Cyclopropanations chiral electrophiles

Since the first experiments with chiral copper complexes reported by Nozaki [650] and Aratani [1027] many different catalysts have been examined, both for intermolecular and intramolecular cyclopropanations (for a review, see [1369]). Syntheses of natural products [955,1370] and drugs [1371] using asymmetric cyclopropanation with chiral electrophilic carbene complexes have been reported. A selection of useful catalysts is given in Figure 4.20 (see also Experimental Procedure 4.1.1). 

Dinuclear Rh(II) compounds are another class of effective catalysts (227). Electrophilic carbenes formed from diazo ketones and dimeric Rh(II) carboxylates undergo olefin cyclopropanation. Chiral Rh(II) carboxamides also serve as catalysts for enantioselective cyclopropanation (Scheme 95) (228). The catalysts have four bridging amide ligands, and... 

Chiral electrophilic cyclopropanes (63) are prepared in high enantiomeric excess starting from butadiene-iron tricarbonyl complexes (60) containing a non-complexed double bond. Reaction with diazomethane and decomposition of the resulting pyrazolines (61) in the presence of Ce" gave the corresponding chiral cyclopropanes (62). Breakdown of the dienic substituent of electrophilic cyclopropane (62) by means of ozonization resulted in the formation of formyl-substituted electrophilic cyclopropane (63) still carrying the asymmetric centre (equation 10) " . ... 

A more common strategy for stepwise asymmetric cyclopropanation is the use of chiral electrophiles. Meyers has used bicyclic lactams (c/. Scheme 3.19, 3.20) [145,146] as electrophilic auxiliaries in sulfur ylide cyclopropanations [147]. These auxiliaries, for reasons that are not entirely clear, are preferentially attacked from the a-face. After separation of the diastereomers, the amino alcohol auxiliary may be removed by refluxing in acidic methanol or reductively [145]. This methodology has been used in asymmetric syntheses of cw-deltamithrinic acid and dictyopterene C, illustrated in the inset of Scheme 6.40 [145]. 

Among the transition-metal catalysts that have been used, only those of Pd(II) are productive with diazomethane, which may be the result in cyclopropanation reactions [7,9,21] of a mechanism whereby the Pd-coordinated alkene undergoes electrophilic addition to diazomethane rather than by a metal carbene transformation in any case, asymmetric induction does not occur by using Pd(II) complexes of chiral bis-oxazolines [22],... 

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... 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

The Simmons-Smith reaction is an efficient and powerful method for synthesizing cyclopropanes from alkenes [43]. Allylic alcohols are reactive and widely used as substrates, whereas a,j8-unsaturated carbonyl compounds are unreactive. In 1988, Ambler and Davies [44] reported the electrophilic addition of methylene to a,/3-unsaturated acyl ligands attached to the chiral-at-metal iron complex. The reaction of the racemic iron complex 60 with diethylzinc and diiodomethane in the presence of ZnCl2 afforded the c/s-cyclopropane derivatives 61a and 61b in 93 % yield in 24 1 ratio (Sch. 24). 

Reissig and coworkers have devised an indirect method of enantioselective alkylation of ketones via cyclopropanation of silyl enol ethers in the presence of the chiral copper catalyst 16, followed by ring opening to provide the substituted ketones. Overall, the transformation corresponds to alkylation of ketones using methyl diazoacetate as the electrophile. Enantioselectivities up to 88% were realized in the cyclopropanation of aryl substituted olefins, Eq. (20) [63,64]. 

Nitroalkenes are regarded as good electrophiles toward conjugate addition. Chiral organocatalysts effectively promoted an asymmetric MIRC reaction. Connon and coworkers reported that the enantioselective asymmetric cyclopropanation of nitrostyrenes was achieved in the presence of quinine-derived thiourea 6. The enantiomeric excesses reached up to 47% ee (Scheme 1.4) [7]. 

The Zr-Zn transmetalation, aldehyde addition strategy has also been used in the total syntheses of (-)-ratjadone [85] and fostriecin. In the latter example, the substrate was a chiral epoxyketone, which was converted to a tertiary alcohol in excellent diastereoselectivity by chelation control [86]. More recently, the reaction scope has been extended to the addition to C=N electrophiles to form allylic amides [87] as well as allyl hydroxylamines [88], and to the preparation of frans-1,2-disubstituted cyclopropanes [87, 89]. Powell and Rych-novsky found that the BF3-mediated addition to in situ formed oxacarbenium ions led to a mixture of alkyl and alkenyl ligand transfers [90] (Scheme 18). 

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