Stereochemical Control in the Still-Wittig Rearrangement Synthesis of Cyclohexyl (Z)-Alkene Inhibitors of Pin1

Simple item page
dc.contributor.authorChen, Xingguo R.en
dc.contributor.authorFan, Shuang A.en
dc.contributor.authorWare, Rachel I.en
dc.contributor.authorEtzkorn, Felicia A.en
dc.contributor.departmentChemistryen
dc.date.accessioned2018-09-10T18:52:20Zen
dc.date.available2018-09-10T18:52:20Zen
dc.date.issued2015-10-07en
dc.description.abstractThree 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.en
dc.description.sponsorshipNIH: R01 CA110940en
dc.description.sponsorshipNational Science Foundationen
dc.description.sponsorshipNSF: LC-MS Grant No. CHE0722638en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0139543en
dc.identifier.eissn1932-6203en
dc.identifier.issue10en
dc.identifier.issue10en
dc.identifier.othere0139543en
dc.identifier.pmid26445009en
dc.identifier.urihttp://hdl.handle.net/10919/84986en
dc.identifier.volume10en
dc.identifier.volume10en
dc.language.isoenen
dc.publisherPLOSen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleStereochemical Control in the Still-Wittig Rearrangement Synthesis of Cyclohexyl (Z)-Alkene Inhibitors of Pin1en
dc.title.serialPLOS ONEen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
journal.pone.0139543.PDF
Size:
1.28 MB
Format:
Adobe Portable Document Format
Description:
Download

Collections

Scholarly Works, Chemistry