Leveraging the Reactivity of Thioesters in the Development of New Methods for Carbon–Carbon

181 Pages·2009·3.18 MB·English

Leveraging the Reactivity of Thioesters in the Development of
New Methods for Carbon–Carbon Bond Formation
by
Julianne Marie Yost
Department of Chemistry
Duke University
Date:_______________________
Approved:
___________________________
Don M. Coltart, Supervisor
___________________________
Steven W. Baldwin
___________________________
Katherine J. Franz
___________________________
Eric J. Toone
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
2009
v
ABSTRACT
Leveraging the Reactivity of Thioesters in the Development of
New Methods for Carbon–Carbon Bond Formation
by
Julianne Marie Yost
Department of Chemistry
Duke University
Date:_______________________
Approved:
___________________________
Don M. Coltart, Supervisor
___________________________
Steven W. Baldwin
___________________________
Katherine J. Franz
___________________________
Eric J. Toone
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
2009
Copyright by
Julianne Marie Yost
2009
Abstract
Z
O ZH O
polyketide and
R2 H
SR R2 SR alkaloid-based
R1 soft enolization R1 structures
conditions
Carbon–carbon bond-forming reactions comprise the most important class of
synthetic transformations. The development of improved and simplified approaches to
these reactions will make important and useful contributions not only to the field of
synthetic organic chemistry, but also to the many other areas of science that rely on it.
Enolate based carbon–carbon bond formation is fundamental to synthetic organic
chemistry and has provided the foundation for advancement to its present state. Herein,
an important aspect of enolate chemistry is explored: the development of direct methods
for carbon–carbon bond formation based on soft enolization of thioesters. Both metal-
mediated and organocatalytic approaches to soft enolization are described.
MgBr ·OEt -promoted soft enolization conditions were developed and
2 2
successfully applied to the aldol addition and Mannich reactions, resulting in a mild and
efficient direct reaction that is inexpensive and can be used under atmospheric
conditions. A conjugate addition approach to chemoselective deprotonation was also
explored and applied to the aldol. In addition, the first organocatalytic Mannich
reaction based on proximity-accelerated intramolecular soft enolization of thioesters was
developed. Given the advantages of soft enolization, including the inherent operational
simplicity, and the accessibility of thioesters, we expect these methods to meet with
wide application.
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Dedicated to my loving husband, Matthew.
v
Table of Contents
Abstract................................................................................................................................................iv
Table of Contents................................................................................................................................vi
List of Tables....................................................................................................................................viii
List of Figures.......................................................................................................................................x
List of Abbreviations......................................................................................................................xiii
Acknowledgements.......................................................................................................................xvii
Leveraging the Reactivity of Thioesters in the Development of New Methods for
Carbon–Carbon Bond Formation.....................................................................................................1
1. Enolate-Mediated Carbon–Carbon Bond Formation..............................................................3
1.1 Pre-LDA Era of Enolate Formation....................................................................................5
1.2 Prior Enolate Formation.......................................................................................................6
1.3 Soft Enolization......................................................................................................................8
1.4 Using Thioesters in Soft Enolization..................................................................................9
1.5 Enolization in Nature.........................................................................................................11
1.6 Organocatalysis...................................................................................................................14
1.6.1 Hydrogen-Bonding Organocatalysis..........................................................................16
1.7 Aldol Addition Reaction....................................................................................................18
1.8 Mannich Reaction................................................................................................................20
2. Results and Discussion................................................................................................................23
2.1 Direct Aldol Addition of Simple Thioesters Employing Soft Enolization................23
2.2 Soft Enolization of Thioesters: Direct Mannich Addition Reaction...........................36
2.3 Stereoselective Aldol Addition of α-Halogenated Thioesters Employing Soft
Enolization...................................................................................................................................43
2.4 Organocatalytic Asymmetric Mannich Reaction via Soft Enolization of Thioesters
........................................................................................................................................................53
vi
2.5 Anti-Selective Four-Component Direct Aldol Addition via Chemoselective
Thioester Enolate Formation....................................................................................................66
3. Conclusion.....................................................................................................................................77
4. Experimental Section...................................................................................................................79
4.1 Direct Aldol Addition of Simple Thioesters Employing Soft Enolization................80
4.2 Soft Enolization of Thioesters: Direct Mannich Addition Reaction...........................95
4.3 Stereoselective Aldol Addition of α-Halogenated Thioesters Employing Soft
Enolization.................................................................................................................................108
4.4 Organocatalytic Asymmetric Mannich Reaction via Soft Enolization of Thioesters
......................................................................................................................................................114
4.5 Anti-Selective Four-Component Direct Aldol Addition via Chemoselective
Thioester Enolate Formation..................................................................................................133
Works Cited......................................................................................................................................147
Biography.........................................................................................................................................163
vii
List of Tables
Table 1: Metal Screen for the Direct Aldol Addition Reaction................................................24
Table 2: Investigations of the Effect of the Thiol on Thioester Reactivity in the MgI -
2
Promoted Direct Aldol Reaction....................................................................................................27
Table 3: Simplifying the Direct Aldol Reaction to Employ MgBr ·OEt Under
2 2
Atmospheric Conditions..................................................................................................................30
Table 4: MgBr ·OEt -Promoted Direct Aldol Addition between S-Phenyl Thioacetate and
2 2
Various Aldehydes using Untreated Solvent under Atmospheric Conditions.....................32
Table 5: MgBr ·OEt -Promoted Direct Aldol Reaction of α-Substituted Thioesters with
2 2
Benzaldehyde.....................................................................................................................................33
Table 6: Reevaluation of the Effect of the Thiol on Reactivity and Comparison to the
Corresponding Oxoesters using MgBr ·OEt ...............................................................................35
2 2
Table 7: Scope of the MgBr ·OEt -Promoted Thioester Mannich Addition Reaction Using
2 2
S-Phenyl Thioacetate........................................................................................................................38
Table 8: Effect of the Thioester on Diastereoselectivity in the MgBr ·OEt -Promoted
2 2
Mannich Addition Reaction............................................................................................................40
Table 9: Scope of the MgBr ·OEt -Promoted Thioester Mannich Addition Reaction Using
2 2
2,4,6-Triisopropylphenyl Thioester T8.11.....................................................................................41
Table 10: Scope of the MgBr ·OEt -Promoted Aldol Addition Reaction Using S-Phenyl
2 2
α-Bromothioacetate...........................................................................................................................45
Table 11: Effect of the Halogen on Rate in the MgBr ·OEt -Promoted Aldol Addition
2 2
Reaction...............................................................................................................................................46
Table 12: Effect of the Thiol Component on Diastereoselectivity in the MgBr ·OEt -
2 2
Promoted Aldol Addition Reaction using α-Halogenated Thioesters....................................51
Table 13: Survey of Catalyst Loading in the Biomimetic Mannich Reaction........................56
Table 14: Survey of Thioesters for the Biomimetic Mannich Reaction...................................58
Table 15: Survey of (Thio)urea Catalysts for the Biomimetic Mannich Reaction.................60
Table 16: Survey of Solvents for the Biomimetic Mannich Reaction......................................61
Table 17: Scope of the Biomimetic Mannich Reaction with Various Sulfonylimines..........62
Table 18: Direct Four-Component Aldol Reaction with Various Aldehydes.......................69
viii
Table 19: Effect of Acrylate Structure on Diastereoselectivity in the Direct Four-
Component Aldol Reaction.............................................................................................................73
Table 20: Selected 1H NMR Shifts and Coupling Constants for Mannich Products T8.12,
T9.1–T9.3...........................................................................................................................................108
Table 21: HPLC Retention Times of the Racemic Controls for the Organocatalytic
Mannich Addition Reaction..........................................................................................................129
ix
List of Figures
Figure 1: Regioselectivity and Chemoselectivity Issues of Deprotonation in Selected
Enolate Reactions................................................................................................................................4
Figure 2: Pre-LDA Methods for Enolization.................................................................................6
Figure 3: Methods for Enolate Formation: Hard and Soft Enolization....................................8
Figure 4: Chemoselective Transformations of Thioesters.........................................................10
Figure 5: Fatty Acid Biosynthesis: Nature's Approach to Prior Enolate Formation using
Thioesters............................................................................................................................................11
Figure 6: Citrate Synthase: Nature's Approach to Direct Bond Formation using
Thioesters............................................................................................................................................12
Figure 7: Chiral Thiourea Catalysis of the Strecker Reaction as Reported by Jacobsen......16
Figure 8: Bidentate Hydrogen-Bonding Activation of a Carbonyl Compound...................17
Figure 9: Selected Examples of Chiral Thioureas and Ureas Used in Hydrogen-Bond
Based Catalysis..................................................................................................................................17
Figure 10: Base-Mediated Aldol Addition Reaction..................................................................18
Figure 11: Selected Examples of Polyketide Natural Products and Drugs Synthesized
Using the Aldol Reaction.................................................................................................................19
Figure 12: A) Mannich Reaction and Subsequent Transformations B) Common
Byproducts in the Direct Mannich Reaction................................................................................21
Figure 13: Selected Examples of Natural Products and Drugs Synthesized Using the
Mannich Reaction..............................................................................................................................22
Figure 14: MgI -Promoted Direct Aldol Reaction of Thioester T1.1 and Oxoester F14.1
2
with Benzaldehyde...........................................................................................................................25
Figure 15: Competition Experiments to Establish Superior Reactivity of Thioesters over
other Carboxylate Derivatives........................................................................................................26
Figure 16: Bis-alkylated Byproduct and Representative Tertiary Amine Bases Screened
..............................................................................................................................................................31
Figure 17: Model Studies of the MgBr ·OEt -Promoted Mannich Addition Employing
2 2
Soft Enolization..................................................................................................................................37
x