Studies directed toward the total synthesis of reiswigin A: and, New insights into the mechanism of the Skattebol rearrangement

Abstract

Retrosynthetic analysis of reiswigin A suggested that the stereochemistry at carbons 1, 7, and 8 could be controlled by using an appropriately substituted bicyclo (2.2.1) heptene. Thus, anti-7-(3$\sp\prime$-keto-1$\sp\prime$-butyl)-1-methylbicyclo (2.2.1) hept-2-ene (76) was synthesized in five steps from 3-methyl-2-cyclohexen-1-one (33). In order for this sequence to be successful, the scope of the Skattebol rearrangement was extended to include the use of various alkyl-lithiums with 3-methyl- and 6-methyl-7,7-dibromobicyclo (4.1.0) hept-2-ene (52 and 52a). The key norbornyl intermediate 76 was subjected to an oxidation/reduction/oxidation sequence to give lactone 24. Protection of the ketone moiety of 24 followed by treatment with lithio tert-butyl acetate give $\beta$-keto ester 102. Cyclization and in situ hydrolysis gave the desired trans-fused hydro-azulene 95, which has the proper stereochemistry for elaboration to the natural product. The mechanism of the Skattebol rearrangement was also investigated. Several experimental observation were not consistent with the literature mechanism including the following: (1) 7-alkyl-7-lithionorbornenes are not configurationally stable; (2) the Skattebol rearrangement is very temperature dependent when primary alkyllithiums such as butyllithium are used; (3) when compared with methyllithium, primary alkyllithiums give rise to increased dimer formation; and (4) syn-7-bromonorbornene and a single isomer of the norbornyl homo dimer 26 are by-products of the reaction. A modification of the literature mechanism is proposed that is consistent with these results.