title: Stereochemical Control in the Still-Wittig Rearrangement Synthesis of Cyclohexyl (Z)-Alkene Inhibitors of Pin1.
abstract: 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-L-Pro, 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.
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, Virginia, 24061, United States of America.
authors.forename: Xingguo R
authors.initials: XR
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, Virginia, 24061, United States of America.
authors.forename: Shuang A
authors.initials: SA
authors.lastname: Fan
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, Virginia, 24061, United States of America.
authors.forename: Rachel I
authors.initials: RI
authors.lastname: Ware
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, Virginia, 24061, United States of America.
authors.forename: Felicia A
authors.initials: FA
authors.lastname: Etzkorn
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000577:Amides / Q000737:chemistry*; D001669:Biochemical Phenomena / Q000502:physiology; D015394:Molecular Structure; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
chemical_list: D000475:Alkenes; D000577:Amides; D019696:Peptidylprolyl Isomerase