BioChem - DOS

Enantioselective bioreduction of benzo-fused cyclic ketones with engineered Candida glabrata ketoreductase 1 - a promising synthetic route to ladostigil (TV3326)

Organic & biomolecular chemistry

Ou-yang, Jingping; Zhang, Wenhe; Qin, Fengyu; Zuo, Weiguo; Xu, Shaoyu; Wang, Yan; Qin, Bin; You, Song; Jia, Xian

<P>Biocatalysis has been recently emerging as a promising alternative to traditional chemical synthesis because of its &ldquo;green&rdquo; characteristics and comparable selectivities, which accord with the concept of sustainable development and demand for asymmetric synthesis. In this study, whole-cell biocatalysts containing glucose dehydrogenase (GDH) and <I>Candida glabrata</I> ketoreductase 1 (CgKR1) variants were constructed. These biocatalysts were applied to the reduction of benzo-fused cyclic ketones and showed good to high activities and enantioselectivities. Particularly, CgKR1 variants displayed high activities (90.6%-98.4% conversions) and enantioselectivities (>99.9% ee) towards <B>5a</B>, a key intermediate of ladostigil (TV3326). Based on these results, a chemoenzymatic synthesis of (<I>S</I>)-<B>5b</B> was developed by using biocatalytic asymmetric reduction as a key step, giving the product with a total yield of 34.0% and 99.9% ee.</P><P>Graphic Abstract</P><P>Engineered <I>Candida glabrata</I> ketoreductase 1 variants are applied to the bioreduction of benzo-fused cyclic ketones. Particularly, these biocatalysts showed excellent enantioselectivity towards a key intermediate of Ladostigil.<BR/><IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c7ob01803g'/><BR/></P>

2017

The Royal Society of Chemistry

1477-0520

1477-0539

15

35

pp.7374-7379

10.1039/c7ob01803g

http://click.ndsl.kr/servlet/OpenAPIDetailView?keyValue=05787966&target=NART&cn=NART79212065