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Enantioselective Syntheses of Conformationally Rigid, Highly Lipophilic Mesityl‐Substituted Amino Acids
Author(s) -
Medina Eva,
Moyano Albert,
Pericàs Miquel A.,
Riera Antoni
Publication year - 2000
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/(sici)1522-2675(20000510)83:5<972::aid-hlca972>3.0.co;2-9
Subject(s) - chemistry , regioselectivity , medicinal chemistry , enantioselective synthesis , diol , enantiomer , ether , aziridine , stereochemistry , organic chemistry , catalysis , ring (chemistry)
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) 2 O (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 (H 2 , Pd/C), followed by alcohol deprotection (Bu 4 NF/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 1 H‐NMR and semi‐empirical (AM1) calculations shows the strong rotational restriction imposed by the mesityl group.