Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

Abstract

The conjugate addition reaction has been a useful tool in the formation of carbon-carbon bonds. The utility of this reaction has been demonstrated in the synthesis of many natural products, materials, and pharmacological agents. In the last three decades, there has been a significant increase in the development of asymmetric variants of this reaction. Unfortunately, conjugate addition reactions using α,β-unsaturated amides and lactams remain underdeveloped due to their inherently low reactivity. This review highlights the work that has been done on both diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams.

Keywords: Michael addition; conjugate addition; α,β-unsaturated amides; α,β-unsaturated lactams.

Scheme 1

Generic mechanism for the conjugate addition reaction.

Figure 1

Methods to activate unsaturated amide/lactam systems.

Scheme 2

DCA of Grignard reagents to an L-ephedrine derived chiral α,β–unsaturated amide.

Figure 2

Chiral auxiliaries used in DCA reactions.

Scheme 3

Comparison between auxiliary 5 and the Oppolzer auxiliary in a DCA reaction.

Scheme 4

Use of Evans auxiliary in a DCA reaction.

Figure 3

Lewis acid complex of the Evans auxiliary [43].

Scheme 5

DCA reactions of α,β-unsaturated amides utilizing (S,S)-(+)-pseudoephedrine and the OTBS-derivative as chiral auxiliaries.

Figure 4

Proposed model accounting for the diastereoselectivity observed in the 1,4-addition of Bn₂NLi to α,β-unsaturated amides attached to (S,S)-(+)-pseudoephedrine. Reprinted with permission from J. Org. Chem., 2005, 70, 8790–8800. Copyright 2005 American Chemical Society.

Scheme 6

An example of a tandem conjugate addition–α-alkylation reaction of an α,β-unsaturated amide utilizing (S,S)-(+)-pseudoephedrine.

Scheme 7

Conjugate addition to an α,β-unsaturated bicyclic lactam leading to (+)-paroxetine and (+)-femoxetine.

Scheme 8

Intramolecular conjugate addition reaction to α,β-unsaturated amide.

Scheme 9

Conjugate addition to an α,β-unsaturated pyroglutamate derivative.

Scheme 10

Cu(I)–NHC-catalyzed asymmetric silylation of α,β-unsaturated lactams and amides.

Scheme 11

Asymmetric copper-catalyzed 1,4-borylation of an α,β-unsaturated amide.

Scheme 12

Asymmetric cross-coupling 49 to phenyl chloride.

Scheme 13

Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated lactam.

Scheme 14

Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated amide.

Scheme 15

Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated amide using a chiral bicyclic diene.

Scheme 16

Synthesis of (R)-(−)-baclofen through a rhodium-catalyzed asymmetric 1,4-arylation of lactam 58.

Scheme 17

Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated amide and lactam employing organo[2-(hydroxymethyl)phenyl]dimethylsilanes.

Scheme 18

Rhodium-catalyzed asymmetric 1,4-arylation of an α,β-unsaturated lactam employing benzofuran-2-ylzinc.

Figure 5

Further chiral ligands that have been used in rhodium-catalyzed 1,4-additions of α,β-unsaturated amides and lactams.

Scheme 19

Palladium-catalyzed asymmetric 1,4-arylation of arylsiloxanes to a α,β-unsaturated lactam.

Scheme 20

SmI₂-mediated cyclization of α,β-unsaturated Weinreb amides.

Figure 6

Chiral Lewis acid complexes used in the Mukaiyama–Michael addition of α,β-unsaturated amides.

Scheme 21

Mukaiyama–Michael addition of thioester silylketene acetal to α,β-unsaturated N-alkenoyloxazolidinones.

Scheme 22

Asymmetric 1,4-addition of aryl acetylides to α,β-unsaturated thioamides.

Scheme 23

Asymmetric 1,4-addition of alkyl acetylides to α,β-unsaturated thioamides.

Scheme 24

Asymmetric vinylogous conjugate additions of unsaturated butyrolactones to α,β-unsaturated thioamides.

Scheme 25

Gd-catalyzed asymmetric 1,4-cyanation of α,β-unsaturated N-acylpyrroles [205].

Scheme 26

Lewis acid-catalyzed asymmetric 1,4-cyanation of α,β-unsaturated N-acylpyrazole 107.

Scheme 27

Lewis acid mediated 1,4-addition of dibenzyl malonate to α,β-unsaturated N-acylpyrroles.

Scheme 28

Chiral Lewis acid mediated 1,4-radical addition to α,β-unsaturated N-acyloxazolidinone [224].

Scheme 29

Aza-Michael addition of O-benzylhydroxylamine to an α,β-unsaturated N-acylpyrazole.

Scheme 30

An example of the aza-Michael addition of secondary aryl amines to an α,β-unsaturated N-acyloxazolidinone.

Scheme 31

Aza-Michael additions of anilines to a α,β-unsaturated N-alkenoyloxazolidinone catalyzed by palladium(II) complex 123.

Scheme 32

Aza-Michael additions of aniline to an α,β-unsaturated N-alkenoylbenzamide and N-alkenoylcarbamate catalyzed by palladium(II) complex 126.

Scheme 33

Difference between aza-Michael addition ran using the standard protocol versus the slow addition protocol.

Scheme 34

Aza-Michael additions of aryl amines salts to an α,β-unsaturated N-alkenoyloxazolidinone catalyzed by palladium(II) complex 133.

Scheme 35

Aza-Michael addition of N-alkenoyloxazolidiniones catalyzed by samarium diiodide [244].

Scheme 36

Asymmetric aza-Michael addition of p-anisidine to α,β-unsaturated N-alkenoyloxazolidinones catalyzed by iodido(binaphtholato)samarium [243].

Scheme 37

Asymmetric aza-Michael addition of O-benzylhydroxylamine to N-alkenoyloxazolidinones catalyzed by iodido(binaphtholato)samarium.

Scheme 38

Asymmetric 1,4-addition of purine to an α,β-unsaturated N-alkenoylbenzamide catalyzed by (S,S)-(salen)Al.

Scheme 39

Asymmetric 1,4-addition of phosphites to α,β-unsaturated N-acylpyrroles.

Scheme 40

Asymmetric 1,4-addition of phosphine oxides to α,β-unsaturated N-acylpyrroles.

Scheme 41

Tandem Michael-aldol reaction catalyzed by a hydrogen-bonding organocatalyst.

Scheme 42

Examples of the sulfa-Michael–aldol reaction employing α,β-unsaturated N-acylpyrazoles.

Scheme 43

Example of the sulfa-Michael addition of α,β-unsaturated N-alkenoyloxazolidinones.

Figure 7

Structure of cinchona alkaloid-based squaramide catalyst.

Scheme 44

Asymmetric intramolecular oxa-Michael addition of an α,β-unsaturated amide.

Scheme 45

Formal synthesis atorvastatin.