Enabling Technologies
I. High-load, Soluble ROMP-derived Oligomeric Reagents and Scavengers for Facilitated Protocols
The growing demand for the production of diverse compound libraries in desirable amounts and sufficient purity for high throughput screening (HTS) has presented challenging opportunities in the development of facilitated synthetic protocols, which ultimately serve to uncover molecular leads as potential therapeutic agents aimed at improving human health. In this regard, Ring-Opening Metathesis (ROM) polymerization of functionalized norbornenes has surfaced as a powerful tool in the generation of high-load, immobilized reagents with tunable properties. Utilizing this technology, a variety of high-load, functionalized reagents and scavengers have been developed and utilized in the purification-free synthesis of small libraries. Reagents include, immobilized coupling reagents OACC and ODCT, efficient nucleophile and electrophile scavengers ODCT, OMAm and benzylating and triazolating reagents such as OBP and OTP.
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II. High-load, Surface immobilized ROMP-derived Oligomeric Reagents and Scavengers
The development of new immobilized reagents and scavengers for application in facilitated protocols is an important facet of drug discovery. In particular, utilization of these reagents/scavengers in parallel synthesis and reagent cartridges for continuous flow has surfaced as a seminal area in the field. Recent advancements in automated synthesis, flow-through devices, coupled with the incorporation of microwave technology, have spurred the development of continuous flow methods for the high-throughput production of combinatorial libraries and natural products.
A critical component of the continuous flow platform is the employment of either cartridges packed with commercially available solid-phase reagents and scavengers, grafting of functional groups on the chamber interiors, preparation of polymer monoliths within the chamber, or the incorporation of monolith disks within the flow chamber. In this regard, our research program has developed a variety of ROMP-derived enabling technologies and facilitated protocols to be used in parallel synthesis. One such program is the generation of high-load, surface immobilized reagents, where-by ROMP-derived oligomeric reagents are grown off a variety of surfaces, eg. Silica particles and Co/C magnetic nano-particles.
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III. Microwave-Assisted Continuous Organic Synthesis (MACOS) Flow Platform
The utilization of continuous flow platform technologies in comparison to conventional static batch reactors allows for in-line reaction optimization, analysis and purification of the products. The MACOS platform developed by our collaborator Prof. Organ (York university, Toronoto) combines continuous flow and microwave technology to produce a platform yielding a variety of advantages over batch reactors which include: i. enhance reaction kinetics due to microwave heating; ii. high temperature/pressure reaction; iii. scale-out vs scale-up; and iv. enhanced Safety due to small production or volatile reactive. Through this collaboration, the Hanson and Organ groups aim at utilizing the MACOS platform to facilitate the synthesis of S- & P- heterocyclic scaffolds and their corresponding libraries for HTS screening.
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