Multienzymatic cascade synthesis of an enantiopure (2R,5R)-1,3-oxathiolane anti-HIV agent precursor

Biocatalytic routes to anti-viral agents and their synthetic intermediates

“…By coupling STS-catalysed ringclosing to CAL-B-catalysed resolution, enantiopurity of the protected 1,3-oxathiolane intermediate could be further enhanced. 100 Abacavir is an anti-viral nucleoside analogue in which a cyclopentene unit constitutes the furanose mimic (Scheme 13). 101 The drug is commonly being prepared from Vince-lactam (55) which acts as a versatile building block for a variety of pharmaceuticals.…”

“…145 3.3.1 Unnatural amino acids. A key unnatural amino acid that has proven to be a privileged building block for a large number of anti-viral pharmaceuticals is L-tert-leucine (100). HIV protease inhibitors atazanavir, 160 boceprevir 161 and telaprevir 162 contain this amino acid.…”

“…164 Mucor miehei lipase (MML) selectively catalysed ring-opening of the (S)-enantiomer in the presence of butanol and triethylamine (NEt 3 ). Subsequent twostep chemoenzymatic deprotection afforded L-tert-leucine (100) with 499% ee in 94% yield. More recently, kinetic resolution of N-phenylacetyl-and N-acetyl-protected L-tert-leucine was achieved using Kluyvera citrophila penicillin G acylase and Mycobacterium sp.…”

“…[169][170][171][172][173] Directed evolution of the LeuDH from L. aphaericus resulted in a two-fold increase in specific activity as compared to the wild-type enzyme, which was met with a concomitant increase in space-time yield from 666 to 1170 g (L d) À1 . 174 Complementary to the use of LeuDH, several transaminases were also found capable of converting trimethylpyruvate (101) to L-tert-leucine (100). Transaminases (also called aminotransferases) catalyse the transfer of an amine group from a donor to an amine acceptor, which is a ketone or aldehyde.…”

“…Nitrogen gas was subsequently converted to ammonia at the expense of MV + using a nitrogenase. The presence of ammonia finally allowed LeuDH to convert trimethylpyruvate (101) to L-tert-leucine (100). In situ NADH co-factor recycling was achieved by oxidation of MV + using a diaphorase from Geobacillus stearothermophilus.…”