Anchors, solid-phase synthesis

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. 

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. 

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... 

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... 

M. Megler, R Tanner, J Gosteli, P Grogg. Peptide synthesis by a combination of solid phase and solution methods. 1. A new very acid-labile anchor group for the solid phase synthesis of protected fragments on 2-methoxy-4-alkoxy-benzyl resins. Tetrahedron Lett 29, 4005, 1988. 

H Kunz, B Dombo. Solid phase synthesis of peptides and glycopeptides on polymeric supports with allylic anchor groups. Angew Chem Int Edn Engl 27, 711, 1988. 

During the first decade when solid-phase synthesis was executed using Fmoc/tBu chemistry, the first Fmoc-amino acid was anchored to the support by reaction of the symmetrical anhydride with the hydroxymethylphenyl group of the linker or support. Because this is an esterification reaction that does not occur readily, 4-dimethylaminopyridine was employed as catalyst. The basic catalyst caused up to 6% enantiomerization of the activated residue (see Section 4.19). Diminution of the amount of catalyst to one-tenth of an equivalent (Figure 5.21, A) reduced the isomerization substantially but did not suppress it completely. As a consequence, the products synthesized during that decade were usually contaminated with a small amount of the epimer. In addition, the basic catalyst was responsible for a second side reaction namely, the premature removal of Fmoc protector, which led to loading of some dimer of the first residue. Nothing could be done about the situation,... 

A linker originally designed for solid-phase synthesis of peptides is the backbone amide linker (11) (BAL), this anchoring approach has now been extended to the combinatorial synthesis of diverse amide [31], hydroxamate [32], oligosaccharide [33] and heterocyclic small molecule libraries [34-36]. 

New allylic anchors as the HYCRAM (19) (hydroxycrotonylamide) [50] and HY-CRON (21) (hydroxycrotyl-oligoefhylene glycol-n-alkanoyl) [51] linker have been developed, which exhibit excellent properties for the solid-phase synthesis of protected peptides and glycopeptides. A more flexible spacer was inserted in the HY-CRON (21) linker between the anchor and the polymeric support in order to facilitate an efficient access to the Pd(0) complex during the detachment reaction. 

Scheme 10.10 Solid phase synthesis of tetrahydro-j8-carbolins and subsequent detachment by enzyme initiated fragmentation of the anchor group.

A number of approaches may be adopted to achieve chemical synthesis of a peptide. The Merrifield solid phase synthesis method is perhaps the most widely used. This entails sequential addition of amino acids to a growing peptide chain anchored to the surface of modified polystyrene beads. The modified beads contain reactive chloromethyl (—CH2CI) groups. 

Pinori, M. Di Gregorio, G. Mascagni, P. A New Anchor Group for the Solid-phase Synthesis of C-terminal Peptide Amides Under Neutral Conditions, in Innovation and Perspectives in Solid Phase Synthesis, Epton, R., Ed. Mayflower Worldwide Kingswinford, 1994 pp. 635-638. 

F. Allylic Anchors in the Solid-Phase Synthesis of Glycopeptides... 

O. Seitz and H. Kunz, A novel allylic anchor for solid-phase synthesis. Synthesis of protected and unprotected O-glycosylated mucin-typc glycopeptides, Angew. Chem. lnt. Ed. Engl. 34 803 (1995). 

---