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Home , Carbene, Carbenium ion, Cyclopropanation, Diazo, Grubbs catalyst, Nitrene

Advanced Synthesis and ─ Chen

Free carbene can be generated by α-elimination or decomposition of , , or diazirine compounds. Carbenes can also Carbenes can exist in either singlet or triplet state whereas the be generated by thermolysis. Flash vacuum (FVP) ground state of is always singlet. If there is a large gap allows heating the reactant at very high temperature for a short between the σ and p orbitals of the carbene, the ground state period of time, typically > 500 ºC for 0.01 s in gas phase. will be singlet due to the relatively lower energy cost in Carbene is normally unstable and undergoes rearrangement pairing. Carbenes with a p-donor (N, O, or halogen) can readily. also promote electron pairing. Advanced Synthesis and Catalysis ─ Carbene Chen

Carbenes can also be formed by Bamford–Stevens reaction in The Corey–Fuch reaction is also a one- homologatioin aprotic solvents. In protic solvents, the carbenium is formed reaction that generates terminal from through instead. This reaction is mechanistically similar to the Shapiro a vinylidene–acetylene rearrangement. The Seyferth–Gilbert reaction that generates vinyl . reaction can be viewed as the Horner–Emmons version of the Wittig-type Corey–Fuch reaction. The Bestmann-Ohira reaction is a modified Seyferth–Gilbert reaction with the generation of the diazo by deacetylation under milder conditions.

In and the Arndt–Eistert homologation, carbene is generated by decomposition of diazoketone promoted by photolysis or Ag(I) or Cu(II) catalysts. Advanced Synthesis and Catalysis ─ Carbene Chen

Skattebøl rearrangement generates a carbene from Thiamine (vitamine B1) is a N-heterocyclic carbene (NHC) that dibromocyclopropane. Subsequent rearrangement yields catalyzes benzoin condensation. This organocatalysis reaction allene. When an adjacent olefin is present, cyclopentadiene is was first documented more than six decades ago, and the formed. mechanism of this umpolung reaction was established by Breslow.

Buchner reaction is a method for seven-membered ring synthesis via ring-expansion. of a six- membered aromatic ring with diazo compounds followed by a rearrangement gives cycloheptatrienes. Advanced Synthesis and Catalysis ─ Carbene Chen

Various NHC catalysts, including chiral versions, have been Bode reported the use of NHC to catalyze internal redox of developed. The scope of this carbonyl umpolung reaction has epoxyaldehyde to generate activated carboxylate for also been explored extensively. Stetter demonstrated in 1976 esterification. He has further shown that NHC can catalyze that thiazolium-catalyzed nucleophilc addition also work with asymmetric Diels-Alder reaction of azadienes and electron- Michael acceptors. Both intra- and intermolecular variants of deficient enals. the Stetter reaction have been reported. Glorius also found that cross-condensation of / with enals gives γ- or β-lactones depending on the reaction conditions. Advanced Synthesis and Catalysis ─ Carbene Chen

Metal Fischer carbenes are typically prepared by electrophilic O- of acyl complexes that was synthesized by The reactivity of is largely determined by the nucleophilic alkylation of carbonyl complexes. Cationic π-donor ability of the carbene . Metal carbenoids with carbenoids can be prepared by alkylation or protonation of capable of π-interactions, for example, N, O, Cl, neutral acyl complexes. and Ph, are call Fischer carbenes. These electrophilic complexes react with through the coordinating carbon of the singlet carbene ligand. Metal carbenoids without these substitutions, for example, and alkylidene, require substantial π-donation from the meal are called Schrock carbene. These nucleophilic complexes react with through the coordinating carbon of the triplet carbene ligand. However, reversed reactivity has been observed. For example, methylene on a positively charged metal complex can be electrophilic. Schrock carbenes are typically prepared by removal of an α hydrogen from an ligand. The loss of the α hydrogen atom can be induced by steric crowding or α-elimination. They can also be prepared by alkylidene transfer from phosphoranes or other . Advanced Synthesis and Catalysis ─ Carbene Chen

Dötz discovered in 1975 that Fischer carbenes can react with Wulff has extended the scope of Dötz reaction to vinyl Fischer alkyne to give naphthols. Increasing the electrophilicity of the carbenes. Vinyl and alkynyl Fischer carbenes are also good carbenoids leads to more reactive complexes. The order of dienophiles. The Diels–Alder reaction product of alkynyl

reactivity is :CPh2 > :C(OR)Ph > :C(NR2)Ph and CO >> PR3, Fischer carbenes is a vinyl Fischer carbene that can participate but the reactivity is suppressed when performing the reaction in in Dötz reaction. the presence of excess CO. Terminal react to yield 2- substituted naphtols selectively whereas internal alkynes react with low . Advanced Synthesis and Catalysis ─ Carbene Chen

In addition to participating in Dötz reaction, Fischer carbenes Fischer carbenes can also react with C=X groups through can react with alkynes to give indenes, enones, or pyrones. ketene-type under photolytic conditions and enolate- type chemistry under thermal conditions. Vinyl Fisher carbenes undergo conjugate addition with hindered enolates and 1,2- addition with unhindered enolates. Advanced Synthesis and Catalysis ─ Carbene Chen

Schrock carbenes can be viewed as the metal version of Wittig Tebbe’s reagent is also very reactive toward olefins, forming reagents but much more reactive because of the oxophilicity of stable metallacylces in the presences of . These the metal. In addition to aldehydes, they also react with readily exchange with other olefins via and to give and enamides. The most useful metathesis to give new metallacycles. carbene for this type of reaction is the Tebbe’s reagent

Cp2TiCH2ClAlMe2. In the presence of , Tebbe’s reagent is synthetically equivalent to Cp2Ti=CH2.

Fischer carbenes can react with olefins to form but the efficiency is low. Electrophilic, cationic iron carbenes, however, are exceptionally efficient cyclopropanating agents as first demonstrated by Helquist and Brookhart. Carreira has recently shown that Fe(TPP)Cl catalyzes cyclopropanation in 6 M KOH with in situ generation of . Advanced Synthesis and Catalysis ─ Carbene Chen

Simmons–Smith cyclopropanation reaction can be directed by (I), cobalt(II), (II), irridium(III), (II) and polar functional groups. The generally accepted mechanism, (0/II) complexes can all catalyze the decomposition of however, does not involve copper that consists up to 10% of diazo compounds to give carbenoids that cyclopropanate the alloy. The activation of Zn by Cu possibly at the surface of olefins. Doyle has demonstrated the intermediacy of metal

the alloy is essential to this reaction. The use of Et2Zn/CH2I2 to carbenoid and the coordination of olefin to metal. One or two generate the carbenoid suppresses . Various electron-withdrawing or vinyl/ groups are typically used to chiral auxiliaries and additives have been developed to effect stabilize the diazo compounds. Asymmetric cyclopropanation asymmetric cyclopropanation. was first achieved by Evans using the Cu-BOX catalyst system. In addition to diazos, phenyliodonium can also be used as the carbene source. Advanced Synthesis and Catalysis ─ Carbene Chen

In addition to cyclopropanation, metal carbenoids are also Doyle and Davies have each developed a chiral rhodium highly reactive toward C–H and X–H insertion. The distribution catalyst system for asymmetric C–H insertion reactions. of the products can be controlled by the catalyst ligands. Davies has also coupled C–H insertion with sigmatropic Intramolecular C–H insertion generally gives five-membered rearrangement to establish allylic quaternary centers. ring products. Researchers at Merck successfully applied the rhodium-catalyzed N–H insertion to the synthesis of thienamycin. Advanced Synthesis and Catalysis ─ Carbene Chen

Ibata found in 1974 that decomposition of diazo compounds in Decomposition of diazo compounds in the presence of an the presence of a nearby gives carbonyl ylides allylic , halide, , or gives hetero ylides that that undergo 1,3-dipolar . This type of chemistry undergo sigmatropic rearrangement to give C–X insertion was later studied by Padwa extensively. products. Early studies under photo or thermal conditions leads to considerable cyclopropanation products. Krimse found in 1968 that copper carbenoids favor the of the heteroatom. The scope of this reaction was expanded by Doyle and later by Wood. Advanced Synthesis and Catalysis ─ Carbene Chen

Nitrene Du Bois later developed nitrene insertion chemistry for the synthesis of cyclic and guanidines. Bridged ligands were Breslow showed in 1982 that inter- and intramolecular C–H introduced as mechanistic studies indicated that ligand amination can be catalyzed by Mn(III)-tetraphenylporphyrin dissociation is the major pathway for catalyst decomposition.

(TPP), Fe(III)-TPP, or Rh2(OAc)4. Intermolecular nitrene C–H insertion at the benzylic and tertiary positions and catalytic asymmetric C–H amination with good levels of enantioselectivity have also been achieved.

Du Bois found in 2001 that both 1,2- and 1,3- functionalization can be achieved to form oxazolidinones and oxathiazinanes. Advanced Synthesis and Catalysis ─ Carbene Chen

Metathesis Calderon at Goodyear Tire & Rubber discovered that internal olefins exposed to hexachloride, ethylaluminum In addition to cyclopropanation and C–H insertion, metathesis dichloride and would undergo an interchange process. is another important metal carbenoid-catalyzed reaction that For example, the reaction of 2- gives a mixture of 2- has found wide applications in synthetic, macromolecular and , 2-pentene and 3-. Based on this observation, biological chemistry. First observed as a thermodynamic Calderon concluded that one carbon of the double bond of one reaction of olefins in 1956, Eleuterio at olefin, along with everything attached to it, exchanges place DuPont reported that passing propylene over a - with one carbon of the double bond of the other olefin, along on-aluminum catalyst gave a mixture of propylene, with everything attached to it. Further experiments with butene

and 1-butene that polymerize into a propylene-ethylene and 2-butene-d8 as well as 2-pentene and 6-dodecene copolymer. Furthermore, the polymer obtained from confirmed this conclusion. Mol also independently reached the “looked like somebody took a pair of scissors, same conclusion by studying the metathesis products of 14C- opened up cyclopentene, and neatly sewed it up again.” labeled . Meanwhile, Peters and Evering at Standard Oil found that propylene combined with molybdenum oxide on alumina treated with triisobutyl aluminum yields ethylene and butene. Banks and Bailey at Phillips Petroleum later reported the disproportionation of propylene to ethylene and butene using supported on alumina in 1964. Calderon coined the term “metathesis“, and proposed in 1968 a Natta also found in 1964 that cyclopentene polymerize in the three-step mechanism involving the formation of a metal- presence of tungsten or molybdenum halides. coordinated . Petti suggested the formation of a tetramethylene complex intermediate in 1971, and Grubbs a metallacyclopentane intermediate in 1972. Advanced Synthesis and Catalysis ─ Carbene Chen

Chauvin at the French Petroleum Institute proposed in 1971 The Chauvin mechanism involves the formation of a that is initiated by a metal carbenoid that “nonstabilized”, electron-rich metal carbenoid intermediate with reacts with an olefin to form a metallacyclobutane. This an α-hydrogen on the carbene ligand. Schrock demonstrated intermediate then breaks apart to form a new olefin and a new in 1974 that this type of complexes can be stable. metal carbenoid that propagates the reaction. This mechanism

was inspired by the report of carbenoid (CO)5W=C(CH3)(OCH3) by Fischer, ring-opening polymerization of cyclopentene by Natta, and disproportionation of propylene by Banks all in 1964.

Casey found in 1974 during studying cyclopropanation that

(CO)5W=CPh2 can react with isobutene to give 1,1- diphenylethene and 1-methoxy-1-phenylethylene. These experiments provided the key evidence for the metathesis reactivity of metal carbenoids. Advanced Synthesis and Catalysis ─ Carbene Chen

Katz studied in 1975 the kinetics of the Mo(PPh3)2Cl2(NO)2- Katz showed in 1976 that the Casey carbene (CO)5W=CPh2 is catalyzed metathesis of cyclooctene, trans-2-butene and trans- a well-defined catalyst for metathesis. No Lewis activator

4- in the presence of Me3Al2Cl3. Extrapolation of the is needed. He also delineated the “directional specificity”, i.e., product distribution to time zero suggest that the C14 product regioselectivity of metathesis of unsymmetrical olefins. was formed directly from the starting materials. This experiment rules out the mechanisms proposed by Calderon, Petti and Grubbs wherein the C14 diene would be a secondary product derived from the direct metathesis products.

It has been known since 1970s that Fischer carbenes catalyze polymerization of acetylenes and Katz predicted the feasibility of . Schrock reported in 1981 the first metal At the same time, Grubbs used deuterium labeled olefins to alkylidyne complex-catalyzed alkyne metathesis. Katz later track the exchange pattern of olefinic groups in metathesis. reported the first ene-yne metathesis in 1985. They found that the product distribution agrees with the Chauvin mechanism instead of the pairwise-type mechanism. Advanced Synthesis and Catalysis ─ Carbene Chen

Whereas sterically crowded high oxidation state “homoleptic” or The tantalum neopentylidene (Me3CCH2)3Ta=CHCMe3 is the “peralkyl” metal complexes lacking a β-hydrogen atom, for first example of a stable carbenoid of the

example, M[CH2Si(CH3)3]4, M(CH2C6H5)4, and M[CH2C(CH3)3]4 M=CHR type. The exact mechanism for the unprecedented (M = Ti, Zr, or Hf) are relatively stable as expected, it is intramolecular hydrogen abstraction remains unclear, but it is

intriguing that W(CH3)6 prepared by Wilkinson, unlike M(CH3)4 likely that one α-hydrogen is activated by (M = Ti, Zr, or Hf), is also stable. At the same time, Schrock with the metal. This Schrock carbene, unlike Fischer carbenes, studied the chemistry of high oxidation state peralkyl tantalum is highly electron-deficient and polarize in the way opposite to complexes that is relatively stable in its highest possible that of the Fischer carbenes. Further deprotonation gives the – oxidation state. He found that Ta(CH3)3Cl2 reacts with MeLi to neopentylidyne complex [(Me3CCH2)3Ta≡CCMe3] . The metal- give volatile, yellow, crystalline Ta(CH3)5. While much less methylene species Cp2Ta=CH2(CH3) can also be prepared stable than W(CH3)6, this unhindered, highly electron-deficient through deprotonation. This 18-electron complex decomposes 10-electron complex is much more stable than Hf(CH3)4, slowly at 25 ºC through a bimolecular pathway. decomposing above 0 ºC bimolecularly.

Inspired by Wilkinson’s report of a -bridged tantalum , Schrock probed the limit of steric crowding with the neopentyl ligand. Surprisingly, an orange, crystalline, and thermally stable carbene complex was formed in quantitative yield instead. Electron deficient tantalum and niobium alkylidenes react with olefins readily to give metalacyclobutane intermediates that rearrange via a β- process. The alkylidene chain reaction never started thus giving no metathesis products. Advanced Synthesis and Catalysis ─ Carbene Chen

Schrock later found that replacing the chloride ligand(s) with t- Extending the and neopentyl chemistry, Schrock butoxide gives catalytically active metathesis niobium and successfully prepared stable metal-alkylidyne complexes and tantalum complexes. He also showed that an 18-electron oxo demonstrated the catalytic activity toward alkyne metathesis. neopentylidene complex of tungsten generated from ligand The metallocyclbutadiene intermediate has been isolated and transfer gives an active metathesis complex, especially in the characterized by X-ray. He further showed that W≡W species

presence of a trace amount of AlCl3. undergo metathesis with alkyne and but not dinitrogen. Grubbs has also characterized by NMR and studied the reactivity of the metallocyclobutane obtained from reacting Tebbe’s reagent with isopentene or neohexene.

Based on these observations, Schrock determined that an isolable metathesis catalyst should have a neopentylidene ligand and two oxide ligands. Using hexafluoro-tert-butoxide dramatically increases the electrophilicity of the metal and thus the rate of the reaction of the metal complex with an olefin. Further replacement of the oxo ligand with an imido ligand that is sterically protected by a large R group prevents bimolecular decomposition. Advanced Synthesis and Catalysis ─ Carbene Chen

Schrock has also demonstrated that deprotonation of the amido Because Mo–L is generally weaker than W–L, replacing ligand and protonation of the metal neopentylidyne yields imido tungsten with molybdenum solves issues associated with slow neopentylidene complexes. X-ray analysis reveals that the release of olefin from unsubstituted tungstenacyclobutane. The anti-isomer with tert- pointing toward the imido metathesis reaction favored by the syn or anti isomer is case- ligand is favored. This reaction allows for easy introduction of dependent, and the rotation barrier of the alkylidene ligand can different imido ligands. be tuned by the electronic properities of the alkoxide ligand (by a factor of 106). The rotation is faster with tert-butoxide and slower with hexafluoro-tert-butoxide. Consequently, the metathesis rate and can be tuned by varying the alkoxide and the imido groups. Chiral Schrock catalysts with biaryl ligands have also been developed.

Regarding the cleavage of dinitrogen, certain bacteria catalyze fixation by a two-component metalloprotein system consisting an iron (Fe)-protein coupling hydrolysis of ATP to electron transfer and a molybdenum-iron (MoFe)-protein binding to dinitrogen. Shilov found several transition metal systems promoting the reduction of dinitrogen, and Cummins reported in 1995 a triamido molybdenum species that cleaves N≡N effectively to give N≡Mo through a bimetallic reaction. Advanced Synthesis and Catalysis ─ Carbene Chen

During the synthesis of polymeric ionophores by ring-opening To enable the large-scale synthesis of ruthenium metathesis metathesis polymerization (ROMP) of 7-oxo-, catalyst, Grubbs developed a new method based on the use of Grubbs found that ruthenium salts have better a diazo precursor and reported in 1995 the first air-stable, tolerance than the Schrock tungsten alkylidenes. Based on this “bench-top” catalyst. This “first generation” is observation, he developed the first class of metathesis highly reactive and decomposes in solution within several catalysts stable to protic solvents and compatible with aldehyde hours through biomolecular reactions. and groups. Switching the triphenylphosphine ligands to electron-rich trialkylphosphines significantly improved the reactivity and air-stability (days vs. minutes in the solid state). Because the rate of propagation is much faster than the rate of initiation, the resulting polymer has high molecular weight with broad distribution.

The affinity of electron-rich ruthenium center toward soft Lewis base (olefin) over hard Lewis base (oxygen) is responsible for its high tolerance to air and water. Strongly electron-donating ligands increase the activity of the Grubbs catalyst whereas the opposite is true for Schrock catalyst. Dissociation of one ligand is required to give the catalytically active 14- electron species, making bulky, basic trialkylphosphine ligands more effective than triphenylphosphine. Advanced Synthesis and Catalysis ─ Carbene Chen

The first generation Grubbs catalysts, while good for promoting Grubbs found in 1998 that Ru(H)(H2)Cl(PCy3)2 can be made ROMP, ring-closing metathesis (RCM) of disubstituted olefins, easily from Ru(cod)Cl2 and PCy3 under a hydrogen atmosphere, cross-metathesis (CM) of terminal olefins, and enyne and this hydrido complex reacts rapidly with propargylic halides metathesis, are much less active than the Schrock catalysts, in to give ruthenium vinylcarbenes. Werner later optimized this particular, for hindered substrates. Based on Herrmann’s work reaction to synthesize metathesis catalysts in one pot. Fürstner in 1998, Grubbs developed the “second generation” Grubbs further used this method to prepare ruthenium indenylidene catalyst with a NHC ligand that is highly active. Although the complexes that has good metathesis activities. initiation step is slower than the first generation catalyst, it has significantly greater affinity toward π-acidic olefins. Additionally, the strongly σ-donating NHC ligand stabilizes the Ru(IV) intermediate. The Hoveyda-Grubbs catalyst also has slow initiation rate but excellent stability. Replacing the phosphine ligand with a pyridine ligand leads to extremely fast initiation. This “third generation” Grubbs catalyst is particularly useful for to give polymers with low polydispersity. Advanced Synthesis and Catalysis ─ Carbene Chen

Schrock and Grubbs together showed in 1987 that the Schrock Fu and Grubbs expanded the synthetic utility of metathesis to t carbene W(CH Bu)(NAr)[OCMe(CF3)3] initiated rapidly living small- synthesis in 1994. Since then, RCM coupling polymerization of . Schrock later showed that with has since been a popular way to make ROMP of 2,3-bis(trifluoromethyl)norbonadiene catalyzed by a cyclic of various sizes. The scope of RCM in small- chiral Schrock catalyst with a 2,6-dimethyl substituted molecule synthesis has further been extended to alkyne phenylimido ligand gave a highly regular cis,isotactic polymer. substrates. Fürstner demonstrated in 1998 that alkyne RCM In addition, the cis,isotactic structure could be formed through coupled with partial hydrogenation offers expedient entry to enantiomorphic site control, and the trans,syndiotactic structure macrocycles with (Z)-olefins. He also found that the active t through chain-end control. catalyst can be generated in situ by reacting Ar3Mo=N Bu with CH2Cl2, and noted that terminal alkynes are not compatible with the Schrock catalysts.

Schrock also showed in 1994 that living copolymerization of diethyldipropargylmalonate (DEDPM) can proceed with two types of propagation mechanisms. The ratio of head-to-tail and tail-to-tail cyclopolymerization can be controlled by the choice of the catalyst. Advanced Synthesis and Catalysis ─ Carbene Chen

With the development of highly active and tolerant catalysts, Boehringer Ingelheim has used RCM to produce its HCV olefin metathesis has been used widely to synthesize complex protease inhibitor BILN 2061. Their first-generation process small-molecules. In particular, RCM has joined employing the Hoveyda–Grubbs catalyst has allowed for the and macrolactonization to become a “standard” method for production of >400 kg active pharmaceutical ingredient (API) by macrolide synthesis. RCM performed at 20 kg per batch scale giving no trace amount of the (E)-product.

In their second-generation process using Grela’s catalyst, the turnover frequency (TOF) is ~1000 times higher and the turnover number (TON) ~100 times higher. Performing this reaction at higher temperature suppresses dimerization due to favored reaction entropy change. This RCM reaction can be carried out at normal concentrations without scrupulous degassing. With a much lower catalyst loading, a silica pad and charcoal filtration is not needed to remove the dissolved ruthenium. The E-factor, the amount of waste for each unit of useful product obtained, is reduced from 370 to 52. Advanced Synthesis and Catalysis ─ Carbene Chen

In addition to olefin and alkyne metathesis, ene-yne metathesis Grubbs has systematically compared the reactivity and has also been used to create macrocyles as exemplified in functional group tolerance of different metathesis catalysts. Shair’s biomimetic synthesis of longithorone A. Common and medium sized rings can also be constructed easily by RCM. Phillps has also developed an elegant ROM/RCM strategy for natural product synthesis.

The selectivity rules of CM have also been outlined by Grubbs. Selective cross metathesis can be achieved with a wide variety of electron-rich, electron-deficient, and sterically bulky olefins when using a catalyst with appropriate activity. Advanced Synthesis and Catalysis ─ Carbene Chen

Simple modification of the steric or electronic properties such When an olefin with high reactivity reacts with an olefin with as changing a nearby protecting groups of an olefin often alters lower reactivity (sterically bulky or electron-deficient olefins), its reactivity and lead to selective CM. The reactivity of various selective cross metathesis can be achieved using feedstock olefins toward the first and second generation Grubbs catalysts stoichiometry as low as 1:1. By employing a metathesis and the Schrock catalyst has been summarized by Grubbs. catalyst with appropriate activity, selective cross metathesis can be achieved with a wide variety of electron-rich, electron- deficient, and sterically bulky olefins.

CM with two type I olefins gives a statistical mixture of products because the rates of homodimerization are similar, and the reactivities of both the homodimers and the cross products toward secondary metathesis are high. For example, CM reaction of allylbenzene with two equivalents cis-2-butene-1,4- diacetate gives the cross product in 80% yield with the first and second generation of Grubbs catalyst. As a homodimerization product of allyl acetate, cis-2-butene-1,4-diacetate provides two allyl acetate in CM. The higher (E/Z) ratio provided by the second generation Grubbs catalyst is presumably due to secondary metathesis. Advanced Synthesis and Catalysis ─ Carbene Chen

Selective CM occurs when a type I olefin reacts with a type II or The homodimerization of quaternary allylic olefins (type III) is type III olefin that has a significantly lower homodimerization negligible, but there is a background homodimerization of the rate. The homodimerization product of the type I olefin can unprotected tertiary substrates (type II) resulting in the undergo secondary metathesis with the type II/III olefin to give reduced CM yield. the cross-product; however, the cross-product will not undergo secondary metathesis to give an equilibrium mixture of products. The reaction of a type I and a type III olefin gives (E)- products exclusively.

CM between type II and type III olefins is selective but the yield is low because homodimerization of the type II olefins leads to a unreactive dimer. Differential reactivity of olefins allows for chemo- and regioselective CM, as well as three-component CM. Advanced Synthesis and Catalysis ─ Carbene Chen

Hoveyda and Schrock reported in 2009 the first (Z)-selective Grubbs found in 2011 that C–H insertion of the NHC ligand olefin metathesis catalyst. The free rotation around the Mo–O leads to a series of highly active and (Z)-selective catalysts. bond serves as the basis for high (Z)-selectivity. The flexibility The use of a instead of a carboxylate as the X-ligand of a sterically demanding aryloxide ligand in combination with results in significantly improved activity (~1000 TON) and a smaller imido ligand renders the reaction proceeding through selectivity. The chelation of the NHC ligand leads to olefin the syn alkylidene isomer and the all-cis metallacyclobutane side-bound instead of the traditional bottom-bound mechanism. intermediate. They first used this Mo-chirogenic catalyst to Resolution of the Ru-chirogenic complexes for enantioselective achieve (Z)- and enantioselective ring-opening/cross metathesis was achieved by using a chiral carboxylate ligand. metathesis (ROCM) and later direct CM. Performing RCM in the presence of ethylene promotes of the (Z)-macrocyclic products to give pure (E)- products. Jensen and Hoveyda have both developed other (Z)- selective ruthenium metathesis catalysts. Advanced Synthesis and Catalysis ─ Carbene Chen

The first asymmetric metathesis was reported by Grubbs in Grubbs reported the first chiral ruthenium metathesis catalyst in

1996 despite low krel in kinetic resolution of dienes by RCM. 2001 using a C2-diphenylethylenediamine-derived NHC ligand. Hoveyda later developed new chiral catalysts to achieve high Subsequently, Hoveyda introduced chiral biaryl NHC-alkoxide

krel in kinetic resolution and high ee in desymmetrization. system in 2002. Blechert reported a new chiral NHC-ruthenium catalyst that offers excellent E selectivity and enantioselectivity in asymmetric ring-opening cross metathesis in 2010.