Total Synthesis of Dimeric Securinega Alkaloids ...O H O N O H O H N H O N O O H OMe N O H O N O O H OMe N O H O N OH O OH flueggenine D N O H O O HO N H Figure S1. Dimeric Securinega
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Total Synthesis of Dimeric Securinega Alkaloids (−)-Flueggenines D and I Sangbin Jeon, Jinwoo Lee, Sangbin Park and Sunkyu Han*
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
Supporting Information 1. General Information S02 2. High-Order Securinega Alkaloids with Rauhut–Currier Reaction-based Linkages S03 3. Optimized Synthetic Procedure for the Preparation of γ-Acetoxy Enone 15 S06 4. Experimental Procedures and Physical Data for Newly Synthesized Compounds S07
All reactions were performed in oven-dried or flame-dried round-bottomed flasks. Unless otherwise noted, the flasks were fitted with rubber septa and reactions were conducted under a positive pressure of argon. Stainless steel syringes or cannula were used to transfer air- and moisture-sensitive liquids. Flash column chromatography was performed as described by Still et al. using silica gel (60-Å pore size, 40–63 µm, 4-6% H2O content, Merck).1 Analytical thin–layer chromatography (TLC) was performed using glass plates pre-coated with 0.25 mm silica gel impregnated with a fluorescent indicator (254 nm). Thin layer chromatography plates were visualized by exposure to ultraviolet light, an aqueous ammonium cerium nitrate/ammonium molybdate (Seebach’s staining), 2 and/or a basic aqueous potassium permanganate (KMnO4).
Unless otherwise stated, all commercial reagents and solvents were used without additional purification with the following exceptions as indicated below. Dichloromethane and tetrahydrofuran were purchased from Merck and Daejung Inc., respectively and were purified by the method of Grubbs et al. under positive argon pressure.3
1H and 13C nuclear magnetic resonance spectra were recorded with Bruker Ascend 400 (400 MHz), Bruker Avance III HD Nano bay (400 MHz), Agilent Technologies DD2 (600 MHz), or Bruker AVANCE III HD (800MHz) and calibrated by using the residual undeuterated chloroform (δH= 7.24 ppm) and CDCl3 (δC= 77.23 ppm) as internal references. Data are reported in the following manners: chemical shift in ppm [multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, app = apparent, br = broad), coupling constant(s) in Hertz, integration]. Unless otherwise stated, all nuclear magnetic resonance experiment was carried out at room temperature. 800 MHz NMR experiments were operated by E. H. Kim at Korea Basic Science Institute. High resolution mass spectra were obtained from KAIST Analysis Center for Research (Daejeon) or Korea Basic Science Institute (SYNAPT G2, operated by J. H. Choi) by using ESI method. Specific rotation [𝛼𝛼]𝐷𝐷𝑇𝑇 was obtained by JASCO P-2000polarimeter.
1 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923–2925. 2 D. Seebach, R. Imwinkelried and G. Stucky, Helv. Chim. Acta., 1987, 70, 448–464. 3 A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen and F. J. Timmers, Organometallics., 1996, 15, 1518–1520.
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S2 / S83
2. High-Order Securinega Alkaloids with Rauhut–Currier Reaction-based Linkages
flueggenine B
N
OH
O
N
OH
O
H
flueggenine A
N
OH
O
N
OH
O
H
flueggenine C
N
OH
O
N
OH
O
H
flueggenine G flueggenine H
flueggenine I flueggine Bfluevirine A
N
OH
O
NH
O
H
H
OOHH
N
OH
O
N
OH
O
H
N
OH
O
N
OH
O
H
HOMe
N
OH
O
N
OH
O
H
OMeN
OH
O
N
OHH
O
H
OH
flueggenine D
N
OH
O
HO
O
N
H
HOH
Figure S1. Dimeric Securinega Alkaloids with Rauhut–Currier Reaction-based Linkage.4
4 (a) L.-S. Gan, C.-Q. Fan, S.-P. Yang, Y. Wu, L.-P. Lin, J. Ding and J.-M. Yue, Org. Lett., 2006, 8, 2285–2288. (b) B.-X. Zhao, Y. Wang, D.-M. Zhang, R.-W. Jiang, G.-C. Wang, J.-M. Shi, X.-J. Huang, W.-M. Chen, C.-T. Che and W.-C. Ye, Org. Lett., 2011, 13, 3888−3891. (c) H. Zhang, W. Wei and J.-M. Yue, Tetrahedron, 2013, 69, 3942–3946. (d) H. Zhang, C.-R. Zhang, Y.-S. Han, M. A. Wainbergand J.-M. Yue, RSC Adv., 2015, 5, 107045–107053. (e) X.-H. Li, M.-M. Cao, Y. Zhang, S.-L. Li, Y.-T. Di and X.-J. Hao, Tetrahedron Lett., 2014, 55, 6101–6104.
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Figure S2. Trimeric Securinega Alkaloids with Rauhut–Currier Reaction-based Linkage.4,5
5 (a) H. Zhang, C.-R. Zhang, K.-K. Zhu, A.-H. Gao, C. Luo, J. Li, and J.-M. Yue, Org. Lett., 2013, 15, 120−123. (b) H. Zhang, Y.-S. Han, M. A. Wainberg, and J.-M. Yue, Tetrahedron Lett., 2016, 57, 1798–1800.
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S4 / S83
N
OHO
N
OH
O
H
N
OH
O
H
O
HO
NH
N
OH
O
N
O HO
HN
OH
O
O
HO
N
H
H
N
OH
O
N
O HO
H
N
OH
O
O
HO
N
H
H
N
OH
O
N
O HO
H
N
OH
O
O
HO
N
H
H
N
OH
O
N
O HO
H
NOH
O H
O
HO
N
H
N
OH
O
N
O HO
HN
OH
O
H
O
HO
N
H
N
OH
ON
OH O
N
OH
O
O HO
N
N
OH
O
HH
H
H N
OH
ON
OH O
N
OH
OO HO
N
N
OH
O
HH
H
H N
OH
ON
OH O
N
OH
OO
HO
N
N
OH
O
HH
H
H
NOH
ON
OH
O
N OH
O
O
HO
N
NO HO
HH
H
H
fluevirosinine A fluevirosinine B fluevirosinine C
fluevirosinine D fluevirosinine E fluevirosinine F
fluevirosinine G fluevirosinine H fluevirosinine I
fluevirosinine J
H
H
H
Figure S3. Tetrameric and Pentameric Securinega Alkaloids with Rauhut–Currier Reaction-based Linkage.4,5,6
6 H. Zhang, Y.-S. Han, M. A. Wainberg and J.-M. Yue, Tetrahedron, 2015, 71, 3671−3679.
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S5 / S83
3. Optimized Synthetic Procedure for the Preparation of γ-Acetoxy Enone 15 O
0.30 mmol, 0.1 equiv.) and acetic anhydride (860 μL, 8.93 mmol, 3.0 equiv.) were added to a stirred solution of S17 (1.1 g, 2.98 mmol, 1 equiv.) in dichloromethane (30 mL) at 23 °C. After 30 min, triethylamine trihydrofluoride (2.91 mL, 17.86 mmol, 6.0 equiv.) was added. After 12 h, the reaction was quenched with saturated aqueous sodium bicarbonate solution (30 mL) and 5% aqueous copper sulfate solution (2 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 20 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 5 cm, ht. 13 cm; eluent: ethyl acetate : hexanes = 1 : 2) to afford 15 (951 mg, 94%) as a colorless oil.
7 S. Jeon and S. Han, J. Am. Chem. Soc., 2017, 139, 6302–6305. 8 In ref 7, γ-acetoxy enone 15 was accessed from S1 in a two-step sequence that involves a desilylation and an acetylation. Herein, we optimized this two-step sequence to a single step procedure.
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
4. Experimental Procedures and Physical Data for Newly Synthesized Compounds
O
NBoc
H
HO
OAc
Cl
HCl
PhO
NBoc
H
HO OH
PhO
OAc
NBoc
HO
O
I
AcO
NIS toluene23 °C;
SiO223 →
35 °C
54% (3 steps)
n-BuLi
Et2O−78 °C
→ 23 °C
15 17 18
16
(–)-Iodobutenolide 18: n-BuLi (1.8 M in cyclohexane, 2.51 mL, 4.53 mmol, 4.8 equiv.) was added to a stirred
solution of 1,2-dichlorovinyl ether 16 (428 mg, 2.26 mmol, 2.4 equiv.) in anhydrous diethyl ether (5 mL) at –78 °C under an atmosphere of argon. After 10 min, the resulting mixture was warmed to –20 °C. After 2 h, the reaction mixture was cooled to –78 °C and a solution of 15 (320 mg, 0.94 mmol, 1 equiv.) in anhydrous diethyl ether (5 mL) was added. The resulting mixture was slowly warmed to 23 °C. After 1 h, the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 20 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure.
The resulting crude residue was dissolved in anhydrous toluene (10 mL). N-Iodosuccinimide (318 mg, 1.41 mmol, 1.50 equiv.) was added at 23 °C while stirring. After 1 h, excess SiO2 (3 g) was added and the reaction mixture was heated to 35 °C. After 24 h, the resulting mixture was filtered through a pad of celite and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 4 cm, ht. 12 cm; eluent: ethyl acetate : hexanes = 1 : 4) to afford 18 as a yellow oil (250 mg, 54%).
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S7 / S83
O
NBoc
H
TBSO
OH
O
NBoc
H
TBSO
OH19 20
n-BuLiiPr2NHBu3SnH
THF, 0 °C;
[Pd(allyl)Cl]2diethyl allyl phosphate
60 °C
22%
SnBu3
(−)-β-Stannyl-γ-hydroxy enone 20: n-BuLi (1.76 M in hexane, 1.38 mL, 2.43 mmol, 2.0 equiv.) was added to a stirred
solution of diisopropylamine (360 μL, 2.55 mmol, 2.1 equiv.) in anhydrous tetrahydrofuran (5 mL) via syringe pump over 10 min at 0 °C under an atmosphere of argon. After 10 min, tributyltin hydride (645 μL, 2.43 mmol, 2.0 equiv.) was added slowly via syringe pump over 5 min. After 30 min, a solution of 19 (500 mg, 1.21 mmol, 1 equiv.) in anhydrous tetrahydrofuran (10 mL) was added slowly via syringe pump over 10 min. After 1 h, a solution of [Pd(allyl)Cl]2 (22mg, 0.06 mmol, 0.05 equiv.) and diethyl allyl phosphate (433 μL, 2.43 mmol, 2.0 equiv.) in anhydrous tetrahydrofuran (1 mL) was added at once. The resulting mixture was heated to 60 °C. After 1 h, the reaction was quenched with saturated aqueous ammonium chloride solution (40 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 70 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 4 cm, ht. 14 cm; eluent: ethyl acetate : hexanes = 1 : 30) to afford 20 (188 mg, 22%) as a colorless oil.
0.421 mmol, 1.0 equiv.), and acetic anhydride (122 μL, 1.26 mmol, 3.0 equiv.) were added to a stirred solution of 20 (295 mg, 0.421 mmol, 1 equiv.) in anhydrous dichloromethane (4 mL) at 23 °C. After 1 h, the reaction was quenched with saturated aqueous sodium bicarbonate solution (40 mL) and the layers were separated. The aqueous layer was extracted dichloromethane (3 × 70 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 4 cm, ht. 13 cm; eluent: ethyl acetate : hexanes = 1 : 30) to afford 21 (282 mg, 90%) as a colorless oil.
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S9 / S83
+
Pd(OAc)2AsPh3
CuI
DMF80 °C
76%
NBoc
HO
O
AcO
O
BocNH
OTBS
AcO
NBoc
HO
O
I
AcO18
O
NBoc
H
OTBS
OAcBu3Sn
21 22
(+)-α′-Silyloxy-γ-acetoxy enone 22:
Palladium (II) acetate (11 mg, 0.0507 mmol, 0.2 equiv.), triphenylarsine (31 mg, 0.101 mmol, 0.4 equiv.) and copper (I) iodide (39mg, 0.203 mmol, 0.8 equiv.) were added to a stirred solution of 18 (124 mg, 0.253 mmol, 1.0 equiv.) and 21 (282 mg, 0.380 mmol, 1.5 equiv.) in anhydrous dimethylformamide (3 mL) under an atmosphere of argon. The resulting mixture was heated to 80 °C. After 10 h, the reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 4 cm, ht. 13 cm; eluent: ethyl acetate : hexanes = 1 : 4) to afford 22 (156 mg, 76%) as a colorless oil.
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S10 / S83
NBoc
HO
O
AcO
O
BocNH
OTBS
AcOTBAF
THF, 23 °C
NBoc
HO
O
AcO
O
BocNH
OH
AcO
22 24
1.
2. Ac2O, Et3NDMAP, CH2Cl2
23 °C
65% (2 steps)
(+)-α′-Hydroxy-γ-acetoxy enone 24:
Tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.125 mmol, 1.0 equiv.) was added to a stirred solution of 22 (102 mg, 0.125 mmol, 1.0 equiv.) in anhydrous tetrahydrofuran (3 mL) at 23 °C under an atmosphere of argon. After 1 h, the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 40 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure.
The resulting crude residue was dissolved in anhydrous dichloromethane (3 mL) and triethylamine (210 μL, 1.50 mmol, 12.0 equiv.), 4-(dimethylamino)pyridine (31 mg, 0.250 mmol, 2.0 equiv.) and acetic anhydride (72 μL, 0.751 mmol, 6.0 equiv.) were added at 23 °C. After 20 min, the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 40 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 4 cm, ht. 13 cm; eluent: ethyl acetate : hexanes = 2 : 3) to afford 24 (57 mg, 65% for 2 steps) as a colorless oil.
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S11 / S83
H2(g)
CH2Cl223 °C
63%
NBoc
HO
O
AcO
O
BocNH
OH
25
NBoc
HO
O
AcO
O
BocNH
OH
AcO
24
IrINCy3P
H
PF6-
(−)-α-Hydroxy ketone 25:
Crabtree’s catalyst (57 mg, 0.0706 mmol, 1.1 equiv.) was added to a stirred solution of 24 (45 mg, 0.0642 mmol, 1.0 equiv.) in anhydrous dichloromethane (3 mL) at 23 °C with hydrogen at atmospheric pressure (using hydrogen-filled balloons). After 1 h, the reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 4 cm, ht. 15 cm; eluent: ethyl acetate : hexanes = 2 : 3) to afford 25 (26 mg, 63%) as a yellow oil.
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S12 / S83
O
NBoc
H
HO
OAc
OH
NBoc
H
HO
OAc
NaBH4
MeOH0 °C
TESOTf iPr2EtN
CH2Cl2, –78 °C;
K2CO3MeOH,
23 °C
74% (3 steps)
OTES
NBoc
H
HO
OH15 26 27
CeCl3•7H
2O
(+)-Cyclohexenol 27:
Cerium chloride heptahydrate (962 mg, 2.58 mmol, 2.0 equiv.) was added to a stirred solution of 15 (438 mg, 1.29 mmol, 1 equiv.) in methanol (13 mL) at 0 °C. After 30 min, sodium borohydride (59 mg, 1.55 mmol, 1.2 equiv.) was added portion wise. After 20 min, the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 50 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure.
The resulting crude residue was dissolved in anhydrous dichloromethane (13 mL) and cooled to –78 °C. N,N-diisopropylethylamine (450 μL, 2.58 mmol, 2.0 equiv.) was added and subsequently triethylsilyl trifluoromethanesulfonate (306 μL, 1.36 mmol, 1.05 equiv.) was added slowly via syringe pump over 20 min while stirring. After 40 min, the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and 5% aqueous copper sulfate solution (5 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 50 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure.
The resulting crude residue was dissolved in methanol (13 mL). Potassium carbonate (357 mg, 2.58 mmol, 2.0 equiv.) was added at 23 °C while stirring. After 1 h, the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 50 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 4 cm, ht. 12 cm; eluent: ethyl acetate : hexanes = 1 : 2) to afford 27 (380 mg, 74% for 3 steps) as a colorless oil. 1H NMR (400.1 MHz, CDCl3): δ 6.88 (br s, 1H), 6.00 (dd, J = 9.5, 5.2 Hz, 1H), 5.84 (dd, J = 10.5, 5.2 Hz, 1H), 4.10 (d, J = 10.5 Hz, 1H), 4.04 – 3.85 (m, 3H), 3.70 (dd, J = 10.3, 7.8 Hz, 1H), 3.21 (dt, J = 10.8, 5.4 Hz, 1H), 2.31 – 2.14 (m, 1H), 2.08 (ddd, J = 14.0, 4.8, 1.7 Hz, 1H), 2.03 – 1.92 (m, 1H), 1.82 (d, J = 14.0 Hz, 1H), 1.78 – 1.69 (m, 1H), 1.65 – 1.51 (m, 1H), 1.44 (s, 9H), 0.91 (t, J = 8.0 Hz, 9H), 0.56 (q, J = 8.2 Hz, 6H). 13C NMR (100.6 MHz, CDCl3): δ 158.0, 131.6, 128.2, 80.8, 75.4, 69.2, 67.9, 64.9, 48.8, 34.0, 28.6, 28.6 (3), 24.6, 7.0 (3), 5.8 (3). HRMS (ESI): Calculated for C21H39NO5Si [M+Na]+: 436.2490, found: 436.2485 TLC (ethyl acetate : hexanes = 1 : 1) Rf: 0.52 (KMnO4).
[𝜶𝜶]𝑫𝑫𝟐𝟐𝟐𝟐: 208.7 (c 1.0, CHCl3)
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
methylmorpholine N-oxide (646 mg, 5.51 mmol, 6.0 equiv.) were added to a stirred solution of 27 (380 mg, 0.92 mmol, 1 equiv.) in anhydrous dichloromethane (9 mL) at 23 °C. After 20 h, the reaction mixture was filtered through a pad of celite. The resulting solution was washed with saturated aqueous sodium sulfite solution (10 mL) and 5% aqueous copper sulfate solution (2 mL). The combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure.
The resulting crude residue was dissolved in anhydrous dichloromethane (20 mL). Triethylamine trihydrofluoride (1.5 mL, 9.19 mmol, 10.0 equiv.) was added and the resulting solution was stirred at 23 °C. After 2 h, the reaction was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and 5% aqueous copper sulfate solution (5 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 20 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel: diam. 4 cm, ht. 15 cm; eluent: ethyl acetate : hexanes = 1.5 : 1) to afford 28 (206 mg, 75%) as a colorless oil.
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S14 / S83
OH
NBoc
H
HO
O
I2, pyridine
CHCl3
50 °C
94%28
OH
NBoc
H
HO
O29
I
(+)-α-Iodoenone 29: Iodine (1.20 g, 4.73 mmol, 5.0 equiv.) was added to a stirred solution of 28 (281 mg,
0.95 mmol, 1 equiv.) in anhydrous chloroform (10 mL) and pyridine (10 mL) co-solvent at 23 °C was. The reaction temperature was raised to 50 °C. After 3 h, the reaction was quenched with saturated aqueous sodium thiosulfate solution (30 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 50 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel: diam. 4 cm, ht. 12 cm; eluent: ethyl acetate : hexanes = 1 : 1.5) to afford 29 (377 mg, 94%) as a yellow oil.
tone)dipalladium(0) (26 mg, 0.044 mmol, 0.05 equiv.), and bis(tributyltin) (1.12 mL, 2.22 mmol, 2.5 equiv.) were added to a stirred solution of 29 (377 mg, 0.89 mmol, 1 equiv.) in anhydrous dichloromethane (9 mL) at 23 °C. After 1 h, the reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 4 cm, ht. 13 cm; eluent: ethyl acetate : hexanes = 1 : 2) to afford 30 as a colorless oil (516 mg, 99%).
5.0 equiv.) were added to a stirred solution of 31 (102 mg, 0.15 mmol, 1 equiv.) in anhydrous toluene (1.5 mL) at 23 °C in the glove box. After 3 h, the reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by flash column
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S18 / S83
NBoc
HO
O
AcO
OH
BocNH
OH
O
H
TESOTf iPr2NEt
CH2Cl2–78 °C
67%
NBoc
HO
O
AcO
OTES
BocNH
OH
O
35
H
34
(+)-γ-Silyloxy ketone 35:
N,N-diisopropylethylamine (68 μL, 0.39 mmol, 6.0 equiv.) and triethylsilyl trifluoromethanesulfonate (44 μL, 0.19 mmol, 3.0 equiv.) were added to a stirred solution of 34 (43 mg, 0.065 mmol, 1 equiv.) in anhydrous dichloromethane (5 mL) at –78 °C. After 90 min, the reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) and 5% aqueous copper sulfate solution (3 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 10 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 2.5 cm, ht. 14 cm; eluent: ethyl acetate : hexanes = 1 : 2) to afford 35 as a yellow oil (34 mg, 67%).
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S19 / S83
NBoc
HO
O
AcO
OH
BocNH
OH
O TESOTf iPr2NEt
CH2Cl2–78 °C
82%
NBoc
HO
O
AcO
OTES
BocNH
OH
O
31 36
(+)-γ-Silyloxy-δ-hydroxy enone 36: N,N-diisopropylethylamine (84 μL, 0.48 mmol, 2.0 equiv.) was added to a stirred
solution of 31 (160 mg, 0.24 mmol, 1 equiv.) in anhydrous dichloromethane (8 mL) at –78 °C. A solution of triethylsilyl trifluoromethanesulfonate (55 μL, 0.24 mmol, 1 equiv.) in anhydrous dichloromethane (1 mL) was added via syringe pump over 20 min. After 20 min, the reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and 5% aqueous copper sulfate solution (5 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 20 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 4 cm, ht. 13 cm;
eluent: ethyl acetate : hexanes = 1 : 4 → 1 : 1) to afford 36 as a yellow oil (155 mg, 82%).
mmol, 5.0 equiv.) were added to a stirred solution of 36 (144 mg, 0.186 mmol, 1 equiv.) in anhydrous toluene (3.6 mL) at 23 °C in the glove box. After 3 h, the reaction mixture was concentrated under reduced pressure to yield 38 that was prone to air oxidation. Attempted purification of 38 resulted in at oxidation at C11’ position. Hence, the crude material was directly used for the next step.
The crude mixture of 38 was dissolved in anhydrous tetrahydrofuran and cesium carbonate (182 mg, 0.559 mmol, 3.0 equiv.) was added at 23 °C. After 3 h, the reaction mixture was filtered through a pad of celite and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 4 cm, ht. 14 cm;
eluent: ethyl acetate : hexanes = 1 : 3 → 1 : 2) to afford 35 as a colorless oil. (74 mg, 51%)
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S21 / S83
NBoc
HO
O
AcO
OTES
BocNH
OH
ONaBH4
MeOH, 0 °C
NBoc
HO
O
AcO
OTES
BocNH
OH
AcO
35 39
1.
2.HH
CeCl3•7H
2O
Ac2O, Et3NDMAP, CH2Cl2
23 °C
67% (2 steps)
(+)-Silyl ether 39: Cerium (III) chloride heptahydrate (86 mg, 0.231 mmol, 1.3 equiv.) was added to a
stirred solution of 35 (138 mg, 0.178 mmol, 1 equiv.) in anhydrous methanol (6 mL) at 0 °C. After 30 min, sodium borohydride (8.7 mg, 0.231 mmol, 1.3 equiv.) was added. After 30 min, the reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 × 10 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting crude residue was dissolved in anhydrous dichloromethane (6 mL) and triethylamine (496 μL, 3.561 mmol, 20 equiv.), 4-(dimethylamino)pyridine (22 mg, 0.178 mmol, 1.0 equiv.) and acetic anhydride (171 μL, 1.780 mmol, 10.0 equiv.) was added at 23 °C. After 13 h, the reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) and 5% aqueous copper sulfate solution (2 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 20 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel:
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S22 / S83
NBoc
HO
O
AcO
OTES
BocNH
OH
AcOCH2Cl223 °C
NBoc
HO
O
AcO
O
BocNH
OH
AcO
39 40
1.
2.
HH
Et3N•3HF
DMPNaHCO3 CH
2Cl223 °C
62% (2 steps)
(−)-α-Hydroxy ketone 40: Triethylamine trihydrofluoride (965 μL, 5.921 mmol, 50.0 equiv.) was added to a
stirred solution of 39 (97 mg, 0.118 mmol, 1 equiv.) in anhydrous dichloromethane (2 mL) at 23 °C. After 8 h, the reaction was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and 5% aqueous cooper sulfate solution (5 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 20 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
The resulting crude residue was dissolved in anhydrous dichloromethane (2 mL) and sodium bicarbonate (199 mg, 2.368 mmol, 20.0 equiv.) and Dess−Martin periodinane (502 mg, 1.184 mmol, 10.0 equiv.) were added at 23 °C. After 15 h, the reaction was quenched with saturated aqueous sodium metabisulfite solution (20 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (3 × 20 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel:
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S23 / S83
toluene100 °C
67%
NBoc
HO
O
AcO
O
BocNH
OH
AcO
40
H
S2
NBoc
HO
O
AcO
BocNHAcO
H
O
OO C C PPh3
(+)-ε-Acetoxy butenolide S2: (Triphenylphosphoranylidene)ketene (71 mg, 0.234 mmol, 5.0 equiv.) was added to a
stirred solution of 40 (33 mg, 0.047 mmol, 1 equiv.) in anhydrous toluene at 23 °C and the mixture was heated to 100 °C. After 3 h, the reaction mixture cooled to 23 °C and concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 2.5 cm, ht. 14 cm; eluent: ethyl acetate : hexanes = 2 : 3) to afford S2 (23 mg, 67%) as a yellow oil.
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S24 / S83
K2CO3MeOH
23 °C
88% 41
NBoc
HO
O
HO
BocNHHO
H
O
O
S2
NBoc
HO
O
AcO
BocNHAcO
H
O
O
(+)-ε-Hydroxy butenolide 41: Potassium carbonate (27 mg, 0.091 mmol, 3.0 equiv.) was added to a stirred solution
of S2 (22 mg, 0.030 mmol, 1 equiv.) in methanol, was added at 23 °C. After 1 h, the reaction was quenched with saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 20 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting crude residue was purified by flash column chromatography (silica gel: diam. 2.5 cm, ht. 14 cm; eluent: ethyl acetate : hexanes = 4 : 1) to afford 41 (17.2 mg, 88%) as a colorless oil.
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S25 / S83
MsCl, Et3NCH2Cl2, 0 °C
41
NBoc
HO
O
HO
BocNHHO
H
O
O
N
OH
ON
OH
O
H
(–)-flueggenine D (4)
1.
2.
K2CO3 (aq)THF, 23 °C
51% (3 steps)
TFACH2Cl2, 23 °C
3.
(−)-Flueggenine D (4): Triethylamine (61 μL, 0.436 mmol, 20.0 equiv.) and methanesulfonyl chloride (17 μL,
0.218 mmol, 10.0 equiv.) were added to a stirred solution of 41 (14 mg, 0.022 mmol, 1 equiv.) in anhydrous dichloromethane (700 μL) at 0 °C. After 40 min, brine (10 mL) was added and the aqueous layer was extracted with dichloromethane (3 × 10 mL). The combined organic layer was dried over anhydrous sodium sulfate and the resulting filtrate concentrated under reduced pressure. The resulting crude mixture was dissolved in anhydrous dichloromethane (1 mL) and trifluoroacetic acid (1 mL) cosolvent and the mixture was stirred at 23 °C. After 30 min, the reaction mixture was concentrated under reduced pressure.
The resulting crude mixture was dissolved in a mixture of tetrahydrofuran (1 mL) and saturated aqueous potassium carbonate solution (1 mL). The reaction mixture was stirred at 23 °C. After 1 h, 1 M aqueous sodium hydroxide solution (10 mL) was added. The aqueous layer was extracted with dichloromethane (3 × 10 mL) and the combined organic layer was dried over anhydrous sodium sulfate. The resulting filtrate was concentrated under reduced pressure. The resulting crude residue was purified by flash purified by flash column chromatography (silica gel: diam. 2 cm, ht. 10 cm; eluent: dichloromethane : methanol : ammonium hydroxide = 10 : 1 : 0.1) to afford flueggenine D (4) (4.5 mg, 51%, 3 steps) as a white amorphous solid. 1H NMR (400.1 MHz, CDCl3)11: δ 6.73 (dd, J = 9.2, 6.4 Hz, 1H), 6.45 (d, J = 9.2 Hz, 1H), 5.75 (d, J = 2.2 Hz, 1H), 3.61 (dd, J = 6.4, 4.7 Hz, 1H), 3.43 (dd J = 9.2 Hz, 3.3 Hz, 1H), 3.43 – 3.37 (m, 1H), 3.30 – 3.24 (m, 2H), 3.22 (dd, J = 8.6, 7.0 Hz, 1H), 3.14 (ddd, J = 17.3, 9.2, 7.0 Hz , 1H), 3.13 (dd, J = 8.8, 7.7 Hz, 1H), 3.03 (d, J = 17.3 Hz, 1H), 2.68 – 2.60 (m, 1H), 2.55 (dd, J = 10.6, 4.7 Hz, 1H), 2.56 – 2.48 (m, 1H), 2.30 (dd, J = 11.4, 5.7 Hz, 1H), 2.01 – 1.86 (m, 4H), 1.84 – 1.66 (m, 4H), 1.60 (d, J = 10.6 Hz, 1H), 1.37 (d, J = 11.4 Hz, 1H). 13C NMR (100.6 MHz, CDCl3): δ 174.1, 172.8, 172.7, 161.5, 144.3, 120.6, 119.3, 110.7, 92.4, 90.6, 66.9, 65.9, 65.0, 59.7, 57.7, 55.3, 39.8, 35.8, 30.6, 29.6, 29.3, 27.0, 26.8, 26.5. HRMS (ESI): Calculated for C24H26N2O4 [M+H]+: 407.1965, found: 407.1970 TLC (dichloromethane : methanol : ammonium hydroxide =10 : 1 : 0.1) Rf: 0.26 (UV, KMnO4).
[𝜶𝜶]𝑫𝑫𝟐𝟐𝟐𝟐: –118.2 (c 0.11, MeOH)
11 Proton nuclear magnetic resonance spectra are referenced from the residual protium in the NMR solvent (CDCl3: δ 7.26 (CHCl3)) for direct comparison with the isolation paper.
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S26 / S83
NaOMe
MeOH23 °C
87%
N
OH
ON
OH
O
H
(–)-flueggenine I (5)
N
OH
ON
OH
O
H
(–)-flueggenine D (4)
OMe
(−)-Flueggenine I (5): Sodium methoxide (5 M solution in methanol, 69 μL, 0.344 mmol, 40.0 equiv.) was added to a stirred solution of (−)-flueggenine D (4) (3.5 mg, 0.009 mmol, 1 equiv.) in methanol
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S27 / S83
5. Key NOE Correlations of Compounds 35 and 39 H12
35
N
OOtBu
H
OH
O
TESO
BocN
HOO
OAcH10
H11
H11'
Figure S4. 2D NOESY spectrum of compound 35 (Region of interest (1.6−4.2 ppm) is magnified. See section 7 for copies of comprehensive 2D NMR spectra of compound 35).
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S28 / S83
H12
N
OOtBu
H
OH
OAc
TESO
BocN
HOO
OAcH10
H11
H11'
H7
39
H8
H8'
H12
H12
H7
H7
H8'
H8
H8' H8
H10
H11
H11H11'
H11'
-OAc
-OAcH10
H7
H12
H11'
Figure S5. Selective 1D NOESY spectra of compound 39 (See section 7 for copies of comprehensive 2D NMR spectra of compound 39).
Total Synthesis of Dimeric Securinega Alkaloids (–)-Flueggenines D and I S. Jeon, J. Lee, S. Park and S. Han*
Page S29 / S83
6. Comparison of Spectroscopic Data of Our Synthetic Natural Products with Other Reports
N
OH
ON
OH
O
H
(–)-flueggenine D (4)
23
4
5 15
12
7
8
913
14
1115'
14' 13'
12'11'9'
8'
7' 2' 3'
4'5'
Table S1. Comparison of 1H-NMR spectroscopic data of natural and synthetic flueggenine D (4)
position natural 44c
δ1 (ppm ; multi, J in Hz) synthetic 4
δ2 (ppm ; multi, J in Hz)
deviation Δδ = δ1 – δ2
(ppm) 2 3.12 (dd, 8.8, 7.7) 3.13 (dd, 8.8, 7.7) –0.01 3 a 1.94 (m) a 1.94 (m) 0 b 1.77 (m) b 1.77 (m) 0 4 a 1.96 (m) a 1.96 (m) 0 b 1.76 (m) b 1.76 (m) 0 5 a 3.27 (m) a 3.27 (m) 0 z b 2.51 (m) b 2.52 (m) –0.01 7 3.61 (dd, 6.4, 4.7) 3.61 (dd, 6.4, 4.7) 0 8 a 2.55 (dd, 10.6, 4.7) a 2.55 (dd, 10.6, 4.7) 0 b 1.60 (d, 10.6) b 1.60 (d, 10.6) 0