Orthogonal protection strategy

In general, an Fmoc/Boc orthogonal protecting strategy is most often used in library synthesis. Therefore, the protecting groups P and P3 in Scheme 1 are Fmoc and Boc, respectively. 

The different cleavage conditions for the above urethane protecting groups have enabled so-called orthogonal protection strategies to be developed, which in turn enable selective deprotection to be performed on different amines present in the same molecule. For example in peptide synthesis, the N-Boc group could be cleaved selectively using TMSOTf, followed by aqueous work up. 

A different orthogonal protection strategy was reported by Marlowe [75], who prepared a model peptide cyclized between the /V-terminus and an Asp side chain cyc/o(Glu-Ser-Thr-Arg-Pro-Met-Asp-NH2). The third level of orthogonal protection was obtained using a trimethylsilylethyl (TMSE) ester, which is selectively deprotected by fluoride ions. Accordingly, Fmoc-Asp(OTMSE)-OH was loaded onto Rink amine resin and the linear precursor peptide was constructed using Fmoc/rBu chemistry. Treatment... 

The use of azidosugars and A -phthalimido-protected aminosugars is well established in carbohydrate chemistry. But many new protective groups have been proposed to enable deprotection under milder conditions or to apply orthogonal protection strategies (Scheme 5). 

An obvious outcome of the Hantzsch synthesis is the symmetrical nature of the dihydropyridines produced. A double protection strategy has been developed to address this issue. The protected chalcone 103 was reacted with an orthogonally protected ketoester to generate dihydropyridine 104. Selective deprotection of the ester at C3 could be accomplished and the resultant acid coupled with the appropriate amine. Iteration of this sequence with the C5 ester substituent ultimately gave rise to the unsymmetrical 1,4-dihydropyridine 105. 

Developments of protection strategies in peptide synthesis have led to the introduction of a wider variety of protecting groups for different functionalities and provide orthogonal protection to specific side chains (Table 1). 

We have demonstrated an orthogonal protection/deprotection strategy for preparing a carbohydrate core that could be iteratively deprotected and glycosylated to form... 

Scheme 11.10 Application of an orthogonal protection/deprotection strategy in preparation of a tetrasaccharide.

The general strategy is based on selective deprotection and oxidation of pairwise cysteine residues, as specified by the orthogonal protection scheme selected for this purpose. Since multiple disulfide bonds are formed step-by-step, reaction conditions are required that prevent breaking or scrambling of the disulfide bonds already formed. Therefore, throughout the synthesis, exposure to thiols or alkaline conditions as well as lengthy reaction times that may cause disulfide disproportionation must be avoided. 

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