2003 Conference

Immediately following Exploiting Molecular Diversity at the same venue, February 11-12, 2002


Corporate Support:

Sponsoring Publications:
Drug Discovery & Development
Current Opinion in Drug Discovery & Development
Molecular Diversity

Web Partner
Combichem.net

Combinatorial chemistry has resulted in the rapid expansion of compound libraries to keep pace with the demands of HTS screening. The ability to do novel chemistry on solid support has allowed for a vast array of compounds to be synthesized and subsequently screened for hits. Recent developments in multistep solution-phase synthesis have provided even more expansive ways to create diverse chemical libraries with a general trend toward quality and purity in conjunction with productivity's becoming more prevalent. This conference will highlight recent novel chemistries and reaction strategies, as well as optimization of reactions for library synthesis. Case examples of resins, linkers, and cleavage methods that make compound synthesis easier, faster, and more practical will be presented with emphasis on quality and high-throughput purification techniques.

SCIENTIFIC ADVISORS/SESSION CHAIRS
Dr. Brett C. Bookser, Metabasis Therapeutics, Inc.
Dr. Kevin Burgess, Texas A&M University
Dr. Adam Golebiowski, Procter & Gamble Pharmaceuticals
Dr. C. Oliver Kappe, Karl-Franzens-University
Dr. David E. Portlock, Procter & Gamble Pharmaceuticals
Dr. David S. Thorpe, Selectide/Aventis Pharmaceuticals, Inc.
Dr. Alexander Tropsha, University of North Carolina at Chapel Hill

ADDITIONAL SPEAKERS
Dr. Merritt B. Andrus, Brigham Young University
Dr. David J. Austin, Yale University
Dr. Geoffrey E. Barker, Ontogen Corporation
Dr. Bruce Clapham, The Scripps Research Institute
Dr. Andrew J. de Mello, Imperial College of Science, Technology & Medicine
Dr. Hicham Fenniri, Purdue University
Dr. Timothy F. Herpin, Bristol-Myers Squibb
Dr. Jill Hochlowski, Abbott Laboratories
Dr. Ian James, Mimotopes Pty. Ltd.
Dr. Daniel Kassel, Bristol Myers Squibb
Dr. Tushar Kshirsagar, ChemRx Advanced Technologies, Inc.
Dr. Jeff W. Labadie, Argonaut Technologies
Dr. Mats Larhed, Uppsala University
Dr. Katia Martina, Pharmacia Corporation
Dr. Kenneth L. Morand, Procter & Gamble Pharmaceuticals
Dr. John Reader, Millennium Pharmaceuticals Ltd.
Dr. Thomas Nixey, Amgen
Dr. Gregory Roth, Boehringer Ingelheim Pharmaceuticals Inc.
Dr. Youla S. Tsantrizos, Boehringer Ingelheim (Canada) Ltd.
Dr. David Tumelty, Affymax, Inc.
Dr. Wei Zhang, Fluorous Technologies, Inc.

SUCCESSFUL SOLID-PHASE SYNTHESIS
Solid-Phase Synthesis of Peptidomimetic Inhibitors for the Hepatitis C Virus NS3 Protease
Synthesis of Thematic Libraries for a Platform Target-Based Approach to Drug Discovery
The Synthesis of Heterocyle Libraries Using Solid-Phase Rhodium Carbenoid Reactions
Tools and Tactics for High-Throughput Organic Synthesis
High-Speed Combinatorial Synthesis by Microwave Irradiation
Microwave-Assisted Organic Synthesis
Reaction Optimization and Reaction Analysis in Solid-Phase Chemistry

SUCCESSFUL SOLUTION-PHASE SYNTHESIS
Microwave-Assisted Transition Metal-Catalyzed Reactions
Synthesis and Evaluation of Solution-Phase (-)-Stipiamide-Based Libraries for Reversal of Multidrug Resistance
Microchip-Based Synthesis and Analysis Systems for the On-line Production of Compound Libraries

SPECIFIC EXAMPLES OF NOVEL RESINS, CATALYSTS, AND SCAFFOLDS
Accelerated Synthesis and Screening of Complexes for Discovery and Optimization of Homogeneous Catalysts
Bar-Coded Resins: A New Concept for Resin-Supported Combinatorial Library Self-Deconvolution
The Design, Synthesis, and Use of an ATP-Mimetic Diversity Scaffold
Rapid Assembly of Molecular Diversity: Multicomponent Reactions Lead the Way
Traceless Solid-Phase Synthesis of Heterocycles
Recent Advances in Bound-Reagents for Parallel Synthesis

IMPROVING QUALITY AND PRODUCTIVITY IN CHEMISTRY DEVELOPMENT
Productivity Insights from the First Decade of Combichem
Versatile Approaches for Monitoring Progress and Outcome of Combinatorial Syntheses
Chemical Compound Processing
Multidimensional, Parallel, Solid-Phase Synthesis of Libraries Using StAC Technology
Grafted Surfaces for Multiple Solid-Phase Synthesis

PURIFICATION AND ANALYSIS
Preparative Scale Supercritical Fluid Chromatography
Emerging Techniques for the High-Throughput Purification, Analysis and Profiling of Compound Libraries
Integrated High-Throughput Analysis and Purification: A Reality!
Fluorous Mixture Synthesis
Scavenge/Release Solid-Phase Extraction Purification of Carboxylic Acid Products

 

TUESDAY, FEBRUARY 12

5:00-7:00pm Early Registration and Poster and Exhibit Set-up

 

WEDNESDAY, FEBRUARY 13

7:30am Registration, Poster and Exhibit Viewing, and Light Continental Breakfast

 

SUCCESSFUL SOLID-PHASE SYNTHESIS

8:30 Chairperson's Opening Comments
Dr. David E. Portlock, Research Fellow, Combinatorial Chemistry Section, Procter & Gamble Pharmaceuticals

8:40 Solid-Phase Synthesis of Peptidomimetic Inhibitors for the Hepatitis C Virus NS3 Protease
Dr. Youla S. Tsantrizos, Senior Research Scientist, Boehringer Ingelheim (Canada) Ltd.
The NS3 serine protease enzyme of the Hepatitis C virus (HCV) is essential for viral replication. Short peptides mimicking the N-terminal substrate cleavage products of the NS3 protease are known to act as weak inhibitors of the enzyme and have been used as templates for the design of peptidomimetic inhibitors. Automated solid-phase synthesis of a small library of compounds based on such a peptidomimetic scaffold has led to the identification of potent and highly selective inhibitors of the NS3 protease enzyme.

9:10 Synthesis of Thematic Libraries for a Platform Target-Based Approach to Drug Discovery
Dr. David E. Portlock
Over the past several years, combinatorial chemistry has gradually realigned itself with changing business needs. In many organizations diversity-driven library production intended to broadly cover druglike chemical space has to a large extent been replaced by thematic as well as project-directed libraries. Thematic libraries are particularly useful for a platform target-based approach to drug discovery because the control of a common biochemical theme (e.g., the use of enzyme inhibitors, peptidomimetics of receptor ligands, etc.) can often cross over providing leads in several therapeutic areas. This presentation will focus on the development of practical chemical methods and their application to the high-throughput organic synthesis of thematic libraries for drug discovery.

9:40 The Synthesis of Heterocyle Libraries Using Solid-Phase Rhodium Carbenoid Reactions
Dr. Bruce Clapham, Department of Chemistry, The Scripps Research Institute
Recent research in our laboratory has involved the preparation of soluble microgel polymers for use as supports in synthetic organic chemistry applications that include the preparation of small molecules and polymer-bound catalyst reagents and scavengers. Additionally, many new applications of our insoluble JandaJel polymers will also be presented; these discussions will focus upon the preparation of diverse heterocycle molecules via reactions of rhodium carbenoid intermediates. Finally, the use of microwave irradiation to accelerate reactions of polymer-bound substrates will be addressed. (Coauthor: Dr. Kim Janda)

10:10 Poster and Exhibit Viewing, Refreshment Break

11:00 Tools and Tactics for High-Throughput Organic Synthesis: Recent Examples from Lead Generation and Hit-to-Lead Libraries
Dr. Timothy F. Herpin, Senior Research Investigator, Discovery Chemistry, Bristol-Myers Squibb
The tool kit of the combinatorial chemist has vastly expanded in the past few years. The current challenge is to apply the best tool at each stage of the drug discovery process. The strategy, the design, and the constraints for a lead discovery library are radically different than for a hit optimization library. Examples of both types of libraries will be discussed, and solid-phase chemistry to prepare 1,5-benzodiazepine-2-one and piperidone derivatives will be presented.

11:30 High-Speed Combinatorial Synthesis by Microwave Irradiation
Dr. C. Oliver Kappe, Institute of Chemistry, Karl-Franzens-University
Microwave ovens have been used in rapid organic synthesis for the past several years. This presentation will show how recent developments in microwave reactor technology have enabled its successful use in combinatorial chemistry applications. Specific examples utilizing different commercially available microwave reactors will be presented, including parallel processing in multimode cavities and automated sequential library synthesis employing monomode cavities with integrated robotics.

12:00 Lunch (on your own)

1:50 Microwave-Assisted Organic Synthesis: A New Tool in Combinatorial Library Development and Validation
Dr. Gregory Roth, Associate Director, Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc.
The advent of automated synthesis has moved the library generation bottleneck from compound production back to the design and development stage. Typical design and development time can range from four to eight weeks depending on the rate of reaction optimization and molecular complexity. Microwave technology is a novel tool that allows the chemist to rapidly optimize reactions in parallel, resulting in significantly reduced development time. Further, the use of microwave synthesis can yield novel scaffolds with a high degree of molecular complexity. We will illustrate the pivotal role microwave technology has had in the development of several chemical libraries in our group.

2:20 Reaction Optimization and Reaction Analysis in Solid-Phase Chemistry
Dr. Tushar Kshirsagar, ChemRx Advanced Technologies, Inc. (a Discovery Partners International Company)
The application of solid-phase strategies towards the synthesis of diversity libraries as well as lead optimization libraries continues to be an area of ongoing scientific experimentation. Various resin-linkers such as 4-formyl-3,5-dimethoxyphenoxymethyl, Marshall linker, and the tosyl chloride linker have allowed us to synthesize small-molecule heterocyclic libraries. Analysis of solid-phase reactions during optimization as well as in-process monitoring of production-scale libraries required the development of standardized tests that could afford both qualitative and quantitative estimation of reaction progress. In addition, these tests were employed to carry out detailed studies on reaction kinetics. An additional area of interest has been the recycling of spent resins and some recent results will be discussed.

2:50 Poster and Exhibit Viewing, Refreshment Break

 

SUCCESSFUL SOLUTION-PHASE SYNTHESIS

3:40 Chairperson's Comments
Dr. C. Oliver Kappe

3:45 Microwave-Assisted Transition Metal-Catalyzed Reactions: Medicinal and Combinatorial Chemistry Applications
Dr. Mats Larhed, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University
In both lead identification and lead optimization processes there is an acute need for new organic molecules of relatively small size. Traditional methods of organic synthesis are simply orders of magnitude too slow to satisfy the demand for compounds. In this arena, speed is of the essence. The reduced reaction times, compatibility with efficient separation/analysis methodologies, and experimental convenience offered by automatic single-mode microwave synthesizers make possible significantly faster reaction optimization and substance production. Therefore, a fast expansion of the area of microwave chemistry is expected in the near future. The age of high-speed chemistry is here.

4:15 Synthesis and Evaluation of Solution-Phase (-)-Stipiamide-Based Libraries for Reversal of Multidrug Resistance
Dr. Merritt B. Andrus, Associate Professor, Department of Chemistry, Brigham Young University
Combinatorial two-dimensional solution-phase libraries of polyenes based on the natural product stipiamide have been assembled using a highly efficient Sonogashira coupling reaction. Screenings with these mixtures with MDR cancer cells have led to the discovery of potent new agents. MS-based screening with immobilized Pgp, the protein responsible for MDR, and new dimeric compounds will also be discussed.

4:45 Microchip-Based Synthesis and Analysis Systems for the On-line Production of Compound Libraries
Dr. Andrew J. de Mello, AstraZeneca Lecturer of Analytical Sciences, AstraZeneca/SmithKline Beecham Centre for Analytical Sciences, Department of Chemistry, Imperial College of Science, Technology and Medicine
Miniaturization of conventional analytical instrumentation has been one of the dominant themes within the physical and biological sciences during the last decade. In particular, development of the concept of a miniaturized total analysis system (mTAS) or lab-on-a-chip has yielded distinct systems for clinical diagnostics, genetic analysis, chemical synthesis, drug screening, and environmental monitoring. In analogy to microelectronic development, the downsizing and integration of chemical processes lead to huge gains in performance, speed, size, throughput, cost, and automation. The lecture will describe the use of distinct microfabricated structures for performing ultrafast mixing and small molecule organic reactions. In these studies a continuous-flow approach to sample manipulation allows reactions to be performed in a both rapid and controllable fashion.

5:15 Panel Discussion
Questions from the audience will be answered by speakers from the above two sessions.

5:45-7:00 Reception (sponsored by Cambridge Healthtech Institute)

 

THURSDAY, FEBRUARY 14

8:00am Poster and Exhibit Viewing and Light Continental Breakfast
Specific Examples of Novel Resins, Catalysts, and Scaffolds

8:30 Chairperson's Comments
Prof. Kevin Burgess, Department of Chemistry, Texas A&M University

8:35 Accelerated Synthesis and Screening of Complexes for Discovery and Optimization of Homogeneous Catalysts
Prof. Kevin Burgess
Catalyst discovery and optimization can be accelerated by using parallel syntheses and screening methods. These are easiest to implement if the complexes and ligands involved are simple. This presentation will illustrate how these techniques have been applied to new epoxidation and asymmetric hydrogenation reactions.

9:05 Bar-Coded Resins: A New Concept for Resin-Supported Combinatorial Library Self-Deconvolution
Prof. Hicham Fenniri, H.C. Brown Laboratory of Chemistry, Purdue University
Deconvolution strategies can be grouped into five families, dual-defined scanning, positional scanning, indexed libraries, recursive deconvolutions, and deletion synthesis deconvolution methods. Encoded strategies evolved from DNA- to chemically and radio-frequency-encoded combinatorial libraries. This talk will focus on a recently introduced strategy termed dual recursive deconvolution (DRED). The DRED method is a hybrid strategy, as it adds a new (encoding) dimension to the classical deconvolution strategies and operates through the iterative identification of the first and last randomized positions of active members of combinatorial libraries generated through split synthesis. The last position can be readily obtained from pool screening after the last step of the split synthesis, while the first position can be "encoded" by the unique vibrational fingerprint of the resin beads used. Once the first and last positions are identified, the second and second-to-last positions are subjected to the same deconvolution process. To streamline bead identification and make this technology accessible to the vast majority of academic and industrial laboratories, here we introduce a novel and simple concept. New resins are synthesized with built-in infrared (IR) and Raman spectroscopic bar codes, which are readily identifiable using hyperspectral imaging systems or standard laboratory instrumentation (FTIR or Raman spectrometers). This approach introduces a new paradigm in combinatorial chemistry, as the beads are no longer just carriers for solid-phase synthesis but are rather the repository of the synthetic steps to which they were subjected.

9:35 The Design, Synthesis, and Use of an ATP-Mimetic Diversity Scaffold
Dr. David J. Austin, Associate Professor, Department of Chemistry, Yale University
The design, synthetic development, and utility of a bicyclic scaffold for chemical diversity will be presented. Synthetic methodology will include the development of a chiral auxiliary for facially selective scaffold assembly and solid-phase resin construction with a selective cleavage step that provides pure product without the need for chromatographic separation. Examples of utility will include the synthesis of, and exploration with, ATP-mimetic molecules.

10:05 Poster and Exhibit Viewing, Refreshment Break

10:35 Rapid Assembly of Molecular Diversity: Multicomponent Reactions Lead the Way
Dr. Thomas Nixey, Scientist, Medicinal Chemistry, Amgen
Pressures on the pharmaceutical industry have increased significantly to meet the economic challenges of the new millennium. As a consequence, with the emergence of combinatorial chemistry and high-speed parallel synthesis within the lead discovery arena, the multicomponent reaction (MCR) has witnessed a resurgence of interest. From a practical consideration one-pot reactions, such as the Ugi and Passerini reactions, are easily automated and production of diverse or directed libraries of small organic molecules is thus both facile and high throughput. Interestingly, several novel intramolecular modifications of this versatile reaction have recently been reported where constrained products result from interception of an intermediate nitrilium ion using a bifunctional input. An alternative approach is to constrain the Ugi product via a post-condensation modification after initial formation of the classical Ugi product. This presentation will disclose a series of highly efficient, atom-economic routes to a number of biologically relevant templates.

11:05 Traceless Solid-Phase Synthesis of Heterocycles
Dr. David Tumelty, Senior Scientist, Affymax, Inc.
In recent years, an increasing number of solid-phase strategies have been described that result in final products lacking the obligatory carboxyl or carboxamide group usually present as a result of cleavage from acid-labile (or other) linkers. The development of such a traceless strategy will be described where heterocycles were synthesized on resin and the target compounds released from a modified linker by treatment with base. The synthetic route was devised such that only the target compounds could be released while side-products remained resin-bound, leading to products of high purity.

11:35 Recent Advances in Bound-Reagents for Parallel Synthesis
Dr. Jeff W. Labadie, Vice President of Chemistry, Argonaut Technologies
Reductive amination is an important reaction for the synthesis of pharmacologically important compounds. We describe a series of bound-reagents which used in conjunction with the correct catalysts and scavenger resins can be used to perform parallel reductive amination over a wide scope of substrates. The use of a novel bound triacetoxyborohydride and a strategy for using titanium catalysts with bound boroohydride will be described. A novel bound uronium salt of HOBt has been prepared and optimized to allow fast, efficient parallel synthesis of amides. This method will be compared to those using other active esters regarding reactivity and racemization. Parallel synthesis and automation were leveraged to optimize the reaction protocols, the results of which will be described.

12:05 Panel Discussion
Questions from the audience will be answered by speakers from the above session.

12:35 Luncheon (sponsored by Cambridge Healthtech Institute)

 

IMPROVING QUALITY AND PRODUCTIVITY IN CHEMISTRY DEVELOPMENT

2:00 Chairperson's Comments
Dr. David S. Thorpe, Scientist, Department of Discovery Biology, Selectide/Aventis Pharmaceuticals, Inc.

2:05 Productivity Insights from the First Decade of Combichem
Dr. David S. Thorpe
Pharmaceutical productivity has continued to decline despite the introduction of combinatorial chemistry a decade ago. Lessons learned as this new technology comes of age will be shared from the perspective of a long-term practitioner. The current third generation of combinatorial chemistry is building on its proven strengths, and there is now much potential to improve the productivity of drug discovery in this decade.

2:35 Versatile Approaches for Monitoring Progress and Outcome of Combinatorial Syntheses
Dr. Katia Martina, Pharmacia Corporation
The burgeoning synthetic activities in combinatorial chemistry pose the question of how to characterize the quality of compound libraries and the validity of their preparation process in an efficient and accurate way. Multiple applications of NMR tools were integrated into our combinatorial chemistry workflow. Different analytical techniques and their distinct advantages for a thorough characterization of nonweighable samples have been compared. Efficient monitoring of reaction progress on solid phase and rapid quality assessment of nondeuterated DMSO solutions in microtiterplate format are described, including a novel, accurate quantitation method by NMR.

3:05 Chemical Compound Processing: Ensuring Compound and Data Integrity in Pharmaceutical Repository Collections
Dr. Kenneth L. Morand, Section Head, Organic Structure Elucidation and Compound Repository, Procter & Gamble Pharmaceuticals
Combinatorial chemistry has led to the rapid growth of pharmaceutical compound collections with many repositories maintaining hundreds of thousands to millions of compounds. The significant monetary and drug discovery value of these large collections, as well as their qualification and integrity, has become of paramount importance. Nevertheless, limited data have been published to address broad-scale stability profiling of corporate collections. This presentation will address studies to assess the qualification and chemical stability of the corporate repository to include compound supply, storage, and biological screening. Flow-injection analysis mass spectrometry (FIA-MS) and liquid chromatography-mass spectrometry (LC-MS) techniques were utilized to assess compound ID and purity. The results from two recent studies are discussed, including the long-term stability of compounds stored as room-temperature DMSO solutions and freeze-thaw cycling for compounds stored as frozen DMSO solutions.

3:35 Poster and Exhibit Viewing, Refreshment Break

4:15 Multidimensional, Parallel, Solid-Phase Synthesis of Libraries Using StAC Technology
Dr. John Reader, Associate Director, Chemical Technologies, Millennium Pharmaceuticals Ltd.
StAC (Stratified Addressable Chemistry) combines some of the efficiencies of split-mix synthesis with the advantages of parallel synthesis. The use of modular solid supports arranged in three-dimensional arrays, in a single commercially available or custom-built reactor block, allows the rapid synthesis of libraries of between 100 and 1,000 compounds. The in-house development of some simple tools to facilitate the dispensing, washing, extraction, and cleavage of the solid supports and their use in the preparation of three libraries will be described. Examples of solid supports used in the StAC system include L and D series Mimotopes Lanterns™ and CD plugs, affording approximately 2mg, 10mg, or 20mg of final compound respectively.

4:45 Grafted Surfaces for Multiple Solid-Phase Synthesis
Dr. Ian James, Senior Scientist and Project Leader, Mimotopes Pty. Ltd.
Since their release in 2000, the SynPhase™ Lanterns have been used for a wide range of organic syntheses. The high quality of the grafted surface on the Lantern is a result of nearly 20 years experience. The underlying system has been constantly developed and improved to allow for increased target diversity, purity, and loading. These improvements include the introduction of new graft polymers, both hydrophobic and, more recently, hydrophilic, that have been optimized on the basis of several factors including reaction kinetics, loading, and compatibility with broad chemical and physical reaction conditions. Successive generations of design have been introduced, each with improved loading/volume ratios. Grafted surfaces can be used in a broad range of applications apart from solid-phase organic synthesis, such as affinity purification and scavenging excess reagents from solution-phase reactions. The most recent developments of grafted surfaces as well as future areas of application will be discussed.

5:15 Panel Discussion
Questions from the audience will be answered by speakers from the above session.

5:45 Close of Day Two

 

FRIDAY, FEBRUARY 15

8:00am Poster Viewing and Light Continental Breakfast

 

PURIFICATION AND ANALYSIS

8:30 Chairperson's Comments
Dr. Brett C. Bookser, Manager of Combinatorial and Analytical Chemistry, Metabasis Therapeutics, Inc.

8:35 Preparative-Scale Supercritical Fluid Chromatography in Support of High-Throughput Organic Synthesis
Dr. Jill Hochlowski, Senior Group Leader, Medicinal Chemistry Technologies, Abbott Laboratories
The High Throughout Purification (HTP) group in Pharmaceutical Discovery at Abbott Laboratories offers purification support to the High Throughput Organic Synthesis (HTOS) group. Preparative-scale supercritical fluid chromatography (SFC) has recently been added to the arsenal of purification capabilities available to HTP and is currently being integrated into the purification service. As preliminary synthetic investigations proceed on each core in the HTOS group, the material generated is used by HTP to triage between HPLC and SFC, selecting the most appropriate purification method for each subsequent full library synthesized. When applicable, SFC has proven to offer advantages in terms of increased resolution, decreased purification, and sample dry-down time and purification capabilities complementary to HPLC. This talk will provide data on the purification of multiple library types by Prep-SFC.

9:05 Emerging Techniques for the High-Throughput Purification, Analysis and Profiling of Compound Libraries
Dr. Daniel Kassel, Senior Director, Bristol Myers Squibb
Summary unavailable at time of printing.

9:35 High-Throughput Purification By Supercritical Fluid Chromatography
Dr. Geoffrey E. Barker, Principal Scientist and Project Leader, Ontogen Corporation
Evidence is mounting in support of the notion that pure compounds are essential for the elimination of false positives/negatives observed in high throughput biological screening data (HTS), and to add validity to the original promise of useful structure-activity relationships derived from HTS. Traditional methods for library purification include solid phase extraction, liquid/liquid extraction, in situ clean up (e.g. resin capture), and chromatography. However, many of these techniques have limited applications and suffer from various drawbacks when integrated into the high throughput laboratory. Packed column supercritical fluid chromatography (SFC) is gaining more attention as an alternative to HPLC. In this paper, the integration of proprietary components with commercially available equipment will be demonstrated for high throughput purification of combinatorial libraries. Emphasis will be put on applicability and performance in the high throughput synthesis laboratory.

10:05 Poster Viewing and Refreshment Break

10:45 Fluorous Mixture Synthesis: A New Technique for Solution-Phase Synthesis of Mixtures That Provides for Isolation of the Final Products as Individual Pure Compounds
Dr. Wei Zhang, Senior Scientist, Fluorous Technologies, Inc.
Fluorous-tagged molecules can be separated from nontagged molecules by solid-phase extraction over fluorous reverse-phase silica gel. This technique expedites solution-phase parallel synthesis because it allows simple yet substantive separations of organic reaction mixtures. In a chromatographic variation of this concept, fluorous reverse-phase silica gel can also be used to cleanly separate fluorous molecules from each other based on their fluorine content. This separation forms the basis of a new mixture synthesis technique in which members of a series of unique substrate/fluorous tag pairs are mixed, carried through a series of synthetic transformations, and then demixed using HPLC based on the fluorine content of the tag. A final detagging step facilitated by fluorous solid-phase extraction results in individual compounds of high purity. These fluorous techniques are the first mixture techniques that are amenable to solution-phase synthesis yet still allow for both the separation and the identification of the final products of the mixture. This presentation will focus on the synthesis and isolation of a 560-compound library using these techniques.

11:15 Scavenge/Release Solid-Phase Extraction Purification of Carboxylic Acid Products from 96-Well Format, Solution-Phase Synthesis
Dr. Brett C. Bookser
Solution-phase combinatorial chemistry requires robust product purification methods. The anion exchange resin DOWEX 1x8-400 formate is very effective for the batchwise scavenge/release style, solid-phase extraction (SPE) purification of carboxylic acid reaction products in a 96-well format. Many factors contribute to successful scavenge/release SPE purification such as resin type, substrate and medium pKa values, and solvent. Application of this technique to the crude product mixtures from a 3x3 arrayed reductive amination and a 3x4 arrayed Stille reaction provided product carboxylic acids in yields averaging 57% and purities averaging 89%.

11:45 Panel Discussion
Questions from the audience will be answered by speakers from the above session.

12:15 Close of Conference

TRAVEL INFORMATION
Special Airline Discounts Available
Special zone and discount fares have been established on United Airlines for this conference. Please call United Airlines Meeting Reservations Center directly at 800-521-4041. You must reference ID #579YS.

HOTEL INFORMATION
Hilton San Diego Resort
1775 East Mission Bay Drive, San Diego, CA 92109
T: 619-276-4010 o F: 619-275-8944
Room Rate: $195 S/D
Cut-off Date: January 21, 2002
Please call the hotel directly to make your room reservation. Identify yourself as a Cambridge Healthtech Institute conference attendee to receive the reduced room rate. Reservations made after the cut-off date or after the group room block has been filled (whichever comes first) will be accepted on a space-and-rate-availability basis. Rooms are limited, so please book early.

CALL FOR EXHIBITORS
This meeting will focus on the newest techniques and technologies available for high throughput combinatorial library synthesis, new organic chemistries, and purification techniques. Last year, at least 250 attendees consisting of scientific researchers, executives, managers and lab directors from pharmaceutical and biotechnology industries, as well as academic and research institutes attended the exhibit hall. Companies with services or products related to novel chemistries, drug discovery, library synthesis techniques, solid-phase synthesis, solution-phase synthesis, resins, linkers, scaffolds, as well as new purification and analysis techniques will greatly benefit by sponsoring or exhibiting at this event. Please contact John Rodolewicz at 781-972-5452 for more information or to reserve a booth. Registrations received by October 26, 2001 can save your company up to $750!

CALL FOR POSTERS
Cambridge Healthtech Institute encourages attendees to gain further exposure by presenting their work in the poster sessions. Please fill out the registration form, with the poster title and primary author. To ensure inclusion in the conference binder, a one-page summary must be submitted and registration must be paid in full by January 11, 2002.  Click here for poster instructions

 

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