Asymmetric [4+2] Annulations of Isatins with But‐3‐yn‐2‐one

Abstract

The catalytic asymmetric [4+2] annulations of isatins with but-3-yn-2-one catalyzed by the Cinchona alkaloids-derived oragnocatalyst (DHQD) 2 PHAL have been developed in the presence of 3.0 equivalents of d-diethyl tartrate in the mixed solvent (diphenyl ether/diethyl ether = 1/1) or a slightly modified one, affording the corresponding substituted spiro[indoline-3,2'-pyran]-2,4'-A C H T U N G T R E N N U N G (3'H)-diones in good to excellent yields with high enantioselectivities under mild conditions. Keywords: asymmetric [4+2] annulations; but-3-yn-2-one; Cinchona alkaloids; isatins; spiro[indoline-3,2'-pyran]s Spirooxindoles are privileged structural motifs found in many alkaloids such as gelsemine, mitraphylline or SR 121463 and unnatural biologically active compounds.[1] Encouraged by their unique structural features and significant biological activities, various effective synthetic methods for the construction of spirooxindoles and subsequent applications in natural product synthesis have been extensively explored over the last decade.[2] Previously, we reported that the nitrogen-containing Brønsted bases-mediated [4+2] annulations of isatins with but-3-yn-2-one could proceed smoothly to give the corresponding spiro[indoline-3,2'-pyran]-2,4'A C H T U N G T R E N N U N G (3'H)-diones in good to excellent yields under mild conditions. [3] In this paper, we wish to report the asymmetric variant to afford these products in good yields and good to high ee values with the Cinchona alkaloid-derived organo-A C H T U N G T R E N N U N G catalyst hydroquindine-1,4-phthalazinediyl diether [(DHQD) 2 PHAL] in the presence of d-diethyl tartrate. [4,5] We initially utilized isatin 1a (0.1 mmol, 1.0 equiv.) and but-3-yn-2-one 2a (0.3 mmol, 3.0 equiv.) as the substrates in the presence of several Cinchona alkaloids and 1R,2R-cyclohexanediamine derived organocatalysts (20 mol%) in THF at room temperature to examine the reaction outcomes and the results are shown in Scheme SI-1 in the Supporting Information. It was found that the corresponding cyclic product 3a was obtained in 65% yield along with 25% ee using (DHQD) 2 PHAL (20 mol%) as the catalyst (Scheme 1). In order to improve the reaction outcome, we screened various proton sources (1.0 equiv.) such as 732 cation exchange resin, (R)/(S)-binol, dcamphorsulfonic acid, 2-adamantanol, and d/l-diethyl tartrate or its derivatives for this reaction and the results are summarized in Table SI-1 in the Supporting Information. As can be seen from Table SI-1, we found that 3a could be obtained in 90% yield and 68% ee using (DHQD) 2 PHAL (20 mol%) as the catalyst in the presence of 3.0 equivalents of d-diethyl tartrate. Moreover, after further screening of the emScheme 1. Screening of the catalysts for the asymmetric [4+2] annulation of isatin 1a with but-3-yn-2-one 2a.

Co-catalysis between DABCO and a Brønsted acid in the catalytic [4 + 2] annulation of isatin with but-3-yn-2-one and mechanistic investigations

“…It should be noted that the use of 4-phenylbut-3-yn-2-one in this reaction only afforded the corresponding aldol reaction product without formation of the desired annulation product. 8 While examining the effect of the proton source, another interesting finding was that we identified the formation of (E)-2-(1-benzyl-2-oxoindolin-3-ylidene)-3-oxohexanal 6a in 23% yield in the presence of acetic acid (1.0 eq.) at room temperature when hex-1-yn-3-one 2b instead of but-3-yn-2-one 2a was used as a Michael acceptor (Scheme 2), and the corresponding [4 + 2] annulation product was not observed.…”

“…In our previous work, we proposed that the formation of 3 might undergo a stepwise aldol/intramolecular oxa-Michael addition pathway. 8 In order to gain more mechanistic insights, we performed several isotopic labeling experiments by adding D 2 O (1.0 equiv.) to the reaction systems.…”

“…According to our previous work, 8 we also synthesized the possible deuterated terminal alkyne intermediate 10 in 98% yield along with 66% D content via desilylation with KHF 2 in MeOD after silica gel column chromatography, and it should be noted that the hydroxyl group has been completely protonated (Scheme 4, also see ESI †). Under the standard conditions, 10 could be transformed into [D]-3a in 75% yield in the presence of DABCO (20 mol%) along with the acetylenic deuterium shift to the α-position of the carbonyl group (Scheme 4).…”

Recent applications of <em>Cinchona</em> alkaloid-based catalysts in asymmetric addition reactions

“…14 yields and high enantioselectivity under mild conditions. 74 The authors proposed that the H-bonding interaction between isatin and d-diethyl tartrate may increase the steric hindrance between the organocatalyst and d-diethyl tartrate. Subsequently, nucleophilic attack of the enolate on the Re face of the imine may take place.…”

Organocatalytic Enantioselective Formal [4 + 2] Cycloaddition of Enones with Cyclic N-Sulfonylimines and Methylene Chromene for Chiral Spirocyclic Compounds

“…Inspired by studies, we envisioned that, by taking advantage of enamine–iminium tautomerism of N -sulfonylimines, the enamine intermediates generated from the corresponding imine could be trapped by an appropriate activated diene, and a novel [4 + 2] type cycloaddition reaction should proceed to afford the desired spirocyclic compound. The enones can serve as a capable chiral aminodiene through chiral primary amine catalysis in our design. To test the feasibility of our plan, we first explored the formal [4 + 2] cycloaddition reaction between cyclic α-methyl- N -sulfonylimine 1a and linear enone 2a catalyzed by a series of tert -leucine derived primary amine catalyst 4a – c at ambient temperature.…”