Letter Cite This: Org. Lett. 2017, 19, 5525-5528
pubs.acs.org/OrgLett
Selenium−Iodine Cooperative Catalyst for Chlorocyclization of Tryptamine Derivatives Takahiro Horibe, Shuhei Ohmura, and Kazuaki Ishihara* Graduate School of Engineering, Nagoya University, B2-3(611), Furo-cho, Chikusa, Nagoya 464-8603, Japan S Supporting Information *
ABSTRACT: Chlorocyclization of tryptamine derivatives has been developed with the use of a diphenyl diselenide−iodine cooperative catalyst. Various tryptamine derivatives can be smoothly converted to the corresponding C3a-chlorohexahydropyrrolo[2,3-b]indoles. Additionally, we demonstrate the formal total syntheses of (−)-psychotriasine and (−)-acetylardeemin by introducing nucleophiles to the C3a position of the products.
E
ing reagents strongly affects the chlorocyclization of tryptamines.8 Therefore, a limited number of tryptamines have been used. To expand the substrate scope, it should be important to control the reactivity of chlorinating reagents. We have developed an enantioselective halocyclization catalyzed by a chiral Lewis base.11 The chiral Lewis base activates a halonium ion via nucleophilic attack, and the resulting chiral halonium−Lewis base complex smoothly gives the corresponding halocyclization product.12 By tuning the phosphorus-based Lewis base, both iodonium ion and bromonium ion could be activated.13 In this regard, judicious choice of the Lewis base should be effective for activating a chlorinating reagent for the chlorocyclization of tryptamines.14 Here, we report a selenium−iodine cooperative catalyst for the chlorocyclization of tryptamine derivatives. First, we examined the chlorocyclization of 1a using NCS in the presence of 5 mol % of Lewis base (Table 1). When 2a was used as a Lewis base, no product was obtained (entry 1). In the case of 2b and 2c, the reaction was sluggish (entries 2 and 3). Interestingly, when 2c was used in the presence of 5 mol % of I2, the yield improved to 23% (entry 4). By screening the selenium catalysts, we found that diphenyl diselenide 2d dramatically improved the catalytic activity. As a result, 3a was obtained in 98% yield in only 10 min (entry 5). In the presence of 5 mol % of I2, the amount of 2d could be reduced to 0.1 mol % without decreasing the yield (entry 6). In contrast, control experiments in the absence of I2 and 2d did not give any products (entries 7 and 8). Moreover, other reactive chlorinating reagents did not give the corresponding product (see Scheme S1 in the Supporting Information). These results indicated the activation of NCS and selective chlorocyclization by this selenium−iodine cooperative system. With the optimized conditions in hand, we investigated the substrate scope of tryptamines 1 (Table 2). With regard to the N-protecting group on indole, electron-withdrawing Ts
lectrophilic cyclization of tryptamines has been recognized as a powerful method for constructing C3a-substituted hexahydropyrrolo[2,3-b]indoles,1 which are present in diverse biologically active indole alkaloids (Figure 1A).2,3 Therefore,
Figure 1. (A) Representative C3a-substituted hexahydropyrrolo[2,3b]indole alkaloids. (B) Halocyclization of tryptamine derivatives.
various electrophiles have been explored for the cyclization of tryptamines.4 The halocyclization of tryptamines is one of the most useful cyclizations since the corresponding product can be transformed to various C3a-substituted hexahydropyrrolo[2,3b]indoles (Figure 1B). In particular, several excellent methods for bromocyclization have been developed, and transformations to natural products have been reported.5,6 In contrast, there have been few studies on the chlorocyclization of tryptamines, despite promising transformations of the chlorinated product.7 So far, only five substrates have been used for the chlorocyclization of tryptamines.8 In general, chlorinating reagents, such as N-chlorosuccinimide (NCS), are less reactive than the corresponding brominating reagents.9,10 Furthermore, side reactions, such as the overchlorination of aromatic rings and the oxidation of indoles, decrease the yield of the desired product in the case of a highly active chlorinating reagent. In the conventional methods, the inherent reactivity of chlorinat© 2017 American Chemical Society
Received: August 22, 2017 Published: September 28, 2017 5525
DOI: 10.1021/acs.orglett.7b02613 Org. Lett. 2017, 19, 5525−5528
Letter
Organic Letters Table 1. Screening of Catalystsa
(1m) and tryptophol (1n) (Figure 2). Thus, hydroxycarbonyl and hydroxyl groups in 1 could be tolerated in our catalytic
entry
cat. (mol %)
I2 (mol %)
yieldb (%)
1 2 3 4 5 6 7 8
Ph3PO 2a, 5 Ph3PS 2b, 5 Ph3PSe 2c, 5 2c, 5 PhSeSePh 2d, 5 2d, 0.1 2d, 5 without catalyst
0 0 0 5 5 5 0 5
0 4 7 23 98c,d 98c,e 0 0
a
The reaction was carried out with catalyst (5 mol %), 1a (1 equiv), and NCS (1.2 equiv) in CH2Cl2 at 0 °C for 0.5 h unless otherwise noted. bYield was determined by 1H NMR analysis using 1,3,5mesitylene as an internal standard. cIsolated yield. dThe reaction time was 10 min. eThe reaction time was 24 h. Figure 2. Substrate scope of 3-substituted indoles 1m and 1n and Ltryptophan derivatives 1o−q. The reaction was carried out with 5 mol % each of 2d and I2 in CH2Cl2 at 0 °C unless otherwise noted. (a) Toluene was used as a solvent. (b) The reaction was carried out with 10 mol % each of 2d and I2.
Table 2. Chlorocyclization of Tryptamine Derivatives 1a
1
entry
R
1 2 3 4 5 6 7 8 9 10 11
H H H H Me MeO Br Cl F H H
2
3
4
R
R
R
3
yield (%)
Ts Cbz Troc Boc Boc Boc Boc Boc Boc Boc Boc
H H H H H H H H H Me CH2CH2CO2Et
CO2Me CO2Me CO2Me Boc Boc Boc Boc Boc Boc Boc CO2Me
3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l
98 92 98 97 97 95 92 92 91 99 70b
system. Chlorocyclization of L-tryptophan methyl ester derivatives 1o−q was also demonstrated. The 1 g scale synthesis of 3o was performed in the presence of 5 mol % each of 2d and I2. In Somei’s report, L-tryptophan methyl esters gave a diastereomeric mixture of the product at room temperature (dr = 51:49). 8b In sharp contrast, high diastereoselectivities were achieved at 0 °C. Because of the activated chlorinating reagent in our system, the reaction could proceed in nonpolar solvent at low temperature without a loss of diastereoselectivity. According to Gong’s report, the resulting products, such as 3q, were converted to C3a-aryl-substituted hexahydropyrrolo[2,3-b]indoles by the nickel(II)-catalyzed cross-coupling reaction.7 Due to the remaining challenge of introducing an aromatic group at the C3a position,4f chlorocyclization should be an efficient method for synthesizing various C3a aryl hexahydropyrrolo[2,3-b]indoles. To demonstrate the utility of the chlorinated product 3, we performed transformations to introduce nucleophiles at the C3a position (Scheme 1). Since the C3a-N1′ indole dimeric structure has been discovered in biologically active natural products, introduction of N1′ of indole to the C3a position is important.15 When 3q was treated under basic conditions in the presence of indole, 4a was obtained in 73% yield as a single diastereomer.16 The formal total synthesis of (−)-psychotriasine was also accomplished under similar conditions.5j When 3o was used in the presence of a 3-substituted indole derivative under basic conditions, 4b was obtained in 88% yield as a single diastereomer. Whereas 3-substituted indoles are often problematic with the use of a bromo analogue of 3o, they did not affect the reaction when chlorinated product 3o was used. We also demonstrated the allylation of 3q for the formal total synthesis of (−)-acetylardeemin, which is a promising anticancer agent.5e When prenyltributylstannane was used as a nucleophile, the key intermediate 4c was obtained in 68% yield. In short, chlorinated products should be promising candidates for the introduction of various nucleophiles to the C3a position.
a
The reaction was carried out with 2d (5 mol %), I2 (5 mol %), 1 (1 equiv), and NCS (1.2 equiv) in CH2Cl2 at 0 °C unless otherwise noted. bThe reaction was carried out with 2d (10 mol %) and I2 (10 mol %) for 48 h.
(SO2C6H4-Me), Cbz (CO2Bn), Troc (CO2CH2CCl3), and Boc (CO2tBu) gave the corresponding product 3 in high yield (entries 1−4). These electron-withdrawing N-protecting groups generally decrease the yield in chlorocyclization due to the less nucleophilic indole moiety.7 However, our catalyst system was effective for these substrates 1 because of the highly reactive chlorinating reagent generated by a selenium−iodine cooperative catalyst. Moreover, a variety of 5-substituted tryptamines could be successfully used. Electron-donating methyl and methoxy groups as well as electron-withdrawing halo substituents at the 5-position were tolerated (entries 5−9). 2-Substituted tryptamines could also be used. A methyl group did not affect the yield (entry 10). However, a 3-ethoxy-3oxopropyl group (3l) decreased the yield to 70% in the presence of 10 mol % each of 2d and I2 (entry 11). With regard to the internal nucleophilic moiety of 1, we demonstrated the chlorocyclization of indole-3-acetic acid 5526
DOI: 10.1021/acs.orglett.7b02613 Org. Lett. 2017, 19, 5525−5528
Letter
Organic Letters
iodide. Subsequently, phenylselenyl iodide is oxidized by NCS,18 and the resulting 6 acts as an electrophile for the selenocyclization of tryptamine.19,20 Deselenation of 7 is induced by the electron-rich indole ring to form an iminium cation intermediate. Subsequent nucleophilic attack of Cl− to iminium cation gives the corresponding 3. In summary, we have developed a chlorocyclization of tryptamines through the use of selenium−iodine cooperative catalysts. In the presence of 0.1−5.0 mol % of diphenyl diselenide with 5 mol % of I2, smooth conversion was established at 0 °C within 10 min ∼ 48 h at 0 °C. In sharp contrast to the conventional system,8 this approach offers a broad substrate scope and a short reaction time. Moreover, the formal total syntheses of (−)-psychotriasine and (−)-acetylardeemin were achieved.
Scheme 1. Transformation of 3o and 3q for the Formal Total Synthesis of (−)-Psychotriasine and (−)-Acetylardeemin, Respectively
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02613. Full experimental procedures, characterization data, and NMR spectra data (PDF)
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Next, we turned our attention to the reaction mechanism. A stoichiometric reaction was carried out in the presence of NCS and 50 mol % each of 2d and I2 (Scheme 2). As a result,
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Scheme 2. Isolation of the Intermediate
Kazuaki Ishihara: 0000-0003-4191-3845 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was supported in part by JSPS KAKENHI (Grant Nos. 15H05755, 15H06266, and 17K14484), Program for Leading Graduate Schools “IGER program in Green Natural Sciences”, the Toyoaki Scholarship Foundation, and MEXT, Japan. We thank Dr. Kenji Yamashita (Nagoya University) for his assistance with the NMR analysis and Ms. Mie Torii (Nagoya University) for her assistance with the VT-NMR analysis.
selenocyclized intermediate 5 was obtained in 42% yield after reductive quenching. In situ 1H NMR and 77SeNMR analyses revealed that a selenium(IV) species derived from 5 might be the intermediate of chlorocyclization (see Figures S1 and S2 in the Supporting Information).17 Taking into account these results, we proposed the reaction mechanism (Figure 3). When 2d is mixed with I2, the selenium−selenium bond is cleaved to give phenylselenyl
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02613 Org. Lett. 2017, 19, 5525−5528
