Cydopropanation

The majority of preparative methods which have been used for obtaining cyclopropane derivatives involve carbene addition to an olefmic bond, if acetylenes are used in the reaction, cyclopropenes are obtained. Heteroatom-substituted or vinyl cydopropanes come from alkenyl bromides or enol acetates (A. de Meijere, 1979 E. J. Corey, 1975 B E. Wenkert, 1970 A). The carbenes needed for cyclopropane syntheses can be obtained in situ by a-elimination of hydrogen halides with strong bases (R. Kdstcr, 1971 E.J. Corey, 1975 B), by copper catalyzed decomposition of diazo compounds (E. Wenkert, 1970 A S.D. Burke, 1979 N.J. Turro, 1966), or by reductive elimination of iodine from gem-diiodides (J. Nishimura, 1969 D. Wen-disch, 1971 J.M. Denis, 1972 H.E. Simmons, 1973 C. Girard, 1974),... 

Furthei-more, the cyclization of the iododiene 225 affords the si.x-membered product 228. In this case too, complete inversion of the alkene stereochemistry is observed. The (Z)-allylic alcohol 229 is not the product. Therefore, the cyclization cannot be explained by a simple endo mode cyclization to form 229. This cyclization is explained by a sequence of (i) e.vo-mode carbopallada-tion to form the intermediate 226, (ii) cydopropanation to form 227. and (iii) cyclopropylcarbinyl to homoallyl rearrangement to afford the (F3-allylic alcohol 228[166]. (For further examples of cydopropanation and endo versus e o cyclization. see Section 1.1.2.2.)... 

Tab. 3.6 Tartrate reagent modification in the Simmons-Smith cydopropanation...

Hodgson et al. showed that a series of bis- and tris-homoallylic terminal epoxides underwent intramolecular cydopropanation to give a range of bicydic alcohols. A short asymmetric synthesis of sabina ketone based on this chemistry was demonstrated (Scheme 5.20). A practical advantage with this process is that the volatile epoxides can be replaced with readily available chlorohydrins, an extra... 

Cyclopropane, 1,1 -dibromo-2,2-diplienyl-[Benzene, l,l -(2,2-dibromocyclo-propylidene)bis-], 32 Cyclopropanecarboxyltc acid, 70 Cydopropanes, gem-dihalo, 32 CYCLOUNDECANONE, 107 Cycloundecanone, 2-hydroxy-, 110 Cycloundecene, 1-carboxy- [1-Cyclo-undecene-1-carboxylic acid], 111 Cycloundecene, 1-methoxy-, 111 1-Cycloundecene-l-carboxyhc acid, methyl ester, 108... 

S+1C] Cycloaddition Reactions Cydopropanation of Alkenes and Dienes with Fischer Carbene Complexes... 

The cydopropanation reaction of an unsaturated substrate is one of the most important strategies to access three-membered ring derivatives. The use of Fischer carbene complexes to perform this kind of cyclisation has become an important tool in organic synthesis [4]. In the next few sections the most significant features of this chemistry are briefly described. 

One of the earliest reported thermal reactions of Fischer carbene complexes was the reaction with olefins to give cyclopropanes [127]. More recently it has been shown that photolysis accelerates inter molecular cydopropanation of electron-poor alkenes [128]. Photolysis of Group 6 imine carbenes with alkenes... 

The best known of metal carbene reactions, cydopropanation reactions, have been used since the earliest days of diazo chemistry for addition reactions to the carbon-carbon double bond. Electron-donating groups (EDG) on the carbon-carbon double bond facilitate this catalytic reaction [37], whereas electron-withdrawing groups (EWG) inhibit addition while facilitating noncatalytic dipolar cycloaddition of the diazo compound [39] (Scheme 5). There are several reviews that describe the earlier synthetic approaches [1, 2,4, 5,40-43], and these will not be duplicated here. Focus will be given in this review to control of stereoselectivity. 

The Rh2(DOSP)4 catalysts (6b) of Davies have proven to be remarkably effective for highly enantioselective cydopropanation reactions of aryl- and vinyl-diazoacetates [2]. The discovery that enantiocontrol could be enhanced when reactions were performed in pentane [35] added advantages that could be attributed to the solvent-directed orientation of chiral attachments of the ligand carboxylates [59]. In addition to the synthesis of (+)-sertraline (1) [6], the uses of this methodology have been extended to the construction of cyclopropane amino acids (Eq. 3) [35], the synthesis of tricyclic systems such as 22 (Eq. 4) [60], and, as an example of tandem cyclopropanation-Cope rearrangement, an efficient asymmetric synthesis of epi-tremulane 23 (Eq. 5) [61]. 

Generally, push-pull substituted cydopropanes as 2-364 are flexible building blocks and represent an equivalent for 1,4-dicarbonyl compounds. They show a pronounced tendency to undergo ring opening [202]. 

Rhodium(II) acetate was found to be much more superior to copper catalysts in catalyzing reactions between thiophenes and diazoesters or diazoketones 246 K The outcome of the reaction depends on the particular diazo compound 246> With /-butyl diazoacetate, high-yield cydopropanation takes place, yielding 6-eco-substituted thiabicyclohexene 262. Dimethyl or diethyl diazomalonate, upon Rh2(OAc)4-catalysis at room temperature, furnish stable thiophenium bis(alkoxycarbonyl)methanides 263, but exclusively the corresponding carbene dimer upon heating. In contrast, only 2-thienylmalonate (36 %) and carbene dimer were obtained upon heating the reactants for 8 days in the presence of Cul P(OEt)3. The Rh(II)-promoted ylide formation... 

This new protocol provides easy access to various functionally substituted amino-cydopropanes, including cydopropylamino acid derivatives [119], although the yields and diastereoselectivities obtained with this approach leave room for further improvement. 

Progress has also been reported in applying titanium-mediated cydopropanation reactions as a key step in the preparation of natural products. For example, racemic stigmo-lone (8-hydroxy-2,5,8-trimethylnonan-4-one) 163, a pheromone of the myxobacterium Stigmatella aurantiaca, has been synthesized in 67% overall yield by the titanium-mediated hydroxycyclopropanation of 2-methyl-5-hexen-2-ol 161 with ethyl isovalerate 160 followed by base-induced ring-opening of the resulting 2-(3-hydroxy-3-methylbutyl)-1-isobutyl-l-cyclopropanol 162 (Scheme 11.41) [139]. 

Nitromethane, cyanomethyl phenyl sulfbne 78a, and benzyl cyanoacetate 78b underwent the asymmetric cydopropanation with 2-bromo-2-cydo-... 

In principle, the direct cydopropanation of vinylallenes and related substrates also allows the preparation of cydopropylallenes. However, because of low or no discrimination between the differrent double bonds, complex product mixtures are to be expected. A case in point is provided by 1,2,4,5-hexatetraene (12), which yields the cyclopropylallene 149 on diazomethane/CuX treatment - but only in a (difficult to separate) mixture with all other cydopropanation products of 12 (Scheme 5.21) [61]. 

In semicydic allenic hydrocarbons, one of the terminal allene carbon atoms is part of an alicyclic ring system, as illustrated by the general structure 37 in Scheme 5.3. Numerous hydrocarbons of this type are known, some of them carrying more than one allene group, such as in the case of the conjugated bisallenes 127 and 129 (see Scheme 5.17), and many of them are described in the review literature [2] and will not be repeated here. However, since Chapter 6 on cycloallenes does not treat these derivatives, some new developments in this area will be briefly presented, limited to the two cases in which cydopropane rings form the end groups of the allene moiety, i.e. 246 and 249. 

The cydopropanated version of 3, l,3-di(cyclopropyl)allene (18), has been used as a coupling partner in Heck-type reactions. For example, with iodobenzene the conjugated cyclopropylhexatriene 330 is obtained whereas repetition of the experiment in the presence of dimethyl maleate yields the Diels-Alder adduct 331 [58]. 

Dipolar cydoaddition of ethyl 2-(ethoxycarbonyl)-4,4-diphenyl-2,3-butadieno-ate 518 with CH2N2 or Ph2CN2 afforded bicyclic or monocyclic products 519 and 520, respectively. The possibility of extra cydopropanation depends on the steric effect of the diazo compound [234]. 

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