Selenol protecting groups in organic chemistry: special emphasis on selenocysteine Se-protection in solid phase peptide synthesis

Abstract

The appearance of selenium in organic synthesis is relatively rare, and thus examples in the literature pertaining to the masking of its considerable reactivity are similarly uncommon. Greene's Protecting Groups in Organic Synthesis, the standard reference for the state of the art in this arena, offers no entries for selenium protective methodology, in stark comparison to its mention of the great variety of protecting groups germane to its chalcogen cousin sulfur. This scarcity of Se-protection methods makes it no less interesting and pertinent toward the construction of selenium-containing organic systems which do indeed require the iterative blocking and de-blocking of selenol functionalities. A selenium-containing system which is especially relevant is selenocysteine, as its use in Solid Phase Peptide Synthesis requires extensive protection of its selenol side chain. This review will attempt to summarize the current state of understanding with regard to selenium protection protocol in organic synthesis. Moreover, it will provide a special emphasis on selenocysteine side chain protection, comprising both the breadth of functionality used for this purpose as well as methods of deprotection.

Figure 1

Various functional groups containing selenium and their nomenclature.

Figure 2

Structural comparison between selenocysteine and cysteine.

Figure 3

Synthetic routes into diselenide and disulfide protection schemes and their deprotection pathways to release their corresponding selenol functions.

Figure 4

Synthetic routes into Cyanate protection schemes and their deprotection pathways to release their corresponding free selenol and other selenium-containing functions.

Figure 5

Use of 2-Cyanoethyl protection in the synthesis of Se-containing nucleotide analogs.

Figure 6

Synthesis and deprotection conditions for selenoacetates, selenocarbonates, and selenocarbamates.

Figure 7

Formation of Se-Acetoxymethyl protection via Pummerer rearrangement and deprotection using peroxide.

Figure 8

Synthetic routes into Phthalimide and Succinimide protection schemes and their routes for removal.

Figure 9

Installation and deprotection mechanism of Se-Allyl-based protection scheme.

Figure 10

Synthetic routes into phenylselenyl protection schemes and their oxidative or reductive removal pathways.

Figure 11

Dual synthetic routes into benzyl-templated Sec systems.