Efficient Routes to Carbon–Silicon Bond Formation for the Synthesis of Silicon-Containing Peptides and Azasilaheterocycles

Abstract

Silasubstitution, where silicon is substituted for carbon at specific sites of the substrate, has become a growing practice in medicinal chemistry. Introducing silicon into bioactive compounds provides slight physical and electronic alterations to the parent compound, which in certain instances could make the substrate a more viable candidate for a drug target. One application is in the field of protease inhibition. Various silane diol isosteres can act as potent inhibitors of aspartic and metalloproteases because of their ability to mimic the high-energy tetrahedral intermediate in peptide bond hydrolysis. In particular, since 1998, the Sieburth group has prepared a number of functionalized peptide silane diol isosteres. In a seminal study, they demonstrated that these molecules can bind to the active site of the enzymes. Inspired by these results, we initiated a study to develop a concise and straightforward route to access highly functionalized silicon diol based peptidomimetic analogs, which we describe in this Account. The synthesis of such analogs is challenging because the dipeptide mimics require the formation of two carbon-silicon bonds as well as two chiral carbon centers. Our first strategy was to assemble the two C-Si bonds from diphenylsilane through an initial regioselective hydrosilylation step of a terminal alkene, followed by lithiation of the formed alkyldiphenylsilane by a simple lithium metal reduction. Subsequent diastereoselective addition of this silyllithium species to a tert-butylsulfinimine provided a rapid method to assemble the dipeptide mimic with stereochemical control at the new chiral carbon center adjacent to the silicon. This strategy worked with a wide range of functional groups. However, there were some limitations with the more elaborate targets. In particular, we needed to exchange the phenyl groups of the diphenylsilane with aryl groups that were more labile under acidic conditions in order to introduce Si-O bonds in the end product. We demonstrated that a variety of Ar(2)SiH(2) compounds with methyl substituents on the aromatic core could effectively undergo hydrosilylation and reductive lithiation with a soluble reducing agent, lithium naphthalenide. The electron-rich aromatic groups were more acid labile and, depending on the conditions, could produce either the silane diol or the silanol. In an alternative strategy, we used a highly regioselective Rh-catalyzed sequential double hydrosilylation to form the two C-Si bonds with a single catalyst. This approach is a more efficient, atom economical way to synthesize a wider range of highly functionalized organosilanes with the added possibility of extending this method into an asymmetric protocol. By this method, various functional groups that were not previously tolerated in the lithiation protocol, including OBn, OAc, furyl, and thiophenes, could now be incorporated. Hydrosilylation of a terminal olefin and a peptide functionalized with an enamide at the C-terminus achieved the desired silane in high yields in a one pot r...

Tertiäre α‐Silylalkohole mittels diastereoselektiver Kupplung von 1,3‐Dienen und Acylsilanen, eingeleitet durch enantioselektive kupferkatalysierte Borylierung

“…Eine TBAF-vermittelte [1,2]-Brook-Umlagerung von 4ca ergab das 1,3-Diol 6 in guter Ausbeute und mit hinreichender Diastereoselektivität. Die 1,1-disubstituierte Doppelbindung in 4ca wurde über Pd/C zu 5 in 81 %A usbeute hydriert.…”

“…[1] So finden beispielsweise chirale a-Hydroxysilane (= a-Silylalkohole) und deren Derivate Anwendung in stereokontrollierten C-C-Bindungsknüpfungen und Umlagerungen. [1] So finden beispielsweise chirale a-Hydroxysilane (= a-Silylalkohole) und deren Derivate Anwendung in stereokontrollierten C-C-Bindungsknüpfungen und Umlagerungen.…”

Synthesis, X-Ray Structure and Anti-Bacterial Studies of 1,3-Thiazolylpropylsilatranes

“…Among these compounds are substituted propyl chain linked silatranes that constitute a unique class of penta-coordinated silicon compounds [12][13][14] . Silatranes are intra-complex organosilicon alkoxyamine esters and exhibit a broad spectrum of biological activities [15][16][17][18][19] . The substituent fragment of silatrane influences both type and extent of biological activity of complexes.…”

2-Furancarbinol complexes of silicon: Synthesis, Characterization and Reactivity

“…[1][2][3] The literature is replete with numerous hypervalent organosilicon compounds [4][5][6][7][8] Yields of all the compounds obtained were appreciable. Structures of the compounds were confirmed on the basis of spectral data (IR and multinuclei NMR).…”