Introduction

The overall goal of Chemical Methodologies and Library Development (CMLD) is to discover chemistry and methodologies to create libraries of enhanced diversity and coupled with analytical capabilities for the rapid identification of new compounds capable of perturbing biological systems.

The mission of Harvard CMLD center is to develop efficient, general, state-of-the-art methodologies for the design, synthesis, analysis and handling of chemical diversity libraries. The CMLD platform at Harvard University will enable chemists to perform a wide variety of simultaneous related chemical reactions under different conditions using automated and semi-automated instrumentation, with high throughput analytical capabilities to identify compounds of potential biological activity.

The approach taken by the Harvard CMLD platform is to bring the power of robotic automation to the area of reaction discovery and development. There are three components:

Station 1: setting up/running solid- and solution-phase reactions and washing solid-support systems.

The fully automated Chemspeed ASW2000 provides full integration of synthesis, work-up, purification, and/or analysis. This workstation features the following: a broad temperature range from -70 to +150°C, up to 80 parallel reactions, glass reactors with volumes ranging from 2 to 100 ml on the same system, ability to handle slurries and suspensions, and fully inert environment inside the reactors. The semi-automated Bohdan Miniblock provides a platform that allows synthesis via solid or solution phase, as well as purification. This workstation features the following: high temperature up to 80°C, up to 96 parallel reactions, individual vessels ranging in size from as small as 4 mL to as large as 40 mL, and the ability to easily filter beads/resins for solid phase chemistry.

Station 2: LC MS analysis

The analytical tools available to chemists include an analytical, reverse phase LC MS and an analytical/semi-prep LC MS. Both systems feature ESI/APCI ionizations for mass detection. The analytical/semi-prep LC MS system streamlines pre-analysis, scale-up for purification; UV/MS triggered fraction collection, and automated re-analysis of collected fractions.

Station 3: SFC MS analysis

High throughput analysis is also available on the Berger SFC MS equipped with an APCI source. This system features a typical 3-minute cycle time (injection-to-injection time). The system can be used for fast analysis of a variety of compounds, due to the applicability of APCI MS for small molecular analysis. As well, chiral separations can be achieved within a short time frame.

These individual robotic stations are highly modular, so the chemist can choose to use a single station (i.e. use station 1 to facilitate setting up a screen of various appendages, use station 3 to run SFC MS analysis on pre-prepared samples, etc.). But they can be also fully integrated and operated via a computerized central workstation. Currently, the analytical LC MS is integrated with the ASW 2000 synthesizer. This configuration enables real-time reaction monitoring and/or unattended product analysis right from the reaction vessels. The principle for integrating the synthesizer/LC MS can be readily adapted for the synthesizer/SFC MS system.

These automated tools should greatly facilitate the processes of chemistry discovery including development and optimization of new synthetic methodologies, development and optimization of new DOS pathways, screening of building blocks alone or in combinations, synthesis of pilot libraries, and small-scale quality control analysis of pilot libraries.