A five-step assembly of silicon-protected dipeptide mimics from commercially available reagents is described. This methodology makes silanediol protease inhibitors readily available for the first time. The sequence features asymmetric hydrosilylation, a novel reduction of a silyl ether to a silyllithium reagent, and addition of this dianion to a sulfinimine, to produce the complete inhibitor skeleton with full control of stereochemistry. Oxidation of the primary alcohol to an acid completes the synthesis.Inhibition of proteolytic enzymes remains a fundamental approach to the design of new pharmaceuticals, with recent examples including the treatment of cancer, anti-retrovirus diseases (HIV), treatment for Alzheimer's and hepatitis C. 1 Most protease inhibitors utilize now-standard functionality to mimic the transition state or to intercept the catalytic functional groups: hydroxamic, carboxylic and phosphinic acids (for metalloproteases), hydroxyls (for aspartic acids), and activated carbonyls (for serine proteases).2 Fundamentally different functional groups that can act as transition-state analogs have the potential to give enhanced enzyme binding and pharmacokinetic properties, as well as intellectual property novelty.3 Dialkylsilanediol dipeptide analogs (e.g. 1, Scheme 1) are tetrahedral functional groups that can mimic hydrated carbonyls. 4 When silanediols are embedded in a peptide-like structure such as 1, they are recognized by protease enzymes and, as hydrolytically stable entities, act as inhibitors. Tripeptide analog 1, for example, is a 4 nM inhibitor of the metalloprotease angiotensin-converting enzyme, an important therapeutic target for hypertension. 5 A silanediol has also been shown to be a 3 nM inhibitor of the aspartic acid HIV-protease, an activity that translates to cell-protection assays. 6 An impediment to utilization of these silanediol structures, however, has been the methodology for their assembly. In our original preparation of 1, Scheme 1, diphenylsilane 2 * scott.sieburth@temple.edu .
Supporting Information AvailableDetailed experimentals, characterization data and proton NMR spectra for new compounds is available. This material is available free of charge via the Internet at http://pubs.acs.org. was the direct precursor of the silanediol; the α-amino silane portion of 2 was prepared utilizing a dithiane nucleophile 3 and six synthetic steps, while Roche ester 5 was transformed to the β-silyl acid of 2 in seven steps. In this synthesis, the stereochemistry of the methyl substitution was purchased and the benzyl group stereochemistry relied on separation of diastereomers. While effective, this approach was 13 steps and technically challenging. 7 We report here a short, general, asymmetric preparation of silanediol precursor 2: one that employs intramolecular asymmetric hydrosilylation to set the β-silyl acid stereochemistry, a novel reduction of a silyl ether to a silyl anion, and addition of the resulting dianion to a sulfinimine. The resulting product requires only alcohol...
