Advanced Synthesis and Catalysis ─ Carbene Chen · dienophiles. The Diels–Alder reaction...

Advanced Synthesis and Catalysis ─ Carbene

Free carbene

Carbenes can exist in either singlet or triplet state whereas the

ground state of nitrene is always singlet. If there is a large gap

between the σ and p orbitals of the carbene, the ground state

will be singlet due to the relatively lower energy cost in electron

pairing. Carbenes with a p-donor atom (N, O, or halogen) can

also promote electron pairing.

Chen

Carbenes can be generated by α-elimination or decomposition

of ketene, diazo, or diazirine compounds. Carbenes can also

be generated by thermolysis. Flash vacuum pyrolysis (FVP)

allows heating the reactant at very high temperature for a short

period of time, typically > 500 ºC for 0.01 s in gas phase.

Carbene is normally unstable and undergoes rearrangement

readily.

Carbenes can also be formed by Bamford–Stevens reaction in

aprotic solvents. In protic solvents, the carbenium ion is formed

instead. This reaction is mechanistically similar to the Shapiro

reaction that generates vinyl carbanion.

In Wolff rearrangement and the Arndt–Eistert homologation,

carbene is generated by decomposition of diazoketone

promoted by photolysis or Ag(I) or Cu(II) catalysts.

Chen

The Corey–Fuch reaction is also a one-carbon homologatioin

reaction that generates terminal alkyne from aldehyde through

a vinylidene–acetylene rearrangement. The Seyferth–Gilbert

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 nucleophile by deacetylation under

milder conditions.


Skattebøl rearrangement generates a carbene from

dibromocyclopropane. Subsequent rearrangement yields

allene. When an adjacent olefin is present, cyclopentadiene is

formed.

Buchner reaction is a method for seven-membered ring

synthesis via ring-expansion. Cyclopropanation of a six-

membered aromatic ring with diazo compounds followed by a

rearrangement gives cycloheptatrienes.

Chen

Thiamine (vitamine B1) is a N-heterocyclic carbene (NHC) that

catalyzes benzoin condensation. This organocatalysis reaction

was first documented more than six decades ago, and the

mechanism of this umpolung reaction was established by

Breslow.


Various NHC catalysts, including chiral versions, have been

developed. The scope of this carbonyl umpolung reaction has

also been explored extensively. Stetter demonstrated in 1976

that thiazolium-catalyzed nucleophilc addition also work with

Michael acceptors. Both intra- and intermolecular variants of

the Stetter reaction have been reported. Glorius also found

that cross-condensation of aldehydes/imines with enals gives

γ- or β-lactones depending on the reaction conditions.

Chen

Bode reported the use of NHC to catalyze internal redox of

epoxyaldehyde to generate activated carboxylate for

esterification. He has further shown that NHC can catalyze

asymmetric Diels-Alder reaction of azadienes and electron-

deficient enals.



Metal carbenoid

The reactivity of metal carbenoids is largely determined by the

π-donor ability of the carbene ligand. Metal carbenoids with

substituents capable of π-interactions, for example, N, O, Cl,

and Ph, are call Fischer carbenes. These electrophilic

complexes react with nucleophiles through the coordinating

carbon of the singlet carbene ligand. Metal carbenoids without

these substitutions, for example, methylene and alkylidene,

require substantial π-donation from the meal are called

Schrock carbene. These nucleophilic complexes react with

electrophiles through the coordinating carbon of the triplet

carbene ligand. However, reversed reactivity has been

observed. For example, methylene ligands on a positively

charged metal complex can be electrophilic.

Chen

Fischer carbenes are typically prepared by electrophilic O-

alkylation of acyl complexes that was synthesized by

nucleophilic alkylation of carbonyl complexes. Cationic

carbenoids can be prepared by alkylation or protonation of

neutral acyl complexes.

Schrock carbenes are typically prepared by removal of an α

hydrogen from an alkyl 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 metals.


Dötz discovered in 1975 that Fischer carbenes can react with

alkyne to give naphthols. Increasing the electrophilicity of the

carbenoids leads to more reactive complexes. The order of

reactivity is :CPh2 > :C(OR)Ph > :C(NR2)Ph and CO >> PR3,

but the reactivity is suppressed when performing the reaction in

the presence of excess CO. Terminal alkynes react to yield 2-

substituted naphtols selectively whereas internal alkynes react

with low regioselectivity.

Chen

Wulff has extended the scope of Dötz reaction to vinyl Fischer

carbenes. Vinyl and alkynyl Fischer carbenes are also good

dienophiles. The Diels–Alder reaction product of alkynyl

Fischer carbenes is a vinyl Fischer carbene that can participate

in Dötz reaction.


In addition to participating in Dötz reaction, Fischer carbenes

can react with alkynes to give indenes, enones, or pyrones.

Chen

Fischer carbenes can also react with C=X groups through

ketene-type chemistry 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.


Schrock carbenes can be viewed as the metal version of Wittig

reagents but much more reactive because of the oxophilicity of

the metal. In addition to aldehydes, they also react with esters

and amides to give enol ethers and enamides. The most useful

carbene for this type of reaction is the Tebbe’s reagent

Cp2TiCH2ClAlMe2. In the presence of pyridine, Tebbe’s

reagent is synthetically equivalent to Cp2Ti=CH2.

Chen

Tebbe’s reagent is also very reactive toward olefins, forming

stable metallacylces in the presences of base. These

metallacycles readily exchange with other olefins via

metathesis to give new metallacycles.

Fischer carbenes can react with olefins to form cyclopropanes

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 diazomethane.

Simmons–Smith cyclopropanation reaction can be directed by

polar functional groups. The generally accepted mechanism,

however, does not involve copper that consists up to 10% of

the alloy. The activation of Zn by Cu possibly at the surface of

the alloy is essential to this reaction. The use of Et2Zn/CH2I2 to

generate the carbenoid suppresses polymerization. Various

chiral auxiliaries and additives have been developed to effect

asymmetric cyclopropanation.

Chen

Copper(I), cobalt(II), palladium(II), irridium(III), ruthenium(II) and

rhodium(0/II) complexes can all catalyze the decomposition of

diazo compounds to give carbenoids that cyclopropanate

olefins. Doyle has demonstrated the intermediacy of metal

carbenoid and the coordination of olefin to metal. One or two

electron-withdrawing or vinyl/aryl groups are typically used to

stabilize the diazo compounds. Asymmetric cyclopropanation

was first achieved by Evans using the Cu-BOX catalyst system.

In addition to diazos, phenyliodonium ylides can also be used

as the carbene source.



In addition to cyclopropanation, metal carbenoids are also

highly reactive toward C–H and X–H insertion. The distribution

of the products can be controlled by the catalyst ligands.

Intramolecular C–H insertion generally gives five-membered

ring products. Researchers at Merck successfully applied the

rhodium-catalyzed N–H insertion to the synthesis of

thienamycin.

Chen

Doyle and Davies have each developed a chiral rhodium

catalyst system for asymmetric C–H insertion reactions.

Davies has also coupled C–H insertion with sigmatropic

rearrangement to establish allylic quaternary centers.

Ibata found in 1974 that decomposition of diazo compounds in

the presence of a nearby carbonyl group gives carbonyl ylides

that undergo 1,3-dipolar cycloaddition. This type of chemistry

was later studied by Padwa extensively.

Chen Advanced Synthesis and Catalysis ─ Carbene

Decomposition of diazo compounds in the presence of an

allylic sulfide, halide, amine, or ether gives hetero ylides that

undergo sigmatropic rearrangement to give C–X insertion

products. Early studies under photo or thermal conditions

leads to considerable cyclopropanation products. Krimse found

in 1968 that copper carbenoids favor the nucleophilic addition

of the heteroatom. The scope of this reaction was expanded by

Doyle and later by Wood.


Nitrene

Breslow showed in 1982 that inter- and intramolecular C–H

amination can be catalyzed by Mn(III)-tetraphenylporphyrin

(TPP), Fe(III)-TPP, or Rh2(OAc)4.

Du Bois found in 2001 that both 1,2- and 1,3- functionalization

can be achieved to form oxazolidinones and oxathiazinanes.

Chen

Du Bois later developed nitrene insertion chemistry for the

synthesis of cyclic ureas and guanidines. Bridged ligands were

introduced as mechanistic studies indicated that ligand

dissociation is the major pathway for catalyst decomposition.

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.


Metathesis

In addition to cyclopropanation and C–H insertion, metathesis

is another important metal carbenoid-catalyzed reaction that

has found wide applications in synthetic, macromolecular and

biological chemistry. First observed as a thermodynamic

disproportionation reaction of olefins in 1956, Eleuterio at

DuPont reported that passing propylene over a molybdenum-

on-aluminum catalyst gave a mixture of propylene, ethylene

and 1-butene that polymerize into a propylene-ethylene

copolymer. Furthermore, the polymer obtained from

cyclopentene “looked like somebody took a pair of scissors,

opened up cyclopentene, and neatly sewed it up again.”

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

molybdenum hexacarbonyl supported on alumina in 1964.

Natta also found in 1964 that cyclopentene polymerize in the

presence of tungsten or molybdenum halides.

Chen

Calderon at Goodyear Tire & Rubber discovered that internal

olefins exposed to tungsten hexachloride, ethylaluminum

dichloride and ethanol would undergo an interchange process.

For example, the reaction of 2-pentene gives a mixture of 2-

butene, 2-pentene and 3-hexene. Based on this observation,

Calderon concluded that one carbon of the double bond of one

olefin, along with everything attached to it, exchanges place

with one carbon of the double bond of the other olefin, along

with everything attached to it. Further experiments with butene

and 2-butene-d8 as well as 2-pentene and 6-dodecene

confirmed this conclusion. Mol also independently reached the

same conclusion by studying the metathesis products of 14C-

labeled propene.

Calderon coined the term “metathesis“, and proposed in 1968 a

three-step mechanism involving the formation of a metal-

coordinated cyclobutane. Petti suggested the formation of a

tetramethylene complex intermediate in 1971, and Grubbs a

metallacyclopentane intermediate in 1972.


Chauvin at the French Petroleum Institute proposed in 1971

that olefin metathesis is initiated by a metal carbenoid that

reacts with an olefin to form a metallacyclobutane. This

intermediate then breaks apart to form a new olefin and a new

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.

Chen

The Chauvin mechanism involves the formation of a

“nonstabilized”, electron-rich metal carbenoid intermediate with

an α-hydrogen on the carbene ligand. Schrock demonstrated

in 1974 that this type of complexes can be stable.

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.


Katz studied in 1975 the kinetics of the Mo(PPh3)2Cl2(NO)2-

catalyzed metathesis of cyclooctene, trans-2-butene and trans-

4-octene in the presence of Me3Al2Cl3. Extrapolation of the

product distribution to time zero suggest that the C14 product

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.

At the same time, Grubbs used deuterium labeled olefins to

track the exchange pattern of olefinic groups in metathesis.

They found that the product distribution agrees with the

Chauvin mechanism instead of the pairwise-type mechanism.

Chen

Katz showed in 1976 that the Casey carbene (CO)5W=CPh2 is

a well-defined catalyst for metathesis. No Lewis acid activator

is needed. He also delineated the “directional specificity”, i.e.,

regioselectivity of metathesis of unsymmetrical olefins.

It has been known since 1970s that Fischer carbenes catalyze

polymerization of acetylenes and Katz predicted the feasibility

of alkyne metathesis. Schrock reported in 1981 the first metal

alkylidyne complex-catalyzed alkyne metathesis. Katz later

reported the first ene-yne metathesis in 1985.


Whereas sterically crowded high oxidation state “homoleptic” or

“peralkyl” metal complexes lacking a β-hydrogen atom, for

example, M[CH2Si(CH3)3]4, M(CH2C6H5)4, and M[CH2C(CH3)3]4

(M = Ti, Zr, or Hf) are relatively stable as expected, it is

intriguing that W(CH3)6 prepared by Wilkinson, unlike M(CH3)4

(M = Ti, Zr, or Hf), is also stable. At the same time, Schrock

studied the chemistry of high oxidation state peralkyl tantalum

complexes that is relatively stable in its highest possible

oxidation state. He found that Ta(CH3)3Cl2 reacts with MeLi to

give volatile, yellow, crystalline Ta(CH3)5. While much less

stable than W(CH3)6, this unhindered, highly electron-deficient

10-electron complex is much more stable than Hf(CH3)4,

decomposing above 0 ºC bimolecularly.

Inspired by Wilkinson’s report of a carbyne-bridged tantalum

dimer, 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.

Chen

The tantalum neopentylidene (Me3CCH2)3Ta=CHCMe3 is the

first example of a stable transition metal carbenoid of the

M=CHR type. The exact mechanism for the unprecedented

intramolecular hydrogen abstraction remains unclear, but it is

likely that one α-hydrogen is activated by agostic interaction

with the metal. This Schrock carbene, unlike Fischer carbenes,

is highly electron-deficient and polarize in the way opposite to

that of the Fischer carbenes. Further deprotonation gives the

neopentylidyne complex [(Me3CCH2)3Ta≡CCMe3]–. The metal-

methylene species Cp2Ta=CH2(CH3) can also be prepared

through deprotonation. This 18-electron complex decomposes

slowly at 25 ºC through a bimolecular pathway.

Electron deficient tantalum and niobium alkylidenes react with

olefins readily to give metalacyclobutane intermediates that

rearrange via a β-hydride process. The alkylidene chain

reaction never started thus giving no metathesis products.


Schrock later found that replacing the chloride ligand(s) with t-

butoxide gives catalytically active metathesis niobium and

tantalum complexes. He also showed that an 18-electron oxo

neopentylidene complex of tungsten generated from ligand

transfer gives an active metathesis complex, especially in the

presence of a trace amount of AlCl3.

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.

Chen

Extending the alkoxide and neopentyl chemistry, Schrock

successfully prepared stable metal-alkylidyne complexes and

demonstrated the catalytic activity toward alkyne metathesis.

The metallocyclbutadiene intermediate has been isolated and

characterized by X-ray. He further showed that W≡W species

undergo metathesis with alkyne and nitrile 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.


Schrock has also demonstrated that deprotonation of the amido

ligand and protonation of the metal neopentylidyne yields imido

neopentylidene complexes. X-ray analysis reveals that the

anti-isomer with tert-butyl group pointing toward the imido

ligand is favored. This reaction allows for easy introduction of

different imido ligands.

Regarding the cleavage of dinitrogen, certain bacteria catalyze

nitrogen 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.

Chen

Because Mo–L is generally weaker than W–L, replacing

tungsten with molybdenum solves issues associated with slow

release of olefin from unsubstituted tungstenacyclobutane. The

metathesis reaction favored by the syn or anti isomer is case-

dependent, and the rotation barrier of the alkylidene ligand can

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 stereoselectivity can be tuned by varying

the alkoxide and the imido groups. Chiral Schrock catalysts

with biaryl ligands have also been developed.


During the synthesis of polymeric ionophores by ring-opening

metathesis polymerization (ROMP) of 7-oxo-norbornenes,

Grubbs found that ruthenium salts have better functional group

tolerance than the Schrock tungsten alkylidenes. Based on this

observation, he developed the first class of metathesis

catalysts stable to protic solvents and compatible with aldehyde

and ketone 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.

Chen

To enable the large-scale synthesis of ruthenium metathesis

catalyst, Grubbs developed a new method based on the use of

a diazo precursor and reported in 1995 the first air-stable,

“bench-top” catalyst. This “first generation” Grubbs catalyst is

highly reactive and decomposes in solution within several

hours through biomolecular reactions.

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

phosphine ligand is required to give the catalytically active 14-

electron species, making bulky, basic trialkylphosphine ligands

more effective than triphenylphosphine.


The first generation Grubbs catalysts, while good for promoting

ROMP, ring-closing metathesis (RCM) of disubstituted olefins,

cross-metathesis (CM) of terminal olefins, and enyne

metathesis, are much less active than the Schrock catalysts, in

particular, for hindered substrates. Based on Herrmann’s work

in 1998, Grubbs developed the “second generation” Grubbs

catalyst with a NHC ligand that is highly active. Although the

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

living polymerization to give polymers with low polydispersity.

Chen

Grubbs found in 1998 that Ru(H)(H2)Cl(PCy3)2 can be made

easily from Ru(cod)Cl2 and PCy3 under a hydrogen atmosphere,

and this hydrido complex reacts rapidly with propargylic halides

to give ruthenium vinylcarbenes. Werner later optimized this

reaction to synthesize metathesis catalysts in one pot. Fürstner

further used this method to prepare ruthenium indenylidene

complexes that has good metathesis activities.


Schrock and Grubbs together showed in 1987 that the Schrock

carbene W(CHtBu)(NAr)[OCMe(CF3)3] initiated rapidly living

polymerization of norbornene. Schrock later showed that

ROMP of 2,3-bis(trifluoromethyl)norbonadiene catalyzed by a

chiral Schrock catalyst with a 2,6-dimethyl substituted

phenylimido ligand gave a highly regular cis,isotactic polymer.

In addition, the cis,isotactic structure could be formed through

enantiomorphic site control, and the trans,syndiotactic structure

through chain-end control.

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.

Chen

Fu and Grubbs expanded the synthetic utility of metathesis to

small-molecule synthesis in 1994. Since then, RCM coupling

with hydrogenation has since been a popular way to make

cyclic molecules of various sizes. The scope of RCM in small-

molecule synthesis has further been extended to alkyne

substrates. Fürstner demonstrated in 1998 that alkyne RCM

coupled with partial hydrogenation offers expedient entry to

macrocycles with (Z)-olefins. He also found that the active

catalyst can be generated in situ by reacting Ar3Mo=NtBu with

CH2Cl2, and noted that terminal alkynes are not compatible with

the Schrock catalysts.


With the development of highly active and tolerant catalysts,

olefin metathesis has been used widely to synthesize complex

small-molecules. In particular, RCM has joined Wittig reaction

and macrolactonization to become a “standard” method for

macrolide synthesis.

Chen

Boehringer Ingelheim has used RCM to produce its HCV

protease inhibitor BILN 2061. Their first-generation process

employing the Hoveyda–Grubbs catalyst has allowed for the

production of >400 kg active pharmaceutical ingredient (API) by

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.


In addition to olefin and alkyne metathesis, ene-yne metathesis

has also been used to create macrocyles as exemplified in

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.

Chen

Grubbs has systematically compared the reactivity and

functional group tolerance of different metathesis catalysts.

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.

When an olefin with high reactivity reacts with an olefin with

lower reactivity (sterically bulky or electron-deficient olefins),

selective cross metathesis can be achieved using feedstock

stoichiometry as low as 1:1. By employing a metathesis

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.


Simple modification of the steric or electronic properties such

as changing a nearby protecting groups of an olefin often alters

its reactivity and lead to selective CM. The reactivity of various

olefins toward the first and second generation Grubbs catalysts

and the Schrock catalyst has been summarized by Grubbs.

Chen

The homodimerization of quaternary allylic olefins (type III) is

negligible, but there is a background homodimerization of the

unprotected tertiary alcohol substrates (type II) resulting in the

reduced CM yield.

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.


Selective CM occurs when a type I olefin reacts with a type II or

type III olefin that has a significantly lower homodimerization

rate. The homodimerization product of the type I olefin can

undergo secondary metathesis with the type II/III olefin to give

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.

Chen


Hoveyda and Schrock reported in 2009 the first (Z)-selective

olefin metathesis catalyst. The free rotation around the Mo–O

bond serves as the basis for high (Z)-selectivity. The flexibility

of a sterically demanding aryloxide ligand in combination with

a smaller imido ligand renders the reaction proceeding through

the syn alkylidene isomer and the all-cis metallacyclobutane

intermediate. They first used this Mo-chirogenic catalyst to

achieve (Z)- and enantioselective ring-opening/cross

metathesis (ROCM) and later direct CM.

Chen

Grubbs found in 2011 that C–H insertion of the NHC ligand

leads to a series of highly active and (Z)-selective catalysts.

The use of a nitrate instead of a carboxylate as the X-ligand

results in significantly improved activity (~1000 TON) and

selectivity. The chelation of the NHC ligand leads to olefin

side-bound instead of the traditional bottom-bound mechanism.

Resolution of the Ru-chirogenic complexes for enantioselective

metathesis was achieved by using a chiral carboxylate ligand.

Performing RCM in the presence of ethylene promotes

ethenolysis of the (Z)-macrocyclic products to give pure (E)-

products. Jensen and Hoveyda have both developed other (Z)-

selective ruthenium metathesis catalysts.


The first asymmetric metathesis was reported by Grubbs in

1996 despite low krel in kinetic resolution of dienes by RCM.

Hoveyda later developed new chiral catalysts to achieve high

krel in kinetic resolution and high ee in desymmetrization.

Chen

Grubbs reported the first chiral ruthenium metathesis catalyst in

2001 using a C2-diphenylethylenediamine-derived NHC ligand.

Subsequently, Hoveyda introduced chiral biaryl NHC-alkoxide

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.

Advanced Synthesis and Catalysis ─ Carbene Chen · dienophiles. The Diels–Alder reaction...

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Transcript of Advanced Synthesis and Catalysis ─ Carbene Chen · dienophiles. The Diels–Alder reaction...