First total syntheses of aeruginosin 298-A and aeruginosin 298-B, based ona stereocontrolled route to the new amino acid 6-hydroxyoctahydroindole-2-carboxylic

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 stereoco ntrolled synthesis of (2S,3aS,6R,7aS)-6-hydroxyoctahydroindole-2-carboxylic acid (L-Choi, 5) from L-tyrosine. The synthesis of this new bicyclic a-ami no acid, which is the core of aeruginosins, involves Birch reduction of O-m ethyl-L-tyrosine (6) and amino cyclization 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 equilib rium mixture in which the endo isomer 13 significantly predominates. Hydrog enation of 13 in the presence of (Boc)(2)O gives 16, which on reduction wit h LS-Selectride furnishes the alcohol 22, a protected L-Choi. Successive co uplings of 22 with D-leucine, protected (R)-(4-hydroxyphenyl)lactic acid, a nd L-arginine fragments, followed by reduction to the argininol level and a deprotection end step complete the synthetic sequence to produce aeruginos in 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 nat ural sample of aeruginosin 298-A. These results unequivocally establish tha t the absolute stereochemistry of aeruginosin 298-A, formerly assigned inco rrectly, is D-Hpla-D-LeU-L-Choi-L-Argol, as shown by structure 1. Aeruginos in 298-B was also synthesized and shown to be a mixture of rotamers Of D-Hp la-D-Leu-L-ChoiNH(2) (3), rather than an epimeric mixture of 3 and the L-Le u-incorporating 4.