Reassignment of the absolute configuration of plakinidone from the sponge consortium Plakortis halichondrioides–Xestospongia deweerdtae using a combination of synthesis and a chiroptical approach

Recent work by Wu et al. in connection with the first synthesis of the marine natural product plakinidone revealed that the most salient feature of its purported structure, a six-membered perlactone moiety, was in fact a five-membered lactone, i.e. a 3-methyl-4-hydroxy-2(5H)-furanone or tetronic acid ring. With the planar structure of plakinidone confidently revised, we undertook a new investigation to unambiguously establish its absolute configuration. Upon preparing two stable derivatives 1 and 5 from a sample of naturally occurring plakinidone extracted from the sponge association Plakortis halichondrioides–Xestospongia deweerdtae, the absolute configuration was assigned by synthesis and vibrational and electronic circular dichroism (VCD and ECD) measurements in combination with density functional theory calculations at the B3LYP/aug-cc-pVDZ/PCM(CH3CN) level of theory. Our combined efforts and the agreement between the experimental and calculated VCD/ECD spectra of 1 revealed that the absolute configuration of plakinidone was in fact (11S,17R) and not the formerly reported (11S,17S) diastereomer assigned by Wu et al. Therefore, we propose that natural plakinidone is accurately represented by structure 12.

Figure optionsDownload as PowerPoint slide

(S)-1-(5,9-Dimethyldec-8-en-1-ynyl)-4-methoxybenzeneC19H26O[α]D20 = −11.6 (c 1.31, CHCl3)Source of chirality: (−)-CitronellolAbsolute configuration: (S)

(R)-8-(4-Methoxyphenyl)-4-methyloct-7-ynalC16H20O2[α]D20 = −5.8 (c 0.52, CHCl3)Source of chirality: (−)-CitronellolAbsolute configuration: (S)

(S)-12-(4-Methoxyphenyl)-8-methyldodec-4-en-11-yn-2-oneC20H26O2[α]D20 = −13.0 (c 0.70, CHCl3)Source of chirality: (−)-CitronellolAbsolute configuration: (S)

(S)-12-(4-Methoxyphenyl)-8-methyldodecan-2-oneC20H32O2[α]D20 = +7.3 (c 1.1, CHCl3)Source of chirality: (−)-CitronellolAbsolute configuration: (S)