Protecting Groups and Solid-Phase Synthesis

Seitz and Kunz advanced the art of solid-phase synthesis by developing a novel allylic anchor (Hycron) whose virtues were exemplified in a synthesis of protected and unprotected O-glycosylated Mucin-type ycopeptides. Anchoring though allyl esters not only allows peptide derivatives to be detached without affecting acid- and base-labile structural elements, but also provides orthogonal 

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The major requirements for photoactivatable amino acids are that they should exhibit high optical purity and contain appropriate protecting groups for solid-phase synthesis there is also a particular advantage if they contain the radiolabel. While p-azido-phenylalanines can easily be labeled with 125I and... 

Considering all these features and limitations, it is understandable that currently there is no general procedure available, such as the Fmoc or Boc protocols that are available for nonfunctionalized peptides. However, several approaches have been developed in the last two decades to make lipidated peptides accessible. This chapter describes both the corresponding solution-phase approaches and solid-support approaches for the synthesis of lipidated peptides. In line with the framework sketched above, both the different protecting groups and solid-phase linker systems that have been developed will be reviewed. 

Kessler, M., Glatthar, R., Giese, B. and Bochet, C.G. (2003) Sequentially photo-cleavable protecting groups in solid-phase synthesis. Organic Letters, 5, 1179-1181. 

New Linkers and Protection Groups for Solid-Phase Synthesis... 

Christodoulou C, Agrawal S, Gait MJ. Incompatibility of acid-labile 2 and 5 protecting groups for solid-phase synthesis of oligoribonucleotides. Tetrahedron Lett 27 1521-1522, 1986. 

Truncated sequences, core sequences, incompletely synthesized peptides. Imperfect conversion during acylation or deprotection of the temporary protecting group in solid-phase synthesis may lead to mismatch sequences that lack some amino acids and truncated sequences (core sequences). They occur, when the accessibility or reactivity of the peptide bound to the solid phase is insufficient difficult sequences). Truncated sequences may be classically identified and quantified by a modified Edman degradation, also called preview analysis. Alternatively, mass spectrometry provides efficient tools for the identification of truncated sequences. 

Stral997 Stranix, B.R., Liu, H.Q. and Darling, G.D., Functional Polymers from (Vinyl)polystyrene. Recyclable Polymer-Supported Organosilicon Protecting Groups for Solid-Phase Synthesis, J. Org. Chem., 62 (1997) 6183-6186. 

The Bnpeoc group was developed as a base-labile protective group for solid-phase peptide synthesis. The carbamate is formed from the O-succinimide (DMF, 10% Na2C03 or 5% NaHC03) and is cleaved using DBN, DBU, DBU/AcOH, or piperidine. ... 

Acetals and ketals are very important protecting groups in solution-phase synthesis, but only a few constructs have been used as linkers in solid-phase synthesis (Tab. 3.3). The THP-linker (22) (tetrahydropyran) was introduced by Ellman [54] in order to provide a linker allowing the protection of alcohols, phenols and nitrogen functionalities in the presence of pyridinium toluene sulfonate, and the resulting structures are stable towards strong bases and nucleophiles. Other acetal-linkers have also been used for the attachment of alcohols [55, 56]. Formation of diastereomers caused by the chirality of these linkers is certainly a drawback. Other ketal tinkers tike... 

Carbamates are by far the most common type of amine protection used in solid-phase synthesis. Various types of carbamate have been developed that can be cleaved under mild reaction conditions on solid phase. Less well developed, however, are techniques that enable the protection of support-bound amines as carbamates. Protection of amino acids as carbamates (Boc or Fmoc) is usually performed in solution using aqueous base (Schotten-Baumann conditions). These conditions enable the selective protection of amines without simultaneous formation of imides or acylation of hydroxyl groups. Unfortunately, however, Schotten-Baumann conditions are not compatible with insoluble, hydrophobic supports. Other bases and solvents have to be used in order to prepare carbamates on, for example, cross-linked polystyrene, and more side reactions are generally observed than in aqueous solution. 

Ultraviolet spectrophotometric analysis of the incorporation or deblocking of the a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl (Ddz) group in solid phase synthesis has been used by Birr for the analysis of the coupling and deprotection reactions respectively 18 20). Similar spectroscopic properties of the N-protecting groups have been used for the analysis in the solid phase synthesis involving Nps-amino acids 21,22) and Bpoe-amino acids 23). In all these methods the uptake or release of a soluble reagent or byproduct is analyzed. 

Schmidt and co-workers have also independently developed the self-cleavable diene linker 14 and solid-phase synthesis of the branched hexasaccharide 16 has been achieved (O Scheme 6) [12], The ring-closing metathesis of 15 provided the allyl glycoside 16 from which the allyl protecting group was readily removed by Ir-mediated isomerization followed by hydrolysis. 

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