Stereocontrolled Synthesis of Ketones bearing Stereogenic Centers by Desulfitative Cross-Coupling of Thiol Esters and Organostannanes Público

Abstract

Stereocontrolled Synthesis of Ketones bearing Stereogenic Centers by Desulfitative Cross-Coupling of Thiol Esters and Organostannanes
By Hao Li

An efficient synthesis of high enantiopurity N-protected α-amino ketones is described. Complementing other studies using boronic acids and thiol esters, this palladium-catalyzed, Cu(I) diphenylphosphinate-mediated coupling of α-amino thiol esters with aryl, heteroaryl, allyl and vinyl organostannanes gives N-protected α-amino ketones in high yields with high enantiopurity (in almost all cases) under mild and pH-neutral reaction conditions. Advantages of this new reaction compared to the related boronic acid system are the use of only 1.1 equiv of the organostannane reactant to complete the coupling reaction, and the viability of π-deficient heteroarylstannanes, which are superior to the corresponding boronic acids in overall coupling reactivity.

A stereocontrolled synthesis of α,α′-aminoalkoxy ketones is described. As a new approach to enantioenriched α-alkoxy ketones, this pH-neutral copper(I) thiophene-2-carboxylate-catalyzed cross-coupling of amino acid thiol esters and chiral α-(thiocarbamoyl)alkylstannanes gives α,α′-aminoalkoxy ketones in good to excellent yields with complete retention of configuration at the α-stannyl- and α-alkoxy-substituted stereocenters.

Thiol esters derived from 4-nitrothiophenol were coupled with chiral α-alkoxyalkylstannanes in the presence of stoichiometric Cu(I) thiophene-2-carboxylate to give α-sulfenylated ketones in moderate to good yields through a stereocontrolled O-S rearrangement. Compared with the α,α′-aminoalkoxy ketone synthesis using catalytic amounts of CuTC, this stoichiometric CuTC-mediated thiol ester-α-alkoxyalkylstannane cross-coupling/O-S rearrangement provided an efficient method for the construction of enantioenriched α-sulfenylated ketones. Using only CuTC in this alkylstannane coupling suggests a non-oxidative addition pathway.

Stereocontrolled Synthesis of Ketones bearing Stereogenic Centers by Desulfitative Cross-Coupling of Thiol Esters and Organostannanes
By Hao Li
B.S., Zhejiang University, 2001
M.S., Peking Union Medical College, 2004
Advisor: Lanny S. Liebeskind, Ph.D.
A dissertation submitted to the Faculty of the
James T. Laney School of Graduate Studies of Emory University
in partial fulfillment of the requirements for the degree of
Doctor of Philosophy
in Chemistry
2009

Table of Contents

Table of Contents
Chapter 1

Synthesis of High Enantiopurity N-Protected α-Amino Ketones by Thiol
Ester−Organostannane Cross-Coupling using pH-Neutral Conditions
1.1 Introduction and Background................................................................................... 2
1.2 Results and Discussion ............................................................................................. 7
1.2.1 Preliminary Study .............................................................................................. 7
1.2.2 Scope and Limitations of Peptidic Thiol Ester−Organostannane
Cross-Coupling ........................................................................................................... 9
1.3 Conclusion .............................................................................................................. 14
1.4 Experimental Section .............................................................................................. 15
1.4.1 General Experimental ...................................................................................... 15
1.4.2 Starting Materials............................................................................................. 16
1.4.3 Experimental .................................................................................................... 17
1.5 References ............................................................................................................... 50
Chapter 2
Stereocontrolled α,α′-Aminoalkoxy Ketone Synthesis by Thiol Ester and
α-Alkoxyalkylstannanes Cross-Coupling
2.1 Introduction and Background................................................................................. 55
2.2 Results and Discussion ........................................................................................... 60
2.2.1 Preliminary Study ............................................................................................ 60
2.2.2 Stereocontrolled Desulfitative Coupling of Amino Acid Thiol Esters and
Enantioenriched α-Alkoxyalkylstanne ..................................................................... 62

2.3 Conclusion ..............................................................................................................

67
2.4 Experimental Section .............................................................................................. 67
2.4.1 General Experimental ...................................................................................... 67
2.4.2 Starting Materials............................................................................................. 68
2.4.3 Experimental .................................................................................................... 68
2.5 References ............................................................................................................... 89
Chapter 3
Stereocontrolled α-Sulfenylated Ketone Synthesis by Thiol
Ester−α-(Thiocarbamoyl)alkylstannane Cross-Coupling
3.1 Introduction and Background................................................................................. 93
3.2 Results and Discussion ........................................................................................... 97
3.2.1 Preliminary Study ............................................................................................ 97
3.2.2 Scope and Limitations.................................................................................... 103
3.2.3 Mechanistic Study.......................................................................................... 107
3.3 Conclusion ............................................................................................................ 109
3.4 Experimental Section ............................................................................................ 112
3.4.1 General Experimental .................................................................................... 112
3.4.2 Starting Materials........................................................................................... 113
3.4.3 Experimental .................................................................................................. 113
3.5 References ............................................................................................................. 135

List of Schemes
Chapter 1

Scheme 1.1 Peptidyl Ketones from Thiol Esters and Organostannanes..................... 2
Scheme 1.2 Known Methods for the Synthesis of α-Amino Ketones........................ 3
Scheme 1.3 Ketone Synthesis Using Organozinc Reagents ....................................... 4
Scheme 1.4 Liebeskind-Srogl Cross-Coupling........................................................... 5
Scheme 1.5 A Family of Desulfitative Cross-Couplings............................................ 6
Scheme 1.6 Thiol Ester−Organostannane Cross-Coupling ........................................ 6
Scheme 1.7 N-Protected α-Amino Thiol Esters and Boronic Acids Coupling .......... 7
Chapter 2
Scheme 2.1 α,α′-Aminoalkoxy Ketones from Thiol Esters and Alkylstannanes..... 55
Scheme 2.2 α-Hydroxylation of Enolates Using Chiral
Camphorylsulfonyloxaziridines........................................................................ 56
Scheme 2.3 Asymmetric α-Hydroxylation of Ketone Silyl Enol Ethers.................. 56
Scheme 2.4 Asymmetric α-Hydroxylation Using Chiral Catalysts.......................... 57
Scheme 2.5 Palladium-Catalyzed Cross-Couplings of Acyl Chlorides and
α-Alkoxyalkylstannanes ................................................................................... 57
Scheme 2.6 Copper-Catalyzed Cross-Couplings of Acyl Chlorides and
α-Alkoxyalkylstannanes ................................................................................... 58
Scheme 2.7 1st Generation System Requires Stoichiometric CuI Carboxylate......... 59
Scheme 2.8 This Proposed Chemistry: Thiolate Paired with Bu3Sn-....................... 59
Scheme 2.9 Control Experiments with sp2-Hydridized Coupling Partners .............. 62
Scheme 2.10 Confirmation of Stereochemistry ........................................................ 65

About this Dissertation

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School	Laney Graduate School
Department	Chemistry
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Palabra Clave	Synthesis Thiol Esters Coupling Organostannanes Stereocontrolled Ketone
Committee Chair / Thesis Advisor	Liebeskind, Lanny S, Emory University
Committee Members	Menger, Fred M, Emory University McDonald, Frank, Emory University

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