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Merging lithium carbenoid homologation and enzymatic reduction: A combinative approach to the HIV-protease inhibitor Nelfinavir |
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| Authors: | Laura Castoldi Laura Ielo Pilar Hoyos María J Hernáiz Laura De Luca Andrés R Alcántara Wolfgang Holzer Vittorio Pace |
| Institution: | 1. Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria;2. Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168 Messina, Italy;3. Department of Chemistry in Pharmaceutical Sciences (QUIMCIFARM), Complutense University of Madrid, Pza. Ramón y Cajal s/n, 28040 Madrid, Spain |
| Abstract: | An effective stereocontrolled synthesis of the HIV protease inhibitor Nelfinavir is reported. Two transformations were identified crucial for achieving success: the formation of a densely functionalized α-chloroketone via the homologation of a Weinreb amide with chloromethyllithium (LiCH2Cl), followed by its erythro selective reduction into the corresponding chiral chlorohydrin. A commercially available enzyme P2-C02 was particularly well suited for this purpose, affording the key alcohol (in an excellent 99% de), which was then smoothly converted into the active biologically active agent. |
| Keywords: | Homologation Lithium carbenoids Enzymatic reductions Drug Synthesis a-haloketones Halohydrins Selectivity |
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