Natural Cyclopropanes

Natural Cyclopropanes.—A useful review of the synthesis of pyrethroid acids has been published which includes a discussion of general methods for cyclopropane ring formation.  

Natural Cyclopropanes.—The synthesis of a 2 3 mixture of cis-and tra 5-isomers of racemic ethyl chrysanthemate by addition of ethyl diazoacetate to 2,5-dimethyl-hexa-2,4-diene in the presence of copper powder was first reported in 1924. Aratani et al. have now shown that when the addition is carried out with 1-menthyl diazoacetate in the presence of the chiral (R) copper complex (17), an asymmetric synthesis can be effected leading to a 72 28 mixture of trans-[90% (-l-)-enantiomer] and ci s-[60% (-H )-enantiomer] isomers. Two interesting and new 

Kitatani, H. Yamamoto, T. Hiyama, and H. Nozaki, Bull. Chem. Soc. Japan, 1977, 50, 2158. 

Reagents i, NaNH2-MeI ii, O3 iil, MeOH-HCl iv, KOBu v, LDA-CIPO(OEt)2 vi Li-EtNH2 vii, H viii Collins 

Reagents i, O3 ii, m-ClC6H4C03H iii, CH2N2 iv, MeMgl v, Collins vi, Br2-CHCl3 vii, NaOMe viii, POCI3-C5H5N 

Ishwarane (20) and ishwarone (25) are two novel tetracyclic sesquiterpenes which have been isolated from Aristolochia indica Linn, and other tropical plants a synthesis of ishwarane was reported by Kelly and his co-workers in 1971. Kelly and Alward have now effected an improved synthesis of the hydrocarbon, which 

Hevesi, P. Bayet, and A. Krief, Tetrahedron Letters, 1976, 3911. M. Sevrin, L. Hevesi, and A. Krief, Tetrahedron Letters, 1976, 3915. 

In an entirely new approach to the synthesis of chrysanthemic acid, Bullivant and Pattenden have described the photochemical di-7r-methane rearrangement of diene ester (19), which in hexane produces the cyclopropane in 15% yield the major product from the photolysis is the geometrical isomer (20) of the starting diene ester (c/. ref. 22). 

Matsui, and Y. Takahatake, Tetrahedron Letters, 1976, 4359. M. Apparu and M. Barrelle, Tetrahedron Letters, 1976, 2837. 

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N.m.r. Studies Involving EuCfod),.—Assignments for dichloroketen-olefln adducts induced shifts in a heteronuclear bicyclic amine concerning the relative shifting abilities of Eu(fod)a and Eu(dpm)3 simplification of complex thiosulphinate spectra stereochemical assignments for some natural cyclopropanes C and H n.m.r. spectra of quinoline in the presence of Eu(fod)3 and (fod)3 application to flavones penicillin derivatives differentiation between cis- and trans-forms of cyclic azo-compounds shift differences between diastereotopically related protons in chiral alcohol and diol substrates effect on the spectra of secondary amides concerning alcohol-Eu(fod)3... 

Natural Cyclopropanes.—Synthetic pyrethroids have been the subject of a review.Krief and his co-workers continue their activity in this field. Their one-pot synthesis of chrysanthemic ester is outlined in Scheme 2. A noteworthy feature is their observation that cyclopropanation must occur at the betaine stage (18), since (19) does not react with the ylide to form (20). An alternative route to chrysanthemic acid (23) features the formation of the cyclopropane (22) by addition of cyanide ion to (21). ... 

Most workers have preferred to prepare stable derivatives prior to analysis. For example, cyclopropene fatty acids can be subjected to hydrogenation, or reaction with silver nitrate [449] or methanethiol [746]. Silver nitrate in anhydrous methanol reacts with cyclopropene rings in about 2 hours at 30 C to form predominantly methoxy ether but with some enonic derivatives, which appear as twin peaks (because of reaction on either side of the ring) on analysis by GC [99,241,281]. An application of this procedure to the analysis of kapok seed oil is illustrated in Figure 5.14. Alternatively, a brief reaction with hydrazine will selectively reduce the cyclopropene compounds to the more stable cyclopropanes by examination by GC before and after the reaction, the small amounts of natural cyclopropane components can also be identified [194]. 

Natural Cyclopropanes.—Ficini etal. have outlined a new approach to chrysaU themic acid ester (11) from commercially available 2,5-dimethyl-3-hexyn-2,5-diol, which has as a key stage the palladium-catalysed alkylation of the sulphone ester (10) with the acetate (9) (Scheme 3). cw-Chrysanthemic acid (14, R = H), is obtained by hydrogenation of the cyclopropene (13) produced by addition of diazopropane to the enyne (12). ... 

Natural Cyclopropanes.—Pyrethroids are available by cyclization of the epoxyamide (9) and dehydration with the sulphurane reagent (10) (Scheme 1). 

Natural Cyclopropanes.—In extensions of their earlier investigations of the synthesis of chrysanthemic acid (25) based on elaboration of the cyclopropane ring by reaction between the isopropyl ylide (22) and alkene substrates (see Volume 1, p. 292), Krief and his co-workers have now shown that the ylide (22) can be added to both maleate and fumarate, leading to the frans-cyclo-propanedicarboxylate (23). Conversion of the diester into the aldehydo-ester (24) and Wittig reaction then completes a new synthesis of chrysanthemic acid (Scheme 5). 

Ethylene occurs naturally in small amounts as a plant hormone Hormones are substances that act as messengers to regulate biological processes Ethylene IS involved in the ripening of many fruits in which it IS formed in a complex series of steps from a com pound containing a cyclopropane ring... 

The alkyl-bridged structures can also be described as comer-protonated cyclopropanes, since if the bridging C—C bonds are considered to be fully formed, there is an extra proton on the bridging carbon. In another possible type of structure, called edge-protonated cyclopropanes, the carbon-carbon bonds are depicted as fully formed, with the extra proton associated with one of the bent bonds. MO calculations, structural studies under stable-ion conditions, and product and mechanistic studies of reactions in solution have all been applied to understanding the nature of the intermediates involved in carbocation rearrangements. 

Flammable gases and vapors include acetylene, hydrogen, butadiene, ethylene oxide, propylene oxide, acrolein, ethyl ether, ethylene, acetone, ammonia, benzene, butane, cyclopropane, ethanol, gasoline, hexane, methanol, methane, natural gas, naphtha, and propane. 

In addition to unsaturated fatty acids, several other modified fatty acids are found in nature. Microorganisms, for example, often contain branched-chain fatty acids, such as tuberculostearic acid (Figure 8.2). When these fatty acids are incorporated in membranes, the methyl group constitutes a local structural perturbation in a manner similar to the double bonds in unsaturated fatty acids (see Chapter 9). Some bacteria also synthesize fatty acids containing cyclic structures such as cyclopropane, cyclopropene, and even cyclopentane rings. 

Although the rationalization of the reactivity and selectivity of this particular substrate is distinct from that for chiral ketals 92-95, it still agrees with the mechanistic conclusions gained throughout the study of Simmons-Smith cyclopropa-nations. StOl, the possibility of the existence of a bimetallic transition structure similar to v (see Fig. 3.5) has not been rigorously ruled out. No real changes in the stereochemical rationale of the reaction are required upon substitution of such a bimetallic transition structure. But as will be seen later, the effect of zinc iodide on catalytic cyclopropanations is a clue to the nature of highly selective reaction pathways. A similar but unexplained effect of zinc iodide on these cyclopro-panation may provide further information on the true reactive species. 

There are three main criteria for design of this catalytic system. First, the additive must accelerate the cyclopropanation at a rate which is significantly greater than the background. If the additive is to be used in substoichiometric quantities, then the ratio of catalyzed to uncatalyzed rates must be greater than 50 1 for practical levels of enantio-induction. Second, the additive must create well defined complexes which provide an effective asymmetric environment to distinguish the enantiotopic faces of the alkene. The ability to easily modulate the steric and electronic nature of the additive is an obvious prerequisite. Third, the additive must not bind the adduct or the product too strongly to interfere with turnover. 

For a reaction as complex as catalytic enantioselective cyclopropanation with zinc carbenoids, there are many experimental variables that influence the rate, yield and selectivity of the process. From an empirical point of view, it is important to identify the optimal combination of variables that affords the best results. From a mechanistic point of view, a great deal of valuable information can be gleaned from the response of a complex reaction system to changes in, inter alia, stoichiometry, addition order, solvent, temperature etc. Each of these features provides some insight into how the reagents and substrates interact with the catalyst or even what is the true nature of the catalytic species. 

The 1,2-cyclohexanediamine-derived sulfonamide is not unique in its ability to afford enantiomerically enriched cyclopropanes. The efforts at improving the original protocol led not only to higher selectivity, but to a deeper understanding of the nature of the catalytic process. 

The next step in the calculations involves consideration of the allylic alcohol-carbe-noid complexes (Fig. 3.28). The simple alkoxide is represented by RT3. Coordination of this zinc alkoxide with any number of other molecules can be envisioned. The complexation of ZnCl2 to the oxygen of the alkoxide yields RT4. Due to the Lewis acidic nature of the zinc atom, dimerization of the zinc alkoxide cannot be ruled out. Hence, a simplified dimeric structure is represented in RTS. The remaining structures, RT6 and RT7 (Fig. 3.29), represent alternative zinc chloride complexes of RT3 differing from RT4. Analysis of the energetics of the cyclopropanation from each of these encounter complexes should yield information regarding the structure of the methylene transfer transition state. 

This study suggests a radically new explanation for the nature of Lewis acid activation in the Simmons-Smith cyclopropanation. The five-centered migration of the halide ion from the chloromethylzinc group to zinc chloride as shown in TS2 and TS4 has never been considered in the discussion of a mechanism for this reaction. It remains to be seen if some experimental support can be found for this unconventional hypothesis. The small energy differences between all these competing transition states demand caution in declaring any concrete conclusions. 

Physical properties of cycloalkanes [49, p. 284 50, p. 31] show reasonably gradual changes, but unlike most homologous series, different members exhibit different degrees of chemical reactivity. For example, cyclohexane is the least reactive member in this family, whereas both cyclopropane and cyclobutane are more reactive than cyclopentane. Thus, hydrocarbons containing cyclopentane and cyclohexane rings are quite abundant in nature. 

We ve discussed only open-chain compounds up to this point, but most organic compounds contain rings of carbon atoms. Chcysanthemic acid, for instance, whose esters occur naturally as the active insecticidal constituents of chrysanthemum flowers, contains a three-membered (cyclopropane) ring. 

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