The development of a new strategy towards linear tricyclic polyquinane antitumor/antibiotics is proposed. Favorable evidence bearing on the tandem radical cyclization for single step construction of two cyclopentane rings about a single central cyclopentane precursor is presented. Immediate objectives include facile synthesis of important classes of linear polyquinanes including the hirsutanes (hirsutene, coriolins, hirsutic acid) and the capnellenes and investigation of the general synthetic utility of the key hex-5-enyl radical cyclization with respect to substituent effects, site selectivity, and stereochemistry in complex systems. The work proposed is significant in many respects. In addition to providing a novel strategic entry into this class of compounds, the synthesis has been designed to be short and flexible. This should allow for preparation of both natural products and totally synthetic analogues for biological evaluation, and studies on mechanism of action and biosynthesis. In several places, options for introduction of absolute chirality are available. This is particularly significant in view of the almost complete lack of chiral synthesis in this area. Of particular importance is the generality. Due to the design involving simultaneous cyclization of two outer rings about a pre-formed common central ring, one can prepare both simple (hirsutene) and complex (coriolin, hirsutic acid) structures from the same key intermediate using a similar sequence of reactions, without extensive manipulation of functional groups. Minor modifications of the same general strategy allow preparation of the capnellane series which possesses a different carbon skeleton. This has not been generally possible in previous syntheses which may require extensive transformations or major strategic changes to make closely related compounds. Most routes are targeted towards a single member. This research should also help further explore the synthetic utility of the tandem hexenyl radial cyclization in complex systems and provide information on site selectivity, stereoselectivity, use of various traps (olefin, substituted olefin, acetylene), and mildness and compatability with other functional groups. Design in this respect has been based on the large body of mechanistic evidence.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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University of Pittsburgh
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Moretti, Jared D; Wang, Xiao; Curran, Dennis P (2012) Minimal fluorous tagging strategy that enables the synthesis of the complete stereoisomer library of SCH725674 macrolactones. J Am Chem Soc 134:7963-70
Gudipati, Venugopal; Curran, Dennis P (2011) Synthesis of C1-C20 and C21-C40 fragments of tetrafibricin. Tetrahedron Lett 52:2254-2257
Moura-Letts, Gustavo; Curran, Dennis P (2007) Selective synthesis of (2Z,4E)-dienyl esters by ene-diene cross metathesis. Org Lett 9:5-8
Du, Wu; Curran, Dennis P; Bevins, Robert L et al. (2002) Synthesis and evaluation of a novel E-ring modified alpha-hydroxy keto ether analogue of camptothecin. Bioorg Med Chem 10:103-10