Complementary Syntheses of N,O-Protected-(S)-2-methylserine on a Multikilogram Scale

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• 作者：Michael S. Anson ; Hugh F. Clark ; Paul Evans ; Martin E. Fox ; Jonathan P. Graham ; Natalie N. Griffiths ; Graham Meek ; James A. Ramsden ; Alastair J. Roberts ; Shaun Simmonds ; Matthew D. Walker ; Matthew Willets
• 刊名：Organic Process Research & Development
• 出版年：2011
• 出版时间：March 18, 2011
• 年：2011
• 卷：15
• 期：2
• 页码：389-397
• 全文大小：914K
• 年卷期：v.15,no.2(March 18, 2011)
• ISSN：1520-586X

文摘

Two complementary and scalable approaches have been used to manufacture multikilogram quantities of N,O-protected-(S)-2-methylserine. The first approach uses a diastereomeric salt resolution of 2-methylserine methyl ester as the (1S)-(+)-camphorsulfonate salt, and was used to rapidly access 15 kg of (S)-3-tert-butoxycarbonyl-2,2,4-trimethyl-1,3-oxazolidine-4-carboxylic acid with >99% ee. The second approach involves a stereoselective enolate methylation of a chiral cyclic l-serine derivative under cryogenic conditions. The four-step telescoped process, starting from l-serine methyl ester, was used to manufacture 20 kg of (2R,4S)-2-tert-butyl-3-tert-butoxycarbonyl-4-methyl-1,3-oxazolidine-4-carboxylic acid in 52% overall yield and 98% ee. The advantages and disadvantages for scale-up of both approaches are discussed.