초록
<P>Lipase PS 30 (immobilized on polypropylene) from <I>Pseudomonas cepacia</I> was used for enantioselective esterification of (<I>RS</I>)-1-(2-fluoro-4-iodophenyl)-3-hydroxypyrrolidin-2-one by using succinic anhydride and 2-methyltetrahydrofuran at 4 °C. The isolation of desired alcohol avoided use of column chromatography, a simple solvent extraction of undesired (<I>R</I>)-4-((1-(2-fluoro-4-iodophenyl)-2-oxopyrrolidin-3-yl)oxy)-4-oxobutanoic acid into 5% potassium bicarbonate solution separated pure desired (<I>S</I>)-1-(2-fluoro-4-iodophenyl)-3-hydroxypyrrolidin-2-one into the 2-methyltetrahydrofuran solution. The reaction conditions were optimized, and (<I>S</I>)-1-(2-fluoro-4-iodophenyl)-3-hydroxypyrrolidin-2-one was prepared in high enantiomeric excess >99% and yield ∼40% (theoretically possible yield 50%). Novozym 435 (<I>Candida antarctica</I> lipase B) was found to be a suitable biocatalyst for the resolution of (<I>RS</I>)-1-(6-bromo-2-methylpyridin-3-yl)-2-oxopyrrolidin-3-yl acetate to form the undesired <I>S</I>-acetate and the desired <I>R</I>-alcohol. The optimized reaction conditions gave (<I>R</I>)-1-(6-bromo-2-methylpyridin-3-yl)-3-hydroxypyrrolidin-2-one in ∼37% isolated yield (maximum possible yield 50%) and high enantiomeric excess (ee >99.4%). The enzymatic resolution of (<I>RS</I>)-1-(6-bromo-2-methylpyridin-3-yl)-2-oxopyrrolidin-3-yl acetate followed by chromatography was successfully implemented to deliver material for two successive (4.1 kg, ee >99.4% and 5.5 kg, ee >99.5%) campaigns. The undesired <I>S</I>-alcohol was recycled back to the desired <I>R</I>-alcohol using a Mitsunobu inversion of stereochemistry in gram scale. An increase in the chain length from acetate to hexanoate improved the selectivity and subsequent optimization decreased the enzyme loading and enhanced the substrate input. Separation of the desired (<I>R</I>)-1-(6-bromo-2-methylpyridin-3-yl)-3-hydroxypyrrolidin-2-one from (<I>S</I>)-1-(6-bromo-2-methylpyrrolidin-3-yl)-2-oxopyrrolidin-3-yl hexanoate was achieved using a solvent extraction. The process for the preparation of (<I>S</I>)-1-(2-fluoro-4-iodophenyl)-3-hydroxypyrrolidin-2-one and (<I>R</I>)-1-(6-bromo-2-methylpyridin-3-yl)-3-hydroxypyrrolidin-2-one is scalable, economical, and highly efficient and avoids chromatography.</P><P><B>Graphic Abstract</B><BR><IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2015/oprdfk.2015.19.issue-7/acs.oprd.5b00084/production/images/medium/op-2015-00084c_0008.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/op5b00084'>ACS Electronic Supporting Info</A></P>