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

Chen XR, Fan SA, Ware RI, Etzkorn FA - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Virginia Tech, Blacksburg, Virginia, 24061, United States of America.

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.

No MeSH data available.


Determination of the stereochemistry of of (2S,5S)-14.The 2D NOESY spectrum is shown with lettering of the major conformation showing key nOe interactions. Crosspeaks between Hi and Hh, and between He and Hi’ show the stereochemistry given.
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pone.0139543.g006: Determination of the stereochemistry of of (2S,5S)-14.The 2D NOESY spectrum is shown with lettering of the major conformation showing key nOe interactions. Crosspeaks between Hi and Hh, and between He and Hi’ show the stereochemistry given.

Mentions: Partial epimerization occurred during the Na/NH3 deprotection of (2R,5S)-9 to produce (2S,5S)-10, which was used to synthesize (2S,5S)-1. To determine which stereocenter was epimerized, (2R,3R)-4 was used to resynthesize (2S,5S)-11 (Fig B in S1 Dataset), and the optical rotations were compared (Materials and Methods). The 2D nuclear Overhauser effect spectroscopy (NOESY) of derivative (2S,5S)-14 was used to determine the relative stereochemistry of the Still-Wittig rearrangement product (2S,5S)-6 (Fig 6). The 1H NMR coupling constants between Hi—Hh and Hi’—Hh were 5.6 Hz and 9.2 Hz, respectively, which indicated that on this 6-membered ring, Hi and Hh were syn to each other, while Hi’ and Hh were anti to each other. In the NOESY spectrum of (2S,5S)-14, the nOe correlation He—Hi’ indicated that the CH2OBn group and Hi’ were syn to each other (Fig 6). The NOESY correlation Hi—Hh indicated that Hi and Hh were syn to each other. Therefore the relative position of Hh and the CH2OBn group was confirmed to be anti, and the configuration of the stereogenic center in the 6-membered ring was determined to be (S).


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

Chen XR, Fan SA, Ware RI, Etzkorn FA - PLoS ONE (2015)

Determination of the stereochemistry of of (2S,5S)-14.The 2D NOESY spectrum is shown with lettering of the major conformation showing key nOe interactions. Crosspeaks between Hi and Hh, and between He and Hi’ show the stereochemistry given.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596862&req=5

pone.0139543.g006: Determination of the stereochemistry of of (2S,5S)-14.The 2D NOESY spectrum is shown with lettering of the major conformation showing key nOe interactions. Crosspeaks between Hi and Hh, and between He and Hi’ show the stereochemistry given.
Mentions: Partial epimerization occurred during the Na/NH3 deprotection of (2R,5S)-9 to produce (2S,5S)-10, which was used to synthesize (2S,5S)-1. To determine which stereocenter was epimerized, (2R,3R)-4 was used to resynthesize (2S,5S)-11 (Fig B in S1 Dataset), and the optical rotations were compared (Materials and Methods). The 2D nuclear Overhauser effect spectroscopy (NOESY) of derivative (2S,5S)-14 was used to determine the relative stereochemistry of the Still-Wittig rearrangement product (2S,5S)-6 (Fig 6). The 1H NMR coupling constants between Hi—Hh and Hi’—Hh were 5.6 Hz and 9.2 Hz, respectively, which indicated that on this 6-membered ring, Hi and Hh were syn to each other, while Hi’ and Hh were anti to each other. In the NOESY spectrum of (2S,5S)-14, the nOe correlation He—Hi’ indicated that the CH2OBn group and Hi’ were syn to each other (Fig 6). The NOESY correlation Hi—Hh indicated that Hi and Hh were syn to each other. Therefore the relative position of Hh and the CH2OBn group was confirmed to be anti, and the configuration of the stereogenic center in the 6-membered ring was determined to be (S).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Virginia Tech, Blacksburg, Virginia, 24061, United States of America.

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.

No MeSH data available.