|Peng et al. OPRD|
We also observed a source-dependence for the LHMDS, similar to that observed with the oxazolidinone substrate. (CJ's note: the authors had an oxazolidinone in place of the ethyl ester in structure 23 in a previous route.) With LHMDS prepared from n-BuLi and HN(TMS)2 the yield was consistently 88−90%. However, in the case of one supplier using a lithium metal process (Li metal, 2-methyl-1,3-butadiene, HN(TMS)2), a consistently lower yield of 81% was observed.
Similar observations with LDA prepared from n-BuLi vs Li metal/styrene have also been reported. In the course of investigating the cause of this variation, we identified two additional suppliers who used the lithium metal process, but with those sources the higher yield was consistently obtained (88−90%). We also found that if the “low olefin content” grade of LHMDS was used from the initial supplier, the yield improved to 85−87%.
We studied several potential culprits, including the presence of residual 2-methyl-2-butene and small quantities of other metal contaminants (e.g., sodium amide bases, LiCl, and Li-alkoxides), but none of these accounted for the observed discrepancy. In all cases where the yield decreased, an increased level of elimination impurities was observed (i.e., the total mass balance was consistent). While these results continue to intrigue us, our successful identification of at least three viable commercial suppliers (Optima, BASF, and Chemetall “Low Olefin Content” LHMDS) for the reagent and the relatively modest yield variations have attenuated our concern with this unexplained LHMDS source variation.Below, the proposed elimination pathways and accompanying text that were in the oxazolidinone route (which was covered in the first paper in the series):
|Singer et al. OPRD|
The two elimination pathways are shown in Scheme 6. The first involves elimination of acetic acid from the cyclization substrate 24, to form a mixture of acrylamides 28. An E1CB mechanism via the lithium enolate is shown, but this could also proceed through an E2 elimination in the presence of a weaker base such as the lithiated oxazolidinone generated during the cyclization. The second pathway is a ring-opening elimination of the β-keto lactone product to generate a β-keto acid, which undergoes decarboxylation to generate a mixture of enone isomers 29. The top elimination pathway predominates in “normal addition” mode, i.e. addition of LHMDS to the substrate. We estimate the pKa values of the relevant protons at ∼25 for C3′ and ∼23 for C2. The use of a strong, hindered base such as LHMDS and the low reaction temperature (−20 °C) favor kinetic deprotonation at the more sterically accessible position (C3′). Nonetheless, direct enolization at C2 remains a possibility, and intramolecular proton transfer from the desired C3′ enolate to C2 is also feasible.I don't have any good answers for their questions either. Why would the method of preparation of LiHMDS matter? What is in there that is promoting elimination? Why is potassium and lithium tert-butoxide much worse? Readers, any ideas?
1. (a) Singer, R.A.; Ragan, J.A.; Bowles, P.; Chisowa, E.; Conway, B.G.; Cordi, E.M.; Leeman, K.R.; Letendre, L.J.; Sieser, J.E.; Sluggett, G.W.; Stanchina, C.L.; Strohmeyer, H.; Blunt, J.; Taylor, S.; Byrne, C.; Lynch, D.; Mullane, S.; O’Sullivan, M.M.; Whelan, M. "Synthesis of Filibuvir. Part I. Diastereoselective Preparation of a β‑Hydroxy Alkynyl Oxazolidinone and Conversion to a 6,6-Disubstituted 2H‑Pyranone." Org. Process Res. Dev. ASAP dx.doi.org/10.1021/op4002356 (b) Peng, Z.; Ragan, J.A.; Colon-Cruz, R.; Conway, B.G.; Cordi, E.M.; Leeman, K.; Letendre, L.J.; Ping, L.-J.; Sieser, J.E.; Singer, R.A.; Sluggett, G.W.; Strohmeyer, H.; Vanderplas, B.C.; Blunt, J.; Mawby, N.; Meldrum, K.; Taylor, S. "Synthesis of Filibuvir. Part II. Second-Generation Synthesis of a 6,6-Disubstituted 2H‑Pyranone via Dieckmann Cyclization of a β‑Acetoxy Ester." Org. Process Res. Dev. ASAP dx.doi.org/10.1021/op400236r (c) Ide, N.D.; Ragan, J.A.; Bellavance, G.; Brenek, S.J.; Cordi, E.M.; Jensen, G.O.; Jones, K.N.; LaFrance, D.; Leeman, K.R.; Letendre, L.K.; Place, D.; Stanchina, C.L.; Sluggett, G.W.; Strohmeyer, H.; Blunt, J.; Meldrum, K.; Taylor, S.; Byrne, C.; Lynch, D.; Mullane, S.; O’Sullivan, M.M.; Whelan, M. "Synthesis of Filibuvir. Part III. Development of a Process for the Reductive Coupling of an Aldehyde and a β‑Keto-lactone" Org. Process Res. Dev. ASAP dx.doi.org/10.1021/op400237j