Cyclopropanation of 2-

In 1963, Dauben and Berezin published the first systematic study of this syn directing effect (Scheme 3.15) [37]. They found that the cyclopropanation of 2-cyclohexen-l-ol 32 proceed in 63% yield to give the syn isomer 33 as the sole product. They observed the same high syn diastereoselectivity in a variety of cyclic allylic alcohols and methyl ethers. On the basis of these results, they reasonably conclude that there must be some type of coordinative interaction between the zinc carbenoid and the substrate. 

The change in selectivity is not credited to the catalyst alone In general, the bulkier the alkyl residue of the diazoacetate is, the more of the m-permethric acid ester results 77). Alternatively, cyclopropanation of 2,5-dimethyl-2,4-hexadiene instead of l,l-dichloro-4-methyl-l,3-pentadiene leads to a preference for the thermodynamically favored trans-chrysanthemic add ester for most eatalyst/alkyl diazoacetate combinations77 . The reasons for these discrepandes are not yet clear, the interplay between steric, electronic and lipophilic factors is considered to determine the stereochemical outcome of an individual reaction77 . This seems to be true also for the cyclopropanation of isoprene with different combinations of alkyl diazoacetates and rhodium catalysts77 . 

Cyclopropanation of 2,5-dimethyl-2,4-hexadiene provides chiysanthemic acid, a natural product of the group of pyrethroic acids, used as an insecticide, see Figure 17.3 [3]. The appropriate esters of the 1R stereomers are the active compounds, which are obtained industrially by resolution of the racemates. 

Intermolecular cyclopropanation of 2-substituted terminal diene 121 with rhodium or copper catalysts occurs preferentially at the more electron-rich double bond (equation 109)37162. With a palladium catalyst, considerable differences in regiocontrol can occur, depending on the substituent of the diene. In general, palladium catalysed cyclopropanation occurs preferentially at the less substituted double bond (equation 110). However, with a stronger electron-donating substituent present in the diene, e.g. as in 2-methoxy-l, 3-butadiene, the catalytic process results in exclusive cyclopropanation at the unsubstituted double bond (equation 110)162. 

TABLE 5.1. Cyclopropanation of 2,5-Dimethyl-2,4-hexadiene with Diazo Esters (Eq. 5.6)... 

Well-known is the cyclopropanation of various alkenes. As shown by 329, cyclopropanation starts by electrophilic attack to the alkene. Electron-rich alkenes have higher reactivity. Numerous applications of intramolecular cyclopropanation to syntheses of natural products have been reported. Optically active cyclopropanes are prepared by enantioselective cyclopropanation [100], As the first successful example, asymmetric synthesis of chrysanthemic acid (331) was carried out by cyclopropanation of 2,5-dimethyl-2,4-hexadiene (330) with diazoacetate, catalysed by the chiral... 

Preparation of IZnCH2l from Zn-Cu couple (LeGoff) and CH2I2 11 diastereoselective cyclopropanation of 2-cyclohexen-1-one7... 

Vicinally donor-acceptor-substituted olefins usually are rather unreactive species. Nevertheless cyclopropanation of 2,2-dimethyl-3(2 H)-furanone 70 could be executed with dimethyl oxosulfonium methylide as a methylene source. The bicyclic compound 71 is formed in modest yield accompanied by the spiro epoxide as a second product in almost equal amounts. Carbinols 72 derived from 71 by alkyl lithium addition can be nitrosated and photolyzed to suffer a Barton fragmentation. The resulting y-oxoaldehydes are directly cyclized to afford the 2-substituted cyclopentenones 73 in good yield 41. ... 

Acetylenes and cyclopropenes (37) are related to each other in the same formal way as olefins and cyclopropanes are. Recall that cyclopropanation of ethylene is almost slightly endothermic and the endothermicity was asserted to increase by some (3 2) kJ moT per alkyl group. Cyclopropanation of acetylene to form cyclopropene (37, X = X = H) is endothermic by (48.9 2.6) kJ mol. Cyclopropanation of propyne (monomethy-lacetylene) to form 1-methylcyclopropene (37, X = Me, X = H) has an increased endothermicity of (58.7 1.4) kJ mol. By contrast, the cyclopropanation of 2-butyne (dimethy-lacetylene) using a derived value for the enthalpy of formation of 1,2-dimethylcyclopropene (37, X = X = Me) has an accompanying endothermicity of only 41 kJ moT. We suspect that the last value is in error and so suggest remeasurement of the enthalpy of formation of dimethylcyclopropene as well as measuring the enthalpy of formation of other cyclo-propenes. ... 

Substrate control has also been realized for the intramolecular cyclopropanation of 2-diazo-3-oxohept-6-enoate and -oct-6-enoate esters derived from naphthylbomeol which is readily prepared from (-l-)-camphor. The diastereomeric excess, and for the hept-6-enoates even the preference for one or the other diastereomer, can be partially controlled by the catalyst. As an example of the oct-6-enoate, intramolecular cyclization of 28 gives the bicyclo[3.1.0]hexanes 29 a and 29... 

Whereas cyclopropanation of 2,5-dimethylhexa-2,4-diene by this method did not succeed, that of l,l-dichloro-4-methylpenta-1,3-diene was realized with several alkyl and benzyl esters of cyanoacetic acid, e.g. formation of 4. ... 

It is often difficult to make a comparison between the various results obtained for the same polyenes as different reaction conditions (ratio of reactants, temperature, time) were used in each case. The addition of dichlorocarbene (chloroform/base/phase-transfer catalysis) to straight chain and cyclic unconjugated di- and trienes, carried out under identical conditions but varying the catalysts, showed the peculiar properties of tetramethylammonium chloride. Under precisely tailored conditions, either highly selective mono- or polyaddition of dichlorocarbene to the polyenes is possible tetramethylammonium chloride was the most efficient catalyst for monocyclopropanation. (For the unusual properties of tetramethylammonium salts on the phase-transfer catalyzed reaction of chloroform with electrophilic alkenes see Section 1.2.1.4.2.1.8.2. and likewise for the reaction of bromoform with allylic halides, see Section 1.2.1.4.3.1.5.1.). For example, cyclopropanation of 2 with various phase-transfer catalysts to give mixtures of 3, 4, and 5, ° of 6 to give 7 and 8, ° and of 9 to give 10 and 11. °... 

In this way, esters of chrysanthemic acid (2) [15,16,18] and permethrinic acid [17,18], which are important precursors for the synthesis of pyrethroid insecticides, can be prepared in >90% ee. Although enantioselective cyclopropanation cannot compete with conventional industrial syntheses of optically active pyrethroids, a technical process for the cyclopropanation of 2-methylpropene was successfully implemented at Sumitomo [18]. The product, ethyl (-l-)-2,2-dimeth-ylcyclopropanecarboxylate, serves as a starting material for the production of cilastatin, a dehydropeptidase inhibitor used as a drug to suppress the degradation of the P-lactam antibiotic iminipenem. 

A chiral copper catalyst derived from 3-(trifluoroacetyl)camphor was reported to induce up to 100% ee in the cyclopropanation of styrene with diazodime-done [65] but no further studies of this reaction have been published since. Recently, the same catalyst was used for the cyclopropanation of 2,5-dimethyl-2,4-hexadiene [66] and up to 87% ee was reported for the trans-product derived from menthyl diazoacetate. 

Copper complex catalyzed asymmetric cyclopropanation has been extensively applied to the synthesis of chrysanthemic acid (4, R = H) and other pyrethroid compounds. Cyclopropanation of 2,5-dimethyl-2.4-hexadiene (3) with ethyl diazoacetate in the presence of a copper complex... 

There are a couple of examples of cascade processes starting by a Michael-type addition of a carbon nucleophile proceeding under phase-transfer eatalysis conditions which deserve to be mentioned at this point. The first one eonsists of an enantioselective cyclopropanation of 2-bromocyclopentenone by a cascade Michael/intramolecular nucleophilic displacement in which a variety of C-H acidic carbon pro-nucleophiles such as nitromethane, cyanomethylsulfone and benzyl cyanoacetate reacted with this Michael acceptor in the presence of a quinidinium salt of type 67 (Scheme 7.79). In addition, the conditions needed to be optimized for each Michael donor employed, requiring a different catalyst and inorganic base for each case. Under the best conditions, the final cyclopropanes were obtained in moderate yields and enantioselectivities, albeit as single diastereoisomers. 

Scheme 7.79 Asymmetric cyclopropanation of 2-bromocyclopentenone by cascade Michael/a-alkylation.

Malonate-substituted cyclopropanes are often considered as synthetic building blocks due to the specific reactivity of their carbocyclic ring systems. For instance, total synthesis of ( )-bruguierol A was achieved in several steps that involved cyclopropanation of 2-(2-ally 1-4-methoxyphenyl)-2-methyl-1,3-dioxolane with dimethyl diazomalonate and [Rh2(esp)2] as catalyst (eq 44). The characteristic 2,3-benzofused 8-oxabicyclo-[3.2.1]octane core of bruguierol was constructed via a Sc(OTf)3-catalyzed intramolecular [3+2] cycloaddition of the cor-... 

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