Reactive Intermediate Chemistry

only (E )

ð10Þ

Diazocarbonyl compounds are optimum for these transformations, and they may be readily prepared by a variety of methods. The use of iodonium ylides (17) has also been developed,34 but they exhibit no obvious advantage for selectivity in carbene-transfer reactions. Enantioselection is much higher with diazoacetates than with diazoacetoacetates (18).

2.2. Stable Transition Metal Carbene Complexes

In contrast to transition metal carbene complexes generated catalytically, those of the early transition metals are generally stable (Fischer-type carbenes) and undergo

570 SYNTHETIC CARBENE AND NITRENE CHEMISTRY

major advance in this field—ring-closing metathesis (Eq. 16).11c,d,45 Here the low reactivity of unstrained olefins toward ring-opening metathesis is a major

CH2

consideration in the synthetic viability of the process. The formation of five-, six-, or seven-membered rings, and even macrocyclic compounds, can be made to occur with the appropriate catalysts (Eqs. 17,46 1847).

As indicated by the examples, ruthenium catalysts 5–7 can be used for compounds containing a broad range of functional groups, especially those containing oxygen, and they are also tolerant to water. The greater challenge is the use of these catalysts for ‘‘cross-metathesis’’ for which SHOP (Eq. 15) is one example, and Eq. 1948 represents a recent success.

92% [>20:1 (E/Z )]

2.4. Other Alkylidenes

There is a variety of reagents that undergo carbene-related transformations that do not fit into the categories of nucleophilic and electrophilic metal carbenes described earlier. Those that are the most versatile for organic synthesis, like the Tebbe

reagent (19, Cp ¼ C5H5)49 or ‘‘Zn CH2’’ in the Simmons–Smith reaction,50 occur as adducts. Their reactions are typical of nucleophilic or electrophilic metal carbenes even though these intermediates may not ever be involved in the mechanism of the transformation.

The Tebbe reagent, first reported in 1978,51 has been used extensively for stoichiometric carbonyl oxygen replacement by methylene (e.g., Scheme 12.6 and Eq. 20).52 Aldehydes, ketones, esters, and even selected amides, undergo this transformation. And, since the Tebbe reagent is a source of the nucleophilic Cp2Ti CH2, ring-closing metathesis is the outcome when a second equivalent is used on the diene intermediate. Understanding the Tebbe reagent did, in fact, lead to a basic understanding of homogenous metathesis catalysts.53

Bn = benzyl

The Simmons–Smith reaction54 and its variants55 are widely used for the stereospecific synthesis of cyclopropane compounds. The methodology involves the use of copper-treated zinc metal (the zinc–copper couple) with diiodomethane to add methylene to a carbon– carbon double bond. Alternative use of diazomethane in catalytic reactions does not offer the same synthetic advantages and is usually avoided because of safety considerations.6 As significant as is the Simmons–Smith reaction for cyclopropane formation, its employment for organic synthesis was markedly advanced by the discovery that allylic and homoallylic hydroxyl groups accelerate and exert stereochemical control over cyclopropanation of alkenes56 (e.g, Eq. 21),57 and this acceleration has been explained by a transition state model

572 SYNTHETIC CARBENE AND NITRENE CHEMISTRY

(20 and 21) in which a Lewis acid (ZnX2) is associated to oxygen.50b,58 This latter understanding has allowed the redesign of the Simmons–Smith reaction for

optimum synthetic advantage (e.g., Eq. 22,59 2360). As noted, reagent modification provides significant control of reaction pathway and selectivity. Enantiocontrol is possible with the use of chiral catalysts such as 22.60

E = Br, I, D (85–95% yield)

ð22Þ

i-PrO Oi-Pr

TADDOL-Ti(Oi-Pr)2

22

3. SYNTHETIC ADVANTAGES OF METAL CARBENES

3.1. Applications of Catalytic Methods with Diazo Compounds

The nature of the diazo compound and the identity of the catalyst are important variables for the success of these transformations.6 Catalytic methods are not

successful with simple diazo compounds such as CH2N2 or aliphatic diazo compounds because of a variety of competing reactions. However, diazocarbonyl compounds, which are easy to prepare and handle,61 offer an abundance of uses for organic synthesis. Their reactivity for diazo decomposition is dependent on the number and nature of the groups that stabilize the diazo unit (Scheme 12.7). Ethyl diazoacetate, which is available commercially, has been investigated to the greatest extent, but phenyland vinyldiazoacetates have provided a wealth of pathways not available with the simpler diazo compounds.

Scheme 12.7

3.1.1. Cyclopropanation and Cyclopropenation. At this time, intermolecular cyclopropanation with alkyl diazoacetates is best accomplished with cobalt catalysts 1627 or 2362 to achieve high enantiocontrol with high selectivity for the formation of the trans-disubstituted cyclopropane isomer (Eq. 24). To form the

23

cis-disubstituted cyclopropane isomer, the use of 14 (M ¼ Co) gives optimum results for diastereocontrol and enantiocontrol.63 Enantioselectivity for intramolecular cyclopropanation of allyl diazoacetates is best achieved with chiral dirhodium(II) carboxamidate catalysts ( 94% ee, e.g., Eq. 7),6,28 and chiral dirhodium(II) carboxylates give the highest enantioselectivities for intermolecular cyclopropanation reactions of phenyldiazoacetates (e.g., Eq. 25).23,31 The lesson here is that different chiral catalysts exhibit different selectivities for different applications. The selectivities are often based on the barriers to the approach of the

(E /Z ) = > 95:5 92% ee

carbon–carbon double bond to the metal carbene center (e.g., 24 and 25, where L is a linker), and the outcome is becoming predictable.64 For example, copper catalysts

H

HO

prefer 24, whereas rhodium catalysts prefer approach 25. Applications in total synthesis include the synthesis of the antidepressant sertraline (26),65 the cyclopropane– NMDA receptor antagonist milnacipran (27),66 and sirenin (28).67

H NHMe

The addition to a carbon– carbon triple bond results in the formation of cyclopropene products, and with diazoacetates the catalyst of choice for intermolecular addition is the dirhodium(II) carboxamidate 13 (e.g., Eq. 26).68 The reactions are general, except for phenylacetylene whose cyclopropene product undergoes [2 þ 2]-cycloaddition, and selectivities are high. However, high selectivities have not been reported for reactions with allenes.

Intramolecular cyclopropanation reactions are not limited to the formation of fiveto seven-membered rings, as once believed. They occur with high stereocontrol and yield for reactions that produce large rings.69 Intramolecular cyclopropenation is also a facile process with ring sizes of 10 or higher. High levels of enantiocontrol can be achieved in these reactions with catalysts appropriate to

the transformation (e.g., Eqs. 2770, 2871). Note that the choice of catalyst (Eq. 28) can influence chemoselectivity as well as stereoselectivity. As the length of the chain increases, selectivity approaches outcomes that can be predicted from intermolecular reactions.