(Principal Investigator's) This research proposal reflects our general interest in the development of new reagents in the context of acyclic stereocontrol. Once the reaction methodology has achieved success in the development stage, it is used in the asymmetric synthesis of complex organic molecules that may have relevance in the treatment of human diseases. The long term objectives are the eventual achievement of the asymmetric synthesis of th macrolide antibiotics, rutamycin B, oligomycin C, oleanolide, discodermolide, and the proteosome inhibitor lactacystin. In this regard, we intend to 1. explore the scope of double stereodifferentiating reactions of chiral allylsilane reagents with chiral aldehyde partners. This study will be used to determine their potential utility for polypropionate assemblage as well as vicinal amino alcohols. As a new direction for this technology we will develop novel approaches to the synthesis of new allylsilane reagents bearing C-centered chirality; allylsilanes and beta-substituted (E)-crotylsilanes. These approaches include the development of chiral Lewis acids to promote asymmetric (2,3) and (3,3)-sigmatropic processes. 2. Pursue the completion of the synthesis of polypropionate derived macrolide antibiotics, rutamycin B and oligomycin C. 3. Pursue the total synthesis of the macrolide antibiotic oleanolide. 4. Pursue the total synthesis of the microtubule stabilizing agent discodermolide. 5. Pursue the total synthesis of unusual amino acid (+)-lactacystin.

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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Boston University
Schools of Arts and Sciences
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Zhu, Kaicheng; Panek, James S (2011) Total synthesis of (+)-SCH 351448. Org Lett 13:4652-5
Wu, Jie; Chen, Yu; Panek, James S (2010) Vinylogous aldol products from chiral crotylsilanes obtained by enantioselective Rh(II) and Cu(I) carbenoid Si-H insertion. Org Lett 12:2112-5
Brawn, Ryan A; Panek, James S (2009) Synthesis of enantioenriched homopropargylic sulfonamides by a three component reaction of aldehydes, sulfonamides, and chiral allenylsilanes. Org Lett 11:4362-5
Sarkar, Paramita; Reichman, Charles; Saleh, Tamjeed et al. (2007) Proline cis-trans isomerization controls autoinhibition of a signaling protein. Mol Cell 25:413-26
Youngsaye, Willmen; Lowe, Jason T; Pohlki, Frauke et al. (2007) Total synthesis and stereochemical reassignment of (+)-neopeltolide. Angew Chem Int Ed Engl 46:9211-4
Su, Qibin; Dakin, Les A; Panek, James S (2007) [4 + 2]-annulations of chiral organosilanes: Application to the total synthesis of leucascandrolide A. J Org Chem 72:2-24
Chen, Yu; Porco Jr, John A; Panek, James S (2007) Stereochemical and skeletal diversity employing pipecolate ester scaffolds. Org Lett 9:1529-32
Zhang, Yun; Panek, James S (2007) Total synthesis of herboxidiene/GEX 1A. Org Lett 9:3141-3
Arefolov, Alexander; Panek, James S (2005) Crotylsilane reagents in the synthesis of complex polyketide natural products: total synthesis of (+)-discodermolide. J Am Chem Soc 127:5596-603
Su, Qibin; Panek, James S (2005) Total synthesis of (+)-leucascandrolide A. Angew Chem Int Ed Engl 44:1223-5

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