The development of new methods for the regio- and stereospecific synthesis of highly substituted heterocycles (dihydro- and tetrahydro- pyrans, furans, piperidines and pyrroles) is proposed. Successful achievement of the proposed chemistry should provide a novel strategy for the synthesis of general classes of organic molecules with demonstrated biologically activity (antiviral, antibiotics, etc.). Unsaturated heterocycles (furan, pyranyl, pyrrole, pyridinyl) will be pi- complexed to transition metal moieties to provide cationic eta4-furan, eta5-pyranyl, eta4-pyrrole, and eta5-pyridinyl species that will be reacted sequentially with nucleophiles and electrophiles in order to prepare highly derivatized oxygen and nitrogen heterocycles in a regio- and stereodefined manner. The metal template in the pi-complexes serves a number of useful roles. It will be used to 1) stabilize otherwise unstable species 2) active unsaturated heterocycles for reaction with nucleophiles, and 3) control the stereochemistry and regiochemistry of the introduction of various organic units to the heterocycle core.

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National Institute of General Medical Sciences (NIGMS)
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Metallobiochemistry Study Section (BMT)
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Emory University
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Wong, Heilam; Garnier-Amblard, Ethel C; Liebeskind, Lanny S (2011) Organometallic enantiomeric scaffolding: a strategy for the enantiocontrolled construction of regio- and stereodivergent trisubstituted piperidines from a common precursor. J Am Chem Soc 133:7517-27
Coombs, Thomas C; Huang, Wenwei; Garnier-Amblard, Ethel C et al. (2010) Novel Substitutions of 1-Alkoxy- and 1-Arylsulfonyloxy-?-Allylmolybdenum Complexes. A Case for ?-Alkenyl Carbene Complexes as Intermediates. Organometallics 29:5083-5097
Cheng, Bo; Liebeskind, Lanny S (2009) Organometallic enantiomeric scaffolding. A molybdenum-mediated intramolecular nucleophilic ketalization-demetalation cascade. Total synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin. Org Lett 11:3682-5
Coombs, Thomas C; Zhang, Yongqiang; Garnier-Amblard, Ethel C et al. (2009) Organometallic enantiomeric scaffolding. Sequential semipinacol/1,5-""Michael-like"" reactions as a strategic approach to bridgehead-quaternary center aza[3.3.1]bicyclics: application to the total synthesis of (-)-adaline. J Am Chem Soc 131:876-7
Chen, Wenyong; Liebeskind, Lanny S (2009) A new reaction motif: ""homo-S(N)2'-like"" direct nucleophilic addition to neutral eta(3)-allylmolybdenum complexes. total synthesis of the antimalarial (+)-isofebrifugine. J Am Chem Soc 131:12546-7
Garnier, Ethel C; Liebeskind, Lanny S (2008) Organometallic enantiomeric scaffolding: general access to 2-substituted oxa- and azabicyclo[3.2.1]octenes via a Bronsted acid catalyzed [5 + 2] cycloaddition reaction. J Am Chem Soc 130:7449-58
Coombs, Thomas C; Lee 4th, Maurice D; Wong, Heilam et al. (2008) Practical, scalable, high-throughput approaches to eta3-pyranyl and eta3-pyridinyl organometallic enantiomeric scaffolds using the Achmatowicz reaction. J Org Chem 73:882-8
Arrayas, Ramon Gomez; Yin, Jingjun; Liebeskind, Lanny S (2007) The enantiomeric scaffold approach to highly functionalized 1-oxadecalines: enantio- and regiocontrolled [4 + 2] cycloadditions of 5-alkenyl-eta3-pyranylmolybdenum complexes. J Am Chem Soc 129:1816-25
Arrayas, Ramon Gomez; Liebeskind, Lanny S (2003) Eta3-pyranyl and eta3-pyridinyl molybdenum pi-complexes as chiral scaffolds for the enantioselective construction of substituted oxa- and aza[3.3.1]bicyclics: first enantio- and regiocontrolled [5+3] cycloaddition reactions. J Am Chem Soc 125:9026-7
Shu, Chutian; Liebeskind, Lanny S (2003) Enantiocontrolled synthesis of 2,6-disubstituted piperidines by desymmetrization of meso-eta-(3,4,5)-dihydropyridinylmolybdenum complexes. application to the total synthesis of (-)-dihydropinidine and (-)-andrachcinidine. J Am Chem Soc 125:2878-9

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