Enantioselective Synthesis of Chromanones via a Tryptophan‐ Derived Bifunctional Thiourea‐Catalyzed Oxa‐Michael–Michael Cascade Reaction

Abstract

Tryptophan-derived tertiary amine-thiourea catalysts were shown to promote a cascade oxaMichael-Michael reaction between ethylene b-keto esters and nitroolefins, resulting in the formation of 3,3-disubstituted 4-chromanones bearing a quaternary center in high diastereoselectivity and enantioselectivity. The chromanone products can be readily converted to biologically important fused and spiro tricyclic chromans.Keywords: bifunctional catalysts; cascade reactions; chromanones; chromans; tryptophan Chiral chromans and chromanones are important structural motifs that are abundant in natural products and a wide range of biologically significant molecules.[1] Due to their favorable biological activities, various catalytic synthetic strategies have been devised for their efficient asymmetric synthesis. Hoveyda and co-workers described an enantioselective synthesis of chromanones via a Cu-catalyzed addition of dialkylzinc to enones.[2] In their recent study, Scheidt et al. utilized an intramolecular conjugate addition strategy for the enantioselective synthesis of flavanones and chromanones.[3] Subsequently, Feng and coworkers reported an enantioselective synthetic strategy, based on chiral N,N'-dioxide Ni(II)-catalyzed intramolecular oxa-Michael addition to a,b-unsaturated ketones.[4] Organocatalytic cascade reactions [5] have also been employed for the construction of chromans and chromanones. Wang and co-workers developed a cascade oxa-Michael-Michael for the facile construction of chiral chromans via an aminal intermeidate. [6] A cascade Michael-aldol sequence has been employed by Hong and Córdova for the asymmetric construction of chromans and chromenes, respectively. [7] Despite the aforementioned elegant synthetic strategies, to the best of our knowledge, an organocatalytic cascade reaction leading to chiral chromanones bearing a quaternary stereogenic center has yet to be reported. [8] It is thus desirable to devise an efficient synthetic strategy to access this type of novel structural motifs.The creation of quaternary stereogenic centers is a challenging task in organic synthesis.[9] As part of our continuing efforts towards the enantioselective generation of quaternary stereocenters, [10] we became interested in the synthesis of chiral chromanones containing an all-carbon quaternary center. We envisioned that an intramolecular oxa-Michael addition of phenol to an activated alkene, followed by a subsequent intermolecular Michael addition to an nitroolefin might provide a facile one-pot synthesis of highly functionalized 3,3-disubstituted 4-chromanones bearing a quaternary stereogenic center (Scheme 1). A bifunctional tertiary amine-thiourea catalyst [11] appears Scheme 1. Synthesis of chromanones and tricyclic chromans via an oxa-Michael-Michael cascade reaction.

Racemic hemiacetals as oxygen-centered pronucleophiles triggering cascade 1,4-addition/Michael reaction through dynamic kinetic resolution under iminium catalysis. Development and mechanistic insights

“…However, with respect to 1,4-addition/Michael cascade processes, all cases reported are strictly limited to the use of aliphatic alcohols or phenols as oxygen-centered pronucleophiles (Scheme 1). 20 …”

Squaramide‐Linked Chloramphenicol Base Hybrid Catalysts for the Asymmetric Michael Addition of 2,3‐Dihydrobenzofuran‐2‐carboxylates to Nitroolefins

“…Using this scaffold to synthesize the spiro‐tricyclic dihydrobenzofuran moiety was thus performed to illustrate the synthetic utility of this method. As shown in Scheme , a single isomer of adduct 8k could be readily converted into spiro‐tricyclic dihydrobenzofuran 9 by two simple procedures, including reduction of the keto group with sodium borohydride to the corresponding alcohol and reduction of the nitro group to an amine group and sequential intramolecular amidation . Spiro‐tricyclic dihydrobenzofuran 9 was obtained as the major diastereoisomer in 72 % yield with 96 % ee over two steps.…”

Recent advances in organocatalytic asymmetric oxa-Michael addition triggered cascade reactions

“…2.3.1 Oxa-Michael/Michael cascade reaction of ethylene β-keto esters with nitroolefins. A novel and efficient strategy for the construction of highly functionalized chiral chromanones via an oxa-Michael/Michael cascade reaction was reported by Lu's group 38 in 2011. Ethylene β-keto esters 81, as starting materials would first be employed in a cascade reaction; then reaction with nitroolefins 15 in dichloromethane could smoothly generate the desired adducts 83 in good yields (up to 83%) with excellent stereoselectivities (up to >20 : 1 dr and 99% ee) under the catalysis of a tryptophan-derived tertiary amine-thiourea catalyst 82 (Scheme 28a).…”