Studies on Application of Silyl Groups in Ring-Closing Metathesis Reactions and Fragment-Based Probe Discovery

 Title: Studies on Application of Silyl Groups in Ring-Closing Metathesis Reactions and Fragment-Based Probe Discovery Author: Wang, Yikai Citation: Wang, Yikai. 2012. Studies on Application of Silyl Groups in Ring-Closing Metathesis Reactions and Fragment-Based Probe Discovery. Doctoral dissertation, Harvard University. Full Text & Related Files: Wang_gsas.harvard_0084L_10115.pdf (71.81Mb; PDF) Abstract: In efforts to search for tool compounds that are capable of probing normal and disease-associated biological processes, both quality and identity of the screening collection are very important. Towards this goal, diversity-oriented synthesis (DOS) has been explored for a decade, which aims to populate the chemical space with diverse sets of small molecules distinct from the traditional ones obtained via combinatorial chemistry. In the practice of DOS, macrocyclic ring-closing metathesis (RCM) reactions have been widely used. However, the prediction and control of stereoselectivity of the reaction is often challenging; chemical transformation of the olefin moiety within the product is in general limited. Chapter I of this thesis describes a methodology that addresses both problems simultaneously and thus extends the utility of the RCM reactions. By installing a silyl group at the internal position of one of the olefin termini, the RCM reaction could proceed with high stereoselectivity to afford the (E)-alkenylsiloxane regardless of the intrinsic selectivity of the substrate. The resulting alkenylsiloxane can be transformed to a variety of functionalities in a regiospecific fashion. The conversion of the (E)-alkenylsiloxanes to alkenyl bromides could proceed with inversion of stereochemistry for some substrates allowing the selective access of both the E- and Z-trisubstituted macrocyclic alkenes. It was also found that the silyl group could trap the desired mono-cyclized product by suppressing nonproductive pathways. Chapter II of this thesis describes the application of the concept of DOS in the area of fragment-based drug discovery. Most fragment libraries used to date have been limited to aromatic heterocycles with an underrepresentation of chiral, enantiopure, $$sp^3$$-rich compounds. In order to create a more diverse fragment collection, the build/couple/pair algorithm was adopted. Starting from proline derivatives, a series of bicyclic compounds were obtained with complete sets of stereoisomers and high $$sp^3$$ ratio. Efforts are also described toward the generation of diverse fragments using methodology described in Chapter I. The glycogen synthase kinase $$(GSK3\beta)$$ was selected as the proof-of-concept target for screening the DOS fragments. Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10085991 Downloads of this work: