Linkers solid-phase synthesis

Scheme 11 A traceless linker solid phase synthesis of 2,6,9-trisubstituted purines from 2-fluoro-6-thiobenzylpurine...

K. Gordon and S. Balasubramanian, Solid phase synthesis - designer linkers for combinatorial chemistry A review J Chem Technol Biotechnol 74 835-851 7999. 

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

The investigation of minor groove-binding polyamides was greatly accelerated by the implementation of solid-phase synthesis [48]. Originally demonstrated on Boc-y9-Ala-PAM resin with Boc-protected monomers, it was also shown that Fmoc chemistry could be employed with suitably protected monomers and Fmoc-y9-Ala-Wang resin (Fig. 3.8) [49]. Recently, Pessi and coworkers used a sulfonamide-based safety-catch resin to prepare derivatives of hairpin polyamides [50]. Upon activation of the linker, resin-bound polyamides were readily cleaved with stoichiometric quantities of nucleophile to provide thioesters or peptide conjugates. 

Jung N, Wiehn M, Brase S (2007) Multifunctional Linkers for Combinatorial Solid Phase Synthesis. 278 1-88... 

Linkers and Resins for Solid-Phase Synthesis 1997-1999 Pan Li, Elaine K. Kolaczkowski, and Steven A. Kates... 

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 further extension to this concept was (dimethylsilyl)propionic acid linker 75 used for the solid-phase synthesis of aryl-containing organic compounds [86], The linker was cleaved smoothly with TFA and has been used for the synthesis of compounds which involved alkylation, acylation, and Mitsunobu reactions. 

Henkel B, Bayer E. 9-Hydroxy-9-(4-carboxyphenyl)fluorene—a new linker for solid phase synthesis. Tetrahedron Lett 1998 39 9401-9402. 

Bhalay G, Dunstan AR. Facile solid phase synthesis of an activated diazo linker. Tetrahedron Lett 1998 39 7803-7806. 

Lee HB, Balasubramanian S. Studies on a dithiane-protected benzoin photolabile safety catch linker for solid-phase synthesis. J Org Chem 1999 64 3454-3460. 

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

Nakamura K, Hanai N, Kanno M, Kobayashi A, Ohnishi Y, Ito Y, Nakahara Y. Design and synthesis of silyl ether-based linker for solid-phase synthesis of glycopeptides. Tetrahedron Lett 1999 40 515-518. 

Millington CR, Quarrell R, Lowe G. Aryl hydrazides as linkers for solid phase synthesis which are cleavable under mild oxidative conditions. Tetrahedron Lett 1998 39 7201-7204. 

Jensen KJ, Alsina J, Songster MF, Vagner J, Albericio F, Barany G. Backbone amide linker (BAL) strategy for solid-phase synthesis of C-terminal-modified and cyclic peptides. J Am Chem Soc 1998 120 5441— 5452. 

Brown EG, Nuss JM. Alkylation of Rink s amide linker on polystyrene resin a reductive amination approach to modified amine-linkers for the solid phase synthesis of /Y-substiuited amide derivatives. Tetrahedron Lett 1997 38 8457-8460. 

Chou Y-L, Morrissey MM, Mohan R. Novel serine-based linker for the solid-phase synthesis of organic compounds. Tetrahedron Lett 1998 39 757-760. 

Parrot I, Wermuth C-G, Hibert M. Resin-bound thiophenols as SNAR-labile linkers Application to the solid phase synthesis of aminopyridazines. Tetrahedron Lett 1999 40 7975-7978. 

Fitzpatrick LJ, Rivero RA. Solid phase synthesis of substituted amino-sulfonylureas using a sulfonylcarbamate linker. Tetrahedron Lett 1997 38 7479-7482. 

Dressman BA, Singh U, Kaldor SW. Solid phase synthesis of urea libraries using a diversifiable thiophenoxy carbonyl linker. Tetrahedron Lett 1998 39 3631-3634. 

Zhong HM, Greco MN, MaryanofF BE. Solid-phase synthesis of arginine-containing peptides by guanidine attachment to a sulfonyl linker. J Org Chem 1997 62 9326-9330. 

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. 

Ede NJ, Bray AM. A simple linker for the attachment of aldehydes to the solid phase. Application to solid phase synthesis by the Multipin method. Tetrahedron Lett 1997 38 7119-7122. 

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. 

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