A New General Approach to Enantiomerically Pure Cyclic and Open‐Chain (R)‐ and (S)‐α,α‐Disubstituted α‐Amino Acids

Abstract

A wide range of cyclic and open-chain c(,z -disubstituted a-amino acids la-p were prepared. The racemic N-acylated a,c( -disubstituted amino acids were resolved by coupling L o chiral amines 15-18 derived from (S)-phenylalanine to form diastereoisomers 19/20 or 21/22 that could be separated by crystalliiation and/or flash chromatography on silica gel (Scheme 3 ) . Selective cleavage via the 1,3-oxazol-5(4H)-ones 10a-p gave the corresponding optically pure &,a -disubstituted amino-acid derivatives 11 or 12 in high yield (Scheme 3 ) . The aboslute configurations of the a,c( -disubstituted amino acids were determined from X-ray structures of the diastereoisomers 20, 21g',22d.Introduction. -There is an ever-growing interest in the synthesis, pharmacology, and conformational properties of non-proteinogenic amino acids. In particular, CI,E -disubstituted a-amino acids of type A or B were the subject of numerous investigations over recent years. A large number of these studies focused on a -aminoisobutyric acid ( = 2-amino-2-methylpropanoic acid; Aib) [ 11 and (-)-(R)-2-amino-2-methylbutyric acid (DIva) [2], which are the main naturally occurring members of this family. These amino acids are important constituents of a class of microbial peptide antibiotics, known as the peptaibols [3]. The presence of a,a -disubstituted amino acids in these peptides is thought to play a crucial role in their ability to form trans-membrane helical ion channels. Conformational-energy calculations and numerous X-ray studies have highlighted the effect of these unusual amino acids on peptide conformation and shown that the nature of the substituents R' and R2 of amino acids of type A or B is of great importance. It is now

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

“…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].…”

“…-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,.…”

“…In a preliminary screening, we studied the separation properties of aminoamides 5c-f when incorporated into amino-acid derivatives of type 6 and 7, especially in cases where we previously observed poor or no separation [6]. It became evident that the L-phenylalanine cyclohexylamide ( 5 ) showed the most promising properties in terms of separation, crystallizability, and solubility of the diastereoisomeric peptides of type 6 and 7.…”

“…5. The diastereoisomers of types 6 and 7 were converted in the presence of CF,SO,H in MeOH at 80" [6] into the optically pure esters (R)-and ( S ) -8a-q in excellent yields ( Table 2). It is interesting to note that the chiral aminoamide 5c could be recovered as the trifluoromethanesulfonate salt in optically pure form in yields greater than 90 %, indicating that the selective amide cleavage is essentially quantitative.…”

An efficient approach for the synthesis of 6,7-dimethoxy-2-tetralone and 5,6-dimethoxy-1-tetralone

“…Its utility has been recorded in the synthesis of natural alkaloids 2 , cyclic amino acids 3 and as novel antagonists 4 of human TRPVI. 5,6-Dimethoxy-1-tetralone 2 is a key intermediate in the synthesis of novel antidepresants 5 which are the α-2-antagonists and norepinephrine uptake inhibitors eg.…”