A significant shortcoming in olefin metathesis, a chemical process that is central to research in several branches of chemistry, is the lack of efficient methods that kinetically favor E-isomers in the product distribution. Here, we show that kinetically E-selective cross-metathesis reactions may be designed to generate thermodynamically disfavored alkenyl chlorides and fluorides in high yield and with exceptional stereoselectivity. With 1.0–5.0 mol % of a molybdenum-based catalyst, which may be delivered in the form of air- and moisture-stable paraffin pills, reactions typically proceed to completion within four hours at ambient temperature. Many isomerically pure E-alkenyl chlorides, applicable to catalytic cross-coupling transformations and found in biologically active entities, thus become easily and directly accessible. Similarly, E-alkenyl fluorides can be synthesized from simpler compounds or more complex molecules.
In situ methylene capping is introduced as a practical and broadly applicable strategy that can expand the scope of catalyst-controlled stereoselective olefin metathesis considerably. By incorporation of commercially available Z-butene together with robust and readily accessible Ru-based dithiolate catalysts developed in these laboratories, a large variety of transformations can be made to proceed with terminal alkenes, without the need for a priori synthesis of a stereochemically defined disubstituted olefin. Reactions thus proceed with significantly higher efficiency and Z selectivity as compared to when other Ru-, Mo-, or W-based complexes are utilized. Cross-metathesis with olefins that contain a carboxylic acid, an aldehyde, an allylic alcohol, an aryl olefin, an α substituent, or amino acid residues was carried out to generate the desired products in 47-88% yield and 90:10 to >98:2 Z:E selectivity. Transformations were equally efficient and stereoselective with a ∼70:30 Z-:E-butene mixture, which is a byproduct of crude oil cracking. The in situ methylene capping strategy was used with the same Ru catechothiolate complex (no catalyst modification necessary) to perform ring-closing metathesis reactions, generating 14- to 21-membered ring macrocyclic alkenes in 40-70% yield and 96:4-98:2 Z:E selectivity; here too, reactions were more efficient and Z-selective than when the other catalyst classes are employed. The utility of the approach is highlighted by applications to efficient and stereoselective syntheses of several biologically active molecules. This includes a platelet aggregate inhibitor and two members of the prostaglandin family of compounds by catalytic cross-metathesis reactions, and a strained 14-membered ring stapled peptide by means of macrocyclic ring-closing metathesis. The approach presented herein is likely to have a notable effect on broadening the scope of olefin metathesis, as the stability of methylidene complexes is a generally debilitating issue with all types of catalyst systems. Illustrative examples of kinetically controlled E-selective cross-metathesis and macrocyclic ring-closing reactions, where E-butene serves as the methylene capping agent, are provided.
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).
A stereoselective synthesis of enantiomerically enriched difluoromethyl tertiary alcohols by tuning the reactivity of difluoromethyl sulfoximines from electrophilic to nucleophilic difluoromethylating agents is reported. The key feature of this chemistry is the diastereoselective addition of the difluoromethyl sulfoximine to the prochiral carbon of the ketone. The present method was used to prepare enantiomerically enriched difluoromethyl secondary alcohols and difluorinated analogues of the natural products gossonorol and boivinian B, demonstrating the potency of the method.
Conjugate (or 1,4-) additions of carbanionic species to α,β-unsaturated carbonyl compounds are vital to research in organic and medicinal chemistry, and there are several known chiral catalysts that facilitate the catalytic enantioselective additions of nucleophiles to enoates1. However, catalytic enantioselective 1,6-conjugate additions are uncommon, and ones that are able to incorporate readily functionalizable moieties, such as propargyl or allyl groups, into acyclic α,β,γ,δ-doubly unsaturated acceptors are unknown2. Chemical transformations that could generate a new bond at the C6 position of a dienoate are particularly desirable, as the resulting products would be subjected to further modifications; such reactions, especially when dienoates contain two equally substituted olefins, are scarce3 and are confined to reactions promoted by a phosphine–copper (with alkyl Grignard4,5, dialkylzinc or trialkylaluminum compounds6,7), a diene–iridium (with arylboroxines)8,9, and a bisphosphine–cobalt catalyst (with monosilyl-acetylenes)10. 1,6-conjugate additions are otherwise limited to substrates where there is full substitution at C411. It is not clear why certain catalysts favor bond formation at C6, and – while there are a small number of catalytic enantioselective conjugate allyl additions12,13,14,15 – related 1,6-additions and processes involving a propargyl unit are non-existent. In this manuscript, we show that an easily accessible organocopper catalyst can promote 1,6-conjugate additions of propargyl and 2-boryl-substituted allyl groups to acyclic dienoates with high selectivity. A commercially available allenylboron compound or a monosubstituted allene may be used. Products can be obtained in up to 83 percent yield, >98 percent diastereo- (for allyl additions) and 99:1 enantiomeric ratio. Mechanistic details, including the origins of high site- (1,6- versus 1,4-) and enantioselectivity as a function of the catalyst structure and reaction type, have been elucidated by means of density functional theory (DFT) calculations.
A practical, high-yielding method for the deoxyfluorination of alcohols is presented using AlkylFluor, a novel salt analogue of PhenoFluor. AlkylFluor is readily prepared on multigram scale and is stable to long-term storage in air and exposure to water. The practicality and applicability of this method is demonstrated with a variety of primary and secondary alcohol substrates.
The selective incorporation of fluorine atoms or fluorinated moieties into organic molecules has become a “hot” research topic in modern organic chemistry. However, selective and efficient synthesis of organofluorine compounds greatly depends on the development of powerful fluorination or fluoroalkylation reagents and reactions. In this context, the past decade has witnessed rapid research progress in the development of α‐fluoro sulfoximines as versatile fluoroalkylation reagents. Many efficient nucleophilic, electrophilic and radical fluoroalkylation reactions based on α‐fluoro sulfoximine reagents have been developed; among these, several chiral sulfoximine reagents were successfully used in the synthesis of enantiomerically enriched organofluorine compounds. It was found that α‐fluoro sulfoximines show unique chemical behaviour characteristics (such as difluorocarbene and fluoroalkyl radical reactivities) significantly different from those of their non‐fluorinated counterparts. In addition to the rapid development of fluorinated sulfoximines in organic synthesis, research into their application in materials science has also attracted increasing attention. Sulfoximines are important bioactive substances, and more recently the synthesis and application of fluorinated sulfoximines has attracted much attention in life sciences and the pharmaceutical industry. In this microreview we summarize the preparation, reactions and applications of fluorinated sulfoximines (mainly α‐fluoro sulfoximines).
Transcriptomic analysis of cultured fungi suggests that many genes for secondary metabolite synthesis are presumably silent under standard laboratory condition. In order to investigate the expression of silent genes in symbiotic systems, 136 fungi-fungi symbiotic systems were built up by co-culturing seventeen basidiomycetes, among which the co-culture of Trametes versicolor and Ganoderma applanatum demonstrated the strongest coloration of confrontation zones. Metabolomics study of this co-culture discovered that sixty-two features were either newly synthesized or highly produced in the co-culture compared with individual cultures. Molecular network analysis highlighted a subnetwork including two novel xylosides (compounds 2 and 3). Compound 2 was further identified as N-(4-methoxyphenyl)formamide 2-O-β-D-xyloside and was revealed to have the potential to enhance the cell viability of human immortalized bronchial epithelial cell line of Beas-2B. Moreover, bioinformatics and transcriptional analysis of T. versicolor revealed a potential candidate gene (GI: 636605689) encoding xylosyltransferases for xylosylation. Additionally, 3-phenyllactic acid and orsellinic acid were detected for the first time in G. applanatum, which may be ascribed to response against T.versicolor stress. In general, the described co-culture platform provides a powerful tool to discover novel metabolites and help gain insights into the mechanism of silent gene activation in fungal defense.
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