Development of O–H insertion for the attachment of phosphonates to nucleosides; synthesis of α-carboxy phosphononucleosides

Development of rhodium catalysed O–H insertion reactions employing α-diazophosphonates with appropriately protected adenosine, uridine and thymidine derivatives is described. This synthetic methodology leads, following deprotection, to novel phosphononucleoside derivatives bearing a carboxylic acid moiety adjacent to the phosphonate. Protection strategies are critical to the success of the key O–H insertion. There are two important aspects: avoiding competing insertion pathways or catalyst poisoning, and being able to achieve deprotection without degradation of the phosphononucleosides.