The goal of this proposal is to develop new methodologies of Fischer carbene complexes for applications to organic synthesis concentrating on existing reactions with promise and new reactions with potential. These are summarized here in the order of their presentation in the proposal. We will continue to seek new and improved methods for the cyclopropanation of olefins with Fischer carbene complexes. Particular emphasis will be given to asymmetric cyclopropanations, the synthesis of helenalin, and to the reaction of carbene complexes with ketene acetals for new approaches for the generation of homo-enolate equivalents, vinyl carbene equivalents, and trimethylene methane equivalents. New C-H insertion reactions were discovered in the study of the reactions with ketene acetals and methodological aspects of this new reaction will be explored. Most prominent in the area of heteroannulation is the development of imino complexes as nitrile ylide equivalents. This is a relatively new reaction discovered in our laboratories about a year ago and we will attempt to demonstrate the utility of these reactions in the synthesis of mesembrine, porphobilinogen, methoxatin, and the first enantioselective synthesis (-)-dendrobine. Heteroannulation of other carbene complexes will be explored as well as attempts to improve these reactions for the synthesis of 3-hydroxypyridines. In the area of cyclohexadienone annulations regioselective versions of the tautomer arrested annulation have been developed and these will be applied to the synthesis of ganoderic acids B and D. We will also pursue a tandem Diels-Alder/benzannulation approach to the synthesis of taxodione and royleanone. A new area is the development of asymmetric annulations made possible by the first preparation of chiral oxazolidinone carbene complexes. Studies will be directed to define the scope of the first asymmetric Michael reactions of carbene complexes and it is proposed that they be applied to the synthesis of (-)-dendrobine. Carbene complexes to be evaluated for there service in asymmetric aldol and Michael reactions include pyrrolidine complexes, the newly prepared oxazolidinone complexes and the as of yet unknown imidazolidinone complexes. The latter two may be considered particularly advantageous since the chiral auxilliary is conformationally restricted by internal chelation to the metal center. Investigations will continue on the more recently initiated programs of intramolecular and inverse-electron demand Diels-Alder reactions of Fischer carbene complexes particularly with regard to the synthesis of indole alkaloids. The first successful enantioselective Diels-Alder reaction of carbene complexes with menthol as chiral auxilliary will be pursued with the goal of developing menthol as a useful chiral auxilliary and to finding solutions to limitations in non-transition metal Diels-Alder reactions. These Diels-Alder reaction will be applied to the synthesis of taxodione, royleanone, and the ganoderic acids. The possibility of heteroatom Diels-Alder reactions of imino carbene complexes will also be investigated. The metal mediated double-cyclization of cross-conjugated ketenes was recently discovered in our laboratories and this reaction will be studied with regard to scope and application to the synthesis of strigol.

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National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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University of Chicago
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Vorogushin, Andrei V; Wulff, William D; Hansen, Hans-Jurgen (2008) Central-to-Axial Chirality Transfer in the Benzannulation Reaction of Optically Pure Fischer Carbene Complexes in the Synthesis of Allocolchicinoids. Tetrahedron 64:949-968
Korthals, Keith A; Wulff, William D (2008) Traceless stereoinduction in the one-pot assembly of all three rings of hexahydrodibenzopyrans. J Am Chem Soc 130:2898-9
Huang, Jie; Wang, Huan; Wu, Chunrui et al. (2007) Intramolecular cyclohexadienone annulations of Fischer carbene complexes: model studies for the synthesis of Phomactins. Org Lett 9:2799-802
Huang, Jie; Wu, Chunrui; Wulff, William D (2007) Total synthesis of (+/-)-phomactin B2 via an intramolecular cyclohexadienone annulation of a chromium carbene complex. J Am Chem Soc 129:13366-7
Rawat, Manish; Prutyanov, Victor; Wulff, William D (2006) Chromene chromium carbene complexes in the syntheses of naphthopyran and naphthopyrandione units present in photochromic materials and biologically active natural products. J Am Chem Soc 128:11044-53
Lian, Yiqian; Wulff, William D (2005) Iron in the service of chromium: the ortho-benzannulation of trans,trans-dienyl Fischer carbene complexes. J Am Chem Soc 127:17162-3
Rawat, Manish; Wulff, William D (2004) Total synthesis of carbazoquinocin C: application of the o-benzannulation of Fischer carbene complexes to carbazole-3,4-quinone alkaloids. Org Lett 6:329-32
Jiang, May Xiao-Wu; Rawat, Manish; Wulff, William D (2004) Contingency and serendipity in the reactions of Fischer carbene complexes with conjugated triynes. J Am Chem Soc 126:5970-1
Vorogushin, Andrei V; Wulff, William D; Hansen, Hans-Jurgen (2003) Steric vs hydrogen-bonding control of atropisomerization: preparation of either diastereomer of configurationally stable allocolchicinoids. J Org Chem 68:9618-23
Vorogushin, Andrei V; Predeus, Alexander V; Wulff, William D et al. (2003) Diels-Alder reaction-aromatization approach toward functionalized ring C allocolchicinoids. Enantioselective total synthesis of (-)-7S-allocolchicine. J Org Chem 68:5826-31

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