The Enantioselective Addition of Alkyne Nucleophiles to Carbonyl Groups

Abstract

Over the past decade, large strides have been achieved in the invention of methods for the direct enantioselective addition of alkynes and metal alkynylide nucleophiles into prochiral aldehydes, ketones, and imines. This review highlights and compares the available methods for these transformations.

Keywords: alkynylation; catalytic asymmetric; propargylic alcohol; propargylic amine.

Figure 1

Propargyl alcohols as synthetic intermediates.

Figure 2

Ligands for the alkynylation of aldehydes.

Figure 3

γ-Hydroxy-α,β-acetylenic ester transformations.

Scheme 1

Common methods for the synthesis of propargylic alcohols.

Scheme 2

First example of an enantioselective alkynylation of an aldehyde.

Scheme 3

Catalytic asymmetric zinc alkynylation of aldehydes.

Scheme 4

Rationale for enantioselectivity of alkyne or alkyl (R) addition to an aldehyde.

Scheme 5

(+)-NME-mediated enantioselective addition of zinc alkynylides.

Scheme 6

Alternative conditions employing catalytic amino alcohol ligands.

Scheme 7

Wang’s bifunctional catalyst for the asymmetric alkynylation of aldehydes.

Scheme 8

Trost’s bifunctional ProPhenol catalyst for the enantioselective alkynylation of unsaturated aldehydes.

Scheme 9

Enantioselective titanium-catalyzed addition of zinc alkynylides to aldehydes.

Scheme 10

Metal salt-mediated alkynylation of aldehydes.

Scheme 11

Stoichiometric N-methylephedrine-mediated alkynylation methodology.

Scheme 12

Catalytic N-methylephedrine-mediated alkynylation methodology.

Scheme 13

Shibasaki’s In(III)/BINOL-catalyzed alkynylation.

Scheme 14

Attempted propiolate addition with Carriera’s conditions.

Scheme 15

ProPhenol-catalyzed enantioselective propiolate addition.

Scheme 16

Pu’s titanium-BINOL-HMPA catalyst for the zinc propiolate addition to aldehydes.

Scheme 17

Chan and Wang’s alternative propiolate addition.

Scheme 18

Corey's enantioselective boron alkynylide addition to aldehydes.

Scheme 19

Enantioselective MPV alkyne addition to activated aldehydes.

Scheme 20

First example of enantioselective alkynylide addition to a ketone.

Scheme 21

Enantioselective alkynylation of activated ketones with catalytic zinc.

Scheme 22

Cozzi’s salen-catalyzed alkynylation of ketones.

Scheme 23

Enantioselective copper-catalyzed zinc alkynylide addition to ketones.

Scheme 24

Titanium(IV)-BINOL catalyzed alkynylations of ketones.

Scheme 25

Wang’s enantioselective addition of zinc alkynylides to unactivated ketones.

Scheme 26

Catalytic enantioselective alkynylation of trifluoromethyl ketones.

Scheme 27

First example of an enantioselective imine alkynylation.

Scheme 28

Li’s three-component coupling reaction.

Scheme 29

Alternative ligand for alkynylation of N-aryl imines.

Scheme 30

Knochel’s QUINAP system for the alkynylation of imines.

Scheme 31

Zirconium-catalyzed alkynylation with mixed zinc species.

Scheme 32

Zinc alkynylide addition to cyclic ketimine 150.

Scheme 33

Enantioselective addition of alkynyl borane to N-acyl imines.

Scheme 34

Dimethylzinc-mediated alkynylation of N-tosyl imines.

Scheme 35

First example of enantioselective conjugate addition of an alkyne.

Scheme 36

Asymmetric conjugate addition of alkynyl boronates.

Scheme 37

Corey’s enantioselective conjugate addition to cyclic enone.

Scheme 38

Aminoalcohol zinc alkynylide-mediated asymmetric conjugate additions.

Scheme 39

Copper-catalyzed enantioselective conjugate alkynylation of alkylidene Meldrum’s acids.

Scheme 40

Rh-catalyzed asymmetric conjugate addition of alkynes to enones.