Saturday, September 29, 2012

The Cycloalkenone Diels-Alder Approach to Substituted Hydrindenes

          Hydrindane and hydrindene structures such as 7 are important synthetic building blocks for the stereocontrolled assembly of complex carbocyclic frameworks found in triterpenoids and steroids. For example, an optically active hydrindane structure served as an important advanced intermediate in Corey's synthesis of the sesterpenoid retigeranic acid. Danishefsky's laboratory at Columbia University has recently described a general approach to the hydrindane system that exploits a unique intramolecular Diels-Alder reaction (IMDA) followed by an oxidative fragmentation of the tricyclic cycloadduct (JACS 2012). 
          As depicted in the scheme above, a diene tethered to a highly dienophilic cyclobutenone (4) was synthesized in three straightforward steps from 1 and 2. Upon exposure of this substrate to a catalytic amount of Lewis acid, IMDA reaction proceeded smoothly to provide 5 (92% yield) with a high level of stereoselectivity, wherein an endo transition state arrangement (shown above in brackets) gave rise to the cis ring junction between the six- and four-membered rings. The suprafacial [4+2] cycloaddition reaction also established a trans relationship between the six- and five-membered rings of the tricyclic adduct (5). Subsequent Baeyer-Villiger oxidation of 5 led to a ring-expanded lactone structure (6) without epoxidation of the C-C double bond. Finally, reductive cleavage of the lactone with lithium aluminum hydride secured the unique, angularly substituted trans hydrindene 7, a synthon that is inaccessible by a conventional Diels-Alder strategy due to its ring junction stereochemistry and double bond position. The olefin functionality also affords the opportunity for additional diversification and elaboration. The trans hydrindenoid 7 will likely serve as a useful intermediate in future syntheses of architecturally complex carbocyclic structures.

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