A Concise Synthesis of Silanediol-Based Transition-State Isostere Inhibitors of Proteases

Abstract

[reaction: see text] An efficient synthesis of silanediol-based transition-state inhibitors of proteases is described. A new convergent synthesis has been optimized by using a two-step sequence of hydrosilylation followed by the addition of a silyllithio species to an imine. The method should be applicable to the synthesis of a wide variety of silanediol isosteres to probe the utility of this unique transition-state isostere.

Activation of the Si−B Linkage: Copper-Catalyzed Addition of Nucleophilic Silicon to Imines

“…Due to ongoing interest in silicon-containing peptide isosteres − and α-amino acids, a copper-catalyzed addition of silicon nucleophiles to imines to form α-silylated amines would also be a useful method. There were only isolated examples of Si−Li and Si−Cu additions to iminium ions prior to the systematic elaboration of diastereoselective imine additions by the laboratories of Scheidt and Skrydstrup, employing various functionalized , Si−Li reagents . Activating groups at the imine nitrogen atom, for example, S(O) t -Bu, are usually required, , and ketone-derived imines were not sufficiently reactive .…”

Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds

“…The biological activity of silanediols prompted organic chemists to develop efficient synthetic routes to access them . Studies were also carried out to understand the mechanism of inhibition as this knowledge is essential for taking the compounds forward .…”

“…The biological activity of silanediols prompted organic chemists to develop efficient synthetic routes to access them. 53 Studies were also carried out to understand the mechanism of inhibition as this knowledge is essential for taking the compounds forward. 54 Since protease inhibitors represent an important class of therapeutic agents, silanediols have great potential and further research in this area can lead to more potent and selective inhibitors.…”

Reductive Lithiation and Multilithiated Compounds in Synthesis

“…Indeed, silicon in the form of a dialkylsilanediol was successfully incorporated into peptide-derived peptidomimetics, showing activities as selective inhibitors of proteolytic enzymes [51]. In 2002, Organ et al [52] reported the first concise and efficient synthesis of such derivatives, as described in Scheme 12.27. Accordingly, catalyzed hydrosilylation of methoxymethyl (MOM)-protected allyl alcohol, 111, with chlorodiphenylsilane afforded the corresponding chlorosilane 112, which underwent clean reductive lithiation with Li in THF.…”