Rigid P-Chiral Phosphorus Ligands for Highly Selective Palladium-Catalyzed (4+2) and (4+4) Annulations

Abstract

We developed novel shackled P-chiral ligands based on 1-phosphanorbornenes and oxazolines. They were subsequently evaluated in palladium-catalyzed (4+2) annulations, producing enantioenriched tetrahydropyran scaffolds in good yields with high site selectivity and enantioselectivity. Moreover, chemoselective (4+4) products were also achieved by using acyclic imines. In addition, density functional theory calculations were performed to afford the energy profile of the Michael addition step and ring formation step. This demonstrated that the enantioselective (4+2) annulations and the chemoselective reaction between (4+2) and (4+4) products were mostly under thermodynamic control.

Recent advances in [4 + 4] annulation of conjugated heterodienes with 1,4-dipolar species for the synthesis of eight-membered heterocycles

“…In 2022, the Liu, Li and Duan group applied the selective palladium-catalyzed [4 + 2] and [4 + 4] annulations in the assembly of tetrahydropyran and oxazocine derivatives, respectively. 59 Catalyzed by Pd 2 (dba) 3 ·CHCl 3 /shackled P-chiral ligand ( L10 ), numerous enantioenriched tetrahydropyran derivatives were produced in high yields with moderate to excellent enantioselectivities from the [4 + 2] annulation reactions between benzo[ e ]oxathiazine-2,2-dioxide-fused azadienes and t -butyl (2-(hydroxymethyl)allyl)carbonate 124 ; however, when the diene substrates were switched to sulfamate-derived acyclic unsaturated imines 123 , the reactions effectively afforded the multi-substituted oxazocine derivatives 125 through [4 + 4] annulation (Scheme 19). A diazocine-type compound was also synthesized by using this method through the reaction with t -butyl (2-((4-methylphenylsulfonamido)methyl)allyl)carbonate.…”

“…56 In recent years, several series of oxazocine derivatives have been assembled from cascade reactions through [4 + 4] annulation. 57–60…”

Pd-catalyzed oxa-[4 + n] dipolar cycloaddition using 1,4-O/C dipole synthons for the synthesis of O-heterocycles

“…The construction of enantiomerically enriched tetrahydropyran scaffolds via Pd-catalyzed asymmetric oxa-[4 + 2] cycloadditions of oxa-1,4-dipoles with sulfamate-derived cyclic imines 44 was enabled using the newly designed rigid chiral P,N-ligand L17 (Scheme 13). 25 L17 was synthesized by introducing a flexible chiral oxazole motif into 1-phosphanorbonene containing a shackled P atom. This P atom can easily become a chiral center while preventing chiral resolution during the synthetic step.…”

Palladium-catalyzed asymmetric [4 + 3] cycloaddition of acyclic α,β-unsaturated imines with trimethylenemethane donors: access to chiral non-fused azepines

“…16 Over the past decade, the asymmetric [4 + 1] and [4 + 2] cycloaddition reactions involving acyclic α,β-unsaturated imines have been extensively studied to access structurally diverse five- and six-membered nitrogen-containing heterocycles. 17,18 Recently, these imines have also been utilized in the catalytic [4 + 4] 19 and [4 + 5] 20 cycloaddition reactions. Inspired by these elegant works, we envisaged that the highly reactive Pd-TMM species could be trapped by acyclic α,β-unsaturated imines as four-atom synthons in the absence of aromatization force and the ring structure to constrain the conformation.…”