Grau Brendan T, Devine Paul N, DiMichele Lisa N, Kosjek Birgit
Department of Process Research, Merck Research Laboratories, Merck and Co., Inc., PO Box 2000, Rahway, New Jersey 07065, USA.
Org Lett. 2007 Nov 22;9(24):4951-4. doi: 10.1021/ol701810v. Epub 2007 Oct 31.
Chiral fluorinated hydroxyketones were synthesized with excellent ee (>98%) and yield by a chemo- and stereoselective reduction of prochiral methyl/trifluoromethyl diketones using commercially available ketoreductase enzymes. By using p- and m-trifluoroacetyl substituted acetophenones, we demonstrate that ketoreductases can selectively differentiate between methyl and trifluoromethyl ketones within the same molecule. As a result, useful catalysts were identified that eliminated the need for costly and time-consuming protection/deprotection of the ketone moiety, enabling a more convergent synthesis of hydroxyketones. Further, a route to chiral methyl hydroxyketones is provided where an enzyme selectively reduces the unactivated ketone.
通过使用市售的酮还原酶对手性前体甲基/三氟甲基二酮进行化学和立体选择性还原，合成了对映体过量（ee）优异（>98%）且产率高的手性氟化羟基酮。通过使用对三氟乙酰基和间三氟乙酰基取代的苯乙酮，我们证明了酮还原酶可以在同一分子内选择性地区分甲基酮和三氟甲基酮。结果，鉴定出了有用的催化剂，无需对酮部分进行昂贵且耗时的保护/脱保护，从而能够更汇聚式地合成羟基酮。此外，还提供了一条合成手性甲基羟基酮的路线，其中一种酶选择性地还原未活化的酮。
