Novel and enantioselective syntheses of (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid: a synthon for sitagliptin and its derivatives

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• 作者：Meryem Fistikci^a ; Ozlem Gundogdu^a ; Derya Aktas^a ; Hasan Secen^a ; M. Fethi Sahin^b ; Ramazan Altundas^a ; ; Yunus Kara^a ; ^{yukara@atauni.edu.tr}
• 关键词：(R)- and (S)-3-Hydroxy-4-(2 ; 4 ; 5-trifluorophenyl)butanoic acid ; Sitagliptin ; d- andl-Proline ; Aminoxylation
• 刊名：Tetrahedron
• 出版年：2012
• 期刊代码：107_00404020
• 类别：ch
• 出版时间：25 March, 2012
• 卷：68
• 期：12
• 页码：2607-2610
• 文件大小：217 K

摘要

A new synthetic strategy for (m>Rm>)- and (m>Sm>)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid, a building block in the preparation of sitagliptin and its derivatives, was developed. Pd(OAc)₂ catalyzed coupling of 2,4,5-trifluoro-1-iodobenzene with allyl alcohol gave 3-(2,4,5-trifluorophenyl)propanal in a yield of 95%. l-Proline catalyzed reaction of the 3-phenylpropanal (in only 1.2 molar equiv) with nitrosobenzene followed by reduction with NaBH₄ and Pd/C catalyzed hydrogenation gave (m>Rm>)-3-(2,4,5-trifluorophenyl)propane-1,2-diol with >99%ee and 65%yield. Selective tosylation of primary hydroxyl group of the 1,2-propandiol unit followed by cyanide displacement afforded (m>Rm>)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanenitrile (80%). The nitrile was converted to the title 尾-hydroxy acid under basic hydrolysis in a yield of 90%. Thus, (m>Rm>)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid was prepared enantioselectively from the starting material in four steps and 45%overall yield. The reaction sequence was repeated with d-proline as the catalyst to give (m>Sm>)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid in 45%overall yield and >99%enantiomeric excess.