Acyl palladium species in synthesis: single-step synthesis of α,β-unsaturated ketones from acid chlorides

Cox, Russell J.; Evitt, Andrew

doi:10.1039/b616582f

Cited by 113 publications

(179 citation statements)

References 19 publications

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“…Interestingly, 1-epi-bacillisporin F (3) was also isolated. 1 H NMR data revealed that the sole differences between compound 2 and 3 were the chemical shifts of the methoxy group in CD3OD…”

Section: Resultsmentioning

confidence: 99%

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Antimicrobial Oligophenalenone Dimers from the Soil Fungus Talaromyces stipitatus

et al. 2016

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New polyketide-derived oligophenalenone dimers, 9a-epi-bacillisporin E (1) and bacillisporins F−H (2−5), along with the known bacillisporin A (6), were isolated from the fungus Talaromyces stipitatus. Their structures and absolute configurations were determined on the basis of spectroscopic analyses, electronic circular dichroism, and GIAO NMR shift calculation followed by DP4 analysis. The antimicrobial activity of these compounds was evaluated against a panel of human pathogenic bacteria. Among them, bacillisporin H (5) exhibited antimicrobial activity together with modest cytotoxicity against HeLa cells.

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“…Interestingly, 1-epi-bacillisporin F (3) was also isolated. 1 H NMR data revealed that the sole differences between compound 2 and 3 were the chemical shifts of the methoxy group in CD3OD…”

Section: Resultsmentioning

confidence: 99%

“…1 These complex structures have attracted great interest because of their biological activities which may lead to new medicinal or agrochemical applications. Soil-inhabiting fungi constitute an extremely diverse fungal community and the soil fungus Talaromyces stipitatus ATCC 10500 (syn.…”

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confidence: 99%

Antimicrobial Oligophenalenone Dimers from the Soil Fungus Talaromyces stipitatus

et al. 2016

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“…1A) (18,19), the carbon scaffold of radicicol is synthesized by the collaborative functions of two type I iterative polyketide synthases (IPKSs). IPKSs are megasynthases in which linearly juxtaposed catalytic domains function in an iterative and a highly programmed fashion (20). Genetic knock-out experiments with two different radicicol-producing fungi, Pochonia chlamydosporia and Chaetomium chiversii (16,21), confirmed that a highly reducing PKS (HRPKS) and a nonreducing PKS (NRPKS) are required for the biosynthesis of radicicol.…”

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confidence: 88%

Insights into Radicicol Biosynthesis via Heterologous Synthesis of Intermediates and Analogs

Zhou

Qiao

Gao

et al. 2010

Journal of Biological Chemistry

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Resorcylic acid lactones are fungal polyketides that display diverse biological activities, with the potent Hsp90 inhibitor radicicol being an important representative member. Two fungal iterative polyketide synthases (IPKSs), Rdc5, the highly reducing IPKS, and Rdc1, the nonreducing IPKS, are required for the biosynthesis of radicicol in Pochonia chlamydosporia. In this study, the complete reconstitution of Rdc5 and Rdc1 activities both in vitro and in Saccharomyces cerevisiae uncov- Polyketides of fungal origin represent an important family of natural products that display a wide range of biological activities (1, 2). One structurally distinct group of fungal polyketides is the resorcylic acid lactones (RALs) 4 (Fig. 1A), of which several members have clinically relevant bioactivities (3, 4). A well known RAL is radicicol (1) (Fig. 1), which is a nanomolar (IC 50 ϭ 20 nM) inhibitor of the heat shock protein 90 (Hsp90) (5, 6). Hsp90 chaperones the maturation of a wide range of oncogenic proteins (7) and is therefore an attractive target for anticancer drug development. Radicicol inhibits the ATPase activity of Hsp90 via competitive binding to the ADP/ ATP binding pocket, leading to the inactivation of Hsp90 chaperoning ability (8). Despite the highly potent activity, radicicol has not been developed as a drug due to its poor activity in vivo. Radicicol can be readily inactivated through attack at the strained C7Ј-C8Ј epoxide, as well as facile Michael addition at C6Ј facilitated by the conjugated dienone (9). To overcome these limitations, chemically derived radicicol analogs that do not contain these labile moieties have been pursued (10 -13). Recently, C2Ј oxime derivatives of (R)-monocillin II (6) and pochonin D (11) (Fig. 1B) screened from a chemically synthesized library showed greatly enhanced in vivo activity (14). A phosphate prodrug strategy was developed based on a lead compound to further increase the oral bioavailability (15). These promising results suggest that the radicicol-based RAL scaffold remains an attractive starting point for development of Hsp90 inhibitors, and this prompted us to examine the biosynthesis of the compound in detail.Like other RALs studied to date, such as hypothemycin (2) (16, 17) and zearalenone (4) (Fig. 1A) (18, 19), the carbon scaffold of radicicol is synthesized by the collaborative functions of two type I iterative polyketide synthases (IPKSs). IPKSs are megasynthases in which linearly juxtaposed catalytic domains function in an iterative and a highly programmed fashion (20). Genetic knock-out experiments with two different radicicol-producing fungi, Pochonia chlamydosporia and Chaetomium chiversii (16,21), confirmed that a highly reducing PKS (HRPKS) and a nonreducing PKS (NRPKS) are required for the biosynthesis of radicicol. The domain structures and putative functions of the two P. chlamydosporia PKSs are shown in Fig. 1B. The HRPKS Rdc5 contains the following domains: ketosynthase (KS) that performs the decarboxylative condensation; malonyl-CoA:ACP transacylase ...

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“…Fungal PKSs are large megasynthases that assemble single copies of catalytic domains in one polypeptide. The domains function in an iterative fashion and use built-in programming rules to dictate chain length, cyclization, reductive tailoring, and other structural features (11). Therefore, understanding the relationships between protein sequence and catalytic activity, as well as substrate specificity, of each domain is essential to unlocking the biosynthetic potential of fungal PKSs.…”

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confidence: 99%

Classification, Prediction, and Verification of the Regioselectivity of Fungal Polyketide Synthase Product Template Domains

Tang

2010

Journal of Biological Chemistry

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The fungal iterative nonreducing polyketide synthases (NRPKSs) synthesize aromatic polyketides, many of which have important biological activities. The product template domains (PT) embedded in the multidomain NRPKSs mediate the regioselective cyclization of the highly reactive polyketide backbones and dictate the final structures of the products. Understanding the sequence-activity relationships of different PT domains is therefore an important step toward the prediction of polyketide structures from NRPKS sequences and can enable the genome mining of hundreds of cryptic NRPKSs uncovered via genome sequencing. In this work, we first performed phylogenetic analysis of PT domains from NRPKSs of known functions and showed that the PT domains can be classified into five groups, with each group corresponding to a unique product size or cyclization regioselectivity. Group V contains the formerly unverified PT domains that were identified as C6-C11 aldol cyclases. The regioselectivity of PTs from this group were verified by product-based assays using the PT domain excised from the asperthecin AptA NRPKS. When combined with dissociated PKS4 minimal PKS, or replaced the endogenous PKS4 C2-C7 PT domain in a hybrid NRPKS, AptA-PT directed the C6-C11 cyclization of the nonaketide backbone to yield a tetracyclic pyranoanthraquinone 4. Extensive NMR analysis verified that the backbone of 4 was indeed cyclized with the expected regioselectivity. The PT phylogenetic analysis was then expanded to include ϳ100 PT sequences from unverified NRPKSs. Using the assays developed for AptA-PT, the regioselectivities of additional PT domains were investigated and matched to those predicted by the phylogenetic classifications.

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Acyl palladium species in synthesis: single-step synthesis of α,β-unsaturated ketones from acid chlorides

Abstract: Conditions are reported for the facile, one-pot synthesis of alpha,beta-unsaturated ketones via the palladium-catalysed cross-coupling of acyl chlorides with hydrozirconated acetylenes, and its use in the 2-step synthesis of D-5-O-benzyl deoxyxylulose.

Cited by 113 publications

References 19 publications

Antimicrobial Oligophenalenone Dimers from the Soil Fungus Talaromyces stipitatus

Antimicrobial Oligophenalenone Dimers from the Soil Fungus Talaromyces stipitatus

Insights into Radicicol Biosynthesis via Heterologous Synthesis of Intermediates and Analogs

Classification, Prediction, and Verification of the Regioselectivity of Fungal Polyketide Synthase Product Template Domains

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