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Tandem catalysis of ring-closing metathesis/atom transfer radical reactions with homobimetallic ruthenium-arene complexes.

ABSTRACT: The tandem catalysis of ring-closing metathesis/atom transfer radical reactions was investigated with the homobimetallic ruthenium-indenylidene complex [(p-cymene)Ru(?-Cl)?RuCl(3-phenyl-1-indenylidene)(PCy?)] (1) to generate active species in situ. The two catalytic processes were first carried out independently in a case study before the whole sequence was optimized and applied to the synthesis of several polyhalogenated bicyclic ?-lactams and lactones from ?,?-diene substrates bearing trihaloacetamide or trichloroacetate functionalities. The individual steps were carefully monitored by ¹H and ³¹P NMR spectroscopies in order to understand the intimate details of the catalytic cycles. Polyhalogenated substrates and the ethylene released upon metathesis induced the clean transformation of catalyst precursor 1 into the Ru(II)-Ru(III) mixed-valence compound [(p-cymene)Ru(?-Cl)?RuCl(2)(PCy?)], which was found to be an efficient promoter for atom transfer radical reactions under the adopted experimental conditions.

SUBMITTER: Borguet Y

PROVIDER: S-EPMC3002019 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Tandem catalysis of ring-closing metathesis/atom transfer radical reactions with homobimetallic ruthenium-arene complexes.

Borguet Yannick Y Sauvage Xavier X Zaragoza Guillermo G Demonceau Albert A Delaude Lionel L

Beilstein journal of organic chemistry 20101208

The tandem catalysis of ring-closing metathesis/atom transfer radical reactions was investigated with the homobimetallic ruthenium-indenylidene complex [(p-cymene)Ru(μ-Cl)₃RuCl(3-phenyl-1-indenylidene)(PCy₃)] (1) to generate active species in situ. The two catalytic processes were first carried out independently in a case study before the whole sequence was optimized and applied to the synthesis of several polyhalogenated bicyclic γ-lactams and lactones from α,ω-diene substrates bearing trihaloa ...[more]

PMID: 21160564

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Project description:Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order to bring together and fuse the two ends of an acyclic precursor such as an alkene (also known as an olefin). To this end, the catalytic process known as ring-closing metathesis (RCM) has allowed access to countless biologically active macrocyclic organic molecules, even for large-scale production. Stereoselectivity is often critical in such cases: the potency of a macrocyclic compound can depend on the stereochemistry of its alkene; alternatively, one isomer of the compound can be subjected to stereoselective modification (such as dihydroxylation). Kinetically controlled Z-selective RCM reactions have been reported, but the only available metathesis approach for accessing macrocyclic E-olefins entails selective removal of the Z-component of a stereoisomeric mixture by ethenolysis, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization-a particularly serious problem when the E-alkene is energetically less favoured. Here, we show that dienes containing an E-alkenyl-B(pinacolato) group, widely used in catalytic cross-coupling, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E-macrocyclic alkenes. The reaction is promoted by a molybdenum monoaryloxide pyrrolide complex and affords products at a yield of up to 73 per cent and an E/Z ratio greater than 98/2. We highlight the utility of the approach by preparing recifeiolide (a 12-membered-ring antibiotic) and pacritinib (an 18-membered-ring enzyme inhibitor), the Z-isomer of which is less potent than the E-isomer. Notably, the 18-membered-ring moiety of pacritinib-a potent anti-cancer agent that is in advanced clinical trials for treating lymphoma and myelofibrosis-was prepared by RCM carried out at a substrate concentration 20 times greater than when a ruthenium carbene was used.

Dataset Information

Tandem catalysis of ring-closing metathesis/atom transfer radical reactions with homobimetallic ruthenium-arene complexes.

Publications

Tandem catalysis of ring-closing metathesis/atom transfer radical reactions with homobimetallic ruthenium-arene complexes.

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