We describe an efficient
catalytic strategy for enantio- and diastereoselective
synthesis of homochiral β-CF3, β-SCF3, and β-OCF3 benzylic alcohols. The approach is
based on dynamic kinetic resolution (DKR) with Noyori–Ikariya
asymmetric transfer hydrogenation leading to simultaneous construction
of two contiguous stereogenic centers with up to 99.9% ee, up to 99.9:0.1
dr, and up to 99% isolated yield. The origin of the stereoselectivity
and racemization mechanism of DKR is rationalized by density functional
theory calculations. Applicability of the previously inaccessible
chiral fluorinated alcohols obtained by this method in two directions
is further demonstrated: As building blocks for pharmaceuticals, illustrated
by the synthesis of heat shock protein 90 inhibitor with in vitro
anticancer activity, and in particular, needle-shaped crystals of
representative stereopure products that exhibit either elastic or
plastic flexibility, which opens the door to functional materials
based on mechanically responsive chiral molecular crystals.
Heat shock protein 90 (Hsp90) is a chaperone responsible for the maturation of many cancer-related proteins, and is therefore an important target for the design of new anticancer agents. Several Hsp90 N-terminal domain inhibitors have been evaluated in clinical trials, but none have been approved as cancer therapies. This is partly due to induction of the heat shock response, which can be avoided using Hsp90 C-terminal-domain (CTD) inhibition. Several structural features have been shown to be useful in the design of Hsp90 CTD inhibitors, including an aromatic ring, a cationic center and the benzothiazole moiety. This study established a previously unknown link between these structural motifs. Using ligand-based design methodologies and structure-based pharmacophore models, a library of 29 benzothiazole-based Hsp90 CTD inhibitors was prepared, and their antiproliferative activities were evaluated in MCF-7 breast cancer cells. Several showed low-micromolar IC50, with the most potent being compounds 5g and 9i (IC50, 2.8 ± 0.1, 3.9 ± 0.1 μM, respectively). Based on these results, a ligand-based structure–activity relationship model was built, and molecular dynamics simulation was performed to elaborate the binding mode of compound 9i. Moreover, compound 9i showed degradation of Hsp90 client proteins and no induction of the heat shock response.
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