Biomimetic Total Synthesis of (±)‐Merochlorin A

Abstract

Dedicated to Professor Sir Jack E. Baldwin on the occasion of his 75th birthday Merochlorins A (1) and B (2) are isomeric chlorinated meroterpenoids with unique polycyclic ring systems, and were recently isolated from the marine bacterium Streptomyces sp. strain CNH-189. [1] Merochlorin A has a compact bicyclo[3.2.1]octanone [2] core with four contiguous stereocenters, three of which are quaternary. The structure of 1 was initially elucidated using 2D NMR studies. [1b] However, later X-ray studies [1a] and our synthetic work indicate that its structure should be represented as shown in Scheme 1 (the configurations of the stereocenters at C9 and C10 of 1 were originally misassigned). Further to its structural interest, 1 is a potent antibiotic against Clostridium difficile (MIC = 0.15 mg mL À1 ) and various multi-drug resistant Staphylococcus aureus strains (MIC = 2-4 mg mL À1 ). [1b] It is therefore an excellent lead candidate for the development of novel antibiotics. However, the mechanism of action of 1 is unknown, and given its scarcity in nature a chemical synthesis is desirable.Merochlorin B has a 6-5-5-fused ring system with three contiguous stereocenters and an a-chloroenone motif. The unprecedented structures of 1 and 2 suggest an unusual biosynthesis. This was investigated by Moore et al., [1a] who partially sequenced the genome of the CNH-189 bacterium to reveal a merochlorin gene cluster containing 41 genes (mcl1-mcl41). The key genes implicated in the biosynthesis of the merochlorins were found to encode a 1,3,6,8-tetrahydroxynaphthalene synthase (mcl17), an aromatic prenyl transferase (mcl23), a vanadium-dependent haloperoxidase [3] (VHPO; mcl24), and a protein containing an iron-sulfur cluster (mcl30). On the basis of their bioinformatic analysis, Moore and co-workers proposed a biosynthesis of 1 and 2 involving VHPO-dependent chlorination or oxidation of an alkene as the prelude to a cyclization cascade to form the polycyclic ring systems. [1a] However, their proposed cyclization mechanism is (by their own admission) highly speculative, and we herein propose an alternative biosynthetic mechanism (Scheme 1). In common with the biosynthesis described by Moore et al., we suggest that the starting point for the biosynthesis of 1 and 2 is the formation of 1,3,6,8-tetrahydroxynaphthalene (4) by aromatization of the acyclic polyketide 3, catalyzed by the mcl17 polyketide synthase. We then propose that 4 undergoes alkylation (mcl23) to give 5 and chlorination (mcl24) to give 6. Oxidative dearomatization of 6 (perhaps catalyzed by the putative protein that contains the Fe-S cluster and is encoded by mcl30) would then generate phenoxonium ion 7 which could cyclize through a [5+2] cycloaddition to give 1 or a [3+2] cycloaddition to give 2. These cycloadditions are presumably stepwise in mechanism. Previously, intramolecular [5+2] cycloadditions have been proposed to occur between para-quinones and alkenes in the biosynthesis of aand b-pipitzol [4] and elisapterosin B, [5] which has inspired elegant biom...

A unifying paradigm for naphthoquinone-based meroterpenoid (bio)synthesis

“…Subsequent oxidative dearomatization to forma benzylic carbocation intermediate 12 , followed by intramolecular cyclization gives rise to 5 and 6 , as reported previously (path a) 31 . A similar benzylic carbocation intermediate was also proposed in previous total syntheses of both merochlorin A and B (refs 32,33). Alternatively, trapping of the intermediate benzylic carbocation 12 by water gives α-hydroxyketone 13 , which undergoes a second chlorination at C2 to give the geminal dichloride 14 (path b).…”

“…Selective C4 geranylation was achieved through a palladium-mediated allylation using ethyl geranyl carbonate ( 28 ) as the electrophile 30,39 . The resulting naphthol 29 was subsequently subjected to Pb(OAc) 4 -mediated oxidative dearomatization 32,40 followed by in situ dichlorination of the intermediate enol at C2 using NCS to give dichlorodiketone 30 . Selective removal of one chlorine substituent from C2 of 30 was achieved using a lithium diisopropylamide (LDA)-mediated reduction to give a monochloride that is protected from further dechlorination by enolization 41 .…”

Total Synthesis of (−)‐Merochlorin A

“…This challenging motif in conjunction with its promising biological activity render 1 an otable target for synthetic studies and led to considerable interest from the biochemical and synthetic communities. [3] Herein, we report the first asymmetric total synthesis of (À)-merochlorin A ( 1), which led to the assignment of the previously unknown absolute configuration of the natural product.…”

One‐Pot Enzymatic Synthesis of Merochlorin A and B

“…Recently, routes for the chemical synthesis of 1 and 2 were established, [2] yet how these molecules are synthesized in nature remained largely unknown. Genetic analyses revealed that Streptomyces sp.…”