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First Total Syntheses of Aeruginosin 298‐A and Aeruginosin 298‐B, Based on a Stereocontrolled Route to the New Amino Acid 6‐Hydroxyoctahydroindole‐2‐carboxylic Acid
Author(s) -
Valls Nativitat,
LópezCanet Meritxell,
Vallribera Mercè,
Bonjoch Josep
Publication year - 2001
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/1521-3765(20010817)7:16<3446::aid-chem3446>3.0.co;2-0
Subject(s) - diastereomer , chemistry , stereochemistry , amino acid , total synthesis , alcohol , carboxylic acid , peptide , bicyclic molecule , absolute configuration , peptide synthesis , organic chemistry , biochemistry
The first total syntheses of aeruginosin 298‐A ( 1 ) and aeruginosin 298‐B ( 3 ) are described. The syntheses of the alternative putative structures 2 and 4 were also accomplished. The key common strategic element is the stereocontrolled synthesis of (2 S ,3a S ,6 R ,7a S )‐6‐hydroxyoctahydroindole‐2‐carboxylic acid ( L ‐Choi, 5 ) from L ‐tyrosine. The synthesis of this new bicyclic α ‐amino acid, which is the core of aeruginosins, involves Birch reduction of O ‐methyl‐ L ‐tyrosine ( 6 ) and aminocyclization of the resulting dihydroanisole 7 in acid medium, followed by N ‐benzylation to give the diastereoisomers 12 and 13 . Upon acid treatment with HCl‐MeOH, the last two produce an equilibrium mixture in which the endo isomer 13 significantly predominates. Hydrogenation of 13 in the presence of (Boc) 2 O gives 16 , which on reduction with LS‐Selectride furnishes the alcohol 22 , a protected L ‐Choi. Successive couplings of 22 with D ‐leucine, protected ( R )‐(4‐hydroxyphenyl)lactic acid, and L ‐arginine fragments, followed by reduction to the argininol level and a deprotection end step complete the synthetic sequence to produce aeruginosin 298‐A ( 1 ). Spectral comparison showed that peptide 2 , with the structure previously proposed for aeruginosin 298‐A, was different from the natural product. However, synthetic 1 was found to be identical to the isolated natural sample of aeruginosin 298‐A. These results unequivocally establish that the absolute stereochemistry of aeruginosin 298‐A, formerly assigned incorrectly, is D ‐Hpla‐ D ‐Leu‐ L ‐Choi‐ L ‐Argol, as shown by structure 1 . Aeruginosin 298‐B was also synthesized and shown to be a mixture of rotamers of D ‐Hpla‐ D ‐Leu‐ L ‐ChoiNH 2 ( 3 ), rather than an epimeric mixture of 3 and the L ‐Leu‐incorporating 4 .