Potential Pitfalls of Using Epichlorohydrin as Starting Material for Oxazolidinone Antibacterials

Abstract

The importance of oxazolidinone functional group has been well documented in synthetic and medicinal chemistry. In the latter area, recent interests are focused on N-arylsubstituted oxazolidin-2-one structures, as exemplified by linezolid and eperezolid, which represent a new class of antibacterials with activity against drug-resistant Grampositive pathogens, including MRSA. Biologically active enantiomers of the oxazolidinone antibacterials are those with the (S)-configuration. Synthesis of the (S)-enantiomers have been achieved in enantiopure form starting from various glycidol derivatives such as (R)-glycidyl butyrate, (S)and (R)-epichlorohydrin, N-Boc-glycidylamine, and more recently, (R)-glycidyl tosylate. Other enantiopure starting materials include 3-chloro-1,2-propanediol, mannitol, protected glyceraldehyde, and aziridine-2carboxamide. Several routes employing asymmetric reactions have also been reported. Of those enantiopure starting materials, epichlorohydrin and glycidyl tosylate are particularly useful as they are doubly activated (at both C-1 and C-3) toward nucleophilic substitutions. The tandem, three-step sequence of the epoxide ring-opening, carbamate formation and oxazolidin-2one ring-closure (sometimes referred to as “1,3-cycloaddition”) represents an atom-economic key step in the synthesis of oxazolidinone antibacterials (Scheme 1). Yu et al. first employed this process with epichlorohydrin as the starting material; we then followed it up with glycidyl tosylate, and showed that this crystalline and storage-stable compound was a viable starting material for oxazolidinone antibacterials. Our work with glycidyl tosylate reminded us how the issues of regioand stereochemistry were entwined together for the doubly activated glycidol derivatives. It also prompted us to wonder how these issues had played out in Yu’s work with epichlorohydrin. As the details were not discussed in their original communication, we decided to reexamine the tandem, three-step sequence with epichlorohydrin as the starting material. The 1,3-cycloaddition reaction of (R)-epichlorohydrin and phenyl isocyanate was performed with a catalytic amount of LiBr. In the absence of detailed experimental procedure in the original work, also to make a meaningful comparison with our findings with glycidyl tosylate, we maintained the reaction conditions as close as possible to the ones employed in the glycidyl tosylate process [in THF (0.067 M) at reflux with phenyl isocyanate (3 eq) and LiBr (0.1 eq)]. Epichlorohydrin underwent the tandem, three-step sequence more slowly with LiBr than glycidyl tosylate did with LiI. The reaction took 8 h to complete (vs ~30 min for glycidyl tosylate/LiI). The desired chloro oxazolidinone product was isolated in 93% yield, seemingly validating the results in the original report. A careful examination, however, revealed the presence of a by-product, suggesting concurrent sidereaction pathway(s) and potential complications in the process. In order to gain a fuller picture of the process, we postulated possible reaction pathways for the 1,3-cycloaddition reaction of epichlorohydrin/PhNCO/LiBr and set out to assess the significance of each pathway quantitatively (Scheme 2). Model reactions revealed that the products could undergo secondary displacements, not one-way, but in both ways, hence Paths IV and V in addition to Path III. This raised an extra issue for the epichlorohydrin process. In the glycidyl tosylate process, a single reaction pathway was responsible for the formation of the desired product, whose stereochemical integrity was therefore maintained through the entire course of the reaction. In the epichlorohydrin process, on the other hand, we now needed to consider multiple pathways for the formations of the desired as well as undesired products (Paths I, IV and V for 2; Paths II and III for 3), each resulting in a distinct stereochemical outcome. Significance of these pathways may be assessed in a time study in which the enantiomeric purities as well as the chemical yields of both products would be determined at various reaction times.