Lithium enolates axial alkylation

After reaction of the excess lithium with isoprene the enolate is alkylated with allyl bromide diastereoselectively from the less hindered face, opposite to the axial methyl group at the bridge head, to provide allyl ketone 3 as the single diastereomer. 

The lithium enolate remains and can be alkylated with an alkyl halide in the usual way. When there are hydrogen atoms at both ring junction positions, axial alkylation occurs just as you should now expect, and a new ketone with three stereogenic centres is formed with >95% stereoselectivity. 

Lithium enolates having a-methyl substituents, such as (33b) and the related species (37b), derived from S-t-butylcyclohexanone, show a somewhat greater stereoselectivity of axial alkylation than the corresponding a-unsubstituted compounds. For example, the enolate (37a) gave the products (38a) and (39a) in a 68 32 ratio upon treatment with methyl iodide in THF, while the 2-methyl-substituted derivative (37b) gave an 83 17 mixture of (38b) and (39b) upon reaction with trideuteriomethyl iodide in DME (Scheme 18). Similarly, a greater stereoselectivity for axial alkylation has been observed for other a-substituted enolates compared with their counterparts lacking a-substituents. - ... 

A comparison of the data for alkylation of the lO-methyl-2-decalone lithium enolate (44) with those for enolate (43a) clearly shows that if axial alkylation involves development of a 1,3-interaction with an... 

Studies pertaining to diastereoselectivity in Lewis acid catalyzed alkylations of enol derivatives have been limited. Reetz has reported that r-butylation of l-trimethylsiloxy-4-f-butylcyclohex-l-ene gave an 8S 1S mixture of cis- and frafu-2,4-di-f-butylcyclohexanone, which could result from kinetic equatorial and axial alkylation, respectively. However, equilibration of the products, which would favor formation of the former isomer, was not ruled out. Titanium tetrachloride promoted phenylthiomethylation of the more-substituted TMS enol ether of 1-decalone gave a 4 1 mixture of cis- and rranj-fused 1-deca-lones. In this case, where equilibration of the product could not occur, the diastereoselectivity was similar to that of methylation of the corresponding lithium enolate (49). ... 

For more conformationally-constrained chiral substrates, however, diastereoselectivity can be expected to be good to excellent. Lithium enolates derived from sterically unencumbered cyclohexanones undergo preferential axial acylation as illustrated by the reductive acylation of (R)-(-)-carvone 4 to afford a 3 1 mixture of esters 5 and 6. whereas equatorial acylation is favored in compounds that possess an alkyl substituent in a 1,3-syn-axial relationship to the reacting center, as in the conversion of tricyclic enone 7 to ester 8 (epimeric with the product from the more traditional sequence of acylation followed by alkylation). (In substrates of this kind it is assumed that the transition state structure is based on a twist-boat conformation which permits the reagent to approach along an axial-like trajectory on the less encumbered, lower face of the substrate.) ... 

Both of these reactions result in the alkylation of 4-t-butylcyclohexanone, but the selectivity obtained is very different. The lithium enolate produced on reaction with LDA is sterically undemanding, and hence approach of the methyl iodide is possible either axially or equatorially there is a marginal preference for the more stable equatorial product. However, the pyrrolidine ring of the enamine is much bulkier and inhibits approach to the equatorial position more than it does to the axial position. 

Lithium enolates derived from sterically unencumbered cyclohexanones undergo preferential axial acylation (eq 6), whereas equatorial acylation is favored with A -2-octalones (eq 7), even in the absence of an alkyl substituent at C-10. ... 

This technique was used to synthesize some cyclohexane derivatives by substitution with electrophiles specifically in the axial or equatorial position. Whereas alkylation with dimethyl sulfate occurred smoothly, alkylation with haloalkanes failed completely. Rather nonstereoselective protonation of the lithium compound, as well as dehydrogenation to enol ethers, occurred. Operation of single electron transfer processes are believed to account for these results27. 

We reasoned that the /-butyl group is still too small for an efficient chiral induction therefore, the optically pure 0-TBDPS lactaldehyde was chosen for the formation of the N,O-acetal. But only amides 39 and 41 are now non-racemic 39 exhibits a satisfactory chiral induction on allylation, because the enolate carbon is shielded by the adjacent axial bulky substituent. In 41, both sidechains at C-2 and C-4 are equatorial and the stereocontrol drops significantly.The use of a chiral aldehyde for acetal formation even allows the use of the achiral O-aminobenzylalcohol (43) as a template. Acetals 44 and 45 are formed and separated due to the allylic 1,3-strain of the amide moiety both derivatives have axial sidechains (as detectable in the crystal structure of alkylation product 46d) (Fig. 2) and the chiral induction is similarly high in both cases. The chiral auxiliary is removed with lithium aluminium hydride without any racemization of the newly created stereocenter (6). 

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