Annulation, 3 + 2-, alkyl methyl ketone enolates

Takeda, K., Nakajima, A., and Yoshii, E. (1997) Synthesis of clavulones (claviridenones) via [3+2] annulation using reaction of (P-(phenyllhio)actyloyl)silane with lithium enolate of alkyl methyl ketone. Synlett, 255—256. 

Two explanations have been suggested for this anomalous result83,84. Huffman and coworkers84 have proposed that the 2,2-disubstituted cyclohexanone (38) is derived directly from a 2,6-disubstituted enolate intermediate by simultaneous alkylation at C2 and dealkylation at C6. This is in effect a S 2 mechanism for which there is no precedent in enamine chemistry (Scheme 24). The basis for this suggestion is the anomalous solvent-dependent annulation of 2-substituted cyclohexanone enamines with methyl vinyl ketone (MVK) and the assumption that direct C-alkylation of a tetrasubstituted enamine is improbable for it is known that there is considerably less overlap of the unshared electrons on nitrogen with the n system of the double bond in this isomer relative to the more stable trisubstituted isomer, thereby greatly decreasing the rate of alkylation . 

Therefore several reactions were subjected to various antibody catalyses, e. g., ester and enol ether cleavage, transesteiification, ketone reduction. Cope rearrangement, ring closure via epoxide opening, or Diels-Alder cycloaddition [74, 75]. An exceptional reaction is the antibody-catalyzed Robinson annulation of triketone 28 to the Wieland-Miescher ketone 29 on a preparative scale. Surprisingly, even the alkylation of diketone 27 with methyl vinyl ketone was catalyzed by the same antibody, but at moderate rates (Scheme 15) [76]. 

The reaction of endocyclic enamines with a,p-unsaturated ketones to afford cu-fused hydroindolones or hydroquinolones constitutes a complementary and highly useful annulation sequence developed extensively by Stevens and coworicers, see the reaction of (5) to give (6) in Scheme 7. ° The importance of stereoelectronic effects is highlighted in the reaction of (7) with methyl vinyl ketone, which provided only the alkylated product (8) and none of the expected ci5-hydroindolone (9)." The failure of intermediate (8) to cyclize in this case was attributed to nonbonded interactions between the aryl group and the side chain. This destabilizing allylic interaction s disfavors formation of conformer (10), the intermediate required for antiperiplanar addition of the enol nucleophile (Scheme 8). Cyclization via the alternate conformation would require a double boat-like transition state. 

For the alkylation of enolates, chromium tricarbonyl complexes of aromatic compounds (benchrotrenes) are useful, as they make simple aromatic compounds chiral. Thus, enantiomer-ically pure (indanone)tricarbonylchromium (2R)-25 has been prepared by resolution of the racemic benchrotrene derivative with cinchonidine and oxidation of the alcohol to the ketone with manganese dioxide60. The chiral ketone is alkylated diastereoselectively via the enolate, leading to the f.vo-2-methyl derivative (2/ )-25 which has been used in enolate alkylations and annulation reactions (Section D.1.5.2.4.). If necessary, complete isomerization to the endo-methyl compound can be achieved by treatment with base. 

Basis and Example of Use. This reagent acts as the alkyla-tive equivalent of 3-buten-2-one (methyl vinyl ketone), permitting regiospecific enolate alkylation under nonequilibrating conditions. As a vinylsilane it can be converted, via the corresponding a,/3-epoxy silane, into a 3-oxobutyl moiety, and hence used in an alkylative equivalent of Robinson annulation. Application of such methodology can be seen (eq 1) in the preparation of bicyclodecenones via the alkylation of dihydrocarvone with this reagent. Apart from this application, and its use in combination with potassium iodide, it has seen little use so far. 

Because the Michael addition step involves the thermodynamic enolate, Robinson annulation reactions are regioselective with unsymmetrical ketones. As entry 4 illustrates, the methyl group of 2-methylcyclohexanone appears at the ring junction in the annulated product. In order to achieve the opposite regioselectivity in annulation, recourse is taken to enamine methodology. Since the more stable pyrrolidine enamine of 2-methylcyclohexanone is the less substituted one (as discussed in Chapter 1, Section 1.9), annulation via the enamine occurs away from a 2-alkyl group. Entries 4 and 5 illustrate the complementary nature of annulation using enolates and enamines. 

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