Three stereoisomeric inhibitors of Pin1: (2R,5S)-, (2S,5R)- and (2S,5S)-Ac-pSer-ψ[(Z) CH = C]-pipecolyl(Pip)-2-(2-naphthyl)ethylamine 1, that mimic L-pSer-D-Pro, D-pSer-LPro, and D-pSer-D-Pro amides respectively, were synthesized by a 13-step route. The newly formed stereogenic centers in the pipecolyl ring were introduced by Luche reduction, followed by stereospecific [2,3]-Still-Wittig rearrangement. The (Z)- to (E)-alkene ratio in the rearrangements were consistently 5.5 to 1. The stereochemistry at the original Ser α-carbon controlled the stereochemistry of the Luche reduction, but it did not affect the stereochemical outcome of the rearrangement, which consistently gave the (Z)-alkene. The epimerized by-product, (2S,5S)-10, resulting from the work-up after Na/NH3 debenzylation of (2S,5R)- 9, was carried on to the (2S,5S)-1 isomer. Compound (2S,5S)-10 was resynthesized from the Luche reduction by-product, (2R,3R)-3, and the stereochemistry was confirmed by comparison of the optical rotations. The IC50 values for (2R,5S)-1, (2S,5R)-1 and (2S,5S)-1 Pin1 inhibition were: 52, 85, and 140 μM, respectively.
Chen, X. R., Fan, S. A., Ware, R. I., & Etzkorn, F. A. (2015). Stereochemical control in the still-wittig rearrangement synthesis of cyclohexyl (Z)- alkene inhibitors of Pin1. PLoS ONE, 10(10). https://doi.org/10.1371/journal.pone.0139543