Nativitat Valls

Biosynthesis and Structure of Aeruginoside 126A and 126B, Cyanobacterial Peptide Glycosides Bearing a 2-Carboxy-6-Hydroxyoctahydroindole Moiety

Aeruginosins represent a group of peptide metabolites isolated from various cyanobacterial genera and from marine sponges that potently inhibit different types of serine proteases. Members of this family are characterized by the presence of a 2-carboxy-6-hydroxyoctahydroindole (Choi) moiety. We have identified and fully sequenced a NRPS gene cluster in the genome of the cyanobacterium Planktothrix agardhii CYA126/8. Insertional mutagenesis of a NRPS component led to the discovery and structural elucidation of two glycopeptides that were designated aeruginoside 126A and aeruginoside 126B. One variant of the aglycone contains a 1-amino-2-(N-amidino-Delta(3)-pyrrolinyl)ethyl moiety at the C terminus, the other bears an agmatine residue. In silico analyses of the aeruginoside biosynthetic genes aerA-aerI as well as additional mutagenesis and feeding studies allowed the prediction of enzymatic steps leading to the formation of aeruginosides and the unusual Choi moiety.

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.

Synthesis of the octahydroindole core of aeruginosins: a new bicyclic α-amino acid

Abstract The first synthesis of 6-hydroxyoctahydroindole-2-carboxylic acid derivatives with a cis fusion in the azabicyclic nucleus is described. The synthesis involves a Birch reduction of O -methyl-L-tyrosine followed by an aminocyclization in acid medium to give a mixture of 6-oxo-octahydroindole-2-carboxylic acids 3 and 4 , which could be separated after dibenzylation. Transesterification, hydrogenolysis in the presence of acetic anhydride and reduction of the amido ketones 9 and 10 provides the four stereoisomeric alcohols from which alcohol 14 showed nmr data very close to the aeruginosin 298-A core.

Synthesis of the proposed core of aeruginosins 205: the new α-amino acid (2S, 3aS, 6R, 7aS)-2-carboxy-6-chlorooctahydroindole

Abstract The synthesis of enantiomerically pure α-amino acid (2 S ,3a S ,6 R ,7a S )-2-carboxy-6-chlorooctahydroindole ( l -Ccoi) is described. NMR data of l -Ccoi 3 are very different from those reported for the azabicyclic core of aeruginosins 205, indicating that the structure of these aeruginosins needs to be revised.

The Pummerer cyclization route to the ibophyllidine alkaloids. Total synthesis of (±)-deethylibophyllidine

Abstract Pummerer cyclization of β-aminoethyl sulfoxide 6 was effectively achieved using TFAA-TFA in toluene at 80 °C. The cyclized product 7 was then converted to the alkaloid deethylibophyllidine. The required pyrrolo[3,2- c ]carbazole 6 was prepared in five steps from 4-methoxyphenethylamine.

Synthesis of enantiopure (2R,3aS,7aS)-2-ethyloctahydroindol-6-one and its fischer indolization

Abstract A diastereoselective synthesis of (−)-2-ethyloctahydroindol-6-one 12 starting from O- methyl- L -tyrosine 1 is described. The process first involves the synthesis of enantiopure (−)-1-(4-methoxyphenyl)-2-butylamine 8 , which, after Birch reduction, N -benzylation and acid treatment, renders the cis -fused azabicyclo 12 . Studies on the Fischer indolization of 12 are also reported.

A straightforward route to ibophyllidine alkaloids by a double transannular cyclization

Ring cleavage of indolo[2,3-a]quinolizidine 4 to an octahydroazecino[5, 4-b]indole system, followed by introduction of a cyano substituent and double transannular cyclization gives (±)-deethylibophyllidine.

Synthesis of 4-ethyloctahydroindolo[2,3-a]quinolizine-2-carbaldehydes

Abstract The isomerization-cyclization of tetrahydropyridine 7 by AcOH leads to 4-ethyloctahydroindolo[2,3-a]quinolizine-2-carbaldehydes (8). When the process is carried out with aqueous AcOH, indolizidinoindole 9 is formed as a by-product in a competitive way. Compound 7 is available via reductive cyanation of pyridinium salt 1 followed by treatment of nitrile 2 with ethylmagnesium bromide.