Cooperative hydrogen-bonding effects in silanediol catalysis

The importance of cooperative hydrogen-bonding effects and SiOH-acidification is described for silanediol catalysis. NMR binding, X-ray, and computational studies provide support for a unique dimer resulting from silanediol self-recognition. The significance of this cooperative hydrogen-bonding is demonstrated using novel fluorinated silanediol catalysts for the addition of indoles and N,N-dimethyl-m-anisidine to trans-β-nitrostyrene.     

A silanediol inhibitor of the metalloprotease thermolysin: synthesis and comparison with a phosphinic acid inhibitor

A silanediol inhibitor of the metalloprotease thermolysin was prepared for comparison to a known phosphinic acid inhibitor, providing the first comparison of these second-row element based transition-state analogues. Inhibition of thermolysin by the silanediol (K(i) = 41 nM) was comparable to that of the phosphinic acid (K(i) = 10 nM) even though the silanediol is uncharged and thereby lacks the intrinsic Coulombic attraction of the phosphinate anion to the active-site zinc cation. This silanediol protease inhibitor is the least sterically encumbered example prepared to date and, therefore, the most prone toward polymerization. Hydrolysis of a difluorosilane intermediate to the silanediol leads cleanly to a monomeric product.     

Stereocontrolled synthesis of methyl silanediol peptide mimics

The treatment of chiral sulfinimines with (methyldiphenylsilyl)lithium gives alpha-(methyldiphenylsilyl)sulfinamides with excellent diastereoselectivity, and in good yield. The presence of alpha-protons on the imines is also well tolerated. The sulfinamide auxiliary is easily removed via treatment with methanolic HCl and the resulting amine extended into peptide chains accordingly. The diphenylsilyl moiety is a resilient protecting group for the corresponding silanediol, which can be unmasked via treatment with TfOH, followed by aqueous hydrolysis. The crude silanediol may be isolated and purified as its corresponding bis-TMS siloxane via protection with TMSCl, and converted back to the desired silanediol via hydrolysis with aqueous KOH. Efforts to apply this approach to biologically relevant silanediol peptide mimics, with a view to protease inhibition, are described.     

Serine protease inhibition by a silanediol peptidomimetic

Silanediol peptidomimetics are demonstrated to inhibit a serine protease. Asymmetric synthesis of the inhibitor was accomplished using Brown hydroboration and CBS reduction of an acylsilane intermediate. The silanediol product was found to inhibit the serine protease chymotrypsin with a K(i) of 107 nM. Inhibition of the enzyme may involve exchange of a silane hydroxyl with the active site serine nucleophile, contrasting with previous silanediol protease inhibitors.     

Efficient, enantioselective assembly of silanediol protease inhibitors

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.     

Silicon-based metalloprotease inhibitors: synthesis and evaluation of silanol and silanediol peptide analogues as inhibitors of angiotensin-converting enzyme

Silanols are best known as unstable precursors of siloxane (silicone) polymers, substances generally considered stable and inert, but have the potential to mimic a hydrated carbonyl and inhibit protease enzymes. While previous testing of simple silanediol and silanetriol species as inhibitors of hydrolase enzymes found them ineffective, this study reports polypeptide mimics with a central methylsilanol [SiMeOH] or silanediol [Si(OH)(2)] group and their assessment as effective transition state analogue inhibitors of the well-studied metalloprotease angiotensin-converting enzyme (ACE). Central to the synthesis strategy, phenylsilanes were employed as acid-hydrolyzable precursors of the silanol group. The N-benzoyl Leu-[SiMeOH]-Gly benzyl amides proved to be stable and readily characterized. In contrast, the Leu-[Si(OH)(2)]-Gly structure was difficult to characterize, possibly because of self-association. Capping the silanediol with chlorotrimethylsilane gave a well-defined trisiloxane, demonstrating that the silanediol was monomeric. The Leu-[Si]-Gly structures were converted to Leu-[Si]-Ala analogues by enolate alkylation. Coupling of the silanol precursors with proline tert-butyl ester gave N-benzoyl Leu-[Si]-Gly-Pro and N-benzoyl Leu-[Si]-Ala-Pro tripeptide analogues. Treatment of these with triflic acid formed the corresponding methylsilanols and silanediols, all of which were monomeric. The silanediol tripeptide mimics inhibited ACE with IC(50) values as low as 14 nM. Methylsilanols, in contrast, were poor inhibitors, with IC(50) values above 3000 nM. These data, including comparisons with inhibition data from carbon analogues, are consistent with binding of the silanediols by chelation of the ACE active site zinc, whereas the methylsilanols ligate poorly.     

A concise synthesis of silanediol-based transition-state isostere inhibitors of proteases

[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.     

Silanediol inhibitors of angiotensin-converting enzyme. Synthesis and evaluation of four diastereomers of Phe[Si]Ala dipeptide analogues

Four stereoisomers of a Phe-Ala silanediol dipeptide mimic have been evaluated as inhibitors of angiotensin-converting enzyme (ACE) and compared to ketone-based inhibitors reported by Almquist et al. One stereogenic center of the isomers was derived from the individual enantiomers of methyl 3-hydroxy-2-methylpropionate, with separation of diastereomers after introduction of the second stereogenic center. The diastereomeric identities were established by X-ray crystallography of an intermediate. Inhibition of ACE by three of the silanediol diastereomers (IC(50) = 3.8-207 nM) closely paralleled that of the corresponding diastereomeric ketones (IC(50) = 1.0-46 nM). The fourth diastereomer, corresponding to the least inhibitory ketone (IC(50) = 3200 nM), exhibited an unexpected level of inhibition in the silanediol (IC(50) = 72 nM), suggesting an alternative mode of binding to the enzyme.     

Stepwise synthesis of siloxane chains

Siloxane chains of designated lengths can be synthesized with high yields by reacting tris(tert-butoxy)silanol alternately with dichlorosilane and silanediol.     

Anion recognition by 1,3-disiloxane-1,1,3,3-tetraols in organic solvents

Anion recognition by 1,3-disiloxane-1,1,3,3-tetraols has been elucidated by ¹H NMR titrations and ESI-MS in organic solvents. The association constants of the receptors for halide anions are larger than those of silanediol and 1,3-disiloxane-1,3-diol due to the cooperative hydrogen bonds by four silanol hydroxy groups of 1,3-disiloxane-1,1,3,3-tetraols.     

Sequential C-Si bond formations from diphenylsilane: application to silanediol peptide isostere precursors

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.     

Drug design with a new transition state analog of the hydrated carbonyl: silicon-based inhibitors of the HIV protease

BACKGROUND: Silicon is the element most similar to carbon, and bioactive organosilanes have therefore been of longstanding interest. Design of bioactive organosilanes has often involved a systematic replacement of a bioactive molecule's stable carbon atoms with silicon. Silanediols, which are best known as unstable precursors of the robust and ubiquitous silicone polymers, have the potential to mimic an unstable carbon, the hydrated carbonyl. As a bioisostere of the tetrahedral intermediate of amide hydrolysis, a silanediol could act as a transition state analog inhibitor of protease enzymes. RESULTS: Silanediol analogs of a carbinol-based inhibitor of the HIV protease were prepared as single enantiomers, with up to six stereogenic centers. As inhibitors of this aspartic protease, the silanediols were nearly equivalent to both their carbinol analogs and indinavir, a current treatment for AIDS, with low nanomolar K(i) values. IC(90) data from a cell culture assay mirrored the K(i) data, demonstrating that the silanediols can also cross cell membranes and deliver their antiviral effects. CONCLUSIONS: In their first evaluation as inhibitors of an aspartic protease, silanediol peptidomimetics have been found to be nearly as potent as currently available pharmaceutical agents, in enzyme and cell protection assays. These neutral, cell-permeable transition state analogs therefore provide a novel foundation for the design of therapeutic agents.     

Applicability of silanol to sensitizing dye for dye-sensitized solar cell

Applicability of silanols to dye-sensitized solar cells was investigated for the first time with bis(4-azobenzene)silanediol as a model compound. The silanol dye showed high adsorption ability on the surface of TiO₂ electrode and effective electron transfer from the light-excited dye to the electrode was confirmed, exhibiting the effectiveness of the silanol dyes for the sensitizers.     

Conjugate addition of organocopper reagents in dichloromethane to α,β-unsaturated esters

Organocopper reagents in conjunction with Lewis acid activators provide greater stability than traditional cuprate reagents while maintaining the reactivity needed for conjugate addition reactions in dichloromethane. Whereas cuprates engage in cross-coupling pathways, organocopper nucleophiles are more selective for conjugate addition. The utility of organocopper reagents in dichloromethane for the conjugate addition to α,β-unsaturated esters is expanded upon herein.     

Hydrolysis and etherification of (o-carboranylisopropyl)dichloro(methyl)silane

The behavior of (o-carboranylisopropyl)dichloro(methyl)silane in hydrolysis and etherification reactions has been studied. (o-Carboranylisopropyl)(methyl)silanediol and (o-carboranylisopropyl)diethoxy(methyl)silane have been obtained for the first time and characterized.     

Alkynenitriles: stereoselective chelation controlled conjugate addition-alkylations

Chelation-controlled conjugate addition of Grignard reagents to γ-hydroxyalkynenitriles stereoselectively generates tri- and tetra-substituted alkenenitriles. t-BuMgCl-initiated deprotonation of hydroxyalkynenitriles followed by addition of a second Grignard reagents triggers a facile conjugate addition leading to a cyclic magnesium chelate. Protonation of the chelate stereoselectively generates trisubstituted nitriles whereas the addition of t-BuLi causes conversion to an ‘ate’ complex that allows alkylation with aldehyde electrophiles. The chelation-controlled conjugate addition-alkylation generates tri- and tetra-substituted alkenenitriles that are otherwise difficult to synthesize.     

Catalytic asymmetric conjugate addition of Grignard reagents to coumarins--synthesis of versatile chiral building blocks

A new protocol for the Cu-catalysed asymmetric conjugate addition of Grignard reagents to coumarins has been developed. The corresponding products are formed in high yields and enantioselectivities. Through a sequential protocol involving conjugate addition followed by nucleophilic ring opening of the chiral enolate, chiral esters and amides are readily accessible.     

KF负载氧化物高效催化缺电子烯与胺类的共轭加成反应

提供了一种新型高效的催化缺电子烯与胺类的共扼加成的反应体系。首先合成了一系列负载型氟化钾固体碱,并用于催化上述反应。通过对不同载体选择考察,筛选出氟化钾负载氧化镁固体碱为最佳催化剂。在进一步的催化反应过程中发现,该催化剂对反应具有很高的催化活性,能催化该反应在短短数分钟内完成。操作简单方便,不需要任何溶剂,催化剂价格低廉,反应收率高,可重复使用,具有化学选择性,适用范围广泛等均为该催化体系的主要特征。     

Synthesis and properties of a sterically unencumbered δ-silanediol amino acid

An amino acid carrying a 1-(4-dihydroxymethylsilyl)butyl side chain has been prepared in enantiomerically pure form as a potential inhibitor of the enzyme arginase, a pharmaceutical target. As a water-soluble silanediol, this compound was anticipated to be entropically stabilized against polymerization and siloxane formation. At 50 mM in D(2)O, the degree of oligomerization was found to be pH dependent, with diastereomeric mixtures formed on condensation. Above pH 11 the silane is largely monomeric.     

Enantioselective conjugate addition of fluorobis(phenylsulfonyl)methane to α,β-unsaturated ketones catalyzed by chiral bifunctional organocatalysts

The catalytic enantioselective conjugate addition reaction of fluorobis(phenylsulfonyl)methane to α,β-unsaturated ketones promoted by chiral bifunctional organocatalysts is described. The treatment of fluorobis(phenylsulfonyl)methane to α,β-unsaturated ketones under mild reaction conditions afforded the corresponding Michael adducts with high enantioselectivity. The conjugate addition adducts are useful for the synthesis of chiral monofluoromethylated compounds.