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Complex: The synthesis of the glycolipid PGL‐tb1 present in the outer membrane of hypervirulent strains of Mycobacterium tuberculosis has been accomplished for the first time by using a highly convergent strategy featuring a Sonogashira coupling to unite a phenolic trisaccharide with the phthiocerol. Efficient asymmetric Cu‐catalyzed 1,4‐additions to unsaturated thioesters and cyclic enones have been employed to introduce the methyl groups.

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Beta-secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-beta peptides, is an attractive target for the treatment of Alzheimer's disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of non-peptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC 50 of 323 M to 27 M following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity.This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors.3

The phenolic glycolipid mycoside B, present in Mycobacterium bovis and hypervirulent strains of Mycobacterium tuberculosis, has been synthesized for the first time. Multiple methyl groups were introduced by the extensive use of catalytic asymmetric 1,4‐addition reactions, asymmetric hydrogenation of a β‐keto ester afforded the basis for the central 1,3‐diol moiety, and introduction of the 2‐O‐methyl‐α‐L‐rhamnoside unit was achieved by stereoselective glycosylation with p‐iodophenol and subsequent Sonogashira coupling, providing a basis for the generation of analogues. In addition, the related monosaccharide HBAD‐I, present in the same species, has been efficiently synthesized for the first time by selective methylation of the hydroxy group at C‐2 of a rhamnoside.