The long-term objective of this project is to develop an environmentally friendly method for the preparation of 2-deoxy-C-aryl glycosides, a family of natural products which demonstrate important biological properties such as antitumor, antibiotic and antifungal activities. Previous approaches to the synthesis of this class of compounds have involved the use of corrosive Lewis acids or toxic metals for the preparation of the carbon-carbon linkage between carbohydrate and aromatic moieties. Although we have previously shown that benign organoindium reagents may be employed in fashioning the glycosidic carbon-carbon bond efficiently, we wish to explore a new method that will allow the construction of this bond with the stereochemical configuration found in the natural products. With this goal in mind, we will investigate the preparation and reactivity of benign glycosyl zinc reagents as key intermediates in the synthesis of C-aryl glycosides. It is anticipated that temperature will be a key factor in determining the orientation of the carbon-zinc bond, which ultimately will determine the stereochemistry of the glycosidic carbon-carbon bond. Optimal conditions for the transition-metal catalyzed cross-coupling reaction between the glycosyl zinc reagent and aryl halides or triflates for the formation of the C-glycosides will also be explored. Finally, to assess the broad utility of this method, the preparation of the glycosidic core of the angucycline natural product Sch 47555 will be undertaken, and the mildness of the reaction conditions will be gauged by attempting a late-stage joining of fully functionalized carbohydrate and aromatic units bearing a sensitive O-glycosidic linkage. Because of the pronounced biological activities of the C-aryl glycosides, it is likely that even structural variants and simplified analogs of these natural products will have intriguing properties; as a result, a further aim of our synthetic efforts is to produce sufficient quantities of these substances for pharmacological evaluation. If successful, this research will provide scientists with an additional tool for the assembly of medicinally relevant compounds to fight sickness and infectious disease. Furthermore, if such environmentally benign protocols are widely adopted in the chemical industries, the negative impacts of large-scale chemical processes on fragile ecosystems and the biosphere will be diminished, which in the long term will result in improved human health. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Pilot Research Project (SC2)
Project #
1SC2GM081064-01
Application #
7287967
Study Section
Special Emphasis Panel (ZGM1-MBRS-1 (SC))
Program Officer
Schwab, John M
Project Start
2007-09-01
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
1
Fiscal Year
2007
Total Cost
$96,500
Indirect Cost
Name
California State University Northridge
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
055752331
City
Northridge
State
CA
Country
United States
Zip Code
91330
Tudjarian, Armen A; Minehan, Thomas G (2011) [3,3]-Sigmatropic rearrangement/5-exo-dig cyclization reactions of benzyl alkynyl ethers: synthesis of substituted 2-indanones and indenes. J Org Chem 76:3576-81
Yepremyan, Akop; Salehani, Baback; Minehan, Thomas G (2010) Concise total syntheses of aspalathin and nothofagin. Org Lett 12:1580-3
Dhanjee, Heemal; Minehan, Thomas G (2010) Indium-mediated allylation of aldehydes, ketones and sulfonimines with 2-(alkoxy)allyl bromides. Tetrahedron Lett 51:5609-5612
Moral, John Alec; Moon, Seong-Jin; Rodriguez-Torres, Samuel et al. (2009) A sequential indium-mediated aldehyde allylation/palladium-catalyzed cross-coupling reaction in the synthesis of 2-deoxy-beta-C-aryl glycosides. Org Lett 11:3734-7
Papoian, Vardan; Minehan, Thomas (2008) Palladium-catalyzed reactions of arylindium reagents prepared directly from aryl iodides and indium metal. J Org Chem 73:7376-9
Pham, Minh; Allatabakhsh, Amir; Minehan, Thomas G (2008) An environmentally benign synthesis of cis-2,6-disubstituted tetrahydropyrans via indium-mediated tandem allylation/Prins cyclization reaction. J Org Chem 73:741-4
Sosa, Juan R; Tudjarian, Armen A; Minehan, Thomas G (2008) Synthesis of alkynyl ethers and low-temperature sigmatropic rearrangement of allyl and benzyl alkynyl ethers. Org Lett 10:5091-4