Traceless linker

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]. 

Linear polarization, and NLO properties, 12, 102 Linear polymers, siloxanes, synthesis, 3, 660 Linkage isomerism, for photochromic behavior, 1, 245 Linked cages, metallacarboranes, 3, 245 Linkers, traceless, chromium carbonyls as, 5, 251 Lipids, in bioorganometallic chemistry, 1, 904 Liquefied noble gases, in low-temperature infrared studies, 1, 264... 

PS-TsCl was used in the solid-phase synthesis of indoles. Loading of anilines 8 onto PS-TsCI was followed by Sonogashira coupling (eq 9). The coupled products cyclized under the reaction condihons to provide the corresponding indoles this cycliza-tion was promoted by the electron-withdrawing sulfonyl linker. Traceless cleavage of the sulfonyl linker with TBAF provided the indoles in 85-100% yield. 

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. 

Traceless linker 60 based on a benzotriazole scaffold was reacted with amines and aldehydes to produce Mannich-type amine products [69]. Final product release was achieved by treatment with Grignard reagents (Scheme 29). 

Cleavage of all the linkers described above provide a functional group (carboxylic acid, amide, amine, etc) at the anchoring position. Silyl-based handles 71,72, and 73 as well as germanium-based handle 74 insert a C-H bond at the anchoring position and are referred to as traceless (Fig. 15) [82-... 

Aryl hydrazide-based linker 79 was developed as a traceless handle that released products under mild oxidative conditions (Scheme 42) [91]. Polymeric bound p-iodophenylhydrazide was subjected to a variety of Pd°-catalyzed coupling reactions (Heck, Suzuki, Sonogashira, and Stille). Oxidation with Cu(OAc)2 in MeOH and pyridine released the final products in 50-96% yield. 

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

Gayo KM, Suto MJ. Traceless linker Oxidative activation and displacement of a sulfur-based linker. Tetrahedron Lett 1997 38 211-214. 

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. 

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

Woolard FX, Paetsch J, Ellman JA. A silicon linker for direct loading of aromatic compounds to supports. Traceless synthesis of pyridinc-bascd tricylics. J Org Chem 1997 62 6102-6103. 

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. 

An application of Stille couplings to the solid phase using a traceless A-glycerol linker with 2-stannylindoles has been developed [177]. Only a few examples of the use of 3-stannylindoles in Stille reactions have been described. Ortar and co-workers prepared 169 and 170 and effected Pd-catalyzed cross coupling reactions with several aryl, heteroaryl, and vinyl substrates (bromides, iodides, triflates) to give the expected products 171 in high yields [178]. Enol triflates behave exceptionally well under the Ortar conditions, e.g., 172 to 173. 

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

F. X. Woolard, J. Paetsch, J. A. Ellman, A Silicon Linker for Direct Loading of Aromatic Compounds to Supports. Traceless Synthesis of Pyridine-Based Tricyclics , J. Org Chem. 1997, 62, 6102-6103. 

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. 

Scheme 4.11 Application of the traceless silyl linker strategy.

To our knowledge, only one attempt has been made toward the preparation and use of a fixed glucosyl trichloroacetimidate.9 Takahashi et al. described the synthesis of an attached O-glucosyl trichloroacetimidate and extended the use of the well known traceless silyl linker strategy (Scheme 4.11). 

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]. 

T1 resin traceless linker [131-134], synthesis of phenols [135], biaryls, alkyl arenes [136, 137], azides [138], aromatic hydrazines, halides [cf. 128, 129, 139], ester, azo compounds, cinno-lines [140], benzotriazoles [141]... 

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. 

An illustrative example for the alternative strategy, (cf Figure 7c) by the use of a traceless linker, is found in the multi-step synthesis of 6- f-dysidiolide 434 and several dysidiolide-derived phosphatase inhibitors by Waldmann and co-workers outlined in Scheme 83. During the synthesis, the growing skeleton of 434 remained attached... 

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. 

The triazene linker featured above is a traceless one that efficiently yields an aryl iodide upon treatment with methyl iodide. It is perhaps not well known to the combinatorial chemistry community. 

This chemistry was repeated with a traceless photolabile linker.60 The desired biphenyl was formed, but the couplings gave side products, and all yields of the desired biphenyl were lower than 30%. 

Chemistry similar to this was used in Ellman s paper to promote application of a silicon-based traceless linker.62 The full report on this work63 shows that both aliphatic and aromatic acid chlorides may be used in the coupling step. The same,approach is also shown to be successful with a germanium-based linker in place of the silicon. The couplings were typically performed for 1 h only, with equilibration time of a few minutes... 

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