Protecting groups 2-cyanoethyl group

DBU, CH3CN, 140 s. The 2-(4-nitrophenyl)ethyl (Npe) phosphate protective group and the 2-(4-nitrophenyl)ethoxycarbonyl (Npeoc) group are stable to these conditions, but the cyanoethyl group is not. 

Na, ammonia. These conditions also remove cyanoethyl- and benzyl-protective groups. Phosphorothioates are similarly deprotected. 

Propose a mechanism to account for cleavage of the /3-cyanoethyl protecting group from the phosphate groups on treatment with aqueous ammonia. (Acrylonitrile, H2C=CHCN, is a by-product.) What kind of reaction is occurring ... 

The 5 -dimethoxytrityl or /5-cyanoethyl group of the fully protected mononucleotide could then be selectively cleaved. 

Example 19 Crich and Dudkin have used phosphoroamidite containing two different protecting groups 0-benzyl-0-2-cyanoethyl-iV,Ar-diisopropyl-phosphoroamidite [48]. This phosphitylating reagent was prepared in excellent yield from 2-cyanoethyl NyN diisopropylchlorophosphoroamidite, which was immediately used for coupling with an appropriate alcohol in the presence of tetrazole and oxidized without delay with TBHP. This kind of phosphorylation procedure was used in the synthesis of 4,8,12,16,20-pen-tamethyl-pentacosylphosphoryl / -o-mannopyranoside, an unusual / -man-nosyl phosphoisoprenoid from Mycobacterium avium. 

The phosphitylation procedure activated by tetrazole led to the phosphite structure (step a) which was effectively oxidized by TBHP to yield the corresponding phosphate (step b). Finally all 2-cyanoethyl protecting group were removed by the action of DBU in the presence of the silylating reagent bis(trimethylsilyl)acetamide BSA (step c). The latter is indispensable to secure total deprotection. 

Example 30 Bialy and Waldman in their synthesis of protein phosphates 2A inhibitor (4S, 5S, 6S, lOS, US, 12S) cytostatin have found that application of the fluorenylmethyl protecting group (Fm) allowed successful formation of the phosphate moiety [62]. Initial experiments with the methoxybenzyl group, successfully employed in the synthesis of fostriecin [63] failed. The 2-cyanoethyl protecting group was also not suitable because that one 2-cya-noethyl group could be removed without destroying the whole molecule (Examples 25 and 26). 

Of course, the product does not have a phosphate linker between the two nucleosides, and phosphorus is still in the wrong oxidation state. This is remedied by oxidation of the dinucleotide phosphite to a phos-photriester using iodine. We now have the required phosphate linker, though it is still protected with the cyanoethyl group. This is retained at this stage. 

The dimethoxytrityl ester protecting group is now removed by treatment with mild acid (CCI3CO2H), which is insufficiently reactive to hydrolyse the amide protection of bases, or the cyanoethyl protection of the phosphate. The coupling cycle can now be repeated using a phosphoramidite derivative of the next appropriate nucleoside. The sequences will be continued as necessary until the desired oligonucleotide is obtained. 

It then remains to remove protecting groups and release the product from the support. All of these tasks, except for the removal of the dimethoxytrityl group, are achieved by use of a single deprotection reagent, aqueous base (ammonia). The cyanoethyl groups are lost from the phosphates by base-catalysed elimination, and amide protection of the bases is removed by base-catalysed hydrolysis. The latter process also achieves hydrolysis of the succinate ester link to the support. 

In an analogous way, secondary amines can be protected through attachment of / -cyanoethyl or a similar function. The cyanoethyl group undergoes facile Cope elimination from initially formed A-oxide (e.g. 137, equation 91) thus giving the corresponding hydroxylamine 138 in a good yield . ... 

One astute way to obtain macrocyclic systems with TTF is the stepwise method of deprotection/alkylation of cyanoethyl-protected TTF-thiolates. With this method molecular units can be built but with the precaution of preserving one cyanoethyl group in order to be able to iteratively proceed with the oligomerization. Combining such units, larger units can be produced. An example of a TTF dendrimer containing 21 TTFs is shown in Fig. 2.15 (Christensen et al, 1998). Here only the main philosophy of the synthesis is discussed. 

Remove protecting groups from bases Remove cyanoethyl groups from phosphates Cleave chain from silica support... 

Solid-phase synthesis is usually done on a silica support with a covalently attached succinamide as shown in Eq. 5-25. The first nucleotide at the 3 end of the chain to be synthesized is attached by an ester linkage to the bound succinamide (step a, Eq. 5-25). The 5 -protecting group is removed in step b and the 5 -OH reacts with the activated phosphine of the second nucleotide (step c, Eq. 5-25). Steps b and c are then repeated as often as necessary to complete the chain. The finished polynucleotide can be removed from the solid support, the cyanoethyl groups removed... 

Tertiary amine oxides can be converted into TV-hydroxy secondary amines provided that one of the TV-substituents can be selectively eliminated. This procedure has been applied to the synthesis of secondary A-hydroxy-a-amino acids 34 from the corresponding secondary a-amino acids using the /V-cyanoethyl group for transient protection of the secondary amine (Scheme 10) J40l More recently, direct oxidation with 2,2-dimethyldioxirane of a primary amine has been described for H-L-Val-OMe (82% yield) and H-L-Phe-OMe (54% yield))13 The reaction proceeds smoothly without epimerization, but no experimental details have been reported. 

Removal of the jS-cyanoethyl protecting group occurs according to the following equation. Show a mechanism for this reaction. What is the role of the cyano group in this reaction ... 

The synthesis of this hybrid TTF-dithiolene illustrates the use of the cyanoethyl group to protect the sulfur atoms of the dithiolene (81, 136, 137). The trimethylene-capped tetrathiafulvalenetetrathiolate forms a molecular... 

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