Linkers in Solid-Phase Synthesis

Fraser-Reid et al. [21,22] reported the synthesis of polymer supported oligosaccharides using n-pentenyl glycosides, while Seeberger et al. [23] accomplished the synAesis of p-(l- 4)- and p.(2 6)-linked oUgosaccharides using glycosyl phosphates combined with an octenediol linker. 

SCHEME 14.9 Schmidt s repetitive solid-phase glycosylation. 

---

Peukert S, Giese B. The pivaloyglycol anchor group A new platform for a photolabile linker in solid-phase synthesis. J Org Chem 1998 63 ... 

Acetals and ketals are very important protecting groups in solution-phase synthesis, but only a few constructs have been used as linkers in solid-phase synthesis (Tab. 3.3). The THP-linker (22) (tetrahydropyran) was introduced by Ellman [54] in order to provide a linker allowing the protection of alcohols, phenols and nitrogen functionalities in the presence of pyridinium toluene sulfonate, and the resulting structures are stable towards strong bases and nucleophiles. Other acetal-linkers have also been used for the attachment of alcohols [55, 56]. Formation of diastereomers caused by the chirality of these linkers is certainly a drawback. Other ketal tinkers tike... 

The sulfonimidoyl group acts in the asymmetric synthesis of the unsaturated oxiranes shown in Schemes 1.3.20 and 1.3.21 as both a chiral auxiliary and a nucleofuge. These results suggested the application of the sulfonimidoyl group as a chiral linker in solid-phase synthesis. 

May P, Bradley M, Harrowven D, Pallin D, A new method of forming resin bound thioesters and their use as traceless linkers in solid phase synthesis, Tetrahedron Lett., 41 1627-1630, 2000. 

Numerous linkers have been developed with the aim of immobilizing substrates on a solid support. Commercially available (+)-a-lipoic acid has been employed as a novel, chemically stable linker for the immobilization of ketones. The utility of this thioacetal-based linker in solid-phase synthesis has been demonstrated by the synthesis of several 4-acetylbiphenyls by means of the Suzuki reaction. The products were readily cleaved from the solid support by treatment with [bis(trifluoroacetoxy)iodo]benzene [PhI(OCOCF3)2] [107]. 

In CHEC-II(1996) the detailed discussion of thiophenes as intermediates was, somewhat arbitrarily, limited to photochemical and electrocyclic processes. Additionally, reactions were included which destroy the aromatic thiophene skeleton to give rise to open chain molecules. In this scheme very recent applications of thiophenes such as thiophene-based amide linkers in solid-phase synthesis <2006JOC6734> or V-(2-thienyl)sulfonyl aldimins in chiral Mannich reactions <2006OL2977> did not be fit in. 

Reviews on Linkers in Solid-Phase Synthesis 42 Reviews on the Synthesis of Complex Targets Including Discussion of Protecting Group Problems and Strategies 42... 

There are only a few examples for germanium-based linkers in solid phase synthesis, hi general, the linker systems and the cleavage conditions are very similar to the silicon-based linkers that were introduced before. Two important germanium linkers are shown in Fig. 18. 

Boas U, Brask J, Jensen KJ (2009) Backbone amide linker in solid-phase synthesis. Chem 12. Rev 109 2092-2118... 

Norrby P-O, Jensen K (2006) Steric effects in release of amides from linkers in solid-phase synthesis. Molecular mechanics modeling of key step in peptide and combinatorial chemistry. Int J Pept Res Ther 12 335-339... 

---