Trifluoroacetic acid → methyl (S)-phenyl((R)-piperidin-2-yl)acetate

Participants

Reaction Steps

As shown above in Scheme V and Table III, Rh2(S-DOSP)4 7 catalyzed decomposition of methyl phenyldiazoacetate 9a in the presence of N-BOC-piperidine (15, 4 equiv) in 2,3-dimethylbutane at room temperature followed by treatment with trifluoroacetic acid resulted in the formation of a mixture of threo and erythro methyphenidate, 16 and 17, in 49% yield. However, the threo isomer 16 was the minor diastereomer and was formed in only 34% ee. The combined yield of 16 and 17 was improved to 86% by using the N-BOC-peperidine as the limiting reactant. This result is different to what was observed with N-BOC-pyrrolidine, which gave bis C—H insertion when an excess of phenyldiazoacetate was used. A major improvement in enantioselectivity and diastereoselectivity was achieved by carrying out the reaction with the Rh2[bridged (S-TBSP)2]2 8 catalyst. The ratio of 16:17 (73% yield) was improved to 2.5:1 and (2R, 2′R)-threo isomer 16 was, formed in 86% ee and 52% isolated yield. As shown in Table III, Rh2[bridged (S-TBSP)2]2 8 results in opposite asymmetric induction to Rh2(S-DOSP)4 7, and, in the reaction of 9a and 15 catalyzed by 8, the biologically active enantiomer of threo-methylphenidate is formed.

Provenance & Evidence