Synthetic Studies Toward the Total Synthesis of (±)-Ajmaline and the Development of, Investigation

347 Pages·2014·6.17 MB·English

by  Brian Blank

UCLA
UCLA Electronic Theses and Dissertations
Title
Synthetic Studies Toward the Total Synthesis of (±)-Ajmaline and the Development of,
Investigation into, and Application of a Phosphine-Catalyzed [4+1] Annulation
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https://escholarship.org/uc/item/4j06b397
Author
Blank, Brian Richard
Publication Date
2014

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UNIVERSITY OF CALIFORNIA
Los Angeles

Synthetic Studies Toward the Total Synthesis of (±)-Ajmaline and the Development of,
Investigation into, and Application of a Phosphine-Catalyzed [4+1] Annulation

A dissertation submitted in partial satisfaction of the
requirements for the degree of Doctor of Philosophy
in Chemistry

by

Brian Richard Blank

2014

ABSTRACT OF THE DISSERTATION

Synthetic Studies Toward the Total Synthesis of (±)-Ajmaline and the Development of,
Investigation into, and Application of a Phosphine-Catalyzed [4+1] Annulation

by

Brian Richard Blank
Doctor of Philosophy in Chemistry
University of California, Los Angeles, 2014
Professor Ohyun Kwon, Chair

Several synthetic routes toward the synthesis of the indole alkaloid (±)-ajmaline have
been explored. The retrosynthetic plan was devised around two key transformations, one being a
tandem aza-Michael–Michael reaction, and the other a phosphine-catalyzed [4+2] annulation.
While these approaches have not allowed for the completion of ajmaline, they have provided a
great deal of insight into the chemistry of many intermediates. For example, it was discovered
that following installation of the D-ring, functionalization of the tricyclic scaffold to deliver a
precursor for the aza-Michael–Michael sequence was a futile undertaking. As such, the necessary
functionality had to be installed prior to the [4+2] annulation. For this purpose, ethyl 3-allyl-1H-
indole-2-carboxylate was prepared by way of a stepwise Japp–Klingemann reaction, and a
subsequent Fischer indolization. Successful conversion of this compound into the N-sulfonyl

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imine required the employment of 2,6-lutidine to impede isomerization of the allyl moiety. This
imine was converted into the tetrahydropyridine through a phosphine-catalyzed [4+2] annulation
with ethyl 2-methyl-2,3-butadienoate. Cross-metathesis with methyl acrylate provided the first
precursor to the desired aza-Michael–Michael reaction sequence. Unfortunately, only mono-
Michael addition was observed when this substrate was employed in the reaction, providing a
tetracyclic structure instead of the desired pentacyclic scaffold. As a result, we are currently
pursuing tricyclic derivatives that feature either alternative Michael donors or an increased
strength of the second Michael acceptor.
A phosphine-catalyzed [4+1] annulative rearrangement has been developed to prepare 3-
pyrrolines from allenylic carbamates through phosphonium diene intermediates. This
methodology was employed to synthesize an array of 1,3-disubstituted- and 1,2,3-trisubstituted-
3-pyrrolines, including the often difficult to prepare 2-alkyl variants. A mechanistic investigation
employing allenylic acetates and mononucleophiles unexpectedly unveiled that a phosphine-
catalyzed [4+1] reaction previously reported by Tong might not occur through a phosphonium
diene as was proposed, but rather involves multiple mechanisms working in concert to construct
cyclopentene products. Consequentially, our phosphine-catalyzed rearrangement is most likely
the first reaction that unequivocally forms a phosphonium diene intermediate along the reaction
pathway. Concise formal syntheses of pyrrolizidine alkaloids (±)-trachelanthamidine and (±)-
supinidine were completed, demonstrating the synthetic utility of this newly developed reaction.

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The dissertation of Brian Richard Blank is approved.
Jerome A. Zack
Neil K. Garg
Ohyun Kwon, Committee Chair

University of California, Los Angeles
2014

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TABLE OF CONTENTS

Table of Contents………………………………...v
List of Figures………………………………….viii
List of Schemes………………………………...viii
List of Tables………………………………..….xv
Acknowledgments……………..…………..….xviii
Vita……………………………………….…….xix

CHAPTER 1
Progress Toward the Total Synthesis of (±)-Ajmaline
1.1 Isolation………………………………………………………………………………......2
1.2 Biological Activity……………………………………………………………………….6
1.3 Biosynthesis of Ajmaline………………………………………………………………...9
1.4 Previous Total Syntheses of Ajmaline…………………………………………………..16
Masamune’s total synthesis……………………………………………………………..16
Mashimo and Sato’s total synthesis of isoajmaline……………………………………..23
Mashimo and Sato’s formal synthesis of ajmaline…………………………………...…32
van Tamelen’s total synthesis of ajmaline………………………………………………34
Cook’s first generation synthesis of ajmaline – 1998…………………………………...44
Cook’s second generation total synthesis – 2001…………………………………...…..59
1.5 Our Synthetic Strategy toward Ajmaline………………………………………………..67
Our initial retrosynthetic analysis of ajmaline…………………………………………..69

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Our initial forward progress toward ajmaline……………………………………………71
Second generation retrosynthetic analysis……………………………………………….82
Second generation forward progress toward ajmaline……………………………….…..84

Third generation retrosynthetic analysis…………………………………………….…...86
Third generation forward progress…………………………………………………..…..87
Fourth generation retrosynthetic analysis………………………………………………..97
Fourth generation forward progress……………………………………………………..99
Revised retrosynthetic analysis…………………………………………………………104
Forward synthetic progress……………………………………………………………..105
Updated retrosynthetic analysis…………………………………………………..…….123
Forward synthetic progress……………………………………………………………..123
Future directions………………………………………………………………………..129
Conclusions…………………………………………………………………………….132
1.6 Experimental……………………………………………………………………………134

1.7 References………………………………………………………………………….…..187

CHAPTER 2
Phosphine-Catalyzed [4+1] Annulation: Rearrangement of Allenylic Carbamates to
3-Pyrrolines through Phosphonium Diene Intermediates

2.1 Phosphine-Catalyzed Syntheses of 1,2,3-Trisubstituted 3-Pyrroline-3-
Carboxylates from Unsaturated Esters and Aldimines………………………………....197

2.2 Phosphine-Catalyzed Syntheses of 1,2,3,5-Tetrasubstituted-3-Pyrroline-
3-Carboxylates from Unsaturated Esters and Aryl Aldimines…………………………201

Phosphine-catalyzed approaches toward 1,2,3,5-tetrasubstituted-3-pyrroline 3-
carboxylates through phosphonium dienolates…………………………………………201

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Phosphine-catalyzed approaches toward 1,2,3,5-tetrasubstituted-3-
pyrrolines through alternative 3-carbon synthons……………………………………...209

2.3 Application of Phosphine-Catalyzed [3+2] Annulation Between
Allenoates and Benzaldimines in Total Synthesis…………………………………..….214

2.4 Preparation of 2-Alkyl Substituted-3-Pyrroline-3-Carboxylates
through Phosphine Catalysis………………………………………………………...….217

2.5 Application of Phosphine-Catalyzed [3+2] Annulation Between
Allenoates and Aliphatic Aldimines in Total Synthesis……………………………..…222

2.6 Our Synthesis of 2-Alkyl Substituted-3-Pyrroline-3-Carboxylates through
a Phosphine-Catalyzed [4+1] Annulative Rearrangement…………………………...…224

Our discovery of the phosphine-catalyzed [4+1] annulation…………………………...224

Previous phosphine-catalyzed [4+1] annulations proceeding through
a proposed phosphonium diene intermediate…………………………………………...227

Substrate modifications in attempt to improve the efficiency of our
newly discovered [4+1] annulation……………………………………………….…….230

Reaction optimization…………………………………………………………………. 234

Exploration of the substrate scope……………………………………………..……….241

Mechanistic investigation………………………………………………………………244

Mechanism Proposal…………………………………………………………..………..250

Application in total synthesis……………………………………………………..…….255

Conclusion………………………………………………………………………….…..258

2.7 Experimental………………………………………………………………………...….259

2.8 References………………………………………………………………………....……320

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LIST OF FIGURES

CHAPTER 1

Figure 1.1.1 Structures of indole alkaloids isolated from Rauwolfia
Serpentina by Siddiqui and Siddiqui………………………….……..……3

Figure 1.1.2 Structures of ajmaline proposed by Robinson and Woodward………..…..4

Figure 1.1.3 Scaffolds for the corynantheine, akuammidine, and quebrachidine
groups along with a representative member of each group………….…....5

Figure 1.4.1 Model proposed by Cook to predict that kinetic quench of
enolate 121 would lead to the desired aldehyde epimer…………………64

Figure 1.5.1 Alternate compounds of interest as potential precursor to
alkylidene malonate 198……………………………………………..…130

CHAPTER 2

Figure 2.6.1 Representative pyrrolizidine alkaloids……………………………...…..256

LIST OF SCHEMES

CHAPTER 1

Scheme 1.3.1 Proposed biosynthesis of secologanin (26) from pyruvate (10)
and D-glyceraldehyde-3-phosphate (11)…………………………………11

Scheme 1.3.2 Proposed biosynthesis of ajmaline (1) from tryptophan (27)
and secologanin (26)…………………………………………………..…14

Scheme 1.4.1 Masamune’s approach toward ajmaline commences upon
preparation of tricyclic hemiaminal 48…………………...………….…..18

Scheme 1.4.2 Preparation of tetracyclic nitrile 52 from hemiaminal 48…………….….19

Scheme 1.4.3 Degradation of ajmaline oxime (53) to primary alcohol 52, and
subsequent reoxidation to aldehyde 55a………………………………....20

Scheme 1.4.4 Observed equilibrium mixture of C16 epimers obtained upon
subjecting aldehyde 55a to alumina………………………………….…..21

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