Catalytic Cross-metathesis Research Articles

Synthesis of Z-gem-Cl,CF3-Substituted Alkenes by Stereoselective Cross-Metathesis and the Role of Disubstituted Mo Alkylidenes.

Stereochemically defined organofluorine compounds are central to drug discovery and development. Here, we present a catalytic cross-metathesis method for the synthesis of Z-trisubstituted olefins that contain a Cl- and a CF3-bound carbon terminus. Notably, the process is stereoselective, which is in contrast to the existing stereoretentive strategies that also involve a trisubstituted olefin as starting material. Reactions are catalyzed by a Mo monoaryloxide pyrrolide alkylidene, involve a trisubstituted alkene and gem-Cl,CF3-substituted alkene, and are fully Z-selective. Catalytic cross-coupling can be used to convert the C-Cl bond of the trisubstituted olefin to C-B, C-D, and different C-C bonds. We elucidate the role of Cl,CF3-disubstituted Mo alkylidenes. Experimental and computational (DFT) data show that in some instances a disubstituted alkylidene is formed and then transformed to a more active complex. In other cases, the Cl,CF3-disubstituted alkylidene is a direct participant in a catalytic cycle. The studies described shed new light on the chemistry of high oxidation-state disubstituted alkylidenes-scarcely investigated entities likely to be pivotal to approaches for stereocontrolled synthesis of tetrasubstituted alkenes through olefin metathesis.

Catalytic Cross-Metathesis Reactions That Afford E- and Z-Trisubstituted Alkenyl Bromides: Scope, Applications, and Mechanistic Insights.

Stereochemically defined trisubstituted alkenes with a bromide and a methyl group at a terminus can be readily and stereoretentively derivatized through catalytic cross-coupling, affording unsaturated fragments found in many bioactive natural products. A direct method for generating such entities would be by stereocontrolled catalytic cross-metathesis (CM). Such methods are scarce however. Here, we present a stereoretentive strategy for CM between tri-, Z- or E-di, or monosubstituted olefins and Z- or E-2-bromo-2-butene, affording an assortment of E- or Z-trisubstituted alkenyl bromides. The majority of the transformations were catalyzed by two Mo monoaryloxide pyrrolide (MAP) complexes, one purchasable and the other accessible by well-established protocols. Substrates, such as feedstock trisubstituted olefins, can be purchased; the alkenyl bromide reagents are commercially available or can be prepared in two steps in a multigram scale. The catalytic process can be used to generate products that contain polar moieties, such as an amine or an alcohol, or sterically hindered alkenes that are α- or β-branched. The utility of the approach is highlighted by a brief and stereocontrolled synthesis of an unsaturated fragment of phomactin A and a concise total synthesis of ambrein. An unexpected outcome of these investigations was the discovery of a new role for the presence of a small-molecule alkene in an olefin metathesis reaction. DFT studies indicate that this additive swiftly reacts with a short-lived Mo alkylidene and probably helps circumvent the formation of catalytically inactive square pyramidal metallacyclobutanes, enhancing the efficiency of a transformation.

Z-Trisubstituted α,β-Unsaturated Esters and Acid Fluorides through Stereocontrolled Catalytic Cross-Metathesis.

Catalytic cross-metathesis (CM) reactions that can generate trisubstituted alkenes in high stereoisomeric purity are important but remain limited in scope. Here, CM reactions are introduced that generate Z-trisubstituted α-methyl, α,β-unsaturated, alkyl and aryl esters, thiol esters, and acid fluorides. Transformations are promoted by a Mo bis-aryloxide, a monoaryloxide pyrrolide, or a monoaryloxide chloride complex; air-stable and commercially available paraffin tablets containing a Mo complex may also be used. Alkyl, aryl, and silyl carboxylic esters as well as thiol esters and acid fluoride reagents are either purchasable or can be prepared in one step. Products were obtained in 55-95% yield and in 88:12->98:2 Z/E ratio (typically >95:5). The applicability of the approach is highlighted by a two-step conversion of citronellol to an isomintlactone precursor (1.7 g, 73% yield, and 97:3 Z/E) and a single-step transformation of lanosterol acetate to 3-epi-anwuweizic acid (72% yield and 94:6 Z/E). Included are the outcomes of DFT studies, regarding several initially puzzling catalyst activity trends, providing the following information: (1) it is key that a disubstituted Mo alkylidene, generated by a competing homo-metathesis (HM) pathway, can re-enter the productive CM cycle. (2) Whereas in a CM cycle the formation of a molybdacyclobutane is likely turnover-limiting, the collapse of related metallacycles in a HM cycle is probably rate-determining. It is therefore the relative energy barrier required for these steps that determines whether CM or HM is dominant with a particular complex.

Organometallic Chemistry of Transition Metal Alkylidyne Complexes Centered at Metathesis Reactions.

Transition metals form a variety of alkylidyne complexes with either a d0 metal center (high-valent) or a non-d0 metal center (low-valent). One of the most interesting properties of alkylidyne complexes is that they can undergo or mediate metathesis reactions. The most well-studied metathesis reactions are alkyne metathesis involving high-valent alkylidynes. High-valent alkylidynes can also undergo metathesis reactions with heterotriple bonded species such as N≡CR, P≡CR, and N≡NR+. Metathesis reactions involving low-valent alkylidynes are less known. Highly efficient alkyne metathesis catalysts have been developed based on Mo(VI) and W(VI) alkylidynes. Catalytic cross-metathesis of nitriles with alkynes has also been achieved with M(VI) (M = W, Mo) alkylidyne or nitrido complexes. The metathesis activity of alkylidyne complexes is sensitively dependent on metals, supporting ligands and substituents of alkylidynes. Beyond metathesis, metal alkylidynes can also promote other reactions including alkyne polymerization. The remaining shortcomings and opportunities in the field are assessed.

E- and Z-, di- and tri-substituted alkenyl nitriles through catalytic cross-metathesis.

Nitriles are found in many bioactive compounds, and are among the most versatile functional groups in organic chemistry. Despite many notable recent advances, however, there are no approaches that may be used for preparation of di- or trisubstituted alkenyl nitriles. Related approaches which are broad in scope and can deliver the desired products in high stereoisomeric purity are especially scarce. Here, we describe the development of several efficient catalytic cross-metathesis strategies, which provide direct access to a considerable range of Z- or E-disubstituted cyano-substituted alkenes or their corresponding trisubstituted variants. Depending on the reaction type, a molybdenum-based monoaryloxide pyrrolide (MAP) or chloride (MAC) complex may be the optimal choice. The utility of the approach, enhanced by an easy-to-apply protocol for utilization of substrates bearing an alcohol or a carboxylic acid moiety, is highlighted in the context of applications to synthesis of biologically active compounds.

Synthesizing Stilbene by Olefin Metathesis Reaction Using Guided Inquiry To Compare and Contrast Wittig and Metathesis Methodologies

In this experiment, students are asked to conduct a catalytic cross-metathesis experiment and compare this reaction to the Wittig reaction within the confines of green chemistry. Students synthesize stilbene from styrene using Grubbs second-generation catalyst. Products can be minimally characterized by IR spectroscopy and melting point, but using 1H NMR spectroscopy is preferred. Students find that the Wittig reaction is selective for cis-stilbene while the metathesis reaction produces >98% trans-stilbene. Students determine the cis/trans selectivity, turnover number, and maximum turnover frequency of the reaction. The experiment is conducted alongside the synthesis of stilbene using Wittig chemistry from a published procedure.

Synthesis of E- and Z-trisubstituted alkenes by catalytic cross-metathesis.

Catalytic cross-metathesis is a central transformation in chemistry, and yet, corresponding methods for stereoselectively generating acyclic trisubstituted alkenes in either isomeric form do not exist. The key problems are lack of chemoselectivity, namely, the preponderance of side reactions involving only the less hindered starting alkene, ensuing nonproductive processes of homo-metathesis byproducts, and formation of short-lived methylidene complexes. In contrast, in catalytic cross-coupling, another widely used process, substrates are more distinct and homocoupling is less of a problem. Here, we show that through cross-metathesis reactions involving E- or a Z-trisubstituted alkenes, easily prepared from commercially available starting materials by cross-coupling processes, many otherwise desirable and difficult-to-access linear E- or Z-trisubstituted alkenes can be synthesized efficiently and in exceptional stereoisomeric purity (up to >98% E or 95% Z). Utility is highlighted through concise stereoselective syntheses of biologically active compounds such as indiacen B (anti-fungal) and coibacin D (anti-inflammatory).

In Situ Methylene Capping: A General Strategy for Efficient Stereoretentive Catalytic Olefin Metathesis. The Concept, Methodological Implications, and Applications to Synthesis of Biologically Active Compounds.

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.

Synthesis of Linear (Z)-α,β-Unsaturated Esters by Catalytic Cross-Metathesis. The Influence of Acetonitrile.

Kinetically controlled catalytic cross-metathesis reactions that generate (Z)-α,β-unsaturated esters selectively are disclosed. A key finding is that the presence of acetonitrile obviates the need for using excess amounts of a more valuable terminal alkene substrates. On the basis of X-ray structure and spectroscopic investigations a rationale for the positive impact of acetonitrile is provided. Transformations leading to various E,Z-dienoates are highly Z-selective as well. Utility is highlighted by application to stereoselective synthesis of the C1-C12 fragment of biologically active natural product (-)-laulimalide.

Direct synthesis of Z-alkenyl halides through catalytic cross-metathesis

Olefin metathesis has made a significant impact on modern organic chemistry, but important shortcomings remain: for example, the lack of efficient processes that can be used to generate acyclic alkenyl halides. Halo-substituted ruthenium carbene complexes decompose rapidly or deliver low activity and/or minimal stereoselectivity, and our understanding of the corresponding high-oxidation-state systems is very limited. In this manuscript, we show that previously unknown halo-substituted molybdenum alkylidene species are exceptionally reactive and are able to participate in high-yielding olefin metathesis reactions that afford acyclic 1,2-disubstituted Z-alkenyl halides. Transformations are promoted by small amounts of an in situ-generated catalyst with unpurified, commercially available and easy-to-handle liquid 1,2-dihaloethene reagents and proceed to high conversion at ambient temperature within four hours. Many alkenyl chlorides, bromides and fluorides can be obtained in up to 91 percent yield and complete Z selectivity. This method can be used to easily synthesize biologically active compounds and to perform the site- and stereoselective fluorination of other organic compounds.

ChemInform Abstract: Assisted Tandem Catalytic Cross Metathesis—Oxidation: In One Flask from Styrenes to 1,2‐Diketones and Further to Quinoxalines.

1,2-Diketones were synthesized from styrenes by combining a cross metathesis and a Ru-catalyzed alkene oxidation to an assisted tandem catalytic sequence. The synthesis relies on the use of just one metathesis precatalyst, which was in situ converted to the oxidation catalyst by addition of an alkyl hydroperoxide as a chemical trigger and oxidant. The one-flask sequence can be extended beyond 1,2-diketones to quinoxalines, by condensation of the oxidation products with ortho-phenylenediamine.

Catalytic Z‐Selective Cross‐Metathesis with Secondary Silyl‐ and Benzyl‐Protected Allylic Ethers: Mechanistic Aspects and Applications to Natural Product Synthesis

Get me a­ Z (olefin): Efficient catalytic cross-metathesis reactions that afford Z-disubstituted allylic silyl or benzyl ethers are reported (see scheme, MAP=monoalkoxide pyrrolide). The approach, in combination with catalytic cross-coupling, provides a general entry to otherwise difficult-to-access alkyne-containing Z olefins.

Assisted Tandem Catalytic Cross Metathesis–Oxidation: In One Flask from Styrenes to 1,2-Diketones and Further to Quinoxalines

1,2-Diketones were synthesized from styrenes by combining a cross metathesis and a Ru-catalyzed alkene oxidation to an assisted tandem catalytic sequence. The synthesis relies on the use of just one metathesis precatalyst, which was in situ converted to the oxidation catalyst by addition of an alkyl hydroperoxide as a chemical trigger and oxidant. The one-flask sequence can be extended beyond 1,2-diketones to quinoxalines, by condensation of the oxidation products with ortho-phenylenediamine.

Synthesis of Z-(pinacolato)allylboron and Z-(pinacolato)alkenylboron compounds through stereoselective catalytic cross-metathesis.

The first examples of catalytic cross-metathesis (CM) reactions that furnish Z-(pinacolato)allylboron and Z-(pinacolato)alkenylboron compounds are disclosed. Products are generated with high Z selectivity by the use of a W-based monoaryloxide pyrrolide (MAP) complex (up to 91% yield and >98:2 Z:E). The more sterically demanding Z-alkenylboron species are obtained in the presence of Mo-based MAP complexes in up to 93% yield and 97% Z selectivity. Z-selective CM with 1,3-dienes and aryl olefins are reported for the first time. The utility of the approach, in combination with catalytic cross coupling, is demonstrated by a concise and stereoselective synthesis of anticancer agent combretastatin A-4.

ChemInform Abstract: A Green Route to Nitrogen‐Containing Groups: The Acrylonitrile Cross‐Metathesis and Applications to Plant Oil Derivatives

AbstractReview: 123 refs.

A green route to nitrogen-containing groups: the acrylonitrile cross-metathesis and applications to plant oil derivatives

Acrylonitrile has become a renewable material arising from glycerol. It can now be used as an available key product to introduce a nitrogen-containing functionality into a molecule by cross-metathesis. This review successively presents the developments of catalytic cross-metathesis of acrylonitrile with functional alkenes: (i) the first steps of cross-metathesis of acrylonitrile with simple terminal alkenes, of which the successes were linked to the progressive discoveries of efficient alkene metathesis catalysts, (ii) some contributions of this catalytic reaction to synthesis of complex molecules and (iii) the access to renewable α,ω-bifunctional compounds by acrylonitrile cross-metathesis with fatty acid derivatives, arising from plant oils. The combination of the renewable acrylonitrile and fatty acid derivatives, by catalysis under mild conditions with only ethylene as a by-product, constitutes a clear contribution to green chemistry for the production of useful intermediates.

Catalytic Nitrile-Alkyne Cross-Metathesis

The first catalytic cross-metathesis reaction of an alkyne with a nitrile is described. The nitride complex N⋮W(OC(CF3)2CH3)3(DME) undergoes reversible triple-bond metathesis reactions with alkynes (RC⋮CR; R = Et, 4-C6H4OMe), forming the alkylidyne complexes RC⋮W(OC(CF3)2CH3)3(DME) (R = Et, 4-C6H4OMe) along with the corresponding nitrile RC⋮N. This has been exploited to effect catalytic cross-metathesis of nitriles with alkynes, in which the organic CR fragments of two nitriles are coupled to yield an alkyne. A simple “sacrificial” alkyne (3-hexyne) acts as the N-atom acceptor, forming two equivalents of nitrile byproduct (propionitrile).

A Highly Selective Synthesis of Dialkenyl Sulfones via Cross-Metathesis of Divinyl Sulfone

Catalytic cross-metathesis of commercial divinyl sulfone allowed direct access to novel (E)-alkenylvinyl sulfones and (E,E)-dialkenyl sulfones with excellent stereoselectivity. These compounds are useful building blocks, e.g., in the synthesis of substituted thiomorpholine 1,1-dioxide derivatives. [reaction: see text]