Synthesis of the Proposed Isomers of the Deep-Sea Mussel Metabolites Bathymodiolamides A and B

Abstract

The first total synthesis of bathymodiolamides A and B, ceramide-like metabolites of the deep-sea hydrothermal vent mussel Bathymodiolus thermophilus, was accomplished in eight linear steps starting from Garner’s aldehyde and three carboxylic acids. A sequence of vinylation of Garner’s aldehyde, N-acylation with lauric acid, dihydroxylation of the terminal alkene, and stepwise Steglich–Hassner esterifications of the resulting vicinal diol with the respective saturated and unsaturated carboxylic acids, which had to be prepared separately, afforded the target products in 38 and 39% yield. We found distinct discrepancies between their NMR data and antiproliferative activities and those reported for the natural isolates.

Bathymodiolamides C, D, and E, Necrosis Inducers from a Deep-Sea Hydrothermal Vent Invertebrate Mussel, Bathymodiolus azoricus

“…Rigorous assignment of this chiral center requires the synthesis of authentic standards (E)-(4 R )-4-hydroxyhexadec-5-enoic acid and (E)-(4 S )-4-hydroxyhexadec-5-enoic acid for comparison with the (E)-4-hydroxyhexadec-5-enoic acid residue of 3 , which is the subject of a future research project. The synthesis of (2 R , 3 S , 4 R ) isomers of bathymodiolamides A and B was published in 2021 (Bär et al 2021). Understandably, the NMR data and coupling constant patterns, as well as the biological activities of the two synthesized compounds are different from the target natural products (bathymodiolamides A and B), as well as bathymodiolamides C–E ( 1–3 ) reported here.…”

“…The reported syntheses further confirm that the configuration of the natural products is not (2 R , 3 S , 4 R ). Importantly, the choice of (2 R , 3 S , 4 R )-bathymodiolamides A and B as synthetic targets (Bär et al 2021) likely resulted from their misrepresentation of the (2 S , 3 S , 4 R ) configuration in the structures of bathymodiolamides A and B, and typographical misstatement of L-arabinophytosphingosine (2 R , 3 S , 4 R ) as a reference standard with the same relative configuration and sign of optical rotation as the natural products. The correct reference standard for their proposed (2 S , 3 S , 4 R ) configuration of the bathymodiolamides is D-ribophytosphingosine (Park et al 2008).…”

Marine natural products

“…625 Synthesis of the proposed structures of bathymodiolamides A and B, originally isolated from the deep-sea hydrothermal vent mussel Bathymodiolus thermophilus, gave products that exhibited discrepancies in NMR data and in vitro cytotoxicity proles. 626 The seasonal and location variations of levels of cyclic imine toxins in northern Adriatic Sea mussels, oysters, scallops and edible ascidians, 627 gymnodimine A in Spanish molluscs, 628 lipophilic toxins in shellsh from SE China, 629 and Southern Gulf of California, 630 and okadaic acids and pectenotoxin-2 toxins and associated algal species in a lagoon in Sardinia, 631 have been reported. The distribution of other mollusc/bivalve…”

“…Synthesis of the proposed structures of bathymodiolamides A and B, originally isolated from the deep-sea hydrothermal vent mussel Bathymodiolus thermophilus , gave products that exhibited discrepancies in NMR data and in vitro cytotoxicity profiles. 626…”