Showing papers by "K. Barry Sharpless published in 2005"
TL;DR: Huisgen's 1,3-dipolar cycloadditions become nonconcerted when copper(I) acetylides react with azides and nitrile oxides, providing ready access to 1,4-disubstituted 1,2, 3-triazoles and 3, 4-disubsided isoxazoles, respectively.
Abstract: Huisgen's 1,3-dipolar cycloadditions become nonconcerted when copper(I) acetylides react with azides and nitrile oxides, providing ready access to 1,4-disubstituted 1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively. The process is highly reliable and exhibits an unusually wide scope with respect to both components. Computational studies revealed a stepwise mechanism involving unprecedented metallacycle intermediates, which appear to be common for a variety of dipoles.
1,486 citations
TL;DR: This workFloat their problematic reactions on water and to send observations of success or failure to us at onwater@scripps.edu for public dissemination with attribution.
Abstract: [*] Dr. S. Narayan, Dr. J. Muldoon, Prof. M. G. Finn, Prof. V. V. Fokin, Prof. H. C. Kolb, Prof. K. B. Sharpless Department of Chemistry and the Skaggs Institute of Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 (USA) Fax: (+ 1)619-554-6738 E-mail: sharples@scripps.edu [**] We thank Dr. Vladislav Litosh for carrying out preliminary work. Support from the National Institutes of Health, National Institute of General Medical Sciences (GM 28384), the National Science Foundation (CHE9985553), the Skaggs Institute for Chemical Biology, and the W. M. Keck Foundation is gratefully acknowledged. S.N. thanks the Skaggs Institute for a postdoctoral fellowship. We also thank Dr. Suresh Suri, Edwards Air Force Base, California, for a generous gift of quadricyclane. We urge our fellow chemists to float their problematic reactions on water and to send observations of success or failure to us at onwater@scripps.edu for public dissemination with attribution. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Angewandte Chemie
1,393 citations
TL;DR: Unsymmetrical dendrimers, containing both mannose binding units and coumarin fluorescent units, have been prepared using click chemistry and shown to be highly efficient, dual-purpose recognition/detection agents for the inhibition of hemagglutination.
419 citations
TL;DR: The target-guided, in situ click chemistry approach to lead discovery has been successfully employed for discovering acetylcholinesterase (AChE) inhibitors by incubating a selected enzyme/tacrine azide combination with a variety of acetylene reagents that were not previously known to interact with the enzyme's peripheral binding site.
Abstract: The target-guided, in situ click chemistry approach to lead discovery has been successfully employed for discovering acetylcholinesterase (AChE) inhibitors by incubating a selected enzyme/tacrine azide combination with a variety of acetylene reagents that were not previously known to interact with the enzyme's peripheral binding site. The triazole products, formed by the enzyme, were identified by HPLC-mass spectrometry analysis of the crude reaction mixtures. The target-guided lead discovery search was also successful when performed with reagent mixtures containing up to 10 components. From 23 acetylene reagents, the enzyme selected two phenyltetrahydroisoquinoline (PIQ) building blocks that combined with the tacrine azide within the active center gorge to form multivalent inhibitors that simultaneously associate with the active and peripheral binding sites. These new inhibitors are up to 3 times as potent as our previous phenylphenanthridinium-derived compounds, and with dissociation constants as low as 33 femtomolar, they are the most potent noncovalent AChE inhibitors known. In addition, the new compounds lack a permanent positive charge and aniline groups and possess fewer fused aromatic rings. Remarkably, despite the high binding affinity, the enzyme displayed a surprisingly low preference for one PIQ enantiomer over the other.
309 citations
227 citations
TL;DR: The bisaryloxime ether library provides valuable structure-activity relationship insight for the development of structurally analogous inhibitors with superior stability profiles, should that prove necessary.
Abstract: Amyloid fibril formation by the plasma protein transthyretin (TTR), requiring rate-limiting tetramer dissociation and monomer misfolding, is implicated in several human diseases. Amyloidogenesis can be inhibited through native state stabilization, mediated by small molecule binding to TTR's primarily unoccupied thyroid hormone binding sites. New native state stabilizers have been discovered herein by the facile condensation of arylaldehydes with aryloxyamines affording a bisarylaldoxime ether library. Of the library's 95 compounds, 31 were active inhibitors of TTR amyloid formation in vitro. The bisaryloxime ethers selectively stabilize the native tetrameric state of TTR over the dissociative transition state under amyloidogenic conditions, leading to an increase in the dissociation activation barrier. Several bisaryloxime ethers bind selectively to TTR in human blood plasma over the plethora of other plasma proteins, a necessary attribute for efficacy in vivo. While bisarylaldoxime ethers are susceptible to degradation by N-O bond cleavage, this process is slowed by their binding to TTR. Furthermore, the degradation rate of many of the bisarylaldoxime ethers is slow relative to the half-life of plasma TTR. The bisaryloxime ether library provides valuable structure-activity relationship insight for the development of structurally analogous inhibitors with superior stability profiles, should that prove necessary.
99 citations
TL;DR: Allylic azides undergo a rapid [3.3]-sigmatropic rearrangement which results in dynamic equilibrium of several isomers, so even small differences in reactivity of the isomeric allylic azide isides can be amplified to result in a single product in good to excellent yields.
Abstract: Allylic azides undergo a rapid [3.3]-sigmatropic rearrangement which results in dynamic equilibrium of several isomers. Thus, reactions of allylic azides usually result in mixtures of products. However, even small differences in reactivity of the isomeric allylic azides can be amplified to result in a single product in good to excellent yields. For example, the Cu(I)-catalyzed cycloaddition with alkynes selectively captures primary and secondary allylic azide isomers, whereas MCPBA epoxidation favors isomers which contain more electron-rich double olefins.
94 citations
Patent•
22 Jul 2005TL;DR: Adhesive polymers are formed when polyvalent azides and alkynes are assembled into crosslinked polymer networks by copper-catalyzed 1,3-dipolar cycloaddition as discussed by the authors.
Abstract: Adhesive polymers are formed when polyvalent azides and alkynes are assembled into crosslinked polymer networks by copper-catalyzed 1,3-dipolar cycloaddition. The condensation polymerization is efficiently promoted by Cu ions either leached from the metal surface or added to the monomer mixture, and strong interactions with metal surfaces are provided by the multiple triazole binding elements produced. The adhesive polymers may be formed either as adhesive polymer coatings or as adhesive polymer cement.
48 citations
TL;DR: The recently solved structures of the mAChE mutant, Tyr337Ala, complexed with the TZ2PA6 isomers now reveals distinctive and time-dependent conformations of the complexes that are consistent with the triazole contribution to the energetics of inhibitor binding manifested in the respective dissociation rates of thecomplex.
36 citations
TL;DR: In this paper, the copper-catalyzed 1,3-dipolar cycloaddition between terminal alkynes and three N-protected organic azides, azidomethyl pivalate, N-methyl morpholine-4-carboxylate, and N-diethyl carbamate, was used.
Abstract: NH-1,2,3-triazoles have been prepared via the copper(I)-catalyzed 1,3-dipolar cycloaddition between terminal alkynes and three N-protected organic azides, azidomethyl pivalate, azidomethyl morpholine-4-carboxylate, and azidomethyl N,N-diethylcarbamate. These organic azides were easily prepared on 0.1-mol scale in one or two steps from inexpensive commercially available materials. The cleaving properties of N-substituents in the resulting 1,2,3-triazole products with aqueous sodium hydroxide vary from <10 minutes at room temperature in the case of N-methyl pivalate, to 24 hours at room temperature in the case of N-methyl morpholine-4-carboxylate, to 24 hours at 85 "C in the case of N-methyl diethylcarbamate.
23 citations
TL;DR: Analysis of the linear free energy relationships of binding to both mouse and Electrophorus AChE reveals independent contributions of individual structural elements of inhibitors to their binding with the triazole ring emerging as an independently contributing pharmacophore.
14 Feb 2005
TL;DR: A series of polyfunctional NH-1,2,3-triazoles were prepared directly from propargyl halides and nucleophiles using a powerful, albeit little appreciated, synthetic sequence we call the Banert cascade.
Abstract: A series of polyfunctional NH-1,2,3-triazoles were prepared directly from propargyl halides and nucleophiles using a powerful, albeit little appreciated, synthetic sequence we call the Banert cascade. Propargyl azides, prepared in situ from propargyl halides or sulfonates, underwent a thermal rearrangement sequence to triazafulvene intermediates, potent electrophiles, which were readily captured by diverse nucleophiles. Using this cascade, a series of racemic azidomethyl(hydroxymethyl)-NH-1,2,3-triazoles were prepared by a two-step protocol that commences with the addition of propargyl chloride to aldehydes and ketones.
TL;DR: A series of polyfunctional NH-1,2,3-triazoles were prepared directly from propargyl halides and nucleophiles using a powerful, albeit little appreciated, synthetic sequence we call the Banert cascade as mentioned in this paper.
Abstract: A series of polyfunctional NH-1,2,3-triazoles were prepared directly from propargyl halides and nucleophiles using a powerful, albeit little appreciated, synthetic sequence we call the Banert cascade. Propargyl azides, prepared in situ from propargyl halides or sulfonates, underwent a thermal rearrangement sequence to triazafulvene intermediates, potent electrophiles, which were readily captured by diverse nucleophiles. Using this cascade, a series of racemic azidomethyl(hydroxymethyl)-NH-1,2,3-triazoles were prepared by a two-step protocol that commences with the addition of propargyl chloride to aldehydes and ketones.
14 Feb 2005
TL;DR: Huisgen's 1,3-dipolar cycloadditions become nonconcerted when copper(I) acetylides react with azides and nitrile oxides, providing ready access to 1,4-disubstituted 1,2,3triazoles and 3,4disubstantituted isoxazoles, respectively as discussed by the authors.
Abstract: Huisgen's 1,3-dipolar cycloadditions become nonconcerted when copper(I) acetylides react with azides and nitrile oxides, providing ready access to 1,4-disubstituted 1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively. The process is highly reliable and exhibits an unusually wide scope with respect to both components. Computational studies revealed a stepwise mechanism involving unprecedented metallacycle intermediates, which appear to be common for a variety of dipoles.
TL;DR: With proper activation of the leaving group, sulfur mustards react with Grignard reagents with neighboring group participation of the sulfur atom, providing clean reactivity with organomagnesium nucleophiles on a topologically constrained scaffold.
Abstract: With proper activation of the leaving group, sulfur mustards react with Grignard reagents with neighboring group participation of the sulfur atom. 2,6-Dichloro-9-thiabicyclo[3.3.1]nonane is especially useful in this regard, providing clean reactivity with organomagnesium nucleophiles on a topologically constrained scaffold.