Deprotection, cleavage reactions

The protection-deprotection reaction sequences constitute an integral part of organic syntheses such as the preparation of monomers, fine chemicals, and reaction intermediates or precursors for pharmaceuticals. These reactions often involve the use of acidic, basic or hazardous reagents and toxic metal salts [30], The solvent-free MW-accelerated protection/deprotection of functional groups, developed during the last decade, provides an attractive alternative to the conventional cleavage reactions. 

The deprotection of the polyamine-thioethers 40a,b can also be accomplished in similar good yields with Li/naphthalene in THF (214). Cleavage of the thioether functions also commenced with [PdCl2(NCMe)2] in the case of 40b (216), and it is likely that the other macrobicycles will also undergo this metal-ion mediated cleavage reaction as well (Scheme 2). Note that this reaction cleaves only one of the two thioether bonds forming a macrocyclic ligand with one thiophenolate and one vinyl-thioether moiety, as... 

The 1,3-dioxolane and 1,3-dioxane systems are stable to an extremely wide range of reaction procedures provided that an acidic medium is avoided. Deprotection is effected under a wide variety of mild acid conditions such as, for example, aqueous tartaric acid,134 perchloric acid,135 or moist silica gel either alone or in the presence of oxalic or sulphuric acids.136 The mild oxidative cleavage reaction with triphenylmethyl tetrafluoroborate in dichloromethane is... 

The methodology was successfully extended to a one-pot total synthesis of complex heterocyclic systems such as pyrazino [2,1-b] quinazolines 79, encountered in nature as alkaloids 80-82 (Scheme 50) [125]. To assemble the pyrazino[2,l-fo]quinazoline core, N-Boc protected amino acid 76 was employed instead of carboxylic acid 72 (Scheme 49) in the synthesis of the corresponding intermediate benzoxazinones 77. The subsequent reaction with an amine moiety of another amino acid ester 78 was accompanied by concomitant cleavage of the N-Boc protecting group and diketopiperazine-like cyclization (for the one-pot deprotection-cyclization reaction of N-Boc dipeptide esters to afford 2,5-piperazinedione under microwave dielectric heating, see [128]) to afford the target heterocycle 79. Hence, the total... 

Then another N-protected amino acid is coupled to the free amino group of the polymer-bound substrate using the dicyclohexylcarbodiimide activation or the active ester method. The N-deblocking and coupling steps are repeated until the desired sequence is formed. Finally the resin-peptide bond is split by a suitable acid cleavage reaction with HBr—AcOH, trifluoroacetic acid or HF. This results in a simultaneous N-deblocking and deprotection of most of the side-chain functionalities. 

The purpose of this chapter is to delineate strategic considerations and provide practical procedures to enable non-experts to synthesize peptides with a reasonable chance of success. This chapter focuses on Fmoc chemistry, which is now the most commonly employed strategy for solid phase peptide synthesis (SPPS). Protocols for the synthesis of fully deprotected peptides are presented, together with a review of linkers and supports currently employed for SPPS. The principles and the different steps of SPPS (anchoring, deprotection, coupling reaction, and cleavage) are all discussed, along with their possible side reactions. 

Key Words Solid phase peptide synthesis side reaction coupling anchoring deprotection cleavage linker. 

Cleavage reactions of radical ions may be conveniently applied in deprotection processes like the cathodic scission of sulfonamides (deprotection of amines) and the anodic cleavage of gemdithioacetals (deprotection of carbonyl groups). 

Aqueous ammonia, dioxane. - The addition of nitromethane in the cleavage reaction will scavenge the released acrylonitrile and prevent it from reacting with the nucleohase during deprotection of oligonucleotides/ ... 

The trityl linkers were introduced to permit anchoring of carboxylic acids and other nucleophiles to a solid support and to effect cleavage reactions under very mild acidic conditions [64-67]. Various trityl resins, such as Ib-le (Table 1), have been developed that differ in the substitution pattern of the aromatic ring substituents in order to modify the cleavage properties by their influence on the stability of the trityl cation. For carboxylic acids, amines, and phenols, the chlorotrityl resin Ic affords a more stable anchor [65-67] than does resin lb. Similarly, resin le, which contains both fluoro and carbonyl ring substituents, proved to be very stable toward nucleophiles and was fully compatible with piperidine / / -Fmoc (9-fluorenylmethoxycar-bonyl) deprotections used in a model peptide synthesis. Cleavage of acids from le could be effected using dilute TFA in dichloromethane [68]. 

---