The synthesis of protease inhibitors targeting the Human Immunodeficiency Virus (HIV) is an ongoing challenge. N-(tert-butoxycarbonyl)-(3S)-3-amino-1-chloro-4-phenyl-(2R)-butanol (abbreviated R,S-CMA) and N-(tert-butoxycarbonyl)-(3S)-3-amino-1-chloro-4-phenyl-(2S)-butanol (abbreviated S,S-CMA) are key intermediates in the synthesis of the current commercial  drugs. For example, the Meerwein-Ponndorf-Verley reduction of the N-(tert-butoxycarbonyl)-(3S)-3-amino-1-chloro-4-phenyl-2-butanone (abbreviated S-CMK) produces S,S-CMA in 98% diastereomeric ratio, subsequently yielding the Saquinavir� and Atazabavir�. However, a competitive process to prepare the R,S-CMA with high diastereoselectivity is still lacking. Therefore, developing an efficient, stereo- and chemo-selective synthesis of the R,S-CMA is central to the production of drugs such as Amprevanir�. A variety of reducing agents have been investigated to reach high yields and stereoselectivity toward the R,S-CMA and will be presented.

Investigation into the asymmetric reduction of an alpha-chloromethyl ketone important in the synthesis of HIV protease inhibitors

239th National Meeting (2010)

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