A Catalytic Asymmetric Bioorganic Route to Enantioenriched Tetrahydro- and Dihydropyranones

Abstract

A conceptually novel approach to hetero Diels-Alder adducts of carbonyl compounds is described using as the key steps an antibody-mediated kinetic resolution of hydroxyenones followed by a ring-closure process. Various beta-hydroxyenones proved to be very good substrates for antibodies 84G3- and 93F3-catalyzed retro-aldol reactions, allowing the preparation of highly enantiomerically enriched (up to 99% ee) precursors of pyranones. An attractive feature of this methodology is the possibility to convert these acyclic-enantioenriched beta-hydroxyenones into tetrahydropyranones by a conventional Michael-type addition procedure or into the corresponding dihydropyranones using an alternative palladium-catalyzed oxidative ring closure. For the palladium-mediated cyclization, a biphasic system has been implemented that allows the direct preparation of enantiopure dihydropyranones from the corresponding racemic aldol precursors using a sequential antibody-resolution/palladium-cyclization strategy, without isolation of the intermediate enantioenriched hydroxyenones. This bioorganic route is best applied to the preparation of hetero Diels-Alder adducts otherwise derived from less nucleophilic dienes and unactivated dienophiles.

Synthesis of the next-generation therapeutic antibodies that combine cell targeting and antibody-catalyzed prodrug activation

“…Interestingly, however, complete consumption of either 7 or 9-12 was not seen, even when the reaction mixture was left at 37°C for an extended period. We anticipated that the critical lysine residues in the Ab 38C2-binding sites underwent conjugate addition to methyl vinyl ketone (MVK), which was produced during the prodrug activation, thereby inhibiting the catalytic activity of the Ab (25). ʈ To test this, Ab 38C2 (1 M solution) was treated with a prodrug linker 30 (100 equivalent) that possessed the aldol-Michael motif (Eq.…”

Theoretical Study on Hetero‐Diels–Alder Reaction of Butadiene with Benzaldehyde Catalyzed by Chiral InIII Complexes

“…Therefore, In-Lm-α was selected as the conformation of the catalyst in our models. Here, two models were used in the following investigations to probe the mechanism and stereochemistry of the catalytic reaction between benzaldehyde and Danishefsky's diene catalyzed by chiral N,NЈ-dioxide/In(OTf) 3 complexes. To reduce the computational cost and obtain reliable results, in model I, Danishefsky's diene was replaced by a simple butadiene, and benzaldehyde was replaced by formaldehyde.…”

“…[3] Many chiral Lewis acids based on metal complexes, such as the complexes based on titanium, [4] boron, [5] chromium, [6] magnesium, [7] aluminum, [8] and dirhodium, [9] have been successfully designed as catalysts for this type of reaction. Very recently, indium complexes [10] as effective Lewis acid catalysts have been developed for carbon-carbon bond-forming reactions and other synthetic processes.…”

“…Very recently, indium complexes [10] as effective Lewis acid catalysts have been developed for carbon-carbon bond-forming reactions and other synthetic processes. [11] The Feng group [12] synthesized a series of novel and efficient chiral catalysts based on N,NЈ-dioxide/In-(OTf) 3 complexes and used them in asymmetric HDA reactions. Remarkable improvements were obtained with an extremely broad range of substrates, and this reaction produced highly substituted chiral pyranones in good yields with up to 99 % ee (Scheme 1).…”

“…For the sake of gaining a better understanding of this reaction and providing useful clues to the asymmetric synthesis, the present theoretical simulation on the mechanism and stereochemical nature of the catalytic enantioselective hetero-Diels-Alder reaction of benzaldehyde with Danishefsky's diene catalyzed by chiral N,NЈ-dioxide/In(OTf) 3 complexes was carried out. This work is expected to be useful for the design of new catalysts based on chiral metal-N,NЈ-dioxide ligand complexes.…”