One-Pot Total Synthesis of Evodiamine and Its Analogues through a

Letter Cite This: Org. Lett. 2018, 20, 6380−6383

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One-Pot Total Synthesis of Evodiamine and Its Analogues through a Continuous Biscyclization Reaction Zi-Xuan Wang,† Jia-Chen Xiang,† Miao Wang,† Jin-Tian Ma,† Yan-Dong Wu,† and An-Xin Wu*,†,‡ †

Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China ‡ State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China Org. Lett. 2018.20:6380-6383. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 10/19/18. For personal use only.

S Supporting Information *

ABSTRACT: The one-pot total synthesis of evodiamine and its analogues is achieved using a three-component reaction. Through continuous biscyclization, various readily available substrates with good functional group tolerance were easily incorporated into biologically active quinazolinocarboline backbones. The use of triethoxymethane as a cosolvent was crucial for this quick and straightforward transformation.

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Scheme 1. Conventional Methods and Our Approach to the Synthesis of Evodiamine

vodiamine is a kind of natural quinazolinocarboline alkaloid isolated from Evodia rutaecarpa1a and an important ingredient in the Chinese herbal medicine WuChu-Yu. The polycyclic evodiamine and its analogues containing a privileged indole moiety1b−d exhibit various pharmaceutical activities,2 such as anti-inflammation2b and antiobesity. Although much attention has been attracted for the study of their biological and pharmaceutical properties,3 synthetic methods toward them are limited, especially regarding one-pot protocols. Common stepwise synthetic routes for this scaffold are divided into two categories: (i) preferential construction of the C ring4 and (ii) preferential construction of the D ring.5 For instance, the reaction of tryptamine and ethyl formate could afford the key imine intermediate i through a two-step reaction which requires toxic oxidants. The intermediate i could then undergo cyclization with ii or iii4c to afford the evodiamine skeleton involving an imine acylation (Scheme 1a,b).4i Alternatively, Pal et al. first prepared the D ring (product iv) with tryptamine, isatoic anhydride, and glyoxylic acid as substrates through a spontaneous decarboxylation reaction. The subsequent trifluoroacetic anhydride (TFAA)-promoted Pictet−Spengler reaction led to the formation of C ring (Scheme 1c).5c Using a similar strategy, the Zhu group reported a silver nitrate catalyzed isocyanide lactamization of tryptamine and prepared methyl 2-isocyanobenzoate to construct the D ring (product iv). Without further purification, the intermediate iv could smoothly react with MeOTf and hexamethylphosphoramide (HMPA) to afford evodiamine (Scheme 1d).5d However, the methyl 2-isocyanobenzoate substrate needs two synthetic steps for preparation. These stepwise but complex protocols inspired us to develop a more concise synthetic methodology. Furthermore, one-pot © 2018 American Chemical Society

total synthesis of natural products from easily available materials is still challenging but rewarding in organic synthesis. Based on our continued interest in one-pot total syntheses of natural products,6 we have achieved the installation of the C and D rings continuously in one step through a tandem amidation/decarboxylation/Pictet−Spengler reaction to Received: August 21, 2018 Published: October 4, 2018 6380

DOI: 10.1021/acs.orglett.8b02667 Org. Lett. 2018, 20, 6380−6383

Letter

Organic Letters achieve the first one-pot synthesis of evodiamine and its analogues (Scheme 1e). We first optimized the reaction conditions for one-pot synthesis of evodiamine from tryptamine (1a) and Nmethylisatoic anhydride (2a) with triethoxymethane as the cosolvent (Table 1). Pleasingly, when 1.0 equiv of TFAA and

Scheme 2. One-Pot Synthesis of Evodiamine and Its Analoguesa

Table 1. Reaction Optimizationa

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

variation from “standard conditions” no change use DUB as base use K2CO3 as base use DMAP as base without base use TFA as acid use CF3SO3H as acid use HOAc as acid use DMF instead of DMA use NMP instead of DMA use dioxne instead of DMA use formaldehyde as carbon doner use (CH2O)n as carbon doner

time (h)/temp (°C) 3ab (%) 5/100 5/100 5/100 5/100 5/100 5/100 5/100 5/100 5/100 5/100 5/100 5/100 5/100 5/80 12/100

71 trace trace 53 12 36 48 31 70 10 52 trace trace trace 66

a

Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), TFAA (1.0 mmol), and DABCO (1.5 mmol) were added in triethoxymethane (2.0 mL) and DMA (1.0 mL), stirred at 100 °C for 5 h. Reactions were conducted in a pressure vessel. Isolated yields.

a

Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), TFAA (1.0 mmol), and DABCO (1.5 mmol) in triethoxymethane (2.0 mL) and DMA (1.0 mL), stirred at 100 °C for 5 h. Reactions were conducted in a pressure vessel. bIsolated yields.

that 3e exhibited a high antitumor efficacy as reported in the literature.7 To our satisfaction, N-methylisatoic anhydride derivatives bearing different substituents on the phenyl ring were also well tolerated. For the phenyl ring decorated with electron-donating and halogen substituents (4-OMe, 4-F, 4-Cl, 4-Br, and 5-Cl), the corresponding products (3f−j) could be obtained with good yields. Meanwhile, isatoic anhydrides with N-linear alkyl substituents were also investigated (3k−n), and good to high yields were obtained. The reaction scope was then extended to N-cycloalkyl substrates, which afforded the desired products with reasonable yields (3o, 55%; 3p, 37%). To our satisfaction, a moderate to good yield was obtained when N-propene-, N-propargyl-, and N-benzyl-substituted isatoic anhydrides were used as substrates (3s−u, 58−73%). Unfortunately, no desired product was obtained when NHisatoic anhydride was used as the substrate. The experiments were then conducted to investigate the reaction mechanism (Scheme 3). The reaction of 1a and 2a under the standard conditions without addition of triethoxymethane afforded the acylation product 4 in 86% yield, while the reaction of compound 4 with triethoxymethane under the same reaction conditions afforded the desired product 3a in 92% yield (Scheme 3a). Furthermore, compound 1a was employed to react with triethoxymethane, and compound 5 was isolated with 24% yield. However, reacting 5 with 2a did not afford 3a (Scheme 3b), which suggests that compound 5 is not the reaction intermediate. The reaction of compound 2a with triethoxymethane afforded the ring-opening product 6, which was observed as a byproduct in our model reaction.

1.5 equiv of 1,4-diazabicyclo[2.2.2]octane (DABCO) were added, the transformation proceeded smoothly in dimethylacetamide (DMA) at 100 °C (entry 1). Various bases were then screened. Although 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and K2CO3 could not promote the reaction (entries 2 and 3), 4-(dimethylamino)pyridine (DMAP) produced a mild yield (entry 4). Furthermore, a sharp decrease of yield was observed in the absence of base (entry 5). Different acids, such as trifluoroacetic acid (TFA), trifluoromethanesulfonic acid, and acetic acid, were then tested, but the yields were poor (entries 6−8). Among the solvents screened, DMA afforded the highest yield (entries 9−11). Triethoxymethane is critical for this reaction, and formaldehyde or polyoxmethyene could not afford the desired product (entries 12 and 13). The decrease of temperature from 100 to 80 °C significantly affected the reaction efficiency, and almost no desired product was obtained (entry 14). By prolonging the reaction time, a similar yield was obtained compared with the standard reaction conditions (entry 15). Based on the optimal conditions, the substrate scope was then explored (Scheme 2). Tryptamines bearing electronneutral and -donating groups at the 5-position (5-Me and 5OMe) afforded 3b and 3c in moderate yields (43 and 56%, respectively). Moreover, the halogenated (5-Cl) and hydroxyl (5-OH) substituted tryptamine derivatives were compatible with the reaction conditions, and the desired products were obtained in 68 and 28% yields, respectively. It is noteworthy 6381

DOI: 10.1021/acs.orglett.8b02667 Org. Lett. 2018, 20, 6380−6383

Organic Letters

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Scheme 3. Control Experiments and Proposal of the Reaction Mechanism

Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

An-Xin Wu: 0000-0001-7673-210X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (Grant Nos. 21472056, 21602070, and 21772051) and the Fundamental Research Funds for the Central Universities (CCNU15ZX002 and CCNU16A05002) for financial support. This work was also supported by the 111 Project B17019.

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However, no reaction was observed when compounds 6 and 1a were used as substrates (Scheme 3c). Based on these results, we proposed a possible reaction mechanism (Scheme 3d): the reaction of compound 1a with 2a first afforded the acylation intermediate 4, which was trapped by triethoxymethane to afford the cyclic intermediate 7. The compound 7 then underwent elimination reaction to afford the imide intermediate 8, which further underwent Pictet−Spengler reaction to afford the evodiamine product. In summary, we have developed the first one-pot total synthetic method for preparation of evodiamine and its analogues through a continuous biscyclization reaction. A library of polycyclic indole scaffolds bearing various substituents have been easily produced efficiently. Compared with the traditional stepwise synthetic methods, this multicomponent reaction holds the advantages of pot economy and material availability, which offers a new strategy for the preparation of the corresponding alkaloid derivatives. However, due to the limitations of the reaction, a few of products are moderate to low yield. There is space to improve the yield for one-pot total synthesis of natural products.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02667. Experimental procedures, product characterizations, crystallographic data, and copies of the 1H and 13C NMR spectra (PDF) Accession Codes

CCDC 1856975 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 6382

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DOI: 10.1021/acs.orglett.8b02667 Org. Lett. 2018, 20, 6380−6383