Geminally activated cyclopropanes

A large number of cyclopropanes geminally substituted with two electron-withdrawing groups have been synthesized by cyclopropanation of olefins with carbenes substituted with two electron-withdrawing groups (equation 36) Spiro-activated cyclopropanes... 

In our last look at prostaglandins, we can see this put to use in an approach to some prostaglandin derivatives. The plan was to construct PG derivatives from an intermediate of type 216. This j8-ketoester was to be derived from a Dieckmann condensation (construction of the C9-C10 bond). The Dieckmann precursor was to be derived from the reaction of malonate 215 with geminally activated cyclopropane 214. Note that control of absolute stereochemistry in this route leads back to 209, which was resolved as its brucine salt. It is also notable that 214 reacts selectively with malonate 215 at the more hindered secondary (but allylic) carbon of the cyclopropane with clean inversion of configuration. 

This brings to a close to our examination of routes to prostaglandins. I have chosen the geminally activated cyclopropane route as the last route to provide an entree to our next topic, synthesis of pyrrolizidine alkaloids discussed in Chapter 4. This is not the only connection between these two topics. Prostaglandins and pyrrolizidines both contain 5-membered rings as important substructures, and the acyclic diastereoselection problem rears its head in both families of natural products. Thus, there will be some overlap in chemistry as well as some new strategies to study as we move forward. 

Recall the geminally activated cyclopropane chemistry we saw in Chapters 3 and 4. Propose diastereoselective syntheses of 14 and 15 that revolve around this methodology. (Juvabione-21)... 

Indeed, in a study of reaction rate and efficiency as a function of geminal substitution of the VCP, it was found that heteroatom substitution was not required to activate the VCP for intermolecular [5+2] cydoaddition (Tab. 13.14) [51]. Substitution for -H at the 1-position of the cyclopropane with -Me, -TMS, or - Pr led to an acceleration of the reaction that correlated with size of the substituent. Significantly, good to excellent yields and high, if not complete, regioselectivities are observed with a variety of mono-substituted alkynes and simple, unactivated VCPs. 

The cyclopropanation reaction originally developed by Simmons and Smith utilized for eliminating iodine from a geminal diodide the reducing agent zinc, which had previously been activated by copper.23... 

Chemistry of cyclopropane derivatives, which combine different sorts of activating substituents, has less definitely been investigated and their synthetic potentials have only recently been explored. Whereas geminally donor-acceptor-substituted systems 6 were treated in preceeding contributions to this series 5 6 7), this review will be confined to vicinally activated compounds 7. 

Most of the nucleophilic openings of cyclopropanes have involved two geminally placed activating groups, usually esters. Thus, cyclopropanedicarboxylates (18) have undergone... 

A convenient procedure for the preparation of geminally disubstituted cyclopropanes is the successive alkylation and cyclization of active methylene compounds with 1,2-dihaloal-kanes. - This reaction can be termed a substitution initiated ring-closure reaction (SIRC), in analogy with the Michael initiated ring-closure reaction discussed in Section 1.1.3.7. 

Cyclopropane with two geminal benzenesulfonyl groups as activating functions as in 3 reacted with benzenethiolate with ring opening. The carbanion formed as an intermediate could be trapped by alkyl halides such as iodomethane and allyl bromide. ... 

The 1,3-dipolar cycloaddition of diazomethane to bicyclic 2,/S-unsaturated /-lactams produces pyrazolidines which are transformed photolytically into cyclopropane derivatives80. The overall yields arc moderate to good while the diastereomeric ratio is at least 95 5. Reaction of the thiomethyl-substituted lactam with 2-diazopropane provides the corresponding geminal dimethyl-substituted cyclopropane with a d.r. of 95 5. These cyclopropane derivatives have been used for the synthesis of optically active cyclopropanecarboxylates and ethenylcyclopropanes80. 

It soon became evident that the ester structure is necessary for their activity and both the acidic and the alcoholic hydrolysis products are inactive. Also the geminal methyl groups on the cyclopropane ring and the unsaturated side chains proved to favour insecticidal action. Based on these considerations Schechter et al. (1949) synthesised the ( )-3-allyl-2-methyl-4-oxo-cyclopent-2-en-l-yl ester of ( )-( ,. chrysanthemic iund (27) which became known under the name allethrin. 

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