Racemic and enantiomerically enriched Nα-protected methyl 6-amino-1,11-(20-crown-6)-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-6-carboxylates (Boc-[20-C-6]-Bip-OMe) (RS)-Ia, (R)-Ia and (S)-Ia have been synthesized by phase-transfer dialkylation of the 4-chlorobenzylidene derivative of glycine tert-butyl ester, with both racemic and resolved (both enantiomers) 2,2′-bis(bromomethyl)-6,6′-dimethoxy-1,1′-biphenyl being used as alkylating agents. Demethylation of the resulting (RS)-, (R)- and (S)-H-[MeO]2-Bip-OtBu, followed by esterification and Nα-Boc protection, gave (RS)-, (R)- and (S)-Boc-[HO]2-Bip-OMe. Cyclization with Cs2CO3/DMF and pentaethylene glycol ditosylate afforded the crown-carrier Cα,α-disubstituted glycines (RS)-Ia, (R)-Ia and (S)-Ia, possessing only axial dissymmetry. Although (R)-Ia and (S)-Ia are enantiomerically stable in solution at 110 °C, they were obtained with only 64% ee and 48% ee, respectively, because of racemization occurring both at the demethylation/esterification and at the crown formation stages of the synthesis. Solution synthesis provided access to: (i) a number of [20-C-6]-Bip/Gly peptides up to the pentapeptide Boc-[20-C-6]-Bip-Gly-Gly-[20-C-6]-Bip-Gly-OMe (RR,SS)- and (RS,SR)-Va as a mixture of two racemic isomers, and (ii) the heptapeptide Boc-[20-C-6]-Bip-(Aib)6-OtBu (S)-VI. Conformational analysis of (S)-VI by FT-IR absorption and 1H NMR indicated a high degree of folding, with spectral patterns typical of a 310-helical peptide. The absolute configuration of the [20-C-6]-Bip residue was correlated with the CD pattern in the 200−300 nm region

Synthesis of the first axially dissymmetric, C-alpha,C-alpha-disubstituted glycine containing a crown ether receptor, and the conformational preferences of a model peptide

PEGGION, CRISTINA;FORMAGGIO, FERNANDO;TONIOLO, CLAUDIO
2002

Abstract

Racemic and enantiomerically enriched Nα-protected methyl 6-amino-1,11-(20-crown-6)-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-6-carboxylates (Boc-[20-C-6]-Bip-OMe) (RS)-Ia, (R)-Ia and (S)-Ia have been synthesized by phase-transfer dialkylation of the 4-chlorobenzylidene derivative of glycine tert-butyl ester, with both racemic and resolved (both enantiomers) 2,2′-bis(bromomethyl)-6,6′-dimethoxy-1,1′-biphenyl being used as alkylating agents. Demethylation of the resulting (RS)-, (R)- and (S)-H-[MeO]2-Bip-OtBu, followed by esterification and Nα-Boc protection, gave (RS)-, (R)- and (S)-Boc-[HO]2-Bip-OMe. Cyclization with Cs2CO3/DMF and pentaethylene glycol ditosylate afforded the crown-carrier Cα,α-disubstituted glycines (RS)-Ia, (R)-Ia and (S)-Ia, possessing only axial dissymmetry. Although (R)-Ia and (S)-Ia are enantiomerically stable in solution at 110 °C, they were obtained with only 64% ee and 48% ee, respectively, because of racemization occurring both at the demethylation/esterification and at the crown formation stages of the synthesis. Solution synthesis provided access to: (i) a number of [20-C-6]-Bip/Gly peptides up to the pentapeptide Boc-[20-C-6]-Bip-Gly-Gly-[20-C-6]-Bip-Gly-OMe (RR,SS)- and (RS,SR)-Va as a mixture of two racemic isomers, and (ii) the heptapeptide Boc-[20-C-6]-Bip-(Aib)6-OtBu (S)-VI. Conformational analysis of (S)-VI by FT-IR absorption and 1H NMR indicated a high degree of folding, with spectral patterns typical of a 310-helical peptide. The absolute configuration of the [20-C-6]-Bip residue was correlated with the CD pattern in the 200−300 nm region
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/141368
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