Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors

Abstract

The copper-catalyzed enantioselective conjugate addition (ECA) of organometallic nucleophiles to electron-deficient alkenes (Michael acceptors) represents an efficient and attractive methodology for providing a wide range of relevant chiral molecules. In order to increase the attractiveness of this useful catalytic transformation, some Michael acceptors bearing challenging electron-deficient functions (i.e., aldehydes, thioesters, acylimidazoles, N-acyloxazolidinones, N-acylpyrrolidinones, amides, N-acylpyrroles) were recently investigated. Remarkably, only a few chiral copper-based catalytic systems have successfully achieved the conjugate addition of different organometallic reagents to these challenging Michael acceptors, with excellent regio- and enantioselectivity. Furthermore, thanks to their easy derivatization, the resulting chiral conjugated products could be converted into various natural products. The aim of this tutorial review is to summarize recent advances accomplished in this stimulating field.

Keywords: Michael acceptor; N-acyloxazolidinone; N-acylpyrrole; N-acylpyrrolidinone; acylimidazole; aldehyde; amide; copper catalysis; electron-deficient alkenes; enantioselective conjugate addition; thioester.

Scheme 1

Competitive side reactions in the Cu ECA of organometallic reagents to α,β-unsaturated aldehydes.

Scheme 2

Cu-catalyzed ECA of α,β-unsaturated aldehydes with phosphoramidite- (a) and phosphine-based ligands (b).

Scheme 3

One-pot Cu-catalyzed ECA/organocatalyzed α-substitution of enals.

Scheme 4

Combination of copper and amino catalysis for enantioselective β-functionalizations of enals.

Scheme 5

Optimized conditions for the Cu ECAs of R₂Zn, RMgBr, and AlMe₃ with α,β-unsaturated aldehydes.

Scheme 6

CuECA of Grignard reagents to α,β-unsaturated thioesters and their application in the asymmetric total synthesis of (–)-lardolure.

Scheme 7

Improved Cu ECA of Grignard reagents to α,β-unsaturated thioesters, and their application in the asymmetric total synthesis of (−)-mintlactone.

Scheme 8

Catalytic enantioselective synthesis of vicinal dialkyl arrays via Cu ECA of Grignard reagents to γ-substituted α,β-unsaturated thioesters.

Scheme 9

1,6-Cu ECA of MeMgBr to α,β,γ,δ-bisunsaturated thioesters: an iterative approach to deoxypropionate units.

Scheme 10

Tandem Cu ECA/intramolecular enolate trapping involving 4-chloro-α,β-unsaturated thioester 22.

Scheme 11

Cu ECA of Grignard reagents to 3-boronyl α,β-unsaturated thioesters.

Scheme 12

Cu ECA of alkylzirconium reagents to α,β-unsaturated thioesters.

Scheme 13

Conversion of acylimidazoles into aldehydes, ketones, acids, esters, amides, and amines.

Scheme 14

Cu ECA of dimethyl malonate to α,β-unsaturated acylimidazole 31 with triazacyclophane-based ligand L12.

Scheme 15

Cu/L13-catalyzed ECA of alkylboranes to α,β-unsaturated acylimidazoles.

Scheme 16

Cu/hydroxyalkyl-NHC-catalyzed ECA of dimethylzinc to α,β-unsaturated acylimidazoles.

Scheme 17

Stereocontrolled synthesis of 3,5,7-all-syn and anti,anti-stereotriads via iterative Cu ECAs.

Scheme 18

Stereocontrolled synthesis of anti,syn- and anti,anti-3,5,7-(Me,OR,Me) units via iterative Cu ECA/BCA.

Scheme 19

Cu-catalyzed ECA of dialkylzinc reagents to α,β-unsaturated N-acyloxazolidinones.

Scheme 20

Cu/phosphoramidite L16-catalyzed ECA of dialkylzincs to α,β-unsaturated N-acyl-2-pyrrolidinones.

Scheme 21

Cu/(R,S)-Josiphos (L9)-catalyzed ECA of Grignard reagents to α,β-unsaturated amides.

Scheme 22

Cu/Josiphos (L9)-catalyzed ECA of Grignard reagents to polyunsaturated amides.

Scheme 23

Cu-catalyzed ECA of trimethylaluminium to N-acylpyrrole derivatives.