Chiral syntheses of methyl (R)‐2‐Sulfanylcarboxylic esters and acids with optical purity determination using HPLC. Issue 6 (16th April 2018)

• Record Type: Journal Article
• Authors: Sasaki, Ryosuke; Tanabe, Yoo
• Is Part Of: Chirality. Volume 30:Issue 6(2018)
• Page Start: 816
• Page End: 827
• Publication Date: 2018-04-16
• Subjects: 2‐sulfanylmandelic ester -- 2‐sulfanylsuccinic ester -- drug discovery -- HPLC analysis -- process chemistry -- SN2 inversion -- thiazolidin‐4‐one -- thiolactic acid; Chirality -- Periodicals; Pharmaceutical chemistry -- Periodicals; 541.22
• DOI: 10.1002/chir.22860
• Languages: English
• ISSNs: 0899-0042

Abstract

Abstract: Accessible chiral syntheses of 3 types of ( R )‐2‐sulfanylcarboxylic esters and acids were performed: ( R )‐2‐sulfanylpropanoic (thiolactic) ester (53%, 98%ee) and acid (39%, 96%ee), ( R )‐2‐sulfanylsucciinic diester (59%, 96%ee), and ( R )‐2‐mandelic ester (78%, 90%ee) and acid (59%, 96%ee). The present practical and robust method involves (i) clean SN 2 displacement of methanesulfonates of ( S )‐2‐hydroxyesters by using commercially available AcSK with tris(2‐[2‐methoxyethoxy])ethylamine and (ii) sufficiently mild deacetylation. The optical purity was determined by the corresponding (2 R, 5 R )‐ trans ‐thiazolidin‐4‐one and (2 S, 5 R )‐ cis ‐thiazolidin‐4‐one derivatives based on accurate high‐performance liquid chromatography analysis with high‐resolution efficiency. Compared with the reported method utilizing AcSCs (generated from AcSH and CsCO3 ), the present method has several advantages, that is, the use of odorless AcCOSK reagent, reasonable reaction velocity, isolation procedure, and accurate, reliable optical purity determination. The use of accessible AcSK has advantages because of easy‐to‐handle odorless and hygroscopic solid that can be used in a bench‐top procedure. The Ti(O i Pr)4 catalyst promoted smooth trans ‐cyclo‐condensation to afford (2 R, 5 R )‐ trans ‐thiazolidin‐4‐one formation of ( R )‐2‐sulfanylcarboxylic esters with available N ‐(benzylidene)methylamine under neutral conditions without any racemization, whereas (2 S, 5 R )‐ cis ‐thiazollidin‐4‐ones were obtained via cis ‐cyclo‐condensation and no catalysts. Direct high‐performance liquid chromatography analysis of methyl ( R )‐mandelate was also performed; however, the resolution efficiency was inferior to that of the thaizolidin‐4‐one derivatizations. Abstract :