Diastereoselective Synthesis of Pyrroloindolines by Palladium–Dihydroxyterphenylphosphine-Catalyzed C3-Dearomative Arylation/Cyclization of Substituted Tryptamines

Abstract

Pyrroloindolines are promising compounds, yet reports on their syntheses remain scarce. Herein, we report the diastereoselective synthesis of C3a-arylated pyrroloindolines bearing substituents on the pyrrolidine ring by a facile palladium–dihydroxyterphenylphosphine-catalyzed C3-dearomative arylation of substituted tryptamine derivatives, followed by the intramolecular cyclization of the resulting indolenine. The reaction with various tryptamine derivatives showed that the position and bulkiness of the substituents on the aminoethyl chain of the tryptamines strongly influenced the site- and diastereoselectivity of the arylation. The steric hindrance of the arylating agents also determined the reactivity and diastereoselectivity. This study presents an efficient diastereoselective method to synthesize pyrroloindolines with C3a-aryl groups from widely available substituted tryptamine derivatives.

Introduction

The pyrroloindoline skeleton is a ubiquitous scaffold found in natural products.^1–3) C3a-substituted pyrroloindolines are of particular interest owing to their broad biological activities, such as acetylcholine esterase inhibition,⁴⁾ antitumor activity,^5,6) and antinociceptive activity.⁷⁾ They often have substituents on their pyrrolidine rings because they are biosynthesized from tryptophan. Several synthetic methods have been developed to obtain these pyrroloindolines.^3,8–11) However, despite their attractive structures, synthetic methods for 1- or 2-substituted C3a-arylpyrroloindolines remain limited. Reductive cyclization of 3,3-disubstituted oxindoles is the most common route for the formation of C3a-arylated pyrroloindolines.^12–16) Arylation of the pyrroloindoline skeleton^17–19) is another method, which includes silver-mediated arylation of C3a-brominated pyrroloindoline^17,18) and photolysis of C3a-diazenated pyrroloindoline.¹⁹⁾ Dearomative C3-arylation of the tryptamine derivatives followed by intramolecular cyclization is also an effective method to synthesize C3a-arylated pyrroloindolines.^20–24) However, there is only 1 reported example of diastereoselective synthesis with a substrate bearing substituents on the aminoethyl moiety.²²⁾ While the reported example exhibits high diastereoselectivity, the scope of the substituents is restricted to amido groups, and diaryliodonium salts are required as arylating agents. We previously reported the synthesis of C3a-arylated pyrroloindolines by Pd–dihydroxyterphenylphosphine (DHTP: 1)²⁵⁾ catalyst-assisted C3-selective dearomative arylation of amine-protected tryptamines followed by intramolecular cyclization²⁶⁾ (Chart 1a). One of the characteristic features of this reaction is that aryl nonaflates (Ar-ONfs), easily prepared from the corresponding phenols, can be used as arylating agents. Leveraging this success, herein we employ our Pd–1 catalyst for the diastereoselective synthesis of various C3a-arylpyrroloindolines from tryptamine derivatives bearing substituents on the aminoethyl moiety (Chart 1b).

Chart 1. C3a-Arylated Pyrroloindoline Synthesis by Dearomative C3-Arylation/Intramolecular Cyclization of Tryptamines

Results and Discussion

First, we optimized the reaction conditions using (±)-α-methyltryptamine derivative 2 and 4-methylphenyl nonaflate 3 as model compounds (Table 1). Following our previous pyrroloindoline synthesis,²⁶⁾ palladium(II) acetate was used as the Pd source, 1 as the ligand, lithium tert-butoxide as the base, and toluene as the solvent. The initial screening (Supplementary Table S1) of the amine-protecting groups on the substrate showed that the mesitylenesulfonyl-protected derivative 2 was the best for obtaining the desired C3a-arylated pyrroloindoline 4. We found that the reactivity of 2 was lower than that of the tryptamines without the α-methyl group of 2²⁶⁾ (Chart 1a); therefore, the reaction time was extended to 20 h (entry 1). As a result, 4 was obtained in 44% yield as a mixture of the 2 diastereomers at a ratio of 3.5 : 1. Based on the previous reports,¹⁰⁾ we assumed that 4 showed a cis-configuration between the 8a-hydrogen and the C3a-aryl moiety. The formation of an N1-arylated derivative 5 (9% yield) was also observed. The reaction conditions were optimized to further improve yield and site- and diastereoselectivity. Since sufficient complex formation between 1 and Pd is important to achieve a high C3- and diastereoselectivity in arylation, we examined the effect of the pre-stirring time at room temperature (r.t.). Shorter pre-stirring time (0.25 h) resulted in lower diastereoselectivity (entry 2), while longer pre-stirring time (1 h) improved the yield of 4 (entry 3). Finally, the yield and diastereomeric ratio of 4 were dramatically improved by increasing the reaction temperature to 130°C. The reason for the higher diastereoselectivity remains unclear (entry 4).

Table 1. Pyrroloindoline Synthesis from (±)-α-Methyltryptamine Derivative 2

Entry	Conditions	Yield (%)
		4 (d.r.)	5
1	r.t., 0.5 h; then 110°C, 20 h	44 (3.5 : 1)	9
2	r.t., 0.25 h; then 110°C, 20 h	43 (2.0 : 1)	7
3	r.t., 1 h; then 110°C, 20 h	58 (3.3 : 1)	14
4	r.t., 1 h; then 130°C, 20 h	73 (6.1 : 1)	13

We then evaluated the effect of the arylating agents on reactivity, site-selectivity, and diastereoselectivity (Chart 2). Reactions of 2 with various Ar-ONfs were conducted. When 3-methylphenyl nonaflate was used, the yield of the corresponding pyrroloindoline 6 was low. The diastereomeric ratio of 6 was almost the same as that of 4. The reaction with 2-methylphenyl nonaflate also afforded 7 in low yield with lower diastereoselectivity. In the case of 3-trifluoromethylphenyl nonaflate, 42% of 8 was obtained with a diastereomeric ratio of 2.2 : 1, along with 35% of the N1-arylated 8′. The reaction with 4-methoxyphenyl nonaflate afforded 9 in moderate yield and with moderate diastereoselectivity. However, the use of 3-methoxyphenyl nonaflate resulted in a low yield of 10 with a good diastereomeric ratio and a large amount of the N1-arylated 10′. The reaction with 2-methoxyphenyl nonaflate did not proceed smoothly, and a small amount of 11 with low diastereoselectivity was obtained. From these results, we deduce that the steric hindrance of the Ar-ONf is the cause of the poor reactivity and low diastereoselectivity.

Chart 2. Effect of the Arylating Agents on Reactivity, Site-Selectivity, and Diastereoselectivity

To examine the effect of the substituents on the tryptamine, various substituted tryptamines were subjected to this reaction (Chart 3). α-Methyltryptamines bearing substituents at the C5- or C7-position of the indole ring gave the corresponding pyrroloindolines 12–15 in moderate yield with good site- and diastereoselectivity. The major diastereomer of 15 was analyzed using single-crystal X-ray crystallography, and its relative configuration was successfully determined as the cis-syn form. Next, tryptamines bearing substituents on the aminoethyl moiety were subjected to the reaction. When (±)-α-ethyltryptamine was employed, the pyrroloindoline formation proceeded smoothly, and 16 was obtained in moderate yield and with high diastereoselectivity. Notably, (±)-α-phenyltryptamine afforded 17 as a single diastereomer. Single-crystal X-ray crystallography revealed that the relative configuration of 17 is the cis-syn form, the same as that of the major diastereomer of 15. In the case of (±)-β-methyltryptamine, the yield of product 18 was dramatically decreased, and a certain amount of N1-arylated product 18′ was formed. The high diastereomeric ratio of 18 indicates that the C3-arylation proceeded diastereoselectively. Because no indolenine intermediate was recovered, we assumed that the N1-arylation proceeded more smoothly than the C3-arylation. In addition, (±)-β-phenyltryptamine did not provide 19 or the indolenine, and a large amount (52% yield) of the N1-arylated product 19′ was obtained. C3-arylation was suppressed due to the presence of sterically hindered β-substituents, which inhibited palladation at the C3 position of the indole. These results indicate that both the site- and diastereoselectivity of the arylation are strongly influenced by the position and bulkiness of the substituents on the aminoethyl chain.

Chart 3. Effect of the Substituents on Reactivity, Site-Selectivity, and Diastereoselectivity

The proposed catalytic cycle is shown in Chart 4. First, deprotonation of the NH of the tryptamine derivative and the OH of 1 by t-BuOLi gives the corresponding Li salts, forming a heteroaggregate A. Then, the oxidative addition of the Ar-ONf to Pd affords intermediate B. Because the C3-position of the indole moiety of tryptamine is close to that of Pd, palladation occurs C3-selectively to give intermediate C. Reductive elimination of the arylated product from C, followed by intramolecular cyclization of the C3-arylated indolenine D, provides the pyrroloindoline. Based on the observations that indolenine, which could be formed in the work-up step, and other diastereoisomers, which could be formed in the intramolecular cyclization step, were absent in the crude mixture, we postulate that the diastereoselectivity of the reaction is determined in the formation of intermediate C.

Chart 4. Proposed Catalytic Cycle

Finally, the removal of the mesitylenesulfonyl group from 4 was examined (Chart 5). Based on our previous report,²⁶⁾ deprotection was conducted using a Mg/MeOH mixture.²⁷⁾ After optimizing the reaction conditions, 210 equivalents of Mg were used and the reaction temperature was increased to 40°C. The reaction of the isolated major diastereomer of 4 resulted in a moderate yield of product 20, and 45% of the starting material 4 was recovered (Chart 5a). In contrast, the removal of the isolated minor diastereomer of 4 proceeded smoothly to give the deprotected product 20 in an 87% yield (Chart 5b). These results suggest that the minor diastereomer can be deprotected more easily than the major diastereomer of 4, although the reason for this remains unclear.

Chart 5. Removal of the Mesitylenesulfonyl Group from 4

Conclusion

In summary, various C3a-arylpyrroloindolines bearing substituents on the pyrrolidine ring were synthesized diastereoselectively via a facile C3-selective dearomative arylation/cyclization of readily available substituted tryptamine derivatives using a Pd–1 catalyst. It was revealed that the arrangement of the substituents in the tryptamine derivatives and the arylating agents influenced the yield and the diastereomeric ratio of the resulting pyrroloindolines. We believe that this synthesis protocol, along with the amine-deprotection strategy, will boost the development of similar pyrroloindolines with C3a-aryl groups from substituted tryptamine derivatives.

Acknowledgments

This work was partially supported by JSPS KAKENHI (Grant Numbers 20H03368, 21K06457, 24K09731), the Hamamatsu Foundation for Science and Technology Promotion, the Tokyo Ohka Foundation for the Promotion of Science and Technology, and the Nagase Science Technology Foundation.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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