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Further C ‐Alkylations of Cyclotetrapeptides via Lithium and Phosphazenium (P4) Enolates: Discovery of a New Conformation
Author(s) -
Seebach Dieter,
Bezençon Olivier,
Jaun Bernhard,
Pietzonka Thomas,
Matthews Jennifer L.,
Kühnle Florian N. M.,
Schweizer W. Bernd
Publication year - 1996
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19960790303
Subject(s) - chemistry , stereocenter , electrophile , stereochemistry , chirality (physics) , nuclear magnetic resonance spectroscopy , alkylation , thiazole , enantioselective synthesis , organic chemistry , chiral symmetry breaking , physics , quantum mechanics , quark , nambu–jona lasinio model , catalysis
Four cyclotetrapeptides containing one ( 1, 2 ) or two ( 3, 4 ) chiral amino acids have been C ‐alkylated or C ‐hydroxyalkylated through Li + or phosphazenium (P4 · H + ) enolates. The reactions are completely diastereoselective (by NMR or HPLC analysis) with respect to the newly formed backbone stereogenic centres ( Tables 2 and 3 ). The reactivity of the polylithiated species responsible for these alkylations is such that only highly reactive electrophiles (MeI, BnBr, primary allylic halides, aldehydes, CO 2 ) can be employed. It is shown that the position, and thus the chirality sense, of the newly formed stereogenic centre in a given cyclotetrapeptide backbone is controlled by the positioning of N ‐methyl groups in the starting material ( cf. cyclo(‐MeLeu‐Gly‐ D ‐Ala‐Sar‐) ( 3 ) and cyclo(‐Leu‐Sar‐Me D Ala‐Gly‐) ( 4 ) in Scheme 1 ). With Schwesinger 's phosphazene P4‐base, all NH groups are first benzylated and C ‐benzylation then takes place at a sarcosine, rather than an N ‐benzylglycine residue ( Table 3 ). In contrast to open‐chain N ‐benzyl peptides, the N ‐benzylated cyclotetrapeptides could not be debenzylated under dissolving‐metal conditions (Na/NH 3 ). Conformational analysis (NMR spectroscopy and X‐ray diffraction) shows that the prevailing species have cis/trans/cis/trans(ctct) peptide bonds (zigzag conformation of C i backbone symmetry, Figs. 2–4 ). However, a hitherto unknown conformation of cyclotetrapeptides has been found in CDCl 3 solutions of the hydroxyalkylated products 18–21 (obtained with EtCHO and PhCHO as electrophiles; Fig.4 ). The new conformation has four trans peptide bonds and is believed to result mainly from intramolecular H‐bond formation, involving the newly generated alkyl‐ or arylserine residue. This assumption has also been supported by modelling (TRIPOS force field, SYBYL, see Fig.5 and Table 6 ). The structure may be considered as a β‐turn mimic.