Amir H. Hoveyda

The remarkable metal-catalysed olefin metathesis reaction

Catalytic olefin metathesis—through which pairs of C = C bonds are reorganized—transforms simple molecules to those that are complex and precious. This class of reactions has noticeably enriched chemical synthesis, which is the art of preparing scarce molecules with highly desirable properties (for example, medicinal agents or polymeric materials). Research in the past two decades has yielded structurally well-defined catalysts for olefin metathesis that are used to synthesize an array of molecules with unprecedented efficiency. Nonetheless, the full potential of olefin metathesis will be realized only when additional catalysts are discovered that are truly practical and afford exceptional selectivity for a significantly broader range of reactions.

Catalytic Z-selective olefin cross-metathesis for natural product synthesis

Alkenes are found in many biologically active molecules, and there are a large number of chemical transformations in which alkenes act as the reactants or products (or both) of the reaction. Many alkenes exist as either the E or the higher-energy Z stereoisomer. Catalytic procedures for the stereoselective formation of alkenes are valuable, yet methods enabling the synthesis of 1,2-disubstituted Z alkenes are scarce. Here we report catalytic Z-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously, and of allylic amides, used until now only in E-selective processes. The corresponding disubstituted alkenes are formed in up to >98% Z selectivity and 97% yield. These transformations, promoted by catalysts that contain the highly abundant and inexpensive metal molybdenum, are amenable to gram-scale operations. Use of reduced pressure is introduced as a simple and effective strategy for achieving high stereoselectivity. The utility of this method is demonstrated by its use in syntheses of an anti-oxidant plasmalogen phospholipid, found in electrically active tissues and implicated in Alzheimer’s disease, and the potent immunostimulant KRN7000.

Ru complexes bearing bidentate carbenes: from innocent curiosity to uniquely effective catalysts for olefin metathesis

The discovery and development of a new class of Ru-based catalysts for olefin metathesis is described. These catalysts, particularly those that do not bear a phosphine ligand, have been demonstrated to promote unique levels of reactivity in a variety of olefin metathesis reactions. The design and development of supported and chiral optically pure variants of this class of Ru catalysts for use in enantioselective metathesis are discussed as well. All catalysts are air stable, reusable, and can be employed with unpurified solvents.

Efficient C−B Bond Formation Promoted by N-Heterocyclic Carbenes: Synthesis of Tertiary and Quaternary B-Substituted Carbons through Metal-Free Catalytic Boron Conjugate Additions to Cyclic and Acyclic α,β-Unsaturated Carbonyls

Metal-free nucleophilic activation of a B-B bond has been exploited in the development of a highly efficient method for conjugate additions of commercially available bis(pinacolato)diboron to cyclic or acyclic alpha,beta-unsaturated carbonyls. The reactions are readily catalyzed by a simple N-heterocyclic carbene (NHC) present at 2.5-10 mol %. A variety of cyclic and acyclic unsaturated ketones and esters can serve as substrates. The transformations deliver beta-boryl carbonyls bearing tertiary or quaternary B-substituted carbons in up to >98% yield. Preliminary studies indicate that although related Cu-NHC-catalyzed reactions are equally efficient, the metal-free variant is more functional-group-tolerant; in contrast to the Cu-catalyzed reactions, the metal-free processes proceed readily in the presence of a terminal alkyne and do not promote concomitant diboration of an aldehyde. Representative functionalization of the resulting boron enolates demonstrates the strong influence of the Lewis acidic B atom of the beta-boronate.

Efficient boron-copper additions to aryl-substituted alkenes promoted by NHC-based catalysts. enantioselective Cu-catalyzed hydroboration reactions.

A Cu-catalyzed method for efficient boron-copper addition processes involving acyclic and cyclic disubstituted aryl olefins are reported. Reactions are promoted with 0.5-5 mol % of a readily available N-heterocyclic carbene (NHC) complex; the presence of MeOH promotes in situ protonation of the C-Cu bond and leads to efficient catalyst turnover, constituting a net Cu-catalyzed hydroboration process. Reactions proceed in >98:<2 site selectivity and furnish secondary organoborane isomers that complement those obtained through reactions of boron-hydride reagents or by Rh- or Ir-catalyzed hydroborations (benzylic secondary C-B bonds). Initial observations regarding processes catalyzed by chiral NHC complexes, delivering products in up to 99:1 enantiomeric ratio, are disclosed.

Highly efficient molybdenum-based catalysts for enantioselective alkene metathesis

Discovery of efficient catalysts is one of the most compelling objectives of modern chemistry. Chiral catalysts are in particularly high demand, as they facilitate synthesis of enantiomerically enriched small molecules that are critical to developments in medicine, biology and materials science. Especially noteworthy are catalysts that promote—with otherwise inaccessible efficiency and selectivity levels—reactions demonstrated to be of great utility in chemical synthesis. Here we report a class of chiral catalysts that initiate alkene metathesis with very high efficiency and enantioselectivity. Such attributes arise from structural fluxionality of the chiral catalysts and the central role that enhanced electronic factors have in the catalytic cycle. The new catalysts have a stereogenic metal centre and carry only monodentate ligands; the molybdenum-based complexes are prepared stereoselectively by a ligand exchange process involving an enantiomerically pure aryloxide, a class of ligands scarcely used in enantioselective catalysis. We demonstrate the application of the new catalysts in an enantioselective synthesis of the Aspidosperma alkaloid, quebrachamine, through an alkene metathesis reaction that cannot be promoted by any of the previously reported chiral catalysts.

Catalytic Asymmetric Olefin Metathesis

This paper provides a survey of the first examples of efficient catalytic enantioselective olefin metathesis reactions. Mo-catalyzed asymmetric ring-closing (ARCM) and ring-opening (AROM) reactions allow access to myriad optically enriched compounds that are otherwise difficult to access.

Enantioselective conjugate silyl additions to cyclic and acyclic unsaturated carbonyls catalyzed by Cu complexes of chiral N-heterocyclic carbenes.

An efficient Cu-catalyzed protocol for enantioselective addition of a dimethylphenylsilanyl group to a wide range of cyclic and acyclic unsaturated ketones, esters, acrylonitriles, and alpha,beta,gamma,delta-dienones is disclosed. Reactions are performed in the presence of 1-2 mol % of commercially available and inexpensive CuCl, a readily accessible monodentate imidazolinium salt, and commercially available (dimethylphenylsilyl)pinacolatoboron. Cu-catalyzed enantioselective conjugate additions proceed to completion within only 2 h to afford the desired silanes in 87-97% yield and 90:10-99:1 enantiomeric ratio (er). Use of a proton source (e.g., MeOH) is not required; accordingly, synthetically versatile alpha-silyl boron enolates can be obtained. The special utility of the present protocol, in comparison with the related catalytic enantioselective aldol and boronate conjugate additions, is discussed and illustrated through various functionalizations of the enantiomerically enriched beta-silylcarbonyls.

Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis

Many natural products contain a C = C double bond through which various other derivatives can be prepared; the stereochemical identity of the alkene can be critical to the biological activities of such molecules. Catalytic ring-closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings; however, cyclizations often proceed without control of alkene stereochemistry. This shortcoming is particularly costly when the cyclization reaction is performed after a long sequence of other chemical transformations. Here we outline a reliable, practical and general approach for the efficient and highly stereoselective synthesis of macrocyclic alkenes by catalytic RCM; transformations deliver up to 97% of the Z isomer owing to control induced by a tungsten-based alkylidene. Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3–5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM. The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity. As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.

Enantioselective Synthesis of Boron-Substituted Quaternary Carbons by NHC−Cu-Catalyzed Boronate Conjugate Additions to Unsaturated Carboxylic Esters, Ketones, or Thioesters

A Cu-catalyzed method for enantioselective boronate conjugate additions to trisubstituted alkenes of acyclic alpha,beta-unsaturated carboxylic esters, ketones, and thioesters is disclosed. All transformations are promoted by 5 mol % of a chiral monodentate NHC-Cu complex, derived from a readily available C(1)-symmetric imidazolinium salt, and in the presence of commercially available bis(pinacolato)diboron. Reactions are efficient (typically, 60% to >98% yield after purification) and deliver the desired beta-boryl carbonyls in up to >98:2 enantiomer ratio (er). Processes involving unsaturated thioesters proceed with higher enantioselectivity (vs carboxylic esters or ketones), and the resulting products can be functionalized by Ag-mediated or Pd-catalyzed reactions that furnish the derived carboxylic ester or various ketones. Routine oxidation affords beta-hydroxy ketones or carboxylic esters, ketone aldol products that cannot be otherwise prepared efficiently by an alternative catalytic enantioselective protocol.