Cyclopropanes using Michael addition

Although the base-catalyzed addition of nitroalkanes to electron-deficient olefins has been extensively used in organic synthesis (see Michael addition Chapter 4), it is only recently that the reaction has been extended to the cyclopropanation reaction. In 1978, it was reported that the anion of nitromethane reacts with certain highly electron-deficient olefins to produce cyclopropanes in good yield (Eq. 7.36).36 More recently, this reaction has been extended to more general cyclopropanations, as shown in Eqs. 7.37 and 7.38, in which potassium salts of nitroalkanes are employed in DMSO as alkylidene transfer reagents.37-39... 

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... 

The synthetic implications of this discovery were slow to be exploited. Base-initiated dimerizations of 2-cycloalkenones, known to give crystalline solids,3233 remained puzzling for some time before conjugate additions were suggested to account for some of the possible products 34 indeed, the product of base-catalyzed dimerization of 4,4-dimethyl-2-cyclopentenone, which proceeds via a double Michael addition sequence, was not identified until 1969 (Scheme 2).35 An unanticipated cyclopropanation reaction of acrylaldehyde36 37 using ethyl bromomalonate and proceeding by means of a similar Michael addi-tion-Sw enolate alkylation represents an early synthetic use of tandem vicinal difunctionalization. 

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... 

An interesting feature of Michael addition reactions is that Michael acceptors with a leaving group (mostly halides) in y-position can be used for the synthesis of cyclopropanes. The so-called Michael-initiated ring closure reaction (MIRC reaction) starts with an addition of a nucleophile to the a,/3-unsaturated carbonyl, and afterwards the intermediate enolate displaces the leaving group to give the desired cyclopropanes. ... 

Addition reactions to olefins can be used both for the construction and for the functionalization of molecules. Accordingly, chiral catalysts have been developed for many different types of reactions, often with very high enantioselectiv-ity. Unfortunately, most either have a narrow synthetic scope or are not yet developed for immediate industrial application due to insufficient activities and/ or productivities. These reactions include hydrocarbonylation [Ilf], hydrosilyla-tion [12 i], hydroboration [12j], hydrocyanation [12 k], Michael addition [11 g, 121, 12 m], Diels-Alder reaction [11 h, 12n] and the insertion of carbenes in C-H bonds [Hi, 12p, 12q, 38], Cyclopropanation [Hi, 12p, 12q] and the isomerization of allylamines [12 s] are already used commercially for the manufacture of Cilastatin (one of the first industrial processes) [12 r], and citronellol and menthol (presently the second largest enantioselective process) [12t] respectively. 

Alkenes susceptible to Michael additions react with sulfur ylides to form cyclopropanes. Examples of typical ylides used in the cyclopropanation reaction of Michael acceptors are presented in Scheme 4. Best results were obtained with stabilized ylides, i.e. ylides of type C, D or E, and yields were enhanced with increase of the electron-withdrawing capacity of the anion stabilizing group in the alkene. The mechanism of the cyclopropanation reaction (Scheme 5) is known, and proceeds in a nonstereospecific manner. The E/Z geometry of the alkene is frequently retained in the product and a high degree of asymmetric induction can be achieved with optically active Michael acceptors or ylides. 

The use of the carbanion derived from the chloroallylphosphonate (163) in the enantioselective synthesis of cyclopropanes (164) by Michael addition to a,P-unsaturated ketones has been the subject of a short review (Scheme 18). Denmark s group have published full details of the asymmetric Michael addition reactions of cyclic enones with carbanions derived from l,3,2-oxa2aphosphor-inane 2-oxides (165) and (167). y-Addition to give (166) predominates although the extent of this depends on the ring size of the Michael acceptor. The level of diastereoselectivity depends on the stereochemistry of the allylphosphonate used ... 

This type of acyclic nucleoside could be prepared by a Michael addition process. Thus, when 2-amino-6-chloropurine was reacted with 485, and 8 1 mixture of the N-9 (486) and N-7 cyclopropylpurines was produced. When the chloroethylidene malonate was used, the ratio became 40 1. Catalytic hydrogenation of 486 in presence of base effected both dehalogenation and 1,2-cyclopropane bond fission to provide 487. Its reduction and acetylation gave Famciclovir 488 (91EUP420559 92TL4609). 

A bicyclo[3.1.0]hexane system was catalytically prepared by cyclopropanation of cyclo-pentenone through Michael addition followed by displacement using TMG (1) as a catalyst in high yield and high diastereoselectivity [95] (Scheme 4.38). TMG (1) used was quantitatively recovered as the hydrobromide salt by simple filtration. DBU was found to react less. 

Sulfur ylides are useful as nucleophilic alkylidene transfer agents in reactions with electron-deficient functional groups, forming epoxides with carbonyls, and either undergoing carbonyl addition with epoxide formation or conjugate addition with cyclopropanation with Michael acceptors, depending on the structure of the Michael acceptor [113]. 

If the nucleophile utilised in the Michael addition carries a leaving group, subsequent nucleophilic displacement can take place. This concept was realised using halomalonates or ketoesters (Scheme 8.31). Several teams developed various strategies to achieve chiral cyclopropanes in this... 

Condensatioii Reactions.—Little emphasis has been placed on the use of condensation reactions in cyclopropane synthesis during the past year. Dimethylsulphoxonium methylide has been used for cyclopropanation of the side-chain double bond in brassicasterol, a A steroidal diene, due to the failure of carbene and carbenoid additions. Michael addition of the ylide (136) to acrolein affords an isomeric mixture of cyclopropanes, whereas addition to acrylonitrile stereoselectively gives only one isomer, the identity of which has not been established. An analogous... 

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