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Isotopically Labelled and Unlabelled β ‐Peptides with Geminal Dimethyl Substitution in 2‐Position of Each Residue: Synthesis and NMR Investigation in Solution and in the Solid State
Author(s) -
Seebach Dieter,
Sifferlen Thierry,
Bierbaum Daniel J.,
Rueping Magnus,
Jaun Bernhard,
Schweizer Bernd,
Schaefer Jacob,
Mehta Anil K.,
O'Connor Robert D.,
Meier Beat H.,
Ernst Matthias,
Glättli Alice
Publication year - 2002
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 - 10.1002/1522-2675(200209)85:9<2877::aid-hlca2877>3.0.co;2-w
Subject(s) - chemistry , stereochemistry , amino acid , folding (dsp implementation) , peptide , derivative (finance) , nuclear magnetic resonance spectroscopy , side chain , organic chemistry , biochemistry , financial economics , electrical engineering , economics , engineering , polymer
The preparation of ( S )‐ β 2,2,3 ‐amino acids with two Me groups in the α ‐position and the side chains of Ala, Val, and Leu in the β ‐position (double methylation of Boc‐ β ‐HAla‐OMe, Boc‐ β ‐Val‐OMe, and Boc‐ β ‐Leu‐OMe, Scheme 2 ) is described. These β ‐amino acids and unlabelled as well as specifically 13 C‐ and 15 N‐labelled 2,2‐dimethyl‐3‐amino acid ( β 2,2 ‐HAib) derivatives have been coupled in solution ( Schemes 1, 3 and 4 ) to give protected ( N ‐Boc, C ‐OMe), partially protected ( N ‐Boc/ C ‐OH, N ‐H/ C ‐OMe), and unprotected β 2,2 ‐ and β 2,2,3 ‐hexapeptides, and β 2,2 ‐ and β 2,2,3 ‐heptapeptides 1 – 7 . NMR Analyses in solution ( Tables 1 and 2 , and Figs. 2–4 ) and in the solid state (2D‐MAS NMR measurements of the fully labelled Boc‐( β 2,2 ‐HAib) 6 ‐OMe ([ 13 C 30 , 15 N 6 ]‐ 1e ; Fig. 5 ), and TEDOR/REDOR NMR investigations of mixtures ( Fig. 6 ) of the unlabelled Ac‐( β 2,2 ‐HAib) 7 ‐OMe ( 4 ) and of a labelled derivative ([ 13 C 4 , 15 N 2 ]‐ 5 ; Figs. 7–11 , and 19 ), a molecular‐modeling study ( Figs. 13–15 ), and a search in the Cambridge Crystallographic Data Base ( Fig. 16 ) allow the following conclusions: i ) there is no evidence for folding (helix or turn) or for aggregation to sheets of the geminally dimethyl substituted peptide chains in solution; ii ) there are distinct conformational preferences of the individual β 2,2 ‐ and β 2,2,3 ‐amino acid residues: close to eclipsing around the C(O)C(Me 2 (CHR)) bond ( τ 1,2 ), almost perfect staggering around the C(2)C(3) ethane bond ( τ 2,3 ), and antiperiplanar arrangement of H(C3) and H(N) ( τ 3, N ; Fig. 12 ) in the solid state; iii ) the β 2,2 ‐peptides may be part of a turn structure with a ten‐membered H‐bonded ring; iv ) the main structure present in the solid state of F 3 CCO( β 2,2 ‐HAib) 7 ‐OMe is a nonfolded chain (>30 Å between the termini and >20 Å between the N‐terminus and the CH 2 group of residue 5) with all CO bonds in a parallel alignment (±10°). With these structural parameters, a simple modelling was performed producing three (maybe four) possible chain geometries: one fully extended, two with parallel peptide planes (with zick‐zack and crankshaft‐type arrangement of the peptide bonds), and (possibly) a fourth with meander‐like winding ( D – G in Figs. 17 and 18 ).