Development of a Catalytic Enantioselective Conjugate Addition of 1,3-Dicarbonyl Compounds to Nitroalkenes for the Synthesis of Endothelin-A Antagonist ABT-546. Scope, Mechanism, and Further Application to the Synthesis of the Antidepressant Rolipram

Abstract

The enantioselective synthesis of endothelin-A antagonist ABT-546 has been accomplished via the discovery and development of a highly selective catalytic asymmetric conjugate addition of ketoesters to nitroolefins. Employing just 4 mol % bis(oxazoline)-Mg(OTf)(2) complex with an amine cocatalyst, we obtained the product nitroketone with 88% selectivity at the aryl-bearing stereocenter and in good yield on scales ranging to 13 mol. The effects of ligand structure, metal salt, and solvent on the reaction are described. Particularly important to the reaction is the water content. While water is necessary during the generation of the catalyst, the water must be then removed to maximize stereoselectivity and reactivity. The reaction has been extended to other dicarbonyl substrates, and a variety of substitution patterns are tolerated on the nitroolefin partner. The reaction has also been employed in the synthesis of the antidepressant rolipram. Investigations relating to the mechanism of the reaction are also described.

Stereocontrolled Construction of Quaternary Stereocenters by Inter‐ and Intramolecular Nitro‐Michael Additions Catalyzed by Bifunctional Thioureas

“…[e] The stereochemistry of these adducts has been tentatively assigned by generalization of the stereochemical outcome of the reaction. The known nitroolefin 6 [12] was reacted with ethyl 2-methylacetoacetate in the presence of 1 (10 mol%) at À18 8C in toluene leading to 7 (89% ee) and its epimer (91% ee) in 95% yield and 80/20 dr (Scheme 3). After chromatographic purification, 7 was reduced to a mixture of epimeric alcohols 8 by reaction with sodium borohydride in methanol.…”

Flow “Fine” Synthesis: High Yielding and Selective Organic Synthesis by Flow Methods

“…Moreover, rolipram is known as a possible antidepressant and has been reported to have anti‐inflammatory, immunosuppressive, and antitumor effects 47, 48. Rolipram has also been proposed as a treatment for multiple sclerosis, and has been suggested to have antipsychotic effects 50.…”

Stereospecific approach to α,β-disubstituted nitroalkenes via coupling of α-bromonitroalkenes with boronic acids and terminal acetylenes

“…However, better diastereoselectivity (3.2:1) 40 was obtained when the addition was performed under Lewis acid catalyzed (BOX, Mg(OTf) 2 ) conditions. 41 Similarly, 1,3-dipolar cycloaddition of 12a with benzonitrile oxide, generated in situ from benzaldoxime, 42 …”