Asymmetric synthesis of tertiary thiols and thioethers

Abstract

Enantiomerically pure tertiary thiols provide a major synthetic challenge, and despite the importance of chiral sulfur-containing compounds in biological and medicinal chemistry, surprisingly few effective methods are suitable for the asymmetric synthesis of tertiary thiols. This review details the most practical of the methods available.

Keywords: asymmetric synthesis; organolithium; substitution; sulfur; thiol.

Figure 1

Seven out of the ten top selling drugs in the USA in 2009 contain sulfur. Figures in italics are total retail sales in dollars [1].

Figure 2

Naturally occurring organosulfur compounds glutathione and (R)-thioterpineol.

Figure 3

Methods for the synthesis of chiral tertiary thiol 1.

Scheme 1

Preparation of thioethers 4 from α-hydroxy esters.

Scheme 2

Nucleophilic substitution in α-aryl-α-hydroxy esters.

Scheme 3

Preparation of α,α-dialkylthioethers.

Scheme 4

Preparation of α-cyanothioacetate 12.

Scheme 5

Synthesis of (R)-(+)-spirobrassinin.

Scheme 6

Opening of cyclic sulfamidates with thiol nucleophiles.

Scheme 7

Synthesis of androgen 20.

Scheme 8

Synthesis of (+)-BE-52440A.

Scheme 9

The Mitsunobu reaction.

Scheme 10

Mitsunobu substitution at a quaternary centre.

Figure 4

Initially assigned structure of hexacyclinol.

Scheme 11

Preparation of thioether 29.

Scheme 12

Thioethers 33 prepared from phosphinites 31.

Scheme 13

Preparation of enantiomerically pure thiol 39.

Scheme 14

Thioethers prepared by a modified Mitsunobu reaction.

Scheme 15

Nucleophilic conjugate addition.

Scheme 16

Asymmetric addition to cyclic enones.

Scheme 17

Preparation of thioether 45.

Scheme 18

Catalytic kinetic resolution of the enantiomers of enone 46.

Scheme 19

Organocatalytic conjugate addition to nitroalkenes 49.

Scheme 20

Preparation of β-amino acid 54.

Scheme 21

Sulfur migration within oxazolidine-2-thiones 56.

Scheme 22

Preparation of thiols 62 by self-regeneration of stereocentres.

Scheme 23

Synthesis of (5R)-thiolactomycin.

Scheme 24

Preparation of tertiary thiols and thioethers via α-thioorganolithiums.

Scheme 25

Diastereoselective methylation of organolithium 71.

Scheme 26

Addition to lithiated thiocarbamate 75.

Scheme 27

Configurational lability in unhindered α-lithiothiocarbamates.

Scheme 28

Configurational stability in bulky α-lithiothiocarbamates.

Scheme 29

Asymmetric functionalisation of secondary benzylic thiocarbamates.

Scheme 30

Methylation of lithioallyl thiocarbamates.

Scheme 31

Asymmetric preparation of tertiary allylic thiols.

Scheme 32

Asymmetric preparation of thiols 96 by aryl migration in lithiated thiocarbamates.