Recent Advances in Asymmetric Catalytic Metal Carbene Transformations

Doyle, Michael P.; Forbes, David C.

doi:10.1021/cr940066a

Cited by 1,301 publications

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“…The highly reactive carbenoid species then inserts into a C-H bond to form the C-H activation product and liberates the metal catalyst for another cycle. The challenges of regioselectivity associated with the carbeneinduced C-H functionalization meant that most of the early advances in this field were achieved in systems capable of intramolecular reactions [21][22][23] . Because the rhodium carbenoid and the reacting C-H bond are connected by a suitable tether, they are brought into close proximity, leading to a favourable regioselective transformation.…”

Section: C-h Functionalization By Metal Carbenoidsmentioning

confidence: 99%

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Davies

Manning

2008

Nature

2,147

812

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Novel reactions that can selectively functionalize carbon-hydrogen bonds are of intense interest to the chemical community because they offer new strategic approaches for synthesis. A very promising 'carbon-hydrogen functionalization' method involves the insertion of metal carbenes and nitrenes into C-H bonds. This area has experienced considerable growth in the past decade, particularly in the area of enantioselective intermolecular reactions. Here we discuss several facets of these kinds of C-H functionalization reactions and provide a perspective on how this methodology has affected the synthesis of complex natural products and potential pharmaceutical agents.I n 2006, 31 new chemical entities were introduced to the world pharmaceutical market and 2,075 molecules were in phase I or II of clinical development 1 . The majority of these were smallmolecule (relative molecular mass ,1,000) organic compounds 2 . As knowledge about the specific interactions of drugs in vivo increases, often so does the structural complexity of new drug targets. A major obstacle to the development of such drugs is the difficulty associated with synthesizing large quantities in an economical fashion, because complex multi-step syntheses are usually required. In the general media, it is often overlooked that the accessibility of the components required for these new treatments will often govern their eventual success or failure. Likewise, a design element of any pharmaceutical agent is the expectation that the target compounds can be made economically. Therefore, new strategies for synthesis can become enabling technologies, making available new targets and materials that would have been previously out of range. For example, new methodologies such as metal-catalysed crosscoupling 3 and olefin metathesis 4-6 have rapidly become central transformations in the synthesis of new pharmaceutical agents. Selective C-H functionalization is a class of reactions that could lead to a paradigm shift in organic synthesis, relying on selective modification of ubiquitous C-H bonds of organic compounds instead of the standard approach of conducting transformations on pre-existing functional groups. The reactive sites in each type of transformation are very different, as illustrated in Fig. 1.The many opportunities associated with C-H functionalization has made this field an active area of research. Organometallic chemists have focused much attention on developing 'C-H activation' strategies, whereby a highly reactive metal complex inserts into a C-H bond, activating the system for subsequent transformations 7-9 . One of the major challenges associated with this chemistry has been to render it catalytic in the metal complex 10 . A partial solution to this problem has been to use neighbouring functionality to direct less reactive metal complexes to the site for functionalization. Numerous reviews have been written about this method for C-H functionalization [11][12][13][14][15][16][17] . Here, however, we highlight another approach, in which a divalent c...

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Section: C-h Functionalization By Metal Carbenoidsmentioning

confidence: 99%

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Davies

Manning

2008

Nature

2,147

812

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“…A two‐step hydrolysis of the orthoester then gave the unstable epoxy acid 8 , which was immediately coupled to TMS‐diazomethane to afford the diazoketone 9 . As a key design element, we envisaged coincident formation of the bicyclo[4.1.0]heptane core and the all‐carbon quaternary center at C6 through an intramolecular rhodium‐carbenoid cycloaddition reaction 17. In contemplating the stereochemical outcome of this annulation event ( 9 → 10 ), it was expected that the transition‐state structure leading to the l ‐ altro cyclopropane (not shown) would involve considerable strain and, consequently, that this process should favor formation of the desired d ‐ galacto ‐configured 10 .…”

mentioning

confidence: 99%

“…In contemplating the stereochemical outcome of this annulation event ( 9 → 10 ), it was expected that the transition‐state structure leading to the l ‐ altro cyclopropane (not shown) would involve considerable strain and, consequently, that this process should favor formation of the desired d ‐ galacto ‐configured 10 . We were delighted then that our initial attempts to effect the intramolecular cycloaddition17 by using Rh 2 (OAc) 4 in anhydrous18 CHCl 3 delivered a mixture of the desired cyclopropane 10 and the unexpected C−H insertion product 11 ( 10 / 11 =2:1). While reaction in benzene afforded a 1:1 mixture of cyclopropane 10 / 11 , in CH 2 Cl 2 , an acceptable 3:1 mixture of these compounds was produced in around 60 % yield 19.…”

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confidence: 99%

Structural Snapshots for Mechanism‐Based Inactivation of a Glycoside Hydrolase by Cyclopropyl Carbasugars

et al. 2016

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Glycoside hydrolases (GHs) have attracted considerable attention as targets for therapeutic agents, and thus mechanism‐based inhibitors are of great interest. We report the first structural analysis of a carbocyclic mechanism‐based GH inactivator, the results of which show that the two Michaelis complexes are in 2H3 conformations. We also report the synthesis and reactivity of a fluorinated analogue and the structure of its covalently linked intermediate (flattened 2H3 half‐chair). We conclude that these inactivator reactions mainly involve motion of the pseudo‐anomeric carbon atom, knowledge that should stimulate the design of new transition‐state analogues for use as chemical biology tools.

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“…[1][2][3] The intermolecular cyclopropanation reaction of styrene, 1, with ethyl diazoacetate is frequently used as a model reaction to measure the stereo-and enantioselectivity of the new catalyst (Scheme 1).…”

mentioning

confidence: 99%

“…In general, chiral dirhodium(II) catalysts do not provide high selectivities. 10 Dirhodium(II) catalysts of general formula Rh 2 (O 2 CR) 2 (PC) 2 , containing two ortho-metalated aryl phosphines (PC) in a head to tail arrangement, 11 (Figure 1), have backbone chirality and they can be isolated as pure enantiomers by conventional resolution methods. 12 We have recently reported some of these dirhodium(II) catalysts as the most enantioselective among dirhodium(II) catalysts, giving enantioselectivities up to 91% and up to 87%, for ethyl cis-and trans-2-phenylcyclopropanecarboxylate, respectively.…”

mentioning

confidence: 99%

Enantio- and diastereocontrol in intermolecular cyclopropanation reaction of styrene catalyzed by dirhodium(ii) complexes with bulky ortho-metalated aryl phosphines

et al. 2004

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Enantiomerically pure dirhodium(II) complexes with orthometalated p-substituted aryl phosphines have been shown to be enantio-and diastereoselective in the cyclopropanation of styrene by ethyl diazoacetate. Enantioselectivities up to 91% and diastereoselectivities up to 90% are observed for ethyl cis-2-phenylcyclopropanecarboxylateThe design of new chiral catalysts to induce enantiocontrol in carbene transfer reactions is presently a subject of interest. [1][2][3] The intermolecular cyclopropanation reaction of styrene, 1, with ethyl diazoacetate is frequently used as a model reaction to measure the stereo-and enantioselectivity of the new catalyst (Scheme 1).Chiral copper catalysts, 4-8 especially those with bis-oxazoline ligands, have been found to induce the highest levels of enantiocontrol. Thus, enantioselectivities up to 99% for ethyl 2-phenylcyclopropanecarboxylates have been obtained in the cyclopropanation of styrene with ethyl diazoacetate catalyzed by Cu catalysts. Ruthenium catalysts have also produced high level of enantiocontrol in the cyclopropanation of olefins, 9 but their carbenoids are less reactive than those of copper. In general, chiral dirhodium(II) catalysts do not provide high selectivities. 10 Dirhodium(II) catalysts of general formula Rh 2 (O 2 CR) 2 (PC) 2 , containing two ortho-metalated aryl phosphines (PC) in a head to tail arrangement, 11 (Figure 1), have backbone chirality and they can be isolated as pure enantiomers by conventional resolution methods. 12 We have recently reported some of these dirhodium(II) catalysts as the most enantioselective among dirhodium(II) catalysts, giving enantioselectivities up to 91% and up to 87%, for ethyl cis-and trans-2-phenylcyclopropanecarboxylate, respectively. 13 However, these catalysts induce low diastereoselectivities, about 60:40 or lower.According to the transition state model proposed for the cyclopropanation reaction of styrene catalysed by enantiomers of Rh 2 (O 2 CR) 2 (PC) 2 , 13 the presence of bulky substitutents on the metalated ring might improve the diastereocontrol of the catalyst. In order to probe such hypothesis we have studied four dirhodium(II) catalysts with different substituents in the para positions of the aryl groups. These catalysts are represented in Fig. 1.Catalysts 5 and 7 were prepared by standard methods 14 from the reaction of rhodium tetraacetate and the corresponding phosphines.Catalyst 6 was prepared according to the method reported in the literature. 13 We now report the catalytic results obtained in the cyclopropanation of styrene with ethyl diazoacetate using catalysts 5-7 following the procedure described in ref. 13. These results are compared in Table 1 with those previously reported using catalyst 4.As indicated in Fig. 1, all these catalysts contain different groups in the para position of all the aryl groups of the phosphine. The influence of the substituents on the diastereoselectivities of the cyclopropanation reaction is clear, increasing with the size of the substituent Br v Me 3 C v Me 3 Si, w...

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Recent Advances in Asymmetric Catalytic Metal Carbene Transformations

Cited by 1,301 publications

References 187 publications

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Structural Snapshots for Mechanism‐Based Inactivation of a Glycoside Hydrolase by Cyclopropyl Carbasugars

Enantio- and diastereocontrol in intermolecular cyclopropanation reaction of styrene catalyzed by dirhodium(ii) complexes with bulky ortho-metalated aryl phosphines

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