eCombiChem Leads

Solid-Phase Synthesis on Dual Linkers with a Reference Cleavage Site

Professor Viktor Krchnák, University of Notre Dame, presents the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/:

Solid-Phase Synthesis on Dual Linkers with a Reference Cleavage Site

Optimization of reaction conditions is a key factor for successful solid-phase synthesis. The assessment of a chemical transformation on solid phase includes cleavage of the resin-bound reaction components followed by analysis of the cleaved sample. To obtain meaningful information regarding the composition of components on solid phase, all components need to be cleaved from the support. Information that cannot be obtained from this simple experiment is the rate of cleavage from the solid support. An independent quantification analysis is required in order to assess the cleavage yield.

We report a general, yet very simple, concept that secures cleavage of all polymer-supported components and, at the same time, estimates the cleavage rate. The synthesis is carried out on a polymer-supported dual linker with a reference cleavage site consisting of two sequential linkers separated by a spacer. The spacer is designed to allow its cleavage from the Linker 1 under standard conditions. Linkers 1 and 2 have to be cleavable with the same reagent. In a cleaved sample, the presence of the desired compound still attached to Linker 2 reveals incomplete cleavage; its absence indicates complete cleavage of compound from Linker 2.

The dual linker contributes in development of solid-phase transformations in several aspects: (i) It ensures cleavage of all resin-bound components. (ii) It allows simple estimation of the cleavage rate of polymer-supported compounds. (iii) It is suitable for straightforward optimization of cleavage protocol, including evaluation of new cleavage cocktails. (iv) It assists in selection of the most suitable linker for given compound classes. (v) It can be used for design of new linkers with altered sensitivity towards cleavage conditions.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: ecombichem.com
eCombiChemLeads Blog: http://barryhardy.blogs.com/ecombichemleads/

Making real molecules in virtual space

Gyorgy Pirok, Chief Technology Officer at ChemAxon, will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Making real molecules in virtual space

Good quality virtual enumeration of combinatorial libraries requires the manual intervention of an experienced chemist (selecting appropriate reactants, assignment of the corresponding reaction sites, removing unlikely products) slowing down the entire enumeration process. Encoding the valuable knowledge of preparative organic chemists into the reaction schemes decreases the human factor in the library generation phase and opens new possibilities for researchers.

ChemAxon builds a reusable "smart" reaction library consisting of the most important synthetic reactions. These reaction definitions contain a generic transformation scheme and additional chemo-, regio- and stereoselectivity rules. The virtual synthesis application based on this technology is not only able to enumerate entire combichem libraries in a single pass, but also to build a diverse molecular space of synthetically feasible virtual compounds from available chemicals.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/
eCombiChemLeads Blog: http://barryhardy.blogs.com/ecombichemleads/

Discovery and Development of a Library of Novel (Pyrrolidino)diketopiperazines

Kevin Short, Johnson & Johnson will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Discovery and Development of a Library of Novel (Pyrrolidino)diketopiperazines

Over the last 10 years, there has been great interest in the development of solid-phase synthetic approaches to small molecules, particularly those that embrace polyfunctional heterocyclic targets. As part of Ontogen's Combinatorial Chemistry program, we had an interest in developing synthetic strategies and chemistries applicable to combinatorial libraries of multisubstituted heterocycles. Following our early successes in the area of multisubstituted imidazoles, we applied the highly powerful Ugi reaction to the synthesis of hydantoin imides, tetrazoles and lactams. In addition, we reported on an Ugi-based library of diketopiperazines.

This seminar will describe the discovery of a novel bicyclic chemotype, prepared via a facile 2-step procedure, thus:

• an azomethine ylide-olefin [3+2] cycloaddition, followed by;
• a lactam forming reaction.

The procedure was adapted for use in an on-resin format, and a cyclative cleavage procedure utilizing the 2nd step furnished products in high purity. This presentation will detail the extensive optimization of the individual steps, both in solution and on-resin, followed by a ‘screening' of reagent inputs. Solid phase ‘rehearsal' of the library was carried out in ‘Test Plates', using the OntoBLOCK (TM) system. Extensive use of LC-MS and 1 H NMR analyses ensured a high information content for the rehearsal Test Plates, and ultimately a high confidence level for the ultimate production library's overall quality. The goal was to prepare a moderately large library of compounds.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/
eCombiChemLeads Blog: http://barryhardy.blogs.com/ecombichemleads/