Beyond Classical Reactivity Patterns: Shifting from 1,4- to 1,6-Additions in Regio- and Enantioselective Organocatalyzed Vinylogous Reactions of Olefinic Lactones with Enals and 2,4-Dienals

Organocatalysis
is shown to expand the classical reactivity pattern
for conjugate addition reactions. It is demonstrated that the site
selectivity can be extended from 1,4- to 1,6-additions for the enantioselective
vinylogous additions of methyl-substituted vinylogous lactones to
enals and 2,4-dienals. This novel reactivity is demonstrated for methyl-substituted
olefinic azlactones and butyrolactones. Their synthetic potential
is first highlighted by the development of the organocatalytic regioselective
vinylogous 1,4-addition to enals which proceeds with a very high level
of double-bond geometry control and excellent enantioselectivity.
The concept is developed further for the unprecedented intermolecular
enantioselective organocatalyzed vinylogous 1,6-addition to linear
2,4-dienals, by which the site selectivity of the process is extended
from the β-position to the remote δ-position of the 2,4-dienal.
The organocatalyst controls the newly generated stereocenter six bonds
away from the stereocenter of the catalyst with a high level of enantiocontrol,
and the products are obtained with full control of double-bonds configuration.
The scope of these new reaction concepts is demonstrated for a series
of aliphatic and aryl-substituted enals and 2,4-dienals undergoing
enantioselective vinylogous reactions with methyl-substituted olefinic
azlactones and butyrolactones. Furthermore, mechanistic considerations
are presented which can account for the change from 1,4- to 1,6-selectivity.
Finally, a number of different transformations of the optically active
1,4- and 1,6-addition products are demonstrated.