Enantioselective Organocatalyzed Formal [4+2] Cycloaddition of Ketimines with Allenoates: Easy Access to a Tetrahydropyridine Framework with a Chiral Tetrasubstituted Stereogenic Carbon Center

Abstract

Enantioselective organocatalytic synthesis of tetrahydropyridines bearing a chiral tetrasubstituted carbon stereogenic center has been achieved. The spiro-type monoaryl phosphine catalyst, (R)-SITCP, was found to promote the formal [4 + 2] cycloaddition of saccharin-derived ketimines and a-methyl allenoate to afford the corresponding six-membered N-heterocycles in high yields and excellent regioselectivities with up to 93% ee.[a] Dr. Scheme 1. Formal [4+2] cycloaddition of cyclic ketimine 1 with a-methyl allenoate 2.

Applications of Chiral Phosphine‐Based Organocatalysts in Catalytic Asymmetric Reactions

“…Sasai and co‐workers reported a highly enantioselective formal [4+2] cycloaddition reaction of ketimines with allenoates catalyzed by a chiral phosphine 39. A spiro‐type monoaryl phosphine catalyst, ( R )‐SITCP ( 57 ), was identified as an efficient catalyst for promoting the formal [4+2] cycloaddition reaction of saccharin‐derived ketimines 58 with α‐methyl allenoate 59 to afford the corresponding six‐membered N‐heterocycles ( 60 ) in high yields with excellent regioselectivities and up to 93 % ee .…”

“… Enantioselective formal [4+2] cycloaddition reaction of ketimines with allenoates and a proposed mechanism 39…”

Phosphine‐mediated Highly Enantioselective Spirocyclization with Ketimines as Substrates

“…There are only two reports to date in which ketimines are employed for phosphine catalysis in anon-stereoselective manner, [4] and only one enantioselective example by Sasai and co-workers,which describes the use of cyclic ketimines in [4+ +2] annulation with allenoates. [5] Notably,t he cyclic ketimines utilized by Sasai et al were rather special and the reaction suffered from arelatively narrow substrate scope.As part of our continued interests in phosphine catalysis, [6] we became interested in developing an efficient strategy for the use of ketimine substrates in common phosphine-mediated annulation reactions for the construction of molecular structures of biological significance (Scheme 1).…”

Phosphine‐mediated Highly Enantioselective Spirocyclization with Ketimines as Substrates

“…There are only two reports to date in which ketimines are employed for phosphine catalysis in anon-stereoselective manner, [4] and only one enantioselective example by Sasai and co-workers,which describes the use of cyclic ketimines in [4+ +2] annulation with allenoates. [5] Notably,t he cyclic keti-mines utilized by Sasai et al were rather special and the reaction suffered from arelatively narrow substrate scope.As part of our continued interests in phosphine catalysis, [6] we became interested in developing an efficient strategy for the use of ketimine substrates in common phosphine-mediated annulation reactions for the construction of molecular structures of biological significance (Scheme 1).…”

“…l-Threonine-derived phosphine amide catalysts (4a-4d)d isplayed remarkable catalytic activity, affording the desired spirocyclic3 -oxindolo-pyrrolines in good yields and with excellent ee values,and O-TBS-derived 4a was found to be the best catalyst (Table 1, entries 1-4). All the other amino acid based phosphines were less effective ( Table 1, entries [5][6][7][8][9]. We further tested various Nsubstituents on the ketimine scaffords and found that the N-Boc substrate 1a was the most suitable (Table 1, entries [10][11][12][13].…”