Letter Cite This: Org. Lett. 2018, 20, 4015−4019
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Base-Mediated Cascade Cyclization: Stereoselective Synthesis of Benzooxazocinone Chiranan Pramthaisong,† Rattana Worayuthakarn,‡ Vannapha Pharikronburee,‡ Tanwawan Duangthongyou,§,⊥ Ramida Rattanakam,§,⊥ Somsak Ruchirawat,†,‡,∥ and Nopporn Thasana*,†,‡,∥ †
Chemical Biology Program, Chulabhorn Graduate Institute, Laksi, Bangkok 10210, Thailand Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand § Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok 10903, Thailand ∥ Center of Excellence on Environmental Health and Toxicology, Ministry of Education, Bangkok, Thailand
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‡
S Supporting Information *
ABSTRACT: A new strategy for the synthesis of the oxa-azabicyclo[3.3.1]nonane subunit, a component of the naucleamide E core structure, has been developed. This annulation reaction between 1-substituted 3,4-dihydroisoquinolines and coumarin derivatives conveniently affords the oxa-azabicyclo[3.3.1]nonane framework via a base-mediated cascade cyclization under aqueous conditions. The value of this work lies in the efficient formation of the oxa-azabicyclo[3.3.1]nonane skeleton via a process whereby all the C−C, C−O, and C−N bond formations occur in a single chemical operation. In addition, the subsequent ring opening of these compounds furnished pyridoisoquinoline derivatives.
T
indole alkaloid which contains a pentacyclic ring system with an amide acetal bridge. It was isolated from the bark and wood of Nauclea latifolia (Rubiaceae) and exhibits antiproliferative, antiparasitic, and antimicrobial activities.1 Larutensine (3) is an alkaloid isolated from the bark and stems of Kopsia larutensis (Plumerioideae).2 Calycinumine B (4) was isolated from Daphniphyllum calycinum (Daphniphyllaceae) and has been found to exhibit cytotoxic activity against some tumor cell lines.3 Spiramide A (5), isolated from Spiraea japonica L. fil var. acuminata (French), has anti-inflammatory activities. 4 Although syntheses of some of these compounds have been reported,5−9 efficient construction of the oxa-azabicyclo[3.3.1]nonane core remains a challenge. Yang and co-workers constructed the oxa-azabicyclo[3.3.1]nonane subunit using four components: anisidines 8, aromatic aldehydes 9, isobutylaldehyde 10, 4-hydroxycoumarins 11, and Yb(OTf)3 as the catalyst in a tandem one-pot reaction (Scheme 1, eq 1).5 They further studied oxa-azabicyclo[3.3.1]nonane-containing compounds for their photophysical properties and discovered photochromism of the o-nitrophenyl substituted oxa-azabicycles.6 The reaction of 2-hydroxychalcones 13, 4-
he heterobicyclic N,O-acetal-containing framework 1 can be found embedded in numerous natural products such as naucleamide E (2),1 larutensine (3),2 calycinumine B (4),3 and spiramide A (5)4 (Figure 1). They display interesting biological activities. Naucleamide E (2) is a monoterpene
Figure 1. Natural products containing the oxa-azabicyclo[3.3.1]nonane and pyridoisoquinoline subunits. © 2018 American Chemical Society
Received: May 18, 2018 Published: June 25, 2018 4015
DOI: 10.1021/acs.orglett.8b01573 Org. Lett. 2018, 20, 4015−4019
Letter
Organic Letters
The requisite starting materials, 3,4-dihydroisoquinoline derivatives (22), were obtained by acetylation of the arylethylamines which gave the corresponding acetamide derivatives.15 Then, the acetamide derivatives were subjected to Bischler−Napieralski cyclization using POCl3 to give the iminium salts which were subsequently basified to form the imines 22.15 1-Methyl-3,4-dihydroisoquinoline 22a and 2Hchromen-2-one 23a were used as model substrates in order to screen for the optimal conditions as shown in Table 1.
Scheme 1. Reported Synthetic Methodologies for the Preparation of the Oxa-azabicyclo[3.3.1]nonane Subunit
Table 1. Optimization of Reaction Conditions for a MetalFree Cascade Cyclization of 1-Methyl-3,4dihydroisoquinoline (22a) and Coumarin (23a)
entry 1 2 3 4 5 6 7 8 9
hydroxycoumarin 11, and aqueous ammonia under catalystfree conditions which chemoselectively furnished the corresponding functionalized 2,8-oxa-azabicyclo[3.3.1]nonanes 14 is another synthetic approach reported by Yin (Scheme 1, eq 2).7 The Krawczyk and Katritzky groups described the stereoselective synthesis of benzo[1,3]oxazocine products 18 and 21 using three components: coumarins 15 or 19, containing electron-withdrawing groups at position 13, enolizable ketones 16 or 20, and nonbulky primary amines 17 (Scheme 1, eqs 3 and 4).8,9 As previously developed by our group, the synthesis of tricyclic benzo[a]quinolizin-4-ones from the annulation of 1substituted 3,4-dihydroisoquinoline with azlactones, under neutral conditions, can be achieved in only one step.10,11 With the aim of synthesizing this heterobicyclic N,O-acetal moiety via a new synthetic strategy, we investigated a new annulation between 1-substituted 3,4-dihydroisoquinoline 22 and coumarin derivatives 23. It was anticipated that this tandem C−C, C−O, and C−N bond-forming reaction would occur under aqueous conditions (Scheme 1, eq 5). Moreover, the chemoselective C−O bond cleavage ring opening of compound 24 was anticipated to furnish the corresponding pyridoisoquinoline 25 (Scheme 1, eq 5), which can be found as a core structure in some bioactive natural products. For example, anthirine or antirhine 6, isolated from Rhazya stricta, showed a convulsive effect, muscle-relaxant activity, and antiplasmodial activity against Plasmodium falciparum. Protoemetine 7, isolated from Cephaelis ipecacuanha, can be used to stimulate the central nervous system and induce vomiting by triggering the center of the medulla (Figure 1).12−14
10 11 12 13 14 15b 16c 17d
base 0.2 equiv of K2CO3 0.2 equiv of K2CO3 0.2 equiv of K2CO3 0.2 equiv of K2CO3 0.3 equiv of DBU 0.5 equiv of NaOAc 0.2 equiv of Na2CO3 0.2 equiv of Na2CO3 0.2 equiv of Na2CO3 0.2 equiv of Na2CO3 0.3 equiv of Na2CO3 0.4 equiv of Na2CO3 0.5 equiv of Na2CO3 1 equiv of Na2CO3 0.3 equiv of Na2CO3 0.3 equiv of Na2CO3 −
temp (°C)
time (h)
yield (%)a
MeCN MeCN DMSO DMSO DMSO DMSO
rt 80 80 100 80 80
168 16 16 18 16 16
trace trace 17 72 trace trace
DMSO
80
16
86
DMSO:H2O
80
16
77
MeOH
80
24
89
H2O
80
24
89
H2O
80
16
98
H2O
80
20
84
H2O
80
20
89
H2O H2O
80 80
20 20
77 95
H2O
80
20
96
H2O
80
24
N/A
solvent
a
Isolated yield. bCoumarin (2.3 equiv). cCoumarin (5.3 equiv). dN/A = no reaction.
Initially, a 1:1.3 mixture of compounds 22a and 23a in acetonitrile was treated with 0.2 equiv of K2CO3 at room temperature. The reaction was monitored by TLC and was allowed to stir for 1 week. Only a trace amount of the desired product 24a was observed (Table 1, entry 1). Therefore, the reaction was heated to 80 °C for 16 h, but again, only a trace amount of 24a was formed (Table 1, entry 2). The product 24a was obtained in higher yield (17%) when DMSO was used as a solvent at 80 °C (Table 1, entry 3). Raising the reaction temperature from 80 to 100 °C dramatically increased the yield of the desired product to 72% (Table 1, entry 4). Motivated by this result, we decided to vary both the type and the amount of the bases (Table 1, entries 4−7). The results revealed that using 0.2 equiv of Na2CO3 at 80 °C gave the product in a very good yield (86%) (Table 1, entry 7). Then, 4016
DOI: 10.1021/acs.orglett.8b01573 Org. Lett. 2018, 20, 4015−4019
Letter
Organic Letters Scheme 2. Substrate Scope for Compounds 24a−ta
other more environmentally friendly solvent systems were employed as alternatives. A solvent mixture of DMSO/H2O (1:1) gave a lower yield (77%) of 24a than DMSO alone (Table 1, entry 8). However, when either MeOH or water was used alone, the yields increased up to 89% (Table 1, entries 9 and 10). Therefore, we focused on the use of environmentally friendly conditions. Various amounts of the base Na2CO3 were studied in aqueous solution (Table 1, entries 10−14). An excellent 98% yield of the product was obtained when 0.3 equiv of Na2CO3 was employed in aqueous solution at 80 °C (Table 1, entry 11). The effect of increasing the amount of nonsubstituted coumarin 23a was also studied (Table 1, entries 15 and 16). We found that the products were obtained in very high yields (95−96%) when 1.3 equiv of 23a were used. When base-free conditions were used in aqueous solution at the same temperature, no reaction was observed (Table 1, entry 17). Hence, the optimal conditions utilized 0.3 equiv of Na2CO3 in aqueous solution at 80 °C for 16 h (Table 1, entry 11). The conditions were employed for our subsequent study of the scope of substrates. With the optimal reaction conditions in hand, the annulation of two substrates, 1-substituted dihydroisoquinoline or dihydro-β-carboline derivatives 22 and coumarin derivatives 23, was studied to provide a library of oxa-azabicyclo[3.3.1]nonane derivatives 24a−t as shown in Scheme 2. In the first series, nonsubstituted coumarin 23a was coupled with three different derivatives of compound 22: 6,7dimethoxy-1-methyl-3,4-dihydroisoquinoline 22a, 6,7-dimethoxy-1-ethyl-3,4-dihydroisoquinoline 22b, and 6,7-methylenedioxy-1-methyl-3,4-dihydroisoquinoline 22c. All the reactions gave the corresponding products 24a−c in good to excellent yields (88−98% yields). Furthermore, the reactions of imines 22a−c with the 7-substituted coumarins 23b−c, which possessed a hydroxyl group (R5 = OH) or methoxy group (R5 = OCH3) as the substituents, provided the desired products 24d−h in moderate to good yields (44−88% yields). Our reaction conditions could be used to synthesize the annulated products 24i−m from disubstituted coumarins in moderate to good yields as well. More structurally complex products 24n−p were also obtained from the annulation between dihydro-β-carboline and coumarin derivatives in moderate to very good yields. The reaction of 6,7dimethoxy-1-benzyl-3,4-dihydroisoquinoline and coumarin 23a gave the desired product 24q in a 59% yield. Three 3substituted coumarins were evaluated with 1-methyl-3,4dihydroisoquinoline and provided the corresponding products 24r−t in moderate to good yields (33−70% yields). The following observations were made concerning the above reaction. The R1 substituent of 3,4-dihydroisoquinolines had little effect on the product yield, while the size of R2 substituents affected the yield. For 22f, the bulkiness of the phenyl group caused an unfavorable conformation during the cyclization process. Another explanation could be that the benzylic position of 1-benzyl-3,4-dihydroisoquinoline is easily oxidized to a carbonyl, which would prevent the 1,4-addition with coumarins. A limitation of this method was observed in the annulation of imine 22a with 4-hydroxycoumarin (23i), 2-quinolone (23j), and ethyl cinnamate (26a), all of which gave no reaction. However, the reaction was found to proceed with more potent Michael acceptors such as diethyl 2-(benzylidene) malonate (26b) and 5-(benzylidene)-1,3-dioxane-4,6-dione
a
Unless otherwise noted, the reactions were carried out using 1 equiv of 1-substituted dihydroisoquinoline or dihydro-β-carboline derivatives 22a−f and 1.3 equiv of coumarin derivatives 23a−h in water (1.0 mL) at 80 °C for 16−20 h on a 0.2 mmol scale. Isolated yields are shown.
(27) to give 2-aryl-6,7-dihydropyrido[2,1-a]isoquinolin-4ones (28a−b) as shown in Scheme 3. Given that the reaction did not proceed in the absence of base, we concluded that a base was required for the imine-enamine tautomerization. To demonstrate the role of the base in the reaction, deuterium oxide was used as the reaction solvent, instead of water, to monitor the incorporation of deuterium atoms in the desired products 22a-d3, 24a-d3, and 24b-d2 (Scheme 3). Imine− enamine tautomerization of the intermediate I-1 might incorporate the deuterium atom(s) from the deuterated solvent. Tautomerization between an enolate and a ketone of the intermediate I-3 could also trap the deuterium atom from the deuterated solvent at the α-carbonyl to give compounds 24a-d3 4017
DOI: 10.1021/acs.orglett.8b01573 Org. Lett. 2018, 20, 4015−4019
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Organic Letters
group on the ring-bridge carbon was anti to the oxygen atom of the oxa-azabicyclo[3.3.1]nonane subunit and syn to the methine proton.
Scheme 3. Control Experiments
Figure 2. An ORTEP drawing of compound 24b by X-ray crystallographic analysis.
The pyrido[2,1-a]isoquinoline scaffold 25 could easily be obtained via reduction of the products 24a and 24b by using LiAlH4 (Scheme 5).16,17 This scaffold is found in a number of Scheme 5. Synthesis of Pyrido[2,1-a]isoquinolines 25a−b
and 24b-d2. No deuterium was incorporated when compound 24a was subjected to the optimal conditions, suggesting that intermediate I-3 could not be generated from compound 24a under such conditions. Taking into account the deuteration results, a plausible mechanism is proposed in Scheme 4. Under basic conditions
natural products as shown in Figure 1. We envision that the development of this chemistry will be useful for the synthesis of such derivatives. The cytotoxicity of compounds 24a−q and 25a−b was evaluated using MTT and XTT assays.18 Cell lines used in this test were hepatocarcinoma (HepG2), acute lymphoblastic leukemia (MOLT-3), lung carcinoma (A549), and cholangiocarcinoma (HuCCA-1).18 Compound 24h showed toxicity against HepG2 and MOLT-3 cell lines having IC50 values of 20.2 and 14.7 μM, respectively. The IC50 values of compounds 24p and 25b for MOLT-3 cell lines were 20.6 and 32.2 μM, respectively (Table S8). The inhibition of acetylcholinesterase activity by the synthetic compounds 24a−q and 25a−b was evaluated by Ellman’s method,19 using AChE (from Electrophorus electricus), acetylthiocholine iodide (as a substrate), and Donepezil (as a positive control).20 The results showed that all of the synthetic compounds were inactive against acetylcholinesterase with inhibition at less than 50% at 10 μM (Table S8). In summary, in this study, we report a useful chemistry approach for the synthesis of oxa-azabicyclo[3.3.1]nonanes via the annulation between imine and coumarin derivatives, in the presence of Na2CO3 as a base under mild aqueous conditions. The one-pot tandem C−C, C−O, and C−N bond formation described in this work affords methanobenzooxazocinoisoquinolinone products in moderate to excellent yields (up to 98%). Our protocol was also extended to the synthesis of the pentacyclic indole alkaloid ring system found in some unique natural products such as naucleamide E. The ring of the product methanobenzooxazocinoisoquinolinones, which contained the oxa-azabicyclo[3.3.1]nonane subunit, was chemo-
Scheme 4. Proposed Reaction Mechanism
the imine 22 could tautomerize to an enamine and undergo a 1,4-addition reaction to the β-position of the coumarin 23, which would construct the first C−C bond to generate intermediate I-1. The ring opening of chromenolate I-1 could form the ketene phenolate intermediate I-2 which would cyclize to form the pyridoisoquinolinone I-3 by simultaneous nucleophilic attack of the phenoxide on the imine followed by the imine on the ketene. Subsequent protonation (or deuteration) would yield the N,O-acetal 24. The relative stereochemistry of 24b was determined to be trans with respect to the ring oxygen and the methyl group by X-ray crystallography (Figure 2). The orientation of the methyl 4018
DOI: 10.1021/acs.orglett.8b01573 Org. Lett. 2018, 20, 4015−4019
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Organic Letters
(5) Lai, J.; Shieh, P.; Huang, W.; Yang, D. J. Comb. Chem. 2008, 10, 381−386. (6) Lin, W.; Yang, D. J. Org. Chem. 2013, 78, 11798−11806. (7) Rao, Y.; Liu, M.; Wu, L.; Yin, G. RSC Adv. 2014, 4, 64551− 64558. (8) Deredas, D.; Albrecht, Ł.; Maniukiewicz, W.; Wojciechowski, J.; Wolf, W. M.; Paluch, P.; Janecki, T.; Rózȧ lski, M.; Krajewska, U.; Janeckae, A.; Krawczyk, H. RSC Adv. 2013, 3, 6821−6832. (9) Detistov, O.; Panda, S.; Steel, P.; Asiri, A.; Hall, C.; Katritzky, A. Synlett 2014, 25, 2654−2660. (10) Worayuthakarn, R.; Thasana, N.; Ruchirawat, S. Org. Lett. 2006, 8, 5845−5848. (11) Nealmongkol, P.; Tangdenpaisal, K.; Sitthimonchai, S.; Ruchirawat, S.; Thasana, N. Tetrahedron 2013, 69, 9277−9283. (12) Massiot, G.; Thepenier, T.; Jacquier, M.; Men-Olivier, L.; Verpoorte, R.; Delaude, C. Phytochemistry 1987, 26, 2839−2846. (13) Ishikawa, H.; Shiomi, S. Org. Biomol. Chem. 2016, 14, 409−424. (14) Chen, W.; Seidel, D. Org. Lett. 2016, 18, 1024−1027. (15) Pabuccuoglu, V.; Hesse, M. Heterocycles 1997, 45, 1751−1758. (16) Dolfen, J.; Vervisch, K.; De Kimpe, N.; D’hooghe, M. Chem. Eur. J. 2016, 22, 4945−4951. (17) Hou, S.; Tu, Y.; Wang, S.; Xi, C.; Zhang, F.; Wang, S.; Li, Y.; Liu, L. Angew. Chem., Int. Ed. 2016, 55, 4456−4460. (18) Boonya-udtayan, S.; Yotapan, N.; Woo, C.; Bruns, C. J.; Ruchirawat, S.; Thasana, N. Chem. - Asian J. 2010, 5, 2113−2123. (19) Ellman, G. L.; Courtney, K. D.; Andres, V.; Featherstone, R. M. Biochem. Pharmacol. 1961, 7, 88−95. (20) Nilsu, T.; Thorroad, S.; Ruchirawat, S.; Thasana, N. Planta Med. 2016, 82, 1046−1050.
selectively cleaved at the N,O-acetal to give the 2-(hexahydropyridoiso-quinoline-2-yl)phenol derivatives under reductive conditions using LiAlH4. This scaffold can also be found in many alkaloid natural products.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01573. Experimental procedures, biological activity testing table, X-ray crystallographic analysis, and spectral data for all new compounds (PDF) Accession Codes
CCDC 1413117 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.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Nopporn Thasana: 0000-0002-0572-4871 Author Contributions ⊥
T.D. and R.R. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was partially supported by the Thailand Research Fund (TRF; BRG5680005 for N.T.) and Mahidol University, The Scientists Development Scholarship in Honour of His Magesty the King (for C.P.). Support from the Center of Excellence on Environmental Health and Toxicology, Science & Technology Postgraduate Education and Research Development Office (PERDO), Ministry of Education is also gratefully acknowledged. The authors thank Dr. Christian Fuchs, Chulabhorn Research Institute for the preliminary experiment; Ms. Pakamas Intachote and Ms. Busakorn Saimanee, Chulabhorn Research Institute for MTT and XTT assays; and Mr. Thanasan Nilsu and Dr. Pornkanok Pongpamorn, Chulabhorn Graduate Institute, for acetylcholinesterase inhibitory assay. The authors thank Emeritus Prof. Minoru Isobe, Nagoya University, Japan, and Assoc. Prof. Roderick Bates, Nanyang Technology University, Singapore, for their comments on the manuscript.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b01573 Org. Lett. 2018, 20, 4015−4019
