α- and β‑Functionalized Ketones from 1,3-Dienes and Aldehydes: Control of Regio- and Enantioselectivity in Hydroacylation of 1,3-Dienes

Ketones are among the most widely used intermediates in organic synthesis, and their synthesis from inexpensive feedstocks could be quite impactful. Regio- and enantio­selective hydro­acylation reactions of dienes provide facile entry into useful ketone-bearing chiral motifs with an additional latent functionality (alkene) suitable for further elaboration. Three classes of dienes, 2- or 4-monosubstituted and 2,4-disubstituted 1,3-dienes, undergo cobalt­(I)-catalyzed regio- and enantio­selective hydro­acylation, giving products with high enantio­meric ratios (er). These reactions are highly dependent on the ligands, and we have identified the most useful ligands and reaction conditions for each class of dienes. 2-Substituted and 2,4-disubstituted dienes predominantly undergo 1,2-addition, whereas 4-substituted terminal dienes give highly enantio­selective 4,1- or 4,3-hydro­acylation depending on the aldehyde, aliphatic aldehydes giving 4,1-addition and aromatic aldehydes giving 4,3-addition. Included among the substrates are feedstock dienes, isoprene (US$1.4/kg) and myrcene (US$129/kg), and several common aldehydes. We propose an oxidative dimerization mechanism that involves a Co­(I)/Co­(III) redox cycle that appears to be initiated by a cationic Co­(I) intermediate. Studies of reactions using isolated neutral and cationic Co­(I) complexes confirm the critical role of the cationic intermediates in these reactions. Enantio­selective 1,2-hydro­acylation of 2-trimethyl­siloxy-1,3-diene reveals a hitherto undisclosed route to chiral siloxy-protected aldols. Finally, facile syntheses of the anti-inflammatory drug (S)-Flobufen (2 steps, 92% yield, >99:1 er) and the food additive (S)-Dihydro­tagetone (1 step, 83% yield; 96:4 er) from isoprene illustrate the power of this method for the preparation of commercially relevant compounds.