Kinetically E-selective macrocyclic ring-closing metathesis

Abstract

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.

Extended Data 1. Byproducts from RCM with an E-β-substituted styrene

Mass spectromery analysis of the crude mixture of the reaction of compound 1c confirmed the existence of A, E, G and H and desired ring-closing metathesis product. ¹H NMR analysis of the mixture confirmed the existence of stilbene. A: HRMS [M+H]⁺: Calcd for C₂₃H₃₅O₂: 343.26370; found: 343.26277; E: HRMS[M+H]⁺: Calcd for C₄₄H₆₅O₄: 657.48828; found: 657.48808; G: HRMS[M+H]⁺: Calcd for C₃₈H₆₁O₄: 581.45730; found: 581.45698; H: HRMS[M+H]⁺: Calcd for C₂₉H₃₉O₂: 419.29500; found: 419.29383; RCM product: HRMS[M+H]⁺: Calcd for C₁₅H₂₇O₂: 239.20110; found: 239.20019.

Extended Data 2. Performance of other catalyst types

Examination of alternative Mo MAP complexes (cf. Mo-2-3) shows that the precise identity of the aryloxide ligand is crucial for achieving optimal efficiency and E selectivity. Furthermore, with two widely employed achiral complexes (i.e., Mo-4 and Ru-4), efficiency and E:Z selectivity are low. Two of the more recently introduced Z-selective Ru complexes (Ru-5,6) afford only homocoupling products. Abbreviation: Mes, 2,4,6-(Me)₃C₆H₂; R, functional group; ND, not determined. Reactions were performed under N₂ atm. Conversion values and E:Z ratios were determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%). See the Supplementary Information for all experimental and analytical details.

Extended Data 3. Reported RCM reactions with bis(α-olefin) compounds and promoted by Ru complexes

Figure 1. The strategy and the optimal substituent

a, One way to achieve high kinetic E selectivity in macrocyclic RCM would be to utilize a substrate where one of the reacting alkene sites is E-1,2-disubstituted, such that preferential transformation through mode of association I and via metallacyclobutane II (vs. III) affords the desired stereochemical preference. The starting acyclic E-alkene must meet several key criteria: it must be readily accessible as the pure E isomer, sufficiently electron withdrawing to facilitate metallacyclobutane formation (cf. I→II), resistant to post-metathesis isomerization, not too large to diminish reaction rates and generate an alkylidene intermediate (syn-i) that is not detrimental to the reaction outcome. b, A model RCM process performed with 5.0 mol % Mo-1 and affording sixteen-membered ring lactone 2 indicated that the (pin)B-substituted E-alkene (cf. 1e) represents the most effective option. In most cases, the major side product is derived from homocoupling of the two terminal alkenes. Abbreviations: R, functional group; L_n, ligands; ND, not determined. Reactions were performed under N₂ atm. Conversion values and E:Z ratios were determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%); stereoselectivity for reaction with 1c could not be determined due to formation of a comparatively complex mixture. See the Supplementary Information for all experimental and analytical details.

Figure 2. Kinetically E-selective macrocyclic RCM

Dienes accessed with high E-selectivity by catalytic hydroboration of a terminal alkyne, can be converted to 12- to 21-membered ring macrocyclic alkenes with high E:Z ratios. Transformations carried out with complexes Ru-1 or Ru-2 typically proceed with minimal selectivity or afford the Z isomer preferentially (cf. 13), reactions with Mo-1 are substantially more E-selective (91:9 to >98:2 E:Z). The difference between percent conversion and yield values (of isolated and purified products) is largely due to competitive homocoupling through the α-olefin terminus. Abbreviations: NR, not reported; pin, pinacolato; Boc, tert-butoxycarbonyl; Ad, adamantyl; Cy, cyclohexyl; Cp, cyclopentadienyl; DCC, N,N′-dicyclohexylcarbodiimide; DMAP, 4-dimethylaminopyridine. Reactions were performed under N₂ atm. Conversion (disappearance of the starting diene) and E:Z ratios were determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%). Yields are for isolated and purified products and correspond to the RCM step (±2%). In cases where the transformations have been previously reported, a specific citation is provided. See the Supplementary Information for all experimental and analytical details.

Figure 3. Application to stereoselective synthesis of recifeiolide

a, Application of the catalytic RCM strategy to the synthesis of antibiotic agent recifeiolide helps underscore the utility of the Mo MAP-catalyzed process. It was previously illustrated that macrocyclic RCM with slow addition of diene 15 to a refluxing dichloromethane solution of carbene complex Ru-1 affords recifeiolide in 82:18 E:Z selectivity after a total of 32 hours of reaction time. The present approach delivers the target molecule with complete E selectivity (>98:2) after only 6 hours at ambient temperature and without the need for slow addition. Further simplifying the E-selective protocol is the possibility of using an air and moisture stable paraffin tablet that contains Mo-1 complex to obtain the desired macrocycle with similar efficiency and stereoselectivity. b, Efficiency of macrocyclic RCM is lower without a methyl substituent, underlining the importance of structural pre-organization to the facility of ring formation. Abbreviations: R, functional group; Cy, cyclohexyl; Cp, cyclopentadienyl; pin, pinacolato; DCC, N,N′-dicyclohexylcarbodiimide; DMAP, 4-dimethylaminopyridine. Reactions were performed under N₂ atm. Conversion values (disappearance of the starting diene) and E:Z ratios were determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%). Yields are for isolated and purified products (±2%). See the Supplementary Information for all experimental and analytical details.

Figure 4. Application to synthesis of pacritinib

Treatment of bis(allyl ether) 20 with 10 mol% Ru-3 under acidic conditions (to counter catalyst deactivation) affords 21 in 85:15 E:Z selectivity. RCM with E-alkenyl–B(pin) derivative 22 with Mo-1 affords higher stereoselectively but less efficiently (17% yield). When the latter transformation was performed in the presence of tris(pentafluorophenyl)borane (to avoid catalyst deactivation), 23 was isolated in 60% yield and 95:5 E:Z selectivity. The same procedure with triether 24 was highly stereoselective but yield was lower (34%). Installation of a Boc unit (cf. 25) to diminish the Lewis basicity of the pyrimidine and the ether moieties furnished the macrocycle with similar E:Z selectivity and in 74% yield (after deprotection). A feature of the RCM with Mo-1 is that a relatively high concentration of the diene substrates (0.02 M vs. 0.001 M for 22, 24 and 25). Abbreviations: Mes, 2,4,6-(Me)₃C₆H₂; pin, pinacolato; Cy, cyclohexyl; Boc, tert-butoxycarbonyl. Reactions were performed under N₂ atm. Conversion values and E:Z ratios were determined by analysis of ¹H NMR spectra of unpurified product mixtures (±2%) relate to the disappearance of the starting diene. Yields are for isolated and purified products (±2%). See the Supplementary Information for all experimental and analytical details.