Conjugate addition-enantioselective protonation reactions

Abstract

The addition of nucleophiles to electron-deficient alkenes represents one of the more general and commonly used strategies for the convergent assembly of more complex structures from simple precursors. In this review the addition of diverse protic and organometallic nucleophiles to electron-deficient alkenes followed by enantioselective protonation is summarized. Reactions are first categorized by the type of electron-deficient alkene and then are further classified according to whether catalysis is achieved with chiral Lewis acids, organocatalysts, or transition metals.

Keywords: asymmetric catalysis; conjugate addition; enantioselective protonation; enolate.

Figure 1

Two general pathways for conjugate addition followed by enantioselective protonation.

Scheme 1

Tomioka’s enantioselective addition of arylthiols to α-substituted acrylates.

Scheme 2

Sibi’s enantioselective hydrogen atom transfer reactions.

Scheme 3

Mikami’s addition of perfluorobutyl radical to α-aminoacrylate 11.

Scheme 4

Reisman’s Friedel–Crafts conjugate addition–enantioselective protonation approach toward tryptophans.

Scheme 5

Pracejus’s enantioselective addition of benzylmercaptan to α-aminoacrylate 20.

Scheme 6

Kumar and Dike’s enantioselective addition of thiophenol to α-arylacrylates.

Scheme 7

Tan’s enantioselective addition of aromatic thiols to 2-phthalimidoacrylates.

Scheme 8

Glorius’ enantioselective Stetter reactions with α-substituted acrylates.

Scheme 9

Dixon’s enantioselective addition of thiols to α-substituted acrylates.

Figure 2

Chiral phosphorous ligands.

Scheme 10

Enantioselective addition of arylboronic acids to methyl α-acetamidoacrylate.

Scheme 11

Frost’s enantioselective additions to dimethyl itaconate.

Scheme 12

Darses and Genet’s addition of potassium organotrifluoroborates to α-aminoacrylates.

Scheme 13

Proposed mechanism for enantioselective additions to α-aminoacrylates.

Scheme 14

Sibi’s addition of arylboronic acids to α-methylaminoacrylates.

Scheme 15

Frost’s enantioselective synthesis of α,α-dibenzylacetates 64.

Scheme 16

Rovis’s hydroheteroarylation of α-substituted acrylates with benzoxazoles.

Scheme 17

Proposed mechanism for the hydroheteroarylation of α-substituted acrylates with benzoxazoles.

Scheme 18

Sodeoka’s enantioselective addition of amines to N-benzyloxycarbonyl acrylamides 75 and 77.

Scheme 19

Proposed catalytic cycle for Sodeoka’s enantioselective addition of amines.

Scheme 20

Sibi’s enantioselective Friedel–Crafts addition of pyrroles to imides 84.

Scheme 21

Kobayashi’s enantioselective addition of malonates to α-substituted N-acryloyloxazolidinones.

Scheme 22

Chen and Wu’s enantioselective addition of thiophenol to N-methacryloyl benzamide.

Scheme 23

Tan’s enantioselective addition of secondary phosphine oxides and thiols to N-arylitaconimides.

Scheme 24

Enantioselective addition of thiols to α-substituted N-acryloylamides.

Scheme 25

Kobayashi’s enantioselective addition of thiols to α,β-unsaturated ketones.

Scheme 26

Feng’s enantioselective addition of pyrazoles to α-substituted vinyl ketones.

Scheme 27

Luo and Cheng’s addition of indoles to vinyl ketones by enamine catalysis.

Scheme 28

Curtin–Hammett controlled enantioselective addition of indole.

Scheme 29

Luo and Cheng’s enantioselective additions to α-branched vinyl ketones.

Scheme 30

Lou’s reduction–conjugate addition–enantioselective protonation.

Scheme 31

Luo and Cheng’s primary amine-catalyzed addition of indoles to α-substituted acroleins.

Scheme 32

Luo and Cheng’s proposed mechanism and transition state.

Figure 3

Shibasaki’s chiral lanthanum and samarium tris(BINOL) catalysts.

Scheme 33

Shibasaki’s enantioselective addition of 4-tert-butyl(thiophenol) to α,β-unsaturated thioesters.

Scheme 34

Shibasaki’s application of chiral (S)-SmNa₃tris(binaphthoxide) catalyst 144 to the total synthesis of epothilones A and B.

Scheme 35

Shibasaki’s cyanation–enantioselective protonation of N-acylpyrroles.

Scheme 36

Tanaka’s hydroacylation of acrylamides with aliphatic aldehydes.

Scheme 37

Ellman’s enantioselective addition of α-substituted Meldrum’s acids to terminally unsubstituted nitroalkenes.

Scheme 38

Ellman’s enantioselective addition of thioacids to α,β,β-trisubstituted nitroalkenes.

Scheme 39

Hayashi’s enantioselective hydroarylation of diphenylphosphinylallenes.

Scheme 40

Hayashi’s enantioselective hydroarylation of diphenylphosphinylallenes.

Figure 4

Togni’s chiral ferrocenyl tridentate nickel(II) and palladium(II) complexes.

Scheme 41

Togni’s enantioselective hydrophosphination of methacrylonitrile.

Scheme 42

Togni’s enantioselective hydroamination of methacrylonitrile.