One application is in the Zonisamide field of protease inhibition. Various silane diol isosteres can act as potent inhibitors of aspartic and metalloproteases because of their means to mimic the high-energy tetrahedral intermediate in peptide bond hydrolysis. Specifically, considering the fact that 1998, the Sieburth group has prepared many functionalized peptide silane diol isosteres. Within a seminal review, they demonstrated that these molecules can bind to the active web page in the enzymes. Inspired by these success, we initiated a examine to create a concise and straightforward route to entry very functionalized silicon diol based peptidomimetic analogs, which we describe in this Account. The synthesis of such analogs is difficult because the dipeptide mimics require the formation of two carbon-silicon bonds likewise as two chiral carbon centers.
Our 1st strategy was to assemble the 2 C-Si bonds from diphenylsilane by an initial regioselective hydrosilylation phase of a terminal alkene, followed by lithiation with the formed alkyldiphenylsilane by a straightforward lithium metal reduction. Subsequent diastereoselective addition of this silyllithium species to a tert-butylsulfinimine supplied a rapid method to assemble the dipeptide mimic with stereochemical management in the new chiral carbon center adjacent towards the silicon. This tactic worked with a broad variety of practical groups. Having said that, there have been some limitations with the far more elaborate targets. Particularly, we desired to exchange the phenyl groups of the diphenylsilane with aryl groups that have been far more labile underneath acidic conditions in an effort to introduce Si-O bonds in the long run product or service.
We demonstrated that various Ar2SiH2 compounds with methyl substituents around the aromatic core could efficiently undergo hydrosilylation and reductive lithiation using a soluble decreasing agent, lithium naphthalenide. The electron-rich aromatic groups had been much more acid labile and, depending on the circumstances, could make either the silane diol or even the silanol.
In an option method, we employed a extremely regioselective Rh-catalyzed sequential double hydrosilylation to kind the two C-Si bonds which has a single catalyst. This strategy is really a much more productive, atom economical method to synthesize a wider array of remarkably functionalized organosilanes with the additional possibility of extending this process into an asymmetric protocol.
By this approach, many practical groups that had been not previously tolerated in the lithiation protocol, which includes OBn, OAc, furyl, and thiophenes, could now be incorporated. Hydrosilylation of a terminal olefin and also a peptide functionalized with an enamide at the C-terminus accomplished the preferred silane in large yields within a one pot reaction without the need of compromising the stereochemical integrity with the peptide. As an extension of this get the job done, we made use of these techniques to effectively make a range of chiral azasilaheterocycles, together with silapiperidines and silaindolizidines.