Dioxane monoesters

The possible mechanisms for solvolysis of phosphoric monoesters show that the pathway followed depends upon a variety of factors, such as substituents, solvent, pH value, presence of nucleophiles, etc. The possible occurrence of monomeric metaphosphate ion cannot therefore be generalized and frequently cannot be predicted. It must be established in each individual case by a sum of kinetic and thermodynamic arguments since the product pattern frequently fails to provide unequivocal evidence for its intermediacy. The question of how free the PO ion actually exists in solution generally remains unanswered. There are no hard boundaries between solvation by solvent, complex formation with very weak nucleophiles such as dioxane or possibly acetonitrile, existence in a transition state of a reaction, such as in 129, or SN2(P) or oxyphosphorane mechanisms with suitable nucleophiles. 

The study of the monoanions of a third class of phosphorus-containing monoesters, the phosphoramidates, has been restricted for the present to p- and o-substituted aryl phosphoramidates, and phosphoramidate and its O-methyl derivatives13-16. Two striking differences from the behavior of O- and S-phos-phate monoester monoanions are noted in the experimental criteria compiled in order to postulate mechanism (a) solvolysis in mixed organic solvents, particularly 50% v/v dioxan-water, results in a 50% decrease in the rate of hydrolysis of o- and p-substituted aryl phosphoramidate monoanions and all ionic forms of phosphoramidate and its O-methyl derivatives excepting the parent monoanion, and (b) partitioning of the aryl phosphoramidates and phos-... 

An obvious difficulty arises with this rather elaborate rationale when phosphoramidate and aryl phosphoramidate monoanions are compared for example, the dissimilarity of the dioxan effect yet the identity of product distribution observed in methanol-water competition experiments. Preliminary studies in the author s laboratory have revealed striking differences in the hydrolytic behavior between a series of phosphoramidafes derived from primary aliphatic amines and the above aryl systems. No linear structure-reactivity relationship between the logarithmic rate of hydrolysis of the monoanion species and the pKa of the amine is observed19. Moreover, the rate of hydrolysis of phosphoramidate monoanions derived from aliphatic amines is at least 104 times slower than those formed from aryl amines. In contrast, only a thirtyfold decrease in rate is observed for the corresponding ApKa in the O-phos-phate monoester series. The suspicion that mechanism (1), even with the above proposed modification, is not an accurate description of phosphoramidate monoanion hydrolysis derives some further support from the observation that the monoanion is subject to nucleophilic attack by substituted pyridines al-... 

Scheme I. Synthesis of[(S)-,60, 17O, lsO phosphate monoesters Reagents i, PhU ii, HOCH2CH2OH, p-MeC6H4S03H Hi, H2laO, dioxan, p-MeC6H4S03H iv, LiAlH4 v, P 7OCI3, CSHSN ROH. CdUN vi, H2, Pd/C.

The 2-substituted malonic acid monoester 13 required for the synthesis of PMRI peptides can be prepared by alkylation of malonate diesters 9 with alkyl halides and subsequent hemisaponification. Alternatively, reductive alkylation of Meldrum s acid (2,2-dimethyl-l,3-dioxane-4,6-dione) 11 with the... 

In order to mimic the C-terminal end of the parent peptide (37), we introduced a 2-isobutyl malonyl derivative in place of the original C-terminal leucine residue. The malonyl residue was incorporated in the peptide chain as a tert-hutyl monoester (40) obtained by alcoholysis of the 2,2-dimethyl-5-isobutyl-l,3-dioxane-4,6-dione (39) (Fig. 5). 

A spectroscopic study (i.r. and n.m.r.) of the monoesters of trifluoroacetic acid with the diols HO-CHa-CHa-OH, HO CHaCMea-OH, and HO CMea CMea OH has shown that with the pinacol ester (27), significant amounts of the cyclic tautomer (28) are present at equilibrium in various solvents (CCI4, 60% CsHe, 72% MeCN, 95% 1,4-dioxan, 95%) considerably smaller amounts of the corresponding trichloroacetate cyclic tautomer are present at equilibrium (CCU, 7% MeCN, 13%). ... 

Phosphorous acid diesters. Di- -butyl phosphorochloridate added in small portions to a highly dispersed, stirred suspension of NaBH4 in dioxane, refluxed for 5 h, cooled, water added cautiously, and acidified to pH < 2 with 6 M HCl - dibutyl phosphite. Y 85.4%. F.e., incl. phosphonous acid monoesters, s. R. Engel, S. Chakraborty, Synth. Commun. 18, 665-70 (1988). 

Malonic acid monoesters from l,3-dioxane-4,6-diones Asym. alcoholysis... 

Malonic acid monoesters from 4,6-dioxo-m-dioxanes C... 

Uridylic acid dissolved in dry dioxane by addition of tri-n-butylamine, then l-fluoro-2,4-dinitrobenzene added, and kept 72 hrs. at 37° 2, 3 -cyclouridylic acid. Y 92-95%. J. Stockx and M. Van Montagu, Bl. Soc. chim. Belg. 71, 634 (1962) fluorophosphoric acid monoesters cf. Synth. Meth. 17, 584. 

---