Highly selective asymmetric hydrogenation using a three hindered quadrant bisphosphine rhodium catalyst.

A concise synthesis of both enantiomers of ligand 2 and rhodium complex 5 is presented. The crux of the synthesis is a chiral HPLC separation of the enantiomers of 4. Rhodium complex 5 possesses three hindered quadrants in the steric environment within which a substrate binds. Evidence is presented that this configuration leads to high enantioselectivity (>99% ee) for rhodium-catalyzed asymmetric hydrogenation of alpha-acetamido dehydroamino acids, 6a-e. High enantioselectivities are also reported for the hydrogenation of a substrate precursor, 8, of pharmaceutical candidate, pregabalin. Advantages for large-scale hydrogenation of 8 using catalyst 5a vs Rh-Me-DuPhos are discussed.

Further utilization of mucohalic acids: palladium-free, regioselective etherification and amination of alpha,beta-dihalo gamma-methoxycarbonyloxy and gamma-acetoxy butenolides.

Palladium-free etherification and amination of mucohalic acid methyl carbonates 1e (3,4-dichloro-5-methoxycarbonyloxy-5H-furan-2-one) and 1f (3,4-dibromo-5-methoxycarbonyloxy-5H-furan-2-one) and mucochloric acid acetate 1h (3,4-dichloro-5-acetoxy-5H-furan-2-one) was achieved to afford gamma-functionalized alpha,beta-unsaturated gamma-butyrolactones in good to excellent yield. [reaction: see text]

First application of tunable alkyl or aryl sulfinamides to the stereoselective synthesis of a chiral amine: asymmetric synthesis of (R)-didesmethylsibutramine ((R)-DDMS) using (R)-triethylmethylsulfinamide ((R)-TESA).

A highly diastereoselective addition of i-BuLi to a triethylmethylsulfinamide derived aldimine was used as the key step in the first asymmetric synthesis of (R)-didesmethylsibutramine, a metabolite of sibutramine for the potential treatment of CNS disorders. [reaction: see text]