Although not endogenous in nature, the sulfonamide functionality is widely found in organic molecules with biological activity. A search of Thomson Reuters Integrity reveals that the sulfonamide motif appears in 111 approved drugs or agents in clinical trials, [1] and the total number of organic molecules containing this functional group is enormous. In contrast, the sulfonamide isostere [2] in which one of the sulfonamide oxygen atoms have been replaced by a nitrogen atom, thus creating a sulfonimidamide has received little attention in the literature. The first reports on sulfonimidamides were published in the early 1960s, [3] however, it was only during the last few years that the research groups of Malacria [4] and Dodd [5] explored the use of sulfonimidamides as reagents in organic synthesis, while Bolm et al. explored sulfonimidamides as chiral organocatalysts [6a] and as ligands for transition metal-catalyzed asymmetric synthesis.[6b]
By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 μM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds.
A new concept for the construction of β-D-fructofuranosides based on the idea of locking the anomeric CH 2 OH group to the R-side through an internal bridge to the 4-hydroxyl group is presented. Thioglycoside fructose donors containing an internal 1,4-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl) (TIPS) acetal bridge have been constructed and used in glycosylations with dimethyl(thiomethyl)sulfonium triflate (DMTST) as promoter. The couplings were stereospecific to give β-D-fructofuranosyl disaccharides in high yields. Using this approach, sucrose has been synthesized stereospecifically in 80% yield.
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