Enantioselective Reactions of Carbenoids

There are three leading reviews on metal carbenoid transformation, written by Doyle (1986), by Brookhart and Studabaker (1987), and by Maas (1987). They include aspects of synthesis and of mechanism. The more recent reviews in Trost and Fleming s Comprehensive Organic Synthesis were written by Helquist (1991, use of diazoalkanes) and by Davies (1991, diazo carbonyl compounds). The review of Ye and McKervey (1994) on a-diazocarbonyl compounds also contains examples of metal carbenoid transformations. The book of Hegedus (1994) contains representative syntheses of complex organic molecules obtained by transition metal-catalyzed reactions of diazo compounds. 

The enormously increased activity in the organometallic chemistry of rhodium is reflected in the review of Sharp (1995). For the period 1981 -1992, Sharp found 20000 compounds with Rh — C bonds. He considered 2000 references and he gives 1319 formulae of stable rhodium complexes. His review does not include catalysis by transient Rh catalysts  

It is interesting to note that for the assymmetric formation of cyclopropanes of high enantioselectivity, the use of ketocarbenoids with chiral auxiliaries, e. g., diazoacetates as borneol or menthol esters, has been fairly common for a long time. 

A pioneering discovery was made, however, relatively early by Noyori s group (Nozaki et al., 1966, 1968 see also Noyori, 1990, 1994), which found some enantioselectivity ( 6 7o = enantiomeric excess) with the chiral copper catalyst 8.158. 

After additional work by various authors using more selective chiral copper catalysts in the late 1960 s and 1970 s (review Aratani, 1985), two very succesful copper catalysts and a useful cobalt complex were found by the groups of Matlin (8.159), Pfaltz (8.160) and Nakamura (8.161). 

---

Rhodium(n) carboxamidates are clearly superior to all other types of catalysts in effecting highly chemo-, regio-, diastereo-, and enantioselective intramolecular C-H activation reactions of carbenoids derived from diazoacetates. Specifically, Rh2(4Y-MPPIM)4 is the catalyst of choice for C-H activation reactions of simple primary and secondary alkyl diazoacetates. Likewise, Rh2(4Y-MACIM)4 thus far has been the most successful catalyst with tertiary alkyl diazoacetates, whereas for primary acceptor-substituted diazoacetates with a pendant olefin side chain, Rh2(4A-MEOX)4 has proved to be highly selective. 

A vast array of chiral catalysts have been developed for the enantioselective reactions of diazo compounds but the majority has been applied to asymmetric cyclopropanations of alkyl diazoacetates [2]. Prominent catalysts for asymmetric intermolecular C-H insertions are the dirhodium tetraprolinate catalysts, Rh2(S-TBSP)4 (la) and Rh2(S-DOSP)4 (lb), and the bridged analogue Rh2(S-biDOSP)2 (2) [7] (Fig. 1). A related prolinate catalyst is the amide 3 [8]. Another catalyst that has been occasionally used in intermolecular C-H activations is Rh2(S-MEPY)4 (4) [9], The most notable catalysts that have been used in enantioselective ylide transformations are the valine derivative, Rh2(S-BPTV)4 (5) [10], and the binaphthylphosphate catalysts, Rh2(R-BNP)4 (6a) and Rh2(R-DDNP)4 (6b) [11]. All of the catalysts tend to be very active in the decomposition of diazo compounds and generally, carbenoid reactions are conducted with 1 mol % or less of catalyst loading [1-3]. 

A promising synthetic transformation is the reaction of carbenoid intermediates with heteroatoms to form ylides that are capable of undergoing further transformations [5,6]. Enantioselective transformations in which the ylide intermediates undergo either 1,2- or 2,3-sigmatropic rearrangement were briefly reviewed in the previous issue (Vol. II, pp. 531-532) and several recent examples have appeared [37]. A major breakthrough has been made in the enantioselective transformation of carbonyl ylides derived from capture of the metal carbenoid intermediates by carbonyl groups. The carbonyl ylides have been ex-... 

Diastereoface-differentiating reactions of a carbenoid with an alkene bearing an easily removable, chiral substituent have been used only ocassionally for the enantioselective production of a cyclopropane 216). A recent example is given by the cyclopropanation of the (—)-ephedrine-derived olefin 223 with CH2N2/Pd(OAc)2 after removal of the protecting group, (1/ , 2R )-2-phenylcyclopropane carbaldehyde was isolated with at least 90% e.e. 37). 

Using the results of an earlier study concerning enantioselective copper-catalyzed intramolecular C—H insertion of metal carbenoids,109 an interesting system for optimizing the proper combination of ligand, transition metal, and solvent for the reaction of the diazo compound (75) was devised (see Scheme 19).110 The reaction parameters were varied systematically on a standard 96-well microtiter/filtration plate. A total of five different ligands, seven metal precursors, and four solvents were tested in an iterative optimization mode. Standard HPLC was used to monitor stereoselectivity following DDQ-induced oxidation. This type of catalyst search led to the... 

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. 

Carbenoids derived from the aryldiazoacetates are excellent donor/acceptor systems for the asymmetric cyclopropanation reaction [22]. Methyl phenyldiazoacetate 3 cyclopropanation of monosubstituted alkenes catalyzed by Rh2(S-DOSP)4 is highly diaster-eo- and enantioselective (Tab. 14.5) [22]. Higher enantioselectivities can be obtained when these reactions are performed at -78°C, as the catalyst maintains high solubility and activity at this temperature. The phenyldiazoacetate system has been evaluated using many popular rhodium(II) and copper catalysts the rhodium(ll) prolinates have proven to be superior catalysts for this class of carbenoids [37, 38]. 

The most spectacular application of the donor/acceptor-substituted carbenoids has been intermolecular C-H activation by means of carbenoid-induced C-H insertion [17]. Prior to the development of the donor/acceptor carbenoids, the intermolecular C-H insertion was not considered synthetically useful [5]. Since these carbenoid intermediates were not sufficiently selective and they were very prone to carbene dimerization, intramolecular reactions were required in order to control the chemistry effectively [17]. The enhanced chemoselectivity of the donor/acceptor-substituted carbenoids has enabled intermolecular C-H insertion to become a very practical enantioselective method for C-H activation. Since the initial report in 1997 [121], the field of intermolecular enantioselective C-H insertion has undergone explosive growth [14, 15]. Excellent levels of asymmetric induction are obtained when these carbenoids are derived... 

The use of ketocarbenoids with chiral auxiliaries has not been terribly effective at chiral induction. Menthol and bomeol esters of diazoacetates resulted in very low enantioselectivity.38 Some improvements were obtained by using the chiral amide (29 equation 13), but low overall yields were obtained due to competing intramolecular side reactions.39 Related studies with other types of carbenoids, however, have resulted in high enantioselectivity.60... 

A related allylic C-H insertion that has considerable promise for strategic organic synthesis is the reaction with enol silyl ethers [23]. The resulting silyl-protected 1,5-dicarbonyls would otherwise typically be formed by means of a Michael addition. Even though with ethyl diazoacetates vinyl ethers are readily cyclopropanated [l],such reactions are generally disfavored in trisubstituted vinyl ethers with the sterically crowded donor/acceptor carbenoids [23]. Instead, C-H insertion predominates. Again, if sufficient size differentiation exists at the C-H activation site, highly diastereoselective and enantioselective reactions can be achieved as illustrated in the reaction of 20 with 17 to form 21 [23]. 

Hammerschmidt, F. Hanninger, A. Enantioselective deproto nation of benzyl phosphates by homochiral lithium amide bases. Configurational stability of benzyl carbanions with a dialkoxyphosphoryloxy substituent and their rearrangement to optically active a-hydroxy phosphonates. Chem. Ber. 1995, 328, 823-830. Avolio, S. Malan, C. Marek, I. Knochel, P. Preparation and reactions of functionalized magnesium carbenoids. Synlett 1999, 1820-1822. 

In summary, the C-H insertion chemistry of rhodium carbenoids is a very powerful method for transformation of C-H bonds. Highly regioselective and stereoselective reactions are possible and several classes of chiral catalyst are capable of very high asymmetric induction. The chemoselectivity in this chemistry is exceptional, as illustrated by the numerous intermolecular and intramolecular reactions described in this overview. Most notably, this chemistry offers new and practical strategies for enantioselective synthesis of a variety of natural products and pharmaceutical agents. 

Dirhodium(ll) tetrakis[methyl 2-pyrrolidone-5(R)-oarboxylate], Rh2(5R-MEPV)4, and its enantiomer, Rh2(5S-MEPY)4, which is prepared by the same procedure, are highly enantioselective catalysts for intramolecular cyclopropanation of allylic diazoacetates (65->94% ee) and homoallylic diazoacetates (71-90% ee),7 8 intermolecular carbon-hydrogen insertion reactions of 2-alkoxyethyl diazoacetates (57-91% ee)9 and N-alkyl-N-(tert-butyl)diazoacetamides (58-73% ee),10 Intermolecular cyclopropenation ot alkynes with ethyl diazoacetate (54-69% ee) or menthyl diazoacetates (77-98% diastereomeric excess, de),11 and intermolecular cyclopropanation of alkenes with menthyl diazoacetate (60-91% de for the cis isomer, 47-65% de for the trans isomer).12 Their use in <1.0 mol % in dichloromethane solvent effects complete reaction of the diazo ester and provides the carbenoid product in 43-88% yield. The same general method used for the preparation of Rh2(5R-MEPY)4 was employed for the synthesis of their isopropyl7 and neopentyl9 ester analogs. 

---