Cyclopropanes highly substituted, synthesis

Dimerization and trimerization of alkylbromocyanoacetates (a self-alkylation reaction) has been used for the synthesis of highly substituted cyclopropanes and dialkyl-( )-2,3-dicyanobutendioates (equation 71). The latter products are potentially very useful for the synthesis of a wide range of heterocyclic compounds. 

Transition metal catalyzed decomposition of unsaturated a-diazo ketones or a-diazo esters is a powerful method for the synthesis of certain 2-oxobicyclo[n.l.0]alkanes. In contrast to the thermal (see Section 1.2.1.2.4.2.6.1.) and photochemical (see Section I.2.I.2.4.2.6.2.) methods, which have only been applied successfully in a few cases, the carbenoid version has been extensively utilized for the construction of simple or highly substituted bicyclic, tricyclic or higher systems of predictable stereochemistry (for reviews, see refs 2, 82, 320). Several of the cyclopropanes so obtained have been transformed further into natural products with diverse molecular skeletons. As examples and procedures have already been presented in Houben-Weyl, Vol. E19b, ppl088ffand 1271 ff, only some important aspects concerning the scope and limitation of the method as well as recent developments concerning its stereochemistry will be discussed here. 

Although the Simmons-Smith reaction has found considerable use in organic synthesis, it is not readily applicable to the formation of highly substituted cyclopropanes, since 1,1 -diiodoalkanes (other than diiodomethane) are not readily available. Substituted zinc carbenoids can be prepared from aryl or a,p-unsaturated aldehydes (or ketones) with zinc metal, and these species can be trapped with an alkene to give substituted cyclopropanes.The addition of chromium carbenes (see Section 1.2.2) to alkenes can be used to effect cyclopropanation to give substituted cyclopropanes. Thus, addition of excess 1-hexene to the chromium carbene 113 gave the cyclopropane 114 as a mixture of diastereomers, with the isomer 114 predominating (4.92). ... 

Highly enantioselective synthesis of cycloheptadienes is obtained when Rh2(S-DOSP)4 is used as the catalyst (Table 5). Examples of the control possible in this chemistry is seen in the reactions with cis-and rranj-piperylenes. Rh2(5-DOSP)4 catalyzed decomposition of the vinyldiazoacetate 14 in the presence of tranj-piperylene results in the formation of the cis-cycloheptadiene 31 in 98% ee, whereas reaction with cw-piperylene results in the formation of the tranj-cycloheptadi-ene 32 in 95% ee (Scheme 12). In both of these reactions, there is full control of relative stereochemistry due to the stereochemical demands of the Cope rearrangement, and the regiochemistry results from preferential cyclopropanation of the least substituted double bond. 

Hudlicky and coworkers also reported an elegant synthesis of the iridoid sesquiterpene (-)-specionin, by utilizing the low-temperature anion-accelerated VCP-CP rearrangement developed in their lab. The precursor siloxyvinylcyclopropane 38 was synthesized as a mixture of exo/endo isomers by the cyclopropanation of substituted cyclopentenone 36 with the lithium dienolate 37 derived from4-(dimethyl-tert-butylsilo5q )-2-bromocrotonate tScheme 11.321. Rearrangement of the diastereomeric VCP substrates was achieved by the use of TMSI/HMDS at -78 °C to afford the tricyclic ketone in high yield as a mixture of diastereomers, which was then converted to the natural product. ... 

More recently, Carreira reported a [Fe(TPP)Cl]-catalyzed diastereoselective synthesis of trifluoromethyl-substituted cyclopropane in aqueous media [56]. The carbene precursor trifluoromethyl diazomethane is difficult to be handled, generated in situ from trifluoroethyl amine hydrochloride, and reacts with styrene in the presence of [Fe(TPP)Cl] to give the corresponding cyclopropanes in high yields and with excellent diastereoselectivities (Scheme 12). 

Scheme 10.12 gives some examples of enantioselective cyclopropanations. Entry 1 uses the W.s-/-butyloxazoline (BOX) catalyst. The catalytic cyclopropanation in Entry 2 achieves both stereo- and enantioselectivity. The electronic effect of the catalysts (see p. 926) directs the alkoxy-substituted ring trans to the ester substituent (87 13 ratio), and very high enantioselectivity was observed. Entry 3 also used the /-butyl -BOX catalyst. The product was used in an enantioselective synthesis of the alkaloid quebrachamine. Entry 4 is an example of enantioselective methylene transfer using the tartrate-derived dioxaborolane catalyst (see p. 920). Entry 5 used the Rh2[5(X)-MePY]4... 

The (ri" -diene tricarbonyliron)-substituted diazocarbonyl compounds 25 have been found to undergo 1,3-dipolar cycloaddition with methyl acrylate in high yield, but with little or no diastereoselectivity (56). Nevertheless, the facile chromatographic separation of the diastereomeric products 26a,b and 27a,b (Scheme 8.8), permits the synthesis of pure enantiomers when optically active diazo compounds (25) [enantiomeric excess (ee) >96%] are employed. When the reaction of 25 (R = C02Et) with methyl acrylate was carried out at 70 °C, cyclopropanes instead of A -pyrazolines were formed. The enantiomerically pure... 

In a preliminary study toward the total synthesis of the kopsane alkaloid 140, which may exhibit cholinergic activity, the formal [3 + 2] annulation reaction of 3-alkylindoles with 1,1-cyclopropane diesters was studied in the presence of Yb(OTf)3 either at elevated temperature or at high pressure. For example, N-methyltetrahydrocarbazole (141) with styryl-substituted cyclopropane 142 produced a mixture of diastereomeric adducts 143a and 143b (3 1) in 49% yield at 1.3 GPa for 7 days (Scheme 39) [89]. 

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]. 

The synthesis of dihydrofuran derivatives such as 177 has been performed to explore scope and limitations of the Lewis acid promoted hydroxyalkylation of siloxycyclopropanes. Table 6 shows that aromatic as well as aliphatic ketones can efficiently be incorporated. Enolization of ketones does not occur and a 1-methyl group at the cyclopropane is no obstacle for the reaction, which now binds the carbonyl compound to a quartemary center with surprisingly high efficiency (entry 5). Albeit there are some restrictions with regard to the substitution pattern of the cyclopropanes, bicyclic siloxycyclopropanes also give good yields (e.g. entry 6 and Eq. 76). Further examples of the tetrahydrofuran synthesis from intermediate y-lactols with... 

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