Dirhodium carboxamidate

The use of chiral dirhodium carboxamidates has made possible the highly enantioselective synthesis of presqualene alcohol (4) from farnesyl diazoacetate (14) through cyclopropane 15 [9] (Eq. 1). Highly enantiomerically en-... 

The use of chiral dirhodium carboxylate, 17 or 18, is preferred over chiral dirhodium carboxamidates for chemical transformations of a-diazo-p-ketocarbonyl compounds primarily because of reactivity considerations, that is, these diazo compounds do not undergo dinitrogen loss with the carboxamidate catalysts even at elevated temperatures. In addition, the orientation of the chiral ligands in 17 and 18 provides closer access to bulky diazo compounds. When the two attachments to the di azomethane unit are vastly unequal in size, high levels of enantiocontrol can result. 

Although exceptional diastereocontrol and enantiocontrol can now be achieved in C-H insertion reactions of catalytically generated metal carbenes, further improvements are needed. Insertion into tertiary C-H bonds occurs with diminished enantiocontrol and regiocontrol [131,132], In addition, chiral dirhodium carboxamidates do not react with a-diazo-p-ketocar-bonyl compounds. Thus, the potential for their impact on a broad range of C-H insertion processes is yet to be tested. 

Diazoacetamides are also exceptional substrates for dirhodium carboxamidate-catalyzed reactions, although with these substrates a mixture of /3-lactam and y-lactam products are formed [8]. The rhodium carboxamidate catalyst can have a major effect on the ratio of products formed. A good synthetic example is the Rh2(4S-MPPIM)4)-catalyzed synthesis of (-)-hcliotridanc 11 (Scheme 5) [9]. The key C-H insertion step of 9 generated the indolizidine 10 in 86 % yield and 96 % de, whereas reaction of 9 with achiral catalysts tended to favor the opposite diaster-eomer. 

Chiral dirhodium carboxamide complexes have attracted considerable interest as enantioselective catalysts [13]. As model reactions the Si-H insertion of methyl phenyldiazoacetate (I) with dimethylphenylsilane (2) (reaction (1)) as well as the cyclopropanation of styrene (4) with diazoacetates (5a/b) (reaction (2)) were investigated (scheme 2). 

Dirhodium carboxamidates are effective catalysts for aziridination reactions most likely due to their low oxidation potentials, for example, dirhodium caprolactamate Rh2(cap)4 (53) successfully catalyzes the aziridination of olefins. To this effect, the use of / -toluenesulfonamide (TsNH ), N-bromosuccinimide (NBS), and potassium carbonate affords aziridines in high yields (95%), under extremely mild conditions (Scheme 9.14). It is postulated that the reaction proceeds via the mixed-valence dirhodium(II,III) complex Rhjlcapl CllOHCHj) (54), which was synthesized (Scheme 9.15 NCS = chlorosuccinimide) and characterized by X-ray crystallography (Figure 9.19) [139]. 

Chiral dirhodium(II) carboxamidate catalysts are, by far, the most effective for reactions of allylic diazoacetates [44, 45] and allylic diazoacetamides [46]. Product yields are high, catalyst loading is low (less than 1 mol%), and enan-tioselectivities are exceptional (Scheme 6). The catalysts of choice are the two... 

Although dirhodium(II) carboxamidates are less reactive toward diazo decomposition than are dirhodium carboxylates, and this has limited their uses with diazomalonates and phenyldiazoacetates, the azetidinone-ligated catalysts 11 cause rapid diazo decomposition, and this methodology has been used for the synthesis of the cyclopropane-NMDA receptor antagonist milnacipran (17) and its analogs (Eq. 2) [10,58]. In the case of R=Me the turnover number with Rh2(45-MEAZ)4 was 10,000 with a stereochemical outcome of 95% ee. 

Addition to a carbon-carbon triple bond is even more facile than addition to a carbon-carbon double bond, and there are now several reports of intermolec-ular [71] and intramolecular reactions [72-74] that produce stable cyclopropene products with moderate to high enantioselectivities. One of the most revealing examples is that shown in Scheme 9 [72] where the allylic cyclopropanation product (30) is formed by the less reactive Rh2(MEPY)4 catalyst, but macrocy-clization is favored by the more reactive Rh2(TBSP)4 and Rh2(IBAZ)4 catalysts and, as expected, the highest enantioselectivities are derived from the use of chiral dirhodium(II) carboxamidate catalysts. 

It is noteworthy that, in the carboxamidate-ligated dirhodium(II) complexes (86), (87), and (89), the rhodium core is coordinated by four ligands and two N and two O atoms are bound to each rhodium center, constituting a unique coordination sphere (Figure 10).225... 

Activation of a C-H bond requires a metallocarbenoid of suitable reactivity and electrophilicity.105-115 Most of the early literature on metal-catalyzed carbenoid reactions used copper complexes as the catalysts.46,116 Several chiral complexes with Ce-symmetric ligands have been explored for selective C-H insertion in the last decade.117-127 However, only a few isolated cases have been reported of impressive asymmetric induction in copper-catalyzed C-H insertion reactions.118,124 The scope of carbenoid-induced C-H insertion expanded greatly with the introduction of dirhodium complexes as catalysts. Building on initial findings from achiral catalysts, four types of chiral rhodium(n) complexes have been developed for enantioselective catalysis in C-H activation reactions. They are rhodium(n) carboxylates, rhodium(n) carboxamidates, rhodium(n) phosphates, and < // < -metallated arylphosphine rhodium(n) complexes. 

Chiral dirhodium(II) catalysts with carboxylate or carboxamidate ligands have recently been developed to take advantage of their versatility in metal carbene transformation, and these have now become the catalysts of choice for cyclopropanation. Chiral carboxylate ligands 195,103 196,104 and 197105 have been used for tetrasubstitution around a dirhodium(II) core. However, the enantioselectivity in intermolecular reactions with simple ketenes is marginal. 

Chiral Dirhodium(ll) Carboxamidates for Asymmetric Cyclopropanation and Carbon-Hydrogen Insertion Reactions... 

Chiral dirhodium(II) carboxamidates are preferred for intramolecular cyclopropanation of allylic and homoallylic diazoacetates (Eq. 2). The catalyst of choice is Rh2(MEPY)4 when R " and R are H, but Rh2(MPPIM)4 gives the highest selectivities when these substituents are alkyl or aryl. Representative examples of the applications of these catalysts are listed in Scheme 15.1 according to the cyclopropane synthesized. Use of the catalyst with mirror image chirality produces the enantiomeric cyclopropane with the same enantiomeric excess [33]. Enantioselectivities fall off to a level of 40-70% ee when n is increased beyond 2 and up to 8 (Eq. 2) [32], and in these cases the use of the chiral bisoxazoline-copper complexes is advantageous. 

Diazoacetamides undergo intramolecular cyclopropanation with similarly high enantios-electivities (Eq. 4) [33, 36, 37]. In these cases, however, competition from intramolecular dipolar cycloaddition can compHcate the reaction process. Therefore, the use of R = Me or Bu has been required to achieve good yields of reaction products. Representative examples of applications of chiral dirhodium(II) carboxamidates for enantioselective intramolecular cyclopropanation of diazoacetamides are compiled in Scheme 15.2. 

Scheme 15.8 Diastereocontrol in C-H insertion reactions with chiral dirhodium(II) carboxamidate catalysts.

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

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