strategies for the concise synthesis of the akuammiline alkaloids

280 Pages·2015·18.32 MB·English

by  Columbia University

STRATEGIES FOR THE CONCISE SYNTHESIS OF THE
AKUAMMILINE ALKALOIDS

Myles Warwick Smith

Submitted in partial fulfillment of the
requirements for the degree of
Doctor of Philosophy
in the Graduate School of Arts and Sciences

COLUMBIA UNIVERSITY
2015
© 2015
Myles Warwick Smith
All rights reserved
ABSTRACT
Strategies for the Concise Synthesis of the Akuammiline Alkaloids
Myles Warwick Smith
The akuammiline alkaloids are an intriguing class of natural products that display
an array of biological activities and structural diversity. Despite being known for over 125
years, it is surprising that these complex monoterpene indole alkaloids have only recently
elicited sustained interest from the synthetic community, especially given the storied
history of this broad family in the development of the art of total synthesis, and, in
particular, heterocyclic chemistry. This dissertation details our efforts to address these
deficiencies through work initially directed at the unique akuammiline alkaloid
scholarisine A, ultimately yielding a concise and enantiospecific preparation of this
challenging target. Hereafter, we showcase our studies aiming to extend these advances to
the akuammiline class as whole, through the development of a readily generalizable
approach to this alkaloid family.
Thus, Chapter 1 will serve to introduce this exciting class of alkaloids, beginning
with the details of their proposed biosynthesis, followed by a summary of the diverse
biological activities they display. Lastly, the reported synthetic approaches to this family
will be described, starting with a select number of early efforts and culminating in the few,
but impressive examples of completed total syntheses that have recently appeared.
Next, Chapter 2 will detail the evolution of our synthetic approach to the highly
rearranged akuammiline alkaloid scholarisine A, a strategy guided throughout by a key
pyrone Diels–Alder logic. That discussion will include out early attempts to fashion its
characteristic framework through intramolecular Diels–Alder approaches and how those
efforts informed the development of our eventual synthetic solution based on an
intermolecular process. Finally, it will be demonstrated that advances made during our
early work have led to a method with potential utility in both natural product synthesis and
the assembly of medicinally-relevant building blocks.
Finally, in Chapter 3, our efforts to develop a general approach to the akuammiline
alkaloids will be described, studies that initially focused on the prototypical member of this
class, strictamine. These efforts have culminated in a concise and readily scalable route to
a number of advanced tetracyclic intermediates, empowered by a number of
methodological advances. These intermediates, many embodying all the carbon atoms of
strictamine and related targets, are poised for a final ring formation to complete their total
syntheses. In addition, we disclose promising discoveries that should allow for broad
access to akuammiline class, having identified facile means to transition from the
strictamine series to other subfamilies.
TABLE OF CONTENTS
List of Abbreviations iv
Acknowledgements vii
Chapter 1. The Akuammiline Alkaloids: Background, Biosynthesis and Previous
Synthetic Approaches 1
1.1 Introduction 2
1.2 Biological Activity and Biosynthesis 3
1.2.1 Biological Activity 3
1.2.2 Biosynthesis 5
1.3 Synthetic Studies in the Akuammiline Class 6
1.3.1 Early Synthetic Efforts 7
1.3.2 Total Syntheses of Vincorine 9
1.3.3 Total Syntheses of Aspidophylline A 15
1.3.4 The Smith Synthesis of (+)-Scholarisine A 19
1.3.5 The Garg Synthesis of (±)-Picrinine 22
1.4 Conclusions 24
1.5 References 25

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Chapter 2. A Concise Total Synthesis of (+)-Scholarisine A 28
2.1 Introduction 29
2.2. Isolation and Proposed Biosynthesis 30
2.3. Our Synthetic Approach to Scholarisine A: Pyrone Diels–Alder Logic 31
2.4. Early, Unsuccessful Intramolecular Pyrone Diels–Alder Approaches 37
2.4.1 Initial Macrocylic Pyrone IMDA Strategy 37
2.4.2. Pyrone IMDA Strategy Employing a Traceless Sulfide Tether 43
2.5. Intermolecular Pyrone Diels–Alder Approach 48

2.5.1. Initial 3,5-dibromopyrone-based Strategy 48
2.5.2. Optimization of the Synthesis of Alcohol 125 54
2.5.3. Regiochemistry of the Diels–Alder reaction 57
2.5.4. Studies with a Carbon-based Radical Trap –
Forging the C-20 Quaternary Center 60
2.5.5. Completion of the Full Cage Framework of Scholarisine A 63
2.5.6. Arylation Studies 68
2.5.7. Elaboration of 174 to Scholarisine A 78
2.6. Extension of Early Unsuccessful IMDA Method to the Preparation of Aromatic and
Non-aromatic Heterocycles 88
2.7 Conclusions and Outlook 94
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2.8 References 97
2.9 Experimental Section 100

Chapter 3. Studies toward Strictamine and Related Akuammiline Alkaloids 171
3.1. Introduction 172
3.2 Isolation, Biological Activity and Biosynthesis of Strictamine 173
3.2.1 Isolation and Structure Determination 173
3.2.2 Biological Activity 174
3.2.3 Biosynthesis 175
3.3 Previous Synthetic Efforts toward Strictamine 175
3.4 Our Approach to Strictamine 179
3.5 Development of Expedient Access to the Akuammiline Core 181
3.6 Carbonylative Heck Approach 186
3.7 Traditional Heck Approach 196
3.8 Alternate Radical Cyclization Approach 208
3.9 Conclusions and Outlook 216
3.10 References 220
3.11 Experimental Section 224

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LIST OF ABBREVIATIONS
ACCN 1,1’-azobis(cyclohexanecarbonitrile)
AIBN azobisisobutyronitrile
BHT 2,6-di-tert-butyl-4-methylphenol
brsm based on recovered starting material
Bt 1-benzotriazole
BTPP tert-Butylimino-tri(pyrrolidino)phosphorane
COD 1,4-cyclooctadiene
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
DCE 1,2-dichloroethane
DMA N,N-dimethylacetamide
DMAP 4-(N,N-dimethylamino)pyrine
DMF N,N-dimethylformamide
DMP Dess–Martin periodinane
HAT hydrogen-atom transfer
HRMS high-resolution mass spectrometry
IMDA intramolecular Diels–Alder
IR infrared
iv
LR Lawesson’s reagent
LRMS low-resolution mass spectrometry
mCPBA meta-chloroperbenzoic acid
MeOH methanol
Ms methanesulfonyl
MS molecular sieves
NMM N-methylmorpholine
NMR nuclear magnetic resonance
NOESY nuclear Overhauser effect spectroscopy
Ns 2-nitrobenzenesulfonyl
o-DCB 1,2-dichlorobenzene
pin pinacolato
PMP 1,2,2,6,6-pentamethylpiperidine
PPTS pyridinium p-toluenesulfonate
PTSA p-toluenesulfonic acid
Ra-Ni Raney nickel
TBAF tetrabutylammonium fluoride
TBDPS tert-butyldiphenylsilyl
v
TBS tert-butyldimethylsilyl
TEMPO 2,2,6,6-Tetramethylpiperidine 1-oxyl
Tf trifluoromethanesulfonyl
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
THF tetrahydrofurn
TIPB 1,3,5-triisopropylbenzene
TMG N,N,N’,N’-tetramethylguanidine
TMS trimethylsilyl
Ts p-toluenesulfonyl
UV ultraviolet
VT-NMR variable temperature nuclear magnetic resonance

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