Synergistic organocatalysis in the kinetic resolution of secondary thiols with concomitant desymmetrization of an anhydride.

Kinetic resolution is an important method for the separation of racemates into their component enantiomers. Thiols are precursors to a variety of organosulfur compounds, with high utility in both chemistry and chemical biology, yet there is a surprising dearth of methodologies for their direct and efficient catalytic kinetic resolution. Here, we demonstrate an organocatalytic process involving the highly enantioselective desymmetrization of an achiral electrophile with the simultaneous kinetic resolution of a racemic thiol. The preparative potential of the methodology is exemplified by the synthesis of a drug precursor antipode in excellent yield and enantioselectivity as a by-product of a process that also resolves a sec-thiol substrate with a selectivity of S = 226 (that is, both thiol antipodes produced in >95% ee at 51% conversion). In a second example a racemic sec-thiol representing the stereocentre-containing core of the anti-asthma drug (R)-Montelukast was resolved with synthetically useful selectivity under mild conditions.

Unexpected catalysis: aprotic pyridinium ions as active and recyclable Brønsted acid catalysts in protic media.

Simple pyridinium salt derivatives have been (rather unexpectedly) shown to promote highly efficient acetalization reactions of both aldehydes and ketones at ambient temperature. The optimum catalyst is aprotic, yet it can promote the formation of benzaldehyde dimethyl acetal at 0.1 mol % loading more efficiently than a protic Brønsted acid catalyst with a pKa of 2.2. The process is of wide scope with respect to both the nucleophilic and electrophilic components, and the ionic catalyst can be readily recovered by precipitation and reused without loss of activity.

A reductase-mimicking thiourea organocatalyst incorporating a covalently bound NADH analogue: efficient 1,2-diketone reduction with in situ prosthetic group generation and recycling.

A new class of bifunctional organocatalyst promotes the chemoselective reduction of diketone electrophiles at catalytic loadings in the presence of an inorganic co-reductant.

Enantioselective synthesis of beta2-amino acids using rhodium-catalyzed hydrogenation.

A series of protected beta2-dehydroamino acids has been prepared in three steps from commercially available starting materials in good yields. These were used as substrates in rhodium-catalyzed asymmetric hydrogenation applying a mixed ligand system of monodentate phosphoramidites and phosphines. Optimization of the catalyst structure was achieved by high throughput experimentation. High enantioselectivities were obtained (up to 91%) with full conversion for a number of beta-amino acids.