orbital overlap occurs at 90° or 270°), suggesting that only moderate orbital overlap exists
between the ring pi system and the breaking carbon/hydrogen bond. Also, the dihedral
angle of the departing nitrogen with the carbonyl bond was calculated to be 158° (optimum
orbital overlap occurs at 90° or 270°), suggesting that very little orbital overlap exists
between the breaking nitrogen-carbon bond and the carbonyl pi bond. Furthermore,
molecular modeling performed on elimination product 141 suggests that a geometry in
which the extended pi system maintains perfect orbital overlap would result in a
significantly strained eight membered ring, since in the optimized structure, conjugation of

the extended pi system is significantly compromised. (Double bond/indole ring dihedral

64
angle = 27°. Double bond/carbonyl dihedral angle = 144°. Optimum orbital overlap occurs

at 0° or 180°.)

While we were never certain that deamination of 92 would occur, we were
surprised to find that nucleophilic attack of the lactone by DBU had occurred. Though
renowned for its non-nucleOphilic nature, a review of the literature revealed several other
examples where DBU behaves as a nucleophile.72b The reactions illustrated in Figure 55

demonstrate that both the betaine (eq. 2) or the hydrolyzed product (eq. 1) can be isolated.

PhCOON

PhCOON
Br
I
”am-3U (ow we'd) NH

74%

148ph
Figure 55 - Examples of Nucleophilic Behavior of DBU

The apparent hyper-sensitivity of 92 to nucleophilic cleavage of the lactone moiety,
as well as the failure to isolate any elimination products in the reaction with DBU,
caused us to halt our deamination efforts. However, we did gain some insight into the
stability of the bridged, tetracyclic ring system generated in these intramolecular Pictet-
Spengler reactions. It appears that there is sufficient ring strain present to make the
cleavage of the lactone unusually facile. This has implications for the case involving the
formation of 123, which was discussed earlier (Figure 46). Whether methanolysis occurs

before or after the Pictet-Spengler reaction is central to the maintenance of reaction

65
stereocontrol. That the lactone is so susceptible to nucleophilic cleavage agrees with the

scenario in which methanolysis occurs after the Pictet-Spengler reaction, and that strain in

the newly formed framework drives the cleavage.

CONCLUSION

We have demonstrated that our temporary tethering strategy for stereocontrol in the
Pictet-Spengler reaction can be employed to effect the stereospecific conversion of
tryptophan into THBC's bearing a new asymmetric center at the C-1 position. The
exclusive formation of 1,3-cis disubstituted THBC 123a from tethered aldehyde 103 is
significant in that the configuration of the C-1 stereocenter matches that of most alkaloids
containing this substructure. This also compliments the asymmetric Pictet-Spengler
technology of Cook et al., which gives 100% trans diastereoselectivity.

In addition to providing stereocontrol, tethering of the reaction components renders
them more reactive. This makes it possible to perform asymmetric Pictet-Spengler
reactions in which the carbonyl component is a ketone, resulting in the formation of an
asymmetric quaternary center at the crucial C-1 of a THBC. Specifically, we achieved the
transformation of N-protected tethered ketones 75 (Cbz protecting group) and 96 (Boc
protecting group) to the bridged tetracyclic lactone 77a, which gave the 1,1,3-tn'substituted
THBC 102 upon ammonolysis.

We were unable to apply our temporary tethering strategy to the asymmetric
synthesis of THIQ’s from L-tyrosine, as imine 134 failed to cyclize. However, it is likely
that success in this area could be achieved if the benzene ring were to bear an electron-
donating group at the 3-position.

Notable among the many difficulties encountered in this study was the susceptibility
of the acyl ester tethering linkage toward hydrogenolysis during removal of the N-Cbz

protecting group. This was especially troublesome in the case of tethered aldehyde 103.

66

67
For this reason, tethered aldehydes may be better suited for the one step

deprotection/cyclization route, in which a Boc protecting group is employed.

Interesting variations of this strategy may result from the use of different protecting
groups and more complex carbonyl components. Also worthy of future investigation is the
elaboration of the functionalized appendages at the C-1 and C-3 positions to provide more

complex alkaloids.

ADDENDUM

After the completion of this writing, we learned that Corey and coworkers had
employed a strategy similar to our own as a key part of their recently reported
enantioselective total synthesis of ecteinasicidin 743 (152, Figure 56).73 They
accomplished the conversion of acetal 150 to its corresponding aldehyde using BF3-Et20
and H20 (10 equivalents of each) in methylene chloride at 0 °C. Treatment of the aldehyde
with BF3-Et20 and 4A molecular sieves in methylene chloride at 23 °C gave the bridged
lactone 151 in 73% yield from the acetal. It is interesting to note that in their hands the
intramolecular Pictet-Spengler reaction was carried out with the N—carbobenzoxy protecting

group still in place.

68

69

OBn O
H3C OCH3

0 OCH3
NHCbz H

 

150
151 R = Cbz

 

152 Ecteinascidin 743

Figure 56 - Corey's Synthesis of Et 743

EXPERIMENTAL

General Methods

All reactions sensitive to moisture or oxygen were performed in oven dried
glassware under an atmosphere of argon or nitrogen. Reagents were used as received from
commercial suppliers unless otherwise specified. Solvents were purified by distillation
from the appropriate drying reagents. Small scale reactions were stirred magnetically, and
large scale reactions were agitated with paddle stirrers. Reaction progress was monitored
by thin layer chromatography, with visualization by ultraviolet fluorescence, alkaline
aqueous potassium permanganate, or ammonium molybdate in 10% aqueous sulfuric acid
with subsequent heating. Concentration of solutions after workup was conducted on a
Buchi rotary evaporator. Flash chromatography was performed using Merck Silica Gel 60
(230-400 mesh, ASTM), according to the method of Still.74

Melting points were determined on a Thomas-Hoover capillary melting point
apparatus or on a Reiterate hot-stage microscope and are uncorrected. Optical rotations
were measured on a Perkin-Elmer 141 polarimeter. Infrared (IR) spectra were recorded on
a Nicolet PC/IR Fourier transform spectrometer, equipped with a Nicolet IR/42 optical
bench. NMR spectra were obtained on Varian Gemini 300 (300 MHz), VXR-300 (300
MHz), or VXR-500 (500 MHz) spectrometers. Chemical shifts for proton signals are
reported in parts per million (8) relative to residual solvent, or to tetramethylsilane (TMS)
as an internal standard. Signal splitting patterns are indicated as follows: 3 = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet. Coupling constants are reported in Hertz.
13C NMR data are reported as chemical shift in parts per million (5) relative to residual
solvent, or to TMS as an internal standard. Mass spectra (MS) were obtained by electron

ionization (E1) on a TRIO-1 GC/MS mass spectrometer, or by fast atom bombardment

70

7 1
(FAB) on a JEOL-HX-l 10 double focusing mass spectrometer operating in the positive ion

mode. High resolution mass measurements (HRMS) were carried out by E1 on a JEOL—

AX-505H double-focusing mass spectrometer, or by FAB as noted above.

Preparation of N -Cbz Protected Ester 73

To a solution of N—carbobenzyloxy-L-tryptophan (2.00 g, 5.91 mmol) in freshly
distilled pyridine (19 mL) was added p-toluenesulfonyl chloride (2.25 g, 11.8 mmol) under
an argon atmosphere at room temperature. This solution was cooled to 0 °C and 1-
hydroxy-2-butanone (0.547 g @ 95%, 6.21 mmol) was added dropwise via syringe over a
period of 10 minutes. Stirring was continued on ice for 1.5 hr at which time the contents
were poured into 90 mL of ice water. The mixture was extracted with ethyl acetate,
washed with 1N HCl until the washings were acidic, then with saturated sodium
bicarbonate solution, and dried over anhydrous sodium sulfate. The solvent was removed
in vacuo and the residue purified by column chromatography to give ester 73 as an oil
(2.04 g, 85%). The oil was crystallized from ethanol/petroleum ether to give a white solid:
mp 101-102 °C; [00211) _—.. -l7° (c = 0.28 g/ 100 mL in methanol); IR (KBr disk) 3422,
3380, 3034, 2986, 2940, 1740, 1705 (w/ shoulder), 1524, 1217 cm'l; 1H NMR (300
MHz, CDC13) 5 1.03 (3H, t, J = 7.3 Hz), 2.31 (2H, q, J = 7.3 Hz), 3.31 (1H, dd, J =
6.0, 14.8 Hz), 3.42 (1H, dd, J = 5.5, 14.8 Hz), 4.55 (1H, d, J = 16.6 Hz), 4.68 (1H, d,
J = 16.6 Hz), 4.8 (1H, m), 5.0-5.1 (2H, m), 5.38 (1H, d, J = 8.0 Hz), 7.0—7.6 (10 H,
m), 8.33 (1H, 3) ppm; 13C NMR (75 MHz, CDC13) 5 7.0, 27.7, 31.9, 54.5, 66.9, 68.1,
109.4, 111.3, 118.3, 119.5, 122.0, 123.4, 127.5, 128.0, 128.1, 128.4, 136.1, 155.8,
171.5, 204.1 ppm; MS (70 eV) m/z (relative intensity) 408 (M+, 1.7), 130 (100), 91 (35),
77 (6.4) ppm; HRMS (EI) calcd. for C23H24N205 m/z 408.1685, found m/z 408.1686.

 

72
Preparation of Imine 75

To a 0 °C solution of N-protected ester 73 (0.169 g, 0.414 mmol) in 24 mL of
absolute ethanol was added 0.031 g of 10% Pd/C. The solvent was degassed by alternate
evacuation (aspirator) and purging with hydrogen via a gas buret hydrogenator. This was
repeated three times. Hydrogenation was commenced by vigorous magnetic stirring. After
4 h the reaction mixture was filtered through celite and the solvent removed in vacuo. The
oil obtained was then passed through a 2 inch column of flash grade silica, eluting with
hexane/ethyl acetate (3/7). Removal of the solvent left 0.98 g (92%) of pure imine 75,
which crystallized on standing. Recrystallization from methanol gave white elongated
platelets: mp 149-150 °C. [00231) = -19° (c = 2.6 g/ 100 mL in methanol); IR (KBr disk)
3426, 3177, 2932, 1744, 1696, 1451, 1244, 745 cm'l; 1H NMR (300 MHz, CDC13) 8
1.0 (3H, t, J = 7.4 Hz), 1.8-2.1 (2H, m), 3.4-3.6 (3H, m), 4.3 (1H, dd, J = 2.0, 16.5
Hz,), 4.7 (m, 1H), 7.0 (m, 1H), 7.1(2H, m) 7.3 (1H, d, J = 8.1 Hz,), 7.6 (1H, d, J =
8.2 Hz,), 8.3 (1H, broad s) ppm; 13C NMR (75 MHz, CDC13) 5 9.2, 28.5, 28.9, 60.5,
68.6, 110.4, 111.0, 119.4, 119.5, 122.1, 123.5, 127.6, 135.8, 167.4, 169.7; MS (70
eV) m/z (relative intensity) 256 (M+, 91), 169 (7.6), 143 9 (8.6), 142 (8.6), 131 (60), 130
(100), 115 (53), 103 (60), 77 (67) ppm; HRMS (EI)ca1cd. for C15H15N202 m/z
256.1212, found m/z 256.1187.

Pictet-Spengler Cyclization of Imine 75

To a stirred solution of the imine 75 (0.542 g, 2.11 mmol) and methylene chloride
(57 mL) at room temperature under an argon atmosphere was added trifluoroacetic acid
(0.284 g, 2.49 mmol) over a period of 5 minutes. As the reaction progressed an oily
precipitate formed. After 18 hours the solvent was removed in vacuo. The residue was
dissolved in ethyl acetate, washed with water, then with saturated sodium bicarbonate
solution, and dried over anhydrous magnesium sulfate. Concentration of this solution in
vacuo induced crystallization. The crystals were filtered and washed with cold ether to

yield 778 ( 0.374 g). Second and third crops were taken to yield an additional 0.074 g.

73
(Total mass 0.448 g, 83%): mp 224-225 °C; [00241) = -55° (c = 0.20 g/100 mL in
acetone); IR (KBr disk) 3285, 3195, 2986, 2936, 1721, 1449, 1179, 752 cm]; 1H NMR
(300 MHz, acetone-d5) 5 0.90 (3H, t, J = 7.4 Hz), 1.73 ( 1H, overlapping dq, J = 7.3,
14.1 Hz), 2.19 (1H, overlapping dq, J = 7.4, 14.0 Hz), 2.84 (1H, broad s), 2.92 (1H,
dd, J = 1.5, 15.3 Hz), 3.10 (1H, dd, J = 5.6, 15.4 Hz), 4.18 (1H, dd, J = 1.6, 5.6 Hz),
4.30 (1H, d, J = 10.5 Hz), 4.45 (1H, d, J = 10.2 Hz), 7.0-7.1 (2H, m), 7.32 (1H, m),
7.44 (1H, m), 10.10 (1H, broad 3) ppm; 1H NMR (300 MHz, CDC13) 8 0.90 (3H, t, J =
7.5 Hz), 1.73 (1H, overlapping dq, J = 7.3, 14.4 Hz), 1.88 (1H, broad s), 1.94 (1H,
overlapping dq, J = 7.3, 14.4 Hz), 3.10 (2H, d, 3.6 Hz), 4.23 (1H, d, J = 10.5 Hz), 4.33
(1H, overlapping dd, J = 3.6, 3.6 Hz), 4.42 (1H, d, J = 10.5 Hz), 7.1-7.2 (2H, m), 7.32
(1H, m), 7.44 (1H, m), 7.90 (1H, broad 8) ppm; 13c NMR (75 MHz, acetone-d5) 8 7.5,
27.3, 28.5, 52.6, 54.6, 79.5, 110.5, 112.0, 118.6, 119.8, 122.4, 127.9, 134.8, 137.4,
171.7 ppm; MS (70 eV) m/z (relative intensity) 256 (M+, 22), 197 (100), 182 (12), 168
(4.7), 154 (6.3), 99 (6.0), 91 (12), 77 (4.6) ppm; HRMS (E1) calcd. for C15H16N202 m/z
256.1212, found m/z 256.1194

Preparation of N -Boc Protected Ester 96

In a dry, 100 mL round bottom flask under argon, N—(tert-butoxycarbonyl)-L-
tryptophan (3.90 g, 12.8 mmol) was dissolved in pyridine (41 mL). To this solution was
added p—toluenesulfonyl chloride (4.89 g, 25.6 mmol), which caused the solution to turn a
bright yellow color. The flask was placed in an ice bath and 1-hydroxy-2-butanone
(Aldrich 95%, 1.18 g, 13.4 mmol) was added via syringe over a period of 45 minutes.
After stirring for 9 hours the contents were poured into 150 mL of ice water and extracted
with ethyl acetate. The organic extract was washed with water, then with saturated sodium
bicarbonate solution, and dried with anhydrous sodium sulfate. The solvent was removed
in vacuo to give an oily residue contaminated with a small quantity of precipitated material
which was insoluble in ethyl acetate. The residue was filtered through a plug of silica,

eluting with ethyl acetate, and the solvent removed in vacuo to give ester 96 (2.87 g, 60%)

74
as a foam. Recrystallization from ethyl acetate/hexane produced a white powder: mp 80-

81 °C; [00231) = -4.2° (c = 0.26 g/ 100 mL in methylene chloride); IR (NaCl thin film) 3382
(br), 2978, 2936, 1751, 1729, 1700, 1503, 1368, 1165, 743 cm]; 1H NMR (300 MHz,
CDCl3) 8 1.03 (3H, t, J = 7.3 Hz), 2.33 (2H, 2 q, overlapping, J = 7.3 Hz), 3.29 (1H,
dd, J = 6.0, 14.9 Hz), 3.39 (1H, dd, J = 5.5, 14.8 Hz), 4.53 (1H, d, J = 16.8 Hz), 4.68
(1H, d, J = 16.8 Hz), 4.7-4.8 (1H, m), 5.06 (1H, d, J = 8.0 Hz), 7.1-7.2 (3H, m), 7.32
(1H, d, 7.4 Hz), 7.56 (1H, d, 7.7 Hz), 8.31 (1H, broad 8) ppm; 13C NMR (75 MHz,
CDC13) 5 7.0, 27.8, 28.3, 32.0, 54.2, 68.1, 80.0, 109.7, 111.2, 118.6, 119.6, 122.1,
123.3, 127.7, 136.1, 155.3, 171.9, 204.4 ppm; MS (70 eV) m/z (relative intensity) 374
(M+, 0.53), 318 (1.0), 257 (1.3), 159 (9.1), 141 (8.6), 130 (100), 86 (28), 84 (42), 71
(23); HRMS (EI) calcd. for C20H26N205 m/z 374.1842, found m/z 374.1817.

One-Step Deprotection and Pictet-Spengler Cyclization of 96

To a stirred solution of N—Boc protected ester 96 (0.100 g, 0.267 mmol) in
methylene chloride (10 mL) at room temperature under an argon atmosphere was added
dimethyl sulfide (0.0166 g, 0.267 mmol), then trifluoroacetic acid (0.200 mL, 2.96 g,
2.60 mmol). Stirring was continued for 2 days, at which time the solvent was removed in
vacuo. The residue was dissolved in ethyl acetate and shaken with 3% NH40H solution,
and the organic layer dried with anhydrous sodium sulfate. The solvent was removed in
vacuo and the residue purified by flash column chromatography to give 77a (0.041 g,

60%)

Preparation of Amide 100

A 5 mL tear drop flask was charged with bridged lactone 77a (42 mg), flushed
with nitrogen, and cooled in an ice bath. The solid was then dissolved in a saturated
solution of ammonia in methanol (3.5 mL, 0 °C), and sealed with a rubber septa. The flask
was placed in a freezer (-10 °C) overnight, then vented with a needle and allowed to come

to room temperature. Removal of the solvent in vacuo yielded pure amide 100 (45 mg,

75
100 %) as an oil: [0023]) = -103° (c = 0.45 g/ 100 mL in acetone); IR (NaCl thin film) 3414
and 3291 (broad, overlapping), 2969, 2932, 2880, 1671, 1620 and 1578 (broad,
overlapping), 1462, 1410, 1302, 1055, 745 cm'l; 1H NMR (300 MHz, acetone-d6) 5 0.96
(3H, t, J = 7.5 Hz), 1819 (2H, m), 2.62 (1H, dd, J = 11.0, 15.2 Hz), 3.10 (1H, dd,
J = 4.4, 15.2 Hz), 3.61 (1H, d, J = 10.5 Hz), 3.75 (1H, dd, J = 4.4, 11.0 Hz), 3.97 (1H,
d, J = 10.8 Hz), 6.62 (1H, broad s), 6.9-7.1 (2H, m), 7.3 (1H, broad s, overlapping),
7.31 (1H, d, overlapping, J = 7.5 Hz), 7.42 (1H, dd, J = 0.6, 7.5 Hz), 9.88 (1H, broad
s) ppm; 13C NMR (75 MHz, acetone-d5) 5 8.8, 26.5, 30.1 (overlapping with solvent
signal), 54.3, 59.0, 67.5, 109.4, 111.8, 118.4, 119.3, 121.6, 128.1, 137.4, 139.1,
176.5 ppm; MS (21 eV) m/z (relative intensity) 256 (M+ - NH3 or OH, 2.9), 242 (100),
197 (98), 182 (35), 181 (21), 169 (7.2), 144 (7.6), 130 (5.9); MS (FAB+ in glycerol
matrix) m/z (relative intensity) 274 (MH+, 100), 244 (11), 242 (58), 200 (14), 197 (29),
184 (19), 182 (11), 130 (9.8) ; HRMS (FAB+) calcd. MH+ for [C15H20N30]+ m/z
274.1555, found m/z 274.1563.

Preparation of N -Cbz Protected Allyl Ester 103

N-carbobenzyloxy-L-tryptophan (2.66 g, 7.85 mmol) was reacted with p-
toluenesulfonyl chloride (3.38 g, 17.74 mmol) and allyl alcohol (0.541 g, 9.31 mmol) in
pyridine (25.4 mL) as described above for the preparation of 73 to give, on
recrystallization from ether, allyl ester 103 (2.58 g, 87 %): mp 88-89 °C; [0021]) = -17°
(c = 0.23 g/100 mL in methanol); IR (KBr disk) 3366, 1740, 1707, 1618, 1528, 1217 cm'
1; 1H NMR (300 MHz, CDC13) 5 3.30 (2H, d, J = 5.5 Hz), 4.54 (2H, d, J = 5.5 Hz), 4.7
(1H, m), 5.0-5.l (2H, m), 5.2-5.3 (2H, m), 5.36 (1H, d, J = 8.2 Hz), 5.7-5.9 (1H, m),
6.9-7.5 (10H, m), 8.17 (1H, s) ppm; 13C NMR (75 MHz, CDCl3) 5 27.9, 54.6, 66.0,
66.9, 109.7, 111.3, 118.6, 118.8, 119.6, 122.2, 122.9, 127.5, 128.09, 128.14, 128.5.
131.5, 136.1, 136.3, 155.8, 171.7 ppm; MS (70 eV) m/z (relative intensity) 378 (M+,
3.5), 130 (100), 1439 (3.9), 103 (4.4) 91 (24), 77 (9.6) ppm; HRMS (EI) calcd. for
C22H22N204 m/z 378.1579, found m/z 378.1571.

76

Preparation of Diol 104

In a 250 mL 3-neck flask equipped with a mechanical stirrer was dissolved allyl
ester 103 (1.61 g, 4.26 mmol) in 36 mL of t-butanol. Water (36 mL) was then added
followed by potassium ferricyanide (4.16 g, 12.6 mmol), potassium carbonate (1.74 g,
12.6 mmol), 1,4-diazabicyclo[2.2.2]octane (0.238 g, 2.12 mmol), and finally 2 mL of
0.05M osmium tetroxide/t-butanol solution (0.100 mmol). The mixture was stirred
vigorously at room temperature for 5 hours, at which time TLC showed an absence of
starting material. Sodium sulfite (3.2 g) was added and stirring continued for 1 hour. The
reaction mixture was extracted with ethyl acetate repeatedly and the organic layers dried
with anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue
purified by flash column chromatography to yield, as an oil, diol 104 ( 1.16 g, 66%) as a
mixture of diastereomers: [0023]) = +8.6° (c = 0.49g/ 100 mL in methylene chloride, for
diastereomeric mixture); IR (NaCl, thin film, isomeric mixture) 3409 (br), 3059, 2951,
1701 (br), 1518, 1456, 1265, 1213, 1055, 743 cm'l; 1H NMR (300 MHz, CDC13) 5 (for
major isomer) 2.0-2.2 (1H, m, D20 exchangeable), 2.5-2.6 (1H, m, D20 exchangeable),
3.2-3.7 (5H, m), 4.0-4.1 (2H, m), 4.6-4.7 (1H, m), 5.0-5.1 2H, m), 5.36 (1H, d, J =
7.5 Hz, D20 exchangeable), 7.0-7.6 10 H, m), 8.17 (1H, broad s, D20 exchangeable)
ppm (* spectrum looks significantly different at higher concentrations); 13C NMR (75
MHz, CDC13) 5 (for major isomer) 27.8, 54.9, 62.9, 66.0, 67.1, 69.7, 109.4, 111.4,
118.4, 119.6, 122.2, 123.2, 127.3, 128.1, 128.2, 128.5, 136.0, 136.1, 156.2, 172.3
ppm; MS (20 eV) m/z (relative intensity) 412 (M+, 4.7), 304 (3.1), 261 (4.6), 230 (3.9),
185 (3.3), 130 (100), 108 (9.6), 107 (6.5); HRMS (El) calcd. for C22H24N205 m/z
412.1634, found m/z 412.1633.

77
Preparation of Aldehyde 101

The mixture of diastereomeric diols 104 obtained above (0.960 g, 2.33 mmol) was
dissolved, under argon at room temperature, in 34 mL degassed acetone. To this solution
was added 24 mL of degassed water, followed by the dropwise addition of a solution of
sodium metaperiodate (0.697 g, 3.26 mmol, in 10 mL of water) over a period of 1 hour
and 45 minutes, during which time a white precipitate began to form. Stirring was
continued for an additional 22 hours, at which time the contents were poured into 425 mL
of water. The mixture was extracted repeatedly with ethyl acetate and the organic layers
dried with anhydrous sodium sulfate. The solvent was removed in vacuo and the residue
purified by flash column chromatography to give aldehyde 101 (0.700 g, 79%) as an oil,
along with unreacted starting material 104 (0.11 g, 11%). The oil crystallized with
difficulty from methylene chloride/petroleum ether to give a white solid: mp 93-97 °C;
[00241) = -2° (c = 0.51 g/ 100 mL in ethyl acetate); IR (KBr disk) 3378, 3059, 2932, 1756,
1736, 1715, 1531, 1213., 1188, 745 cm‘l; 1H NMR (300 MHz, CDCl3) 5 3.3—3.4 (2H,
m), 4.53 (1H, d, J = 17.4 Hz), 4.64 (1H, d, J = 17.4 Hz), 4.8 (1H, m), 5.0 (2H, m),
5.34 (1H, d, J = 8.1 Hz), 7.0-7.3 (9H, m), 7.53 (1H, d, J = 7.5 Hz), 8.18 (1H, s), 9.35
(1H, s) ppm; 13C NMR (75 MHz, CDC13) 5 27.8, 54.5, 67.0, 109.3, 111.3, 118.4,
119.7, 122.3, 123.2, 127.4, 128.1, 128.2, 128.5, 136.1, 155.8, 171.6, 195.3 ppm; MS
(20 eV) m/z (relative intensity) 380 (M+, 2.32), 130 (100), 108 (8.1), 107 (5.1), 91 (7.6);
HRMS (El) calcd. for C21H20N205 m/z 380.1372, found m/z 380.1380.

Preparation of N-Cbz Protected Methyl Acetal 109

To a solution of aldehyde 101 (0.34 g, 0.89 mmol), methanol (3.0 mL), and
trimethylorthoformate (3.0 mL) was added para-toluenesulfonic acid (5 mg, 0.026 mmol).
The solution was stirred under argon for 1 hour and 10 minutes at room temperature, then
poured into ether (16 mL) and washed first with a 1:1 mixture of 5% sodium hydroxide
solution and brine, then with water, and dried with anhydrous sodium sulfate. In vacuo

removal of the solvent and purification via flash column chromatography gave methyl acetal

78
109 (0.289 g, 76%) as an oil: [00231) = +17° (c = 0.72 g/ 100 mL in methylene chloride);
IR (NaCl thin film) 3349 (br), 2938, 1743 and 1709 overlapping, 1513, 1457, 1193,
1135, 743 cm'l; 1H NMR (300 MHz, CDC13) 5 3.31 (3H, s), 3.33 (3H, s), 3.33 m (2H,
m, overlapping), 4.07 (2H, d, J = 5.1 Hz), 4.42 (1H, dd, overlapping, J = 5.1, 5.7 Hz),
4.74 (1H, m), 5.0-5.1 (2H, m), 5.29 (1H, d, J = 8.4 Hz), 7.00 (1H, d, J = 2.1 Hz), 7.07
(1H, t, J = 7.4 Hz), 7.16 (1H, t, J = 7.6 Hz), 7.3-7.4 (6H, m), 7.51 (1H, d] = 7.5 Hz),
8.6 (1H, s); 13C NMR (75 MHz, CDC13) 5 27.81, 53.81, 54.16, 54.59, 63.74, 66.88.
101.03, 109.53, 111.23, 118.50, 119.61, 122.12, 123.04, 127.54, 128.06, 128.11,
128.46, 136.08, 136.20, 155.78, 171.64 ppm; MS (70 eV) m/z (relative intensity) 426
(M+, 0.72), 394 (0.80), 318 (1.65), 1,57 (1.01), 130 (100), 108 (7.36), 91 (81), 75 (17);
HRMS (El) calcd. for C23H26N205 m/z 426.2791, found m/z 426.1771.

Deprotection of Methyl Acetal 109

To a solution of N-carbobenzoxy protected methyl acetal 109 (0.231 g, 0.542
mmol) in ethanol (31 mL) was added 10% Pd/C (0.039 g, 0.037 mmol Pd). The solvent
was degassed and hydrogen introduced by alternate evacuation (aspirator) and purging by
way of a three-way st0pcock equipped with a balloon filled with hydrogen. The solution
was stirred magnetically at room temperature for 2.5 hours. The catalyst was removed by
filtration and the solvent removed in vacuo to yield deprotected methyl acetal 111 (0.153 g,
97%) as an oil: [00231) = -18° (c = 0.11 g/ 100 mL in acetone); IR (NaCl thin film) 3368
(br), 3173 (br), 3055, 2926, 2836, 1740, 1588, 1458, 1342, 1190, 1134, 1074, 743 cm'
1; 1H NMR (300 MHz, CDC13) 5 1.67 (2H, broad s), 3.05 (1H, dd, J = 7.5, 14.5 Hz),
3.26 (1H, dd, J = 5.1, 14.4 Hz), 3.34, (3H, s), 3.35 (3H, s), 3.84 (1H, dd, J = 5.2, 7.4
Hz), 4.12 (2H, d, J = 5.4 Hz), 4.47 (1H, overlapping dd, J = 5.3, 5.3 Hz), 6.99 (1H, d,
J = 2.2 Hz), 7.1-7.2 (2H, m), 7.30 (1H, d, J = 8.0 Hz),7.60 (1H, d, J = 7.7 Hz), 8.57
(1H, broad s) ppm; 13C NMR (75 MHz, CDC13) 5 30.2, 53.5, 53.6, 54.6, 62.9, 100.8,
110.3, 110.8, 118.3, 119.0, 121.6, 122.8, 127.1, 135.9, 174.7 ppm; MS (70 eV) m/z
(relative intensity) 292 (M+,9.8), 204 (1.1), 159 (9.6), 158 (5.5), 130 (100), 103 (8.2),

79
77 (7.0), 75 (38); HRMS (EI) calcd. for C15H20N204 m/z 292.1423, found m/z

292.1425.

Preparation of N -Cbz Protected Ethyl Acetal 110

To a solution of aldehyde 101 (0.681 g, 1.79 mmol) in 10 mL absolute ethanol
was added 10 mL triethylorthoforrnate, followed by p-toluenesulfonic acid (0.014 g, 0.074
mmol). After stirring at room temperature for 2.5 hours the solution was poured into 100
mL of ether and washed first with a 1:1 mixture of 5% sodium hydroxide solution and
brine, then with water, and dried with anhydrous sodium sulfate. In vacuo removal of the
solvent and purification via flash column chromatography gave ethyl acetal 110 (0.647 g,
80%) as an oil: [0023]): +17° (c = 0.72 g/ 100 mL in methylene chloride); IR (NaCl thin
film) 3351 (br), 2977, 1717 (br), 1507, 1456, 1206, 1132, 1063, 743 cm'l; 1H NMR
(300 MHz, CDC13) 5 1.18 (3H, t, J = 7.0 Hz), 1.19 (3H, t, J = 7.0 Hz), 3.31 (2H, d, J =
5.2 Hz), 3.4-3.6 (2H, m,), 3.6-3.7 (2H, m), 4.09, (2H, d, J = 5.5 Hz, 4.56) (1H, dd
overlapping, J = 5.4, 5.4 Hz), 4.7-4.8 (1H, m), 5.0-5.1 (2H, m), 5.36 (1H, d, J = 8.1
Hz), 6.98 (1H, d, J = 1.9 Hz), 7.07 (1H, t, J = 7.4 Hz), 7.16 (1H, t, J = 7.2 Hz), 7.2-
7.4 (6H, m), 7.53 (1H, d, J = 7.9 Hz), 8.24 (1H, 8) ppm; 13C NMR (75 MHz, CDC13) 5
15.2, 27.8, 54.6, 62.4, 62.8, 64.7, 66.8, 99.4, 109.6, 111.2, 118.5, 119.6, 122.1,
123.0, 127.6, 128.0, 128.1. 128.4, 128.5, 136.0. 136.2, 155.7, 171.6 ppm; MS (70 eV)
m/z (relative intensity) 454 (M+,14), 408 (18), 346 (9.4), 292 (31), 249 (5.5), 220 (12),
185 (7.4), 158 (15), 157 (15), 130 (100), 103 (95), 91 (95), 79 (26), 77 (33), 75 (57);
HRMS (EI) calcd. for C25H30N206 m/z 454.2104, found m/z 454.2119.

Deprotection of Ethyl Acetal 110

To a solution of N-carbobenzoxy protected ethyl acetal 110 (0.638 g, 1.40 mmol)
in ethanol (90 mL) was added 10% Pd/C (0.100 g, 0.094 mmol Pd). The solvent was
degassed and hydrogen introduced by alternate evacuation (aspirator) and purging by way

of a three-way stopcock equipped with a balloon filled with hydrogen. The solution was

80
stirred magnetically at room temperature for 7.5 hours. The catalyst was removed by

filtration and the solvent removed in vacuo to yield deprotected ethyl acetal 112 (0.443 g,
98%) as an oil: [00231) = +3.5° (c = 0.37 g/ 100 mL in methylene chloride); IR (NaCl thin
film) 3364 (br), 2977, 1738, 1458, 1188, 1132, 1069, 743 cm'l; 1H NMR (300 MHz,
CDC13) 8 1.19 (6H, dt, J = 1.2, 7.0 Hz), 1.66 (2H, broad s), 3.06 (1H, dd, J = 7.5,14.4
Hz), 3.27 (1H, dd, J = 5.0, 14.6 Hz), 3.5-3.6 (2H, m), 3.6-3.7 (2H, m), 3.85 (1H, dd,
J = 5.0, 7.4 Hz), 4.11 (2H, d, J = 5.5 Hz), 4.59 (1H, dd, overlapping, J = 5.4, 5.4 Hz),
7.0-7.2 (3H, m), 7.32 (1H, d, J = 7.9 Hz), 7.61 (1H, d, J = 7.5 Hz), 8.3 (1H, broad 8)
ppm; 13C NMR (75 MHz, CDC13) 8 15.2, 30.6, 55.0, 62.4, 62.5, 64.3, 99.5, 111.0,
111.2, 118.7, 119.5, 122.1, 123.0, 127.5, 136.2, 175.1 ppm; MS (70 eV) m/z (relative
intensity) 320 (M+,1.2), 232 (3.8), 159 (8.3), 149 (5.3), 130 (100), 111 (5.2), 83 (8.5),
77 (7.9), 71 (13); HRMS (EI) calcd. for C17H24N204 m/z 320.1736, found m/z
320.1734.

Preparation of 123a from Aldehyde 101

A solution of N—protected aldehyde 101 (1.00 g, 2.63 mmol) in methanol (500
mL) was prepared under an atmosphere of argon. The reaction vessel was placed in an ice
bath, and 10% Pd/C (0.70 g, 0.66 mmol) was added, followed by the dropwise addition of
88% formic acid (21 mL) over a period of 25 minutes. The mixture was stirred for 5
hours, then trifluoroacetic acid (2.30 mL, 29.9 mmol) was added over a period of 15
minutes. The ice bath was removed and the mixture stirred slowly for an additional 4 days
at room temperature. The catalyst was removed by filtration through celite,vand the solvent
removed in vacuo. The residue was dissolved in ethyl acetate, washed with saturated
sodium bicarbonate solution, and dried with anhydrous sodium sulfate. Removal of the
solvent in vacuo and purification by flash chromatography gave 123a (0.199 g, 29%) as a
white solid: mp 190-191 °C (decomposed); [@2313 = -118° (c = 0.11 g/100 mL in
methanol); IR (KBr disk) 3426 (br), 3298, 3295, 2853, 1725, 1441, 1220, 1044, 731

81
cm‘l; 1H NMR (300 MHz, DMSO) 5 2.63 (1H, ddd, J = 2.4, 11.1, 14.7 Hz), 2.6-2.7

( 1H, broad s, coalesces with H20 and broadens over time), 2.95 (1H, ddd, J = 1.2, 4.1,
14.4 Hz), 3.6-3.7 (1H, m), 3.7-3.8 (1H, m), 3.72 (3H, s), 4.10 (1H, m), 5.00 (1H, t,

J = 5.2, coalesces with H20 over time to give a broad singlet), 6.9-7.1 (2H, m), 7 .30 (1H,
d, 8.1 Hz), 7.38 (1H, d, 7.8 Hz), 10.70 (1H, s) ppm; 13C NMR (75 MHz, DMSO) 8
25.5, 51.8, 54.6, 55.6, 63.4, 106.8, 111.1, 117.4, 118.3, 120.6, 126.6, 124.2, 136.0.
173.2 ppm; MS (70 eV) m/z (relative intensity) 260 (M+, 3.6), 229 (98), 228 (6.3), 169
(100), 168 (11), 154 (6.2), 130 (6.2), 115 (14); HRMS (E1) calcd. for C14H15N203 m/z
260.1161, found‘m/z 260.1156.

Preparation of N -Cbz Protected Ester 132

A solution of N-Cbz-L—tyrosine (2.0 g, 6.34 mmol) in freshly distilled pyridine (20
mL) was prepared under argon. To this magnetically stirred, room temperature solution
was added l-hydroxy-2-butanone (2.84 g @ 95%, 27.9 mmol), followed by the addition
of p—toluenesulfonic acid (0.56 g, 0.29 mmol), and finally 1,3-dicyclohexylcarbodiimide
(1.57 g, 7.6 mmol). After a few minutes a precipitate began to form. Stirring was
continued for 24 hours, at which time glacial acetic acid (0.63 mL) was added. The
mixture was for stirred 15 minutes, then placed in a refrigerator (-4 °C) overnight). The
precipitated 1,3-dicyclohexylurea was removed by filtration through celite, rinsing with 10
mL of cold pyridine. The filtrate was mixed with 20 mL each of ethyl acetate and ice, and
acidified with 5N hydrochloric acid. The layers were then separated, and the organic layer
washed successively with water, saturated sodium bicarbonate solution, and again with
water, then dried over saturated anhydrous sodium sulfate. Removal of the solvent in
vacuo and purification with flash column chromatography gave ester 132 (1.64 g, 67%)
along with a significant amount of by-product 133.

Characteristic properties of 132: mp 102 °C; IR (KBr disk) 3403, 3355, 1761,
1713, 1688 cm-1; 1H NMR (300 MHz, CDC13) 8 1.06 ( 3H, t, J = 7.3 Hz), 2.39 (2H, q,

82
J = 7.3 Hz), 3.01 (1H, dd, J = 6.6, 14.3 Hz), 3.15(1H, dd, J = 5.8, 14.2 Hz), 4.63 (1H,

d, overlapping, J = 16.7 Hz), 4.74 (1H, d, overlapping, J = 16.7 Hz), 4.6-4.7 ( 1H, m,
overlapping), 5.0-5.1 (2H, m), 5.30 ( 1H, d, J = 8.5 Hz), 6.02 ( 1H, s, concentration
dependent), 6.68 ( 2H, d, J = 8.2 Hz), 6.99 ( 2H, d, J = 8.3 Hz), 7.2-7.4 ( 5H, m) ppm;
13C NMR (75 MHz, CDC13) 5 7.1, 32.1, 37.2, 54.8, 67.1, 68.2, 115.6, 127.2, 128.1,
128.2, 128.5, 130.5, 136.0, 155.0, 155.9, 171.3, 204.1 ppm; MS (70 eV) m/z (relative
intensity) 386 (MH+, 3.2), 385 (Mb 2.2), 342 (13), 234 (33), 147 (15), 108 (12), 107
(100), 91 (100), 77 (11) ppm.

Characteristic pr0perties of 133: mp 157 °C; IR (KBr disk) 3421, 3333, 3035,
2943, 1757, 1717, 1693, 1529, 1516, 1267, 1215 cm]; 1H NMR (300 MHz, CDC13) 5
1.07 ( 3H, t, J = 7.3 Hz), 2.38 (2H, q, J = 7.3 Hz), 3.1-3.2 (4H, m), .4.6-4.8 (4H, m),
5.06 (2H, s), 5.10 (2H, s), 5.26 ( 1H, d, J = 8.3 Hz), 5.35 (1H, d, J = 8.0 Hz), 6.73
(2H, d, J = 8.3 Hz), 6.88 ( 2H, d, J = 8.2 Hz), 7.02 ( 2H, d, J = 8.5 Hz), 7.15 ( 2H, d,
J = 8.2 Hz), 7.2-7.4 ( 10H, m) ppm; 13C NMR (75 MHz, CDC13) 5 6.67, 31.63, 36.97,
54.17, 54.71, 66.73, 67.77, 115.25, 120.94, 126.61, 127.72, 127.83, 128.10,128.l3,
130.00, 130.15, 133.26, 135.58, 148.89, 154.78, 155.34, 169.86, 170.56, 203.38,
ppm; MS (FAB+ in glycerol matrix) m/z (relative intensity) 683 (MH’t, 17), 640 (11), 639
(27), 307 (55), 289 (29), 226 (14), 197 (18), 154 (100), 138 (49), 137 (94), 136 (100),
107 (45).

Preparation of Schiff Base 134

To a 0 °C solution of N-protected ester 132 (0.500 g, 1.30 mmol) in 80 mL of
absolute ethanol was added 0.099 g of 10% Pd/C, and 0.25 g of 3A molecular sieves. The
solvent was degassed by alternate evacuation (aspirator) and purging with hydrogen from
balloon attached to a 3-way stopcock. This was repeated three times. Hydrogenation was
commenced by vigorous magnetic stirring. After 5 h the reaction mixture was filtered
through celite and the solvent removed in vacuo. To the residue was added ethyl acetate,

which precipitated a white substance. The mixture was filtered through a two inch column

83
of silica, eluting with ethyl acetate. The filtrate was reduced in vacuo, and purification by
flash chromatography gave, as an oil, Schiff base 134 (0.050 g, 16%): H NMR (300
MHz, CDC13) 5 1.10 ( 3H, t, J = 7.5 Hz), 2.1-2.3 (2H, m), 3.11 (1H, dd, J = 4.6, 13.7
Hz), 3.31 (1H, dd, J = 4.8, 13.7 Hz), 3.54 (1H, dd, J = 1.6, 16.7 Hz), 4.39 (1H, dd, J =
2.0, 16.8 Hz), 4.62 ( 1H, broad s), 6.72 (2H, d, J = 8.5 Hz), 7.00 ( 2H, d, J = 8.3 Hz)
ppm; 13C NMR (75 MHz, CDC13) 5 9.7, 28.5, 38.2, 60.1, 68.7, 115.3, 127.6, 131.3,

155.1, 168.1, 169.1 ppm.

Preparation of Tosylate 92

A stirred solution of 77a (0.357 g, 1.39 mmol) and pyridine (4.5 mL) under argon
was cooled in an ice bath and charged with p-toluenesulfonyl chloride (0.531 g, 2.79
mmol). After 1.5 h the ice bath was removed and stining continued at room temperature
for 17 h at which time additional p-toluenesulfonyl chloride (0.133 g, 0.70 mmol) was
added to the reaction vessel. After an additional 11 h (total reaction time 28 h) TLC
showed that all starting material had been consumed and the reaction mixture was poured
into approximately 20 mL of ice water. The mixture was extracted with ethyl acetate and
the organic portion washed with 1N HCl until the washings were acidic, then with
saturated sodium bicarbonate solution, and dried with anhydrous sodium sulfate. The
solvent was removed in vacuo and the residue purified by flash column chromatography to
give crystalline 92 (0.533 g, 93%). An analytical sample was obtained by recrystallization
from ethyl acetate/hexane: mp 262-267 °C; [007-31) = -34° (c = 0.24 g/ 100 mL in ethyl
acetate); IR (KBr disk) 3407, 2924, 1728, 1466, 1331, 1157, 1082, 708 cm'l; 1H NMR
(300 MHz, CDC13) 5 0.89 (3H, t, J --= 7.0), 1.86 (1H, dq, overlapping, J = 7.3, 14.8 Hz),
2.41 (3H, s), 2.78 (1H, dq, overlapping, J = 7.1.14.7 Hz), 3.11 (2H, m), 4.11 (1H, d,
J = 11.2 Hz), 4.52 (1H, d, J = 11.2 Hz), 5.01 (1H, dd, overlapping , J = 3.4, 3.4 Hz),
7.1-7.2 (3H, m), 7.32 (2H, d, J = 8.3 Hz), J = 7.4 1H, m), 7.79 (2H, d J = 8.3 Hz),
8.34 (1H, s) ppm; 13C NMR (75 MHz, CDC13) 5 8.1, 21.6., 24.5, 27.1, 56.6, 61.5,
76.7, 110.8, 111.4, 118.4, 120.1, 123.1, 126.0, 127.5, 130.2, 131.0, 136.5, 136.6,

 

84
145.0, 169.2 ppm; MS (70 eV) m/z (relative intensity) 410 (M+, 9.0), 351 (1.3), 255 (35),
227 (6.2), 197 (100), 196 (9.0), 195 (15), 182 (36), 168 (10), 171 (13), 154 (13), 91
(20) ppm; HRMS (El) calcd. for C22H22N204S m/z 410.1300, found m/z 410.1298.

Reaction of 92 with DBU

In a 10 mL round bottom flask sealed with a rubber septa and equipped with an
argon inlet was dissolved tosylate 92 (0.100 g, 0.244 mmol) in 3 mL of tetrahydrofuran,
followed by the dropwise addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (2.00 mL, 13.4
mmol) was then added dropwise via syringe. The flask was then fitted with a condenser
and the solution refluxed for 19 hours. The solvent was removed in vacuo and the residue
dissolved in chloroform. The solution was washed successively with 1N HCl, water, and
saturated sodium bicarbonate solution, and dried over sodium sulfate. Removal of the
solvent in vacuo and purification with flash column chromatography gave DBU adduct
145 (0.097 g, 69%) as a glasslike solid: [or]23D = +79° (c = 0.81 g/ 100 mL in methylene
chloride); IR (NaCl thin film) 3250 (broad, with shoulder at 3373), 3092, 2930, 1646,
1622, 1327, 1159, 1090 cm'l; 1H NMR (300 MHz, CDC13) 5 0.77 (3H, t, J = 7.4), 1.1-
1.3 (3H, m), 1.3-1.5 (1H, m), 1.5-1.8 (5H, m), 1.91 (1H, dq, overlapping, J = 7.2, 14.0
Hz), 2.2-2.3 (2H, m), 2.35 (3H, s), 2.4—2.5 (2H, m), 2.54 (1H, dq, overlapping, J =
7.3, 14.0 Hz), 2.8-3.0 (3H, m), 3.07 (1H, dd, J = 6.3, 15.0 Hz), 3.46 (1H, dd, J = 1.6,
15.5 Hz), 4.35 (1H, dd, J = 5.7, 13.2 Hz), 4.90 (1H, d, J = 4.8 Hz), 5.10 (1H, dd, J =
6.2, 13.5 Hz), 6.38 (1H, t, J = 6.3 Hz), 7.0-7.1 (3H, m), 7.24 (2H, d, J = 8.4 Hz), 7.85
(2H, d, J = 8.7 Hz), 8.66 (1H, d, J = 6.6 Hz), 8.74 (1H, s) ppm; 13C NMR (75 MHz,
CDC13) 5 8.7, 21.4, 23.1, 24.9, 25.1, 27.6, 29.6, 33.0, 35.9, 36.8, 45.6, 50.2, 58.6,
65.0, 70.4, 108.8, 111.0, 118.1, 119.3, 121.6, 126.4, 127.9, 129.3, 133.6, 136.1,
137.6, 143.3, 171.4, 176.6 ppm; MS (70 eV) m/z (relative intensity) 580 (M+, 3.3), 562
(3.7), 408 (8.1), 395 (10.7), 226 (37), 225 (40), 211 (25), 200 (100), 197 (33), 172 (73),
154 (37), 91 (27); HRMS (FAB’t) calcd. MH” for [C31H41N4OSS]+ m/z 581.2797, found
m/z 581.2791.

APPENDIX

APPENDIX

SPECTRA

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BIBLIOGRAPHY

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