1.3- Dienes, bicyclic esters, synthesis

In a continuation of his work on dendrobine synthesis, Roush132 has found that the intramolecular Diels-Alder reaction of the diene-ester (265) gives predominantly the bicyclic compound (266). This was an unexpected result because... 

An improved synthesis of glutinosone (1) was also accomplished by Masamune and coworkers6 and this was based on procedure developed by Dastur7,8 for the synthesis of sesquiterpenes nootkatone. (Scheme 2) Diels-Alder reaction of 3,6-dihydro-3,5-dimethyl anisole with methyl acrylate in absence of Lewis acids afforded a 1 3 mixture of esters (17) and (18) which were converted to a,(3-unsaturated aldehydes (19) in 77% yield by oxidation with selenium (IV) oxide in dioxane. Wittig reaction of aldehydes under the usual condition yielded the dienes (20) in 63% yield which on being subjected to Grignard reaction with an excess of methyllithium produced tettiary alcohols (21) in quantitative yield. This on treatment with formic acid at room temperature gave bicyclic enone (22) and its formate (23) in 45% and 41% yield respectively. Formates (23) were hydrolyzed to enone (22) in 88% yield. 

The elimination of bicyclic allylic esters was applied to the synthesis of a steroidal intermediate for vitamin The elimination can be carried out from the allylic a-trifluoroacetate to the homoannular diene, and the regioselective reaction is rationalized by easy eliminaion of the C(8)-axial proton syn to palladium, which is probably caused by agostic interactions (Scheme 8). 

With these results in mind, we were attracted to two key points. The first was that building the complex bicyclic core system (20), with the four stereocenters as desired, could be achieved by diene-ene [2+2+1] cycloaddition of bis-diene (21) followed by reduction. The second attractive point was the diversification that could be achieved by cross metathesis at a late stage to get different analogs from the same bicyclic core (20). As a result, a retro-synthesis was conceived (Scheme 1) of isocarbacyclin methyl ester, or clinprost (3), having only nine steps.The first part of the synthesis, and most difficult part, was to generate bis-diene (21). 

Ester 55 was then subjected to a Pd(0)-catalyst, which resulted in a simultaneous decarboxylation of the allyl ester and allylic rearrangement to form the building block of this synthesis (56 Scheme 9). It was determined that bis-diene 56 was relatively stable when pure, but trace impurities sometimes led to rapid polymerization. For this reason, bis-diene 56 was typically used in subsequent reactions within 1 week. Bis-diene 56 was reacted with 10 mol% of a rhodium(I) catalyst under a carbon monoxide atmosphere, followed by reduction using sodium borohydride, to yield the completed bicyclic core (58). 

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