Organic synthesis solid-phase

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In the 1990s the technique of solid-phase organic synthesis (SPOS) became generally popular, but especially in the medicinal chemistry community, for lead detection and lead optimization via combinatorial techniques. The combination with microwave irradiation brought an elegant solution for the problem of the notoriously slower reactions compared to those in solution phase. 

Solid-Phase Organic Synthesis and Combinatorial Chemistry. 80... 

Fig. 8 Modified Smith process vial for microwave-assisted solid-phase organic synthesis...

K. Burgess, Solid Phase Organic Synthesis, John Wiley Sons, New York, 2000. 

Photolabile linkers play an important role in solid-phase organic synthesis (SPOS) due to their stability under both acidic and basic conditions. The ONb photolabile linker was modified to improve cleavage rates and yields Fmoc-Tos-OFI was released in 87% yield after 23 h (Scheme 4) [24]. Specifically, the primary alcohol was changed to a secondary benzylic alcohol and the attachment to the resin was through an alkyl chain as opposed to an amide function. Linker 20 was used for the production of carboxylic acids or carbohydrates. A second example... 

Routledge A, Stock HT, Flitsch SL, Turner NJ. New fluoride-labile linkers for solid-phase organic synthesis. Tetrahedron Lett 1997 38 8287-8290. 

Kobayashi S, Aoki Y. />-Benzyloxybenzylamine (BOBA) resin. A new polymer-supported amine used in solid-phase organic synthesis. Tetrahedron Lett 1998 39 7345-7348. 

Brase S, Kobberling J, Enders D, Lazny R, Wang M, Brandtner S. Nitrogen-based linker. 3. Triazenes as robust and simple linkers for amines in solid-phase organic synthesis. Tetrahedron Lett 1999 40 2105-2108. 

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Hu Y, Porco JA, Jr, Labadie JW, Gooding OW, Trost BM. Novel polymer-supported trialkylsilanes and their use in solid-phase organic synthesis. J Org Chem 1998 63 4518 1521. 

Other microwave-assisted parallel processes, for example those involving solid-phase organic synthesis, are discussed in Section 7.1. In the majority of the cases described so far, domestic multimode microwave ovens were used as heating devices, without utilizing specialized reactor equipment. Since reactions in household multimode ovens are notoriously difficult to reproduce due to the lack of temperature and pressure control, pulsed irradiation, uneven electromagnetic field distribution, and the unpredictable formation of hotspots (Section 3.2), in most contemporary published methods dedicated commercially available multimode reactor systems for parallel processing are used. These multivessel rotor systems are described in detail in Section 3.4. 

Combinatorial Chemistry and Solid-Phase Organic Synthesis... 

One of the key technologies used in combinatorial chemistry is solid-phase organic synthesis (SPOS) [2], originally developed by Merrifield in 1963 for the synthesis of peptides [3]. In SPOS, a molecule (scaffold) is attached to a solid support, for example a polymer resin (Fig. 7.1). In general, resins are insoluble base polymers with a linker molecule attached. Often, spacers are included to reduce steric hindrance by the bulk of the resin. Linkers, on the other hand, are functional moieties, which allow the attachment and cleavage of scaffolds under controlled conditions. Subsequent chemistry is then carried out on the molecule attached to the support until, at the end of the often multistep synthesis, the desired molecule is released from the support. 

Solid-phase organic synthesis (SPOS) exhibits several shortcomings, due to the nature of the heterogeneous reaction conditions. Nonlinear kinetic behavior, slow reactions, solvation problems, and degradation of the polymer support due to the long reaction times are some of the problems typically experienced in SPOS [2], Any technique which is able to address these issues and to speed up the process of solid-... 

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