Total Synthesis of (±)-Minfiensine via a Formal [3+2] Cycloaddition

San Diego , California 92121 , United States. J. Nat. Prod. , Article ASAP. DOI: 10.1021/acs.jnatprod.7b00873. Publication Date (Web): March 30, 2...
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Total Synthesis of (±)-Minfiensine via a Formal [3+2] Cycloaddition Chao Zhang,†,‡,⊥ Wenzhi Ji,†,⊥ Yahu A. Liu,§ Chun Song,*,‡ and Xuebin Liao*,† †

School of Pharmaceutical Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, People’s Republic of China ‡ Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Science, Shandong University, Jinan 250012, People’s Republic of China § Discovery Chemistry, Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, United States S Supporting Information *

ABSTRACT: (±)-Minfiensine (1) was synthesized in 10 steps in 26% overall yield with the 1,2,3,4-tetrahydro-9a,4aiminoethanocarbazole core constructed through a [3+2] cycloaddition reaction between indole and an azaoxyallylic cation.

M

infiensine (1), an indole alkaloid isolated in 1989,1 features a rare 1,2,3,4-tetrahydro-9a,4a-iminoethanocarbazole skeleton (2) in Strychnos alkaloids,2 but can be found in akuammiline alkaloids such as echitamine (3), vincorine (4), and corymine (5) (Figure 1). Since this type of alkaloid exhibits

Soon thereafter, Wang’s group reported a synthesis with a transition-metal-catalyzed reaction as the key step.7 In 2011, Li and Padwa reported a synthesis of (±)-minfiensine (1) employing an intramolecular Dies-Alder cycloaddition/rearrangement cascade of an amidofuran derivative.8 Subsequently, Qiu and co-workers described a practical total synthesis of (±)-minfiensine (1), which utilized inexpensive starting material.9 Recently, Zu’s group reported a synthesis of (±)-minfiensine (1) using an intramolecular cyclization to generate the framework.10 Thereafter, a synthesis of (±)-minfiensine (1) was described by Jiao’s group, and the core skeleton was constructed through an enantioselective palladium-catalyzed cascade cyclization.11 While a variety of methods exist to obtain minfiensine (1), our research group has completed another synthetic route that features a [3+2] cycloaddition using an azaoxyallyl cation as a synthon.13 Herein an account of the total synthesis of (±)-minfiensine (1) completed by using a [3+2] cycloaddition reaction is discussed. Jeffrey, Wu, and our group have developed a dearomative [3+2] cycloaddition reaction using an azaoxyallyl cation as a synthon to construct a pyrroloindololine core.12,13 As a result of that study, we envisioned that the 9a,4a-iminoethanocarbazole framework 8 could be constructed through a cycloaddition reaction of 1,2,4,9-tetrahydrospiro(carbazole-3,2′-[1,3]dioxolane) (6) and N-(benzyloxy)-2,2,2-trichloroacetamide (7) (Scheme 1). Allylation of 8 would provide intermediate 9a, from which minfiensine (1) would be accessed in three more steps. Previously, Overman and Qin demonstrated the synthesis of minfiensine (1) from 9b and 9c, indole Nprotected forms of 9a.

Figure 1. Minfiensine and core skeleton of akuammiline alkaloids.

significant biological activities including anticancer, antiinflammatory, antibacterial, and antimalarial activities,3 there has been a growing interest in the synthesis of minfiensine (1). Since Overman’s first enantioselective total synthesis of minfiensine (1),4 several groups have reported their research endeavors to minfiensine via various synthetic strategies.5−11 In Overman’s synthesis, a sequential enantioselective intramolecular Heck/iminium ion addition was used to generate core 2.4 Qin’s group constructed core 2 via a three-step, onepot cyclopropane-mediated reaction.5 Impressively, the MacMillan group in 2009 completed a nine-step enantioselective synthesis of minfiensine (1) through an organocatalyzed route.6 © 2018 American Chemical Society and American Society of Pharmacognosy

Received: October 18, 2017 Published: March 30, 2018 1065

DOI: 10.1021/acs.jnatprod.7b00873 J. Nat. Prod. 2018, 81, 1065−1069

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an azaoxyallyl cation generated from 7, the 1,2,3,4-tetrahydro9a,4a-iminoethanocarbazole core 16 was constructed in 87% yield, a yield higher than that of the reaction from unprotected indole 6. Both C−Cl and N−O bonds in 16 were cleaved using RuCl3/Zn−Cu to afford framework 17, which was subjected to a LiAlH4 reduction and hydrolysis to afford framework 19. Alkylation of 19 with (Z)-1-bromo-2-iodobut-2-ene afforded 20 in 88% yield. Notably, a similar intermediate was obtained in Qin’s work.5 Following similar sequences, the cyclization product 21 was successfully obtained by a Pd-catalyzed enolate coupling in 65% yield.15 Conversion of the ketone 21 into enol triflate 22 was carried out with Comins’ reagent, followed by a Stille cross-coupling reaction of 22 with tri-n-butylstannylmethanol to generate allylic alcohol 23.16 Finally, deprotection using PhSH in trifluoroacetic acid afforded (±)-minfiensine (1) in 94% yield. In conclusion, a 10-step total synthesis of (±)-minfiensine (1) in 26% overall yield was developed. The 1,2,3,4-tetrahydro9a,4a-iminoethanocarbazole core 2 was constructed through a [3+2] cycloaddition reaction between indole and azaoxyallylic cationic synthons. This work demonstrated the usefulness of azaoxyallylic cations in indole alkoloid synthesis, and it is anticipated that the [3+2] cycloaddition strategy will be applied to synthesize other akuammiline alkaloids.

Scheme 1. Synthesis Plan

Initially,13 the synthesis began with a [3+2] annulation between carbazole 6 and trichloroacetamide 7 and resulted in the formation of the framework 10 in 72% yield (Scheme 2). In Scheme 2. Synthetic Sequence from Unprotected Indole 6

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EXPERIMENTAL SECTION

General Experimental Procedures. 1H and 13C NMR spectra were recorded on a Bruker 400 MHz spectrometer using tetramethylsilane as internal standard set at 0 ppm. Thin-layer chromotography analysis was carried out on silica gel 60 F254 precoated aluminum sheets, and UV light was used for detection. Flash column chromatography was done using silica gel (200−400 mesh). High-resolution mass spectra (HRMS) were recorded on a Waters Xevo G2 QTOF MS. 9-(4-Methoxybenzyl)-1,2,4,9-tetrahydrospiro(carbazole3,2′-[1,3]dioxolane) (15). To a suspension of NaH (1.85 g, 46.2 mmol, 60 wt % mineral oil) in anhydrous dimethylformamide (DMF) (30 mL) was added a solution of indole 6 (4.6 g, 20.1 mmol) in anhydrous DMF (20 mL) at 0 °C. The resulting suspension was warmed to room temperature for 30 min and then cooled to 0 °C. After 4-methoxybenzyl chloride (2.8 mL, 20.1 mmol) was added dropwise over 5 min, the reaction mixture was stirred for 3 h, poured slowly into saturated aqueous NH4Cl (300 mL), and extracted with EtOAc (3 × 100 mL). The combined organic extracts were washed with water (2 × 100 mL), dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (EtOAc/ petroleum ether, 1:4) to give 15 as a pale yellow solid (6.8 g, 97%): 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.1 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.15−7.03 (m, 2H), 6.97 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 5.19 (s, 2H), 4.22−3.96 (m, 4H), 3.76 (s, 3H), 3.03 (s, 2H), 2.86 (t, J = 6.4 Hz, 2H), 2.08 (t, J = 6.5 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 158.8, 137.3, 133.8, 130.0, 127.4, 127.2, 121.0, 118.9, 117.7, 114.1, 109.1, 109.0, 107.6, 64.6, 55.2, 46.0, 32.0, 31.8, 20.6; HRMS(ESI) m/z 350.1749 [M + H]+ (calcd for C22H24NO3+, m/z 350.1751). 10′-(Benzyloxy)-12′,12′-dichloro-9′-(4-methoxybenzyl)7′,8′-dihydro-5′H,9′H-spiro{[1,3]dioxolane-2,6′-[8a,4b](epiminoethano)carbazol}-11′-one (16). To a solution of 15 (350 mg, 1.0 mmol) and N-(benzyloxy)-2,2,2-trichloroacetamide (7) (534 mg, 2.0 mmol) in a solvent mixture of hexafluoroisopropanol and CH2Cl2 (5 mL, 9:1, v/v) was added K2CO3 (276.0 mg, 2.0 mmol). The resulting mixture was stirred at room temperature overnight, filtered, and concentrated to give a crude, which was subjected to flash column chromatography (EtOAc/petroleum ether, 1:4) to afford 16 as a pale yellow solid (505.0 mg, 87%): 1H NMR (400 MHz, CDCl3) δ 7.44−7.28 (m, 7H), 7.22 (d, J = 7.2 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.93−6.80 (m, 3H), 6.19 (d, J = 7.8 Hz, 1H), 5.32 (d, J = 9.6 Hz, 1H),

order to cleave both C−Cl and N−OBn bonds in 10 in one step, various reaction conditions were attempted. SmI2 was initially found to cleave both C−Cl and N−OBn bonds to afford compound 11, but the cost of SmI2/THF prohibited its use in a large-scale preparation of 11. An inexpensive mixture of RuCl3 and Zn−Cu could reductively cleave both C−Cl and N− O bonds in excellent yield.14 Amine 8, formed from the reduction of amide 11, was readily converted into 9a through alkylation and hydrolysis in good yield. The intramolecular enolate coupling reaction of 9a was anticipated to afford the cyclized product 13, but only 14 was obtained under various reaction conditions including the use of palladium and nickel. Therefore, a protection of the indole nitrogen is probably a prerequisite for this synthetic route. As illustrated in Scheme 3, a revised synthesis commenced from an N-protected indole 15, which was readily obtained by adding a 4-methoxybenzyl (PMB) group to the nitrogen atom of 6. Through a dearomative [3+2] cycloaddition reaction using 1066

DOI: 10.1021/acs.jnatprod.7b00873 J. Nat. Prod. 2018, 81, 1065−1069

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Scheme 3. Total Synthesis of (±)-Minfiensine

40.9, 40.2, 31.1, 29.3; HRMS(ESI) m/z 393.2169 [M + H]+ (calcd for C24H29N2O3+, m/z 393.2173). 9-(4-Methoxybenzyl)-7,8-dihydro-9H-8a,4b(epiminoethano)carbazol-6(5H)-one (19). To a solution of amine 18 (50.0 mg, 0.13 mmol) in THF (1.0 mL) was added HCl (1.0 M, 0.76 mL), and the mixture was stirred at 60 °C for 3 h, poured into a saturated aqueous K2CO3 solution (20 mL), and extracted with EtOAc (3 × 5 mL). The combined organic extracts were dried over Na2SO4, concentrated, and subjected to flash column chromatography (CH2Cl2/MeOH/Et3N, 200:10;1) to afford 19 as a pale yellow oil (38 mg, 86%): 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.0 Hz, 2H), 6.98 (t, J = 7.0 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.60 (t, J = 7.3 Hz, 1H), 6.22 (d, J = 8.0 Hz, 1H), 4.50 (d, J = 16.5 Hz, 1H), 4.33 (d, J = 16.5 Hz, 1H), 3.79 (s, 3H), 3.03−2.98 (m, 1H), 2.91−2.70 (m, 3H), 2.28−2.22 (m, 2H), 2.20−2.12 (m, 2H), 2.09−2.01 (m, 2H), 1.90− 1.82 (m 1H); 13C NMR (101 MHz, CDCl3) δ 211.0, 158.6, 150.9, 132.0, 131.6, 128.5, 127.9, 123.0, 117.1, 114.0, 104.8, 89.7, 55.2, 55.0, 49.2, 45.6, 44.3, 44.2, 34.9, 30.5; HRMS(ESI) m/z 349.1909 [M + H]+ (calcd for C22H25N2O2+, m/z 349.1911). (Z)-10-(2-Iodobut-2-en-1-yl)-9-(4-methoxybenzyl)-7,8-dihydro-5H-8a,4b-(epiminoethano)carbazol-6(9H)-one (20). A mixture of ketone 19 (15.0 mg, 0.043 mmol), (Z)-1-bromo-2-iodobut-2ene (22.4 mg, 0.086 mmol), K2CO3 (17.8 mg, 0.13 mmol), and KI (4.0 mg, 0.022 mmol) in CH3CN (4 mL) was heated at 80 °C for 24 h, poured into water (20 mL), and extracted with EtOAc (3 × 5 mL). The combined extracts were dried over Na2SO4, concentrated, and subjected to flash column chromatography (EtOAc/petroleum ether, 1:9) to afford 20 as a pale yellow solid (20.0 mg, 88%): 1H NMR (400 MHz, CDCl3) δ 7.23−7.18 (m, 2H), 7.01−6.92 (m, 2H), 6.90−6.86 (m, 2H), 6.66 (t, J = 7.3 Hz, 1H), 6.15−6.07 (m, 1H), 5.66 (q, J = 6.0 Hz, 1H), 4.54 (d, J = 17.0 Hz, 1H), 4.26 (d, J = 17.0 Hz, 1H), 3.81(s, 3H), 3.61 (d, J = 13.0 Hz, 1H), 3.11 (d, J = 13.4 Hz, 1H), 2.88−2.75 (m, 4H), 2.49−2.44 (m, 2H), 2.28−2.20 (m 1H), 2.14−2.00 (m, 2H), 1.91−1.83 (m 1H), 1.72 (d, J = 6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 210.8, 158.5, 151.3, 133.4, 131.7, 130.4, 128.3, 127.5, 122.4, 117.7, 114.1, 110.3, 106.4, 90.3, 59.5, 56.3, 55.3, 49.9, 47.9, 47.3, 39.2, 35.5, 26.4, 21.6; HRMS(ESI) m/z 529.1358 [M + H]+ (calcd for C26H30IN2O2+, m/z 529.1346). (E)-3-Ethylidene-12-(4-methoxybenzyl)-2,3,4,6,7,12-hexahydro-1H-2,7a-ethanoindolizino[8a,1-b]indol-14-one (21). A mixture of 20 (100.0 mg, 0.19 mmol), PdCl2(dppf)CH2Cl2 (16.0 mg, 0.019 mmol), and K2CO3 (105.0 mg, 0.76 mmol) in MeOH (10 mL) was heated at 70 °C for 1 h, concentrated, diluted with EtOAc (50

5.04 (d, J = 9.5 Hz, 1H), 4.74 (d, J = 15.8 Hz, 1H), 4.20 (d, J = 15.8 Hz, 1H), 4.01 (s, 1H), 3.91−3.83 (m, 3H), 3.80 (s, 3H), 2.62 (d, J = 14.7 Hz, 1H), 2.50−2.44 (m, 1H), 2.26 (d, J = 14.7 Hz, 1H), 2.20− 2.06 (m, 1H), 1.60 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 162.9, 158.7, 150.9, 133.9, 129.9, 129.5, 129.3, 129.1, 128.5, 127.6, 126.2, 124.0, 118.7, 114.1, 107.9, 107.0, 88.0, 87.7, 78.2, 64.4, 64.0, 60.0, 55.1, 48.6, 38.1, 29.5, 25.6; HRMS(ESI) m/z 581.1606 [M + H]+ (calcd for C31H3135Cl2N2O5+, m/z 581.1605), m/z 583.1582 [M + H]+ (calcd for C31H3135Cl37ClN2O5+, m/z 583.1575). 9-(4-Methoxybenzyl)-5,7,8,9-tetrahydrospiro{8a,4b(epiminoethano)carbazole-6,2′-[1,3]dioxolan}-11-one (17). A mixture of 16 (58.0 mg, 0.1 mmol), RuCl3 (4.0 mg, 0.02 mmol), and Zn−Cu (65.0 mg, 1.0 mmol) in EtOH (2.0 mL) was heated at 100 °C for 48 h, diluted with EtOAc (10.0 mL), filtered, and concentrated. The residue was subjected to flash column chromatography (CH2Cl2/MeOH, 4:1) to give 17 as a pale yellow solid (38.0 mg, 93%): 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.26 (d, J = 7.6 Hz, 2H), 7.02 (dd, J = 7.1, 4.6 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.74 (t, J = 7.4 Hz, 1H), 6.36 (d, J = 8.0 Hz, 1H), 4.45 (d, J = 16.2 Hz, 1H), 4.13 (d, J = 16.2 Hz, 1H), 4.00−3.86 (m, 4H), 3.79 (s, 3H), 3.18 (d, J = 16.8 Hz, 1H), 2.69 (d, J = 16.8 Hz, 1H), 2.36−2.27 (m, 1H), 2.12−1.98 (m, 2H), 1.85−1.73 (m, 2H), 1.66−1.58 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 176.0, 158.8, 148.5, 135.7, 130.5, 128.4, 127.9, 122.2, 119.1, 114.1, 108.7, 107.5, 85.5, 64.5, 63.9, 55.2, 50.8, 47.2, 40.9, 40.6, 30.3, 29.9; HRMS(ESI) m/z 407.1963 [M + H]+ (calcd for C24H27N2O4+, m/z 407.1966). 9-(4-Methoxybenzyl)-5,7,8,9-tetrahydrospiro{8a,4b(epiminoethano)carbazole-6,2′-[1,3]dioxolane} (18). To a solution of 17 (1.1 g, 2.7 mmol) in dioxane (40 mL) was added LiAlH4 (308.0 mg, 8.1 mmol), and the mixture heated at 100 °C for 3 h, poured into an aqueous solution of NaOH (1.0 M, 150 mL), extracted with EtOAc (3 × 100 mL), dried over Na2SO4, and concentrated. The residue was subjected to flash column chromatography (Et3Nsaturated silica gel, CH2Cl2/MeOH/Et3N, 120:10:1) to give 18 as a pale brown solid (970 mg, 92%): 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.08−6.92 (m, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.64 (t, J = 7.4 Hz, 1H), 6.21 (d, J = 7.8 Hz, 1H), 4.40 (d, J = 16.3 Hz, 1H), 4.22 (d, J = 16.2 Hz, 1H), 4.01−3.81 (m, 4H), 3.79 (s, 3H), 3.14−3.02 (m, 1H), 2.94−2.74 (m, 1H), 2.33−2.21 (m, 1H), 2.15−1.97 (m, 5H), 1.90−1.80 (m, 1H), 1.76−1.68 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 158.4, 149.7, 135.5, 131.9, 127.8, 127.7, 122.1, 117.4, 113.9, 108.6, 106.7, 90.6, 64.1, 63.8, 55.2, 54.2, 46.5, 44.7, 1067

DOI: 10.1021/acs.jnatprod.7b00873 J. Nat. Prod. 2018, 81, 1065−1069

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mL), washed with brine (3 × 15 mL), dried over Na2SO4, and concentrated. The residue was purified by using flash column chromatography (EtOAc/petroleum ether, 1:9) to afford 21 as white solid (49.0 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.4 Hz, 2H), 6.97 (t, J = 7.0 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.59 (t, J = 7.3 Hz, 1H), 6.15 (d, J = 8.0 Hz, 1H), 5.53 (q, J = 6.4 Hz, 1H), 4.40 (s, 2H), 3.94 (d, J = 15.6 Hz, 1H), 3.78 (s, 3H), 3.45 (s, 1H), 3.18−3.07 (m, 2H), 2.95−2.81 (m, 3H), 2.33−2.29 (m, 1H), 2.12−2.04 (m, 2H), 1.98−1.90 (m, 1H), 1.74 (d, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 209.7, 158.5, 148.1, 132.8, 132.7, 131.9, 128.4, 128.1, 123.7, 122.3, 116.5, 113.8, 105.5, 91.4, 55.9, 55.7, 55.2, 53.3, 47.0, 45.7, 45.3, 41.5, 28.0, 14.3; HRMS(ESI) m/z 401.2231 [M + H]+ (calcd for C26H29N2O2+, m/z 401.2224). (E)-3-Ethylidene-12-(4-methoxybenzyl)-2,3,4,6,7,12-hexahydro-1H-2,7a-ethenoindolizino[8a,1-b]indol-14-yl Trifluoromethanesulfonate (22). To a solution of 21 (50.0 mg, 0.125 mmol) in tetrahydrofuran (THF) (5.0 mL) was added NaHMDS in THF (2.0 M, 125 μL, 0.25 mmol) dropwise at −78 °C. After the resulting mixture was stirred for 20 min, a solution of Comins’ reagent (98.0 mg, 0.25 mmol) in THF (2.0 mL) was added dropwise. The reaction mixture was stirred at −78 °C for 20 min, poured into a saturated NH4Cl solution (20.0 mL), and extracted with EtOAc (3 × 15 mL). The combined extracts were dried over Na2SO4, concentrated, and subjected to flash column chromatography (EtOAc/petroleum ether, 1:9) to afford 22 as a white solid (62 mg, 94%): 1H NMR (400 MHz, CDCl3) δ 7.31−7.23 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.83 (d, J = 8.5 Hz, 2H), 6.60 (t, J = 7.3 Hz, 1H), 6.11 (d, J = 7.8 Hz, 1H), 5.97 (s, 1H), 5.50 (q, J = 6.7 Hz, 1H), 4.41 (d, J = 15.4 Hz, 1H), 4.10 (d, J = 15.4 Hz, 1H), 3.78 (s, 3H), 3.49 (brs, 1H), 3.28 (t, J = 8.2 Hz, 1H), 3.15 (d, J = 16.0 Hz, 1H), 2.80−2.67 (m, 1H), 2.24−2.16 (m, 1H), 2.11−2.07 (m, 1H), 2.02−1.92 (m, 2H), 1.72 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 158.5, 151.8, 146.7, 132.7, 131.5, 130.0, 128.4, 128.2, 122.7, 122.0, 117.2, 116.6, 113.8, 106.7, 91.8, 55.8, 55.2, 53.2, 53.0, 45.3, 37.5, 34.8, 29.7, 27.4, 13.9; HRMS(ESI) m/z 533.1730 [M + H]+ (calcd for C27H28F3N2O4S+, m/ z 533.1717). (E)-(3-Ethylidene-12-(4-methoxybenzyl)-2,3,4,6,7,12-hexahydro-1H-2,7a-ethenoindolizino[8a,1-b]indol-14-yl)methanol (23). A mixture of 22 (53.0 mg, 0.1 mmol), LiCl (13.0 mg, 0.3 mmol), Pd(PPh3)4 (12.0 mg, 0.001 mmol), and (tributylstannyl)methanol (97.0 mg, 0.3 mmol) in THF (3.0 mL) was heated at 105 °C for 8 h, concentrated, and subjected to flash chromatography (Et3N-saturated silica gel, EtOAc/petroleum ether, 1:3) to give 23 as a white solid (34.0 mg, 82%): 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 7.1 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 6.57 (t, J = 7.3 Hz, 1H), 6.07 (d, J = 7.8 Hz, 1H), 6.01 (s, 1H), 5.35 (q, J = 6.6 Hz, 1H), 4.45 (d, J = 15.4 Hz, 1H), 4.12 (s, 2H), 4.03 (d, J = 15.4 Hz, 1H), 3.78 (s, 3H), 3.70 (d, J = 15.4 Hz, 1H), 3.42 (s, 1H), 3.35−3.26 (m, 1H), 3.18 (d, J = 15.4 Hz, 1H), 2.67 (dd, J = 16.3, 9.2 Hz, 1H), 2.16−2.09 (m, 1H), 2.05−1.93 (m, 2H), 1.77−1.73 (m, 1H), 1.71 (d, J = 6.8 Hz, 3H), 1.57 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 158.3, 147.4, 141.1, 136.3, 132.9, 131.8, 128.2, 127.6, 124.3, 121.9, 119.0, 116.4, 113.7, 106.8, 93.3, 65.7, 55.2, 55.0, 54.4, 53.7, 45.7, 38.2, 31.1, 27.6, 13.8; HRMS(ESI) m/z 415.2389 [M + H]+ (calcd for C27H31N2O2+, m/z 415.2381). (±)-Minfiensine (1). A mixture of 23 (10.0 mg, 0.024 mmol) and thiophenol (25 μL, 0.24 mmol) in trifluoroacetic acid (1 mL) was stirred at room temperature for 2 h and concentrated. The residue was dissolved in MeOH (5.0 mL), poured into a saturated aqueous K2CO3 solution (10.0 mL), and extracted with CH2Cl2 (5 × 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, concentrated, and purified by flash column chromatography (Et3Nsaturated silica gel, EtOAc/acetone, 1:1) to afford 1 as a white solid (6.7 mg, 94%): 1H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 7.3 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.68 (t, J = 7.4 Hz, 1H), 6.52 (d, J = 7.8 Hz, 1H), 6.03 (s, 1H), 5.36 (q, J = 6.7 Hz, 1H), 4.08 (s, 2H), 3.90 (brs, 1H), 3.64 (d, J = 14.9 Hz, 1H), 3.40 (s, 1H), 3.33−3.23 (m, 1H), 3.13 (d, J = 15.0 Hz, 1H), 2.65−2.59 (m, 2H), 2.07−1.95 (m, 2H), 1.92 (s, 2H), 1.70 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 147.3, 140.9, 135.5, 133.5, 127.6, 124.3, 122.5, 119.4, 118.4, 109.7,

90.1, 65.2, 55.2, 53.8, 53.2, 38.4, 32.0, 31.3, 13.7; HRMS(ESI) m/z 295.1810 [M + H]+ (calcd for C19H23N2O+, m/z 295.1805).

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.7b00873. 1 H and 13C NMR spectral data for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Chao Zhang: 0000-0002-5497-982X Wenzhi Ji: 0000-0002-6217-1839 Xuebin Liao: 0000-0002-0290-894X Author Contributions ⊥

C. Zhang and W. Ji contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua-Peking Centre for Life Sciences, and “1000 Talents Recruitment Program”. We thank Dr. D. Raymond (Genomics Institute of Novartis Research Foundation) for his critical reading of the manuscript.

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DOI: 10.1021/acs.jnatprod.7b00873 J. Nat. Prod. 2018, 81, 1065−1069