MEPY catalyst

In the carboxamidate class of complexes, the MeOX catalyst (entry 10) showed more /9-elimination than the MEPY catalyst (entry 8), while the MPPIM amide analog (entry 9) showed the least /9-elimination product. We were concerned that the application of an enantiomerically pure catalyst to a racemic substrate might bias the results, so we repeated one of the cyclizations using racemic (1 1 R/S) catalyst. The resulting product ratios (entry 11) were equivalent to those observed for the enantiomerically pure catalyst. 

In the carboxylate series, the TPA catalyst (entry 4) was the most selective for methine over methylene insertion. Should this remarkable chemoselectivity prove to be general, this complex may add a possibility for high chemoselectivity not previously observed with rhodium(ll) catalysts. The other carboxylate catalysts show less preference for CH over CH2 insertion. We expect that the CH/CH2 ratios would be more pronounced with a less carefully balanced substrate. In the carboxamidate class, MPPIM catalyst (entry 9) was more selective than the corresponding MeOX catalyst (entry 10), with the MEPY catalyst (entry 8) being the least discriminating for CH over CH2 insertion. 

The work of Martin and co-workers [49] has shown that excellent diastereo-control can be achieved in cyclopropanation of single enantiomers of chiral secondary diazoesters by catalyst matching. Thus, while Rh2(5R-MEPY)4 and the (S)-diazoester in Eq. (27) react to afford a 37 63, endo exo mixture of diastereoi-someric cyclopropanes, the 5S-MEPY catalyst affords a >95 <5 ratio of the same products. A final illustrative example of the versatility of this methodology is shown in Eq. (28). Here diazoacetates of prochiral divinyl carbinols undergo intramolecular cyclopropanation catalysed by Rh2(5S-MEPY)4 with exceptional enantiocontrol [49]. 

Conformational considerations restrict the number of possible transition state geometries in intramolecular cyclopropanations, which are quite selective, as shown by the examples from Doyle, Martin, and Muller illustrated in Scheme 6.38a [140,141]. Intramolecular cyclopropanation of diazo esters of chiral allylic alcohols are subject to double asymmetric induction, as shown by the series of examples in Scheme 6.38b. For all of these substrates, the exo product is slightly preferred when cyclopropanation is mediated by an achiral catalyst [142], but this selectivity is reversed dramatically when the S ester is allowed to react with the 5-S-MEPY catalyst. This pronounced endo selectivity persists for both the E and the Z-alkenes, although it is higher for the Z alkenes. Note also that when the chirality sense of the substrate and the catalyst are mismatched (5 substrate and R catalyst), the endo selectivities are low, unless R1/R2 are trimethylsilyl. For the matched case of double asymmetric induction, the same features that cause the endo selectivity can be used... 

The mechanism by which selectivity is induced in rhodium mediated asymmetric cyclopropanations is not clear. What is known is that the pyrrolidinone of the MEPY catalyst is bonded to the rhodiums through the carboxamide, with the nitrogens cis to each other, as shown in Figure 6.11 [113]. This arrangement places the two carbomethoxy groups cis to each other on both sides of the catalyst. With... 

Cyclopropanation reactions have not been limited only to applications with olefinic substrates. Doyle documented the asymmetric synthesis of cyclopropenes in the presence of Rh-MEPY catalysts (63, Equation 11) [53, 54]. Treatment of propynal diethyl acetal (80) with methyl diazoacetate in the presence of the Rh catalyst 63 thus afforded cyclopropene 81 in 42 % yield and >98% ee [53]. 

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. 

Scheme 10.12 gives some examples of enantioselective cyclopropanations. Entry 1 uses the W.s-/-butyloxazoline (BOX) catalyst. The catalytic cyclopropanation in Entry 2 achieves both stereo- and enantioselectivity. The electronic effect of the catalysts (see p. 926) directs the alkoxy-substituted ring trans to the ester substituent (87 13 ratio), and very high enantioselectivity was observed. Entry 3 also used the /-butyl -BOX catalyst. The product was used in an enantioselective synthesis of the alkaloid quebrachamine. Entry 4 is an example of enantioselective methylene transfer using the tartrate-derived dioxaborolane catalyst (see p. 920). Entry 5 used the Rh2[5(X)-MePY]4... 

Having established that pure enantiomer ( S,ZR)-77 was capable of undergoing remarkably regioselective and diastereoselective C-H activation, it followed that highly efficient enantiomeric differentiation of rac-77 could be accomplished.199 Hence, the Rh2(5Y-MEPY)4-catalyzed reaction of rac-77 effectively gave close to a 1 1 mixture of enantioenriched (lY)-78 (91% ee) and ( R)-79 (98% ee) (Equation (68)). Other equally spectacular examples of diastereo- and regiocontrol via chiral rhodium carboxamide catalysts in cyclic and acyclic diazoacetate systems have been reported.152 199 200 203-205... 

Fig. 4.20. Complexes for asymmetric cyclopropanation with acceptor-substituted diazomethanes. 1 [1372], 2 [1373], 3 [1033], Rh2(55-MEPY>4, Rh2(55-MPPIM)4 [1001,1074], For related rhodium-based catalysts, see, e.g., [997,1000,1002].

The full potential of this C-H activation process, as a surrogate Mannich reaction, was realized in the direct asymmetric synthesis of threo-methylphenidate (Ritalin) 217 (Eq. 28) [140]. C-H insertion of N-Boc-piperidine 216 using second-generation Rh2-(S-biDOSP)2 and methyl phenyldiazoacetate resulted in a 71 29 diastereomeric mixture, where the desired threo-diastereomer was obtained in 52% yield with 86% enantiomeric excess. Winkler and co-workers screened several dirhodium tetracarboxami-dates and found Rh2(R-MEPY)4 to be the catalyst that gives the highest diastereoselec-tivity for this reaction [142]. 

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. 

Cyclopropenation reactions are also effectively catalyzed by dirhodium(II) compounds, and high enantiocontrol has been achieved with the Rh2(MEPY)4 catalysts (Scheme 15.3) [47]. A striking example of the catalyst effect on selectivity is found in the behavior of substrate 25 toward Rh2(5S-MEPY)4 and the more reactive Rh2(4S-IBAZ)4 (Eq. 10) [48]. With the less reactive Rh2(5S-MEPY)4 it preferentially undergoes allyhc cyclopropanation with high chemoselectivity and enantiocontrol. With the more reactive Rh2(4S-IBAZ)4 addition to the carbon-carbon triple bond is favored even though this involves construction of a ten-membered ring. 

Hodgson et al. (138) chose to investigate a system that had previously been shown to undergo an effective intramolecular addition of a tethered olehn (Scheme 4.72). In his first attempt, using Doyle s Rh2[(5/ )-MEPY]4, the yield of cycloadduct 270 obtained was comparable to that with rhodium acetate, but no asymmetric induction was observed. Changing to the Davies catalysts in dichloromethane resulted in a... 

In intramolecular cyclopropanation, Doyle s catalysts (159) show outstanding capabilities for enantiocontrol in the cyclization of allyl and homoallyl diazoesters to bicyclic y-and <5-lactones, respectively (equations 137 and 138)198 205. The data also reveal that intramolecular cyclopropanation of Z-alkenes is generally more enantioselective than that of E-alkenes in bicyclic y-lactone formation198. Both Rh(II)-MEPY enantiomers are available and, through their use, enantiomeric products are accessible. In a few selected cases, the Pfaltz catalyst 156 also results in high-level enandoselectivity in intramolecular cyclopropanation (equation 139)194. On the other hand, the Aratani catalyst is less effective than the Doyle catalyst (159) or Pfaltz catalyst (156) in asymmetric intramolecular cyclo-propanations201. In addition, the bis-oxazoline-derived copper catalyst 157b shows lower enantioselectivity in the intramolecular cyclopropanation of allyl diazomalonate (equation 140)206. 

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]. 

An interesting aspect of the allylic C-H insertion is that the products are y,6-unsaturated esters. Traditionally, y,6-unsaturated esters are most commonly prepared by a Claisen rearrangement, especially if stereocontrol is required. Diastereocontrol is also possible in the C-H insertion as long as the reaction occurs at a methylene site where there is good size differentiation between the two substituents [21]. An example is the reaction between 17 and the silylcyclohex-ene 18 which forms the C-H insertion product 19 in 88% de and 97% ee [21]. Other catalysts such as Rh2(.R-BNP)4 and Rh2(S-MEPY)4 have been explored for allylic C-H activation of cyclohexene but none were was as effective as Rh2(S-DOSP)4 [22]. 

The reaction of methyl phenyldiazoacetate with N-Boc-piperidine (36) is a good illustration of the potential of this chemistry because it leads to the direct synthesis of f/ireo-methylphenidate (37) [27]. The most efficient rhodium car-boxylate catalyst for carrying out this transformation is Rh2(S-biDOSP)2 (2), which results in the formation of a 71 29 mixture of the readily separable threo and erythro diastereomers. The threo diastereomer 37 is produced in 52% isolated yield and 86% ee [Eq. (19)]. Other catalysts have also been explored for this reaction. Rh2(R-DOSP)4 gives only moderate stereoselectivity while Rh2(R-MEPY)4 gave the best diastereoselectivity in this reaction (94% de) [29]. 

The synthesis of 2-deoxyxylolactone in high yield and 94% ee from 1,3-dichloro-2-propanol (Scheme 5.7) requires the exclusive use of Rh2(5ff-MEPY)4 catalysts [123], Insertion results in the predominant formation of one stereoisomer that is the thermodynamically less stable one. Here again, the success of the synthesis is determined as much by diastereocontrol as by enantiocontrol. As little as 0.1 mol % of catalyst is required to bring about complete reaction. 

A-Cu,N-Co, and P-Cu to carbenoid transformations have been limited to intermolecular reactions, for which they remain superior to chiral dirhodium(II) catalysts for intermolecular cyclopropanation reactions. Few examples other than those recently reported by Dauben and coworkers (eq 1) (35) portray the effectiveness of these chiral catalysts for enantioseleetive intramolecular cyclopropanation reactions, and these examples demonstrate their limitations. However, with Rh2(5S-MEPY)4 intramolecular cyclopropanation of 3-methyl-2-buten-1 -yl diazoacetate (eq 2) occurs in high yield and with 92% enantiomeric excess (36). 

Chiral rhodium(II) carboxamides are exceptional catalysts for highly enantio-selective intermolecular cyclopropenation reactions (50). With ethyl diazoacetate and a series of alkynes, use of dirhodium(II) tetrakis[methyl 2-pyrrolidone-5-(R)-carboxylate], Rh2(5R-MEPY)4, in catalytic amounts ( 1.0 mol %) results in the formation of ethyl eyelopropene-3-earboxylates (eq 4) with enantiomeric excesses... 

Table 2. Diastereoseleetivities for the Cyelopropanation of Styrene by Representative Diazo Esters with Rh2(5S-MEPY)4 Catalyst...

Alternative rhodium(II) carboxamide catalysts derived from 4-(R)-benzyloxa-zolidinone (47 -BNOXH) and 4-(S)-isopropyloxazolidinone (4S-IPOXH) provided only a fraction of the enantioselection obtained with Rh2(MEPY)4 catalysts. Whereas cyclopropenation of 1-hexyne with ethyl diazoacetate in the presence of Rh2(5R-MEPY)4 resulted in 15 (eq 4, R = n-Bu) with 54% ee, Rh2(47 -BNOX)4 gave the same compound in 5% ee, and Rh2(4S-IPOX)4 provided only 6% ee. 

Enantioeontrol in cyclopropenation reactions is obviously highly dependent on the carboxylate substituent of the dirhodium(II) carboxamide ligand and on the carboxylate substituent of the intermediate carbene. High enantioseleetivity is achieved with the use of Rh2(MEPY)4 catalysts and menthyl diazoacetates in reactions with 1-alkynes, and further enhancement in % ee can be anticipated. 

The suitability of Rh2(5S-MEPY)4 and Rh2(5/ -MEPY)4 for enantioselective intramolecular C-H insertions is exemplified in the results from preliminary experiments with a series of 2-alkoxyethyl diazoacetates and 2-phenethyl diazoacetate (67). Addition of diazo ester 17 to a solution of the chiral Rh2(MEPY)4 catalyst (0.5-1.0 mol %) in refluxing anhydrous CH2CI2 provided the corresponding 3-substituted y-butyrolactones 18 (eq 6) in moderate to high yields and with consistently high enantioselectivities. The exceptional correspondence in enantioselection between... 

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. 

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