This work describes L-phenylalanine cyclohexylamide (512) as a simple, cheap, and powerful chiral auxiliary for the synthesis of a series of optically pure z,ri -disubstituted ( R ) -and (S)-amino acids of type 1, such as ( R ) -and (S)-2-methyl-phenylalanine (la), ( R ) -and (S)-2-methyl-2-phenylglycine (lb), and (R)-and (S)-2-methylvaline (lc; Scheme 3). These amino acids were efficiently transformed into the suitably protected and activated aminoacid building blocks ( R ) -and (S)-12b and (R)-and (S)-12c (Scheme 4) which are ready for incorporation into peptides by solution or solid-phase techniques. Based on the crystal structures of 6b, 6c, and 7a belonging to the diastereoisomeric peptides series 6 and 7, the absolute configurations of each member of the series were determined. /?-Turn geometries of type 11' and I were observed for 6b and 7a, respectively, whereas 6c crystallized in an extended conformation. The impacts of side-chain variation on conformation and crystal packing of these triarnides are discussed.1. Introduction. -Among the growing number of non-coded synthetic and naturally occurring amino acids, the open-chain and cyclic CI,CI -disubstituted amino acids of type 1 (Scheme 1 ) play an important role [I] [2] due to their inherent propensities to stabilize small peptides in rather well defined conformations, depending on the nature of the substituents R1 and R2 [3-61 (for further refs., see [6]). Especially the a-methylated a-amino acids of type 1 ((R)-1: R2 = Me, R' # H, Me; (S)-1: R' = Me, R2 # H, Me) have been the focus of many investigations as building blocks in the design of enzyme inhibitors [7] and due to their ability to stabilize Jl0-and a-helical as well as P-turn-type conformations in peptides [5].Recently, we have shown [6] that a large variety of novel and interesting open-chain and cyclic CI,M -disubstituted ( R ) -and (S)-amino acids could be synthesized in optically pure form using the strategy outlined in Scheme I. Treatment of the 4,4-disubstituted 1,3-0xazol-5(4H)-ones 4 (which were obtained either from the hydantoins 2 via the classical Bucherer-Bergs reaction [8] or by CI -alkylation of the 4-monosubstituted 2-phenyl-l,3-oxazol-5(4H)-ones 3 (R' = Ph) [9-113) with an optically pure amine 5 derived from L-phenylalanine, yielded the diastereoisomeric peptides 6 and 7, which were separated by crystallization and/or flash chromatography (FC) [12] on SO,. Selective amide cleavage using trifluoromethanesulfonic acid (CF,SO,H) in MeOH gave the optically pure esters ( R ) -and (S)-8, which could be converted into the pure amino acids ( R ) -and (S)-1 in good overall yields. We were able to show that the separation of the diastereoisomeric peptides 6 and 7 depended largely on the nature of R' (Ph > > Me) and, even more importantly, on the amines 5a, b.

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Abstract:The present work describes three novel nonpolar host peptide sequences that provide a ready assessment of the 3 10 -and a-helix compatibilities of natural and unnatural amino acids at different positions of small-to medium-size peptides. The unpolar peptides containing Ala, Aib, and a C-terminal p-iodoanilide group were designed in such a way that the peptides could be rapidly assembled in a modular fashion, were highly soluble in solvent mixtures of nmr spectroscopic analyses, and showed excellent crystallinity suited for x-ray structure analysis. To validate our approach we synthesized 9-mer peptides 79a-96 (Table IV), 12-mer peptides 99-110c (Table V), and 10-mer peptides 120a-125d and 129-133 (Table VI and Scheme 8) incorporating a series of optically pure cyclic and open-chain (R)-and (S)-a,a-disubstituted glycines 1-10 (Figure 2). These amino acids are known to significantly modulate the conformations of small peptides.Based on x-ray structures of 9-mers 79a, 80, and 87 (Figures 4-7), 10-mers 124c, 131, and 132 (Figures 9-12), and 12-mer peptide 102b (Figure 13)

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