Kejing
Xie‡
a,
Zeyuan
Shen‡
b,
Peng
Cheng
a,
Haoxiang
Dong
a,
Zhi-Xiang
Yu
*b and
Liansuo
Zu
*a
aSchool of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing 100084, China. E-mail: zuliansuo@tsinghua.edu.cn
bBeijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China. E-mail: yuzx@pku.edu.cn
First published on 5th July 2024
The Pictet–Spengler type condensation of tryptamine derivatives and aldehydes or ketones is a classic reaction, and has been previously applied to assemble indole-annulated 5-, 6- and 8-membered heterocyclic rings. In this work, we further expand the synthetic scope of this reaction to the 7-membered azepino[4,5-b]indole skeleton through the direct C–H functionalization of 2-alkyl tryptamines, in which the non-activated methylene group participates in a 7-membered ring formation with aldehydes. By combining this unprecedented ring-forming process with a second C–H olefination at the same carbon, the concise total synthesis of natural products ngouniensines is achieved, demonstrating the synthetic potential of the developed chemistry in simplifying retrosynthetic disconnections.
The 7-membered azepino[4,5-b]indole skeleton (IV, Fig. 1) is characteristic of a variety of indole alkaloids, as exemplified by the structures of ngouniensines (1a, 1b), ibogaine and many others.6–16 The significance of the azepino[4,5-b]indole skeleton as an essential therapeutic pharmacophore has been recently highlighted by the structural simplification of ibogaine, leading to the development of tabernanthalog (Fig. 1) as a safer and non-hallucinogenic psychedelic analog with therapeutic potential.17 In contrast to the structural and biological importance of the azepino[4,5-b]indole skeleton (IV), relatively few synthetic methods have been developed for its synthesis, which mainly have relied on the inherent reactivity of functional groups toward ring forming processes.18–31 While a variety of azepino[4,5-b]indoles with varied substitution patterns could be thus generated, the resulting structural diversity could not fully meet the demand for the synthesis of natural products and diversified synthetic analogs. Herein, we report an unprecedented approach for the synthesis of the azepino[4,5-b]indole skeleton by the direct C–H functionalization of 2-alkyl tryptamines, and showcase the synthetic utility in the concise total synthesis of ngouniensines.
The application of C–H functionalization logic in chemical synthesis has become a vibrant research area due to the admirable ability in simplifying retrosynthetic disconnections by avoiding the preinstallation of requisite functional groups.32 The indole alkaloids ngouniensines (1a, 1b)33,34 structurally feature the azepino[4,5-b]indole core and an exocyclic conjugated alkene, which were both constructed by the manipulation of preinstalled functional groups in the previous synthesis.6 We surmised to develop a C–H functionalization based approach, not only to offer a concise entry to ngouniensines, but also to facilitate the preparation of azepino[4,5-b]indole containing molecules in general. Specifically, as depicted in Fig. 1, we envisioned to construct the azepino[4,5-b]indole skeleton by the direct C–H functionalization of 2-alkyl tryptamines 2, in which the non-activated methylene at C2 would participate in a 7-membered ring formation with aldehydes 3. The direct coupling of 2 and 3 could be regarded as a homologated Pictet–Spengler condensation, which, if realized, would further expand the synthetic scope of this classic reaction beyond the indole-annulated 5-, 6- and 8-membered heterocyclic skeletons (I–III, Fig. 1). The exocyclic conjugated alkene in ngouniensines could be introduced by a second C–H functionalization of the same carbon with formaldehyde (R1 = H). Based on the above hypothesis, the chemical synthesis of ngouniensines could be attempted with unconventional bond disconnection tactics.
Entry | Acid | Solvent | Yieldb (%) |
---|---|---|---|
a A mixture of 2a (0.2 mmol) and 3a (0.4 mmol) in the specified solvent (0.2 M) was stirred at rt in the presence of the specified acid. b Isolated yield. rt = room temperature. TFA = trifluoroacetic acid. CSA = camphorsulfonic acid. p-TsOH = p-toluenesulfonic acid. | |||
1 | AcOH (2.0 equiv.) | CHCl3 | 11 |
2 | CSA (2.0 equiv.) | CHCl3 | Trace |
3 | p-TsOH (2.0 equiv.) | CHCl3 | Trace |
4 | (PhO)2POOH (2.0 equiv.) | CHCl3 | Trace |
5 | TFA (2.0 equiv.) | CHCl3 | 52 |
6 | TFA (1.0 equiv.) | CHCl3 | Trace |
7 | TFA (4.0 equiv.) | CHCl3 | 85 |
8 | TFA (6.0 equiv.) | CHCl3 | 60 |
9 | TFA (4.0 equiv.) | CH2Cl2 | 80 |
10 | TFA (4.0 equiv.) | Toluene | 56 |
With the reaction conditions identified, the substrate scope of the condensation of tryptamine derivatives 2 with different aliphatic aldehydes 3 was investigated (Scheme 1). It turned out that the reaction represented a general approach for the synthesis of azepino[4,5-b]indoles 4, tolerating significant structural variations of both partners. A variety of linear aldehydes of different size were successful substrates, generating the corresponding products with good to excellent yield (4a–f). The steric more hindered branched aldehydes containing isopropyl-, cyclopentyl- and cyclohexyl-groups also proved to be efficient substrates (4g–i). Of note, the reaction could tolerate the presence of heterocyclic furan (4j), which is also a good nucleophile for the Pictet–Spengler type reaction and could potentially interact with the related active intermediates. When R1 was a methyl (4k) or phenyl group (4l), both reactions proceeded well with good yields, but the diastereoselectivity was different. The poor diastereoselectivity of 4k and excellent diastereoselectivity of 4l indicated the importance of steric effect of R1 in governing the stereochemistry. The relative stereochemistry of 4l was determined by single crystal X-ray diffraction of a derivative. Substituents (X) on the benzenoid part of 2 were also well tolerated, including both electron donating and withdrawing groups at the varied positions (4m–4r, 4u, 4w). Finally, the substrate with a methyl group on indole-N also participated in the condensation process with good yield (4s). While attempts to make the process catalytically enantioselective using chiral Brønsted acids were not successful at this stage, the direct condensation for 7-membered ring formation could be rendered asymmetric by using a chiral tryptophan derivative, affording product 4t with 7:
1 diastereoselectivity. The relative stereochemistry of 4t was determined by single crystal X-ray diffraction of a derivative. Of note, when aromatic benzaldehyde was allowed for the condensation with tryptamine derivatives 2a, the reaction did not lead to the formation of the related 7-membered ring, instead the generation of alkene 5 was observed under slightly varied conditions.
The total synthesis of ngouniensines was then realized based on the developed sequential C–H functionalization (Scheme 2). The first C–H functionalization involving the coupling of 2a and rac-3v41 successfully built up the azepino[4,5-b]indole core, affording rac-4v in 86% yield with 1:
1 dr. The second C–H functionalization of rac-4v with formaldehyde rapidly installed the exocyclic conjugated alkene, delivering rac-7 upon subsequent amide formation with K2CO3. Finally, reduction of the amide group produced the natural products (±)-ngouniensines (1a
:
1b = 1
:
1). While the synthesis was carried out using rac-3v, the absolute chirality could be easily introduced by the known enantioselective hydrogenation (3v–a to 3v–b).42
While it was difficult to validate the proposed mechanism by the synthesis of a substrate resembling B or C due to its reversible transformation back to A under the acidic reaction conditions, some experimental observations supported the presence of intermediate C and the essential role of D. The reaction of bulky 2-iPr tryptamine 8 with aldehyde 3a afforded the oxindole 9 as the major product, presumably involving the oxidation of enamine C by oxygen (intermediate F).43,44 In another control study, the Bn-protected 2-Me-tryptamine 10 failed to give the corresponding product 11. According to the proposed reaction mechanism, this could be explained by the fact that the resulting G could not lead to the formation of intermediate D due to the presence of the Bn group.
To gain more insight, DFT calculations were carried out (Scheme 3). The reaction of substrate 2a and acetaldehyde was chosen as the model reaction, and calculated at the SMD(CHCl3)/PBE0-D3BJ/6-311+G(d,p)//PBE0-D3BJ/6-31+G(d,p) level. One of the key steps, the tautomerization of the spiroindolenine (Int2) to enamine (Int3) has an activation free energy of 13.6 kcal mol−1 (viaTS2). The key ring forming event probably undergoes a Mannich/retro-Mannich pathway with the activation free energy of 3.8 kcal mol−1 (TS3) and 7.9 kcal mol−1 (TS4), respectively. The Gibbs free energy profile involving the concerted [3,3]-sigmatropic rearrangement pathway could not be located. Of note, a similar retro-Mannich reaction was previously reported by the group of You, involving an intermediate resembling Int5.25
Footnotes |
† Electronic supplementary information (ESI) available. CCDC 2284681, 2284682 and 2284683. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4sc02802c |
‡ These authors contributed equally to this work. |
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