Solid-phase organic synthesis resins

A. R. Vaino and K.D. Janda, Solid-Phase Organic Synthesis A Critical Understanding of the Resin, J Comb Chem 2 579-596 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... 

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

Kroll FEK, Morphy R, Rees D, Gani D. Resin-immobilized benzyl and aryl vinyl sulfones New versatile traceless linkers for solid-phase organic synthesis. Tetrahedron Lett 1997 38 8573-8576. 

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. 

N. K. Terret, Combinatorial Chemistry, Oxford University Press, New York, 1998 M. Winter, R. Warrass, Resins and Anchors for Solid-Phase Organic Synthesis, in Combinatorial Chemistry (Ed. H. Fenniri), Oxford University Press, New York, p. 117-138, 2000. 

F. E. K. Kroll, R. Morphy, D. Rees, D. Gani, Resin-Immobilized Benzyl and Aryl Vinyl Sulfones New Versatile Traceless Linkers for Solid-Phase Organic Synthesis , Tetrahedron Lett. 1997, 38, 8573-8576. 

To fully use the advantages afforded by multicomponent reaction systems in solid-phase organic synthesis, strategies in which each component is immobilized on the resin must be devised. In this way, individual components can be explored in terms of diversity without the restrictions imposed by immobilization. We have described solid-phase Mannich reactions1 of a resin-bound alkyne (see chapter 5), and we show here that the diversity of products using this chemistry can be enhanced when a different component of the reaction system is immobilized. Specifically, a secondary amine, piperazine, is bound to a resin and then treated with... 

The proper choice of the solid support and the connected linker is important for the success of solid-phase organic synthesis. To date, the possibihty of reactions on the resins have been limited by the number of linkers, because most of them were initially developed for peptide synthesis. 

Resin-bound triarylbismuth(III) reagents have been prepared for solid phase organic synthesis [72, 73]. As shown in Sect. 2.5, triarylbismuths are efficient... 

O. W. Gooding, S. Baudart, T. L. Deegan, K. Heisler, J. W. Labadie, W. S. Newcomb, J. A. Porco and P. van Eikeren, On the development of new poly(styrene-oxyethy lene) graft copolymer resin supports for solid-phase organic synthesis,./. Comb. Chem., 1999, 1, 113-122. 

R. Hany, D. Rentsch, B. Dhanapal and D. Obrecht, Quantitative determination of resin loading in solid-phase organic synthesis using C-13 MAS NMR, J. Comb. Chem., 2001, 3, 85-89. 

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. 

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. 

Another key strategy in solid-phase organic synthesis is to cleave molecules from the resin by means of intramolecular cyclization as the last step. This strategy normally leads to very pure compounds since only those molecules will be cleaved from the resin that have gone through the whole reaction sequence. This concept was used for a versatile synthesis of quinazolinones of type 151 and 152 as shown in Scheme 9.215... 

Sucholeiki reviews the selection of supports for solid-phase organic synthesis. To address many of the problems presented above, we are seeing the use of a wide range of solid supports from the traditional Merrifield resin to newer composites, cellulose, silica, and others. This chapter presents the pros and cons of many of these potential supports, reviews modifications to enhance the solution-like behavior of the bound materials, and methods to increase the loading capacities. 

MacDonald AA, Dewitt SH, Ghosh S, Elogan EM, Kieras L, Czarnik AW, Ramage R, The impact of polystyrene resins in solid-phase organic synthesis, Mol. Diversity, 1 183-186, 1996. 

A 9-phenylfluoren-9-yl polystyrene-based resin has been described for the attachment of nitrogen and oxygen nucleophiles. Greater acid stability compared to the standard trityl resins that are widely used in solid-phase peptide synthesis make this solid support an interesting alternative in solid-phase organic synthesis. This resin can be used in Suzuki coupling reactions to furnish biaryls in good yields [100]. 

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