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Synthesis of the First Axially Dissymmetric, C α,α ‐Disubstituted Glycine Containing a Crown Ether Receptor, and the Conformational Preferences of a Model Peptide
Author(s) -
Mazaleyrat JeanPaul,
Goubard Yolaine,
Azzini MariaVittoria,
Wakselman Michel,
Peggion Cristina,
Formaggio Fernando,
Toniolo Claudio
Publication year - 2002
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/1099-0690(200204)2002:7<1232::aid-ejoc1232>3.0.co;2-i
Subject(s) - chemistry , stereochemistry , racemization , stereocenter , moiety , enantiomer , peptide synthesis , pentapeptide repeat , tripeptide , peptide , enantioselective synthesis , organic chemistry , catalysis , biochemistry
Racemic and enantiomerically enriched N α ‐protected methyl 6‐amino‐1,11‐(20‐crown‐6)‐6,7‐dihydro‐5 H ‐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‐O t Bu, followed by esterification and N α ‐Boc protection, gave ( RS )‐, ( R )‐ and ( S )‐Boc‐[HO] 2 ‐Bip‐OMe. Cyclization with Cs 2 CO 3 /DMF and pentaethylene glycol ditosylate afforded the crown‐carrier C α,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 ‐O t Bu ( S )‐ VI . Conformational analysis of ( S )‐ VI by FT‐IR absorption and 1 H NMR indicated a high degree of folding, with spectral patterns typical of a 3 10 ‐helical peptide. The absolute configuration of the [20‐C‐6]‐Bip residue was correlated with the CD pattern in the 200−300 nm region. (© Wiley‐VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)