Ian D. Linney

The total synthesis of epibatidine

Abstract A total synthesis of the potent non-opiate analgesic alkaloid epibatidine is described, in which the key step is a reductive palladium-catalysed Heck-type coupling. The synthesis is concise (two steps from known compounds), highly convergent, and completely stereoselective for the desired exo-isomer.

A new class of recoverable chiral sulphoxide : application to the asymmetric synthesis of β-hydroxy esters

Enantiomerically pure cyclic sulphinadime S(S)R-(+)-2 was prepared from homochiral sulphinic acid R-(−)-1 and subsequently converted to the ester S(S)R-(−)-3 via ring opening with an ester enolate. Aldol reactions of S(S)R-(−)-3 with aromatic aldehydes gave, with one exception, aldol products4 in high diastereoisomeric excess. Reductive cleavage of the aldol adducts4 gave β-hydroxy esters5 in high (>95%) enantiomeric excess, and thiol6 which may be recycled to S(S)R-(+)-2. Thus S(S)R-(+)-2 represents a source of recoverable chiral sulphoxide.

The asymmetric synthesis of allylic alcohols using a recoverable chiral sulphoxide

The enantiomerically pure cyclic sulphinamide S(S)R-(+)-3 reacts with the sodium enolates of ketones to give the corresponding homochiral sulphoxides. Reduction of the carbonyl group in these products using DIBAL-H or DIBAL-H/ZnBr2 gives complementary products of high diastereoisomeric excess. This methodology has been applied to the synthesis of an allylic alcohols in high enantiomeric excess.

Recoverable chiral sulfoxides for asymmetric synthesis: application to stereoselective carbonyl reduction and the asymmetric synthesis of allylic alcohols

The enantiomerically pure cyclic sulfinamide S(s)R-(+)-3 reacts with the sodium enolates of ketones to give the corresponding homochiral sulfoxides. Reduction of the carbonyl group in these products may be achieved using a variety of reducing agents the best of which were DIBAL-H or DIBAL-H/ZnBr2, which give complementary products of high diastereoisomeric excess. Reduction of the hydroxy sulfoxides with Raney nickel proceeds in low yield and causes partial racemisation of the products. However the combined use of a directed reduction followed by a facile sulfenic acid elimination provides a synthesis of allylic alcohols in high enantiomeric excess.

Recoverable chiral sulfoxides for asymmetric synthesis: preparation, regeneration and application to the asymmetric aldol reaction

The synthesis of a novel source of chiral sulfoxide and its application to the control of asymmetric aldol reactions is described. The sulfoxide precursor S(s)R-(+)-cis-4 may be recycled and thus affords a considerable advantage over currently available methodology. Studies of the origin of the stereochemical outcome of the aldol reactions of the derived enolate S(s)R-(–)-10b reveal that it is the result of thermodynamic, not kinetic, control.