Oxadendralenes in asymmetric organocatalysis for the construction of tetrahydroisochromenes.

Oxadendralenes are integrated in a novel manner into a one-pot cascade utilizing synergistic catalysis for the construction of valuable and complex bicyclic heterocyclic scaffolds. The construction is based on the organocatalytic activation of the oxadendralenes generating a vinylogous iminium-ion intermediate which is set-up for a 1,6-addition with an enamine formed from an aldehyde and the same organocatalyst. This reaction generates a cyclic oxadendralenic intermediate, which acts as an electron-deficient heterodiene reacting in a Lewis-acid catalyzed hetero-Diels-Alder reaction with vinyl ethers to form tetrahydroisochromenes with five continuous stereocenters in high yields, >20 : 1 dr and 99% ee. This synergistic organo- and Lewis-acid catalysed system also displays high tolerance for variation in oxadendralenes and aldehydes, which provides tetrahydroisochromenes with high diversity in the substituent pattern and the same excellent stereoselectivities. Mechanistic studies have been performed to account for the activation modes and stereochemical outcome of the reaction. The reaction concept has been extended to also include a sequential organocatalytic reaction of oxadendralenes with aldehydes, in which the enamine formed from the aldehyde and the organocatalyst act both in the first catalytic cycle forming the cyclic oxadendralenic intermediate and in a second catalytic cycle leading to tetrahydroisochromenes in good yields and excellent stereoselectivities. Mechanistic studies reveal that the stereochemistry of the organocatalyst has an influence on the diastereoselectivity of the reaction sequence. Some transformations of the tetrahydroisochromenes are also presented. The chiral tetrahydroisochromenes formed might be applied in the diversified synthesis of important drugs.

Novel organocatalytic activation of unmodified Morita-Baylis-Hillman alcohols for the synthesis of bicyclic α-alkylidene-ketones.

The organocatalytic activation of Morita-Baylis-Hillman alcohols via H-bonding-iminium-ion formation is demonstrated for the first time. This activation strategy enables the Morita-Baylis-Hillman alcohols to undergo a formal SN2' reaction. In combination with the well-established enamine reactivity, this creates a new reactivity pattern. The application of this new activation mode for the synthesis of bicyclic α-alkylidene-ketones is demonstrated. The developed reaction sequence proceeds efficiently affording nature-inspired target products with four contiguous stereogenic centers in a highly stereoselective manner.

Asymmetric organocatalytic epoxidations: reactions, scope, mechanisms, and applications.

Chiral epoxides serve as versatile building blocks in the synthesis of complex organic frameworks. The high strain imposed by the three-membered ring system makes epoxides prone to a variety of nucleophilic ring-opening reactions. Since the development of the Sharpless epoxidation, there have been many important contributions and advances in this area. With the rapid development of the field of asymmetric organocatalysis, a wide range of organocatalysts is now able to catalyze the epoxidation of broad class of unsaturated carbonyl compounds. In this Minireview, recent progress in the development of organocatalytic asymmetric epoxidation methods, the proposed mechanisms of these reactions and their applications as intermediates is reported.

Enantioselective α- and γ-alkylation of α,ß-unsaturated aldehydes using dienamine activation.

The enantioselective alkylation of α,ß-unsaturated aldehydes with stabilized carbocations as electrophiles via the activation as dienamine intermediates is described. This unique application of dienamine catalysis allows for the first enantioselective γ-alkylation of linear α,ß-unsubstituted enals.