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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.


Synthesis of the Ac–L-pSer–Ψ[(Z)CH = C]-D-Pip–NEA inhibitor (2R,5S)-1.
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pone.0139543.g002: Synthesis of the Ac–L-pSer–Ψ[(Z)CH = C]-D-Pip–NEA inhibitor (2R,5S)-1.

Mentions: In the synthesis of (2R,5S)-1, Luche reduction was used to set up for the synthesis of the D-Pro mimic in the key Still-Wittig rearrangement (Fig 2). We were not certain if the initial Ser stereochemistry would affect the outcome of the Still-Wittig rearrangement. It did not––the stereochemistry depended only upon the stereochemistry of the allylic alcohol resulting from the Luche reduction.[10,22] The Weinreb amide of Boc–L-Ser(OBn)–OH was synthesized as reported.[24,27] 1-Iodocyclohexene was prepared from cyclohexanone by the method of Barton.[25] Nucleophilic addition of cyclohexenyl lithium, prepared from 1-iodocyclohexene in situ, to the Weinreb amide afforded the new cyclohexenyl ketone (S)-2 (Fig 2). Luche reduction of (S)-2 gave two inseparable diastereomers (2S,3R)-3 and (2S,3S)-3 in a ratio of 6-to–1. The stereochemistry and the ratio of the intermediate alcohols (2S,3R)-3 and (2S,3S)-3 from the Luche reduction[22] was determined by 1D coupling constants of cyclic oxazolidinone derivatives (2S,3R)-13 and (2S,3S)-13 (Fig 3). The yield and diastereoselectivity were comparable to the Luche reduction step in the synthesis of the (E)-alkene 5-membered ring analogue.[10]


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)

Synthesis of the Ac–L-pSer–Ψ[(Z)CH = C]-D-Pip–NEA inhibitor (2R,5S)-1.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0139543.g002: Synthesis of the Ac–L-pSer–Ψ[(Z)CH = C]-D-Pip–NEA inhibitor (2R,5S)-1.
Mentions: In the synthesis of (2R,5S)-1, Luche reduction was used to set up for the synthesis of the D-Pro mimic in the key Still-Wittig rearrangement (Fig 2). We were not certain if the initial Ser stereochemistry would affect the outcome of the Still-Wittig rearrangement. It did not––the stereochemistry depended only upon the stereochemistry of the allylic alcohol resulting from the Luche reduction.[10,22] The Weinreb amide of Boc–L-Ser(OBn)–OH was synthesized as reported.[24,27] 1-Iodocyclohexene was prepared from cyclohexanone by the method of Barton.[25] Nucleophilic addition of cyclohexenyl lithium, prepared from 1-iodocyclohexene in situ, to the Weinreb amide afforded the new cyclohexenyl ketone (S)-2 (Fig 2). Luche reduction of (S)-2 gave two inseparable diastereomers (2S,3R)-3 and (2S,3S)-3 in a ratio of 6-to–1. The stereochemistry and the ratio of the intermediate alcohols (2S,3R)-3 and (2S,3S)-3 from the Luche reduction[22] was determined by 1D coupling constants of cyclic oxazolidinone derivatives (2S,3R)-13 and (2S,3S)-13 (Fig 3). The yield and diastereoselectivity were comparable to the Luche reduction step in the synthesis of the (E)-alkene 5-membered ring analogue.[10]

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.