Methods to synthesize small molecules are in transition in many pharmaceutical and biotechnology companies. The value of solution phase parallel synthesis is now widely recognized. Small targeted (focused) libraries made up of 50-200 compounds are increasingly popular for lead optimization projects, and compound libraries with high molecular diversity are given more consideration for discovery libraries. Quantities for testing or deposition in compound collections are increasing to the 10-50 mg range, and requirements for purity have stiffened (90% or better is now common). These needs tax current solution phase methodology to its limits because of time-consuming and often difficult separations. Fluorous Technologies, Inc. (FTI) is developing a broad-based technology platform that comprehensively addresses the demanding synthetic chemistry needs in a modem drug discovery environment. Based on two successful Phase I projects, the current Phase II grant strives to develop a rapid fluorous synthesis toolkit for solution-phase parallel library synthesis.
The specific aims of this research effort are: 1) to develop new fluorous scavengers, tags, and protecting groups while simultaneously expanding the scope to include new fluorous reagents, catalysts, and reactants; 2) to expand the scope of microwave technology in fluorous synthesis; 3) to further strengthen the fluorous separation technology by developing new fluorous chromatographic and parallel SPE methods; 4) to develop a """"""""rapid fluorous synthesis"""""""" toolkit by using a combination of fluorous chemicals, microwave technology, and fluorous silica gel-based separations. The toolkit includes three different protocols: a one-hour single reaction, one-day one-step parallel synthesis, and one-week multi-step library synthesis; 5) to validate rapid fluorous synthesis in solution phase library production by making 5 prototype libraries with pharmaceutically interesting scaffolds, containing 100-200 analogs, 10-50 mg each, and in greater than 90% purity. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44GM067326-02A1
Application #
6833550
Study Section
Special Emphasis Panel (ZRG1-SSS-L (10))
Program Officer
Schwab, John M
Project Start
2002-09-30
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2004
Total Cost
$743,784
Indirect Cost
Name
Fluorous Technologies, Inc.
Department
Type
DUNS #
010561103
City
Pittsburgh
State
PA
Country
United States
Zip Code
15238
Zhang, Wei (2007) Fluorous-enhanced multicomponent reactions for making drug-like library scaffolds. Comb Chem High Throughput Screen 10:219-29
Chu, Qianli; Yu, Marvin S; Curran, Dennis P (2007) New fluorous/organic biphasic systems achieved by solvent tuning. Tetrahedron 63:9890-9895
Zhang, Wei; Williams, John P; Lu, Yimin et al. (2007) Fluorous synthesis of sclerotigenin-type benzodiazepine-quinazolinones. Tetrahedron Lett 48:563-565
Zhang, Wei; Lu, Yimin (2007) 96-well plate-to-plate gravity fluorous solid-phase extraction (F-SPE) for solution-phase library purification. J Comb Chem 9:836-43
del Pozo, Carlos; Keller, Adam I; Nagashima, Tadamichi et al. (2007) Amide bond formation with a new fluorous carbodiimide: separation by reverse fluorous solid-phase extraction. Org Lett 9:4167-70
Lu, Yimin; Zhang, Wei (2006) Fluorous 2,4-Dichloro-1,3,5-triazines (F-DCTs) as Nucleophile Scavengers. QSAR Comb Sci 25:728-731
Chu, Qianli; Zhang, Wei; Curran, Dennis P (2006) A recyclable fluorous organocatalyst for Diels-Alder reactions. Tetrahedron Lett 47:9287-9290
Zhang, Wei; Curran, Dennis P (2006) Synthetic applications of fluorous solid-phase extraction (F-SPE). Tetrahedron 62:11837-11865
Zhang, Wei (2006) Microwave-Enhanced High-Speed Fluorous Synthesis. Top Curr Chem 266:145-166
Zhang, Wei; Nagashima, Tadamichi (2006) Palladium-Catalyzed Buchwald-Hartwig Type Amination of Fluorous Arylsulfonates. J Fluor Chem 127:588-591

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