Chiral π–Cu(ii)-catalyzed site-, exo/endo-, and enantioselective dearomative (3 + 2) cycloadditions of isoquinolinium ylides with enamides, dienamides, and a trienamide

Here, we report a highly effective dearomative (3 + 2) cycloaddition reaction between isoquinolinium ylides and α,β-enamides, α,β–γ,δ-dienamides, or an α,β–γ,δ–ε,ζ-trienamide, which is catalyzed by a chiral π–Cu(ii) complex (1–10 mol%) and proceeds in a site-selective, exo/endo-selective, and enantioselective manner. The (3 + 2) cycloaddition involving the α,β-enamides proceeds with high exo-selectivity and enantioselectivity. This method is applicable to various substrates including α-substituted, α,β-disubstituted, or β,β-disubstituted α,β-enamides, which are compounds with an intrinsically low reactivity. This method provides synthetic access to pyrroloisoquinoline derivatives with up to three chiral carbon centers, including those featuring fluorine and trifluoromethyl groups, as well as quaternary carbon centers. The (3 + 2) cycloaddition involving α,β–γ,δ-dienamides proceeds with high γ,δ-site-selectivity and enantioselectivity, whereby the exo/endo-selectivity depends on the substrates and ligands. Remarkably, the (3 + 2) cycloaddition of δ-phenyl-α,β–γ,δ-dienamide proceeds with high α,β-site-selectivity, exo-selectivity, and enantioselectivity. In a manner similar to the reaction with the α,β–γ,δ-dienamides, α,β–γ,δ–ε,ζ-trienamide furnishes a (3 + 2) cycloadduct with good ε,ζ-site-selectivity, endo-selectivity, and enantioselectivity.


Introduction
Catalytic enantioselective (3 + 2) cycloaddition reactions have emerged as important synthetic methods that facilitate the precise and enantioselective construction of numerous valuable heterocyclic motifs. 1 In these reactions, acryloyl derivatives such as 2 are typically employed as dipolarophiles (Schemes 1 and 2).However, the use of these acryloyl derivatives is primarily restricted to b-substituted acryloyl derivatives, whilst asubstituted, a,b-disubstituted or b,b-disubstituted derivatives are rarely used due to their intrinsically low reactivity, thus signicantly limiting the versatility and scope of these reactions.1d If the substrate scope of enantioselective (3 + 2) cycloaddition reactions could be expanded to include acryloyl derivatives with more complex substitution patterns, the synthetic utility of these reactions would be signicantly enhanced, thus enabling the construction of valuable heterocyclic moieties with all-carbon-substituted quaternary stereocenters bearing alkyl or uoroalkyl groups. 2,3At the same time, enhancing other selectivity such as site-, chemo-, exo/endo-, or regioselectivity would improve the overall applicability of these transformative methods.
The pursuit of g,d-site-selective and enantioselective (3 + 2) cycloaddition reactions of a,b-g,d-dienamides (4) is highly attractive because it not only allows for the establishment of remote chiral carbon centers but also retains the a,b-unsaturation of the starting material, therefore enabling further Despite the challenges associated with these reactions, some elegant strategies have already been designed that allow remote and enantioselective 1,6-additions. 4 However, the methods for remote and enantioselective (3 + 2) cycloaddition reactions remain relatively underdeveloped.A breakthrough was made by the Jørgensen group in 2016 when they reported the rst g,dsite-selective, exo-selective, and enantioselective (3 + 2) cycloadditions of nitrones with a,b-g,d-dienals via a vinylogous iminium-ion activation mode where 20 mol% of a chiral diarylprolinol silyl ether catalyst was employed. 5In 2020, a similar strategy was applied by Zhang and Guo et al. to achieve g,d-siteselective, endo-selective, and enantioselective (3 + 2) cycloadditions of phthalazinium dicyanomethanides with a,b-g,d-dienals using 20 mol% of MacMillan's catalyst. 6In general, the turnover frequency (TOF) of secondary-amine catalysts is relatively inefficient because a dehydrative condensation step between the amine catalyst and the aldehyde and a hydrolysis step are included in the catalytic cycle.

Results and discussion
Chiral p-Cu(II)-complex-catalyzed site-selective, exo/endoselective and enantioselective dearomative (3 + 2) cycloaddition reactions between isoquinolinium ylides and a,b-enamides In recent years, bench-stable isoquinolinium ylides (1) have garnered signicant attention in synthetic organic chemistry due to their efficiency in the construction of pyrroloisoquinoline scaffolds, which are crucial structural motifs in various natural products and pharmaceutically active compounds. 8owever, only a few examples for their use as dipolar compounds in dearomative (3 + 2) cycloaddition reactions have been reported so far.7l,8e Therefore, the development of a catalytic enantioselective (3 + 2) cycloaddition reaction of 1 with a,benamides (2) for the construction of pyrroloisoquinoline derivatives (3) would be of considerable signicance.As shown in Table 1, in our initial attempt, the enantioselective (3 + 2) cycloaddition reaction of 1a with 2a was conducted in the presence of 10 mol% of a chiral p-Cu(II) complex of Cu(OTf) 2 with L-alanine-derivatized ligand L in dichloromethane at −10 °C for 24 h.To our delight, when N-cyclopentyl-b-(2-naphthyl)-Lalanine amide (L1) was employed as the ligand, the reaction smoothly provided 3aa in high yield, albeit with poor enantioselectivity (Table 1, entry 1; 92%, −20% ee).Interestingly, the diastereoselectivity toward 3aa was 97% exo.The use of Ncyclobutyl-based L2 instead of N-cyclopentyl-based L1 did not improve the enantioselectivity (Table 1, entry 2).However, the use of N-dibenzosuberyl (Dbs)-based L3 signicantly increased the ee to +88% with >99% exo-selectivity (Table 1, entry 3).This observed switch in the enantioselectivity can be interpreted in terms of a switch of the p-Cu(II) interaction, which creates the asymmetric environment, from p(naphthyl)-Cu(II) to p(Dbs)-Cu(II).Inspired by these results, we investigated several other 3substituted N-Dbs-alanine amides as chiral ligands.When L- leucine-derived L4 was employed, the reaction afforded 3aa in 97% yield with +94% ee and >99% exo-selectivity (Table 1, entry 4).When b-tert-butyl-L-alanine-derived ligand L5 was used, exo-3aa was obtained in a 98% yield with +98% ee (Table 1, entry 5).
The incorporation of the triuoromethyl group into organic molecules has garnered considerable attention due to the unique properties it induces and the important applications of CF 3 -substituted compounds in the pharmaceutical industry. 11Furthermore, the enantioselective (3 + 2) cycloaddition of prochiral CF 3 -substituted substrates has become a popular method in recent years to build chiral CF 3 -containing pyrrolidine derivatives. 3Thus, we examined the use of prochiral b-tri-uoromethyl-a,b-enamide 2n as a dipolarophile.To our delight, the reaction was exceptionally efficient, furnishing the desired product (3an) in 99% yield with >99% ee.
To show the synthetic applicability of the (3 + 2) cycloaddition reaction between 1a and 2m, a gram-scale synthesis was undertaken (Scheme 3A).Even when employing a lower catalyst loading (1 mol%) of L5, the reaction efficiently yielded 3am in 92% yield with >99% ee.Subsequent transformations of 3am, including chlorination and elimination, were carried out successfully without any loss of enantioselectivity (Scheme 3B and C).
Based on these ndings, our attention shied to investigating the introduction of a chiral quaternary carbon center into the pyrroloisoquinoline structure using the enantioselective (3 + 2) cycloaddition of 1a with a-substituted a,b-enamides (2o-2s) (Table 3).Our initial attempt involved using a dipolarophile 2o, which contains a 3,5-dimethylpyrazolyl group (X 1 ).However, even aer 24 h, almost no reaction occurred, and 2o was recovered.Encouragingly, when we used 2p, which bears a monomethyl-substituted pyrazolyl group (X 2 ), the reaction efficiently furnished the desired product (3ap) in 97% yield with 99% ee, resulting in a chiral quaternary carbon center at the a-position.The rst result was attributed to the steric repulsion between the 5-Me group in X 1 and the asubstituent of 2o, which disfavors activation by the chiral p-Cu(II) complex.Consequently, rotation can be expected to occur, and the inherently low reactivity of this substrate results in almost no reaction.However, when X 2 was employed in place of X 1 , the steric hindrance between the 5 H group of the X 2 moiety and the a-substituent of 2p decreased signicantly.Consequently, 2p is readily activated by the chiral p-Cu(II) catalyst, which enables an efficient reaction with 1a.Furthermore, as the conguration of activated 2p is xed by the chiral p-Cu(II) catalyst, the enantioselectivity is very high.Subsequently, using X 2 instead of X 1 , a,b-dimethyl-a,b-enamide 2q was examined, and the desired product (3aq) was obtained in a 93% yield with 99% ee.However, the reaction of a-methyl-a,b-enamide 2r with 1a gave 3ar in a relatively low ee value of 89%.Inspiringly, a-uoro-a,b-enamide 2s was also well tolerated under the applied conditions.This led to the formation of the expected product (3as), which features a chiral quaternary carbon center that contains a uoro group, in a 97% yield with >99% ee.Table 3 Exo-selective and enantioselective (3 + 2) cycloaddition reaction between 1a and a-substituted a,b-enamides 2 a a Unless otherwise noted the following reaction conditions were applied: 2 (0.2 mmol), 1 (0.24 mmol), Cu(OTf) 2 (10 mol%), L5 (11 mol%), and 4A MS (150-200 mg) in dichloromethane (1.3 mL) at −10 °C for 24 h.Isolated yields are given.Enantiomeric-excess (ee) values were determined using HPLC.In all the cases where the product was obtained, the exo-selectivity was >98%.b −40 °C, overnight.
To explore the substrate scope of the g,d-site-selective, exo/ endo-selective and enantioselective (3 + 2) cycloaddition reaction between 1 and 4, several substrates were examined in the presence of 10 mol% of Cu(OTf) 2 $L5 under the conditions shown in Table 4 (Table 5).The exo/endo-selectivity for g,dadducts 6 was inuenced by the structure of substrates 1 and 4. As expected, the reaction of 1a with 4a exhibited excellent g,d-  Interestingly, 6ac could be obtained endoselectively and with more pronounced g,d-site-selectivity but lower enantioselectivity by using L7 instead of L5.Electron-rich isoquinolinium ylides such as 1e and 1f also reacted with 4a in a highly g,d-site-selective manner, furnishing the corresponding products exo-6ea and endo-6fa in good yield with high ee.
When employing electron-poor isoquinolinium ylides such as 1b, 1g, and 1d, 1 : 1 mixtures of exo-5 and endo-6 were obtained in high yields with high enantioselectivity but almost without site-selectivity.Fortunately, exo-5 and endo-6 could be separated using column chromatography over silica gel.Moreover, the use of L7 instead of L5 signicantly enhanced the g,d-site-selectivity and endo-selectivity, albeit at the expense of a decrease in enantioselectivity.Remarkably, d-phenyl-a,b-g,d-dienamide 4d exhibited complete a,b-site-selectivity, yielding the corresponding products exo-5ad, exo-5bd, and exo-5dd in good yield with >99% ee due to the steric and resonance effects introduced by the d-phenyl group of 4d.

Mechanistic studies
The site-selective, exo/endo-selective, and enantioselective (3 + 2) cycloaddition between 1 and 4 induced by Cu(OTf) 2 $L5 can be rationally interpreted in terms of the mechanism proposed in Scheme 4, which is based upon our previous related studies.As shown in Table 5, when Cu(OTf) 2 $L5 was used as the catalyst for the (3 + 2) cycloaddition between 1 and 4a, the electron density of 1 inuences the site-selectivity.Both a,b-exo-TS and g,d-endo-TS would be somewhat destabilized by the steric hindrance arising from the apical-OTf, which is conformationally restricted by a hydrogen-bonding interaction with the N-H moiety of L5 (Fig. 2).7k Nevertheless, in the (3 + 2) cycloaddition of electron-rich 1, g,d-endo-TS would be stabilized to exhibit g,d-site-selectivity because the strong HOMO-LUMO interaction overcomes the steric hindrance.On the other hand, in the (3 + 2) cycloaddition of electron-poor 1, the site-selectivity is low because the steric hindrance cannot be overcome by the weak HOMO-LUMO interaction.
When Cu(OTf) 2 $L7 was used as the catalyst for the (3 + 2) cycloaddition between electron-poor 1 and 4a, the g,d-siteselectivity increased (see Table 5).A hydrogen-bonding interaction between the apical-OTf group and the N-H moiety of L7 would not be expected due to the high steric demand of the a-Ph group of L7. 7k The apical-OTf group in the transition state would be oriented in the direction opposite to the N-acyl group of 4a due to steric hindrance with the a-Ph group of L7 (Fig. 4).Therefore, the a,b-exo-TS would be destabilized by the steric hindrance of the apical-OTf group.Thus, the g,d-endo-selectivity would be increased independent of the electron-density of 1.However, L5 has a more pronounced effect on the enantioselectivity than L7 in most cases, because the p-Cu(II) interactive conformation in the g,d-endo-TS containing L7 may be more sensitive to the steric factor of 1 and 4 due to the lack of room in the gap between the a-Ph group and N-Dbs in L7.

Conclusions
In summary, we have developed a chiral p-Cu(II) complexcatalyzed multi-selective dearomative (3 + 2) cycloaddition reaction between various substituted alkenes and isoquinolinium ylides for the construction of pyrroloisoquinoline derivatives.The key highlights of this catalytic method include: (1) highly effective chiral ligands L5 and L7 were developed and can be used in catalytic quantities as low as 1-10 mol%; (2) the reaction demonstrates an excellent ability to construct pyrroloisoquinoline derivatives with up to three chiral carbon centers; (3) poorly reactive a-substituted-, a,b-disubstituted, and b,b-disubstituted unsaturated N-acylpyrazoles are highly compliable in the reaction and in most cases furnished enantiopure or highly enantioenriched products in excellent yields; (4) valuable chiral F-containing and CF 3 -containing quaternary carbon centers can be accessed efficiently; (5) the rst examples for chiral Lewis-acid-catalyzed g,d-site-selective, exo/endo-selective, and enantioselective (3 + 2) cycloaddition reactions that involve a,b-g,d-dienamides have been developed; and (6) the rst example of an 3,z-site-selective, endo-selective, and enantioselective (3 + 2) cycloaddition reaction involving an a,b-g,d-3,z-trienamide has been developed, which signicantly expands the boundaries of this synthetic approach.

Fig. 1
Fig.1Molecular structure of (1R,2S,10bR)-3de in the single crystal.10 site-selectivity and enantioselectivity to afford endo-6aa in high yield.On the other hand, d-ethyl-a,b-g,d-dienamide 4b and d-npropoyl-a,b-g,d-dienamide 4c resulted in the formation of exo-6ab and exo-6ac in good yield with high g,d-site-selectivity and enantioselectivity.

Fig. 2
Fig. 2 Steric effect of the a-substituent (R 1 = t-BuCH 2 ) of L5 on the g,d-site-selectivity and the endo-selectivity.

Table 2
Exo-selective and enantioselective