Cyclopropanation allyl diazoacetate

The Ru(Pybox- -Pr) complex (91), which induces high trans- and enantioselectivity in intermolecular cyclopropanation, has also been applied to the cyclization of allyl diazoacetates (Scheme 80) 252 The enantioselectivity observed depends largely on the susbstitution pattern of the allyl moiety. 

In the simplest case, the reaction of allyl diazoacetate, the catalyst (iS )-198 or (f )-198 in a concentration as low as 0.1 mol% can still catalyze the formation of enantiomeric-3-oxabicyclo[3.1.0]hexan-2-ones with 95% ee (Scheme 5-60). Substituted alkyl diazoacetates undergo intramolecular cyclopropanation, with similarly high enantiomeric excess (Scheme 5-61).110... 

Kinetic resolution (enantiomer differentiation) of cycloalkenyl diazoacetates has been achieved (for example, according to Eq. 3) [34]. In these cases one enantiomer of the racemic reactant matches with the catalyst configuration to produce the intramolecular cyclopropanation product in high enantiomeric excess, whereas the mismatched enantiomer preferentially undergoes hydride abstraction from the allylic position [35] to yield the corresponding cycloalkenone. With acyclic secondary allylic diazoacetates the hydride abstraction pathway is relatively unimportant, and diastereoselection becomes the means for enantiomer differentiation [31]. 

Doyle, Martin, Muller, and co-workers communicated exceptional enantiocontrol for intramolecular cyclopropanation of a series of allyl diazoacetates (Eq. 5.16) by using dirhodium(II) tetrakis(methyl 2-oxopyrrolidine-5-carboxylates), Rh2(MEPY)4, in either their R- or S-configurations [87], and they have fully elaborated these results in a subsequent report [88],... 

TABLE 5.7. Enantioselective Intramolecular Cyclopropanation of Allyl Diazoacetates [87,88,91]... 

Intramolecular cyclopropanation of the next higher homologs of the allyl diazoacetates (Eq 5.19) catalyzed by Rh2(MEPY)4 give moderate-to-high percent of ee s for the addition product and isolated yields are also high (Table 5.9) [88]. 

Once again, cis-disubstituted olefins lead to higher enantioselectivities than do trans-disubstituted olefins, but here the differences are not as great as they were with allyl diazoacetates. Both allylic and homoallylic diazoacetamides also undergo highly enantioselective intramolecular cyclopropanation (40-43) [93,94], However, with allylic a-diazopropionates enantiocontrol i s lower by 10-30% ee [95], The composite data suggest that chi ral dirhodium(II) carboxamide catalysts are superior to chiral Cu or Ru catalysts for intramolecular cyclopropanation reactions of allylic and homoallylic diazoacetates. 

Dirhodium(II) tetrakis(carboxamides), constructed with chiral 2-pyrroli-done-5-carboxylate esters so that the two nitrogen donor atoms on each rhodium are in a cis arrangement, represent a new class of chiral catalysts with broad applicability to enantioselective metal carbene transformations. Enantiomeric excesses greater than 90% have been achieved in intramolecular cyclopropanation reactions of allyl diazoacetates. In intermolecular cyclopropanation reactions with monosubsti-tuted olefins, the cis-disubstituted cyclopropane is formed with a higher enantiomeric excess than the trans isomer, and for cyclopropenation of 1-alkynes extraordinary selectivity has been achieved. Carbon-hydro-gen insertion reactions of diazoacetate esters that result in substituted y-butyrolactones occur in high yield and with enantiomeric excess as high as 90% with the use of these catalysts. Their design affords stabilization of the intermediate metal carbene and orientation of the carbene substituents for selectivity enhancement. 

Intramolecular cyclopropanation of allyl diazoacetates gives rise to interesting cyclopropane-fused y-butyrolactones. A chiral ruthenium bis(oxa-zolinyl)pyridine complex 85 was employed for the catalytic cyclization of trans-cinnamyl diazoacetate 83 at room temperature to obtain an optically active lactone 84 in 93% yield with 86% ee (Eq. 34, Fig. 2) [85]. Chiral porphyrin and salen complexes of ruthenium 86 [86] and 87 [87] also catalyzed the asymmetric intramolecular cyclopropanation of 83 to afford 84 in similar yields and enantiomeric excess. 

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. 

This collection begins with a series of three procedures illustrating important new methods for preparation of enantiomerically pure substances via asymmetric catalysis. The preparation of 3-[(1S)-1,2-DIHYDROXYETHYL]-1,5-DIHYDRO-3H-2.4-BENZODIOXEPINE describes, in detail, the use of dihydroquinidine 9-0-(9 -phenanthryl) ether as a chiral ligand in the asymmetric dihydroxylation reaction which is broadly applicable for the preparation of chiral dlols from monosubstituted olefins. The product, an acetal of (S)-glyceralcfehyde, is itself a potentially valuable synthetic intermediate. The assembly of a chiral rhodium catalyst from methyl 2-pyrrolidone 5(R)-carboxylate and its use in the intramolecular asymmetric cyclopropanation of an allyl diazoacetate is illustrated in the preparation of (1R.5S)-()-6,6-DIMETHYL-3-OXABICYCLO[3.1. OJHEXAN-2-ONE. Another important general method for asymmetric synthesis involves the desymmetrization of bifunctional meso compounds as is described for the enantioselective enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene to (1R,4S)-(+)-4-HYDROXY-2-CYCLOPENTENYL ACETATE. This intermediate is especially valuable as a precursor of both antipodes (4R) (+)- and (4S)-(-)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE, important intermediates in the synthesis of enantiomerically pure prostanoid derivatives and other classes of natural substances, whose preparation is detailed in accompanying procedures. 

Semicorrinato)copper catalysts have also been used for intramolecular cyclopropanation reactions of alkenyl diazo ketones (eq 9 and eq 10). In this case the (semicorrinato)copper catalyst derived from complex (5) proved to be superior to related methylene-bis(oxazoline)copper complexes. Interestingly, analogous allyl diazoacetates react with markedly lower enantioselectivity under these conditions, in contrast to the results obtained with chiral Rh complexes which are excellent catalysts for intramolecular cyclopropanations of allyl diazoacetates but give poor enantioselectivities with alkenyl diazo ketones (see Dirhodium(II) Tetrakis(methyl 2-pyrrolidone-5(S -carboxylate ) Moderate enantioselectivities in the reactions... 

Rh2(5/ -MEPY)4 catalysts for enantiocontrol are evident in results obtained with a series of allyl diazoacetates (eq 1). Both high product yields and enantiomeric excess (ee s) are characteristic. Intramolecular cyclopropanation of (Z)-alkenes proceeds with a higher level of enantiocontrol than does intramolecular cyclopropanation of ( )-alkenes. In preparative scale reactions, less than 0.25 mol% of catalyst can be employed to achieve high yields of pure product. ... 

On the other hand, the exceptional capabilities of these catalysts for enantiocon-trol are evident in results obtained in intramolecular cyclopropanations, which usually occur with greater enantioselectivity than they do with copper catalysts. The example shown in eq. (8) illustrates the synthesis of a strained bicyclic lactone from a readily available allyl diazoacetate [24]. Similarly, high enantioselec-tivities for intramolecular cyclopropanations of homoallylic diazoacetates and homoallylic diazoacetamides have been reported [24 b]. A comparative evaluation of enantiocontrol for cyclopropanation of allylic diazoacetates with chiral Cu, Rh", and Ru" catalysts showed the superiority of Rh-based catalysts in these intramolecular reactions [24 c], an observation that cannot however be extrapolated to different substrates [24 d]. 

A polyethylene-bound soluble recoverable dirhodium(II) tetrakis(2-oxapyrrolidine-(55 )-carb-oxylate) was also highly efficient in enantioselective intramolecular cyclopropanation of allyl diazoacetates and could be used repeatedly without significant loss of enantiocontrol. Some enantiomerically pure, secondary allylic diazoacetates showed the expected substrate-induced diastereofacial selectivity in intramolecular cyclopropanation, when they were decomposed with bis(A-n-r/-butylsalicylamidinato)copper(II). ° This selectivity could be significantly enhanced or reversed with the chiral catalyst 30 or its antipode. Furthermore, catalysts 30 and 32 allowed a highly efficient kinetic resolution of racemic secondary allylic diazoacetates. 

Table I.Enantioselective intramolecular cyclopropanation of allylic diazoacetates (n=l) catalyzed by Rh2(5S-MEPY)4, Eq. (19)...

Similarly, significant improvements with methallyl and ( -butyl)allyl diazoacetates can be achieved by switching catalysts from Rh2(MEPY)4 to Rh2(MP-PIM)4. Allyl diazo esters other than diazo acetates have not yet been examined in detail. Encouragingly, Doyle s group [41] have found that high levels of enantio-control in intramolecular cyclopropanation can be realized with allyl diazopropionates and the Rh2(4S-MEOX)4 catalyst, Eq. (25). 

In a useful extension of this methodology for enantioselection in intramolecular cyclopropanation, Doyle s group have used chiral rhodium (II) carbox-amidates to effect enantiomer differentiation in reactions of racemic secondary allylic diazoacetates [47]. The catalyst-enantiomer matching approach has also been applied very successfully to intramolecular C-H insertion reactions vide infra). The (R)- and (S)-enantiomers, (10) and (11), respectively, of cyclohex-2-en-1 -yl diazoacetate are displayed in Scheme 7. On exposure to Rh2(4i -MEOX)4 the (R)-enantiomer (10) undergoes cyclopropanation to form tricyclic ketone... 

In spite of the low reactivity of 1,2-disubstituted and trisubstituted olefins in the intermolecular cyclopropanation, some allyl diazoacetates were easily cyclopropanated to give the corresponding 3-oxabicyclo[3.1.0]hexan-2-one derivatives [44]. The trans isomers gave good results (from 76 to 86% ee),but low enan-tioselectivities were observed for the cis derivatives, Eq. (9). The diazo substrates containing a 2-alkyl substituent did not undergo intramolecular cyclopropanation under a variety of reaction conditions. In these cases, carbene dimers were the only isolated products. 

Rhodium complexes generated from A-functionalized (S)-proline 3.60 [933, 934, 935] or from methyl 2-pyrrolidone-5-carboxylates 3.61 [936, 937, 938] catalyze the cyclopropanation of alkenes by diazoesters or -ketones. Diastereoisomeric mixtures of Z- and E-cydopropylesters or -ketones are usually formed, but only the Z-esters exhibit an interesting enantioselectivity. However, if intramolecular cyclopropanation of allyl diazoacetates is performed with ligand 3.61, a single isomer is formed with an excellent enantiomeric excess [936,937], The same catalyst also provides satisfactory results in the cyclopropanation of alkynes by menthyl diazoacetate [937, 939] or in the intramolecular insertion of diazoesters into C-H bonds [940]. 

Rh2(55-mepy)4] is particularly useful for intramolecular cyclopropanation in several examples up to 94% ee was obtained. [17] Highly substituted cyclopropanes are accessible by this reaction an example is given in Equation (b). With the two enantiomeric catalysts both enantiomeric products can be obtained from the same allyl diazoacetate. For this intramolecular variant the (Z) configuration of the olefin proves superior to the (E) configuration. 

On this basis, in a joint effort with Martin and Muller (1991a), Doyle developed a series of dinuclear rhodium 2-pyrrolidone-5-carboxylate complexes that might give better enantiomeric ratios in cyclopropanations (see also Muller and Polleux, 1994). This was indeed the case for a series of intramolecular cyclopropanations of allyl diazoacetates with the complex Rh2((55)-MEPY)4 obtained with chiral methyl 2-pyrrolidone-5-carboxylate (MEPY = 8.178) an ee between 65 and 94 o was found. Doyle et al. (1993 a) continued that work with additional inter- and intramolecular cyclopropanations as well as with intramolecular CH insertions. Doyle and his coworkers again obtained good-to-excellent enantioselectivity with the same catalyst. Examples are given in Schemes 8-75 to 8-77. 

Asymmetric cyclopropanation. The ability to effect ligand exchange between rhodium(II) acetate and various amides has lead to a search for novel, chiral rhodium(II) catalysts for enantioselective cyclopropanation with diazo carbonyl compounds. The most promising to date are prepared from methyl (S)- or (R)-pyroglutamate (1), [dirhodium(ll) tetrakis(methyl 2-pyrrolidone-5-carboxylate)]. Thus these complexes, Rh2[(S)- or (R)-l]4, effect intramolecular cyclopropanation of allylic diazoacetates (2) to give the cyclo-propanated y-lactones 3 in 65 S 94% ee (equation 1). In general, the enantioselectivity is higher in cyclopropanation of (Z)-alkenes. 

Apart from 37, other carboxamidate catalysts are also efficient intramolecular cyclopropanation catalysts. Rh2(4S-MPPIM)4 38, derived from chiral imidazole, is particularly effective in the cyclopropanation of diazoacetates, which contain rans-disubstituted or n-butyl allyl alkenes, with high enantioselectivities (Scheme 25) (117). In addition, this catalyst also proved to be efficient for the substrates of A -methyl substituted A-allyldiazoacetate, with high yields (88-93%) and high percentage of ee values (>92%) of the corresponding cyclopropanes (118). Catalyst Rh2(4S-MEOX)4, based on chiral oxazoline, is another efficient... 

Occasionally, systems with complexes of ruthenium and cobalt have been reported to catalyze intramolecular cyclopropanation of allylic diazoacetate with high enantiocontrols. For cobalt-salen 39, up to 97% ee was observed (Scheme 30) (128). More recently, methods other than diazo decomposition were applied in intramolecular cyclopropanation. Activated by irradiation, [WlCOle] catalyzed the cyclopropanation of alkynol to give good yield of cyclopropane (Scheme 31) (129). The reaction was proposed via a tungsten—carbene intermediate. 

In the asymmetric intramolecular cyclopropanation of 40 (Scheme 32), comparative studies of chiral copper, rhodium, and ruthenium catalysts showed none of the catalysts is omnipotent in providing high enantiocontrol for all substrates (117). Complementary factors between these catalysts were observed. For instance, for the copper/7 catalyzed reaction, whereas high enantioselection was achieved with substituted allylic diazoacetates, any substitution at and R resulted in low percentage of ee. Interestingly, the opposite observation was observed with the rhodium catalyst 37. In the case of ruthenium catalyst 25, while high enantioselectivities were obtained for substrates with substitutions... 

In 2002, in an attempt to prepare poly(2-hydroxymethylcyclopropanecarboxylic acid) via intermolecular cyclopropanation of allyl diazoacetate catalyzed by Cu powder, Liu and co-workers found that the product was not the desired polymer with the cyclopropane-framework in the main chain, but poly(allyloxycarbonyl-methylene) as shown in Scheme 11 [37], Although the polymer yield was not mentioned in the paper, the polymer structure was confirmed by H and NMR and IR spectroscopy, and Mn of the product was reported to be over 3,000 by the estimation with GPC based on polystyrene standards. This is the first report for the polymerization of diazocarbonyl compounds. 

The search for the racemic form of 15, prepared by allylic cyclopropanation of farnesyl diazoacetate 14, prompted the use of Rh2(OAc)4 for this process. But, instead of 15, addition occurred to the terminal double bond exclusively and in high yield (Eq. 6) [65]. This example initiated studies that have demonstrated the generality of the process [66-68] and its suitability for asymmetric cyclopropanation [69]. Since carbon-hydrogen insertion is in competition with addition, only the most reactive carboxamidate-ligated catalysts effect macrocyclic cyclopropanation [70] (Eq. 7), and CuPF6/bis-oxazoline 28 generally produces the highest level of enantiocontrol. 

It has been pointed out earlier that the anti/syn ratio of ethyl bicyclo[4.1,0]heptane-7-carboxylate, which arises from cyclohexene and ethyl diazoacetate, in the presence of Cul P(OMe)3 depends on the concentration of the catalyst57). Doyle reported, however, that for most combinations of alkene and catalyst (see Tables 2 and 7) neither concentration of the catalyst (G.5-4.0 mol- %) nor the rate of addition of the diazo ester nor the molar ratio of olefin to diazo ester affected the stereoselectivity. Thus, cyclopropanation of cyclohexene in the presence of copper catalysts seems to be a particular case, and it has been stated that the most appreciable variations of the anti/syn ratio occur in the presence of air, when allylic oxidation of cyclohexene becomes a competing process S9). As the yields for cyclohexene cyclopropanation with copper catalysts [except Cu(OTf)2] are low (Table 2), such variations in stereoselectivity are not very significant in terms of absolute yields anyway. 

In contrast to ethyl diazoacetate, diethyl diazomalonate reacts with allyl bromide in the presence of Rh2(OAc)4 to give the ylide-derived diester favored by far over the cyclopropane (at 60 °C 93 7 ratio). This finding bespeaks the greater electrophilic selectivity of the carbenoid derived from ethyl diazomalonate. For reasons unknown, this property is not expressed, however, in the reaction with allyl chloride, as the carbenoids from both ethyl diazoacetate and diethyl diazomalonate exhibit a similarly high preference for cyclopropanation. 

Allyl acetals154). Allyl ethers give no or only trace amounts of ylide-derived products in the Rh2(OAc)4-catalyzed reaction with ethyl diazoacetate, thus paralleling the reactivity of allyl chloride. In contrast, cyclopropanation must give way to the ylide route when allyl acetals are the substrates and ethyl diazoacetate or dimethyl diazomalonate the carbenoid precursors. 

Copper(II) triflate is quite inefficient in promoting cyclopropanation of allyl alcohol, and the use of f-butyl diazoacetate [164/(165+166) = 97/3%] brought no improvement over ethyl diazoacetate (67/6 %)162). If, however, copper(I) triflate was the catalyst, cyclopropanation with ethyl diazoacetate increased to 30% at the expense of O/H insertion (55%). As has already been discussed in Sect. 2.2.1, competitive coordination-type and carbenoid mechanisms may be involved in cyclopropanation with copper catalysts, and the ability of Cu(I) to coordinate efficiently with olefins may enhance this reaction in the intramolecular competition with O/H insertion. 

The C-H activation of allylic and benzylic C-H bonds has considerable application in organic synthesis. Studies by Muller [131] and Davies [130] on reactions with cyclohexene revealed that Rh2(S-DOSP)4 in a hydrocarbon solvent is the optimum system for high asymmetric induction (Tab. 14.13). Although this particular example gives a mixture of the C-H activation product 179 and cyclopropane 180, similar reactions with ethyl diazoacetate gave virtually no C-H activation product. Some of the other classic chiral dirhodium catalysts 181 and 182 were also effective in this chemistry, but the en-antioselectivity with these catalysts (45% ee and 55% ee) [131] was considerably lower than with Rh2(S-DOSP)4 (93% ee) [130]. 

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. 

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