Sequential C−Si Bond Formations from Diphenylsilane: Application to Silanediol Peptide Isostere Precursors

Abstract

The report of silanediol peptide isosteres as highly active inhibitors of proteolytic enzymes has triggered an increased interest for these compounds, thereby necessitating a general and direct synthetic access to this unusual class of protease inhibitors. In this paper, we report on the two-step assembly of the carbon-silicon backbone of a silane-containing dipeptide fragment. The synthetic scheme is comprised of an alkene hydrosilylation step with the simple precursor, diphenylsilane, using either a radical initiator or RhCl(PPh3)3, Wilkinson's catalyst, for the creation of a hydridosilane and the first new carbon-silicon bond. The next step is the reduction of this hydridosilane with lithium metal providing a silyl lithium reagent, which undergoes a highly diastereoselective addition to an optically active tert-butanesulfinimine, thus generating the second C-Si bond. This method allows sequential functionalization of the two hydrides in diphenylsilane by chemoselective discrimination.

Reductive Lithiation and Multilithiated Compounds in Synthesis

“…Indeed, although previous literature reports on this topic indicate hydridosilanes as poor substrates for lithium reduction, Skrydstrup and coworkers accomplished the ready lithiation of a series of alkyldiphenylsilanes, 119, by reacting them with Li metal in THF at room temperature for 18 h. The resulting silyl-lithium intermediates reacted with chiral sulfinimine to afford the desired α-silylsulfinamides, 120, with satisfactory to good yields and, in most cases, with excellent diastereoselectivities (Scheme 12.28) [54][55][56]. Finally, a one-pot hydrosilylation, reductive lithiation, and addition to enantiopure tert-butylsulfinyl imines demonstrated the ready applicability of the whole synthetic protocol (Scheme 12.29).…”

“…Following the Skrydstrup procedure [56,57], compound 124 was converted into the corresponding lithium derivative and reacted with a sulfinimine, thus affording sulfinimide 125 as a single stereoisomer. Straightforward elaboration afforded the desired silylated peptide isostere 126 in good overall yields (Scheme 12.31).…”

Bioactive Amino Acids, Peptides and Peptidomimetics Containing Silicon

“…Skyrdstrup and Nielson were the first to demonstrate that this could be done in high yield, converting Ellman [81] sulfinimine 106 to 108 in 76 % yield, with diastereoselectivity > 95 % [64,82].…”

Conformational landscape of small organosilicon compounds from the combined use of gas electron diffraction, IR and Raman spectroscopies and quantum chemical calculations: diethyldichlorosilane

“…[1] More recently, dihalosilanes have also been used as precursors in the synthesis of silanodiols with interesting applications in the development of inhibitors of aspartic and metallo proteases. [2,3] To the best of our knowledge, the study of the molecular structure of the title compound, diethyldichlorosilane (DEDCS), has not been accomplished, either theoretically or experimentally, and previous work in the literature dealing with its vibrational spectra is scarce and rather incomplete. [4] In this work, the use of quantum-mechanical calculations has allowed a search for conformers of DEDCS, in which the two rotating ethyl groups give rise to several molecular conformations, each of which represents a minimum on its potential energy surface.…”