Applications solid-phase organic synthesis

One of the cornerstones of combinatorial synthesis has been the development of solid-phase organic synthesis (SPOS) based on the original Merrifield method for peptide preparation [19]. Because transformations on insoluble polymer supports should enable chemical reactions to be driven to completion and enable simple product purification by filtration, combinatorial chemistry has been primarily performed by SPOS [19-23], Nonetheless, solid-phase synthesis has several shortcomings, because of the nature of heterogeneous reaction conditions. Nonlinear kinetic behavior, slow reaction, solvation problems, and degradation of the polymer support, because of the long reactions, are some of the problems typically experienced in SPOS. It is, therefore, not surprising that the first applications of microwave-assisted solid-phase synthesis were reported as early 1992 [24],... 

The organometallic reagents are very useful in solid-phase organic synthesis, as described in Section 3.3.2. Metal complexes [277] have found application too, as... 

Beaver, K. A. Siegmund, A. C. Spear, K. L. Application of the Sulfonamide Functional Group as an Anchor for Solid Phase Organic Synthesis (SPOS), Tetrahedron Lett. 1996,37, 1145-1148. 

Solution-phase syntheses employing linking reagents provide an alternative to solid-phase organic synthesis when poor conversions and incomplete reactions yield deletion intermediates upon release from resin. Applications are highlighted in various multistep syntheses covered at the end of this chapter. 

SOLID-PHASE ORGANIC SYNTHESIS ON RADIATION-GRAFTED POLYMER SURFACES APPLICATION OF SYNPHASE CROWNS TO MULTIPLE PARALLEL SYNTHESES... 

Several different support materials have proven useful for solid-phase organic synthesis, but not all materials are compatible with all types of solvents and reagents. Therefore, for each application the proper type of support has to be selected. Some review articles on supports for solid-phase synthesis have recently appeared [1,9, 12-15]. 

Tertiary aliphatic alcohol linkers have only occasionally been used in solid-phase organic synthesis [73], This might be because of the vigorous conditions required for their acylation. Esterification of resin-bound linker 4 with /V-Fmoc-prolinc [72,74] could not be achieved with the symmetric anhydride in the presence of DMAP (20 h), but required the use of /V-Fmoc-prolyl chloride (10-40% pyridine in DCM, 25 °C, 10-20 h [72]). A further problem with these linkers is that they can undergo elimination, a side reaction that cannot occur with benzyl or trityl linkers. Hence, for most applications in which a nucleophile-resistant linker for carboxylic acids is needed, 2-chlorotri-tyl- or 4-acyltrityl esters will probably be a better choice than ferf-alkyl esters. 

Notwithstanding the reduced reaction times and improved yields, the need to use column chromatography to purify the target 1,4-DHP encumbers the application of the procedure for the fast preparation of screening libraries. To address the purification issue, various phase-separation techniques could be employed, such as solid-phase organic synthesis (SPOS). 

In 1992, ACT replaced the Model 350 with the Model 396 Multiple Biomolecular Synthesizer. This instrument possesses two robotic arms, a variable speed orbital mixer, nitrogen assisted bottom filtration, a built-in ventilation system, protocols for both Fmoc and Boc synthesis and fully automated on-board cleavage for the Fmoc syntheses. It has reactor blocks of 8, 16, 40, and 96 wells for the synthesis of peptides from 5 pmol to 1 mmol. The Model 396 MBS also has a heater/cooler option for applications in solid-phase organic synthesis. 

Brase, S., Kirchhoff, J. H., Kobberling, J. Palladium-catalyzed reactions in solid phase organic synthesis. Tetrahedron 2003, 59, 885-939. Fairlamb, I. J. S. Transition metals in organic synthesis. Part 1. Catalytic applications. Annu. Rep. Prog. Chem., Sect. B, Org. Chem. 2003, 99,104-137. 

The first publication concerning the solid phase organic synthesis was related to the synthesis of peptides [138], and naturally several groups have been interested by the applications of the OSSOS strategy to the synthesis of natural polymers. 

Yan, B., Yan, H. Combination of single bead FTIR and chemometrics in combinatorial chemistry Application of the multivariate calibration method in monitoring solid-phase organic synthesis J. Comb. Chem., 2001, 3, 78-84... 

JA Porco Jr, TL Deegan, OW Gooding et al. New poly(styrene-oxyethylene) graft copolymers for solid-phase organic synthesis linkers and applications. Book of... 

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