Direct Carbon-Carbon Bond Formation via Base Mediated and Reductive Soft

342 Pages·2012·10.83 MB·English

by  Hugh Crumley

Direct Carbon-Carbon Bond Formation via Base Mediated and Reductive Soft
Enolization of Thioesters, the First Asymmetric Total Synthesis of (+)- and (-)-
Clusianone, and Progress Toward the Asymmetric Total Synthesis of Brasilicardin A
by
Michelle Renee Garnsey
Department of Chemistry
Duke University

Date:_______________________
Approved:

___________________________
Dr. Don M. Coltart, Supervisor

___________________________
Dr. Steven Baldwin

___________________________
Dr. Eric Toone

___________________________
Dr. Cynthia Kuhn

Dissertation submitted in partial fulfillment of
the requirements for the degree of Doctor of Philosophy in the Department of
Chemistry in the Graduate School
of Duke University

2012

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v
ABSTRACT
Direct Carbon-Carbon Bond Formation via Base Mediated and Reductive Soft
Enolization of Thioesters, the First Asymmetric Total Synthesis of (+)- and (-)-
Clusianone, and Progress Toward the Asymmetric Total Synthesis of Brasilicardin A
by
Michelle Renee Garnsey
Department of Chemistry
Duke University

Date:_______________________
Approved:

___________________________
Dr. Don M. Coltart, Supervisor

___________________________
Dr. Steven Baldwin

___________________________
Dr. Eric Toone

___________________________
Dr. Cynthia Kuhn

An abstract of a dissertation submitted in partial
fulfillment of the requirements for the degree
of Doctor of Philosophy in the Department of
Chemistry in the Graduate School
of Duke University

2012
i
v
Copyright by
Michelle Renne Garnsey
2012
Abstract
Three methodology studies and two total synthesis endeavors are presented.
First, a study of Lewis acid and hydrogen bond mediated soft enolization of thioesters
and their addition to imines in the Mannich reaction is reported. MgBr •OEt and
2 2
Hunig’s base are used in concert with bulky thioesters and aromatic aldehydes to
generate syn--aminothioesters with moderate diastereoselectivity and yield. Next, a
biomimetic organocatalytic Mannich reaction is presented using a chiral cinchona
alkaloid to effect the enantioselective addition of an imines to thioesters with high yield
and diastereoselectivity and enantioselectivities up to 88:12.

The direct addition of enolizable aldehydes to -iodo thioesters to produce -
hydroxy thioesters enabled by reductive soft enolization is reported. The transformation
is operationally simple and efficient and has the unusual feature of giving high syn-
selectivity, which is the opposite of that produced in the aldol addition with (thio)esters

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under conventional conditions. This method is tolerant to aldehydes and imines that
contain acidic -protons, as well as electrophiles containing other acidic protons and
base-sensitive functional groups.

The development of a strategy for the asymmetric synthesis of a large portion of
the polycyclic polyprenylated acyl phloroglucinols via N-amino cyclic carbamate
hydrazones, and its application to the first asymmetric total synthesis of both (+)- and (-
)-clusianone is discussed. The clusianones are synthesized with an er of 99:1 and their
anti-HIV activity is found to be 1.53 and 1.13 M, respectively. A library of clusianone-
like compounds is synthesized and their biological activity has been probed.

Finally, efforts towards the total synthesis of brasilicardin A are reported. An
appropriate model system was synthesized, and conditions were established using a
pinene-based aldol reaction to synthesize the -methoxy--amino ester side chain of the
molecule. Next, efforts toward the synthesis of the anti-syn-anti- perhydro-
phenanthrene core are discussed.

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To my family. For always encouraging me to Dream Big.

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Contents
Abstract ......................................................................................................................................... iv
Contents ....................................................................................................................................... vii
List of Tables ................................................................................................................................ xii
List of Figures .............................................................................................................................xiv
List of Schemes ............................................................................................................................ xv
Acknowledgements ................................................................................................................... xxi
Chapter 1. A Study of Lewis Acid and Hydrogen Bond Mediated Soft Enolization in the
Context of the Mannich Reaction................................................................................................ 1
1.1 Introduction ....................................................................................................................... 2
1.1.1 Soft Enolization ............................................................................................................ 2
1.1.1.1 Historical Perspective .......................................................................................... 3
1.1.1.2 Hard vs. Soft Enolization .................................................................................... 4
1.1.1.3 The Aldol Reaction .............................................................................................. 6
1.1.1.4 The Mannich Reaction ....................................................................................... 12
1.1.2 Importance of Thioesters .......................................................................................... 16
1.2 Diastereoselective Mannich Reaction .......................................................................... 18
1.2.1 Results ......................................................................................................................... 18
1.2.2 Stereochemical Model ............................................................................................... 22
1.3 Biomimetic Mannich Reaction ...................................................................................... 23
1.3.1 Results ......................................................................................................................... 23
1.3.2 Determination of the Absolute Stereochemistry ................................................... 30

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1.3.3 Stereochemical Model .............................................................................................. 31
1.4 Conclusion ....................................................................................................................... 32
1.5 Experimental ................................................................................................................... 33
1.5.1 General Considerations .............................................................................................. 33
1.5.2 Magnesium-Promoted Mannich Reaction with Various Sulfonylimines ............ 34
1.5.2.1 Thioester Preparation ............................................................................................. 34
1.5.2.2 Imine Preparation ................................................................................................... 35
1.5.2.3 MgBr ●OEt Promoted Mannich Reaction .......................................................... 36
2 2
1.5.3 Biomimetic Mannich Reaction ................................................................................... 43
1.5.3.1 Thioester Preparation ............................................................................................. 43
1.5.3.2 Catalyst Preparation ............................................................................................... 44
1.5.3.3 Imine Preparation ................................................................................................... 46
1.5.3.4 Biomimetic Mannich Reaction with Various Sulfonylimines .......................... 46
1.5.3.5 Determination of Absolute Stereochemistry of 1.120 ........................................ 54
Chapter 2. Direct Carbon-Carbon Bond Formation via Reductive Soft Enolization: A
Kinetically Controlled syn-Aldol Addition of -Halo Thioesters and Enolizable
Aldehydes .................................................................................................................................... 57
2.1 Introduction ..................................................................................................................... 58
2.2 Results and Discussion .................................................................................................. 64
2.2.1 Development of Conditions for the Reductive Aldol Reaction .......................... 64
2.2.2 Determination of the Scope of the Reductive Aldol Reaction ............................. 68
2.2.3 Mechanistic Studies of the Reductive Aldol Reaction.......................................... 69
2.2.4 A Stereochemical Model for the Reductive Aldol Reaction ................................ 76

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2.3 Conclusion ....................................................................................................................... 77
2.4 Experimental ................................................................................................................... 78
2.4.1 General Considerations ............................................................................................ 78
2.4.2 Procedures and Characterization ............................................................................ 79
2.4.2.1 Synthesis of Thioesters ...................................................................................... 79
2.4.2.2 Synthesis of -Hydroxy Carboxylic Acid Derivatives .................................. 84
2.4.2.3 Synthesis of -Hydroxy Thioesters.................................................................. 85
4.2.2.4 Stereochemical Determination of Aldol Addition Product ......................... 93
Chapter 3. Development of a Strategy for the Asymmetric Synthesis of Polycyclic
Polyprenylated Acylphloroglucinols via Chiral N-Amino Cyclic Carbamate Hydrazones:
Application to the Total Synthesis of (+)- and (–)-Clusianone .............................................. 94
3.1 Introduction ..................................................................................................................... 95
3.1.1 Polycyclic Polyprenylated Acylphloroglucinols ................................................... 95
3.1.2 Prior Synthetic Work ................................................................................................. 97
3.1.2.1 PPAP family ........................................................................................................ 97
3.1.2.2 Clusianone .......................................................................................................... 99
3.1.3 N-Amino Cyclic Carbamate Chiral Auxiliaries in the Asymmetric -Alkylation
of Ketones .......................................................................................................................... 103
3.2 The Asymmetric Total Synthesis of (+)-Clusianone ................................................ 107
3.2.1 Retrosynthetic Analysis ............................................................................................ 107
3.2.2 The Asymmetric Total Synthesis of (+)-Clusianone ............................................. 109
3.2.2.1 The Use of N-Amino Cyclic Carbamate Chiral Auxiliaries ............................ 109
3.2.2.2 Formation of the [3.3.1]-Bicyclic Core ............................................................... 116

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3.2.2.3 Completion of the Asymmetric Total Synthesis of (+)-Clusianone ............... 123
3.3 The Asymmetric Total Synthesis of (-)-Clusianone ................................................. 125
3.4 A General Approach to the PPAP Family of Compounds ..................................... 128
3.5 The Synthesis of a Library of (+)-Clusianone Derivatives and their Anti-HIV
activity .................................................................................................................................. 132
3.5.1 The Anti-HIV Activity of (+)-Clusianone, (-)-Clusianone and (+)- and (-)-
Clusianone Methyl Enol Ether ........................................................................................ 132
3.5.2 Synthesis of a Library of (+)-Clusianone Derivatives ......................................... 134
3.6 Conclusion ..................................................................................................................... 138
3.7 Experimental ................................................................................................................. 139
3.7.1 General Considerations .......................................................................................... 139
3.7.2 Procedures and Characterization .......................................................................... 140
3.7.2.1 Towards the First Asymmetric Total Synthesis of (+)-Clusianone ........... 140
3.7.2.2 Towards the First Asymmetric Total Synthesis of (-)-Clusianone ............ 171
3.7.2.3 A General Method of the Synthesis of the PPAPs Family ......................... 176
3.7.2.4 The Experimental Information for the Anti-HIV Testing .......................... 180
3.7.2.5 The Synthesis of a Library of Clusianone-Like Compounds ..................... 182
3.7.2.6 Auxiliary Synthesis .......................................................................................... 192
Chapter 4. Efforts Toward the Total Synthesis of Brasilicardin A Aglycone ................... 198
4.1 Introduction ................................................................................................................... 199
4.1.1 Isolation and Biological Activity ........................................................................... 199
4.1.2 Structure and Synthetic endeavors ....................................................................... 201
4.2 A Model Study for the -Methoxy--Amino Acid Side Chain .............................. 204

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