Phosphorylation of Per-6-O-[(tert-butyl)dimethylsilyl]-β-cyclodextrin with Tetraethylphosphorodiamidochloridite

Abstract

Phosphorylation of b-cyclodextrin with protected primary hydroxy groups with tetraethylphosphorodiamidochloridite, contrary to phosphorylation with hexaethylphosphorous triamide, proceeds irregularly and leads to compounds with mixed functions, whose ratio depends on reaction conditions. We previously showed that per-6-O-[(tert-butyl)dimethylsilyl]-b-cyclodextrin (I), a representative of b-cyclodextrins with substituted primary hydroxy groups, when treated with hexaethylphosphorous triamide (II), undergoes facile and effective interglucoside 2,3`-cyclophosphorylation to form derivatives with a rigid carcass and a large chiral bowl-shaped cavity [1,2]. Phosphocapping of derivative I with phosphorous diamides proceeded analogously [3], and the reaction conditions were usual for phosphorylation of hydroxy groups with phosphorous amides (C 6 H 6 , 80390oC, 10 h). Reaction progress was controlled by 31 P NMR spectroscopy, and the resulting data gave evidence to show that the fourteen secondary hydroxy groups of derivative I are phosphorylated regularly rather than chaotically: 2-OH groups, as much more active, are phosphorylated first, and interglucoside 2,3`-cyclophosphorylation of 3-OH groups completes at the second stage of the process. It is important to note that good results were achieved only with mild phosphorylating agents, such as phosphorous tri-and diamides. With phosphorus dichlorides as 2,3-cyclophosphorylating agents, a complex mixture of products formed, which was unexpected, because usually, under conditions optimal for each phosphorylation process [P(III)-amide or P(III)-acid chloride], similar results were obtained.In view of the aforesaid, we turned to phosphorylation of silyl derivative I with tetraethylphosphorodiamidochloridite (III). Planning this experiment we born in mind that phosphorylating agent III has two different phosphorylating functions: acid chloride and less active amide. Phosphorylation was carried out in benzene, and triethylamine taken in 10% excess acted as reaction initiator and HCl acceptor. Reaction progress was followed by 31 P NMR spectroscopy.At the first stage of our work we studied the reaction of silyl derivative I with 7 mol (x = 7) of acid chloride III at 20oC. After 5 h, acid chloride III proved to be consumed completely. Therewith, together with the expected acyclic phosphorodiamidite fragments (d P 1353138 ppm) (l = 3.5), 2,3`-cyclic fragments formed (d P 148 ppm) (n = 3.5) IV. 1It is important to note that the cyclophosphite fragments in compound IV were formed under mild conditions without heating. After treatment with sulfur the corresponding thionophosphate fragments of product V, that give characteristic signals near 79 and 87 ppm with equal integral intensities, were detected in the reaction mixture. Product V was isolated by crystallization. Note also that certain secondary hydroxy groups remained unchanged.The same reaction at an elevated temperature (60oC) is complete within 3.5 h. Under these conditions, the content of cyclic fragments increases (n = 5) ...

Specific Features of Phosphorylation of Per-6-O-(tert-butyl)(dimethyl)silyl-β-cyclodextrin with Tetraethylphosphorodiamidous Chloride

“…The relative content of phosphocyclic fragments increased with an increase in temperature from 0 to 40oC, as it was also observed previously [5]. However, the product formed at 80oC contained (after the addition of sulfur) only 2,3`-and 2,3-cyclophosphoramidothioate fragments and no phosphorodiamidothioate groups.…”

“…Phosphorylation primarily proceeds at the hydroxy groups in positions 2 as the most active [4], and this is followed by 2,3`-cyclophosphorylation. At the same time, the phosphorylation of cyclodextrin derivative I with tetraethylphosphorodiamidous chloride II containing two phosphorylating functions of different activity, performed in benzene in the presence of triethylamine, proceeds irregularly, yielding compounds containing diamidophosphite and 2,3`-amidocyclophosphite functions [5].Considering the importance of these compounds for the development of supramolecular chemistry of b-cyclodextrins, we examined the effect of other factors on the pathway of this reaction and on the composition of the reaction products. We have preliminarily studied the phosophorylation of b-cyclodextrin derivative I with the above-mentioned acid chloride II in pyridine, which was used as a solvent and as an acceptor of the released hydrogen chloride.…”

“…Phosphorylation primarily proceeds at the hydroxy groups in positions 2 as the most active [4], and this is followed by 2,3`-cyclophosphorylation. At the same time, the phosphorylation of cyclodextrin derivative I with tetraethylphosphorodiamidous chloride II containing two phosphorylating functions of different activity, performed in benzene in the presence of triethylamine, proceeds irregularly, yielding compounds containing diamidophosphite and 2,3`-amidocyclophosphite functions [5].…”

Phosphorylation of Per-6-O-(tert-butyl)(dimethyl)silyl-β-cyclodextrin with Diethyl phosphorochloridite

“…More complex pattern was observed in phosphorylation of I with tetraethylphosphorochloridous diamide. In this case, the phosphorylation proceeds irregularly and yields compounds with mixed cyclic and acyclic functions in the ratio depending on the reaction conditions [2,3]. Formation of 2,3`-cyclophosphorylated fragments, in particular, by ÄÄÄÄÄÄÄÄÄÄÄÄ intramolecular dephosphorylation [2], was observed.…”