Solid traceless linkers

An illustrative example of an alternative strategy (cf Fig. 11c) involving the use of a novel traceless linker is found in the multistep synthesis of 6-epi-dysidiolide (363) and several dysidiolide-derived phosphatase inhibitors by Waldmann and coworkers [153], outlined in Scheme 70. During the synthesis, the growing skeleton of 363 remained attached to a robust dienic linker. After completion of intermediate 362, the terminal olefin in 363 was liberated from the solid support by the final metathesis process with concomitant formation of a polymer-bound cyclopentene 364. Notably, during the synthesis it turned out that polymer-bound intermediate 365a, in contrast to soluble benzoate 365b, produced diene 367 only in low yield. After introduction of an additional linker (cf intermediate 366), diene 367 was released in distinctly improved yield by RCM. 

A traceless linker for solid-phase homo- and hetero-Diels-Alder reactions was based upon resin bound quinodimethane precursors... 

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. 

Schiemann K, Showalter HDH. Development of polymer-supported benzotriazole as a novel traceless linker for solid-phase organic synthesis. J Org Chem 1999 64 4972 1975. 

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. 

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. 

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

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. 

The proper choice of a suitable linker is a therefore a key consideration in the design of a solid-phase chemical route. Linkers have to be developed in order to be stable in the presence of reagents and to permit orthogonal cleavage under mild conditions. Often, cleavage conditions dictate the requirements for work-up and purification steps of the released compound. Different cleavage strategies have been developed such as photocleavable, safety catch and traceless linkers as mentioned in Section 3.2.2 [20]. 

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. 

Solid-phase strategies associated with the construction of organic molecules and their functionalization are often limited by the nature of the anchoring group or the linker. Traceless linkers allow chemical transformations on the polymer bound molecules, which can be cleavage to the formation of a C-H bond on the seceding molecule and which enables the preparation of pure hydrocarbons (Table 3.13) [134, 190]. 

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. 

For some applications, it is useful to put a substrate on a solid support. Linkers that can be converted directly to desired functionality ( traceless ) are particularly valuable. Andrew M. Cammidge of the University of East Anglia and A. Ganesan of the University of Southampton independently (Chem. Commun. 2004, 1914, 1916) developed the polymeric sulfonyl chloride 9. The derived phenyl sulfonates are useful partners for transition-metal mediated cross coupling. 

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. 

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. 

The high purity (>95%) of the released product from resin 14 prompted us to investigate the potential of radical release as a traceless linker concept. To our knowledge, thermolytic radical fragmentation of covalent bonds is a mechanism of bond dissociation that has not been exploited so far for linker chemistry and for solid-phase transformations. Cleavage yields, determined by releasing nonvolatile products, were found to be higher than 90%. 

In connection with an interest in generating /i-turn dipeptide mimetics, Piscopio and co-workers developed a solid-phase approach to the Freidinger lactam 86 via a solid-phase Ugi condensation and ring-closing metathesis (RCM) methodology [72], The resin-bound amine 85 is the equivalent of a traceless linker and the two-step protocol proceeds in good yield (Scheme 11.17). 

Traceless Linkers for Solid-Phase Organic Synthesis... 

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... 

For the rapid production of analogues, parallel synthesis techniques are often desirable. Morphy and coworkers have published two solid-supported syntheses of benzhydrylpiperazines and related compounds [44,45]. Both of these approaches utilize a displacement of the benzhydryl bromide by an amine (piperazine, e.g.) to build the molecules. However, these two routes are complementary, traceless linker approaches. In one, the piperazine is attached to the solid support while the molecule is built, allowing significant variation on other parts of the molecule. Cleavage is effected via quaterniza-... 

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. 

Braese S, Enders D, Koebberling J, Avemaria F, A surprising solid-phase effect development of a recyclable traceless linker system for reactions on solid support, Angew. Chem., Int. Ed., 37 3413-3415, 1998. 

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. 

Paio A, Crespo RF, Seneci P, Ciraco M, Solid-supported benzotriazoles. 2. Synthetic auxiliaries and traceless linkers for the combinatorial synthesis of unsymmetrical ureas, J. Comb. Chem., 3 354-359, 2001. 

Solid-phase organic synthesis (SPOS) has been revolutionary in the quest to produce libraries of structurally diverse molecules both quickly and cheaply. The utility of benzyl and aryl vinyl sulfones in the traceless linker synthesis of amines... 

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