2- thioethyl, protecting group

Example 40 mononucleoside phosphotriester derivatives with 5-acyl-2-thioethyl bioreversible phosphate-protecting groups have been synthesized by Imbach and his associates [74a,b] in their research on intracellular delivery of 3 -azido-3 -dideoxythymidine-5 -mono-phosphate. 

The concept was based upon the ability to control the reactivity of thioethyl and selenophenyl glycosyl donors by careful choice of anomeric substituent and hydroxyl protecting groups. Selenoglycosides are more reactive than their sulfur analogs and therefore four different levels of reactivity can be attained using only one promoter system (NIS/TfOH) (Fig. 4). As iodonium transfer to the sulfur or selenium atom is rapid and reversible under the conditions of the reaction, only the most reactive glycosyl donor in the mixture is activated when one equivalent of NIS is used. Sequential addition of NIS and acceptor units thus allows the rapid, controlled synthesis of complex carbohydrate structures. 

Trifluoroacetyl function may be used as an acyl protecting group which is removed in mild base. It may be introduced upon reaction of the amino acid with trifluoroacetic anhydride or trifluoroacetic acid thioethyl ester ... 

This unpredicted turn of events is actually rather general [59]. It was found that even monsaccharides consisting of 2-suIfonamide thioethyl galactosides resulted in glycosylation with poor selectivity. In the case at hand, modifying the protecting group on the C4-hydroxyl (see R in 139) failed to reverse selectivity. 

The next plateau to be reached was seen to be that of the full hexasaccharide core (Scheme 26). In an effort to maintain the tempo of the synthesis, we proceeded on to another assembly iteration with minimal protecting group-based transformations. The use of a thioethyl donor was explored however, in the end the direct roll over route proved more reproducible. To this end, iodosulfonamidation of 154 afforded... 

Although the 3 - and 5 -polyphosphate derivatives mentioned above exhibit exquisite inhibitory potency these compounds are not cell permeable. To take advantage ofthepotency of such derivatives for studies with intact cells and tissues, there are two possibilities. One is chemically to protect the phosphate groups from exonucleotidases that also allows the compound to transit the membrane intact. The other is to provide a precursor molecule that is cell permeable and is then metabolized into an inhibitor by intracellular enzymes. The general term for such a compound is prodrug nucleotide precursors are also referred to as pronucleotides. Families of protected monophosphate derivatives were synthesized, based on (3-L- and 3-D-2, 5 -dd-3 -AMP, 3-L-2, 3 -dd-5 -AMP, and the acyclic 9-substituted adenines, PMEA and PMPA. Protective substituents were (i) -( -pivaloyl-2-thioethyl) ... 

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