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Phomactin diterpenoids possess a unique bicyclo[9.3.1]pentadecane skeleton with multiple oxidative modifications, and are good platelet‐activating factor (PAF) antagonists that can inhibit PAF‐induced platelet aggregation. In this study, we identified the gene cluster (phm) responsible for the biosynthesis of phomactins from a marine fungus, Phoma sp. ATCC 74077. Despite the complexity of their structures, phomactin biosynthesis only requires two enzymes: a type I diterpene cyclase PhmA and a P450 monooxygenase PhmC. PhmA was found to catalyze the formation of the phomactatriene, while PhmC sequentially catalyzes the oxidation of multiple sites, leading to the generation of structurally diverse phomactins. The rearrangement mechanism of the diterpene scaffold was investigated through isotope labeling experiments. Additionally, we obtained the crystal complex of PhmA with its substrate analogue FGGPP and elucidated the novel metal‐ion‐binding mode and enzymatic mechanism of PhmA through site‐directed mutagenesis. This study provides the first insight into the biosynthesis of phomactins, laying the foundation for the efficient production of phomactin natural products using synthetic biology approaches. [ABSTRACT FROM AUTHOR]

Covering: up to May 2018 The verticillene family of 6,12-membered ring-fused diterpenes are found in plants, liverworts, corals and insects. Carbocations derived from verticillene hydrocarbons are central intermediates in the biosynthesis of the taxane and the phomactin families of polycyclic natural products. This perspective delineates these unique biosynthetic interrelationships, which are reinforced by recent biomimetic synthesis investigations, alongside quantum chemical calculations and targeted engineering studies of the taxadiene synthase (TXS) cascade. [ABSTRACT FROM AUTHOR]

Abstract Oxidation of a 15-methylenebicyclo[9.3.1]pentadeca-3,7-dien-14-ol with a 10-phenylsulfonyl substituent provided a 14-oxobicyclo[9.3.1]pentadeca-1(15),3,7-triene-15-carbaldehyde that on reduction with DIBAL-H was converted into a 15-hydroxymethylbicyclo[9.3.1]pentadeca-1(15),3,7-triene-14-ol with the relative configuration at C14 required for incorporation into a synthesis of phomactin A. The oxidation and reduction of an analogous 3,4-epoxide that lacked the 10-phenylsulfonyl group gave a diol with the opposite relative configuration at C14. However, the TPAP oxidation and DIBAL-H reduction of a 14-hydroxy-15-methylene-3,4-epoxide that still had the 10-phenylsulfonyl group gave a diol with the required configuration at C14 although the expected spontaneous participation of the 14-hydroxyl group in an intramolecular epoxide ring-opening was only observed under Lewis acidic conditions. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Abstract Previous studies of a synthesis of phomactin A had resulted in the synthesis of a 15-methylenebicyclo[9.3.1]pentadecadiene. The next step in the synthesis was to be the epoxidation of this methylenecyclohexane that was hoped would lead to a 1-(hydroxymethyl)cyclohexene by rearrangement of the exocyclic epoxide, but the epoxidation was difficult to carry out regioselectively on advanced intermediates. However, oxidation of a 15-methylenebicyclo[9.3.1]pentadeca-3,7-dien-14-ol using tetra- n -propylammonium perruthenate and N -methylmorpholine- N -oxide led to conversion of this homoallylic alcohol into the corresponding 14-oxobicyclo[9.3.1]pentadeca-1(15),3,7-triene-15-carboxaldehyde in one step. Reduction of this using DIBAL-H gave a promising intermediate for a synthesis of a phomactin. The scope of this oxidation of homoallylic alcohols was briefly investigated. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Three novel diterpenes, phomactins N ( 1 ), O ( 2 ), and P ( 3 ), were isolated from cultures of an unidentified marine-derived fungus. The structures of 1 – 3 were elucidated from spectroscopic data (NMR, MS, IR) and the absolute configurations of 1 – 3 were determined by X-ray diffraction analysis. [ABSTRACT FROM AUTHOR]

On treatment with n -butyllithium, 4-alkoxy- and 4-silyloxy-2-(tributylstannylmethoxymethyl)-1,6-dimethyl-1-(phenylsulfonylmethyl)cyclohex-2-enes undergo tin–lithium exchange followed by [2,3]-Wittig rearrangements to give 3-alkoxy- and 3-silyloxy-2-hydroxymethyl-5,6-dimethyl-1-methylene-6-(phenylsulfonylmethyl)cyclohexanes in which the 2-hydroxymethyl and 6-phenylsulfonylmethyl residues are cis -disposed about the six-membered ring. In contrast, the corresponding 1-(phenylsulfanylmethyl)cyclohexenes give mainly methylenecyclohexanes with the 2-hydroxymethyl and 6-phenylsulfanylmethyl groups trans -disposed about the six-membered ring. This stereoselectivity is independent of the nature of the alkoxy- or silyloxy-substituent and configuration at C4. The 3- tert -butyldiphenylsilyloxy-1-methylene-6-(phenylsulfonylmethyl)cyclohexane was converted into a macrocyclic precursor of the phomactins. [ABSTRACT FROM AUTHOR]

A dihydroxyepoxide analogous to that proposed as a late intermediate in the biosynthesis of phomactin A was prepared by reduction of the corresponding ketoaldehyde. The structure of the dihydroxyepoxide, specifically its configuration at C14, was confirmed by the X-ray crystal structure of its diacetate. The stereoselectivity of reduction of the ketoaldehyde would appear to be influenced by the presence of a remote phenylsulphonyl moiety at C10. Of interest in the context of the biosynthesis of phomactin A was the observation that this dihydroxyepoxide did not rearrange into the isomeric hydroxytetrahydropyran despite having the configuration at C14 required for this rearrangement. [ABSTRACT FROM AUTHOR]

The continued development of transition-metal-mediated C-C bond activation/cleavage methods would provide even more opportunities to implement novel synthetic strategies. We have explored the Rh(I)-catalyzed C-C activation of cyclobutanols resident in hydroxylated derivatives of pinene, which proceed in a complementary manner to the C-C bond cleavage that we have observed with many traditional electrophilic reagents. Mechanistic and computational studies have provided insight into the role of C-H bond activation in the stereochemical outcome of the Rh-catalyzed C-C bond activation process. Using this new approach, functionalized cyclohexenones that form the cores of natural products, including the spiroindicumides and phomactin A, have been accessed. [ABSTRACT FROM AUTHOR]

An enantioselective synthesis of the ABC-tricyclic furanochroman core of phomactin A has been accomplished by a γ-hydroxylation approach. The C ring was established by γ-hydroxylation of an a-enone. The regioselectivity was optimized by using a strong base with an oxophilic cation (t-BuLi) and a bulky oxygen donor (Davis reagent), which afforded the γ-hydroxylation product selectively in 63% yield. [ABSTRACT FROM AUTHOR]

The article reports on the study of anti-inflammatory agents phomactin natural products, its isolation and total synthesis. It states that the study of Goldring and Pattenden offered credible biogenic connections from the biosynthesis of phomactin A, and potential connection between phomactins C, D, A, and G. The study of Seth and Totah that provides two strategies to demonstrate several features of phomactin A structure that includes furanochroma ring system and ABD ring system.

Abstract: Three novel diterpenes, phomactins K–M (1–3), were isolated from the cultures of an unidentified marine-derived fungus. The structures of 1–3 were elucidated from spectroscopic data (NMR, MS, IR), and the absolute configurations of 1, 2, and the relative configuration of 3 were determined by X-ray diffraction analysis. [Copyright &y& Elsevier]

Our struggles and ultimate success in achieving a total synthesis of phomactin A are described. Our strategy features an intramolecular oxa-[3+3] annulation to construct its unique ABD-tricyclic manifold. Although the synthesis would constitute a distinctly new approach with the 12-membered D-ring of phomactin A being assembled simultaneously with the 1-oxadecalin at an early stage, the ABD-tricycle represents a unique structural topology that would pose a number of unprecedented challenges. One challenge concerned elaborating this tricycle to have oxygenation at the proper carbon atoms. To overcome this, we would utilize a Kornblum-DeLaMare ring-opening of a peroxide bridge as well as a challenging late-stage 1,3-allylic alcohol transposition. Further, the structural intricacies of the ABD-tricycle were uncovered by a conformational analysis that would be critical for the C5a-homologation. [ABSTRACT FROM AUTHOR]

A substrate-controlled asymmetric Prins/Conia-ene cascade cyclization has been developed with In(OTf)3 in CH3CN from 0 to 70 °C. These conditions afforded very good yields of the 1-oxadecalin product in one pot and effectively suppressed the racemization of the 1-oxadecalin product with almost no enantiomeric excess (ee) loss. This cascade cyclization has been successfully employed for the construction of the highly functionalized 1-oxadecalin unit of phomactin A with an acyclic β-keto ester and an alkynal as the substrates via a one-pot operation (66% yield, single diastereomer). The 1-oxadecalin moiety has been readily converted to the tricyclic furanochroman skeleton of phomactin A via the epoxidation/dealkoxycarbonylation protocol under very mild conditions with 5296 yield in three steps. [ABSTRACT FROM AUTHOR]

Conjugate reduction of an enone accompanied by in situ intramolecular aldol condensation was used to construct the tetrasubstituted cyclohexane nucleus of phomactins. Subsequent relay ring-closing metathesis completed the nine-membered ansa bridge of the diterpenoid framework. [ABSTRACT FROM AUTHOR]

The article presents chemical equations related to article "Enantioselective Synthesis of the ABC-Tricyclic Core of Phomactin A by a ˠ-Hydroxylation Strategy" by G. Du, published in the periodical "Organic Letters" in 2015.

Review: 75 refs. [ABSTRACT FROM AUTHOR]

A study of the reactivity and diastereoselectivity of the Lewis acid promoted cascade cyclizations of both acyclic and macrocyclic alkynones is described. [ABSTRACT FROM AUTHOR]