Synthetic study toward the total synthesis of fumigaclavines A–D     
Yongfan Ma,Yanxing Jia*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China   

 
Abstract: In the present study, we developed a novel approach for the synthesis of the tetracyclic core of fumigaclavines A–D. A palladium-catalyzed intramolecular Larock indole synthesis was utilized to assemble the B/C rings of the tetracyclic core in one step. Although all attempts to convert compound 18 to fumigaclavine B failed, this study provided useful information for the total synthesis of fumigaclavines A–D.           
Keywords: Indole alkaloids; Ergot alkaloids;Total synthesis; Palladium-catalyzed   
CLC number: R916                Document code: A                 Article ID: 1003–1057(2017)7–496–08
 
 
1. Introduction
Fumigaclavines A–D (1–6) are a series of indole alkaloids belonging to the large group of ergot alkaloids, which are among the most important pharmaceuticals and natural toxins[1–4]. Structurally, they contain a tetracyclic ergoline ring carrying additional substituents, such as OH or OAc group, at C9 and a reverse prenyl moiety at C2.Interestingly, the (8S,9R) diastereomers of fumigaclavines A and B, called isofumigaclavinesA(5) andB (6)[3] or roquefortinesAand B[4], have alsobeenisolated. Although the biological activity of fumigaclavines A and B is seldom reported, the closely related fumigaclavine C has various pharmacological effects, and it can cause concentration-dependent vasorelaxation in isolated rat aromic rings, improve concanavalin A-induced liver injury in mice via inhibitingTNF alpha production, and enhance experimental colitisin mice via down-regulating Th1 cytokine production[5].The intriguing structures combined with their promising biological profiles render them attractive synthetic targets[6] (Fig. 1). 


Figure 1. Structures of fumigaclavines A–C and isofumigaclavines A–C.  
 
In connection with our ongoing study towards the concise and efficient synthesis of 3,4-indole alkaloids[7], we have recently developed a novel strategy for the construction of 3,4-fused indoles and benzofurans through a palladium-catalyzed intramolecular Larock annulation[8]. We initiated this study in order to facilitatethe preparation of ergot alkaloid analogues bearing deep-seated structural changes, which are not readily accessible by conventional approaches.
Our retrosynthetic analysis is outlined in Scheme 1. We envisioned that fumigaclavinesA (1) andB (2)could be derivatives from the tricyclic indole 7. The tricycle 7 would be readilyassembled by a Pd-catalyzed intramolecular Larock indole annulation of 8. The stereogenic center (5R) of 8 at the propargylic position was introduced by propargylation of chiral N-tert-butylsulfinylimine 9[9]. In turn, 9 could be readily obtained from nitrile 10 and known aldehyde 11[10] by an Aldol reaction[11]. 


Scheme 1. Retrosynthetic analysis. 
2. Results and discussion
Our synthesis commenced with bromide 12, which was prepared in one step from commercially available 2-bromo-1-methyl-3-nitrobenzene, following the reported procedure (Scheme 2)[12]. Cyanidation of bromide 12 with NaCN provided nitrile 10. Treatment of nitrile 10 with LDA followed by the addition of the known aldehyde 11 furnished 13 and its diastereoisomer in 72% yield with a ratio of 1.3:1, which could be separated by column chromatography. The absolute configuration of the major product 13 was determined by the H-H coupling constants of downstream products 17 and 18 (vide infra). However, we did not know the minor diastereoisomer arised from which carbon stereogenic center at this stage. Protection of alcohol 13 with TBSOTf gave 14. Reduction of nitrile 14 with DIBAL-H followed by condensation of the resulting aldehyde with (SR)-N-tert-butanesulfinamide afforded 15 in 80% yield. Reduction of 15 with Zn/HOAc followed by acetylation of the corresponding aniline with Ac2O provided acetanilide 9 with an overall yield of95%. Propargylation of N-tert-butylsulfinylimine 9 with 1-trimethylsilyl allenylzinc bromide proceeded smoothlyto afford the homopropargylic amines 8 anditsdiastereoisomer 5-epi-8 in 75% yield (dr = 4:1), which could be separated by careful column chromatography.


Scheme 2. Synthesis of cyclization precursor 8. 

   With the desired cyclization precursor8 in hand, the intramolecular Pd-catalyzed Larock indole annulation of 8was performed under our optimized catalyst system[Pd(OAc)2 and Me-phos at 100 °C], giving the desired tricyclic indole 7in 85% yield (Scheme 3). Selective removal of TBS group on the primary alcohol of 7 and subsequent protection of the resulting primary alcohol with MsCl and Et3N gave 16in 81% yield. Treatment of 16 with NaH gave the desired cyclization product 17 in 84% yield. Removal of the tert-butanesulfinyl group in 17 followed by reductive amination gave 18in 66% yield. All attempts to remove the TBS protection group of 18 failed. 


Scheme 3. Synthesis of TBS-protected 2.
 
In summary, we developed a general and efficient method for ergoline basic skeleton of fumigaclavines A–D via an intramolecular larock indolization process. Although we did not finally get the natural product fumigaclavine B, it provided useful information for the total synthesis of fumigaclavines A–D.
3. Experimental
All reactions were carried out under an argon atmosphere. Progress of reactions was monitored by thin-layer chromatography on Merck Kieselgel (60 F254).Optical rotation was recorded on an AA-10R Automatic Polarimeter (OPTICAL ACTIVITY LTD). Infrared spectra were recorded on a Thermo Nicolet Nexus-470 FT-IR spectrometer. High resolution mass spectra were recorded on a Bruker APEX IV FT-MS (ESI) spectrometer. 1H and 13C NMR spectra were recorded on Bruker Avance III 400 MHz spectrometer. Chemical shifts δ were reported in ppm with the undeuterated solvent as the internal standard. All reagents were obtained commercially and used as received.
3.1. Synthesis of compound 13
Lithium diisopropylamide (6.3 mL of a 2.0 M solution in THF, 12.6 mmol) was added dropwise to a solution of nitrile 10 (2.5 g, 10.5 mmol) in THF (100 mL) at –78°C. After the mixture was stirred at –78 °C for 30 min, aldehyde 11 (2.1 g in 10 mL THF, 10.5 mmol) was added. Stirring was maintained at –78 °C until the reaction was complete. The mixture was quenched by addition of 20 mL of saturated ammonium chloride. The resultant mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash silica gel chromatography (PE–EtOAc, 10:1, v/v) to afford compound 13 and its diastereoisomer (3.2 g, 69%, brsm 93%) as yellowish oil. +73.6 (c 0.10, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 7.95 (dd, J1 7.9 Hz, J2 1.6 Hz, 1H), 7.70 (dd, J1 8.0 Hz, J2 1.6 Hz, 1H), 7.53 (t, J 7.9 Hz, 1H), 4.88 (d, J 1.4 Hz, 1H), 4.68 (s, 1H), 3.89 (dd, J1 10.3 Hz, J2 3.8 Hz, 1H), 3.81 (dt, J1 9.1 Hz, J2 1.9 Hz, 1H), 3.72–3.58 (m, 1H), 2.11–2.32 (m, 1H), 1.04 (d, J 6.9 Hz, 3H), 0.89 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:136.3, 134.8,128.2, 124.8, 117.4, 114.0, 76.6, 68.8, 42.9, 38.9, 25.8, 25.6, 18.1, 13.0, –5.6, –5.7; IR (KBr) (νmax, cm–1) 3429, 2981, 2932, 2884, 1769, 1758, 1726, 1538, 1461, 1372,1246, 1127, 1087, 1048, 839 cm–1; HRMS (ESI) m/z calcdfor C18H28BrN2O4Si (M+H)+ 443.0996, found 443.0995. 
3.2. Synthesis of compound 14
TBSOTf (4.7 mL, 20.5 mmol) was added dropwise to a solution of compound 13 (1.8 g, 4.1 mmol) and 2,6-lutidine (1.9 mL, 16.4 mmol) in CH2Cl2 (40 mL) in ice bath. The mixture was refluxed for 2 h. The resultant mixture was extracted with CH2Cl2. Thecombined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silicagel chromatography (PE–EtOAc, 10:1, v/v) to afford compound 14 (1.88 g, 80%) as a white flocculent.+17.3 (c 0.10, CHCl3); 1H NMR (400 MHz, CDCl3)δ: 7.91 (dd, J1 7.8 Hz, J2 1.6 Hz, 1H), 7.69 (dd, J1 8.0 Hz,J2 1.6 Hz, 1H), 7.51 (t, J 7.9 Hz, 1H), 4.84 (d, J 2.0 Hz, 1H), 4.11 (dd, J1 5.7 Hz, J2 2.1 Hz, 1H), 3.72 (qd, J1 10.5 Hz, J2 4.7 Hz, 2H), 2.08 (m, 1H), 1.24 (d, J 7.2 Hz, 4H), 0.91 (s, 9H), 0.86 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H), –0.07 (s, 3H), –0.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 151.6, 137.6, 134.9, 128.1, 124.6, 118.5, 114.3, 73.4, 64.4, 42.4, 25.9, 25.8, 18.3, 18. 1, 11.6, –4.3, –5.4, –5.5, –5.8; IR (KBr) (νmax, cm–1) 2928, 2952, 2893, 2857, 2248, 1534, 1471, 1362, 1255, 1131, 1095, 1022, 929, 891, 835, 808, 776, 739, 693, 669 cm–1; HRMS (ESI) m/z calcd for C24H42 BrN2O4Si2 (M+H)+ 579.1681; found 579.1669.
3.3. Synthesis of compound 15
DIBAL-H (3.8 mL of 1 M Hexane solution, 3.8 mmol) was added dropwise to a solution of compound 14 (1.8 g, 3.1 mmol) in toluene (20 mL). After being stirred for 30 min, saturated sodium potassium tartrate was added. The mixture was stirred until the upper part was clear. The resultant mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by flash silica gel chromatography (PE–EtOAc, 15:1, v/v) to afford aldehyde(1.3 g, 75%) as yellowish oil.+46.1 (c 0.10, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 9.94 (d, J 2.1 Hz, 1H), 7.59 (d, J 7.9 Hz, 2H), 7.35–7.50 (m, 1H), 4.62 (m, 2H), 3.36 (dd, J1 10.4Hz, J2 6.0 Hz, 1H), 3.17 (dd, J1 10.3Hz, J2 8.7 Hz, 1H), 2.02 (m, 1H), 1.04 (d, J 7.0 Hz, 3H), 0.91 (s, 10H), 0.80 (s, 9H), 0.11 (s, 3H), –0.02 (s, 3H), –0.04 (s, 3H), –0.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 199.4, 151.7, 139.1, 133.9, 127.7, 123.5, 115.8, 75.30,64.3, 58.4, 42.7, 25.8, 18.1, 11.6, –3.9, –4.9,–5.6; IR (KBr) (νmax, cm–1) 2978, 2931, 2884, 1727, 1538, 1460, 1372, 1246, 1128, 1087, 1046, 839 cm–1; HRMS (ESI)m/z calcd for C24H43BrNO5Si2 (M+H)+ 560.1858, found 560.1856.
Ti(OEt)4 (1.0 mL, 4.8 mmol) was added to the solution of the above aldehyde (1.3 g, 2.4 mmol) and (R)-tert-butysulfinamide (580 mg, 4.8 mmol) in THF (30 mL) at room temperature. The mixture was stirred for overnight. The mixture was quenched with brine and filtered with bergmeal. The resultant mixture was washed with brine, and evaporated to dryness. The crudeproduct was purified by flash silica gel chromatography (PE–EtOAc, 15:1, v/v) to afford compound 15 (1.2 g, 71%) as a colorlessoil.–25.1 (c 0.10, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 8.50 (d, J 5.1 Hz, 1H), 7.56 (dd, J1 7.8 Hz, J2 1.5 Hz, 1H), 7.50 (dd, J1 7.9 Hz, J2 1.5 Hz, 1H), 7.40 (t, J 7.9 Hz, 1H), 4.72 (t, J 5.2 Hz, 1H), 4.46 (t, J 4.9 Hz, 1H), 3.37 (ddd, J1 17.4 Hz, J2 10.2 Hz, J3 6.8 Hz, 2H), 1.09 (s, 9H), 1.03 (d, J 7.0 Hz, 3H), 0.91 (s, 9H), 0.83 (s, 9H), 0.06 (s, 3H), –0.02 (s, 3H), –0.07 (s, 3H), –0.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 169.4, 151.6, 142.3, 134.3, 127.4, 123.2, 115.4, 75.0, 64.5, 57.3, 52.3, 42.5, 29.7, 25.9, 25.8, 22.4, 18.2, 12.3, –4.0, –4.9, –5.5, –5.5; IR (KBr) (νmax, cm–1) 2955, 2929, 2885, 2857, 1714, 1615, 1538, 1472, 1363, 1255, 1088, 1032, 836, 776 cm–1; HRMS (ESI) m/z calcd for C28H52BrN2O5SSi2 (M+H)+ 685.2133, found 685.2132.
3.4. Synthesis of compound 9
Zinc powder (6.65 g, 102.3 mmol) was added to the solution of compound 15 (1.1 g, 1.7 mmol) inCH2Cl2 (21 mL), and then acetic acid was added dropwise at 0 °C. The mixture was filtered with bergmeal after 30 min of stirring, washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and distillated under reduced pressure to dryness. The crude was directly used in next step without purification.
Acetic anhydride (5 mL) was added to the solution of crude phenylamine at room temperature. After being stirred at 70 °C for 30 min, the mixture was extracted with ethyl acetate. The organic phase was combined, washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash silica gel chromatography (PE–EtOAc, 2:1, v/v) to afford compound 9 (917 mg, 80%) asa colorlessoil.+6.0 (c 0.10, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 8.48 (d, J 5.5 Hz, 1H), 8.24 (d, J 7.3 Hz, 1H), 7.71 (s, 1H), 7.25 (t, J1 10.4 Hz, J2 7.4 Hz, 1H), 7.03 (d, J 7.5 Hz, 1H), 4.57 (t, J 5.6 Hz, 1H), 4.44 (t, J 5.2 Hz, 1H), 3.34 (m, 2H), 2.24 (s, 3H), 1.87 (m, J111.5 Hz, J2 6.8 Hz, 1H), 1.10 (s, 9H), 1.00 (d, J 7.0 Hz, 3H), 0.89 (s, 9H), 0.84 (s, 9H), 0.03 (s, 3H), –0.03 (s, 3H), –0.07 (s, 3H), –0.26 (s, 3H); 13CNMR (100 MHz, CDCl3) δ: 170.0, 168.1, 139.1, 136.0, 127.5,126.9, 120.8, 115.6, 74.9, 64.5, 57.0, 53.1, 42.3, 25.8, 22.4, 18.1, 12.7, –4.0, –4.9, –5.5, –5.5; IR (KBr) (νmax, cm–1) 3269, 2955, 2928, 2856, 1694, 1615, 1590, 1519, 1468, 1409, 1388, 1363, 1253, 1080, 1030, 1006, 835, 774, 720, 667, 530 cm–1; HRMS (ESI) m/z calcdfor C30H55BrN2O4SSi2Na (M+Na)+ 692.2943, found 692.2946.
3.5. Synthesis of compound 8 and 5-epi-8
BuLi (11.2 mL, 2.5 M, 28 mmol) was added dropwise to the solution of TMS-propyne (4.2 mL, 28 mmol) in THF (28.5 mL) at –45 °C. The mixture was naturally warmed to –20 °C and stirred 45 min at this temperature. The mixture was cooled to –35 °C, then ZnBr2 (28 mL of 1 M in THF, 28 mmol) was added, and the mixture was stirred 30 min at –35 °C. The mixture was warmed to room temperature, and then compound 9 (966 mg, 1.4 mmol) wasadded. The mixture was stirred at room temperature until the reaction was complete, and it was quenched with NH4Cl–NH3?H2O (2:1, v/v) and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash silica gel chromatography (PE–EtOAc, 3:2, v/v) to afford compound 8 (704 mg, 64%) as a colorless oil, and compound5-epi-8 (230 mg, 21%) as a colorless oil.+28.2 (c 0.10, CHCl3); 1H NMR (400 MHz, CDCl3) δ: 8.22 (d, J 7.2 Hz, 1H), 7.74 (s, 1H), 7.23 (t, J 8.0 Hz, 1H), 7.06 (d, J 7.4 Hz, 1H), 4.41 (m, 1H), 3.93 (dd, J 11.3, 5.7 Hz, 1H), 3.81 (t, J 6.8 Hz, 1H), 3.47 (d, J 11.2 Hz, 1H), 3.12 (dd, J1 9.9 Hz, J2 7.3 Hz, 1H), 2.99 (dd, J1 17.1 Hz, J2 7.9 Hz, 1H), 2.98 (s, 1H), 2.63 (dd, J1 16.9 Hz, J2 7.4 Hz, 1H), 2.24 (s, 3H), 1.90 (m, 1H), 0.99 (s, 9H), 0.96 (s, 9H), 0.94 (d, J 7.0 Hz, 3H), 0.75 (s, 9H), 0.19 (s, 3H), 0.13 (s, 12H), –0.12 (s, 3H), –0.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:141.5, 136.0, 127.2, 126.0, 120.3, 118.2, 103.6, 88.4, 75.2, 67.9, 64.4, 56.5, 56.1, 49.2, 43.2, 28.8, 26.1, 25.7, 22.6, 18.3, 18.0, 11.3, 0.1, –3.8, –4.0, –5.7, –5.7; IR (KBr) (νmax, cm–1) 3287, 2956, 2928, 2856, 2175, 1712, 1591, 1590, 1520, 1466, 1406, 1388, 1362, 1250, 1063, 938, 841, 774, 666, 537 cm–1; HRMS (ESI) m/z calcd for C36H68BrN2O4SSi3 (M+H)+ 787.3386, found 787.3369.
3.6. Synthesis of compound 7
K2CO3 (110 mg, 0.8 mmol) and anhydrous LiCl (16.8 mg, 0.4 mmol) were successively added to the solution of 8 (314 mg, 0.4 mmol) in DMF (80 mL) under argon atmosphere. After discharging oxygen with argon for 0.5 h, Pd(OAc)2 (27.0 mg, 0.12 mmol) and Me-phos (87.5 mg, 0.24 mmol) were added. The mixture was heated to 100 °C and reacted for 3 h under the argon atmosphere. The reaction solution was cooled to room temperature, diluted with water and extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash silica gel chromatography (PE–EtOAc, 5:1, v/v) to afford compound 7 (254 mg, 85%) as a colorless oil.+23.4 (c 0.10, CHCl3);1H NMR (400 MHz, CDCl3) δ: 7.42 (d, J 8.3 Hz, 1H), 7.26 (t, J 8.0 Hz,1H), 7.05 (d, J 7.3 Hz, 1H), 4.10 (m, 1H), 3.93 (dt, J1 15.0 Hz,J2 9.2 Hz, 2H), 3.57 (dd, J1 16.3 Hz, J2 4.9 Hz, 1H), 3.48 (d, J 3.1 Hz, 1H), 3.20 (dt, J1 17.9 Hz,J2 8.6 Hz, 3H), 2.77 (s, 3H), 2.06 (m, 1H), 1.10 (d, J 6.7 Hz, 3H), 0.91 (s, 9H), 0.77 (s, 9H), 0.34 (s, 9H), –0.03 (s, 3H), –0.14 (s, 3H), –0.17 (s, 3H), –0.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 169.0, 135.2, 134.0, 130.7, 129.3, 125.3, 121.6, 112.0, 79.4, 64.5, 57.4, 56.0, 43.9, 42.2, 32.3, 31.9, 29.7, 26.3, 26.2, 25.8, 22.8, 18.2, 18.0, 15.7, 14.1, 2.2, –4.3, –4.7, –5.6; IR (KBr) (νmax, cm–1) 2954, 2927, 2855, 1731, 1697, 1440, 1380, 1329, 1254, 1151, 1079, 1031, 839, 774, 593 cm–1; HRMS (ESI) m/z calcd for C36H67N2O4SSi3 (M+H)+ 707.4124, found 707.4145.
3.7. Synthesis of compound 16
Pyridinium p-toluenesulfonate (2.6 mg, 0.01 mmol) was added to the solution of 7 (35.4 mg, 0.05 mmol) in 95% EtOH (2 mL). The mixture was stirred for 36 h at room temperature, then quenched with NEt3, and evaporated under reduced pressure. The crude product was purified by flash silica gel chromatography (PE–EtOAc, 5:1, v/v) to afford the corresponding alcohol (29.6 mg, 100%) as a yellow solid. 1H NMR (400 MHz,CDCl3) δ: 7.47 (d, J 8.3 Hz, 1H), 7.29 (t, J 7.6 Hz, 1H), 7.11 (d, J 7.3 Hz, 1H), 4.18 (dd, J1 4.2 Hz, J2 3.0 Hz, 1H), 4.03 (d, J 8.2 Hz, 1H), 3.96 (m, 1H), 3.50 (m, 2H), 3.37 (t, J 9.1 Hz, 1H), 3.09 (m, 2H), 2.79 (s, 3H), 2.18 (d, J 7.1 Hz, 1H), 2.07 (s, 1H), 1.31 (s, 9H), 1.04 (d, J 7.0 Hz, 3H), 0.91 (s, 9H), 0.34 (s, 9H), 0.05 (s, 3H), –0.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 169.1, 135.5, 135.2, 132.8, 131.1, 128.7, 125.4, 121.7, 112.4, 80.5, 65.3, 56.7, 56.0, 46.2, 39.0, 32.0, 26.1, 22.8, 18.0, 16.7, 2.3, –4.5, –4.6; HRMS (ESI) m/z calcd for C30H53N2O4SSi2 (M+H)+ 593.3259, found 593.3251.
Et3N (19 μL, 0.135 mmol) and MsCl (4 μL, 0.054 mmol)were added to the solution of the above alcohol (26 mg,0.045 mmol ) in CH2Cl2 (2 mL) in ice bath. After the reaction was reacted for 30 min, saturated sodium bicarbonate was added. The mixture was extracted with CH2Cl2, and the organic phases were combined, washed with saturated brine, dried over Na2SO4, filtered,and evaporated to dryness. The crude product was purified by flash silica gel chromatography (PE–EtOAc, 5:2, v/v) to afford compound 16 (24.4 mg, 81%) asa yellowish oil. 1H NMR (400 MHz, CDCl3) δ: 7.49 (d, J 8.3 Hz, 1H), 7.30 (t, J 7.6 Hz, 1H), 7.13 (d, J 7.3 Hz, 1H), 4.19 (t, J 3.2 Hz, 1H), 3.98 (td, J1 12.5 Hz, J2 5.8 Hz, 1H), 3.54 (m, 4H), 3.39 (dd, J1 9.9 Hz, J2 3.5 Hz, 1H), 3.04 (dd, J1 16.4 Hz, J2 12.5 Hz, 1H), 2.79 (s, 3H), 2.58 (s, 3H), 2.16 (m, 1H), 1.31 (s, 9H), 1.14 (d, J 6.8 Hz, 3H), 0.95 (s, 9H), 0.35 (s, 9H), 0.07 (s, 3H), –0.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 169.1, 136.1, 135.3, 131.7, 130.77, 127.97, 125.4, 122.2, 112.6, 72.0, 56.0, 55.6, 45.4, 38.2, 36.6, 31.6, 26.1, 22.8, 18.2, 16.7, 2.2, 1.0, –0.0, –3.8, –4.7; HRMS (ESI) m/z calcd for C31H55N2O6S2Si2 (M+H)+ 671.3035, found671.3039.
3.8. Synthesis of compound 17
NaH (1.8 mg, 0.072 mmol) was added to the solution of 16 (24 mg, 0.036 mmol) in THF (2 mL) at room temperature. After being stirred for 1 h, the mixture was diluted with water and extracted with CH2Cl2. The organic phases were combined, washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by flash silica gel chromatography (PE–EtOAc, 5:1, v/v) to afford compound 15 (16 mg, 84%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 7.81 (s, 1H), 7.12 (dd, J1 5.3 Hz, J2 3.8 Hz, 2H), 6.79 (d, J 6.4 Hz, 1H), 4.13 (d, J 9.7 Hz, 1H), 3.85 (m, 1H), 3.66 (m, 1H), 3.28 (t, J 12.8 Hz, 1H), 3.21 (m, 1H), 3.00 (m, 3H), 2.10 (d, J 5.2 Hz, 1H), 1.18 (d, J 2.3 Hz, 12H), 0.93 (d, J 6.9 Hz, 4H), 0.57 (s, 10H), 0.33 (s, 12H), 0.07 (s, 3H), –0.20 (s, 4H); 13C NMR (101 MHz, CDCl3) δ:136.3, 132.9, 130.6, 129.1, 123.3, 122.0, 116.2, 108.3, 58.1, 45.7, 38.0, 26.2, 26.0 (2C), 23.0, 17.7, 16.3, 2.2, 1.0, –0.9, –4.6, –6.7.
3.9. Synthesis of compound 18
HCl?dioxane (30 μL, 1:3, v/v) was added to the solution of 17 (16 mg, 0.03 mmol) in MeOH (1 mL) at room temperature. The mixture was stirred for 30 min at room temperature, then quenched with saturated sodium carbonate, and extracted with CH2Cl2. The organic phases were combined, washed with brine, dried over Na2SO4, evaporated under reduced pressure. The crude product was dissolved in methanol (1 mL), and then 37% formaldehyde aqueous solution (5 μL, 0.06 mmol) and sodium borohydride (2.3 mg, 0.06 mmol)were added to the solution. After being stirred for 20 min, the mixture was diluted with water and extractedwith CH2Cl2. The organic phases were combined, washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by flash silica gel chromatography (DCM–MeOH, 10:1, v/v) to afford compound 16 (7 mg, 66%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ:7.84(s, 1H), 7.14–7.15 (m, 2H), 6.84–6.87 (m, 2H), 4.07 (s, 1H), 3.39 (s, 1H), 3.27 (m, 2H), 2.98 (m, 1H), 2.84 (t, J 11.4 Hz, 1H), 2.61 (s, 3H), 2.45 (s, 1H), 2.22 (s, 1H), 0.94 (d, J 6.9 Hz, 3H), 0.59 (d, J 5.2 Hz, 9H), –0.20 (s, 3H), –1.51 (s, 3H).
Acknowledgements
This research was supported by the National Natural Science Foundation of China (Grant No. 21372017).
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Fumigaclavines A–D的全合成研究
马永凡, 贾彦兴*
北京大学医学部 药学院 天然药物及仿生药物国家重点实验室, 北京 100191  
摘要: 本文报道了一种合成麦角生物碱fumigaclavines A–D四环骨架的新方法,利用钯催化的分子内Larock吲哚合成一步即构筑了四环核心骨架的B/C环。尽管将化合物18转化生成fumigaclavine B的所有尝试失败,本研究为fumigaclavines A–D的全合成做了有益的探索。 
关键词: 吲哚生物碱; 麦角生物碱; 全合成; 钯催化
   

  
Received: 2017-05-10, Revised: 2017-05-28, Accepted: 2017-06-05.
Foundation item: National Natural Science Foundation of China (Grant No. 21372017).
*Corresponding author. Tel.: +86-010-82805166, E-mail: yxjia@bjmu.edu.cn      
知识共享许可协议
本作品采用知识共享署名-非商业性使用 4.0 国际许可协议进行许可。