Enantioselective Syntheses of Conformationally Rigid, Highly Lipophilic Mesityl-Substituted Amino Acids

Abstract

Three N‐Boc‐protected amino acids substituted with a mesityl (=2,4,6‐trimethylphenyl) group were synthesized in enantiomerically pure form, either by asymmetric epoxidation or by aminohydroxylation as the source of chirality. The 3‐mesityloxirane‐2‐methanol 7, easily available in high enantiomer purity by Sharpless epoxidation, was converted into 3‐{[(tert‐butoxy)carbonyl]amino}‐3‐mesitylpropane‐1,2‐diol 9 by a regio‐ and stereoselective ring opening with an ammonia equivalent (sodium azide or benzhydrylamine), followed by hydrogenation and in situ treatment with (Boc)2O (Boc=[(tert‐butoxy)carbonyl]) (Scheme 3). Oxidative cleavage of the diol fragment in 9 afforded N‐[(tert‐butoxy)carbonyl]‐α‐mesitylglycine 1 of >99% ee. This amino acid was also prepared in enantiomerically pure form starting from 2,4,6‐trimethylstyrene (11) by a regioselective Sharpless asymmetric aminohydroxylation, followed by a 2,2,6,6‐tetramethylpiperidin‐1‐yloxyl (TEMPO)‐catalyzed oxidation (Scheme 4). On the other hand, 1‐[(tert‐butoxy)carbonyl]‐2‐{{[(tert‐butyl)dimethylsilyl]oxy}methyl}‐3‐mesitylaziridine 14 was prepared from 9 by a sequence involving selective protection of the primary alcohol (as a silyl ether), activation of the secondary alcohol as a mesylate, and base‐induced (NaH) cyclization (Scheme 5). The reductive cleavage of the aziridine ring (H2, Pd/C), followed by alcohol deprotection (Bu4NF/THF) and oxidation (pyridinium dichromate (PDC)/DMF or (TEMPO)/NaClO) provided, in high yield and enantiomeric purity, N‐[(tert‐butoxy)carbonyl]‐β‐mesitylalanine 2. Alternatively, the regioselective ring opening of the aziridine ring of 14 with lithium dimethylcuprate, followed by silyl‐ether cleavage and oxidation lead to N‐[(tert‐butoxy)carbonyl]‐β‐mesityl‐β‐methylalanine 3. A conformational study of the methyl esters of the N‐Boc‐protected amino acids 1 and 3 carried out by variable‐temperature 1H‐NMR and semi‐empirical (AM1) calculations shows the strong rotational restriction imposed by the mesityl group.

Insights into Structure-Activity Relationships of Somatostatin Analogs Containing Mesitylalanine

“…The present knowledge about aromatic side-chain interactions, together with the increased interest in the structure-activity relationships, prompted us to exploit the effect of such interactions in new SRIF analogs. As a part of an ongoing study of 14-amino acid SRIF analogs, we decided to incorporate mesitylalanine residues with higher electron density than phenylalanines, and with the intrinsic rigidity provided by the ortho substitution [38]. To this end, we synthetized ten peptides containing Msa; four of them were previously described [21], but are included here for completeness (Table 1).…”

Practical Synthesis of a Key Intermediate for Lactacystin from (R)-4-Hydroxymethyl-2-phenyl-4,5-dihydrooxazol-4-ylmethyl Acetate

“…43) The aldehyde was then oxidized with NaClO 2 to give the carboxylic acid, and subsequent hydrolysis of the dihydrooxazole ring by treatment with 1 M HCl afforded lactam 7. The primary hydroxy group in lactam 7 was oxidized by TEMPO and bis(acetoxy)iodobenzene (BAIB) to give the carboxylic acid, 44) and subsequent esterification of the carboxylic acid by treatment with CH 2 N 2 afforded methyl ester 8.…”