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1.
Chem Commun (Camb) ; 46(44): 8457-9, 2010 Nov 28.
Article in English | MEDLINE | ID: mdl-20922228

ABSTRACT

A concept of tandem driven dynamic self-inhibition is demonstrated through dynamic inhibitors of acetylcholinesterase (AChE) using reversible transthiolesterification.


Subject(s)
Acetylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Acetylcholinesterase/metabolism , Esterification , Models, Molecular , Sulfhydryl Compounds/chemistry
2.
J Org Chem ; 75(17): 5882-7, 2010 Sep 03.
Article in English | MEDLINE | ID: mdl-20690700

ABSTRACT

The mechanism of a base-catalyzed one-pot reaction of 2-cyanobenzaldehyde and primary nitroalkanes, to produce 3-substituted isoindolinones, has been investigated. A route starting with a nitroaldol (Henry) reaction, followed by a subsequent cyclization and rearrangement, was supported by intermediate analogue synthesis and DFT calculations. Direct diastereoselective crystallization from the reaction mixture was also achieved and studied for a number of substrates. Furthermore, the 3-substituted isoindolinones are an interesting group of compounds, both present important natural products, as well as being precursors to other valuable building blocks.


Subject(s)
Computer Simulation , Indoles/chemical synthesis , Aldehydes/chemistry , Alkanes/chemistry , Crystallography, X-Ray , Indoles/chemistry , Models, Molecular , Molecular Structure , Stereoisomerism
3.
Chem Commun (Camb) ; (6): 768-70, 2008 Feb 14.
Article in English | MEDLINE | ID: mdl-18478718

ABSTRACT

An unexplored type of tandem reaction is used to kinetically resolve a dynamic combinatorial library resulting in quantitative amplification of an interesting 3-substituted isoindolinone,

4.
J Org Chem ; 73(9): 3593-5, 2008 May 02.
Article in English | MEDLINE | ID: mdl-18363377

ABSTRACT

Crystallization-induced secondary selection from a tandem driven dynamic combinatorial library is presented. In a one-pot experiment, an initial nitroaldol equilibrium was kinetically driven by a tandem reaction resulting in a subsequent dynamic library of diastereoisomers. This library was then further driven by a phase change, resulting in amplification and isolation of a highly diastereomerically enriched and synthetically interesting isoindolinone.

5.
J Org Chem ; 72(10): 3694-701, 2007 May 11.
Article in English | MEDLINE | ID: mdl-17439283

ABSTRACT

A neighboring equatorial ester group plays a highly important role in the Lattrell-Dax (nitrite-mediated) carbohydrate epimerization reaction, inducing the formation of inversion compounds in good yields. On the basis of this effect, efficient synthetic routes to beta-D-mannosides and beta-D-talosides, from the corresponding beta-D-galactosides and beta-D-glucosides, have been designed. The present routes are based on multiple regioselective acylation via the respective stannylene intermediates, followed by inversions to the corresponding manno- and talopyranoside structures by nitrite or acetate substitution. It was found that the ester group was able to induce the inversion of its two neighboring groups in high yields following either a double parallel or a double serial inversion process. By combination of direct inversion, and neighboring- as well as remote-group participation, several beta-d-mannoside and beta-D-taloside derivatives were very conveniently obtained in good yields.


Subject(s)
Glycosides/chemical synthesis , Esters/chemistry , Glycosides/chemistry , Methylation , Molecular Structure , Nitrites/chemistry , Polysaccharides/chemical synthesis , Polysaccharides/chemistry , Stereoisomerism
7.
Chembiochem ; 7(9): 1384-91, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16841351

ABSTRACT

Leishmania spp. are human pathogens that utilize a novel beta-1,2-mannan as their major carbohydrate reserve material. We describe a new approach that combines traditional substrate-modification methods and "click chemistry" to assemble a library of modified substrates that were used to qualitatively define the substrate tolerance of the Leishmania beta-1,2-mannosyltransferases responsible for beta-1,2-mannan biosynthesis. The library was assembled by using the highly selective copper(I)-catalysed cycloaddition reaction of azides and alkynes to couple an assortment of azide- and alkyne-functionalized small molecules with complementary alkyne- and azide-functionalized mannose derivatives. All mannose derivatives with alpha-orientated substituents on the anomeric carbon were found to act as substrates when incubated with a Leishmania mexicana particulate fraction containing GDP-mannose. In contrast, 6-substituted mannose derivatives were not substrates. Representative products formed from the library compounds were analysed by mass spectrometry, methylation linkage analysis and beta-mannosidase digestions and showed extension with up to four beta-1,2-linked mannosyl residues. This work provides insights into the substrate specificity of this new class of glycosyltransferases that can be applied to the development of highly specific tools and inhibitors for their study.


Subject(s)
Leishmania mexicana/enzymology , Mannose/analogs & derivatives , Mannosyltransferases/metabolism , Alkynes/chemistry , Animals , Azides/chemistry , Cell-Free System/metabolism , Chromatography, Thin Layer , Combinatorial Chemistry Techniques/methods , Mannose/chemical synthesis , Mannose/metabolism , Mannosides/chemical synthesis , Mannosides/chemistry , Molecular Structure , Spectrometry, Mass, Electrospray Ionization , Substrate Specificity
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