Total Synthesis of Phorbazole B

Abstract

Phorbazoles are polychlorinated heterocyclic secondary metabolites isolated from a marine sponge and several of these natural products have shown inhibitory activity against cancer cells. In this work, a synthesis of the trichlorinated phorbazole B using late stage electrophilic chlorination was developed. The synthesis relied on the use of an oxazole precursor, which was protected with an iodine in the reactive 4-position, followed by complete chlorination of all pyrrole positions. Attempts to prepare phorbazole A and C, which contain a 3,4-dichlorinated pyrrole, were unsuccessful as the desired chlorination pattern on the pyrrole could not be obtained. The identities of the dichlorinated intermediates and products were determined using NMR techniques including NOESY/ROESY, 1,1-ADEQUATE and high-resolution CLIP-HSQMBC.

Marine natural products

“…490 A similar state of affairs exists following the total synthesis of the reported structure of nagelamide D. 491 The rst total syntheses of several other alkaloids have also been achieved. [492][493][494][495][496] Preparation of two semi-synthetic alkaloid libraries were reported in 2020; the rst utilised 290 mg of psammaplysin F from only 46 g of freeze-dried Hyattella to probe prostate cancer cells using multiparametric quantitative single-cell imaging, 497 while the other exploited 780 mg of renieramycin M from 18 kg of Xestospongia to synthesise two series of compounds, many of which exhibit potent (low nM) activity against H292 cells. 498 The total syntheses of several pyridinium alkaloids, along with in-depth spectroscopic analysis using various solvent blends, has revealed that xestocyclamine A is in fact the enantiomer of ingenamine, a conclusion supported by X-ray diffraction data.…”

Exploring Chemical Diversity of Phorbas Sponges as a Source of Novel Lead Compounds in Drug Discovery

“…Phorbazoles, isolated in small amounts from a sample collected in South Africa, differ themselves only by the presence and/or position of the chlorine atoms, and their structures were elucidated using mono-and bi-dimensional NMR data coupled with X-ray diffraction studies [34]. In 2020, the total synthesis of the trichlorinated phorbazole B (10) has been realized in six steps (overall yield of 23%) using an oxazole as precursor and late stage electrophilic chlorination as key mechanism [35],while a synthesis of phorbazole C was reported in 2001 and relied on pyrrole as a precursor [36].…”

An Overview of Bioactive 1,3-Oxazole-Containing Alkaloids from Marine Organisms

“…clathrata (Levi) [22]. Recently, the chemical preparation of phorbazole B (13) has been achieved by simple catalytic chlorination and iodization to protect the oxazole ring [23]. The first chemical analysis of the marine mollusc Aldisa andersoni, collected off Muttom coast, (Kanyakumari, India) afforded two new cytotoxic phorbazole analogs, 9-chloro-phorbazole D ( 16) and N1-methyl-phorbazole A (17), as well as phorbazoles A (2), B (13) and D (15) [24].…”

“…Two novel linear and achiral polyketide-peptides, ariakemicins A (18) and B (19), were obtained as an inseparable mixture from one marine gliding bacterium Rapidithrix sp., collected off the muddy land alongside the Ariake Inland Sea, and displayed selectively antimicrobial activities against Gram-positive bacteria (Brevibacterium sp., S. aureus, and Bacillus subtilis), and weak cytotoxicity against cancer cell lines A549 and BHK [25]. Breitfussins A-H (20)(21)(22)(23)(24)(25)(26)(27) were the first marine natural products containing an indole-oxazolepyrrole framework from hydrozoan Thuiaria breitfussi inhabits in the Arctic ocean, and were found to excellently inhibit PIM1 and DRAK1 kinases [26,27]. Furthermore, breitfussin C (22) strongly exhibited a cytotoxic effect on cancer cell lines (MCF-7, HT-29, MOLT-4, MV-4-11 and MRC-5).…”