The broad goal of this program is to develop new, effective synthetic methods for the synthesis of bioactive peptide natural products with unique structural features. The target that we have chosen as a vehicle for establishing this program is Celogentin C, a bicyclic octapeptide which is a potent antimitotic agent by virtue of its inhibition of the polymerization of tubulin. The unusual molecular architecture of Celogentin C includes a tryptophan residue with substitution at C-2 and C-6 of the indole side chain, a biaryl-type system characterized by the C-N bond between the indole and imidazole moieties, and a beta-substituted amino acid that results from the cross-link between the tryptophan and leucine side chains. We propose three novel synthetic methods for the construction of these interesting structures. The substituted central tryptophan will be prepared via incorporation of phase-transfer-catalyzed asymmetric alkylation chemistry into the Cook tryptophan synthesis. This work will also lead to the development of novel Cinchona alkaloid derived phase- transfer catalysts for both alkylations and aldol reactions. The latter process will afford beta-hydroxy amino acids. The indole-imidazole linkage will be formed by means of a copper- or palladium-catalyzed aryl amination reaction. Our intention is to perform this reaction in an intramolecular fashion in order to develop alternatives to macrolactamization for the cyclization of peptides. Finally, the beta-substituted amino acid system will be constructed via the chiral Lewis acid promoted conjugate addition of nucleophilic radicals to unsaturated nitro esters or amides. These substrates have great potential as intermediates in the preparation of amino acids. However, they have not been utilized in synthesis, likely due to concerns about the acidity of the resulting alpha-proton. After we have fully developed our new methods with model substrates, we will apply them to the total synthesis of Celogentin C. In addition to these methods, areas we will explore in the total synthesis include arginine protecting groups and the intramolecular Knoevenagel condensation. The synthesis is designed in a manner that will allow easy preparation of novel analogues for structure-activity studies. Thus, by generating compounds with potential medicinal value and facilitating the invention of synthetic methods applicable to a wide range of bioactive peptides, this program will have a profound effect on human health.
| Banerjee, Biplab; Litvinov, Dmitry N; Kang, Junghoon et al. (2010) Stereoselective additions of thiyl radicals to terminal ynamides. Org Lett 12:2650-2 |
| Ma, Bing; Banerjee, Biplab; Litvinov, Dmitry N et al. (2010) Total synthesis of the antimitotic bicyclic peptide celogentin C. J Am Chem Soc 132:1159-71 |
| Ma, Bing; Litvinov, Dmitry N; He, Liwen et al. (2009) Total synthesis of celogentin C. Angew Chem Int Ed Engl 48:6104-7 |
| Li, Fang; Tartakoff, Samuel S; Castle, Steven L (2009) Enantioselective total synthesis of (-)-acutumine. J Org Chem 74:9082-93 |
| Banerjee, Biplab; Capps, Steven G; Kang, Junghoon et al. (2008) Second-generation DBFOX ligands for the synthesis of beta-substituted alpha-amino acids via enantioselective radical conjugate additions. J Org Chem 73:8973-8 |
| Ma, Bing; Parkinson, Jared L; Castle, Steven L (2007) Novel Cinchona alkaloid derived ammonium salts as catalysts for the asymmetric synthesis of beta-hydroxy alpha-amino acids via aldol reactions. Tetrahedron Lett 48:2083-2086 |
| Li, Fang; Castle, Steven L (2007) Synthesis of the acutumine spirocycle via a radical-polar crossover reaction. Org Lett 9:4033-6 |
| He, Liwen; Yang, Liping; Castle, Steven L (2006) Synthesis of the celogentin C right-hand ring. Org Lett 8:1165-8 |
| Jones, Spencer B; He, Liwen; Castle, Steven L (2006) Total synthesis of (+/-)-hasubanonine. Org Lett 8:3757-60 |
| Grant, Seth W; Zhu, Koudi; Zhang, Yu et al. (2006) Stereoselective cascade reactions that incorporate a 7-exo acyl radical cyclization. Org Lett 8:1867-70 |
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