Solid traceless synthesis

Wilson LJ, Klopfenstein SR, Li M. A traceless linker approach to the solid phase synthesis of substituted guanidines utilizing a novel acyl isothiocyanate resin. Tetrahedron Lett 1999 40 3999 -002. 

Plunkett MJ, Ellman JA. A silicon-based linker for traceless solid-phase synthesis. J Org Chem 1995 60 6006-6007. 

Stieber F, Grether U, Waldmann H. An oxidation-labile traceless linker for solid-phase synthesis. Angew Chem, Int Ed 1999 38 1073-1077. 

Craig D, Robson MJ, Shaw SJ. Traceless linkers for solid-phase synthesis. Homo- and hetero Diels-Alder reactions of ortho-quinodimethanes. Synlett 1998 12 1381-1383. 

The Larock indole synthesis was adapted to the solid phase both for the synthesis of 1,2,3-trisubstituted indole-5-carboxamides [396] and, as illustrated, for the "traceless" synthesis of 2,3-disubstituted indoles 308 [397], As seen earlier, the trimethylsilyl group is fastened to C-2 with complete regioselectivity. The TMS group is cleaved under the resin cleavage conditions. The original Larock conditions were not particularly successful. 

Scheme 2. Traceless linkers for the solid-phase synthesis of (a) pyridine-based tricycles and (b) isoquinolines.

B. A. Lorsbach, R. B. Miller, M. J. Kurth, Reissert-Based Traceless Solid-Phase Synthesis Isoquinoline, and Isoxazoline-Containing Heterocycles , J. Org. Chem. 1996, 61, 8716-8717. 

Nowadays, solid-phase synthesis has been used as a powerful tool in organic chemistry, especially to prepare small molecule libraries. New linkers to obtain different functionalities after cleavage have been developed. There are different linkers strategies (Fig. 3.2), for example traceless linkers, multifunctional linkers, safety catch linkers, fragmentation/ cycloreversion cleavage linkers, cyclization cleavage linkers, which are useful methods for combinatorial solid-phase chemistry. 

The solid phase synthesis of quinazoline 114 was reported by Abell and co-workers, in which a traceless linker was utilized <99TL1045>. The key step in this procedure was the removal of the desired quinazoline from the resin with concurrent decarboxylation to produce 114 in 69% yield from 113. 

Recently, palladium-catalyzed carbonylation of chloropyrimido[4,5-d]pyrimidines has been reported (Equation 51) <2006W0065703>. Raney nickel-mediated desulfurization of alkylthiopyrimido[4,5-, pyrimidines was described in GHEC(1984), and has been applied recently both in the desulfurization of reduced species (Equation 52) <2001WO64679> and for cleavage of sulfur linkages in traceless solid-phase synthesis <1999BMCL965,... 

T. Ruhland, K. Andersen and H. Pedersen, Selenium-linking strategy for traceless solid-phase synthesis Direct loading, aliphatic C-H bond formation upon cleavage and reaction monitoring by gradient MAS NMR spectroscopy, J. Org. Chem., 1998, 63, 9204-9211. 

Wilson, L. J. Lin, M. A Traceless Linker Approach to the Solid Phase Synthesis of Substituted Guanidines Utilizing a Novel Acyl Isothiocyanate Resin, Tetrahedron Lett. 1999, 40, 3999-4002. 

A solid-phase synthesis of structurally related, pyridine-based tricyclics has been reported Woolard, F. X. Paetsch, J. Ellman, J. A. A Silicon Linker for Direct Loading of Aromatic Compounds to Supports. Traceless Synthesis of Pyridine-Based Tricyclics,/. Org. Chem. 1997, 67, 6102. 

To expand the range of products available by solid-phase synthesis, a series of strategies have been developed that enable the generation of C-H and C-C bonds upon cleavage from a support, and in this way enable the preparation of unfunctionalized hydrocarbons. These linkers are sometimes called traceless linkers, because in some types of product the attachment point to the support can no longer be located. 

P rez, R., Beryozkina, T., Zbruyev, O.I., Haas, W. and Kappe, C.O., Traceless solid phase synthesis of bi-cyclic dihydropyrimidones using multidirectional cyclization cleavage, /. Comb. Chem., 2002,4, 501-510 and references cited therein. 

Schunk and Enders [134] disclosed the first solid-phase synthesis of (5-1 actants via ester enolate-imine condensation employing an immobilized ester enolate in a simple three-step procedure (Scheme 31). The protocol showed high purity, excellent diastereoselectivity, and good yields of the product. The substrates were attached to the polymer with a Tl-triazene linker, which was cleaved traceless. The... 

One prominent class of monofunctional anchor that provides access to molecules having no attachment memory for solid-phase synthesis is called traceless or clean break linkers.7,16-18 Although this definition could be used for the classification of linkers, one would advantageously... 

The Traceless Solid-Phase Synthesis of Organic Molecules... 

Traceless linkers enable the solid-phase synthesis of products which were formerly only accessible by tedious, multistep solution-phase chemistry. Some of these linkers tolerate a broad range of reaction conditions, giving the chemist plenty of freedom in the design of new solid-phase synthetic sequences. Interestingly, polystyrene-bound selenium reagents can also mediate useful chemical transformations of substrates during their attachment to the support, and thereby function both as reagents and as linkers. 

The first traceless linkers for arenes were silyl linkers. This linker type was used in the synthesis of a benzodiazepine library, a milestone in the solid-phase synthesis of small organic molecules (Scheme 6.1.9). Synthesis of the linker involves lithium-halogen exchange and, after chlorosilane attachment, coupling with an... 

Chen Y, Lam Y, Lai YH, Solid-phase synthesis of pyrazolines and isoxazolines with sodium benzenesulfinate as a traceless linker, Org. Lett., 5 1067-69, 2003. 

Hughes I, Application of polymer-bound phosphonium salts as traceless supports for solid phase synthesis, Tetrahedron Lett., 37 7595-7598, 1996. 

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