Cadiolides A and B, New Metabolites from an Ascidian of the Genus Botryllus

Abstract

Marine ascidians are prolific producers of metabolites derived from amino acids.1 Metabolites produced from phenylalanine or tyrosine are especially plentiful and include the tunichromes, 2 lamellarins, 3 the lukianols, 4 rigidin, 5 the polycitrons, 6 the ningalins 7 and the botryllamides. 8 The rubrolides, 9 isolated from Ritterella rubra, are examples of non-nitrogenous members of this group. We now wish to report the isolation of cadiolides A (1) and B (2) from an Indonesian Botryllus sp. The cadiolides do not contain nitrogen and are related in structure to the rubrolides, but possess a novel carbon skeleton.Specimens of Botryllus sp. were collected by hand using scuba (-3 to -15 m) near Barrang Caddi in Indonesia and kept frozen until workup. Thawed samples of Botryllus sp. were homogenized and extracted with either EtOH or MeOH to give a crude extract. This extract was partitioned between hexane, CHCl 3 , and aqueous MeOH. The aqueous MeOH soluble material was further fractionated by size-exclusion chromatography using Sephadex LH-20 (MeOH), resulting in the separation of a number of highly colored bands including yellow, orange, red, and black. Samples were inspected by TLC and 1 H NMR spectroscopy and purified further by gradient silica flash chromatography (0-10% MeOH in CHCl 3 ) to give rubrolide A (3) and cadiolides A (1) and B (2) as amorphous solids.Cadiolide A (1) was obtained as an orange amorphous solid that yielded an abundant ion cluster in both the negative ion ES-MS and MALDI-MS spectra centered at Br 2 O 6 possessing 17 degrees of unsaturation. The 13 C NMR spectrum contained only 18 resonances, implying that there was some element(s) of symmetry present in a highly unsaturated aromatic structure. Only six proton resonances, all with chemical shifts greater that δ 6, were observed in the 1 H NMR spectrum, and integration showed that four of the signals accounted for two protons each (δ 6.88, 7.55, 7.76, and 7.89), one for a single proton (δ 6.33) and one exchangeable signal accounted for three protons (δ 10.41). The UV spectrum showed absorptions at 254 and 406 nm, demonstrating the aromaticity and extended conjugation of 1. The IR spectrum showed absorptions at 1721 and 1683 cm The broad three-proton resonance at δ 10.26 in the 1 H NMR spectrum was assigned to three exchangeable phenolic protons. An HMQC experiment established the proton and carbon one-bond connectivities in the structure. In particular, correlations were observed between carbons resonating at δ 116.2, 132.9, 133.5, and 133.7 and protons resonating at δ 6.88, 7.55, 7.76, and 7.89, respectively. This coupled with the observation of threebond proton-carbon connectivities in an HMBC experiment between carbon resonances at δ 116. 2, 132.9, 133.5, and 133.7 and proton resonances at δ 6.88, 7.55, 7.76, and 7.89, respectively, suggested the presence of a series * To whom correspondence should be addressed. Phone: (801)

Versatile Synthesis of Acylfuranones by Reaction of Acylketenes with α‐Hydroxy Ketones: Application to the One‐Step Multicomponent Synthesis of Cadiolide B and Its Analogues

“…The crude product was purified by chromatography on silica gel using a gradient of EtOAc/MeOH (100:0 to 90:10) to give Cadiolide B as a black solid in 67 % yield (38 mg, 0.044 mmol). Analyses are similar to those described in the literature 3,4a . 1 H NMR (300 MHz, [D 6 ]DMSO): δ = 6.40 (s, 1 H), 7.55 (s, 2 H), 7.91 (s, 2 H), 8.12 (s, 2 H) ppm.…”

“…Functionalized acylfuranones are present in many natural1 and synthetic2 products. Among them, cadiolides A–I (Figure 1), isolated from the Indonesian marine ascidians of the genus Botryllus ,3 present fascinating and similar antibacterial activities to vancomycin and platensimycin 4. Moreover, they also share a common feature with refecoxib, a selective inhibitor of the COX‐2 enzyme, promoting interesting anti‐inflammatory activity 5.…”

Short and Efficient Synthesis of Cadiolide B

“…13 Bromination of 10 with Br 2 /KBr 14 delivered cadiolide B as an amorphous orange solid whose 1 H NMR and 13 C NMR properties were in full agreement with those reported for the natural product. 1 In conclusion, the first synthesis of cadiolide B has been accomplished in concise and efficient fashion (6 steps, 42% overall yield) by a new, inherently flexible pathway that is especially attractive for generating libraries of analogues for biological evaluation. …”

Inibição Do Crescimento De Microrganismos Patogênicos Induzida Por Butenolídeos Análogos Aos Cadiolídeos

“…Os cadiolídeos A e B foram isolados de ascídias do gênero Botryllus, coletadas em Barrang Caddi na Indonésia. 9 Os cadiolídeos B-I são produzidos por ascídias Pseudodistoma antinboja (cadiolídeos C-F) 10 e do gênero Synoicum (cadiolídeos B, E, G-I). 11,12 Os cadiolídeos B-F inibem cepas de Staphylococcus aureus resistentes a meticilina (SARM), com concentração inibitória mínima (MIC) na faixa de 0,3-2,0 µg mL -1 .…”

“…EM, m/z (%) 754 ([M +. ], C 27 H 18 Br 4 O 6 , 15), 755 ([M+1] + , 5), 756 ([M+2] + , 55), 757 ([M+3] + , 16), 758 ([M+4] + , 79), 759 ([M+5] + , 23), 760 ([M+6] + , 53), 761 ([M+7] + , 15), 762 ([M+8] + , 15), 679(9), 677 (9), 411 (13), 410(5), 409(24), 407(13), 295 (49), 294(10), 293 (100), 291 (52), 250(10), 248 (5), 239(16), 237(19), 235(10), 228 (59), 226(60), 215 (29), 213 (47), 211 (20), 200 (11), 199 (10), 198 (10), 119 (54), 103 (11), 89 (15), 77 (8), 76 (9), 75 (10), 63 (5), 57 (6). HRMS [ESI(+), IT-TOF]: calculado [C 27 H 19 Br 4 O 6 ] + 754,7910; encontrado 754,7905.…”