Solid-phase combinatorial synthesis using MicroKan reactors, Rf tagging, and directed sorting

Abstract

A modular system for high‐output solid‐phase combinatorial synthesis has been designed and developed. The system employs three technological innovations to achieve its high efficiency and reliability: (1) application of microreactors as the reaction units in solid‐phase synthesis; (2) use of radiofrequency tagging as the non‐chemical tracking method; and (3) development of the directed sorting technology for split & pool synthesis. The system has been successfully applied in the synthesis of compound libraries of several hundred to several thousand compounds in multi‐milligrams per compound quantity by many organizations. © 2000 John Wiley & Sons, Inc. Biotechnol Bioeng (Comb Chem) 71:44–50, 2000.

Natural product-like combinatorial libraries

“…On the other hand, the introduction of semiautomatic combinatorial synthesis systems using microreactors, radio-frequency tagging and directed sorting, 233 as well as development of analytical and screening techniques, [234][235][236][237][238][239][240] helped to overpass the immense task of identifying and isolate the bioactive agents from large libraries. More recently, advances in genetic engineering allowed the manipulation of genes involved in microbial biosynthetic pathways, which led to the formation of novel natural-product like molecules, particularly, polyketides and macrolide antibiotics.…”

Practical Aspects of Combinatorial Solid‐Phase Synthesis

“…T-bag compartmentalization of resin beads inspired the design of canister-like containers (MacroKan for 300 mg, MiniKan for 100 mg, and MicroKan for 30 mg of resin) for automated handling by IRORI (Figure 3.9). 104,105 The MicroKan reactor was fabricated with high-purity polypropylene mesh, and resin beads were placed inside it. The pore size of the mesh (75 mm) was such that properly sized resin beads (>75 mm) could not cross through the mesh, while reagents and solvents could freely flow in and out of the reactor.…”

“…ToautomatetheprocessofMicroKan redistribution, individual containers were tagged. Radiofrequency tagging 27,85,104 and optical encoding 28,105 of containers enabled computer-assisted reading of the tag and automation of the directed split-and-pool process (Figure 3.16). A Rf tag consists of a microcircuit and an antenna encapsulated in glass.…”

Highlights in the solid-phase organic synthesis of natural products and analogues

“…36 Systematic SPOS and structure activity relationship (SAR) studies of taxol analogs were done by Nicolaou et al 37 They started with an appropriately functionalized taxol core (five steps from baccatin III, 181) that was attached onto 2-chlorotritylchloride polystyrene resin and the loaded resin is distributed into 400 Rftagged MicroKan reactors (Scheme 26). The reactors were treated as one single batch with 5% piperidine/ N,N'-dimethylformamide (DMF) (r.t., 30 min) to deprotect the Fmoc group and, after that, the reactors were sorted into 20 groups that were acylated with a carboxylic acid to yield the resin-bound amides (182).…”