FOLDING STRAIN STEREOCONTROL IN CYCLOHEXANE RING FORMATION BY MEANS OF AN INTRAMOLECULAR ESTER ENOLATE ALKYLATION REACTION

Diastereoselectivity in the cyclization of ethyl 7-bromo-2-methylhepta noates with an additional substituent at various positions in the chai n, by LDA treatment, was investigated in connection with the concept o f folding strain stereocontrol. Cyclization of 3-, 4-, and 6-methyl-su bstituted substrates revealed high selectivity, which demonstrates the prevalence of folding strain stereocontrol and the usefulness of this approach for stereoselective ring construction. In particular, reacti ons of the latter two substrate a re suited in the stereodivergent pre paration of diastereomeric 1,3-dimethylcyclohexanecarboxylates. In the case of the 5-methyl-substituted substrate, the selectivity of ring c losure was only moderate. H-1 and C-13 NMR spectroscopic data were use ful for determining the conformation of 1-methylcyclohexanecarboxylate derivatives. The origin of the diastereoselectivity was examined thro ugh the qualitative comparison of the strain in the diastereomeric fol ding in the transition state. Various factors that might affect stereo selectivity were examined in the cyclization of 5-substituted substrat es to better understand this concept. As predicted, the selectivity in creased as the substituent became bulkier: Ph < Me approximate to Et < i-Pr < t-Bu. The effects of other factors - solvent, base counter cat ion, and leaving group - on selectivity agree with results predicted f rom the reactivity-selectivity relationship.