L‐Phenylalanine Cyclohexylamide: A simple and convenient auxiliary for the synthesis of optically pure α,α‐disubstituted (R)‐ and (S)‐amino acids

Abstract

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.

Is the optical rotation sign/absolute configuration relationship still a problem? Examples taken from unnatural quaternary aminoacids

“…CONCLUSION We have unambiguously established the absolute configuration of (À)-(R)-a-methyl-a-(p-tolyl)glycine 1a and (þ)-(S)-a-methyl-a-(p-bromophenyl)glycine 1b by X-ray diffraction studies of derivatives. These results concur with previous ones 3,4,5,19 to suggest that the assumption that enzymes such as esterases or amidopeptidases react preferentially with L-a-methyl-a-arylglycines ester or amide derivatives (the L configuration being attributed by analogy to proteinogenic aminoacids, the methyl group replacing the hydrogen of tertiary aminoacids) led to the wrong configuration.…”

“…a Several methods have been used for the assignment of the absolute configuration of a-methyl-a-phenylglycine. Several studies demonstrated a (þ)-(S) relationship using complete structural characterization via single crystal X-ray diffraction of a dipeptide, 3 correlation of optical rotation with (þ)-(S)-isovaline after chemical modification, 4 or assumption of the mechanism in the diastereoselective addition of ethylaluminium cyanoisopropylate on a chiral ketosulfinimine. 5 However, the assumption that the hydrolysis of the corresponding amide by an aminopeptidase follows the trend observed with proteinogenic aminoacids led some authors to assign the (S) configuration to (À)-a-methyl-a-phenylglycine.…”

Direct Asymmetric α‐Sulfamidation of α‐Branched Aldehydes: A Novel Approach to Enamine Catalysis

“…Related methods for the alkylation of modified naturally occurring amino acids with self-reproduction of the stereocentre have been developed: for imidazolidinones [17] and oxazolidinones [18] (Seebach [19] ), or oxazaborolidinones [20] and openchained borane-aminoester adducts. [21] Deprotonated oxazolin-5-ones (azlactones) have for some time been used as amino acid enolate equivalents in the synthesis of racemic α-alkylated amino acids, [22,23] often followed by separation of diastereomeric dipeptides. [23] More recent developments have also seen the emergence of asymmetric catalytic variants, [24,25] of which the palladium-catalysed approach devised by Trost et al has been successfully utilised for the total synthesis of sphingofungin F.…”

Horner–Wadsworth–Emmons reaction for the synthesis of unusual alpha,beta-didehydroamino acids with a chiral axis

“…5 We present here our results on the synthesis of this class of axially chiral amino acid through a different approach that gives new and conveniently protected derivatives in racemic form.…”