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

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Abstract
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 (2S,3aS,6R,7aS)‐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)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.

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