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

• Published in: Tetrahedron 2012-03, Vol.68 (12), p.2607-2610
• Main Authors: Fistikci, Meryem, Gundogdu, Ozlem, Aktas, Derya, Secen, Hasan, Sahin, M. Fethi, Altundas, Ramazan, Kara, Yunus
• Format: Article
• Language: English
• Subjects: (R)- and (S)-3-Hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid; Aminoxylation; Catalysis; Catalysts: preparations and properties; Chemistry; d- andl-Proline; Derivatives; Displacement; Exact sciences and technology; General and physical chemistry; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Hydrogenation; Hydrolysis; Joining; Nitriles; Organic chemistry; Preparations and properties; Sitagliptin; Strategy; Tetrahedrons; Theory of reactions, general kinetics. Catalysis. Nomenclature, chemical documentation, computer chemistry
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2012.01.095

A new synthetic strategy for (R)- and (S)-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 (R)-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 (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanenitrile (80%). The nitrile was converted to the title β-hydroxy acid under basic hydrolysis in a yield of 90%. Thus, (R)-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 (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid in 45% overall yield and >99% enantiomeric excess. [Display omitted]