Kinetically E-selective macrocyclic ring-closing metathesis

Abstract

Macrocyclic compounds are central to discovery of new drugs but their preparation is often challenging because of the energy barrier required for bringing together and fusing the two ends of an acyclic precursor1. Ring-closing metathesis (RCM) 2,3,4 is a catalytic process that has allowed access to countless biologically active macrocyclic organic molecules even on large scale (up to 200 kilograms)5. The potency of a macrocyclic compound can depend on the stereochemistry of its alkene, or one isomer might be needed for subsequent stereoselective modification (e.g., dihydroxylation6). Still, while kinetically controlled Z-selective RCM reactions have been reported7,8,9,10, the only available olefin metathesis approach for accessing macrocyclic E olefins entails selective removal of the Z component of a stereoisomeric mixture by ethenolysis10, 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 favored. Here, we show that dienes containing an E-alkenyl–B(pinacolato) group, widely used in catalytic cross-coupling11, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E macrocyclic alkenes. Reactions are promoted by a molybdenum monoaryloxide pyrrolide complex and afford products in up to 73 percent yield and >98:2 E:Z ratio. Utility is highlighted by application to preparation of the twelve-membered ring antibiotic recifeiolide12,13 and the eighteen-membered ring Janus kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor pacritinib14,15 the Z isomer of which has lower potency than the E16. The eighteen-membered ring moiety of pacritinib, a potent in vivo anti-cancer agent in advanced clinical trials for treatment of lymphoma and myelofibrosis, was prepared by an RCM carried out at 20 times higher concentration than when a ruthenium carbene was employed (0.02 vs. 0.001 M; 73% yield, 92% E).

Steric Hindrance in Sulfur Vacancy of Monolayer MoS2 Boosts Electrochemical Reduction of Carbon Monoxide to Methane

“…Scheme a shows that the steric hindrance resulting from repulsive interactions between the “bowl” site and different species determines the preferential intermediates. Such steric hindrance is often found in organic materials and plays a significant role in many fields, such as organic synthesis, catalysis, and batteries . Recently, Xiao and co‐workers reported that steric adsorption in zeolite micropores of a Pd@zeolite system can control the product selectivity …”

Stereoretentive Olefin Metathesis: An Avenue to Kinetic Selectivity

“…[109] Initial studies focused on using a diene with one of the olefins being an E-chloro-olefin, building on the previous success with chlorinated olefins in stereoretentive olefin metathesis. However, low turnovers were observed.…”

Expanding the chemical space of synthetic cyclic peptides using a promiscuous macrocyclase from prenylagaramide biosynthesis

“…[1][2][3] However, the therapeutic scope of cyclic peptides remains underexploited. Synthetic macrocyclizing approaches include metathesis, [4][5][6] click chemistry, 7-9 the use of auxiliaries, [10][11] and intein-mediated ligation, 12 but despite many innovations limitations remain. 13 Enzymes provide an additional tool to create libraries of cyclic peptides for drug discovery.…”