Sulfone traceless linkers

The sulfonate traceless linker was also used in the combinatorial synthesis of trisaccharides. The linker is stable under acidic glycosylation conditions and is effective for the introduction of... 

SCHEME 10.3 Strategy for the solid-phase synthesis of vitamin Dj analogs using a sulfonate traceless linker. 

Aminopyrimidine. Early representative examples of a sulfone traceless linker were demonstrated by Villalgordo et al. and Gayo and Suto in the synthesis of 2-aminopyrimidines. The sulfur linkage was obtained by treating Merrifield resin with thiourea to provide the isothiouronium salts 1 (Scheme 12.5). Condensation of 1 with acetylenic ketones 2 or malononitrile derivatives 3 yielded the pyrimidine skeleton 4. Oxidation of the alkylthio linkage with mCPBA provided the corresponding sulfone derivatives that underwent nucleophilic substitution with various amines to form 2-aminopyrimidines 5. 

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. 

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. 

Resin-bound 7-keto sulfones, prepared in a straightforward, three-step process comprising alkylation of a resin-bound sulfinate salt, alkylation of a sulfone-supported anion with an epoxide, and Jones oxidation of the 7-hydroxy sulfone, provided a source of structurally diverse three-carbon fragments <2004JC0928>. Reaction with a phenylenediamine to give the 1,5-benzodiazepine presumably occurs via initial imine formation followed by expulsion of the resin-bound sulfone, which acts as a traceless linker (Scheme 73). Yields for this process are a modest 10-38%. 

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... 

Oxidative Pd insertion into electron-poor aryl sulfonates is a key step in Pd(0)-mediated C-C coupling reactions. This principle has been turned into a traceless linker concept in which phenols are attached via sulfonates to a solid support [107]. The system has been optimized by employing a perfluoroalkylsulfonyl linker that closely resembles the commonly applied inflates (90, Scheme 41). In this respect, the linker acts as a protecting group and as an activating entity. Reductive cleavage of 91 with Pd(0) and formic acid led to arenes 92 [108]. 

This traceless linker allows fhe synthesis of a number of different heterocycles starting from fhe solid-phase-bound sulfone intermediate 139, which can be built up in a few steps from fhe sulfinate 138. The potential of fhis traceless linker is outlined in Scheme 66 [161, 162]. 

A traceless linker for anchoring secondary amines has been developed [123,124] and is referred to as the REM linker 21 (regenerated after cleavage, functionalized by Michael addition). Tertiary amines can be prepared on this support by conversion to a resin-bound quaternary ammonium salt followed by cleavage by base-induced Hofmann elimination [125]. The analogous vinyl sulfone resin 2m can also be used to anchor secondary amines and is stable to a greater range of reactants [126,127]. 

While attached to the resin, the isolated moiety can undergo further chemical manipulation with the PS-thiophenol acting as a linker moiety. Cleavage is achieved by the addition of an amine (primary or secondary), causing nucleophilic displacement from the resin, which also results in additional modification of the molecule (eq 6). The functionalized polymer acts as a traceless linker without the need for oxidation to the sulfone or sulfoxide. 

Furans. Timm and coworkers have devised a strategy to synthesize 2,5-disubstituted furans using sulfone carbanion-mediated solid support as a traceless linker (Scheme 12.16). They demonstrated the usefulness of the highly reactive basic carbanionic species of the... 

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. 

Solid supported isoxazolines 40 were prepared starting from a sulfmate-functionalised resin 38. Oxidation of the resin linked cyclobutanols 40, with concomitant cleavage of the sulfone linker, produced isoxazolinocyclobutenones 41 in 34-38% overall yield (4 steps) <02OL741>. A five-step solid phase synthesis of isoxazolino-pyrrole-2-carboxylates that employing the same traceless sulfone linker strategy has also been reported <02JOC6564>. 

Amino polystyrene pyrazolone linker resin 58 provided various amide products 59 with a high conversion rate and good purity under mild conditions the resin linker was stable under the reaction conditions, resistant to hydrolysis, and reused repeatedly without loss of activity <03TL8063>. The preparation of pyrazoline derivatives 61 was accomplished with traceless solid-phase sulfone linker 60 with phenylhydrazine <030L1067>. Aniline cellulose-bound enaminones 62 reacted with phenylhydrazine under microwave irradiation to produce pyrazolocarboxylic acid derivatives 63 in high yields <03JCO465>. 

The preparation of pyrazoline derivatives 595 was accomplished by reaction of phenylhydrazine with a traceless solid-phase sulfone linker 594 (Equation 121) <20030L1067>. 

This linker allows for the straightforward attachment of phenols as sulfonate esters and also for their use in reductive traceless cleavage and for C-C bond formations during the release from the support. Its efficiency was demonstrated in the synthesis of valsartan methyl ester by a multi-step solid-phase strategy [111]. 

Activated Vitamin D3 Using a Traceless Sulfonate Linker.228... 

Traceless cleavage of 1,2,3-triazoles has also been accomplished with a sulfone linker. Resin-bound vinyl sulfone was reacted with sodium azide under microwave irradiation, and 1,2,3-triazoles were obtained in a traceless manner (Scheme 11.25). A strongly electron-withdrawing sulfone that is eliminated in the reaction promotes the regioselective cycloaddition in the case of A-substituted 1,2,3-triazoles. Microwave irradiation reduced the reaction times and the products were obtained in higher purity than that with conventional heating. 

Scheme 11.46. Traceless cleavage of isoxazoline derivatives with a sulfone linker.

Traceless cleavage with a sulfone linker has also been utiUzed in the solid-phase synthesis of isoxazolines and isoxazoles. Nitrile oxides generated in situ reacted regioselectively to the solid-supported diene (Scheme 11.46). Subsequent formation of pyrroles released the cycloadducts from the resin in a traceless manner. 

S. H. Hwang, M. J. Kurth, Versatile traceless sulfone linker for SPOS preparation of isoxazolinopyrrole 2-carboxylates. J. Org. Chem. 2002, 67, 6564-6567. 

---