Onchidin B:  A New Cyclodepsipeptide from the Mollusc <i>Onchidium</i> sp.

Abstract

Onchidin B ( 4 ) is a cyclic depsipeptide isolated from the pulmonate mollusc Onchidium sp. Its structure was determined by extensive 2D-NMR, FABMS, tandem FAB MS/MS, selective hydrolysis, and synthesis. It contains four α-amino acids [two units of N -methyl valine (MeVal), two units of proline (Pro)], four α-hydroxy acids [two 2-hydroxyisovaleric acids (Hiv), two 2-hydroxy-3-methylpentanoic acid moieties (Hmp)] and two units of the new β-hydroxy acid: 3-hydroxy-2-methyloct-7-ynoic acid (Hymo)]. Selective hydrolysis and direct comparison by chiral GC-MS with authentic samples of the α-amino and α-hydroxy acids allowed us the assignment of the entire absolute stereochemistry of onchidin B. In this way, the α-hydroxy acids were found to be ( S )-Hiv and ( S, S )-Hmp, and the α-amino acids ( R )-proline, ( S )-proline, and ( R )-MeVal. In order to establish the absolute configuration of the new β-hydroxy acid, Hymo, its four possible stereoisomers were stereoselectively synthesized using chiral N -propionyl oxazolidinones and hex-5-ynal as starting material. Comparison by HPLC-MS of the synthetic samples with the natural Hymo (all derivatized as esters of (−)-( R )-α-methoxy-α-(9-anthryl)acetic acid), affirmed its absolute stereochemistry as (2 R,3 R ). Thus, onchidin B ( 4 ) is cyclo [( R )-MeVal-( R, R )-Hymo-( S )-Pro-( S, S )-Hmp-( S )-Hiv-( R )-MeVal-( R, R )-Hymo-( R )-Pro-( S, S )-Hmp-( S )-Hiv]. It is formed by a head-to-tail linkage of two halves, each one built by five units and identical sequence. The lack of symmetry of onchidin B is thus due to the presence of one ( S )-Pro unit in one half and one ( R )-Pro unit in the other. The structural similarity between onchidin B ( 4 ) and onchidin ( 2 ), both isolated from the same organism, and between the β-hydroxy acid Hymo ( 5 ) and the β-amino acid Amo ( 3 ) found in onchidin is noticed.