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γ 2 ‐, γ 3 ‐, and γ 2,3,4 ‐Amino Acids, Coupling to γ ‐Hexapeptides: CD Spectra, NMR Solution and X‐ray Crystal Structures of γ ‐Peptides
Author(s) -
Seebach Dieter,
Brenner Meinrad,
Rueping Magnus,
Jaun Bernhard
Publication year - 2002
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/1521-3765(20020201)8:3<573::aid-chem573>3.0.co;2-h
Subject(s) - chemistry , amino acid , tetrapeptide , stereochemistry , crystal structure , cyclic peptide , two dimensional nuclear magnetic resonance spectroscopy , peptide , crystallography , biochemistry
There are numerous possible γ ‐amino acids with different degrees of substitution and with various constitutions and configurations. Of these the γ 4 ‐ and the like‐ and unlike ‐ γ 2,4 ‐amino acids have been previously used as building blocks in γ ‐peptides. The synthesis of γ 2 ‐, γ 3 ‐, and γ 2,3,4 ‐peptides is now described. The corresponding amino acids have been prepared by Michael addition of chiral N ‐acyl‐oxazolidinone enolates to nitro‐olefins, with subsequent reduction of the NO 2 to NH 2 groups. Such additions to E ‐2‐methyl‐nitropropene provide (2 R ,3 R ,4 R )‐2‐alkyl‐3‐methyl‐4‐amino‐pentanoic acid derivatives ( 9, 10, 11 ). Stepwise coupling and fragment coupling lead to γ ‐di‐, tri‐, and hexapeptides ( 12 – 23 ), which were fully characterized. The crystal structures of one of the γ ‐amino acids (2,3‐dimethyl‐4‐amino‐pentanoic acid ⋅ HCl, 9 a ), of a γ 2,3,4 ‐di‐ and a γ 2,3,4 ‐tetrapeptide ( 20 , 22 ) are described, and the NMR solution structure in MeOH of a γ 2,3,4 ‐hexapeptide ( 3 ) has been determined (using TOCSY, COSY, HSQC, HMBC and ROESY measurements and a molecular dynamics simulated‐annealing protocol). A linear conformation (sheet‐like), a novel ( M ) helix built of nine‐membered hydrogen‐bonded rings, and ( M ) 2.6 14 helices have thus been identified. NMR measurements at different temperatures (298–393 K) and H/D‐exchange rates obtained for the γ 2,3,4 ‐hexapeptide are interpreted as evidence for the stability of the 2.6 14 helix (no “melting”) and for its non‐cooperative folding mechanism. CD Spectra of the γ ‐peptides have been measured in MeOH and CH 3 CN, indicating that only the protected and unprotected γ 2,3,4 ‐hexapeptide is present as the 2.6 14 helix in solution. The structures of the γ 2 ‐ and γ 3 ‐hexapeptides ( 1 , 2 ) could not be determined.