A Silanediol Inhibitor of the Metalloprotease Thermolysin: Synthesis and Comparison with a Phosphinic Acid Inhibitor¹

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 (Ki = 41 nM) was comparable to that of the phosphinic acid (Ki = 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

α-Trialkylsilyl Amino Acid Stability

α-Trialkylsilyl amino acids have been evaluated for their stability toward methanolysis as a model for physiological conditions. The juxtaposition of amine and carbonyl groups significantly destabilizes the silicon−carbon bond, but changing a single methyl on silicon to an ethyl led to a dramatic stability enhancement. Converting the ester to an amide gave an additional jump in stability, suggesting broad potential for these novel amino acids in bioactive peptides and pharmaceuticals

Enantioselective α-Silyl Amino Acid Synthesis by Reverse-Aza-Brook Rearrangement

Asymmetric reverse-aza-Brook rearrangement of N-Boc-N-trialkylsilyl allylamine yields an enantiomerically enriched α-amino allylsilane. Oxidative cleavage of the alkene leads to a Boc-protected amino acid with the configuration of naturally occurring amino acids (l). Standard coupling protocols, including the use of trifluoroacetic acid for removal of the Boc group, yield a tripeptide with a central silane amino acid

A Practical Synthesis of Difunctional Organosilane Reagents and Their Application to the Diels−Alder Reaction

A Practical Synthesis of Difunctional Organosilane Reagents and Their Application to the Diels−Alder Reactio

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 <i>K</i>_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

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 D2O, the degree of oligomerization was found to be pH dependent, with diastereomeric mixtures formed on condensation. Above pH 11 the silane is largely monomeric

Enyne-2-pyrone [4 + 4]-Photocycloaddition: Sesquiterpene Synthesis and a Low-Temperature Cope Rearrangement

Intramolecular [4 + 4] photoreaction of 2-pyrones with a 1,3-enyne yields an unstable 1,2,5-cyclooctatriene product. Without a C4 pyrone substituent, 1,3-hydrogen migration converts the allene to a 1,3-diene, with a skeleton related to dactylol. With methoxy substitution, Cope rearrangement yields a nine-membered ring fused to a cyclobutane. Both structures were confirmed by X-ray crystallography. The Cope rearrangement is apparently reversible, reforming the allene which undergoes a proton shift to the more stable 1,3-diene product

Asymmetric Synthesis of Silanediol Inhibitors for the Serine Protease Coagulation Cascade Enzyme FXIa

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

A Practical, Two-Step Synthesis of 2-Substituted 1,3-Butadienes

A two-step procedure for preparing 2-alkyl-1,3-butadienes is described. Cuprate addition to commercially available 1,4-dibromo-2-butene yields 3-alkyl-4-bromo-1-butene, a product of SN2′ substitution. Dehydrohalogenation gives 2-alkyl-1,3-butadienes

Pyridone Annulation by 4 + 2 Coupling of Dienolates with Nitriles and Nitrile Equivalents. A Solution to the Acetonitrile Problem

Pyridone Annulation by 4 + 2 Coupling of Dienolates with Nitriles and Nitrile Equivalents. A Solution to the Acetonitrile Proble