‘O-phosphobiotine analogues.’ Isolation, X-ray strurcture, and reactivity of the intermediate of the addition of hindered phosphuric esters and thioesters on the carbodi-imide group. O → N phosphoryl migration versus P–O–P bond formation

Abstract

Addition reactions to carbodi-imides using oxy- and thio-phosphoric diesters crowded around phosphorus have been carried out in order to obtain a better understanding of this reaction, and to trap the intermediate, an O-phosphobiotin analogue. Oxy-compounds give a mixture of pyrophosphate and rearranged N-Phosphorylated urea or react poorly if steric hindrance at phosphorus is important. The same type of addition with thiophosphoric esters has made possible the first isolation of the intermediate of this general reaction which is relevant to pyro-phosphate and to nucleotide synthesis. This difference is rationalized in terms of the C–X–P bond lengths (X = O or S) in the intermediate, as shown by an X-ray crystallorgraphic determination of the structure of the thio-compound. With oxy-compounds, the reaction is very sensitive to steric effects, because of the short C–O–P distances involved. Formation of the intermediate is only likely if the oxyphosphorus nucleophile does not contain bulky groups, and this leads quickly to the pyrophosphate. With thio-compounds, the analogus intermediate is formed even when bulky thiophosphorus groups are present, because of the longer C–S–P distances, and is protected against intermolecular rearrangement both by the poor overlap between the nitrogen and phosphorus orbitals and by protonation if a suitable ratio of ester to dicylohexylcarbodi-imide (DCCD) is used. Moreover this intermediate is not easily attacked by the bulky (RO)₂P(S)S^– nucleophile and therefore accumulates. With a less favourable ratio of ester to DCCD, the reaction gives only the rearranged N-phosphorylated product. Crystals of the isolated intermediate are monoclinic, space group P2₁/a with four molecules in a cell of dimensions a= 15.802(3), b= 13.409(2), c= 15.050(5)Å, β= 96.82(1)°. The structure was solved by direct methods and refined by full-matrix least-squares calculations to an R value of 0.055 for 3 144 observed reflections. Several features of this molecular structure are discussed. Finally, a kinetic study of the rearrangement from C–S–P to N–P compounds shows that this reaction proceeds without the formation of any kinetically significant intermediate.