The overall objective of this proposal renewal is to continue our development of an efficient and general strategy for the asymmetric synthesis of oligosaccharides (X = O) and to expand it to the synthesis of analogous oligo-cyclitols (X = CH2, Scheme 1). The method we propose has the potential to revolutionize the way oligosaccharides are synthesized. Our method revolves around the use of a highly stereoselective palladium catalyzed glycosylation (X = O: 2.1?/2.4? to 2.2 ?/2.5?) and cyclitolization (X = CH2;Scheme 1). There has been an astounding amount of research directed toward the synthesis of oligosaccharides; however, when it comes to unnatural oligosaccharides, the current state of the art is lacking. This deficiency is undoubtedly due to the limited number of carbohydrate starting materials (glucose, mannose, and galactose). A complementary approach would be to start with a significantly simplified structure and to sequentially increase its stereochemical and functional complexity to a range of structures (eg., 1.5/1.6 to 1.1-1.3;Scheme 1). The underlying hypothesis that guides our synthetic approach is the belief that there are many carbohydrate analogs, which remain undiscovered because of synthetic limitations. Thus, we believe a methodology that allows for the facile incorporation of simple sugars (i.e. under-functionalized) into oligosaccharide motifs will drastically enable the discovery of new structures with a wide range of functions.
This project from the department of chemistry at West Virginia University proposes to develop a new technology (glycosylation/cyclitolization) for the preparation of natural and unnatural complex carbohydrates. These structures are based on naturally occurring structural motifs with potent biological properties. This approach will allow chemist to preform medicinal chemistry studies that current methodologies do not allow. Ultimately, we plan to uses these new compounds to development new pharmaceutical based therapies for the treatment of cancer, AIDS, tuberculosis and other microbial infections, etc.
|Guo, Haibing; La Clair, James J; Masler, Edward P et al. (2016) De Novo Asymmetric Synthesis and Biological Analysis of the Daumone Pheromones inCaenorhabditis elegansand in the Soybean Cyst NematodeHeterodera glycines. Tetrahedron 72:2280-2286|
|Mulzer, Michael; Tiegs, Brandon J; Wang, Yanping et al. (2014) Total synthesis of tetrahydrolipstatin and stereoisomers via a highly regio- and diastereoselective carbonylation of epoxyhomoallylic alcohols. J Am Chem Soc 136:10814-20|
|Bajaj, Sumit O; Shi, Pei; Beuning, Penny J et al. (2014) Structure activity relationship study of Mezzettiasides natural products and their four new disaccharide analogues for anticancer/antibacterial activity. Medchemcomm 5:1138-1142|
|Sharif, Ehesan U; Wang, Hua-Yu Leo; Akhmedov, Novruz G et al. (2014) Merremoside D: de novo synthesis of the purported structure, NMR analysis, and comparison of spectral data. Org Lett 16:492-5|
|Pongrakhananon, Varisa; Stueckle, Todd A; Wang, Hua-Yu Leo et al. (2014) Monosaccharide digitoxin derivative sensitize human non-small cell lung cancer cells to anoikis through Mcl-1 proteasomal degradation. Biochem Pharmacol 88:23-35|
|Cuccarese, Michael F; Singh, Amit; Amiji, Mansoor et al. (2013) A novel use of gentamicin in the ROS-mediated sensitization of NCI-H460 lung cancer cells to various anticancer agents. ACS Chem Biol 8:2771-7|
|Aljahdali, Alhanouf Z; Shi, Pei; Zhong, Yashan et al. (2013) De novo asymmetric synthesis of the pyranoses: from monosaccharides to oligosaccharides. Adv Carbohydr Chem Biochem 69:55-123|
|Wang, Hua-Yu Leo; Guo, Haibing; O'Doherty, George A (2013) De novo asymmetric synthesis of oligo-rhamno di- and tri-saccharides related to the anthrax tetrasaccharide. Tetrahedron 69:3432-3436|
|Wang, Yanping; O'Doherty, George A (2013) Cryptocaryols A and B: total syntheses, stereochemical revision, structure elucidation, and structure-activity relationship. J Am Chem Soc 135:9334-7|
|Chen, Qian; Zhong, Yashan; O'Doherty, George A (2013) Convergent de novo synthesis of vineomycinone B2 methyl ester. Chem Commun (Camb) 49:6806-8|
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