Pd-Catalyzed Aerobic Oxidative Heck Cross-Coupling for the Straightforward Construction of Indole δ-Lactams

Summary

The [6.5.6]-tricyclic indole δ-lactam represents a common key intermediate for the synthesis of a broad variety of structurally intriguing indole alkaloids. The development of a method for the versatile and straightforward construction of such structural motif is of great importance for potential synthetic applications. Herein, we present a co-ligand-prompted Pd-catalyzed 6-exo-trig intramolecular cyclization of indolyl amides via the aerobic oxidative Heck cross-coupling. The method provided a general and efficient way for the construction of [6.5.6]-tricyclic indole δ-lactams. A mechanistic study suggests that a Pd^(I)/Pd^(III) catalytic cycle should be responsible for effective coupling, which represents a mechanistically alternative pathway when compared with the Pd⁽⁰⁾/Pd^(II) cycle proposed for other related coupling reactions.

Graphical Abstract

Highlights

• •Construction of indole δ-lactams enabled by a Pd-catalyzed oxidative Heck coupling
• •The phosphinamide L₅ was crucial as a co-ligand for prompting the reaction
• •A Pd^(I)/Pd^(III) catalytic cycle is proposed to be responsible

Catalysis; Chemistry; Organic Chemistry

Introduction

The leuconoxine subfamily of aspidosperma-derived monoterpene indole alkaloids (e.g., 1–8 in Figure 1) was isolated from the plants of the genus Leuconotis (Apocynaceae) (Pfaffenbach and Gaich, 2016, Geng et al., 2016, Tokuyama, 2015). These natural products possess a unique diaza-[5.5.6.6]-fenestrane structural motif that is extremely rare in indole natural products. The latex of the plants was used traditionally to treat worm infections and yaws diseases. Owing to their high structural complexity and interesting biological properties, these and the related natural products have attracted much attention in the synthetic community. The efficient construction of the δ-lactam-containing (Figure 1, highlighted in red) ring-fused system has been the key issue of intensive synthetic efforts. The reported methods include free radical-induced cyclization (Magolan and Kerr, 2006, Magolan et al., 2008, Biechy and Zard, 2009, Zhu et al., 2015, Yu et al., 2016a, Yu et al., 2016b), Heck cross-coupling (Umehara et al., 2014, Iwama et al., 2013), and Friedel-Crafts reactions (Feng et al., 2015, Lv et al., 2014, Zhong et al., 2012, Zhong et al., 2014, Zhong et al., 2015, Liang et al., 2016, Zheng et al., 2018) at C₂₀−C₂₁; the amidation of ester (Xu et al., 2013, Xu et al., 2015, Nakajima et al., 2010, Higuchi et al., 2015, Li et al., 2015) or oxidative amidation of alcohol (Pfaffenbach and Gaich, 2015) at N₁−C₂; and the transannular cyclization (Yang et al., 2014a, Yang et al., 2014b, Dagoneau et al., 2016) of an aryl amide with ketone functionality via N₁−C₂₁.

Figure 1.

Selected Structures of Leuconoxine Subfamily

Having experienced the synthetic studies on tronoharine (Zhong et al., 2015) and mersicarpine indole alkaloids (Zhong et al., 2012, Zhong et al., 2014), we recently became interested in the leuconoxine subfamily, a class of structurally more intriguing and synthetically more challenging indole alkaloids. As mentioned, the key issue toward the efficient synthesis of this class of natural products and potential analogs with structural diversity is the establishment of a straightforward method for effective construction of the common intermediate [6.5.6]-tricyclic indole δ-lactam. To this end, we conceived of a transition-metal-catalyzed oxidative Heck coupling (i.e., dual dehydrogenative coupling) protocol, which, conceptually and strategically, would provide an ideal platform for accessing such structural skeletons as witnessed by the recent great advance in transition-metal-catalyzed oxidative C‒C bonding formation (Shi et al., 2011, Liu et al., 2011, Liu et al., 2015). In fact, there has been rapidly growing interest in oxidative Heck-type coupling of indole and other classes of substrates (Abbiati et al., 2003, Ferreira and Stoltz, 2003, Ferreira et al., 2008, Schiffner et al., 2010, Pintori and Greaney, 2011, Kandukuri et al., 2012, Kandukuri and Oestreich, 2012, Broggini et al., 2012, Yang et al., 2014a, Yang et al., 2014b, Ikemoto et al., 2014, Gao et al., 2016, Meng et al., 2013, Meng et al., 2014), and the great advantage of the related reaction in natural product synthesis has been demonstrated early by the synthesis of a few indole-type natural products (Baran et al., 2003, Meng et al., 2015, Lu et al., 2014).

However, surprisingly, a literature survey showed that among the related reports, methods for the construction of six-membered cycles through oxidative Heck coupling at indole N₁ and C₂ have been rarely reported. Of the very few relevant examples investigated so far, the attempted oxidative Heck coupling of 9 (n = 2) afforded the 6-exo-trig product 11 only in poor yield under a variety of conditions (Schiffner et al., 2010) (Figure 2A). More interestingly, it was found that the substrate 10 (n = 1) with one carbon less than 9 produced exclusively the 5-exo-trig product 12 in moderate to good yields without, however, the observation of the sterically more favored six-membered 6-endo-trig isomers 12a and 12b (Ferreira et al., 2008, Schiffner et al., 2010). Apparently, these unsuccessful precedents imply that the construction of six-membered cycles at indole N₁ and C₂ by means of oxidative Heck coupling is exceptionally challenging.

Figure 2.

Oxidative Heck coupling at indole N₁ and C₂

Reported (A) and our proposed (B) oxidative Heck coupling.

Nevertheless, we decided to investigate this challenging reaction because of the great potential utility in versatile synthesis of various indole natural products such as shown in Figure 1. In our study, a directing group-oriented oxidative coupling of indole derivatives 13 was devised (Figure 2B). Conceptually, we envisaged that the presence of a heteroatom-containing side chain tethered to indole C₃ may serve to act as a directing group to prompt the C−H activation through a geometrically favored intermediate 14, and ultimately, driving the coupling reaction with the olefin functionality to afford the δ-lactam 15. On the other hand, the side chain in the cross-coupled products, without the need to remove, can be further manipulated at the late stage as a latent functionality toward the synthesis of various indole natural products and their analogs. Taking together these advantages, the protocol proposed herein would provide not only a strategically distinctive but also a methodologically much more efficient tool for the construction of indole δ-lactams. The successful demonstration of the devised oxidative Heck cross-coupling protocol and mechanistic study will be presented herein.

Results and Discussion

The Development of Method for Oxidative Heck Coupling

Optimization of the reaction parameters was carried out using indole derivative 13a as a model compound (Table 1). Based on the conditions reported by Stoltz (Ferreira and Stoltz, 2003, Ferreira et al., 2008) and Oestreich (Schiffner et al., 2010, Kandukuri et al., 2012), a broad array of pyridine ligands was examined with the presence of different palladium catalysts in our initial screening because it was suggested that the basicity of pyridine nitrogen was critical to the catalytic activity of metal catalysts owing to their different coordination properties. Disappointedly, an exhaustive optimization of the reaction conditions by means of a free combination of various reaction parameters including ligands, catalysts, oxidants, additives, temperature, and solvents showed that the coupling reaction was almost ineffective in most cases (data not shown). Only a few sets of conditions could afford the desired product 15a in low to moderate yields with 43% as the best outcome in the presence of L₁ ligand (Table 1, entry 1). In addition, L₂ afforded 15a at an yield similar to L₁ (entry 2). In contrast, only a trace amount of product was detected for bidentate L₃ (entry 3).

Table 1.

Optimization of the Reaction Conditions

Entry	Catalyst (10 mol %)	Ligand (mol %)	Solvent	Yield (%)a
1	Pd(OAc)2	L1 (40)	Mesitylene	43
2	Pd(OAc)2	L2 (40)	Mesitylene	40
3	Pd(OAc)2	L3 (40)	Mesitylene	Trace
4	16	L1 (40)	Mesitylene	72
5	16	L1 (40)	Mesitylene	30b
6	16	L1 (40)	tBuO2H	54
7	16	L1 (40)	DMF	45
8	16	L1 (40)	DMSO	30
9	16	L1 (40)	p-Cylene	23
10	16	L1 (40)	PhCl	Trace
11	Pd(OAc)2	L1/L4 (40/10)	Mesitylene	72
12	Pd(OAc)2	L2/L4 (40/10)	Mesitylene	74
13	Pd(OAc)2	L3/L4 (40/10)	Mesitylene	Trace
14	Pd(OAc)2	L1/L5 (40/10)	Mesitylene	76 (70)c
15	Pd(OAc)2	L2/L5 (40/10)	Mesitylene	74
16	Pd(OAc)2	L1/L6 (40/10)	Mesitylene	42
17	Pd(OAc)2	L5 (10)	Mesitylene	20

Conditions: 13a (60 mg, 0.18 mmol), catalyst (10 mol %), ligand (x mol %), O₂ (balloon), and tBuCO₂H (30.0 equiv.) in solvent (0.1 mol/L) at 130°C for 16 h.

^aIsolated yield.

^bThe reaction was performed under air atmosphere.

^cThe data in parentheses was the yield using 1.50 g of 13a.

The dramatic effect of the structural nature of ligands on this reaction prompted us to turn our attention to search an alternative catalyst system or ligand. Accordingly, we shifted our focus to a phosphinamide-based palladacycle catalyst 16, which was developed previously by our group (Du et al., 2015, Guan et al., 2014). A supportive clue, albeit not tightly related with the proposed Heck-type reaction, that encouraged us to inspect this catalyst herein is that 16 exhibited extremely high catalytic activity for mild Suzuki coupling of a broad range of arene (pseudo)halides (Wu et al., 2015, Wu et al., 2018, Cao et al., 2018). To our delight, the use of 16 as catalyst did improve substantially the yield of 15a to 72% (entry 4). In addition, it was found that the presence of O₂ was essential because the yield was markedly decreased under air atmosphere (entries 4 versus 5). A brief screening of solvents showed that mesitylene was superior to others (entries 4 versus 6–10). Interestingly, a further comparison revealed that the direct addition of Pd(OAc)₂ and phosphinamide ligand L₄ to the reaction system gave the product 15a in identical yield to that of utilizing the pre-formed palladium complex 16 (entries 4 versus 11). Finally, an orthogonal evaluation on pyridine and phoshinamide ligands (entries 11–16) demonstrated that an appropriate combination of a catalytic amount of L₁ and L₅ (molar ratio = 4:1) was optimal, affording 15a in 76% yield (entry 14). Notably, the reaction could be reliably performed on gram scale in 70% yield (entry 14). Of note is that when the ligands L₁ and L₅ were used independently, the reaction efficiency was dramatically diminished (entries 1 and 17). Our further control experiments showed that when the pre-formed palladacycle 16 was used, L₄ was dissociated from palladacycle 16 to recover the ligand in quantitative yield after the reaction was completed. On the other hand, a comparison study demonstrated that palladacycle 16 did not form in situ from Pd(OAc)₂ and L₄ either in the presence or absence of substrate 13a. These results coupled with the detection of free L₄ by HRMS (see Figure S5) in the reaction system imply that L₄ may serve to act as a co-ligand rather than the formation of palladacycle 16 with Pd(OAc)₂ in the reaction system. In the case of using palladacycle 16, the protonolysis of C−Pd bond may occur to release the phosphinamide ligand. Thus the effective coupling by using mixed ligands is presumably due to the well-balanced basicity of the two ligands (Ferreira et al., 2008, Kandukuri et al., 2012).

With the optimized conditions established, we then examined the substrate scope (Table 2). Various substrates modified by electron-neutral (15a), electron-donating (15b), and electron-withdrawing (15c−15e) substituents at different positions in indole ring were well tolerated. In addition, different substituents such as Me (15f), Et (15a−15e, 15h–15n), and ester (15g) at olefin terminal were also competent. Importantly, a broad compatibility was also observed for the functional groups at the indole C₃ side chain, including a range of amino functionalities protected by MeOC(O) (15a−15g, 15k), Cbz (15h), Ts (15i), Tf (15j), hydroxy group (15l), and ester groups (15m and 15n). This would be an important advantage for a late-stage flexible manipulation when synthesis of indole alkaloids and potential analogs with structural diversity is under consideration. Of note is that substrates having a simple Me or H at indole C₃ were intact (15o and 15p). These results are in good agreement with our hypothesis that the presence of a heteroatom-containing directing group at C₃ is essential for effective coupling (vide supra). Here, an interesting observation was that except for 15g whose β-hydride elimination took place at the tertiary carbon, the β-hydride elimination for other reactions proceeded exclusively at the secondary or primary carbon to produce the thermodynamically less stable products with non-conjugated double bonds. The outcomes could be rationally explained based on the C‒H activation mechanism and coordination effect at C₃ side chain (see mechanistic study vide infra).

Table 2.

Substrate Scope for the Construction of Tertiary Carbon Center

15b, R = 5-OMe, 16 h, 130°C, 62% 15c, R = 5-CI, 16 h, 130°C, 70% 15d, R = 5-F, 16 h, 130°C, 71% 15e, R = 7-F, 16 h, 130°C, 69%	15f, 130°C, 16 h, 66%	15g, R = H, 130°C, 25 h, 56%
15h, R = Cbz, 16 h, 130°C, 57% 15i, R = Ts, 24 h, 130°C, 47% 15j, R = Tf, 4 h, 130°C, 78%	15k, R = NHCO2Me, 16 h, 130°C, 79% 15l, R = CH2OH, 9 h, 100°C, 72% 15m, R = CO2Me, 16 h, 130°C, 80%	15n, R = CO2Me, 16 h, 160°C, 64% 15o, R = Me, 0% 15p, R = H, 0%

Conditions: 13 (100 mg), Pd(OAc)₂ (10 mol %), L₁ (40 mol %), L₅ (10 mol %), O₂ (balloon), and tBuCO₂H (30.0 equiv.) in mesitylene (0.1 mol/L); isolated yield; E/Z was determined by ¹H NMR.

Next, we expanded the methodology to the construction of quaternary carbon center and bridged cycle. Gratifyingly, the reaction proceeded smoothly to give both types of products in high yields under the standard conditions (Table 3). As for the construction of quaternary carbon center, the substrates decorated by various substituents in indole ring as well as at the C₃ side chain and olefinic positions displayed good viability (15q–15x). Notably, the reaction could be uneventfully performed on gram scale as exemplified by the synthesis of 15w bearing an Et group at the quaternary carbon center, which appears as a common group in a number of related natural products (Figure 1, 1–8). Concerning the construction of aza[3.3.1]-bridged cycle, the substrates tethered with an aminoethyl group at C₃ position were less effective under the standard conditions. For instance, a Tf-protected substrate afforded the product 15y in 21% yield containing a minor amount of inseparable by-products. However, substrates bearing a hydroxyethyl group reacted facilely. The electron-neutral (15z and 15aa), electron-donating (15ab), and electron-withdrawing (15ac) groups in indole cycle had little effect on the reactivity. The reaction could also be reliably performed on large scale (15z). As the aza[3.3.1]-bridged skeleton exists in a range of chippiine-type indole natural products (Kam et al., 1992, Kam et al., 1993, Kam et al., 2000, Kam et al., 2004), the method would also be potentially useful in the synthesis of related natural products. The structures of both types of compounds were confirmed by NMR and HRMS, and were further clarified by the single X-ray crystallography of 15q (CCDC 1866425) and 15ac (CCDC 1866424).

Table 3.

Substrate Scope for the Construction of Quaternary Carbon and Aza[3.3.1]-Bridged Cycle

		15q (X-ray) CCDC 1866425
15q, R = H, 7.5 h, 130°C, 69% 15r, R = OMe, 10 h, 130°C, 53% 15s, R = F, 5 h, 130°C, 66%	15t, 1.5 h, 130°C, 78%	15u, 7 h, 95°C, 69%
15v, 7 h, 95°C, 70%	15w, 7 h, 95°C, 88%, (1.27 g)	15x, 12 h, 95°C, 73%
15y, R = H, X = NHTf, 16 h, 130°C, 21% 15z, R = H, X = OH, 10 h, 95°C, 72% (0.74 g) 15aa, R = Me, X = OH, 10 h, 95°C, 71% 15ab, R = OMe, X = OH, 10 h, 95°C, 68% 15ac, R = F, X = OH, 10 h, 95°C, 68%		15ac (X-ray) CCDC 1866424

Conditions: 13 (100 mg), Pd(OAc)₂ (10 mol %), L₁ (40 mol %), L₅ (10 mol %), O₂ (balloon), and tBuCO₂H (30.0 equiv.) in mesitylene (0.1 mol/L); isolated yield.

Mechanistic Study of Oxidative Heck Coupling

Having verified the broad generality of the methodology, we investigated the reaction mechanism. First, three control experiments by using 13a, deuterated 13a-D (ca. 92% D, see Figure S2), and a 1:1 mixture of 13a and 13a-D as substrates were carried out to confirm whether the C−H bond or alkene activation is involved in the catalytic cycle. Surprisingly, almost identical yields were obtained for the three reactions under standard conditions, indicating no isotopic effect. However, a further analysis on the recovered starting materials revealed that the undeuterated 13a was the major component for the reaction using 13a-D as substrate. The serendipitous result indicates that H/D exchange at indole C₂ may take place during the reaction, which should interrupt the actual observation of isotopic effect. To clarify this point, further detailed control experiments were performed. Accordingly, treatment of the deuterated substrate 13a-D (Scheme 1, Equation 1) under the standard conditions followed by the quantitative NMR and HRMS analyses of the recovered starting material revealed that H/D interchange took place at indole C₂ position (see Figure S3). Moreover, the ratio of H/D interchange increases with the elongation of reaction time (i.e., H/D = ca. 1:1 for 1 h, and ca. 7:3 for 3 h). Alternatively, treatment of undeuterated 13a under conditions identical to that of Equation 1 but just replacing tBuCO₂H with tBuCO₂D (ca. 90% D) resulted in an H/D = ca. 7:3 and 6:4 of the recovered 13a (Scheme 1, Equation 2) after 1 h and 3 h, respectively (See Figure S4). The orthogonal experiments clearly exemplified that significant H/D exchange between the indole C₂‒H of the substrate and tBuCO₂H takes place.

Scheme 1.

The Control Experiments of H/D Exchange (Equations 1 and 2) and Kinetic Isotopic Effect (Equation 3)

Thus, to avoid the interruption of proton scrambling between the substrate and tBuCO₂H in the study of kinetic isotopic effect (KIE), we designed two experiments. One was performed using 13a as substrate under standard conditions and the other one was carried out using deuterated 13a-D as substrate but replacing tBuCO₂H with tBuCO₂D (Scheme 1, Equation 3). As slow decomposition of product 15a was detected (Ferreira et al., 2008), the time-dependent conversion of substrates rather than the formation of product was monitored by high-performance liquid chromatography (Figure 3, left and see also Table S1). The KIE was deduced based on the conversion of substrates versus the reaction time (Figure 3, right). The observation of a large primary KIE with k_H/k_D = ca. 5.5:1 indicates that C‒H activation should be the rate-determining step of the oxidative Heck coupling.

Figure 3.

Kinetic Isotopic Effect

Conversion profile (left) and the linear fitting (right) of the substrates 13a and 13a-D.

Next, we investigated the redox cycle of palladium catalyst. Although a Pd⁽⁰⁾/Pd^(II) cycle was tentatively proposed in the literature (Ferreira et al., 2008, Kandukuri et al., 2012) for the five-membered cyclization reaction, we envisioned that our 6-exo-trig annulation should undergo an alternative pathway based on the experimental phenomena, such as color change of the reaction system (vide infra). We used HRMS to detect any possible Pd-containing species. Four strong peaks and several weak ones related with palladium complexes were captured for the reaction under oxygen atmosphere (see Figure S5). The strong peaks at m/z = 365.9951 and 385.0353 can be assigned to a Pd^(III) species with a formula of [Pd^(III) (MeCO₂^-)₂(tBuCO₂^-) (H₂O)Na⁺] (calculated for C₉H₁₇NaO₇Pd⁺: m/z 365.9901) and a Pd^(II) complex [Pd^(II) (tBuCO₂^-)L₁(MeCN)] (calculated for C₁₄H₁₉N₂O₄Pd⁺: m/z 385.0374), respectively. In addition, all the weak peaks can also be well assigned. However, the other two strong peaks at m/z = 468.0598 and 481.0558 cannot be rationally assigned because either the Pd^(III) complexes [Pd^(III) (MeCO₂^-)₂(tBuCO₂^-) (tBuCO₂H) (H₂O)Na⁺] (calculated for C₁₄H₂₇NaO₉Pd⁺: m/z 468.0582) and [Pd^(III) (MeCO₂^-)₂(tBuCO₂H) (H₂O)L₁] (calculated for C₁₆H₂₅NO₉Pd⁺: m/z 481.0559) or the Pd^(II) complexes [Pd^(II) (tBuCO₂^-)₂L₁Na⁺] (calculated for C₁₇H₂₅NNaO₆Pd⁺: m/z 468.0609) and [Pd^(II) (tBuCO₂^-) (L₁)₂] (calculated for C₁₉H₂₃N₂O₆Pd⁺: m/z 481.0586) are possible. For a further clarification, we inspected the reaction under argon atmosphere. Three signals were detected involving a strong signal of Pd^(II) complex at m/z = 385.0362. In addition, the two peaks at m/z = 468.0609 and 481.0589 as those that appeared under oxygen atmosphere were also observed. However, they were remarkably much weaker than those under oxygen atmosphere. Thus, a comparison of the HRMS analysis under different conditions implies that most probably the two signals should belong to Pd^(III) complexes. The detection of these signals under argon atmosphere may be resulted from the oxidation of some minor oxidants involved in the reaction system. All the above experiments displayed good reproducibility.

Further support for the generation of Pd^(III) complexes is the apparent color change of the reaction solution. Namely, the color changed from pale yellow to deep red-brown for the solution under oxygen atmosphere (see Figures S24 and S25), which indicates typically the generation of Pd^(III) ion according to the literature (Powers and Ritter, 2009, Powers et al., 2009). In comparison, the Pd black that was precipitated out with the pale yellow solution almost remained unchanged for the reaction under argon atmosphere. Moreover, it was found that when the reaction was performed under argon atmosphere in the presence of stoichiometric amount Pd(OAc)₂ and the corresponding ratio of ligands, 15a was obtained only in lower than 20% yield. These results clearly suggest that a Pd^(I)/Pd^(III) should be involved in the catalytic cycle, although a Pd⁽⁰⁾/Pd^(II) cycle cannot be entirely ruled out as a minor catalytic process.

Thus, through an extensive mechanistic study, we could propose a catalytic cycle for the 6-exo-trig annulation. Namely, oxidation of Pd^(II) by oxygen generates the Pd^(III) complexes, which then form an infant transition state I with substrate 13 under the direction of the heteroatom-containing C₃ side chain (Figure 4). Subsequently, C–H bond activation proceeds to produce the intermediate II. Migratory syn insertion followed by syn β-hydride elimination via III delivered the product 15. The sensitive Pd^(I) was reoxidized to Pd^(III) via the more stable Pd^(II) to bring the reaction into the next cycle. Based on the proposed mechanism, the syn insertion results in an anti-orientated R¹ group and Pd^(III) ion. Subsequently, the Pd^(III) coordinates with the heteroatom at the C₃ side chain to form a closed intermediate III, which prevents the elimination of anti-β-hydride at the tertiary carbon (for R¹ = H). As a result, the products with non-conjugated double bonds as shown in Table 2 are formed exclusively. As an exceptional example, the production of 15g (Table 2) should undergo epimerization via an oxa-π-allylpalladium intermediate IV to form V, and ultimately, allowing for anti-β-hydride elimination at the tertiary carbon (Kandukuri et al., 2012).

Figure 4.

Proposed Pd^(I)/Pd^(III) as the Major Catalytic Cycle

Limitations of the Study

A brief examination showed that the present method is not compatible for the construction of seven-membered indole lactams from the corresponding indolyl 5-enamide.

Conclusion

Targeted toward the efficient and collective synthesis of an array of structurally intriguing indole alkaloids as well as their potential analogs, we have designed and developed a Pd-catalyzed aerobic oxidative Heck coupling reaction that could achieve the previously challenging 6-exo-trig annulation using indolyl amides as substrates. The method provides a straightforward pathway for accessing [6.5.6]-tricyclic indole lactams, which may serve as a common intermediate for the synthesis of various indole alkaloids and their analogs. The method also displays a broad generality and could be reliably performed over gram scale as demonstrated by several different types of substrates. The keys for the successful realization of the coupling reaction are highlighted by a mechanism-based design of incorporating a heteroatom-containing directing group at indole C₃ and the utilization of phosphinamide compounds as novel co-ligands. Extensive experimental results revealed that C‒H activation should be the rate-determining step and that Pd^(III) complexes may be responsible for effective reaction. This catalytic cycle differs from the previously proposed Pd⁽⁰⁾/Pd^(II) cycle for the construction of five-membered rings and would be important for the mechanism-based de novo design of relevant reactions. We believe that the method could find extensive applications for the flexible synthesis of various indole alkaloids. The investigations into the enantioselective version of the cross-coupling reaction, as well as its application in the collective synthesis of relevant natural products, are the focus of our future work.

Methods

All methods can be found in the accompanying Transparent Methods supplemental file.

Published: July 26, 2019