ortho-Quinone Methide Cyclizations Inspired by the Busseihydroquinone Family of Natural Products.

A series of cascade reactions of o-quinone methides have been developed based on the proposed biosynthesis of busseihydroquinone and parvinaphthol meroterpenoid natural products. The polycyclic framework of the most complex family members, busseihydroquinone E and parvinaphthol C, was assembled by an intramolecular [4 + 2] cycloaddition of an electron-rich chromene substrate. The resultant cyclic enol ether underwent rearrangements under acidic or oxidative conditions, which led to a new total synthesis of rhodonoid D.

Total Enzyme Syntheses of Napyradiomycins A1 and B1.

The biosynthetic route to the napyradiomycin family of bacterial meroterpenoids has been fully described 32 years following their original isolation and 11 years after their gene cluster discovery. The antimicrobial and cytotoxic natural products napyradiomycins A1 and B1 are produced using three organic substrates (1,3,6,8-tetrahydroxynaphthalene, dimethylallyl pyrophosphate, and geranyl pyrophosphate), and catalysis via five enzymes: two aromatic prenyltransferases (NapT8 and T9); and three vanadium dependent haloperoxidase (VHPO) homologues (NapH1, H3, and H4). Building upon the previous characterization of NapH1, H3, and T8, we herein describe the initial (NapT9, H1) and final (NapH4) steps required for napyradiomycin construction. This remarkably streamlined biosynthesis highlights the utility of VHPO enzymology in complex natural product generation, as NapH4 efficiently performs a unique chloronium-induced terpenoid cyclization to establish two stereocenters and a new carbon-carbon bond, and dual-acting NapH1 catalyzes chlorination and etherification reactions at two distinct stages of the pathway. Moreover, we employed recombinant napyradiomycin biosynthetic enzymes to chemoenzymatically synthesize milligram quantities in one pot in 1 day. This method represents a viable enantioselective approach to produce complex halogenated metabolites, like napyradiomycin B1, that have yet to be chemically synthesized.

Total Synthesis Establishes the Biosynthetic Pathway to the Naphterpin and Marinone Natural Products.

The naphterpins and marinones are naphthoquinone meroterpenoids with an unusual aromatic oxidation pattern that is biosynthesized from 1,3,6,8-tetrahydroxynaphthalene (THN). We propose that cryptic halogenation of THN derivatives by vanadium-dependent chloroperoxidase (VCPO) enzymes is key to this biosynthetic pathway, despite the absence of chlorine in these natural products. This speculation inspired a total synthesis to mimic the naphterpin/marinone biosynthetic pathway. In validation of this biogenetic hypothesis, two VCPOs were discovered that interconvert several of the proposed biosynthetic intermediates.

Biosynthetically Guided Structure-Activity Relationship Studies of Merochlorin†A, an Antibiotic Marine Natural Product.

The onset of new multidrug-resistant strains of bacteria demands continuous development of antibacterial agents with new chemical scaffolds and mechanisms of action. We present the first structure-activity relationship (SAR) study of 16 derivatives of a structurally novel antibiotic merochlorin A that were designed using a biosynthetic blueprint. Our lead compounds are active against several Gram-positive bacteria such as Staphylococcus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE) and Bacillus subtilis, inhibit intracellular growth of Mycobacterium bovis, and are relatively nontoxic to human cell lines. Furthermore, derivative 12 c {(±)-(3aR,4S,5R,10bS)-5-bromo-7,9-dimethoxy-4-methyl-4-(4-methylpent-3-en-1-yl)-2-(propan-2-ylidene)-1,2,3,3a,4,5-hexahydro-6H-5,10b-methanobenzo[e]azulene-6,11-dione} was found to inhibit the growth of Bacillus Calmette-Guérin (BCG)-infected cells at concentrations similar to rifampicin. These results outperform the natural product, underscoring the potential of merochlorin analogues as a new class of antibiotics.

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

Bacterial meroterpenoids constitute an important class of natural products with diverse biological properties and therapeutic potential. The biosynthetic logic for their production is unknown and defies explanation via classical biochemical paradigms. A large subgroup of naphthoquinone-based meroterpenoids exhibits a substitution pattern of the polyketide-derived aromatic core that seemingly contradicts the established reactivity pattern of polyketide phenol nucleophiles and terpene diphosphate electrophiles. We report the discovery of a hitherto unprecedented enzyme-promoted α-hydroxyketone rearrangement catalysed by vanadium-dependent haloperoxidases to account for these discrepancies in the merochlorin and napyradiomycin class of meroterpenoid antibiotics, and we demonstrate that the α-hydroxyketone rearrangement is potentially a conserved biosynthetic reaction in this molecular class. The biosynthetic α-hydroxyketone rearrangement was applied in a concise total synthesis of naphthomevalin, a prominent member of the napyradiomycin meroterpenes, and sheds further light on the mechanism of this unifying enzymatic transformation.

Biosynthetically-inspired oxidations of capillobenzopyranol.

The synthesis of verrubenzospirolactone from its proposed biosynthetic precursor, capillobenzopyranol, has been shown to be chemically feasible via a simple reaction sequence. The key steps are a chemoselective furan oxidation mediated by NaClO2, a stereoselective dehydration of a γ-methoxybutenolide, and an intramolecular Diels-Alder reaction.

Biomimetic Total Synthesis of (±)-Verrubenzospirolactone.

A five-step total synthesis of (±)-verrubenzospirolactone has been achieved using a biomimetic, intramolecular Diels-Alder reaction of a 2H-chromene to form two rings and four stereocenters in the final step. This Diels-Alder reaction occurs spontaneously at 30 °C "on-water", and thus suggests that it is likely to be non-enzymatic in nature. The structure of (±)-verrubenzospirolactone was also used to inspire a quadruple cascade reaction to generate seven stereocenters, four rings, three C-C bonds, and two C-O bonds in one step.

Biomimetic total synthesis of (±)-doitunggarcinone A and (+)-garcibracteatone.

A full account of our oxidative radical cyclization approach to the synthesis of garcibracteatone and doitunggarcinone A is presented. This includes the first enantioselective synthesis of garcibracteatone, which allowed the absolute configuration of the natural compound to be determined. The first synthesis of doitunggarcinone A is also described, which confirms our reassignment of the relative configuration of this molecule. Novel syntheses of monoterpene fragments used to construct the target molecules are also reported.

Biomimetic total synthesis of (±)-garcibracteatone.

The polycyclic polyprenylated acylphloroglucinol natural product garcibracteatone has been synthesized in four steps from phloroglucinol, using a strategy based on biosynthetic speculation. The key biomimetic transformation is a cascade of 7-endo-trig and 5-exo-trig radical cyclizations followed by a terminating aromatic substitution reaction.

Total synthesis of (+)-aureol.

A total synthesis of the marine sponge meroterpenoid (+)-aureol has been achieved in 12 steps (6% overall yield) from (+)-sclareolide. Key steps of the synthesis include a biosynthetically inspired sequence of 1,2-hydride and methyl shifts, and a biomimetic cycloetherification reaction.

Synthesis of a liphagal-frondosin C hybrid and speculation on the biosynthesis of the frondosins.

A hypothesis for the biosynthesis of the frondosins A-E is presented. Synthesis of a liphagal-frondosin C hybrid molecule has been achieved, with the frondosin C 6-7-5-6 ring system being constructed by a photochemical process that follows an intramolecular Paternò-Büchi reaction/fragmentation pathway.