102(P-52) Pathway Development for Library Realization on Carbohydrate and Steroidal Scaffolds by Diversity-Oriented Organic Synthesis

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Library realization of small molecules by split-pool diversity-oriented synthesis (DOS) plays a key role in the chemical genetic approach to the study of cellular events. In order to increase the opportunities for discovering new and important biology by using small molecules, we propose to increase the amount of skeletal diversity found within individual collections of molecules. We speculate that using this strategy will be a more efficient method of identifying new small molecule ligands for proteins. Our first experiments are based on the use of carbohydrate and steroidal scaffolds. All of the chemistries presented were explored on polystyrene macrobeads which are amenable to our "one-bead, one-stock solution approach to chemical genetics". Our experiments toward carbohydrate-based libraries are focusing on a conformational rearrangement using the monosaccharide, 1,6-anhydro-D-glucose 1, which starts in the ^1C_4 conformation. 2-Amino-4-azido-2,4-deoxy-1,6-anhydro-β-glucose 2, prepared in 5 steps, was loaded onto the macrobeads by urea functionality. After derivatization of its 3-hydroxy group, the 5-membered bridge on the pyranose ring was cleaved by nucleophilic attack of a phenylthio group (TMSSPh, ZnI_2, Bu_4NI). This cleavage is accompanied by a ring flip of the pyranose ring to ^4C_1 conformer to achieve a skeletal rearrangement of the carbohydrate scaffold on solid phase. Further chemical transformation of the 4-azide group into amides or triazole functionalities on a solid phase was successful. A second but distinct example of increasing the skeletal diversity of small molecule libraries has been developed using a steroid-based ring system as the starting point. Starting from resin-bound 5,7-diene-17,20-epoxysteroid 13, which was prepared from dehydroisoandrosterone 10 in 5 steps, the epoxy group was opened by secondary amine building blocks 14 to introduce diversity at 17-position. Besides secondary amines, primary amines and thiols can be also used for the epoxide opening. Secondary amines generated by the addition of primary amines are further derivatized by acylation. The epoxide-opened steroid, 15, was next modified by Diels-Alder reaction with ynones 16 possessing diverse substituents. The reaction took place with high regio- and stereoselectivities to add an additional 1,4-cyclohexadiene ring system efficiently onto 15. This transformation thus allows us to increase diversity by the addition of building blocks but also change the basic skeleton of the steroid backbone. The 1.4-cyclohexadiene function of 17 provides further opportunity to change the scaffold. When 17 was heated, a retro-Diels-Alder reaction proceeded smoothly to give the 14-membered ansa-ring system 18. These two-step sequential transformations, Diels-Alder reaction followed by retro-Diels-Alder reaction, drastically modify the scaffold of the starting steroid. When intermediates are kept from each step and included in the final library for biological assays, we feel this will be a truly diverse library. Once hits are identified in biological assays, we require a method of resynthesizing molecules on a larger scale for more detailed analysis (e.g. Titration curves). For the resynthesis of larger quantities of molecules discovered to be biologically interesting, functionalization of Lanterns^<TM> (Mimotopes), which have a grafted-polystyrene surface, has been achieved, resulting in a system that possesses 35μmol of Si/unit. Preliminary experiments using several reactions showed that the alkylsilyl-tethered Lanterns are also useful resins for generation of small molecules.
天然有機化合物討論会の論文
2002-09-01

102(P-52) Pathway Development for Library Realization on Carbohydrate and Steroidal Scaffolds by Diversity-Oriented Organic Synthesis

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