Hetero Diels−Alder-Biocatalysis Approach for the Synthesis of (S)-3-[2-{(Methylsulfonyl) oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol Methanesulfonate, a Key Intermediate for the Synthesis of the PKC Inhibitor LY3335311

• Published in: Organic process research & development Vol. 6; no. 4; pp. 471 - 476
• Main Authors: Caille, Jean-Claude, Govindan, C. K, Junga, Heiko, Lalonde, Jim, Yao, Yiming
• Format: Journal Article
• Language: English
• Published: American Chemical Society 19.07.2002
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/op020202a

A cost-effective and easily scaled-up process has been developed for the synthesis of (S)-3-[2-{(methylsulfonyl)oxy}ethoxy]-4-(triphenylmethoxy)-1-butanol methanesulfonate, a key intermediate used in the synthesis of a protein kinase C inhibitor drug through a combination of hetero Diels−Alder and biocatalytic reactions. The Diels−Alder reaction between ethyl glyoxylate and butadiene was used to make racemic 2-ethoxycarbonyl-3,6-dihydro-2H-pyran. Treatment of the racemic ester with Bacillus lentus protease resulted in the selective hydrolysis of the R-enantiomer and yielded S-2-ethoxycarbonyl-3,6-dihydro-2H-pyran in excellent optical purity, which was reduced to S-3,6-dihdro-2H-pyran-2-yl methanol. Tritylation of this alcohol, followed by reductive ozonolysis and mesylation afforded the product in 10−15% overall yield and with >99% ee and chemical purity. Details of the process development work done on each step are given.