Cyclopropanes Enolate alkylation

Longifolene has also been synthesized from ( ) Wieland-Miescher ketone by a series of reactions that feature an intramolecular enolate alkylation and ring expansion, as shown in Scheme 13.26. The starting material was converted to a dibromo ketone via the Mr-silyl enol ether in the first sequence of reactions. This intermediate underwent an intramolecular enolate alkylation to form the C(7)—C(10) bond. The ring expansion was then done by conversion of the ketone to a silyl enol ether, cyclopropanation, and treatment of the siloxycyclopropane with FeCl3. 

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. 

Diverging results have been reported for the carbenoid reaction between alkyl diazoacetates and silyl enol ethers 49a-c. Whereas Reissig and coworkers 60) observed successful cyclopropanation with methyl diazoacetate/Cu(acac)2, Le Goaller and Pierre, in a note without experimental details u8), reported the isolation of 4-oxo-carboxylic esters for the copper-catalyzed decomposition of ethyl diazoacetate. According to this communication, both cyclopropane and ring-opened y-keto ester are obtained from 49 c but the cyclopropane suffers ring-opening under the reaction conditions. 

Vinyl acetate fails to react with dihalocarbenes, but reacts with the trihalo-methyl anion precursor to produce the l,l,l-trihalo-2-acetoxypropane [33, 166-168], In contrast, where the a-position is substituted by an alkyl group, normal cyclopropanation occurs. Cyclic enol acetates behave in a similar fashion to the enol ethers [12, 88], e.g. bicyclo[3,2,l]oct-2-enyl acetate and its 3-isomer... 

In cyclopropanations with electrophilic carbene complexes, yields of cyclopropanes tend to improve with increasing electron density of the alkene. As illustrated by the examples in Table 3.5, cyclopropanations of enol ethers with aryldiazomethanes often proceed in high yields. Simple alkyl-substituted olefins are, however, more difficult to cyclopropanate with diazoalkanes. A few examples of the cyclopropanation of enamines with diazoalkanes have been reported [650]. 

Intramolecular alkylation of phenol with diazoketone [14] can be analyzed as the following The carbenoid center acts first as an acceptor and then a donor. Since the resulting cyclopropane derivative is vicinally substituted with an acceptor (C=0) and a donor (enol), fragmentation follows instantaneously (vide infra). 

This topological rule readily explained the reaction product 211 (>90% stereoselectivity) of open-chain nitroolefins 209 with open-chain enamines 210. Seebach and Golinski have further pointed out that several condensation reactions can also be rationalized by using this approach (a) cyclopropane formation from olefin and carbene, (b) Wittig reaction with aldehydes yielding cis olefins, (c) trans-dialkyl oxirane from alkylidene triphenylarsane and aldehydes, (d) ketenes and cyclopentadiene 2+2-addition, le) (E)-silyl-nitronate and aldehydes, (f) syn and anti-Li and B-enolates of ketones, esters, amides and aldehydes, (g) Z-allylboranes and aldehydes, (h) E-alkyl-borane or E-allylchromium derivatives and aldehydes, (i) enamine from cyclohexanone and cinnamic aldehyde, (j) E-enamines and E-nitroolefins and finally, (k) enamines from cycloalkanones and styryl sulfone. 

Examples of the preparation of cyclopropanes by intramolecular nucleophilic substitution are illustrated in Scheme9.17. The first example is a synthesis of [l.l.ljpro-pellane, which yields the product in acceptable yields, despite the high strain and poor stability of this compound [66]. The second and third examples illustrate the remarkable ease with which 3-halopropyl ketones cyclize to yield cyclopropanes instead of cyclic, five-membered enol ethers or ketones. Similarly, carbamates of 2-haloethylglycine esters do not undergo intramolecular N- or O-alkylation on treatment with bases, but yield cyclopropanes instead [67, 68]. Some nucleophiles can undergo Michael addition to 3-halomethyl acrylates faster than direct Sn2 reaction, to yield cyclopropanes by cyclization of the intermediate enolates (fourth example, Scheme9.17) [69]. 

Simmons-Smith regioselective cyclopropanation of a-enone alkyl enol ethers also provided 1-alkoxyvinylcyclopropanes in high yields43 . 

For the introduction of further substituents at C-l of methyl 2-siloxycyclopropane-carboxylates 97 the deprotonation and smooth alkylation of the resulting enolates is a very feasible route (Eq. 33) 68). It opens the way to a large variety of cyclopropanes without the necessity of preparing a new diazo compound for every desired substituent at C-l. 

Another site-selective reaction of 35 with a,/3-unsaturated carboxylic acid derivatives in the presence of a Lewis acid has been reported (Scheme 25) [35]. The intermediate 37 possesses two nucleophilic sites the zirconium alkyl and the enol ether moieties. Starting from 37, two competing pathways lead accordingly to cyclopropane (38, path a) and/or cyclobutane (39, path b) derivatives. The... 

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