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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM090259-05
Application #
8330298
Study Section
Special Emphasis Panel (ZGM1-PPBC-3 (CS))
Program Officer
Marino, Pamela
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$304,811
Indirect Cost
$108,791
Name
Northeastern University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
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
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
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
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
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
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
Chen, Qian; Zhong, Yashan; O'Doherty, George A (2013) Convergent de novo synthesis of vineomycinone B2 methyl ester. Chem Commun (Camb) 49:6806-8
Babu, Ravula Satheesh; Chen, Qian; Kang, Sang-Woo et al. (2012) De novo asymmetric synthesis of all-D-, all-L-, and D-/L-oligosaccharides using atom-less protecting groups. J Am Chem Soc 134:11952-5

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