Methodology for the Olefination of Aldehydes and Ketones via the Meyer-Schuster Reaction

Our lab was faced with a synthetic challenge during studies towards the total synthesis of the anti-malaria drug, artemisinin. Known methods such as the Aldol condensation, the Horner-Wadsworth-Emmons and the Wittig reactions were ineffective for the olefination of hindered ketones. We were required to find an alternative approach of olefination that would not be restricted by steric constraints. In 2006, reported on a two-step strategy for the HWE-type olefination of hindered ketones: (1) addition of ethoxyacetylide, then (2) Au3+ catalyzed Meyer–Schuster rearrangement. Alkyne addition to carbonyl groups is relatively insensitive to sterics, whereas the resulting congested tertiary ethoxyalkynyl carbinols are sterically and electronically primed for rearrangement. Having identified this important two-stage synthetic application, we focused our attention on step two; the Meyer–Schuster rearrangement. The Meyer-Schuster reaction is a little-known but potentially powerful rearrangement that converts propargyl alcohols into α, β-unsaturated carbonyl compounds. In our earlier study, which featured highly reactive tertiary propargyl alcohol substrates, rearrangement occurred immediately upon addition of the gold catalyst. In 2007, we expanded our scope and reported a new reaction protocol and important observations with respect to the rearrangement of secondary alcohol substrates. We found that secondary ethoxyalkynyl carbinols could be converted into the corresponding ethyl trans-α, β-unsaturated esters with moderate to good stereocontrol using a mixed catalyst system of gold (I) chloride and silver (I) hexafluoroantimonate. Recent advances in our methodology for the olefination of aldehydes and ketones using the Meyer–Schuster reaction of ethoxyacetylenes focused on four key points: (1) seeking alternative catalysts that are more economical and widely available than gold or silver salts, (2) lowering the catalyst loadings more than our previously reported methods using gold and silver salts, (3) obtain excellent stereoselectivity in the formation of the E-alkene isomer for most disubstituted alkenes, and (4) examine new mechanistic data suggesting that the higher stereoselectivity associated with the new catalysts may stem from a subtle alteration of the reaction mechanism.