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.
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 stereo-controlled synthesis of (2S,3aS,6R,7aS)-6-hydroxyoctahydroindole-2-carboxylic acid (L-Choi, 5) from L-tyrosine. The synthesis of this new bicyclic alpha-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)2O 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-ChoiNH2 (3), rather than an epimeric mixture of 3 and the L-Leu-incorporating 4.
Valls
N
N
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Spain.
López-Canet
M
M
Vallribera
M
M
Bonjoch
J
J
D000991:Antithrombins / Q000138:chemical synthesis / Q000737:chemistry; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D007930:Leucine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism
C436762:6-hydroxyoctahydroindole-2-carboxylic acid; D000991:Antithrombins; D007202:Indicators and Reagents; D007211:Indoles; C419325:aeruginosin 298-A; C436761:aeruginosin 298-B; D007930:Leucine