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Synlett 2009(8): 1189-1207  
DOI: 10.1055/s-0029-1216654
ACCOUNT
© Georg Thieme Verlag Stuttgart ˙ New York

The Catalytic Asymmetric Intramolecular Stetter Reaction

Javier Read de Alaniz, Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Fax: +1(970)4911801; e-Mail: rovis@lamar.colostate.edu;
Further Information

Publication History

Received 30 August 2008
Publication Date:
22 April 2009 (online)

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Abstract

This Account chronicles our efforts in the development of the catalytic asymmetric Stetter reaction using chiral triazolium salts as small molecule organic catalysts. Advances in the mechanistically related azolium-catalyzed asymmetric benzoin reaction are discussed, particularly as they apply to catalyst design. A chronological treatise of reaction discovery, catalyst optimization and reactivity extension follows.

1 Introduction

2 Proposed Mechanism of the Benzoin and Stetter Reactions

3 The Benzoin Reaction

4 Synthesis of Chiral Bicyclic Triazolium Salts

4.1 Aminoindanol-Derived Bicyclic Scaffold

4.2 Phenylalanine-Derived Bicyclic Scaffold

5 The Intermolecular Stetter Reaction

6 The Asymmetric Intramolecular Stetter Reaction

6.1 Recent Contributions to the Asymmetric Intramolecular Stetter Reaction

6.2 Comparison of the Asymmetric Intramolecular Stetter ­Reaction with Two Different Triazolium Carbene Scaffolds

6.3 Scope of the Intramolecular Stetter Reaction with Different Tethers

6.4 Electronic Effects of the Aromatic Backbone of the Aldehyde on the Intramolecular Stetter Reaction

6.5 Effects of the Michael Acceptor on the Asymmetric Intra-molecular Stetter Reaction

6.6 The Asymmetric Intramolecular Stetter Reaction of Aliphatic Aldehydes

7 Effects of Pre-existing Stereocenters on the Intramolecular Stetter Reaction

8 Synthesis of Quaternary Stereocenters via the Asymmetric Intramolecular Stetter Reaction

9 Synthesis of Contiguous Stereocenters via the Asymmetric Intramolecular Stetter Reaction

10 Asymmetric Synthesis of Hydrobenzofuranones via the Intramolecular Stetter Reaction

11 Applications to Total Synthesis

12 Summary and Outlook

Key words

asymmetric synthesis - triazolium salts - quaternary ­stereocenters - carbene catalysis - nucleophilic catalysis - organocata-lysis - Stetter reaction - benzoin reaction

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43

Investigation of the enantioselectivity as a function of conversion revealed that 80 is formed in 80% ee at 10% conversion, with rapid erosion to 50% ee at 30% conversion.

44

Similar observations have been noted by Miller and co-workers; see reference 40.