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41562-AC1
Bridged Synthons Derived from Perhalogenated Cyclopropanes

Dennis L. Wright, University of Connecticut

Our efforts under this grant award have centered around the development of synthetic strategies based on the cycloadduct 1 formed between furan and perbromocyplopropene. These cycloaddition reactions give rise to a highly versatile oxabicyclo[3.2.1] octadiene nucleus that contains a cycloheptane, pyran or furan system embedded within the bicyclic framework. We have been interested in developing methodology to utilize these systems in the preparation of valuable natural products. An important synthon 2 can be reached by a silver promoted hydrolysis in both racemic and enantiopure form. We have been actively studying the use of this synthon as a precursor to troponoid natural products, both simple tropones and annulated tropones such as colchicine, as well as pyran intermediates found in a variety of polyketide natural products. We have also targeted the use of these adducts to build the bridged bicyclic core tetrahydrofuran system found in the eunicellin natural products. In our efforts towards tropones, we have found that reductive cleavage of the oxa-bridge in derivatives such as 3 occurs in a highly regioselective fashion to give the alpha-hydroxy ketone 4 that can be dehydrated to give tropones 6 or oxidized to give tropolones 5. This will give us access to a wide variety of tropone and tropolone derivatives and is being used in conjunction with the cyclization of appended systems related to 1, in a new route to colchicine analogs. We have found that systems related to 1 that contain an aromatic appendage at the bridgehead position undergo cyclization onto a putative trireme ally action generated by treatment with Lewis acids. These tricyclic adducts can be taken on to the colchicine core structure. We have also found that this nucleus undergoes a remarkably regioselective ring-opening cross-metathesis reaction to give pyrans such as 7. The degree of selectivity is highly dependent both on the structural features found within the bicyclic systems as well as the donor olefin used in the cross metathesis reaction. These synthons represent very powerful pyran building blocks as each of the five carbons in the heterocycle is functionalized. This is currently forming the basis of our approach to the synthesis of the natural product pyranicin. We have also made significant progress on exploiting the embedded tetrahydrofuran core to access the oxabridged ring system found in the eunicellin diterpenoids. This strategy centered around the initial elaboration of the dibromoenone 2 by two sequential annulation reactions to give the tricyclic intermediate 8 which was then oxidatively cleaved at the intracyclic olefin to give the bridged bicyclic framework of the eunicellin diterpenes 9.

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