Optically active cyclopropanes

Asymmetric cyclopropanation. Optically active cyclopropanes can be prepared in optical yields as high as by reaction of certain olefins with various dia/o compounds in the presence of this catalyst. Chemical yields are usually 90 95%. However, the reaction is generally limited to terminal double bonds conjugated with an aryl or carbonyl group or with another double bond. The (1 S)-enantiomer is always obtained in large excess. 

This protective group was used to direct the selective cyclopropanation of a variety of enones. Hydrolysis (HCl, MeOH, H2O, it, 94% yield) affords optically active cyclopropyl ketones. 

Asymmetric versions of the cyclopropanation reaction of electron-deficient olefins using chirally modified Fischer carbene complexes, prepared by exchange of CO ligands with chiral bisphosphites [21a] or phosphines [21b], have been tested. However, the asymmetric inductions are rather modest [21a] or not quantified (only the observation that the cyclopropane is optically active is reported) [21b]. Much better facial selectivities are reached in the cyclopropanation of enantiopure alkenyl oxazolines with aryl- or alkyl-substituted alkoxy-carbene complexes of chromium [22] (Scheme 5). 

We have seen before that such diradicals can close up to give cyclopropanes (17-36). Therefore, pyrolysis of cyclopropanes can produce not only propenes but also isomerized (cis trans or optically active inactive) cyclopropanes. See, for example, Berson, J.A. Balquist, J.M. J. Am. Chem. Soc., 1968, 90, 7343 Bergman, R.G. Carter, W.L. J. Am. Chem. Soc., 1969, 91, 7411. 

Chan et al. [38] prepared optically active atropoisomeric 2,2 -bipyridine by nickel(0)-catalyzed homo-couphng of 2-bromopyridylphenol derivatives (structure 28 in Scheme 16). Tested in the model test reaction, the copper catalyst led to frans-cyclopropanes as major products with up to 86% ee. 

Baldwin et al. have used the same catalyst/diazo ester combination for the synthesis of optically active deuterated phenylcyclopropanes (Scheme 28) 197). From cis-1,2-dideuteriostyrene, d/-menthyl a-deuteriodiazoacetate and (+)-195d, the cis- and mnw-cyclopropanes 196 were obtained, both with 90% optical purity. The dominant enantiomer of trans-196 had (+)-(15, IS, 35) configuration. Analogously, the cyclopropanes c -198 and trans-198, obtained from styrene, d/-menthyl a-deuteriodiazoacetate and (+)-195d with subsequent transesterification of cisjtrans-197, had optical purities of 86 and 89%, respectively. The major optical isomer of cis-198 had (IS, 2R) configuration, that of trans-198 (IS, 2S) configuration. 

In 1966, Nozaki et al. reported that the decomposition of o-diazo-esters by a copper chiral Schiff base complex in the presence of olefins gave optically active cyclopropanes (Scheme 58).220 221 Following this seminal discovery, Aratani et al. commenced an extensive study of the chiral salicylaldimine ligand and developed highly enantioselective and industrially useful cyclopropanation.222-224 Since then, various complexes have been prepared and applied to asymmetric cyclo-propanation. In this section, however, only selected examples of cyclopropanations using diazo compounds are discussed. For a more detailed discussion of asymmetric cyclopropanation and related reactions, see reviews and books.17-21,225... 

Among methods of preparing optically active cyclopropane compounds, the Simmons-Smith reaction, first reported in 1958, is of significance. This reaction refers to the cyclopropanation of alkene with a reagent prepared in situ from a zinc-copper alloy and diiodomethane. The reaction is stereospecific with respect to the geometry of the alkene and is generally free from side reactions in contrast to reactions involving free carbenes. 

Noyori et al. (17) applied this catalyst to the asymmetric cyclopropanation of al-lenes and found that carbenoid transfer occurred selectively to the internal alkene, Eq. 4 (17). The product cyclopropanes 9 and 10 were formed in optically active form but the ee could not be determined, a reflection of the lack of analytical techniques available at the time. 

In their seminal report on homogeneous asymmetric copper-catalyzed cyclopropanation, Nozaki et al. (2) showed that racemic 2-phenyloxetane reacts with the diazoester-derived carbenoid to form cis and trans tetrahydrofurans (THF) in optically active form. Unfortunately, the extent of asymmetric induction could not be determined. 

The specific feature of the bonds also affects its chemical behaviour and the stereochemistry of substitution reactions. For example in the conversion of (-) trans -2, 3 diphenyl cyclopropane carboxylic acid into (+) 1, 3 diphenylallene the optical activity is retained. 

Now, let us examine the case where all three carbon atoms of cyclopropane become asymmetric and satisfied by different groups. In such a case because the molecule contains three different chiral centres, therefore, there will be 23 = 8 optically active forms (four pairs of enantiomers) and there will be four geometrical isomers. The different forms are (xxv) a-d). 

A very convenient asymmetric synthesis of cyclopropane or epoxide systems developed by Johnson (184) is based on the use of chiral sulfur ylides as the agents that induce optical activity. Generally, this method consists of the asymmetric addition of a chiral sulfur ylide to the C=C or C=0 bond and subsequent cyclization of the addition product to form a chiral cyclopropane or epoxide system together with chiral sulfinamide. A wide range of chiral... 

Mann and Barnes [45] have discussed the mechanism of reduction of substituted and optically active 1-bromo-and 1-iodocyclopropanes, and Hazard and coworkers [46] have investigated the reduction of l-bromo-l-carboxy-2,2-diphenyl-cyclopropane. At mercury cathodes, electrolyses of 1-bromo- and 1-iodonorbornane proceed via two-electron cleavage of the carbon-halogen bond to give mainly nor-bomane, plus a small amount of bis(l-norbomyl)mercury [47]. 

The asymmetric syntheses of carnosadine (lS,2S)-74 [101] and of its protected derivatives as conformationally constrained surrogates for arginine have also been reported [102]. Different 2-substituted 1-aminocyclopropanecarboxylic acids have also been prepared by azidation of optically active 2-chloro-2-cyclo-propylideneacetates [103] and from the cyclopropanation of chiral bicyclic lactams [104]. 

Mixed ( )-cinnamyl acetals 460 undergo the enantioselective carbolithiation readily in the presence of stoichiometric or catalytic amounts, as low as 1 mol%, of (—)-sparteine (11) (equation 126) °. When quenching the reaction mixture of 461, 462 below —50°C with MeOH/HCl, the alcohols 463 are obtained with good yields and excellent ee values. However, upon warming to 20 °C, a 1,3-cycloelimination from conformation 462 gives rise to the formation of optically active trani-cyclopropanes 464 °. 

Determination of the absolute configurations of these optically active fullerene derivatives was possible by comparison of their experimental and calculated circular dichroism (CD) spectra [96]. Tether controlled bis-cyclopropanation reactions have been extensively used to synthesize extended fimctional architectures such as dyads. 

The (ri" -diene tricarbonyliron)-substituted diazocarbonyl compounds 25 have been found to undergo 1,3-dipolar cycloaddition with methyl acrylate in high yield, but with little or no diastereoselectivity (56). Nevertheless, the facile chromatographic separation of the diastereomeric products 26a,b and 27a,b (Scheme 8.8), permits the synthesis of pure enantiomers when optically active diazo compounds (25) [enantiomeric excess (ee) >96%] are employed. When the reaction of 25 (R = C02Et) with methyl acrylate was carried out at 70 °C, cyclopropanes instead of A -pyrazolines were formed. The enantiomerically pure... 

The spiropyrazohnes obtained from 51 were converted into enantiopure A -pyrazoline-3-carboxylates and 1 -(hydroxyethyl)cyclopropane-1 -carboxylates (128). Those obtained from 54 and 55 were transformed into optically active a-spirocyclopropyllactones and 3-amino-3-(hydroxyethyl)pyrrolidin-2-ones (130). The spiropyrazoline obtained from a chiral propylidene-diketopiperazine and diazomethane was converted into (+)-(lR,25)-l-amino-2-ethyl)cyclopropane-l-carboxylic acid (allocoronamic acid) (135). 

Dihydro-2//-pyran also undergoes a highly stereoselective cyclopropanation reaction with methyl l-(tri-isopropylsiloxy)vinyldiazoacetate in the presence of a chiral rhodium catalyst. Optically active furo[2,3- 5 ]pyran derivatives are generated upon desilylation of the cyclopropanes (Scheme 40) <2005SL1397>. 

The mechanism of this unusual cis addition has not been clarified. The bromoethyl derivative 2 can be further alkylated (intramolecularly) to give the deuterated cyclopropyl derivative 3. Once again, cis addition predominates, with 46% de. Upon hydrolysis of the cyclopropyl derivative, optically active (V)-l-amino-cyclopropane-2-r/2-l-carboxylic acid (4) in 44% yield and 46% ee is obtained. 

Starting from optically active 1-chlorovinyl p-tolyl sulfoxide derived from 2-cyclohex-enone, the asymmetric synthesis of cyclopropane derivative (85) was realized (equation 23) . Addition reaction of lithium enolate of tert-butyl acetate to 83 gave the adduct (84) in 96% yield with over 99% ee. Treatment of the latter with i-PrMgCl in a similar way as described above afforded optically pure (15,6/ )-bicyclo[4.1.0]hept-2-ene (85) in 90% yield. 

The optically active cyclopropane 10 gave the chiral homoenolate of isobutyrate Eq. (14), an ethereal solution of which is both chemically and configurationally stable for a week at room temperature, and consequently can serve as a useful chiral building block [23],... 

These complexes can be isolated in some cases in others they are generated in situ from appropriate precursers, of which diazo compounds are among the most important. These compounds, including CH2N2 and others, react with metals or metal salts (copper, palladium, and rhodium are most commonly used) to give the carbene complexes that add CRR to double bonds.1063 Optically active complexes have been used for enantioselective cyclopropane synthesis.1064... 

The Kyoto group hoped to obtain more definitive evidence for the existence of carbene species bound covalently to copper. If such a species did exist, the use of an optically active copper catalyst should show some asymmetric induction in the cyclopropanation reaction. Indeed,... 

A number of attempts have been made to use optically active sulfur ylides to transfer the chirality of sulfur to carbon in the formation of epoxides and cyclopropanes. The results were somewhat disappointing. Thus, virtually no asymmetric induction was observed with the ylide (1) [475]. With the stabilized ylides (2), e.e. values in the range 7-43% were reported [476]. Better results were obtained with sulfonium ylides derived from Eliel oxathiane [477]. Optically active diaryl epoxides could be prepared under PTC in high yields and good e.e. values. 

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