Lepadiformine, a new marine cytotoxic alkaloid from Clavelina lepadiformis Müller

Alkaloid synthesis via [3+2] cycloadditions

“…The total synthesis of the marine alkaloid lepadiformine [16] has been complicated by the uncertainty surrounding its actual stereostructure. The correct structure of this compound has now been shown to be as depicted in Fig.…”

Development of New Synthetic Methods and Its Application to Total Synthesis of Nitrogen-Containing Bioactive Natural Products

“…This finding strongly implies that the structure of natural lepadiformine reported in the literature 58) was actually that of the hydrochloride salt of structure 59; this is understandable since natural lepadiformine was isolated via evaporation of an HCl extract. 58) These results therefore clearly indicate that structural formula 58 involving the zwitterionic structure originally assigned [49][50][51][52][53][54] to natural lepadiformine should be revised to 59 as shown. Interestingly, the HCl salt of synthetic racemic 59 is crystalline, whereas natural lepadiformine (also the hydrochloride) is an oil.…”

“…3), 77) which revealed the stereochemistry of (Ϯ)-58 · HCl with the B ring in a somewhat unusual boat (twist-boat) form with the preferred adoption of an equatorial orientation of the hexyl side chain. Although both 1 H-and 13 C-NMR spectral data for synthetic (Ϯ)-59 as the free base were distinctly different from those published 58) for natural lepadiformine, measurement of the 1 H-and 13 C-NMR spectra of the synthetic hydrochloride salt (Ϯ)-59 · HCl allowed direct comparison with the spectra on natural lepadiformine kindly provided by Professor Biard, revealing an exact match. This finding strongly implies that the structure of natural lepadiformine reported in the literature 58) was actually that of the hydrochloride salt of structure 59; this is understandable since natural lepadiformine was isolated via evaporation of an HCl extract.…”

“…Although both 1 H-and 13 C-NMR spectral data for synthetic (Ϯ)-59 as the free base were distinctly different from those published 58) for natural lepadiformine, measurement of the 1 H-and 13 C-NMR spectra of the synthetic hydrochloride salt (Ϯ)-59 · HCl allowed direct comparison with the spectra on natural lepadiformine kindly provided by Professor Biard, revealing an exact match. This finding strongly implies that the structure of natural lepadiformine reported in the literature 58) was actually that of the hydrochloride salt of structure 59; this is understandable since natural lepadiformine was isolated via evaporation of an HCl extract. 58) These results therefore clearly indicate that structural formula 58 involving the zwitterionic structure originally assigned [49][50][51][52][53][54] to natural lepadiformine should be revised to 59 as shown.…”

“…[49][50][51][52][53][54] Since the first members were reported in 1993, 11 cylindricines A-K have been identified from the Tasmanian ascidians Clavelina cylindrica as new marine alkaloids [55][56][57] with a tricyclic ring system unprecedented among natural products, possessing a perhydropyrroloquinoline or a perhydropyridoquinoline. Shortly after the first isolation of cylindricines A (56a) and B (56b) 55) the isolation and structure elucidation of a closely related marine alkaloid, named lepadiformine, from the ascidian Clavelina lepadiformis collected in the Mediterranean near Tunisia 58) in 1994 and later from Clavelina moluccensis found along the Djibouti coast 59) was reported by Biard and co-workers. It was found to be moderately cytotoxic toward various tumor cell lines in vitro.…”