Enantioselective Synthesis of Spiro Chroman‐Isoindolinones via Formal (4+2) Cycloaddition of In Situ‐Generated ortho‐Quinone Methides with 3‐Methylene Isoindolinones

Abstract

Using chiral phosphoric acids as organocatalysts, a formal asymmetric (4+2) cycloaddition of 3‐methylene isoindolinone and in situ‐generated ortho‐quinone methide substrates is disclosed. This reaction exhibited a broad substrate scope with various substituted cyclic enamides and ortho‐hydroxybenzyl alcohol derivatives to construct a series of spiro chroman‐isoindolinones containing spiro‐N,O‐heterocycles with 56 to 93% ee. This strategy demonstrates significant potential towards establishing a chiral spiro‐N,O‐aminal systems bearing two chiral carbon centers, including a tetrasubstituted carbon stereocenter.

Synthesis of Chiral Diarylmethylamides via Catalytic Asymmetric Aza-Michael Addition of Amides to ortho-Quinomethanes

“…ortho -Quinomethanes ( o -QMs), featuring highly electrophilic activity and strongly thermodynamic drive to undergo rearomatization, have been recognized as a kind of competent Michael acceptors for synthesizing chiral diarylmethane compounds. − Theoretically, the asymmetric addition of o -QMs with amide nucleophiles would provide direct and atom-efficient approaches to obtain chiral diarylmethylamides. However, despite thorough research and recent breakthroughs in the catalytic conversion of o -QMs, the asymmetric aza-Michael addition of o -QMs has remained to be far from well-developed, which could be demonstrated by the fact that the reaction protocol is limited to using a chiral phosphoric acid catalytic system and strongly nucleophilic nitrogenous synthons such as arenesulfonamides and BocNH 2 .…”

Access to Chiral Tetrahydroquinazolines/1,3-Benzoxazines via Iridium-Catalyzed Asymmetric [4 + 2] Cycloaddition

“…Up to now, catalytic asymmetric hetero [4 + 2] cycloaddition has been considered to be the most straightforward and effective method for the construction of chiral benzo-fused six-heterocycles (Scheme b) . However, these previous studies were mostly focused on using alkenes and enolizable carbonyl compounds as the two-atom reaction partners to form chiral hydroquinoline − ,− and chromane derivatives − ,− (Scheme b). In contrast, using imines (CN) or precursors as two-atom synthons in asymmetric [4 + 2] cycloaddition reactions for the synthesis of the enantioenriched tetrahydroquinazolines or dihydroquinazolinones remains underdeveloped (Scheme b), and no examples on the synthesis of chiral 1,3-benzoxazines have been reported.…”

Diastereodivergent Asymmetric [4 + 2] Cycloaddition of In Situ Generated ortho-Quinone Methides and Allenyl Ketones Enabled by Chiral Phosphoric Acid Catalysis

“…Despite the development of various strategies for the catalytic asymmetric synthesis of chromanes, the enantioselective inverse-electron-demand oxa-Diels–Alder reaction between ortho -quinone methides ( o -QMs), either stable or in situ-generated, and electron-rich olefins represents the most straightforward and efficient protocol . Since the first asymmetric [4 + 2] cycloadditions of β-diketones with the o -QM generated in situ from ortho -hydroxybenzyl alcohols using chiral phosphoric acid (CPA) catalysts by Schneider and co-workers, this strategy has been expanded to encompass various 2π-components, including enamides, enol precursors, vinyl sulfides, vinylindoles, vinylnaphthols, and even the unactivated alkenes (Figure , a). However, these methods typically afford enantioenriched chromanes or chromenes with tertiary stereocenters, while the access to chromanes containing polytetrasubstituted stereocenters is still elusive.…”