De Novo Synthesis of Tamiflu via a Catalytic Asymmetric Ring-Opening of meso-Aziridines with TMSN₃

Abstract

An asymmetric ring-opening reaction of meso-aziridines with TMSN3 was developed using a catalyst prepared from Y(OiPr)3 and chiral ligand 2 in a 1:2 ratio. Excellent enantioselectivity was realized from a wide range of substrates with a practical catalyst loading. The products were efficiently converted to enantiomerically enriched 1,2-diamines, which are versatile chiral building blocks for pharmaceuticals and chiral ligands. This reaction was applied to a catalytic asymmetric synthesis of Tamiflu, a very important anti-influenza drug containing a chiral 1,2-diamino functionality.

Catalytic, Enantioselective Ring Opening of Aziridines

“…[12] A broad range of cyclic, acyclic, and heterocyclic meso aziridines could be ring-opened very selectively by this method. Since the absolute configuration of the products is the same as for the Gd-catalyzed reaction with trimethylsilyl cyanide, it seems reasonable to assume that in this case, too, the bimetallic mechanism described above is active.…”

Synthesis of Marine-Derived Carbasugar Pericosines

“…It had been developed from Zanamivir hydrate (Relenza ® ) which is another potent drug designed from the transition structure of an N-acetylneuramic acid-neuramidase complex based on X-ray analysis [3]. The oral antiinfluenza drug Tamiflu ® has received great attention for its activity against avian flu [4][5][6][7][8][9]. Two recently approved long-acting antiinfluenza drugs, laninamivir (CS-8958, Inavir ® ) and peravimir, also have carbasugar structures [10,11].…”

Separation of Shikimic Acid from Pine Needles

“…Although two separate research groups have described new routes for synthesizing oseltamivir phosphate, circumventing usage of shikimic acid [4,5], these processes have not reached direct commercialization yet and may require a significant period of time before they do so. Consequently, developing new sources of shikimic acid to use as a precursor for the synthesis of oseltamivir phosphate is an attractive option.…”