No abstract

Amines have previously been reported to catalyze the epoxidation of alkenes using Oxone (2KHSO(5)+KHSO(4)+K(2)SO(4)), and significant levels of asymmetric induction were observed. From screening a series of amines based on 2-substituted pyrrolidines, it has now been found that more consistent and reproducible results are achieved with the HCl salt of the amine compared to the amine itself. Up to 66% ee was achieved in epoxidation of 1-phenylcyclohexene. The chiral amine could be reisolated in >90% yield when reactions were conducted at -10 degrees C, indicating that the integrity of the amine was maintained during the oxidation process. At -10 degrees C, (S)-2-(diphenylmethyl)pyrrolidine 1 reacted with Oxone to give a mixture of ammonium salts containing the peroxymonosulfate salt 6b. The enantioselectivity obtained with this salt was compared to the amine.HCl salt catalyzed process and identical results were observed, indicating that the true oxidant was the peroxymonosulfate salt 6b. The relative rates of oxidation of cis- and trans-beta-methylstyrenes together with the rho value of a series of 1-arylcyclohexenes were determined. These studies indicated that the amine catalyzed process involved electrophilic oxidation. On the basis of these findings, a new mechanism is advanced in which the protonated amine not only acts as a PTC but also activates Oxone, through hydrogen bonding, toward electrophilic attack.

Phosphoric esters of secondary alcohols are ubiquitous in biological systems. However, despite the obvious interest of the corresponding difluoromethylene phosphonates as isopolar mimics, a single example of such an analogue featuring this particular substitution pattern has so far been reported in the literature, due to synthetic problems associated with their preparation. The lithium salt of diethyl difluoromethylphosphonothioate 28d provides a solution to this problem, as demonstrated by an 8-step synthesis of all five fully protected analogues of nucleoside 3'-phosphates in 9-18% overall yield, from readily available ketones. Sulfur is shown to play a crucial role in the introduction of the phosphorus-substituted difluoromethylene unit onto the furanose ring. Complete diastereoselectivity is observed in the three steps of the process requiring stereocontrol. The key conversion of the P=S bond into its oxygenated analogue is simply achieved by use of m-chloroperoxybenzoic acid. It is noteworthy that the synthesis can be carried out on large scale: a 31-g batch of compound 26b has been prepared. The deprotected nucleoside 3'-phosphate analogues can be liberated from their precursors as exemplified by the conversion of 7b, 8b, and 9b into the corresponding difluorophosphonic acids, isolated in the form of their disodium salts.