Solid-phase, anchors

The list Solid-phase Anchors in Organic Chemistry can never be absolutely complete. Negative results obtained with novel anchors will be very rarely published and many possible combinations (resin/linker/reaction) have not yet been tried. However, this list can... 

The chapter on solid supports in the first book has now been supplemented by a complete listing of the various solid-phase anchors and linkers used in organic chemistry - information which may be of particular value to newcomers in the field. 

Thioacetals have been widely used as protecting groups for the carbonyl functionality and are stable to a wide range of reaction conditions. They were first employed as solid phase anchors by Bertini [64] (Scheme 17.23). He noted that polymeric... 

The most important family of side reactions, namely potential loss of configuration at various stages of solid-phase anchoring and chain assembly, has been mentioned already (Sections 3.2.1 and 3.2.2). Other problems should be considered as well. Oxidation and alkylation of the thioether of S-protected Cys is always a possibility, but such processes appear to be less severe in the case of Cys than with Met. A number of side reactions are likely to be sequence dependent some of these involve modifications of other residues by species released during deprotection and/or oxidation. 

A short and efficient synthetic approach to hydroxy-substituted ( )-stil-benoids, as exemplified by the natural compound resveratrol (371b) via solid-phase CM, was reported by a Korean group (Scheme 71) [154]. When two different stilbenes were allowed to couple by catalyst C, all three kinds of possible stilbenes were obtained as an inseparable mixture. Anchoring 4-vinylphenol to Merrifield resin, followed by exposing the supported styrenyl ether 368 and diacetoxy styrene 369 (10 equiv) to the catalyst, inhibited self-metathesis of the supported substrate. Sequential separation of the homodimer formed from 369 by washing and subsequent cleavage of the resin 370 with acid provided (E)-stilbene 371a with complete stereocontrol in 61% yield. 

The first example of microwave-promoted solid-phase methodology in heterocyclic chemistry was the arylation of thiophene and indole via Suzuki couplings on TentaGel S RAM resin, as demonstrated by Hallberg and coworkers in 1996, before temperature- and pressure-controlled microwave instruments were even available [189]. Three years later Schotten and coworkers presented analogous but aqueous Suzuki couplings of 5-bromo-thiophene anchored to PEG soluble support via a carboxylic function at its C-2 position [116]. Unfortunately, this work was performed in a do-... 

Trialkylsilane resin (PS-DES) 50 was incorporated for solid-phase glycosylation by anchoring a glycosyl donor via their corresponding thio-phenyl ether or 3-glucopyranosyl fluorides (Scheme 20) [59]. Disaccharides... 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

A versatile approach for the solid-phase synthesis of aminopyr-idazines used the anchoring of 3,6-dichloropyridazine to resin-bound thiophenol 59 (Scheme 28) [68]. Treatment with nucleophilic amines released the aminopyridazine products from the solid support without further oxidation. 

Acetal handle 78 synthesized from Merrifield resin and 4-hydroxy-benzaldehyde was applied to the solid-phase synthesis of carbohydrates and 1-oxacephams (Scheme 41) [90]. For the latter, a 1,3-diol was initially anchored to the support to form a cyclic acetal. A ring opening reaction with DIBAL generated a resin-bound alcohol which was converted to the corresponding triflate for A-alkylation with 4-vinyl-oxyazetidin-2-one. A Lewis acid catalyzed ring closure released 1-oxa-cephams from the support. 

Albericio F, Barany G. Hypersensitive acid-labile (HAL) tris(alkoxy)benzyl ester anchoring for solid-phase synthesis of protected peptide segments. Tetrahedron Lett 1991 32 1015-1018. 

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

Seitz O, Kunz H. HYCRON, an allylic anchor for high-efficiency solid phase synthesis of protected peptides and glycopeptides. J Org Chem 1997 62 813-826. 

Breipohl G, Knolle J, Stuber W. Synthesis and application of acid labile anchor groups for the synthesis of peptide amides by Fmoc-solid-phase peptide synthesis. Int J Peptide Protein Res 1989 34 262-267. 

Seiber P. A new acid-labile anchor groups for the solid phase synthesis of C-terminal peptide amides by the Fmoc method. Tetrahedron Lett 1987 28 2107-2110. 

Hammer RP, Albericio F, Gera L, Barany G. Practical approach to solid-phase synthesis of C-terminal peptide amides under mild conditions based on photolysable anchoring linkage. Int J Peptide Protein Res 1990 ... 

Alsina J, Chiva C, Ortiz M, Rabanal F. Active carbonate resins for solid-phase synthesis through the anchoring of a hydroxyl function. Synthesis of cyclic and alcohol peptides. Tetrahedron Lett 1997 38 883-886 and references cited therein. 

N. K. Terret, Combinatorial Chemistry, Oxford University Press, New York, 1998 M. Winter, R. Warrass, Resins and Anchors for Solid-Phase Organic Synthesis, in Combinatorial Chemistry (Ed. H. Fenniri), Oxford University Press, New York, p. 117-138, 2000. 

A combination of the SNAr feature and the coordination ability of a copper complex has led to the development of a new O-arylation method that makes use of a triazene as an activating and directing group (Equation (2)).32,33 This protocol, though necessitating a three-step removal sequence of the triazene moiety, has been successfully applied to the total synthesis of vancomycin1 6 and extended to a solid-phase synthesis in which the triazene unit serves as an anchor to the resin.37... 

Hence, the implication of combinatorial chemistry for high throughput generation of structurally diverse hydroxamic acids is self-evident. Several solid-phase approaches for their syntheses have been reported,1 7-11 the majority of which are based on the anchoring of iV-hydroxyphthalimide onto an appropriate solid support. After hydrazine-mediated /V-dcprotcction, /V-acylation of the resin-bound hydroxylamine would yield the desired O-anchored hydroxamic acid, which is typically released by acidolysis. 

In 1983, Prasad et al.12 first reported the condensation of chloromethyl polystyrene with /V-hydroxyphthalimide to give the ester, hydrazinolysis of which yielded the desired resin-bound hydroxylamine. However, the sole purpose of this reagent was to react with, and hence extract ketones from, a complex steroidal mixture, and its use for the solid-phase synthesis of hydroxamic acids was not explored. Recently, the exploitation of the above solid-phase approach for the synthesis of hydroxamic acids was independently reported by three groups,7-9 all of which differ only in the method for the initial anchoring of TV-hydroxyphtha-limide to an 4-alkoxybenzyl alcohol functionalized polystyrene or trityl chloride polystyrene. Subsequent /V-deprotection was... 

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