Nucleophilic additions to a hindered 2-(alkylidene)cyclohexanone and synthesis of 1,3,5-trimethylated carbon chain compounds through chirality transfer strategies.

Abstract

An efficient, highly stereoselective methodology utilizing cyclohexenones for the synthesis of 1,3,5-trimethylated carbon chain compounds has been established. (E)-trans-3,5-Dimethyl-2-(ethylidene)cyclohexanone has been synthesized and its conformation shown by proton NMR spectra and molecular mechanics calculation (Macromodel) to be chair-like with the carbonyl and olefinic groups skewed as much as 41$\sp\circ$. Nucleophilic 1,2-additions to this enone give high stereoselectivity favoring the axial attack from the hindered face even when sterically demanding nucleophiles are used. This remarkable selectivity may be explained by the difference between axial and equatorial attacks in maintaining orbital overlap between the newly forming bond and the olefinic $\pi$ orbitals. 1,4-Additions to the enone by some carbanions give unexpected $\alpha$-keto hydroperoxides. Possible causes are discussed. (1R,3R,5R,E)-1-Allyl-3,5-dimethyl-2-(ethylidene)cyclohexanol, obtained highly regio- and stereoselectively in the allyl-Grignard addition to the enone, is used to conduct a chirality transfer through an anionic oxy-Cope rearrangement which stereospecifically creates an asymmetric center on the side chain of the ring system in high yield. Thus, three 1,3,5-disposed trimethylated asymmetric centers are established efficiently and highly stereoselectively (overall diastereoselectivity is over 95:5). This strategy provides a promising route for the synthesis of (1,3-anti-3,5-syn)- and (1,3-syn-3,5-anti)-1,3,5-trimethylated carbon chain compounds. (1R,3R,5R,E)-3,5-Dimethyl-2-(ethylidene)cyclohexanol, also obtained highly regio- and stereoselectively from the hydride addition to the enone, is employed for a (2,3) Wittig rearrangement initiated by tin-lithium exchange of the stannymethyl ether of this alcohol. By carefully controlling the reaction conditions, this stereospecific rearrangement can be carried out in high yield. This is a unique example in which the (2,3) Wittig rearrangement of an allyloxycarbanion occurs on a rigid ring system whose stable conformation does not allow optimal orbital interaction for this concerted reaction. The overall diastereoselectivity for the formation of these three 1,3,5-disposed stereocenters is over 96:4. The product of the rearrangement is easily converted to (1,3-anti-3,5-anti)-1,3,5-trimethylated carbon chains, in both racemic and optically active forms. An attempted total synthesis of a natural antibiotic, pectinatone, is also discussed.