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.