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Scott Mcn. Sieburth - One of the best experts on this subject based on the ideXlab platform.
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asymmetric synthesis of Silanediol inhibitors for the serine protease coagulation cascade enzyme fxia
Journal of Organic Chemistry, 2018Co-Authors: Hoan Quoc Duong, Scott Mcn. SieburthAbstract:Silanediol peptidomimetics have been prepared, designed to inhibit the serine protease enzyme Factor XIa (FXIa) for treatment of thrombosis without complete interruption of normal hemostasis. These Arg-[Si]-Ala analogues of the FXIa substrate (FIX) are the first Silanediol dipeptide analogues to carry a basic guanidine group. Control of stereochemistry was accomplished using catalytic asymmetric hydrosilylation and addition of a silyllithium intermediate to the Davis–Ellman sulfinimine.
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Asymmetric Synthesis of Silanediol Inhibitors for the Serine Protease Coagulation Cascade Enzyme FXIa
2018Co-Authors: Hoan Quoc Duong, Scott Mcn. SieburthAbstract:Silanediol peptidomimetics have been prepared, designed to inhibit the serine protease enzyme Factor XIa (FXIa) for treatment of thrombosis without complete interruption of normal hemostasis. These Arg-[Si]-Ala analogues of the FXIa substrate (FIX) are the first Silanediol dipeptide analogues to carry a basic guanidine group. Control of stereochemistry was accomplished using catalytic asymmetric hydrosilylation and addition of a silyllithium intermediate to the Davis–Ellman sulfinimine
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Silicon Mimics of Unstable Carbon
Topics in Medicinal Chemistry, 2014Co-Authors: Scott Mcn. SieburthAbstract:Silicon–carbon bonds are unknown in nature, yet the search for bioactive organosilanes has a rich and successful history. Substitution of silicon for a stable quaternary carbon in biologically active molecules often leads to bioactive organosilanes. An alternative approach is the substitution of silicon for an unstable carbon, such as a hydrated carbonyl. The proclivity of carbon to favor a carbonyl over a 1,1-diol is reversed for silicon. Tetrahedral, hydrated carbonyls are ubiquitous intermediates in the reactivity of carbonyl compounds including many enzymatic reactions, and hydrolase enzymes are critical mediators of a broad range of biological processes. Proteases, one group of hydrolase enzymes, can be potently inhibited by Silanediol-based peptide mimics when the Silanediol substitutes for the hydrated carbonyl of amide bond hydrolysis. This chapter outlines the key parameters for bioactive organosilanes, the evolution of the Silanediols as protease inhibitors, the supporting chemistry, and the current status.
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Bioactive Amino Acids, Peptides and Peptidomimetics Containing Silicon
Advances in Silicon Science, 2014Co-Authors: Scott Mcn. SieburthAbstract:Amino acids incorporating silicon have altered structural and physical properties relative to their carbon counterparts. When introduced into polypeptides, the resulting structures generally maintain biological activity, have enhanced lipophilicity and are often resistant to metabolism. Peptide analogs in which the backbone contains a Silanediol group, can become an inhibitor of protease enzymes. Synthesis and uses of these structures are reviewed.
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Alpha-amino silanes via metalated imines as an approach to the synthesis of Silanediol protease inhibitors
Tetrahedron, 2013Co-Authors: Paul B. Finn, B. Khatri, Scott Mcn. SieburthAbstract:Abstract Metalation of benzophenone imines for elaboration of the alpha-amino silane component of Silanediol-based protease inhibitors allows for rapid diversification of targets. Coupling this chemistry with recently developed asymmetric hydrosilylation chemistry for preparing beta-silyl acids results in a streamlined process for drug design.
Troels Skrydstrup - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and evaluation of Silanediols as highly selective uncompetitive inhibitors of human neutrophil elastase.
Journal of medicinal chemistry, 2012Co-Authors: Julie L. H. Madsen, Thomas Levin Andersen, Salvatore Santamaria, Hideaki Nagase, Jan J. Enghild, Troels SkrydstrupAbstract:Chronic obstructive pulmonary disease (COPD) is an increasing health problem and is estimated to be the fifth leading cause of death in 2020 according to the World Health Organization. Current treatments are only palliative, and therefore the development of new medicine for the treatment of COPD is urgent. Human Neutrophil Elastase (HNE) is a serine protease that is heavily involved in the progression of COPD through inflammatory breakdown of lung tissue. Consequently, inhibitors of HNE are of great interest as therapeutics. In this article, the development of Silanediol peptide isosters as inhibitors of HNE is presented. Kinetic studies revealed that incorporation of a Silanediol isoster in the inhibitor structure resulted in an uncompetitive mechanism of inhibition, which further resulted in excellent selectivity. The peculiar mechanism of inhibition and the resulting selectivity makes the presented inhibitors promising leads for the development of new HNE-inhibitor-based therapeutics for the treatment ...
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Synthesis and Evaluation of Silanediols as Highly Selective Uncompetitive Inhibitors of Human Neutrophil Elastase
2012Co-Authors: Julie L. H. Madsen, Thomas Levin Andersen, Salvatore Santamaria, Hideaki Nagase, Jan J. Enghild, Troels SkrydstrupAbstract:Chronic obstructive pulmonary disease (COPD) is an increasing health problem and is estimated to be the fifth leading cause of death in 2020 according to the World Health Organization. Current treatments are only palliative, and therefore the development of new medicine for the treatment of COPD is urgent. Human Neutrophil Elastase (HNE) is a serine protease that is heavily involved in the progression of COPD through inflammatory breakdown of lung tissue. Consequently, inhibitors of HNE are of great interest as therapeutics. In this article, the development of Silanediol peptide isosters as inhibitors of HNE is presented. Kinetic studies revealed that incorporation of a Silanediol isoster in the inhibitor structure resulted in an uncompetitive mechanism of inhibition, which further resulted in excellent selectivity. The peculiar mechanism of inhibition and the resulting selectivity makes the presented inhibitors promising leads for the development of new HNE-inhibitor-based therapeutics for the treatment of COPD
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Reductive Lithiation of Methyl Substituted Diarylmethylsilanes: Application to Silanediol Peptide Precursors.
ChemInform, 2011Co-Authors: Dácil Hernández, Rasmus Mose, Troels SkrydstrupAbstract:An effective approach to diarylsilyl lithium reagents and their conversion into silanol and Silanediol peptide precursors is presented.
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Reductive Lithiation of Methyl Substituted Diarylmethylsilanes: Application to Silanediol Peptide Precursors
Organic letters, 2011Co-Authors: Dácil Hernández, Rasmus Mose, Troels SkrydstrupAbstract:Reductive lithiation of methyl-substituted diarylmethylsilanes using lithium naphthalenide represents a practical method for the preparation of the corresponding silyl lithium reagents. Their addition to chiral sulfinimines affords versatile precursors to silanols and Silanediols. The replacement of the currently used diphenylsilane motif by a more labile diarylsilane moiety allows the selective hydrolysis of one or two aryl groups by treatment with TFA.
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Further studies toward the stereocontrolled synthesis of silicon-containing peptide mimics.
The Journal of organic chemistry, 2010Co-Authors: Dácil Hernández, Karl B. Lindsay, Lone Nielsen, Tina Mittag, Klaus Bjerglund, Stig D. Friis, Rasmus Mose, Troels SkrydstrupAbstract:Further studies are reported on the utilization of the versatile reaction between chiral sulfinimines and alkyldiphenylsilyl lithium reagents with the goal of preparing a wide range of Silanediol-based protease inhibitors. In particular, focus has been placed to demonstrate how a number of genetically encoded amino acid side chains such as serine, threonine, tyrosine, lysine, proline, arginine, aspartate and asparagine might be incorporated into the overall approach. Efforts to apply this synthetic methodology for accessing biologically relevant Silanediol dipeptide mimics are also described. This includes the synthesis of a potential inhibitor of the human neutrophil elastase, as well as a diphenylsilane mimic of a hexapeptide fragment of the human islet amyloid polypeptide.
Anita E. Mattson - One of the best experts on this subject based on the ideXlab platform.
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Silanediol Anion Binding and Enantioselective Catalysis.
Synthesis, 2019Co-Authors: Jonathan W. Attard, Kohei Osawa, Yong Guan, Jessica Hatt, Shin-ichi Kondo, Anita E. MattsonAbstract:Silanediols possess unique and complementary catalytic activity in reactions that are likely to proceed through anion binding. This article directly compares Silanediols, thioureas, and squaramides in three separate anion-binding processes. The catalytic abilities of select members of each family are directly correlated to association constants.
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Enantioselective Catalyst Systems from Copper(II) Triflate and BINOL-Silanediol.
Chemistry (Weinheim an der Bergstrasse Germany), 2018Co-Authors: Yong Guan, Jonathan W. Attard, Thomas J. Fisher, Michael D. Visco, Anita E. MattsonAbstract:Silanediol and copper catalysis are merged, for the first time, to create an enhanced Lewis acid catalyst system for enantioselective heterocycle functionalization. The promise of this Silanediol and copper catalyst combination is demonstrated in the enantioselective addition of indoles to alkylidene malonates to give rise to the desirable adducts in excellent yield and high enantiomeric excess. From these studies, 1,1'-bi-2-naphthol (BINOL)-based Silanediols emerge as one-of-a-kind cocatalysts. Their potential role in the reaction pathway is also discussed.
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Silanediol-Catalyzed Chromenone Functionalization
Organic letters, 2016Co-Authors: Andrea M. Hardman-baldwin, Shin-ichi Kondo, Joshua M. Wieting, Michael D. Visco, Charlotte Stern, Anita E. MattsonAbstract:Promising levels of enantiocontrol are observed in the Silanediol-catalyzed addition of silyl ketene acetals to benzopyrylium triflates. This rare example of enantioselective, intermolecular chromenone functionalization with carbonyl-containing nucleophiles has potential applications in the synthesis of bioactive chromanones and tetrahydroxanthones.
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Preparation and Catalytic Activity of BINOL-Derived Silanediols.
ChemInform, 2015Co-Authors: Joshua M. Wieting, Thomas J. Fisher, Andrew G. Schafer, Michael D. Visco, Judith C. Gallucci, Anita E. MattsonAbstract:A series of enantiopure Silanediols are derived from BINOL and applied as catalyst to the asymmetric N-acyl Mannich reaction.
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Silanediol catalyzed carbon dioxide fixation
ChemInform, 2015Co-Authors: Andrea M Hardmanbaldwin, Anita E. MattsonAbstract:Silanediol (DNSD) acts as an effective organocatalyst for the atom-efficient conversion of epoxides to cyclic carbonates (III) under environmentally friendly conditions.
Vadapalli Chandrasekhar - One of the best experts on this subject based on the ideXlab platform.
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Effect of sterically hindered ligands on the solid-state structures of organoSilanediols containing Si-N bonds
Inorganic Chemistry, 2001Co-Authors: Vadapalli Chandrasekhar, Selvarajan Nagendran, Ramamoorthy Boomishankar, Ray J. ButcherAbstract:Organosilicon dichlorides containing Si-N bonds, RN(SiMe3){Si(Me)Cl2}, R = 2,6-i-Pr2-C6H3, 1a, and R = 2,6-Me2C6H3, 1b, serve as excellent precursors for the corresponding Silanediols, RN(SiMe3){Si(Me)(OH)2}, R = 2,6-i-Pr2-C6H3, 2a, and R = 2,6-Me2C6H3, 2b. X-ray crystal structures of 1a, 2a, and 2b have been carried out. The structure of 1a represents the first example of an organosilicon dichloride containing Si-N bonds. The N-bonded Silanediol 2a, which contains the sterically encumbered isopropyl groups on the aromatic amino substituent on silicon, shows the formation of two different types of hexameric hydrogen-bonded clusters in the solid state. In contrast 2b consists of cyclic hydrogen-bonded dimers linked by further intermolecular hydrogen bonding to afford an overall polymeric structure with a crinkled ribbon like arrangement.
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Silanediols derived from silanetriols. X-ray crystal structures of (2,4,6-Me 3 C 6 H 2 )N(SiMe 3 )Si(OSiMe 3 )(OH) 2 and (2,4,6-Me 3 C 6 H 2 )N(SiMe 3 )Si(OSiMe 2 R)(OH) 2 [R = CH 2 (2-NH 2 -3,5-Me 2 C 6 H 2 )]
1996Co-Authors: Ramaswamy Murugavel, Andreas Voigt, Vadapalli Chandrasekhar, Herbert W. Roesky, Hans-georg Schmidt, Mathias NoltemeyerAbstract:The Silanediols RN(SiMe3)Si(OSiMe3)(OH)2 (R = 2,4,6-Me3C6H24, 2,6-Me2C6H35, and 2,6-iPr2C6H36) were prepared by the reactions of the respective silanetriols RN(SiMe3)-Si(OH)31 - 3 with SiMe3Cl in THF/hexane. Silanetriol 1 in CH2Cl2/hexane solution converts over a period of 4 weeks into the Silanediol (2,4,6-Me3C6H2)N(SiMe3)Si(OSiMe2 R)-(OH)2 [R = CH2(2-NH2-3,5-Me2C6H2)] (7). Compounds 4 - 7 were characterized by means of mass, IR and NMR (1H and 29Si) spectroscopy. Additionally, the molecular structures of 4 and 7 were determined by single-crystal X-ray diffraction studies. Compound 4 forms O-H...O hydrogen-bonded tetramers in the solid state. A nine-membered ring formed by an intermolecular O-H...N hydrogen bond is found in the solid-state structure of 7.
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Silanediols Derived from Silanetriols. X‐ray Crystal Structures of (2,4,6‐Me3C6H2)N(SiMe3)Si(OSiMe3)(OH)2 and (2,4,6‐Me3C6H2)N(SiMe3)Si(OSiMe2R)(OH)2 [R = CH2 (2‐NH2‐3,5‐Me2C6H2)]
Chemische Berichte, 1996Co-Authors: Ramaswamy Murugavel, Andreas Voigt, Vadapalli Chandrasekhar, Herbert W. Roesky, Hans-georg Schmidt, Mathias NoltemeyerAbstract:The Silanediols RN(SiMe3)Si(OSiMe3)(OH)2 (R = 2,4,6-Me3C6H24, 2,6-Me2C6H35, and 2,6-iPr2C6H36) were prepared by the reactions of the respective silanetriols RN(SiMe3)-Si(OH)31 – 3 with SiMe3Cl in THF/hexane. Silanetriol 1 in CH2Cl2/hexane solution converts over a period of 4 weeks into the Silanediol (2,4,6-Me3C6H2)N(SiMe3)Si(OSiMe2 R)-(OH)2 [R = CH2(2-NH2-3,5-Me2C6H2)] (7). Compounds 4 – 7 were characterized by means of mass, IR and NMR (1H and 29Si) spectroscopy. Additionally, the molecular structures of 4 and 7 were determined by single-crystal X-ray diffraction studies. Compound 4 forms O H…O hydrogen-bonded tetramers in the solid state. A nine-membered ring formed by an intermolecular OH…N hydrogen bond is found in the solid-state structure of 7.
Mathias Noltemeyer - One of the best experts on this subject based on the ideXlab platform.
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Silanediols derived from silanetriols. X-ray crystal structures of (2,4,6-Me 3 C 6 H 2 )N(SiMe 3 )Si(OSiMe 3 )(OH) 2 and (2,4,6-Me 3 C 6 H 2 )N(SiMe 3 )Si(OSiMe 2 R)(OH) 2 [R = CH 2 (2-NH 2 -3,5-Me 2 C 6 H 2 )]
1996Co-Authors: Ramaswamy Murugavel, Andreas Voigt, Vadapalli Chandrasekhar, Herbert W. Roesky, Hans-georg Schmidt, Mathias NoltemeyerAbstract:The Silanediols RN(SiMe3)Si(OSiMe3)(OH)2 (R = 2,4,6-Me3C6H24, 2,6-Me2C6H35, and 2,6-iPr2C6H36) were prepared by the reactions of the respective silanetriols RN(SiMe3)-Si(OH)31 - 3 with SiMe3Cl in THF/hexane. Silanetriol 1 in CH2Cl2/hexane solution converts over a period of 4 weeks into the Silanediol (2,4,6-Me3C6H2)N(SiMe3)Si(OSiMe2 R)-(OH)2 [R = CH2(2-NH2-3,5-Me2C6H2)] (7). Compounds 4 - 7 were characterized by means of mass, IR and NMR (1H and 29Si) spectroscopy. Additionally, the molecular structures of 4 and 7 were determined by single-crystal X-ray diffraction studies. Compound 4 forms O-H...O hydrogen-bonded tetramers in the solid state. A nine-membered ring formed by an intermolecular O-H...N hydrogen bond is found in the solid-state structure of 7.
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Silanediols Derived from Silanetriols. X‐ray Crystal Structures of (2,4,6‐Me3C6H2)N(SiMe3)Si(OSiMe3)(OH)2 and (2,4,6‐Me3C6H2)N(SiMe3)Si(OSiMe2R)(OH)2 [R = CH2 (2‐NH2‐3,5‐Me2C6H2)]
Chemische Berichte, 1996Co-Authors: Ramaswamy Murugavel, Andreas Voigt, Vadapalli Chandrasekhar, Herbert W. Roesky, Hans-georg Schmidt, Mathias NoltemeyerAbstract:The Silanediols RN(SiMe3)Si(OSiMe3)(OH)2 (R = 2,4,6-Me3C6H24, 2,6-Me2C6H35, and 2,6-iPr2C6H36) were prepared by the reactions of the respective silanetriols RN(SiMe3)-Si(OH)31 – 3 with SiMe3Cl in THF/hexane. Silanetriol 1 in CH2Cl2/hexane solution converts over a period of 4 weeks into the Silanediol (2,4,6-Me3C6H2)N(SiMe3)Si(OSiMe2 R)-(OH)2 [R = CH2(2-NH2-3,5-Me2C6H2)] (7). Compounds 4 – 7 were characterized by means of mass, IR and NMR (1H and 29Si) spectroscopy. Additionally, the molecular structures of 4 and 7 were determined by single-crystal X-ray diffraction studies. Compound 4 forms O H…O hydrogen-bonded tetramers in the solid state. A nine-membered ring formed by an intermolecular OH…N hydrogen bond is found in the solid-state structure of 7.
