DEVELOPMENT OF CATALYTIC ENANTIOSELECTIVE ALDOL, MANNICH, FRIEDLAENDER ...

483 Pages·2010·15.05 MB·English

DEVELOPMENT OF CATALYTIC ENANTIOSELECTIVE ALDOL, MANNICH, FRIEDLAENDER
REACTIONS
by
LE LI
A dissertation submitted to the
Graduate School-New Brunswick
Rutgers, The State University of New Jersey
In partial fulfillment of the requirements
For the degree of
Doctor of Philosophy
Graduate Program in Chemistry and Chemical Biology
Written under the direction of
Professor Daniel Seidel
And approved by
__________________
__________________
__________________
__________________
New Brunswick, New Jersey
October, 2010
ABSTRACT OF THE DISSERTATION
DEVELOPMENT OF CATALYTIC ENANTIOSELECTIVE ALDOL, MANNICH, FRIEDLÄNDER
REACTIONS
By LE LI
Dissertation Director:
Professor Daniel Seidel
In Chapter I, I introduce the explosive development of enantioselective organocatalysis.
Selected significant landmarks in this area are reviewed and highlighted in this chapter.

Chapter II focuses on the development of catalytic enantioselective aldol additions of (cid:1)-
isothiocyanato imides to aldehydes and (cid:1)-ketoesters.

Chapter III outlines the development of enantioselective Mannich reactions of (cid:1)-
isothiocyanato imides with activated imines and the asymmetric synthesis of (cid:1), (cid:2)-
diamino acid derivatives.

In Chapter IV, the first catalytic enantioselective Friedländer condensation is described
which provides access to quinolines and tacrines with remote stereogenic centers.
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ACKNOWLEDGEMENTS

First of all, I would like to truly appreciate my advisor, Dr. Daniel Seidel, for his
guidance and motivation in the last five years at Rutgers University. This thesis would
not have been possible without him. In addition, I am very grateful for having an
outstanding doctoral committee and wish to thank the rest of my committee members, Dr.
Haiming Zhang, Dr. Kai Hultzsch, Dr. Lawrence Williams, and Dr. Xumu Zhang, for
their generous support and helpful discussions.

Also, I would like to thank Prof. Karsten Krogh-Jespersen and Dr. Thomas Emge for
their technical support and beneficial suggestions in computation and crystallography.

I thank all the members of the Seidel Group. In particular, I would like to thank Michael
Haibach and Matthew Vecchione for their helpful suggestions during the preparation of
this thesis. Moreover, I would like to thank a lot of friends in chemistry, in the
department and outside.

Finally, I cannot forget giving my sincere gratitude to my family. Their love and
continuous support make everything easier.
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DEDICATION

I dedicate this thesis to my beloved grandmother, parents and wife. Their love and
continuous support always encourage me to move forward.

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Table of Contents
Abstract of the dissertation.................................................................................................ii
Acknowledgements............................................................................................................iii
Dedication..........................................................................................................................iv
List of figures.....................................................................................................................xi
List of schemes.................................................................................................................xii
List of tables.....................................................................................................................xiv
Chapter 1 Introduction........................................................................................................1
1.1 Background...............................................................................................................1
1.1.1 History................................................................................................................1
1.1.2 Renaissance and Explosive Development..........................................................3
1.2 Major Branches of Organocatalysis..........................................................................4
1.2.1 Enamine Catalysis..............................................................................................4
1.2.2 Iminium Catalysis...............................................................................................6
1.2.3 Hydrogen Bond Catalysis...................................................................................8
1.2.4 Stronger Brønsted Acid Catalysis.....................................................................10
1.2.5 Phase Transfer Catalysis...................................................................................12
1.2.6 N-heterocyclic Carbenes as Organocatalysts...................................................14
1.2.7 Lewis Base Catalysis.......................................................................................15
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1.2.8 Miscellaneous Types........................................................................................18
1.3 Objectives................................................................................................................19
References.....................................................................................................................21
Chapter 2 Catalytic Enantioselective Synthesis of (cid:2)-Hydroxy-(cid:1)-Amino Acid Derivatives
...........................................................................................................................................30
2.1 Background.............................................................................................................30
2.1.1 Significance of (cid:2)-Hydroxy-(cid:1)-Amino Acid Derivatives...................................30
2.2 Proposal and Objective............................................................................................33
2.3 Results and Discussions..........................................................................................33
2.3.1 General Considerations.....................................................................................33
2.3.2 Preliminary Investigation on Aldol Reactions of (cid:1)-Isocyano Acetates with
Benzaldehydes...........................................................................................................33
2.3.3 Development of Organocatalyzed Aldol Reactions of (cid:1)-Isothiocyanato Imides
and Esters with Aldehydes........................................................................................35
2.3.3.1 Reaction Development..................................................................................35
2.3.3.2 Scope of the Reactions..................................................................................39
2.3.3.3 Scale-up Synthesis of Protected (cid:2)-Hydroxy-(cid:1)-Amino Acid.........................41
2.3.3.4 Summary........................................................................................................41
2.3.4 Development of Organocatalyzed Aldol Reactions of (cid:1)-Isothiocyanato Imides
and Esters with (cid:1)-Ketoesters.....................................................................................41
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2.3.4.1 Reaction Development..................................................................................41
2.3.4.2 Substrate Scope..............................................................................................45
2.3.4.3 Summary........................................................................................................46
2.3.5 Latest Progress in this Area..............................................................................46
2.4 Experimental Section..............................................................................................47
2.4.1 Preparation of Substrates and Precursors.........................................................47
2.4.2 Preparation of Catalysts....................................................................................50
2.4.3 General Procedure for the Catalytic Aldol Reaction Between 2.46 and
Aldehyde....................................................................................................................51
2.4.4 General Procedure for Catalytic Aldol reaction between isothiocyanates and a-
ketoesters...................................................................................................................52
2.4.5 Preparation Procedures for Racemic Samples..................................................52
2.4.6 Product Characterization Data..........................................................................53
2.4.7 Scale-up Preparation of 3-((4R,5S)-5-(4-fluoro-3-nitrophenyl)-2-
thioxooxazolidine-4-carbonyl)-4,4-dimethyloxazolidin-2-one (2.51)......................74
References.....................................................................................................................76
Chapter 3 Catalytic Enantioselective Synthesis of (cid:1),(cid:2)-Diamino Acid Derivatives..........81
3.1 Background.............................................................................................................81
3.1.1 Significance of Chiral (cid:1),(cid:2)-Diamino Acid Derivatives.....................................81
3.1.2 Synthetic Methods for (cid:1),(cid:2)-Diamino Acid Derivatives.....................................82
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3.2 Proposal and Objective............................................................................................84
3.3 Results and Discussions..........................................................................................85
3.3.1 General Considerations.....................................................................................85
3.3.2 Reaction Development.....................................................................................86
3.3.3 Substrate Scope.................................................................................................89
3.3.4 Synthesis of a Chiral (cid:1),(cid:2)-Diamino Acid...........................................................91
3.3.5 Conclusion........................................................................................................92
3.3.6 Latest Development in this Area......................................................................92
3.4 Experimental Section..............................................................................................93
3.4.1 Preparation Procedures for Substrates and Catalysts.......................................93
3.4.2 General Procedure for the Catalytic Mannich Reaction Between
Isothiocyanates and Imines........................................................................................93
3.4.3 General Procedure for the Conversion of Primary Products into Their
Corresponding Ethyl Esters.......................................................................................93
3.4.4 Preparation Procedures for Racemic Samples..................................................94
3.4.5 Product Characterization Data..........................................................................94
3.4.6 Procedure for the Conversion of Products 3.36a Into Its Corresponding
Diamino Acids.........................................................................................................122
References...................................................................................................................127
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Chapter 4 Facile Access to Tetrahydroacridine Derivatives with Remote Stereogenic
Centers: Catalytic Enantioselective Friedländer Condensations....................................131
4.1 Background...........................................................................................................131
4.1.1 Significance of Tetrahydroacridine Derivatives.............................................131
4.1.2 Synthetic Methods for Tacrine and Tetrahydroacridine Derivatives.............132
4.1.3 Enamine Catalysis as a Powerful Synthetic Tool...........................................133
4.2 Proposal and Objective..........................................................................................136
4.3 Results and Discussions........................................................................................137
4.3.1 General Considerations...................................................................................137
4.3.2 Evaluation of Catalysts...................................................................................138
4.3.3 Evaluation of Solvents....................................................................................142
4.3.4 Substrate Scope...............................................................................................144
4.3.5 Synthesis of a Chiral Non-Racemic Tacrine Analog......................................146
4.3.6 Computational Study......................................................................................148
4.3.7 Conclusion......................................................................................................150
4.4 Experimental Section............................................................................................150
4.4.1 Preparation Procedures for Catalysts, Cyclohexanones and Amino Aldehydes
.................................................................................................................................150
4.4.2 General Procedure for Catalytic Enantioselective Friedländer Condensations
.................................................................................................................................151
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4.4.3 Product Characterization Data........................................................................151
4.4.4 Synthesis of a Chiral Tacrine Analog.............................................................164
4.4.5 Computational Studies....................................................................................167
References...................................................................................................................185
Appendix: Selected HPLC Profiles and NMR Spectra...................................................194
Curriculum Vitae............................................................................................................469

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