An iterative catalytic route to enantiopure deoxypropionate subunits: asymmetric conjugate addition of grignard reagents to alpha,beta-unsaturated thioesters.

A highly enantioselective (up to 96% ee) conjugate addition of Grignard reagents, in particular, MeMgBr, to alpha,beta-unsaturated thioesters is provided as well as its application to a diastereo- and enantioselective iterative route to syn- and anti-1,3-dimethyl arrays and deoxypropionate subunits. The versatility of the method is illustrated in the synthesis of (-)-lardolure, a multimethyl-branched insect natural pheromone.

Short asymmetric synthesis of (-)- and (+)-cis-lauthisan.

The asymmetric synthesis of both enantiomers of cis-lauthisan (3) is achieved in only six steps from diethyl pimelate (4), the key steps being the diastereodivergent reduction of beta-ketosulfoxide 7 and the highly cis-stereoselective Et(3)SiH/TMSOTf-promoted reductive cyclization of enantiopure hydroxy sulfinyl ketones (S)-14 and (R)-14.

Enantioselective access to 2,7-cis-disubstituted oxepanes: formal synthesis of (+)-isolaurepan.

[reaction: see text] The asymmetric synthesis of 2,7-cis-disubstituted oxepanes bearing a sulfoxide is achieved from commercially available precursors in only five steps. The key step is the highly diastereoselective Et3SiH/TMSOTf-promoted reductive cyclization of enantiopure hydroxysulfinyl aryl or alkyl ketones.

Reductive cyclizations of hydroxysulfinyl ketones: enantioselective access to tetrahydropyran and tetrahydrofuran derivatives.

The stereocontrolled formation of cis-2,5-disubstituted tetrahydrofurans and cis-2,6-disubstituted tetrahydropyrans is achieved from enantiopure ketosulfinyl esters by reduction, Weinreb's amide, and ketone formation, followed by the reductive cyclization (Et3SiH/TMSOTf) of the resulting hydroxysulfinyl ketones. The sulfoxide-bearing heterocycles were transformed into two natural products, (-)-centrolobine (1) and both enantiomers of cis-(6-methyltetrahydropyran-2-yl)acetic acid (2).

First enantioselective total synthesis of (-)-Centrolobine.

[structure: see text] The first enantioselective total synthesis of (-)-Centrolobine is described. The key reaction is the synthesis of the cis-disubstituted tetrahydropyran framework by intramolecular cyclization of the enantiopure hydroxyketone 3 with Et3SiH and TMSOTf. The stereoselective reduction of the beta-ketosulfoxide 4 is the source of chirality.