Stereoselective Construction of Halogenated Quaternary Carbon Centers by Brønsted Base Catalyzed [4+2] Cycloaddition of α‐Haloaldehydes

Abstract

Asymmetric construction of halogenated quaternary carbon centers under mild reaction conditions remains challenging. Reported here is an unprecedented and highly stereoselective Brønsted base catalyzed [4+2] cycloaddition between either α-chloro- or α-bromoaldehydes and cyclic enones. The key intermediate, an α-halogenated enolate, is susceptible to dehalogenation and can be stabilized and stereochemically controlled using bifunctional tertiary amines. This method provides facile access to a collection of optically pure bicyclic dihydropyrans having three contiguous stereocenters, including a halogen-bearing quaternary carbon center. Of note, the product can be transformed in situ into densely functionalized spirocyclopropanes in a highly efficient and stereoselective manner.

Squaramide Catalyzed Asymmetric Synthesis of Five‐ and Six‐Membered Rings

“…α-halo aldehydes 104 and pyrrolidin-2,3-dione 105 containing an exocyclic aleknyl moiety at C-3 position reacted together in presence of J as catalyst directing to a facile access of dihydropyrans as a part of fused bicyclic molecular scaffold 106. [41] Tertiary amine moiety of the catalyst would form an enolate from 104 through deprotonation which acts as electron rich dienophile utilizing the enone moiety of 105 as heterodiene to accomplish the (4 + 2) annulation (Scheme 26). Zhou and co-workers reported (4 + 2) annulation between malononitrile 107 and 5-ylidenethiazol-4-ones 108 to prepare thiazole fused dihydropyran moieties 109 bearing multiple functionalities.…”

Nickel(II)‐Catalyzed Diastereo‐ and Enantioselective [3+2] Cycloaddition of α‐Ketoesters with 2‐Nitrovinylindoles and 2‐Nitrovinylpyrroles

“…It is noteworthy that installation of halogenated cyclic quaternary carbon stereocenters still remains a challenging task in organic synthesis. [9] In addition, the absolute configuration of 3s was assigned as (1S, 2R, 3S) by single crystal X-ray diffraction analysis (see SI).…”

Catalytic Strategies for the Asymmetric Construction of Cyclic Frameworks with a Halogenated Tetrasubstituted Stereocenter

“…Through this protocol, various enantioenriched fused bicyclic dihydropyrans bearing three contiguous stereocenters, including a halogen‐bearing tetrasubstituted carbon center were synthesized under mild conditions. As shown in Scheme , the corresponding 38 were delivered in excellent yields with up to greater than 99% enantiomeric excess …”