Intramolecular hetero-Michael addition of beta-hydroxyenones for the preparation of highly substituted tetrahydropyranones.
Structurally diverse beta-hydroxyenones are shown to undergo nonoxidative 6-endo-trig ring closure to form highly substituted tetrahydropyranones. Amberlyst-15, Al(ClO(4))(3) x 9 H(2)O and [Pd(MeCN)(4)](BF(4))(2) were found to be suitable catalysts for these intramolecular conjugate additions, preventing side reactions, such as dehydration or retroaldolisation. The use of [Pd(MeCN)(4)](BF(4))(2) is particularly effective, as this palladium-mediated reaction is under kinetic control and generates tri- and tetrasubstituted tetrahydropyranones with high levels of diastereocontrol. In the presence of the Lewis acid Al(ClO(4))(3) x 9 H(2)O, the reaction proceeded with a similar level of diastereocontrol; however, in contrast to [Pd(MeCN)(4)](BF(4))(2), this catalyst can promote enolisation. The palladium-mediated reaction was also found to be compatible with an enantioenriched beta-hydroxyenone substrate, giving no loss of enantiopurity upon ring closure. The most distinctive synthetic development to emerge from this new chemistry is the possibility to access tri- and tetrasubstituted 2,6-anti-tetrahydropyranones from anti-aldol precursors. These compounds are particularly difficult to access by using alternative methodologies. Two modes of activation were envisaged for the ring closure, involving metal coordination to either the C=C or C=O functional groups. Experimental results suggest that C=O coordination was the preferred mode of activation for reactions performed in the presence of Al(ClO(4))(3) x 9 H(2)O or [Pd(MeCN)(4)](BF(4))(2).
Reiter
Maud
M
University of Oxford, Chemistry Research Laboratory 12, Mansfield Road, Oxford OX1 3TA, UK.
Turner
Hazel
H
Gouverneur
Véronique
V
D000475:Alkenes / Q000737:chemistry*; D003500:Cyclization; D007659:Ketones / Q000737:chemistry*; D010084:Oxidation-Reduction; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry
D000475:Alkenes; D007659:Ketones; D011714:Pyrans