Activation cyclopropanation

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... 

The increasingly common theme of developing new pyrrole syntheses that involve cyclopropane fragmentations appeared in a type Ilae pyrrole synthesis <06OL835>. Treatment of doubly activated cyclopropane 43 with benzylamine in the presence of magnesium sulfate led to complex pyrrole 44 via a nucleophilic cleavage of the cyclopropane ring, intramolecular condensation, and isomerization of the exocyclic JC-bond. 

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. 

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],... 

Another type of chiral Michael acceptor, the oxazepine derivatives (47), is prepared by condensation of the (-)-ephedrine-derived malonic acid derivative (46) with aldehydes (Scheme 18).51 52 Treatment of (47) with a variety of Grignard reagents in the presence of NiCh affords, after hydrolysis and decarboxylation, the 3-substituted carboxylic acids (48), in most cases with more than 90% ee. Diastereoselective Michael additions to (47) were also used for the preparation of optically active cyclopropane derivatives (49)53 and P-substituted-y-butyrolactones (50 Scheme 18).54 A total synthesis of indolmycin is based on this methodology.55... 

In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

A remarkable complex (33) with a C2-symmetric semicorrin ligand has been recently developed by Pfaltz and coworkers.64 A copper(II) complex was used as a procatalyst, but (33) was shown to be the active cyclopropanation catalyst. As shown in Table 3, this complex resulted in spectacular enantioselecti-vities in the range of 92-97% ee. Once again, the (15,35,4/ )-menthyl group attenuated the selectivity. Unfortunately, even though respectable yields were obtained with dienes and styrenes, the reaction with 1-heptene was rather inefficient. 

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... 

Cyclopropanation of lactams,1 This reagent adds to the chiral bicyclic lactams 2 (13,18-19) to form endo-cyclopropanated adducts (3) in >93% de. These adducts are hydrolyzed to optically active cyclopropanes (4). 

Activated cyclopropanes in the synthesis of 5-membered heterocycles 93UK887. 

Therefore acceptor cyclopropanes 1 will be ring opened by nucleophiles N to provide products like 2 (homo Michael addition) as depicted in Eq. 1. On the other hand, electrophiles E+ cleave donor activated cyclopropanes 3 affording adducts 4 or 5 which demonstrates that the cyclopropane serves as a homoenolate equivalent in this sequence (Eq. 2). Seebach consequently classified these methods as umpolung with the cyclopropane trick 4. ... 

Although methyl 2-siloxycyclopropanecarboxylates are cleaved by certain electrophiles, only tetracyanoethylene (TCNE) as a carbon electrophile could directly be added to phenyl or vinyl activated cyclopropanes providing cyclopentane derivatives 61). 

In principle the addition could be controlled by a chiral centre at C3 or by chiral auxiliaries in the C1 or C2 substituents or the addend. This would provide a versatile route to optically active cyclopropanes, but to date no emphasis has been laid on this possibility. Instead, a wide range of additions leading to racemic cyclopropanes has been examined. 

Allylsilanes act as good acceptors of nitrones and oxyallyl cations. The 1,3-dipole species arising from electronically activated cyclopropanes can be trapped by allylsilanes.203 204 2043 Epoxides as well as aziridines act as 1,3-dipole precursors for inter- and intramolecular [3 + 2]-cycloadditions with allylsilanes.205 2053 206 2063... 

The procedure described here for compound 1 is a scaleup of a published method.6 Phase-transfer catalysis7 and concentrated alkali are used to effect a one-pot conversion of diethyl malonate to the cyclopropane diacid, which is easily obtained by crystallization. Apparently alkylation of the malonate system occurs either at the diester or monocarboxylate, monoester stage since the method fails when malonic acid itself is used as the starting material. This method of synthesizing doubly activated cyclopropanes has been extended to the preparation of 1-cyanocyclopropanecar-boxylic acid (86%) by the use of ethyl cyanoacetate and 1-acetyl-cyclopropanecarboxylic acid (69%) by use of ethyl acetoacetate.6... 

Z)-Disubstituted cyclopropanes. The (Z)-vinylstannane 2 (above) reacts with the Simmons-Smith reagent to give the c/i-l,2-disubstituted cyclopropane 3 in 70% yield. The product is useful for pteparation of optically active cyclopropanes. 

Stereoselectivity) is observed however, for ethylidene complexes of Fe(CO)(PR3)Cp (69) the products reflect trans selectivity. This difference in stereoselectivity has been suggested to be dependent upon which conformer is more reactive. The reaction of a chiral-at-iron cationic carbene complex (70) with styrene or vinyl acetate affords optically active cyclopropane products with high enantioselectivity (Scheme 24). h >3 intramolecular cyclopropanation, as in the case of (71), proceeds moderately well for the formation of norcarane-type ring systems however, intramolecular C-H insertion is a competing pathway when the alkene is highly... 

In 2002, Eaton introduced an even stronger depro-tonating/metallating reagent, BuMgNiPr2, which also is usefully stable in THE, and can completely deprotonate amide-activated cyclopropanes by irreversible formation of butane. This process was applied in a new synthetic route to the antidepressant, Milnacipran (equation 33). 

Activated cyclopropanes 33 react with nucleophilic selenium species to give the ring-opened products 34 in moderate to good yields (Scheme 33) [56]. This reaction has been used for natural product synthesis [57]. 

The opening of activated cyclopropanes with nitrogen nucleophiles has been widely applied to the synthesis of pynolizidine and pyrroline alkaloids by Danishefsky this subject has been reviewed. A number of pyrroline annulations have been based on this principle, illustrated in equation (35a). > Similar opening can be accomplished with halides, cuprates, and sulfur or selenium nucleophiles. ... 

The stereoselectivity of the attack of the enolate on the activated cyclopropane most likely is due to steric factors arising from the preferred pseudoaxial conformation of the incipient methyl group . In other words, the approach of the rather bulky phosphonium salt II is less perturbed by the methyl group when it rests on the opposite side of the molecule in the transition state, presumably in the pseudoaxial conformation, as portrayed in IX. This remarkable stereoselectivity has been put to good use in the synthesis of some natural products of the spirovetivane family. ... 

This experiment, which combines well anticipated and totally unexpected results, was designed to compare the thermal versus the Lewis acid-catalyzed rearrangement of a doubly activated cyclopropane. This twofold activation was understood in terms of the electron donating effect of the p-anisyl substituent at C-2 that is complementary to the familiar electron withdrawal of the 1,1 -diacyl substitution, which closely resembles Problems 15 and 23. This combination, called captodative cyclopropanes, considerably facilitates some of the various ring unraveling pathways open to the trimethylene ring. 

If compound II is electrophilic, the involvement of the 7 carbon of VI now becomes clear. Thus, the sodium hydride generated anion V may be imagined as attacking nucleophilically carbon C-2 of activated cyclopropane II. The resulting anion is precisely the proposed phosphorous ylide postulated as structure VII by our previous fragmentation analysis. What follows then is an intramolecular Wittig reaction with the departure of triphenylphosphine oxide that was predicted by the atom budget procedure (see Scheme 17.2). 

Optically active complexes have been used for enantioselective cyclopropane synthesis. Decomposition of diazoalkanes in the presence of chiral rhodium copper, or ruthenium complexes leads to optically active cyclopropanes. 

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