Phorbasides A−E, Cytotoxic Chlorocyclopropane Macrolide Glycosides from the Marine Sponge Phorbas sp. CD Determination of C-Methyl Sugar Configurations

Abstract

Five new cytotoxic macrolide glycosides phorbasides A-E (3-7), each possessing a macrolide ring appended to a rare ene-yne-trans-2-chlorocyclopropane, were isolated from the same Western Australian sponge (Phorbas sp.) that provided phorboxazoles A and B. The structures of 3-7 were solved by analysis of spectroscopic data including NMR, MS, and CD. A synthesis of methyl 2-O-methyl-alpha-L-evalose from L-rhamnose was completed and used for configurational assignment of the sugar residue in 3. Acid-catalyzed methanolysis of 3 followed by two-step derivatization of the liberated O-methyl glycoside gave a vicinal 4-O-naphthoyl/tertiary 3-N-(2-aminonaphthyl)carbamate derivative that exhibited exciton coupled CD identical with that of the derivative prepared from synthetic 1,2- O-dimethyl-alpha-L-evalose.

Integrated approaches to the configurational assignment of marine natural products

“…Phorbaside F ( 10 ) xiv and hemi-phorboxazole ( 11 ) xv from the marine sponge Phorbas sp. are derivatives of phorbaside A ( 12 ) xvi and phorboxazole A ( 13 ), xvii respectively.…”

“…The phorbasides A ( 12 ), B–E, and F ( 10 ) xvi from the marine sponge Phorbas sp. are recent additions to a group of cytotoxic glycosidic 14-membered ring macrolides from various marine organisms; others include aurisides A ( 161 ) clxxxix and B and dolastatin 19 ( 162 ) cxc from the sea slug Dolabella auricularia , callipeltoside A ( 163 ) from the sponge Callipelta sp., cxci and lyngbyaboulloside ( 164 ) from the cyanobacteria Lyngbya bouillonii .…”

“…xvi Assignment of sugar configuration by exciton coupled CD of dibenzoates was described by Nakanishi, cxcvi however this approach less practical for the tertiary OH in the C–methyl sugar, O –methyl evalose. Consequently, a more reactive aryl-isocyanate was chosen for derivatization.…”

Marine Natural Products: A New Wave of Drugs?

“…collected off Muiron Island in Western Australia in 1995 (Figure 5) [48]. With the use of a 5-mm cryoprobe, phorbasides A–E were later discovered from minor chromatography side fractions (0.78–3 mg) (Figure 5) [49]. Furthermore, with the availability of the more sensitive 1.7-mm, 600-MHz cryomicroprobe, they continued to investigate the chemical diversity in that marine organism and successfully reported the structures of more minor compounds at the nano-mole scale, including four more phorbaside analogues (7–16 μg) [50], hemi-phorboxazole A (16.5 μg, 28 nmol) [51] and the new macrolide muironolide A (90 μg, 152 nmol) (Figure 5), which represented a new carbon skeleton with unprecedented features [52].…”

NMR Quantitation of Natural Products at the Nanomole Scale

“…The previously described CCl 4 -soluble fraction (93-054-B-1, 350 mg)10a,11,from a MeOH extract of Phorbas sp. (93–054) was separated by flash chromatography on a pre-packed cartridge (silica, Analogix RS-12, 12 g, 2 × 7.5 cm) using stepped gradient of hexane-ethyl acetate mixtures (0–100%) to yield seven fractions.…”