Reactive Intermediate Chemistry

in organic synthesis. In most cases, the substrate to catalyst ratio is 100, but ratios up to 10,000 have been reported, so catalyst cost is not a major factor in potential pharmaceutical uses.

3.2. Synthetic Versatility of Fischer Carbene Complexes

Stoichiometric metal carbene reagents undergo reactions that typify those of their catalytic counterparts,7,9,97 but it is often the appendages and carbon monoxide

ligands of the metal that provide the synthetic versatility of these reagents. Both cyclopropanation (Eq. 40)98 and carbon–hydrogen insertion (Eq. 41)99 are well

H

H

known but, as expected from relative metal carbene stabilities, cyclopropanation is sluggish with Fischer carbenes, and they do not undergo C H insertion. As indicated by Eq. 41, the nonheteroatom stabilized metal carbenes are sufficiently reactive to undergo C H insertion.

The major direction taken with Fischer carbenes, however, has been annulation reactions (e.g., Eqs. 11–13) rather than cyclopropanation and insertion. Here, the dissociation of carbon monoxide initiates the sequence of events that lead to product (e.g., Eq. 42).100 Alternatively, an unsaturated unit conjugated with the carbene

ð42Þ

controls the reaction (e.g., Eq. 43).101 This is a mature area for synthesis and includes macrocyclization102 and [3þ2] cycloaddition.103

n-Pr

3.3. Synthetic Advantages of Ring-Closing Metathesis

Functional group tolerance and its suitability for ring formation of any practical size beyond four has made ring-closing metathesis (RCM) one of the most valuable synthetic methodologies now available. Examples include RCM directed toward the synthesis of natural products (37–39) as well as specific strategies for ring constructions based on RCM.104 Among the challenges that remain are stereoselectivity, and here use of the N-heterocyclic carbene-ligated ruthenium (7) shows considerable

promise (Eq. 44).108 Modest enantioselection has been achieved with use of 41 (Eq. 45),109 but much higher selectivities (up to 98% ee for 40)110 have been

ð45Þ

CH2Cl2

40: 85% ee

obtained with 42 and its biphenyl analogues (e.g., Eq. 46).111 Catalytic asymmetric ring-opening metathesis coupled with subsequent cross-metathesis has also been achieved in a clever transformation (Eq. 47)112 that takes advantage of the susceptibility of norbornene to ring opening.

up to 86% ee

New applications continue to demonstrate the enormous versatility of RCM for organic synthesis. Examples include triple ring closing (Eq. 48)113 and alkyne metathesis,114 an example being that of cross-metathesis that provides an efficient synthetic strategy for prostaglandin E2 (Eq. 49).115 Amines and alcohols deactivate metathesis catalysts, but their protection as ethers, esters, and amides allows them to be incorporated into the designated transformation.

t-Bu

N 3Mo

43

4. METAL NITRENES IN ORGANIC SYNTHESIS

If metal carbene chemistry can be said to be mature, metal nitrene chemistry is in its infancy. Although the first report of a catalytic process used benzenesulfonyl azide,116 high temperatures were required, and no one has yet provided a synthetically viable method to use azides as sources of nitrenes. Instead, iminophenyliodinanes (44), formed from the corresponding sulfonamide by oxidation with diacetoxyiodobenzene, PhI(OAc)2,117 and chloramine-T or bromamine-T (45) are the standard precursors for nitrenes.

Catalytic methods are suitable for nitrene transfer,118 and many of those found to be effective for carbene transfer are also effective for these reactions. However, 5- to 10-times more catalyst is commonly required to take these reactions to completion, and catalysts that are sluggish in metal carbene reactions are unreactive in nitrene transfer reactions. An exception is the copper(II) complex of a 1,4,7-triaza- cyclononane for which aziridination of styrene occurred in high yield, even with 0.5 mol% of catalyst.119 Both addition and insertion reactions have been developed.

584 SYNTHETIC CARBENE AND NITRENE CHEMISTRY

However, comparable transformations to those of stable Fischer carbenes are not available.

Copper catalysts were the first to be employed, and with the bis(oxazoline)- ligated catalyst 46 enantioselectivites up to 97% have been achieved (e.g., Eq. 50).120 In contrast to metal carbene reactions using diazo compounds, a,b- unsaturated substrates undergo reaction with the nitrene intermediate. In one study, the

induction of enantioselectivity is proposed to occur by ion pairing of the cationic copper catalyst (46) in a chiral pocket formed from the chiral borate formed with 1,10-bi-2-naphthol (BINOL).121 Chiral bis(salicylidene)ethylenediamine(salen) complexes (47) with CuOTf also gave high selectivities for aziridination.122 With

OTf

dirhodium(II) catalysts, the highest selectivities (50–75% ee) were achieved with

rhodium(II) bis(naphtholphosphate) 48 and the more reactive NsN IPh (Ns ¼ p-NO2C6H4SO2).123

O O

OP O 4Rh2

48

Thus far, enantioselective intramolecular aziridination via metal nitrene intermediates has not been successful. Bromamine-T has recently been shown to be a viable source of nitrene for addition to alkenes in copper halide catalyzed reactions,124 and so has iodosylbenzene (PhI O)125 that forms 44 in situ. Conceptually, aziridination does not necessarily fall between cyclopropanation and epoxidation, as some have suggested. Instead, metal nitrene chemistry has unique problems and potential advantages associated with the electron pair at nitrogen that are yet to be fully overcome.

The mechanism of the copper-catalyzed aziridination of alkenes using 44 as the nitrene source has been described with the steps shown in Scheme 12.10 contributing