Synlett 2008(12): 1759-1772  
DOI: 10.1055/s-2008-1078503
ACCOUNT
© Georg Thieme Verlag Stuttgart ˙ New York

A Novel Organocatalytic Tool for the Iminium Activation of α,β-Unsaturated Ketones

Giuseppe Bartoli, Paolo Melchiorre*
Dipartimento di Chimica Organica ‘A. Mangini’, Alma Mater Studiorum, Università di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
e-Mail: p.melchiorre@unibo.it;
Further Information

Publication History

Received 3 March 2008
Publication Date:
19 June 2008 (online)

Abstract

Asymmetric aminocatalysis has become a well-established and powerful synthetic tool for the chemo- and enantioselective functionalization of carbonyl compounds. Recent studies have established the unique ability of primary amine catalysis to participate in processes between sterically demanding partners, thus overcoming the inherent difficulties of chiral secondary amines in generating congested covalent intermediates. With this in mind, we introduced the primary amine catalyst salt 1, made by combining the easily available 9-amino-9-deoxy-epi-hydroquinine with N-Boc-d-phenylglycine as the chiral counteranion. Salt 1 exhibits high reactivity and selectivity in the enantioselective conjugate additions of a series of different nucleophiles to unsaturated ketones. The rationale behind the development of this general and efficient iminium activator of enones is discussed.

1 Introduction

2 Iminium Catalysis

3 Iminium Activation of Unsaturated Ketones

3.1 Chiral Primary Amines in Iminium Catalysis

3.2 Asymmetric Counteranion-Directed Catalysis

4 A New Catalyst Salt for Iminium Activation of Enones: 9-Amino-9-deoxy-epi-hydroquinine and N-Boc-d-phenylglycine

4.1 Friedel-Crafts Alkylation of Indoles

4.2 Oxa-Michael Addition

4.3 Sulfa-Michael Addition

5 Summary and Outlook

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50

The results obtained when using 9-amino-9-deoxy-epi-hydroquinine (2) in combination with various acidic counterparts (TFA, PTSA, N-Boc-l-phenylalanine) in the organocatalyzed SMA did not show any appreciable improvement in terms of enantioselectivity, confirming the superior efficiency of the catalyst salt 1. Remarkably, consistent with previous observations, use of the opposite enantiomeric counteranion (N-Boc-l-phenylglycine) afforded the same enantiomeric sulfa-Michael adduct with lower reactivity and selectivity, illustrating a marked case of a matched/mismatched catalyst-ion pair combination.

53

Preliminary studies on conjugate additions to (E)-4-phenyl-3-buten-2-one (11) promoted by catalyst salt 1 afforded encouraging results: aza-Michael addition of N-(benzyl-oxycarbonyl)hydroxylamine: 96% ee; phospha-Michael addition of diphenylphosphine: 56% ee.