Highly concise and stereospecific routes to cis and trans fusion, carrying various functionality at one of the bridgehead carbons, have been accomplished. Diels-Alder cycloaddition | cyclobutenone | angular methylation | mechanistic studies O ur group has been studying the synthetic utility of the DielsAlder (DA) reaction of the parent cyclobutenone, 2 (1). Recently reported results demonstrate that 2 is a highly reactive, endo-selective dienophile (Fig. 1, Eq. 1) (2). We have also developed a series of intramolecular Diels-Alder (IMDA) reactions, wherein the cyclobutenone component is tethered to various conjugated dienes (compare 4); cycloaddition of these substrates delivers adducts of the type 5, which can be readily converted to trans-fused systems bearing iso-DA patterns (Fig. 1, Eq. 2, 5→6) (3). Additionally, we have described the synthesis and DA cycloaddition of an even more powerful dienophile, 2-bromocyclobutenone (Fig. 1, Eq. 3, 7) (4). The direct adducts of this [4+2] reaction (compare 8) are readily converted to norcarane carboxylic acids (9) through exposure to hydroxide base. The research described herein was initially focused on efforts to add carbon-based nucleophiles to DA cycloadducts of the type 8. It might well have been expected that such reactions would give rise to products such as 10, wherein a ketone is appended to the junction of the norcarane system (Fig. 1, Eq. 4).
Results and DiscussionWith a view toward accomplishing the transformation envisioned in Fig. 1, Eq. 4, compounds of the type 8 were exposed to methyllithium as described in Fig. 2. Interestingly, exposure of substrate 8a to the conditions shown led to an 81% yield of the angularly methylated product 11a, apparently unaccompanied by any part of the corresponding trans-fused diastereomer (Fig. 2, entry 1). Reactions conducted with related DA adducts 8b and 8c resulted in quite similar outcomes (Fig. 2, entries 2 and 3). Although we were confident that the products obtained were cisfused (Fig. 2, 11a-c), it was the synthesis of the rigorously assignable trans-fused product (vide infra) and its nonidentity with 11a that served to allow for sound assignment of the cisring fusion.An obvious mechanistic proposal to account for the formation of this structure envisions lithium-halogen exchange (5-8) leading to 12a and methyl bromide (Fig. 3). This step is followed by angular methylation (9-11) of 12a. It would not be surprising for such a reaction to have a very high preference for producing cis fusion. Clearly, a great deal of ring strain would be introduced in any transition state en route to trans-fused products.Whereas the enolate alkylation proposal is presumptive, several alternate formulations merited consideration. In principle, one can envision the possibility that lithium enolate 12a is not actually produced (perhaps due to ring strain). Rather, 11 (Fig. 3) arises from the merger of otherwise high-energy species en route to 12a and 12b. For instance, "radicaloid" (5) character could be generated at both the bridgehead ...