Control over the relative stereochemistry at C4 and C5 of 4,5-dihydrooxepins through the cope rearrangement of 2,3-divinyl epoxides and a conformational analysis of this ring system

Article abstract of DOI:10.1021/ja00038a032

The Cope rearrangement of cis-2,3-divinyl epoxides was used to control the relative stereochemistry at C4 and C5 of 4,5-dihydrooxepins. Wadsworth-Horner-Emmons olefination of either (4E)-cis-2,3-epoxy-5-(trimethylsilyl)-4-pentenal (3) or (5E)-cis-3,4-epoxy-6-(trimethylsiIyl)-5-hexen-2-one (4) provided the cis epoxides used in this study. The termini of their 1,5-dienes were thereby substituted at one end with a trimethylsilyl group with fixed E stereochemistry and at the other with either a carboalkoxy or cyano substituent as both the Z and E isomers. The rearrangements were carried out within a temperature range of 95-135°C, and all of the rearrangements were stereospecific, each leading to a single 4,5-dihydrooxepin. Based on a presumed boatlike transition state for these rearrangements, the (1E,5E)-cis-3,4-epoxy-1,5-hexadienes 5a-e led to the cis-4,5-dihydrooxepins 7a-e, and the (1E,5Z)-cis-3,4-epoxy-1,5-hexadienes 6a,c-e led to the trans-4,5-dihydrooxepins 8a,c-e. In general, those 1,5-dienes containing a Z double bond rearranged slower than the corresponding E isomers. A solvent affect was found in the [3,3] sigmatropic rearrangement of substrates containing Z-α,β-unsaturated esters, CH₃CN being a more effective solvent than CCl₄. It was further found that Z-α,β-unsaturated nitiriles rearranged more cleanly than the corresponding esters. The relative stereochemistry at C4 and C5 can greatly affect the subsequent reactivity of the oxepin nucleus, as illustrated by the greater kinetic acidity of the cis isomer of 4-carbomethoxy-5-(trimethylsilyl)-4,5-dihydrooxepin (7a) compared to that of its trans isomer 8a. The ester of the former compound was easily deprotonated at -70°C in THF by LiN(TMS)₂ and the resultant enolate alkylated at the α carbon by MeI, conditions that led to the complete recovery of the trans isomer. These results are consistent with the assignment of cis and trans stereochemistry of these oxepins. From their ¹H NMR spectra, all of the trans-4,5-dihydrooxepins appeared to be similar to each other in terms of their coupling patterns and constants, but the cis-4,5-dihydrooxepins could be divided up into two groups on the basis of their coupling constants. For three of the oxepins, cis-4,5-dihydrooxepins 7a and 7c and trans-4,5-dihydrooxepin 8a, the assignment of their coupling patterns was confirmed by 2-D NMR. The minimum-energy conformations of these three oxepins were determined by molecular mechanics calculations. The conformational preferences were explicable in terms of two steric interactions: allylic A^1,2 strain and the gauche interaction at C4 and C5.