Synthesis
of Filibuvir. Part II. Second-Generation Synthesis of a 6,6-Disubstituted
2H‑Pyranone via Dieckmann Cyclization of a
β‑Acetoxy Ester

Peng, Zhihui; Ragan, John A.; Colon-Cruz, Roberto; Conway, Brian G.; Cordi, Eric M.; Leeman, Kyle; Letendre, Leo J.; Ping, Li-Jen; Sieser, Janice
E.; Singer, Robert A.; Sluggett, Gregory W.; Strohmeyer, Holly; Vanderplas, Brian C.; Blunt, Jon; Mawby, Nicola; Meldrum, Kevin; Taylor, Stuart

doi:10.1021/op400236r.s001

op400236r_si_001.pdf (325.54 kB)

Synthesis of Filibuvir. Part II. Second-Generation Synthesis of a 6,6-Disubstituted 2H‑Pyranone via Dieckmann Cyclization of a β‑Acetoxy Ester

journal contribution

posted on 2014-01-17, 00:00 authored by Zhihui Peng, John A. Ragan, Roberto Colon-Cruz, Brian G. Conway, Eric M. Cordi, Kyle Leeman, Leo J. Letendre, Li-Jen Ping, Janice E. Sieser, Robert A. Singer, Gregory W. Sluggett, Holly Strohmeyer, Brian C. Vanderplas, Jon Blunt, Nicola Mawby, Kevin Meldrum, Stuart Taylor

This paper describes an improved sequence for the conversion of an oxazolidinone (3) to a β-keto lactone (5). The primary drivers behind this change were the modest and variable yields observed in the intramolecular cyclization to generate the β-keto lactone. Changing the cyclization substrate from oxazolidinone to alkyl ester offered a significantly improved cyclization, as well as improvements in the alkyne hydrogenation. Selection of the optimal substrates for methanolysis and intermediate salt formation are also described.