Intramolecular allylic cyclopropanation

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. 

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. 

As discussed in Sect. 2, a-selanylalkyllithiums, generated from selenoacetals, can react with various electrophilic reagents, i. e. chloromethyl isopropyl ether for the synthesis of la-hydroxy vitamin D analogues [25] and with propargylic chloride derivatives for the preparation of alkynols [26]. A synthesis of vinyl-cyclopropane derivatives from l,4-dichloro-but-2-ene was achieved with trans stereoselectivity (>93%) in 68-89% yield. This one-pot cyclization, via an intramolecular allylic substitution, required the presence of two equivalents of u-BuLi [26] (Scheme 23). 

Intramolecular allylic substitution of allyl acetate 15 via the stabilized carbanion is reported to give cyclopropanes 16 and 17. This reaction can be initiated with sodium hydride and leads to a 1 1 mixture of cis- and frawi-chrysanthemic acid precursors 16 and 17. The rate is accelerated if the reaction is carried out in the presence of a palladiumfO) catalyst and the product ratio 16/17 changes to 3 2. Several other examples of this type of cyclopropane formation have been reported. ... 

Allylpalladium complexes with carbanion functions in close vicinity (for formation of vinyl-cyclopropanes via intramolecular allylic alkylation) can also be obtained from other pecursors. 

Intramolecular allylations forming vinyl-substituted carbocycles 142 have been investigated by the Helmchen group. For the construction of cyclopropane and cyclobutane derivatives, salt-free conditions were employed. In case of the five- and six-membered carbocycles, the deprotonation of 141 had to be carried out at —78 °C with wBuLi as the base to suppress noncatalyzed cycHzation (Scheme 12.66) [157]. 

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 distinction between Pd and Rh catalysts was also verified for diazoketone 190. In this case, the carbonyl ylide was trapped by intramolecular [3+2] cycloaddition to the C=C bond195. Decomposition of bis-diazoketone 191 in the presence of CuCl P(OEt)3 or Rh2(OAc)4 led to the pentacyclic ketone 192 most remarkably, one diazoketone unit reacted by cyclopropanation, the second one by carbonyl ylide formation 194). With [(r 3-C3H5)PdCl]2, a non-separable mixture containing mostly polymers was obtained, although bis-diazoketones with one or two allyl side chains instead of the butenyl groups underwent successful twofold cyclopropanation 196). 

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... 

The analogous process involving allylic epoxides is more complex, as issues such as the stereochemistry of substituents on the ring and on the alkene play major roles in determining the course of the reaction [38]. Addition of the Schwartz reagent to the alkene only occurs when an unsubstituted vinyl moiety is present and, in the absence of a Lewis acid, intramolecular attack in an anti fashion leads to cyclopropane formation as the major pathway (Scheme 4.10). cis-Epoxides 13 afford cis-cyclopropyl carbinols, while trans-oxiranes 14 give mixtures of anti-trans and anti-cis isomers. The product of (S-elimi-... 

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. 

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]. 

With respect to the large number of unsaturated diazo and diazocarbonyl compounds that have recently been used for intramolecular transition metal catalyzed cyclopropanation reactions (6-8), it is remarkable that 1,3-dipolar cycloadditions with retention of the azo moiety have only been occasionally observed. This finding is probably due to the fact that these [3 + 2]-cycloaddition reactions require thermal activation while the catalytic reactions are carried out at ambient temperature. /V-Allyl carboxamides appear to be rather amenable to intramolecular cycloaddition. Compounds 254-256 (Scheme 8.61) cyclize intra-molecularly even at room temperature. The faster reaction of 254c (310) and diethoxyphosphoryl-substituted diazoamides 255 (311) as compared with diazoacetamides 254a (312) (x1/2 25 h at 22 °C) and 254b (310), points to a LUMO (dipole) — HOMO(dipolarophile) controlled process. The A -pyrazolines expected... 

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 limited number of other anionic species have been employed as Michael donors in tandem vicinal difunctionalizations. In a manner similar to sulfur ylides described above, phosphonium ylides can be used as cyclopropanating reagents by means of a conjugate addition-a-intramolecular alkylation sequence. Phosphonium ylides have been used with greater frequency261-263 than sulfur ylides and display little steric sensitivity.264 Phosphorus-stabilized allylic anions can display regiospecific 7-1,4-addition when used as Michael donors.265... 

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. 

In the competition between allylic intramolecular cyclopropanation and macrocyclization (Eq. 5.20), the more electrophilic catalyst favors macrocyclization. Doyle has explained this differential selectivity as due to the formation of an intermediate Jt-complex between the C-C double bond and the carbene center. The more electrophilic the carbene carbon or the more electron-rich the double bond, the more that this Jt-complex is favored and the more favorable the pathway to macrocyclization [97]. However, thus far few systems have been examined... 

An enantioselective rhodium(II)-catalysed intramolecular cyclopropanation, follow- (g) ed by a regioselective allylic alkylation and a diastereoselective rhodium(I)-catalysed 5 + 2-cycloaddition has been reported.102 ... 

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