Gold-Catalyzed Diversified Synthesis of 3-Aminosugar ... · S1 Gold-Catalyzed Diversified Synthesis...
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Gold-Catalyzed Diversified Synthesis of 3-Aminosugar
Analogues of Digitoxin and Digoxin
Jing Zeng,*a Guangfei Sun,a Ruobin Wang,a Shuxin Zhang,a Shuang Teng,a Zhiwen Liao,a Lingkui Meng,a Qian Wan*a,b
a Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation,
School of Pharmacy; Huazhong University of Science and Technology, 13 Hangkong
Road, Wuhan, Hubei, 430030, China. b Institute of Brain Research, Huazhong University of Science and Technology.
Corresponding to: [email protected]; [email protected].
Table of Contents
1. General information..............................................................................................S2
2. Preparation of donors 1a, 1b and 1c ...................................................................S3
3. Preparation of digitoxigenin……………………………………………………S4
4. Table1:Glycosylation of 3-aminosugar with digitoxigenin………………….S4
5. Scheme 1: Synthesis of D-3-aminosugar analogues of digitoxin……………...S8
6. Scheme 2: Synthesis of L-3-aminosugar analogues of digitoxin……………...S10
7. Scheme 4a: Synthesis of C12 acetylated digoxigenin 10…………………....S12
8. Scheme 4b: Synthesis of L-3-aminosugar analogues of digoxin…………….S13
9. Scheme 5: Synthesis of N-acetyl L-3-aminosugar analogues of digoxin……..S16
10. Scheme 6: Synthesis of N-acetyl D-3-aminosugar analogues of digoxin……S18
11. References……………………………………………………………………...S22
12. NMR Spectra…………………………………………………………………..S22
Electronic Supplementary Material (ESI) for Organic Chemistry Frontiers.This journal is © the Partner Organisations 2017
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1. General information
All reactions were monitored by thin-layer chromatography over silica-gel-coated
TLC plates (Yantai Chemical Industry Research Institute). The spots on TLC were
visualized by warming 10% H2SO4 (10% H2SO4 in ethanol) sprayed plates on a hot
plate. Column chromatography was performed using silica gel (Qingdao Marine
Chemical Inc., China). NMR spectra were recorded on a Bruker AM-400
spectrometer (400 MHz), and the 1H and 13C NMR chemical shifts were referenced to
the solvent or solvent impurity peaks for CDCl3 at δH 7.24 and δC 77.23, for CD3OD
at δH 3.31 and δC 47.61, for acetone-d6 at δH 2.05 and δC 29.84, for benzene-d6 at δH
7.16 and δC 128.06, for DMSO-d6 at δH 2.50 and δC 39.93. Optical rotations were
measured at 20 °C with a Rudolph Autopol IV automatic polarimeter using a quartz
cell with 2 mL capacity and a 1 dm path length. Concentrations (c) are given in g/100
mL. High resolution mass spectra were recorded on a Bruker micrOTOF II
spectrometer using electrospray ionization (ESI).
Materials
Prior to running the glycosylation reactions, all reagents except Tf2O and those with
low boiling point (<180°C) were dried by repeated azeotropic removal of water using
toluene and a rotary evaporator at 27 °C. Solvents for reactions were dried on an
Innovative Technologies Pure Solv400 solvent purifier. Molecular sieves (4Å, powder
< 50 µm) for reactions were flame dried immediately before use.
PPh3Au(NTf)2 was purchased from J&K, digitoxin and digoxigenin were purchased
from Sigma, digoxin was purchased from TCI, Lithium hydroxide (LiOH), methyl 2-
sulfanylacetate, silver trifluoromethanesulfonate (AgOTf), N-iodosuccinimide (NIS),
and all other commercial available chemicals were purchased from Adamas and used
without further purification.
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2. Preparation of donors 1a, 1b and 1c
Preparation of glycosyl donor 1a
To a solution of S1[1] (126.0 mg, 0.325 mmol, 1.0 equiv) in
dry DCM (3.3 ml, c = 0.1 mol/L) at 0 oC was added p-
thiocresol (48.4 mg, 0.39 mmol, 1.2 equiv) under argon. After
5 min, BF3.Et2O (94 μl, 0.81 mmol, 2.5 equiv) was added
dropwise, the mixture was stirred at 0 oC for 4 h. The reaction
was extracted with EtOAc and the organic layer was washed
with saturated aqueous NaHCO3, water and brine sequentially, the organic layer was
dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel
chromatography (petroleum-EtOAc 6:1) to give 1a (125.0 mg, 80%) as faint yellow
solid as α, β-mixture. the ratio was confirmed as 2:1 by 1H NMR. Analytical data for
1a: Rf = 0.50 (petroleum-EtOAc 3:1). 1H NMR (400MHz CDCl3): δ 8.34 (d, J = 8.8
Hz, 2H, Ph, α-anomer), 8.30 (d, J = 8.8 Hz, 1H, Ph, β-anomer), 8.05 (d, J = 8.8 Hz,
2H, Ph, α-anomer), 8.00 (d, J = 8.4 Hz, 1H, Ph, β-anomer), 7.28 (d, J = 8.0 Hz, 2H,
Ph, α-anomer), 7.27 (d, J = 8.4 Hz, 1H, Ph, β-anomer), 7.11 (d, J = 8.0 Hz, 2H, Ph, α-
anomer), 7.07 (d, J = 7.6 Hz, 1H, Ph, β-anomer), 5.88 (d, J = 9.6 Hz, 1H, -NH, α-
anomer), 5.32 (dd, J = 1.6, 5.6 Hz, 1H, H-1, α-anomer), 5.23 (br s, 0.5H, -NH, β-
anomer), 4.77 (d, J = 11.6 Hz, 0.5H, H-1, β-anomer), 4.47-4.42 (m, 1.5H, H-4, α, β-
anomers), 4.34-4.27 (m, 1H, H-5, α-anomer), 4.04-3.99 (m, 1H, H-3, α-anomer),
3.90-3.87 (m, 0.5H, β-anomer), 3.74-3.66 (m, 0.5H, H-5, β-anomer), 2.32 (s, 4.5H, -
Ac, α, β-anomers), 2.23 (dt, J = 5.6, 14.8 Hz, 1H, H-2, α-anomer), 2.12 (d, J = 14.8
Hz, 0.5H, H-2, β-anomer), 1.93-1.88 (m, 2H, H-2, -Ac, β-anomer), 1.78-1.74 (m, 1H,
H-2, α-anomer), 1.18-1.15 (m, 4.5H, H-6, α, β-anomers). 13C NMR (100 MHz,
CDCl3): δ 170.4(C=O), 169.6(C=O), 150.4(Ph), 150.3(Ph), 150.3(Ph), 147.1(Ph),
145.9(Ph), 138.7(Ph), 138.4(Ph), 132.8(2C), 132.7(2C), 130.2(2C), 129.9(2C), 129.3,
129.2, 128.5(2C), 128.4(2C), 124.7(4C), 81.1(C-1), 79.9(C-1), 72.3(C-4), 72.1(C-4),
70.8(C-5), 63.8(C-5), 50.7(C-3), 49.0(C-3), 36.3(C-2), 34.5(C-2), 21.4(PhCH3),
21.3(PhCH3), 21.1(COCH3), 20.9(COCH3), 18.3(C-6), 17.3(C-6). HRMS calc. for
C21H24N2NaO7S2 [M+Na] +: 503.0917, found: 503.0917.
Glycosyl donors 1b and 1c were synthesized following literature procedures [1]
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3. Preparation of Digitoxigenin [2]
Digitoxin (500 mg, 0.65 mmol) was dissolved in MeOH (13 ml, c = 0.05 mol/L), then
TsOH·H2O (12.4 mg, 0.065 mmol, 0.1 equiv) was added. The mixture was stirred at
room temperament for 24 h and concentrated in vacuo. The residue was purified by
silica gel flash column chromatography (petroleum-EtOAc 3:2) to give Digitoxigenin
(200 mg, 82%). Analytical data for Digitoxigenin: Rf = 0.70 (petroleum-acetone 1:1).
m.p. 242.0-243.0 °C. [α]D17 +14.9 (c, 1.36 in MeOH) [Lit. [3] m.p. 249-250 °C, [α]D
17
+17.8 (c, 1.64 in MeOH)]. 1H NMR (400MHz CDCl3): δ 5.84 (s, 1H, H-22), 4.97 (dd,
J = 1.6, 18.4 Hz, 1H, H-21a), 4.78 (dd, J = 1.6, 18.4 Hz, 1H, H-21b), 4.10 (br s, 1H,
H-3), 2.77-2.74 (m, 1H, H-17), 2.17-2.06 (m, 2H), 1.91-1.81 (m, 3H), 1.75-1.62 (m,
4H), 1.60-1.49 (m, 5H), 1.42-1.33 (m, 5H), 1.26-1.18 (m, 3H), 0.92 (s, 3H, H-19),
0.84 (s, 3H, H-18). 1H NMR data was consistent with reference [2,3].
4. Table1: Glycosylation of 3-aminosugar with digitoxigenin
Entry 1 Coditions Yield of 2a
(α: β)b
1 1a NIS (2.2 equiv), AgOTf (0.4 equiv)
4 Å MS, DCM, 0 oC, 1 h
59% (α only)
(31%)c
2 1b Ph3PAuNTf2 (0.2 equiv), DCM,
4 Å MS, -40 oC, 3 h
96%
(2.1:1)
3 1b Ph3PAuNTf2 (0.1 equiv), DCM,
4 Å MS, -40 oC, 3 h
94%
(2.1:1)
4 1b Ph3PAuNTf2 (0.05 equiv), DCM,
4 Å MS, -40 oC, 3 h
96%
(1.8:1)
5 1b Ph3PAuNTf2 (0.2 equiv), DMF (12 equiv),
4 Å MS, DCM, -40 oC, 12 h
95%
(1.1:1)
6 1b Ph3PAuNTf2 (0.1 equiv), DMF (12 equiv),
4 Å MS, DCM, -40 oC, 12 h
80%
(1:1) a Isolated yield; b α, β ratio was determined by isolated products; c isolated yield of 3 in parenthesis, compound 3 is a mixture of ∆8-14- and ∆14-15-digitoxigenin resulting from elimination of C14-OH, the ratio is 1.7:1. Ns = 4-nitrobenzensulfonyl; Abz = 2-(hex-1-yn-1-yl) benzoate; Digi-OH = digitoxigenin.
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Analytical data for 2α: Rf = 0.60 (petroleum-
EtOAc 1:2). m.p. 140.5-141.0 °C. [α]D20 +93.9
(c, 1.09 in CHCl3). 1H NMR (400MHz CDCl3):
δ 8.32 (d, J = 8.4 Hz, 2H, -Ph), 7.98 (d, J = 8.4
Hz, 2H, -Ph), 6.61 (d, J = 8.8 Hz, 1H, -NH),
5.86 (s, 1H, H-22), 4.97 (d, J = 18.0 Hz, 1H, H-
21a), 4.86 (d, J = 2.8 Hz, 1H, H-1'), 4.81 (d, J =
18.0 Hz, 1H, H-21b), 4.32 (dd, J = 3.6, 10.4 Hz,
1H, H-4'), 4.05-3.90 (m, 3H, H-5', H-3,, H-3'), 2.78-2.75 (m, 1H, H-17α), 2.19-2.06
(m, 5H), 2.02-1.65 (m, 8H), 1.57-1.34 (m, 10H), 1.30-1.22 (m, 4H), 1.17 (d, J = 6.4
Hz, 3H, H-6'), 1.01 (s, 3H, -Me, H-19), 0.87 (s, 3H, -Me, H-18). 13C NMR (100 MHz,
CDCl3): δ 174.7(C=O), 174.7(C-20), 170.8 (C=O), 150.1 (Ph), 147.4 (Ph), 128.1 (Ph),
128.1(Ph), 124.6(Ph), 124.6(Ph), 118.0(C-22), 95.7(C-1'), 85.7(C-14), 73.7(C-3),
73.6(C-21), 72.7(C-4'), 62.6(C-5'), 51.1(C-17), 49.8(C-13), 48.9(C-3'), 42.0, 40.1,
38.2, 35.9, 35.5, 33.9, 33.3, 32.4, 30.7, 27.1, 26.9, 24.8, 24.3(C-19), 21.5, 21.4,
21.2(COCH3), 17.6(C-6'), 16.0 (C-18). HRMS calc. for C37H50N2NaO11S [M+Na] +:
753.3028, found: 753.3004.
Analytical data for 2β: Rf = 0.55 (petroleum-
EtOAc 1:2). m.p. 145.6-146.0 °C. [α]D20
+21.9 (c, 0.9 in CHCl3). 1H NMR (400MHz
CDCl3): δ 8.36 (d, J = 8.0 Hz, 2H, Ph), 8.04
(d, J = 8.8 Hz, 2H, Ph), 5.86 (s, 1H, H-22),
5.08 (br s, 1H, -NH), 4.97 (d, J = 18.0 Hz, 1H,
H-21a), 4.79 (dd, J = 1.2, 18.0 Hz, H-21b),
4.78 (dd, J = 1.6, 7.2 Hz, 1H, H-1'), 4.50 (dd,
J = 4.0, 7.6 Hz, 1H, H-4'), 3.95-3.91 (m, 2H, H-3, H-3'), 3.81-3.75 (m, 1H, H-5'),
2.78-2.74 (m, 1H, 17), 2.18-1.98 (m, 3H), 1.92 (s, 3H, COCH3), 1.87-1.79 (m, 2H),
1.73-1.65(m, 4H), 1.60-1.46 (m, 8H), 1.43-1.32 (m, 5H), 1.21-1.94 (m, 5H), 0.90 (s,
3H, -Me, H-19), 0.85 (s, 3H, -Me, H-18). 13C NMR (100 MHz, CDCl3): δ 174.8(C-
23), 174.8(C-20), 169.8(C=O), 150.4(Ph), 146.1(Ph), 128.6(Ph), 128.6(Ph), 124.7(Ph),
124.7(Ph), 117.9(C-22), 95.2(C-1'), 85.8(C-14), 73.7(C-21), 72.9 (C-3), 72.8(C-4'),
69.2(C-5'), 51.1(C-17), 49.8(C-13), 48.9(C-3'), 42.0, 40.2, 36.5, 36.0, 35.7, 35.4, 33.3,
30.3, 29.8, 27.1, 26.8, 26.6, 23.9 (C-19), 21.6, 21.4, 21.0(COCH3), 18.8(C-6'), 16.0
(C-18). HRMS calc. for C37H50N2NaO11S [M+Na] +: 753.3028, found: 753.3000.
Entry 1
Donor 1a (42.0 mg, 0.087 mmol, 2.0 equiv) and acceptor 27 (16.4 mg, 0.044 mmol,
1.0 equiv) were dissolved in anhydrous CH2Cl2 (0.9 mL, c=0.05 mol/L). Freshly
activated 4 Å molecular sieves (60.0 mg), NIS (21.7 mg, 0.096 mmol, 2.2 equiv) and
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AgOTf (4.6 mg, 0.018 mmol, 0.4 equiv) were added successively. The mixture was
stirred at 0 °C for 1 h under argon, then treated with NaHCO3/Na2S2O3 (sat. aq.),
diluted with EtOAc and filtered through a pad of celite. The organic layer was washed
with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by silica
gel flash column chromatography (petroleum-EtOAc 3:1→1:1) to give 2α (19.0 mg,
59%) and 3 (9.7mg, a mixture of 3a:3b=1.7:1, the ratio was confirmed by 1H NMR).
Analytical data for 3: Rf = 0.7 (petroleum-EtOAc 1:1). 1H NMR (400MHz CDCl3): δ
8.34-8.31 (m, 3.2H, Ph), 8.00-7.97 (m, 2H, Ph), 6.63 (d, J = 8.8 Hz, 1.6H, -NH), 5.87-
5.86 (m, 1.6 H, H-22), 5.23 (d, J = 1.2 Hz, 1H, H-15, 3a), 4.88-4.76 (m, 3.3H), 4.88-
4.76 (m, 3.3H, H-21a, H-1'), 4.72-4.70 (m, 1.6H, H-21b), 4.36-4.31 (m, 1.6H), 4.06-
4.00 (m, 2.2 H), 3.94-3.90 (m, 2.6H), 2.77 (t, J = 9.2 Hz, 1H, H-17, 3a), 2.46-2.44 (m,
1.6H), 2.07 (s, 4.8H, -Ac),1.19-1.17 (m, 4.8H, H-6'), 1.03(s, 3H, H-19, 3a), 0.90 (s,
1.8H, H-19, 3b), 0.81 (s, 3H, H-18, 3a), 0.80 (s, 1.8H, H-18, 3b). 13C NMR (100
MHz, CDCl3): δ 174.2, 170.8, 170.7, 154.2(C-14, 3a), 150.2, 147.5, 147.5, 139.1(C-
14, 3b), 129.3(C-8, 3b), 129.0, 128.1, 124.6, 117.0, 116.8, 116.6(C-15, 3a), 95.6(C-
1'), 95.5(C-1'), 73.9, 73.7, 73.7, 72.8, 62.6, 53.0, 52.0, 51.3, 48.9, 44.1, 41.6, 40.0,
38.8, 38.5, 37.1, 36.1, 35.8, 35.6, 35.5, 33.9, 33.8, 32.4, 32.3, 30.8, 30.4, 27.1, 26.6,
26.1, 26.0, 24.9, 24.8, 24.8, 24.6, 24.1, 24.1, 24.0, 22.1, 21.2, 19.8, 19.5, 18.6, 17.6.
HRMS calc. for C37H48N2NaO10S [M+Na] +: 739.2922, found: 739.2921.
4.1 General Procedure A for gold-catalyzed glycosylation
Glycosyl donor 1b or 1c (1.5 equiv) and acceptor Digi-OH or 10 (1.0 equiv) were
dissolved in anhydrous CH2Cl2 (c=0.025 mol/L). Freshly activated 4 Å molecular
sieves were added and the mixture was stirred for 10 min at -40 °C under argon. After
dropwise addition of Ph3PAuNTf2 (0.05-0.2 equiv) in dry DCM (0.2 ml), the solution
was stirred at -40 °C for 3 h. The mixture was filtered through celite, the filtrate was
concentrated to give a residue, which was purified by silica gel column
chromatograph (petroleum-EtOAc 1:1) to provide α-and β- products.
Entry 2:
According to the General Procedure A, donor 1b (25.7 mg, 0.046 mmol, 1.5 equiv),
acceptor Digi-OH (11.5 mg, 0.031 mmol, 1.0 equiv) and Ph3PAuNTf2 (4.5 mg, 0.006
mmol, 0.2 equiv) in dry DCM (0.2 ml) was reacted to afford 2α (14.6 mg, 65%) and
2β (6.9 mg, 31%).
Entry 3:
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According to the General Procedure A, donor 1b (107 mg, 0.19 mmol, 1.5 equiv),
acceptor Digi-OH (48 mg, 0.13 mmol, 1.0 equiv) and Ph3PAuNTf2 (9.5 mg, 0.013
mmol, 0.1 equiv) in dry DCM (0.2 ml) was reacted to afford 2α (60.0 mg, 64%) and
2β (28.0 mg, 30%).
Entry 4:
According to the General Procedure A, donor 1b (28.4 mg, 0.051 mmol, 1.5 equiv),
Digi-OH (12.7 mg, 0.034 mmol, 1.0 equiv) and 0.2 ml Ph3PAuNTf2 (2.5 mg in 0.4 ml
dry DCM, 0.0034 mmol, 0.1 equiv) was reacted to yield 2α (15.4 mg, 62%) and 2β
(8.5 mg, 34%).
4.2. General Procedure B for gold-catalyzed glycosylation.
Donor 1b (1.5 equiv) and acceptor Digi-OH (1.0 equiv) were dissolved in anhydrous
CH2Cl2 (c=0.025 mol/L). Freshly activated 4 Å molecular sieves and anhydrous DMF
(12.0 equiv) were added to the mixture. The resulting mixture was stirred at room
temperature for 10 min and -40 °C for another 10 min under argon. After dropwise
addition of Ph3PAuNTf2 (X equiv) in dry DCM (0.2 ml), the reaction mixture was
stirred at -40 °C for 12 h. The mixture was filtered through celite, the filtrate was
concentrated to give a residue, which was purified by silica gel column
chromatograph (petroleum-EtOAc 1:1) to provide α- and β-anomer.
Entry 5:
According to the General Procedure B, donor 1b (18.8 mg, 0.034 mmol, 1.5 equiv),
Digi-OH (8.4 mg, 0.022 mmol, 1.0 equiv), anhydrous DMF (21.0 μl, 0.26 mmol, 12.0
equiv) and Ph3PAuNTf2 (3.3 mg, 0.0045 mmol, 0.2 equiv) in dry DCM (0.2 ml) was
reacted to afford 2α (8.2 mg, 50%) and 2β (7.4 mg, 45%).
Entry 6:
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According to the General Procedure B, donor 1b (35.8 mg, 0.064 mmol, 1.5 equiv),
Digi-OH (16 mg, 0.043 mmol, 1.0 equiv), anhydrous DMF (39.0 μl, 0.51 mmol, 12.0
equiv) and Ph3PAuNTf2 (3.2 mg, 0.0043 mmol, 0.1 equiv) in dry DCM (0.2 ml) was
reacted to yield 2 (25.1 mg, 80%, α: β = 1:1), the ratio of 2α and 2β was confirmed by 1H NMR. The recovery yield of Digi-OH was 17%.
5. Scheme 1: Synthesis of D-3-aminosugar analogues of digitoxin
5.1. General Procedure C for deacetylation
To a solution of acetylated compound (1.0 equiv) in mixed solution of MeOH and
H2O (4:1) was added LiOH (3-6 equiv). The reaction mixture was stirred at 0 °C or
room temperament for an appropriate time, then quenched with saturated ammonium
chloride solution. The mixture was extracted with EtOAc and washed with saturated
ammonium chloride solution and brine. The organic layer was dried over Na2SO4 and
concentrated in vacuo. The residue was purified by silica gel chromatography to give
deacetylated product.
5.2. General Procedure D for deprotection of 4-nitrobenzenesulfonamide.
To a solution of 4-nitrobenzenesulfonamide (1.0 equiv) in deoxygenated dry CH3CN
(c=0.02 mol/L) was added K2CO3 (8.0 equiv) and thiol compound (6.0 equiv). After
stirring at room temperament for an appropriate time until complete consumption of
the starting material. The mixture was filtered and concentrated in vacuo. The residue
was purified by silica gel column chromatograph to give the corresponding
deprotected product.
Preparation of 5α
According to the General Procedure C, starting
material 2α (42.0 mg, 0.058 mmol, 1.0 equiv),
and LiOH (8.4 mg, 0.35 mmol, 6.0 equiv) in
MeOH (4.4 ml), H2O (1.1 mL) was stirred at
0 °C for 3 h to give 4α (36.0 mg, 91%) as white
solid after purification by silica gel
chromatography (petroleum-EtOAc 1:1).
According to the General Procedure D, above
compound 4α (36.0 mg, 0.052 mmol, 1.0 equiv), K2CO3 (58 mg, 0.42 mmol, 8.0
equiv), PhSH (33.0 µL, 0.31 mmol, 6.0 equiv) in CH3CN was stirred for 4 h to yield
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5α (24.0 mg, 91%) as white solid after purification by silica gel column
chromatograph (petroleum-EtOAc 3:2→DCM:MeOH 10:1). Analytical data for 5α:
Rf = 0.40 (DCM:MeOH 10:1). m.p. 180.0-181.0 °C. [α]D20 +66.5 (c, 2.43 in CHCl3).
1H NMR (400MHz CDCl3): δ 5.84 (s, 1H, H-22), 4.97 (d, J = 18.0 Hz, 1H, H-21a),
4.90 (d, J = 3.2 Hz, 1H, H-1'), 4.78 (dd, J = 1.2, 18.0 Hz, 1H, H-21b), 3.91 (s, 1H, H-
3), 3.68-3.61 (m, 1H, H-5'), 3.22-3.18 (m, 5H, H-3', H-4', -NH2, -OH), 2.76-2.73 (m,
1H, H-17), 2.17-1.82 (m, 8H), 1.68-1.52 (m, 6H), 1.49-1.27 (m, 10H), 1.24 (d, J = 6.0
Hz, 3H, H-6), 0.91 (s, 3H, H-19), 0.85 (s, 3H, H-18). 13C NMR (100 MHz, CDCl3): δ
174.9(C-23), 174.8(C-20), 117.8(C-22), 95.3(C-1'), 85.7(C-14), 73.7(C-21), 72.2(C-3),
71.0(C-4'), 64.5(C-5'), 51.1(C-17), 49.8(C-13), 48.3(C-3'), 42.0, 40.1, 37.5, 35.8, 35.4,
33.3, 32.4, 30.4, 27.1, 26.8, 24.2, 24.1(C-19), 21.5, 21.4, 18.1(C-6'), 16.0(C-18).
HRMS calc. for C29H46NO6 [M+H] +: 504.3320, found: 504.3324.
Preparation of 5β
According to the General Procedure C, 2β
(26.0 mg, 0.036 mmol, 1.0 equiv) and LiOH
(5.5 mg, 0.21 mmol, 6.0 equiv) in MeOH (2.9
ml), H2O (0.7 mL) was stirred at 0 °C for 8 h
to afford 4β (12.0 mg, 49%) as white solid
after purification by silica gel chromatography
(petroleum-EtOAc 1:1→1:2). According to the
General Procedure D, above compound 4β
(11.5 mg, 0.017 mmol, 1.0 equiv), K2CO3 (18.5 mg, 0.13 mmol, 8.0 equiv) and PhSH
(10.0 µL, 0.1 mmol, 6.0 equiv) in CH3CN was stirred for 4 h to provide 5β (5.8 mg,
69%) as white solid after purification by silica gel column chromatograph (petroleum-
EtOAc 3:2→DCM:MeOH 10:1). Analytical data for 5β: Rf = 0.30 (DCM:MeOH
10:1). m.p. 188.2-188.6 °C. [α]D20 -8.7 (c, 0.31 in MeOH). 1H NMR (400MHz
CD3OD): δ 5.90 (s, 1H, H-22), 5.03 (dd, J = 2.4, 18.4 Hz, 1H, H-21a), 4.94-4.89 (m,
2H, H-21b, H-1', overlapped with H2O peak), 4.08-4.04 (m, 1H, H-3), 3.74-3.67 (m,
1H, H-5'), 3.65-3.62 (m, 1H, H-3'), 3.49 (dd, J = 4.0, 7.6 Hz, 1H, H-4'), 2.85-2.82 (m,
1H, H-17), 2.23-2.04 (m, 3H), 1.93-1.70 (m, 7H), 1.66-1.61 (m, 4H), 1.51-1.41 (m,
5H), 1.30-1.19 (m, 8H), 0.94 (s, 3H, H-19), 0.88 (s, 3H, H-18). 13C NMR (100 MHz,
CD3OD): δ 177.0 (C-23), 175.9 (C-20), 116.4 (C-22), 94.2 (C-1'), 85.0 (C-14), 74.0
(C-21), 72.7 (C-3), 70.7 (C-4'), 68.8 (C-5'), 50.7 (C-17), 49.7 (C-13), 48.9 (C-3'), 41.3,
39.6, 36.7, 35.5, 35.0, 33.2, 32.0, 30.0, 29.3, 26.7, 26.5, 26.0, 22.9 (C-19), 21.2, 21.0,
17.7 (C-6'), 15.0 (C-18). HRMS calc. for C29H46NO6 [M+H] +: 504.3320, found:
504.3319.
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6. Scheme 2: Synthesis of L-3-aminosugar analogues of digitoxin
Preparation of 6α and 6β
According to the General Procedure A, donor 1c (113 mg, 0.21 mmol, 1.5 equiv),
Digi-OH (52 mg, 0.14 mmol, 1.0 equiv) and Ph3PAuNTf2 (10.3 mg, 0.014 mmol, 0.1
equiv) in dry DCM (0.2 ml) was reacted to provide 6α (65.8 mg, 65%) and 6β (31.0
mg, 30%), both are white solids.
Analytical data for 6α: Rf = 0.30 (petroleum-
EtOAc 1:1). m.p. 131.0-131.5 °C. [α]D20 -74.7
(c, 1.68 in CHCl3). 1H NMR (400MHz CDCl3):
δ 8.32 (d, J = 8.8 Hz, 2H, Ph), 7.98 (d, J = 8.8
Hz, 2H, Ph), 6.62 (d, J = 8.8 Hz, 1H, -NH), 5.86
(s, 1H, H-22), 4.97 (d, J = 18.0 Hz, 1H, H-21a),
4.87 (d, J = 2.8 Hz, 1H, H-1'), 4.79 (d, J = 18.0
Hz, 1H, H-21b), 4.32 (dd, J = 3.6, 10.4 Hz, 1H,
H-4'), 4.05-3.98 (m, 1H, H-5'), 3.95-3.90 (m,
2H, H-3, H-3'), 2.78-2.75 (m, 1H, H-17), 2.19-2.07 (m, 2H), 2.05 (s, 3H, Ac), 1.90-
1.53 (m, 13H), 1.45-1.22 (m, 9H), 1.17 (d, J = 6.0 Hz, 3H, H-6'), 1.00 (s, 3H, Me, H-
19), 0.87 (s, 3H, Me, H-18). 13C NMR (100 MHz, CDCl3): δ 174.7(C-23), 174.7(C-
20), 170.8(C=O), 150.1(Ph), 147.4(Ph), 128.1(Ph), 128.1(Ph), 124.6(Ph), 124.6(Ph),
118.1(C-22), 95.4(C-1'), 85.7(C-14'), 73.6(C-21), 73.5(C-3), 72.7(C-4'), 62.5(C-5'),
51.0(C-17), 49.8(C-13), 48.9(C-3'), 42.0, 40.1, 37.3, 35.9, 35.5, 33.9, 33.3, 31.3, 30.0,
27.1, 27.0, 26.8, 24.3(C-19), 21.5, 21.4, 21.2(COCH3), 17.6(C-6'), 16.0(C-18). HRMS
calc. for C37H50N2NaO11S [M+Na] +: 753.3028, found: 753.3033.
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Analytical data for 6β: Rf = 0.25 (petroleum-
EtOAc 1:1). m.p. 249.0-250.0 °C. [α]D20 -4.1
(c, 0.39 in CHCl3). 1H NMR (400MHz
CDCl3): δ 8.35 (d, J = 8.8 Hz, 2H, Ph), 8.04
(d, J = 8.8 Hz, 2H, Ph), 5.86 (s, 1H, H-22),
5.13 (br d, 1H, -NH), 4.97 (d, J = 18.0 Hz, 1H,
H-21a), 4.79 (dd, J = 1.2, 18.0 Hz, 1H, H-
21b), 4.73 (d, J = 7.2 Hz, 1H, H-1'), 4.50 (dd,
J = 4.0, 7.6 Hz, 1H, H-4'), 3.94 (br s, 2H, H-3, H-3'), 3.80-3.74 (m, 1H, H-5'), 2.78-
2.74 (m, 1H, H-17), 2.18-2.05 (m, 2H), 1.93 (s, 3H, Ac), 1.85-1.69 (m, 6H), 1.56-1.12
(m, 19H), 0.88 (s, 3H, Me, H-19), 0.85 (s, 3H, Me, H-18). 13C NMR (100 MHz,
CDCl3): δ 174.8(C-23), 174.8(C-20), 169.8(C=O), 150.4(Ph), 146.1(Ph), 128.6(Ph),
128.6(Ph), 124.7(Ph), 124.7(Ph), 117.9(C-22), 95.0(C-1'), 85.8(C-14), 73.7(C-21),
72.7(C-4'), 72.7(C-3), 69.0(C-5'), 51.1(C-17), 49.8(C-13), 49.2 (C-3'), 42.0, 40.2, 36.5,
35.9, 35.7, 35.3(C-2'), 33.3, 32.0, 30.1, 27.1, 26.6, 24.1, 23.9(C-2'), 21.5, 21.3,
21.1(COCH3), 18.7(C-6'), 16.0(C-18). HRMS calc. for C37H50N2NaO11S [M+Na] +:
753.3028, found: 753.3038.
Preparation of 7α
According to the General Procedure C, starting
material 6α (45.0 mg, 0.062 mmol, 1.0 equiv),
and LiOH (8.9 mg, 0.37 mmol, 6.0 equiv) in
MeOH (4.8 ml), H2O (1.2 mL) was stirred at 0 °C
for 4 h to give deacetylated product (36.0 mg,
85%) as white solid after purification by silica gel
chromatography (petroleum-EtOAc 1.2:1).
According to the General Procedure D, above
deacetylated product (21 mg, 0.031 mmol, 1.0
equiv), K2CO3 (34 mg, 0.25 mmol, 8.0 equiv) and PhSH (19.0 µL, 0.18 mmol, 6.0
equiv) in CH3CN was stirred at room temperament for 3 h to yield 7α (14 mg, 91%)
as white solid after purification by silica gel column chromatograph (petroleum-
EtOAc 1:1→DCM:MeOH 10:1). Analytical data for 7α: Rf = 0.40 (DCM:MeOH
10:1). m.p. 133.0-134.0 °C. [α]D20 -32.8 (c, 0.95 in CHCl3). 1H NMR (400MHz
CDCl3): δ 5.85 (s, 1H, H-22), 4.96 (d, J = 18.0 Hz, 1H, H-21a), 4.92 (d, J = 3.2 Hz,
1H, H-1'), 4.78 (d, J = 18.0 Hz, 1H, H-21b), 3.91 (s, 1H, H-3), 3.70-3.63 (m, 1H, H-
5'), 3.32-3.23 (m, 5H, -OH, -NH2, H-3', H-4'), 2.77-2.73 (m, 1H, H-17), 2.18-2.03 (m,
3H), 1.96-1.78 (m, 3H), 1.72-1.65 (m, 3H), 1.60-1.46 (m, 7H), 1.41-1.30 (m, 4H),
1.25-1.15 (m, 7H), 0.91 (s, 3H, H-19), 0.84 (s, 3H, H-19). 13C NMR (100 MHz,
CDCl3): δ 174.8(C-23), 174.8(C-20), 117.9(C-22), 95.1(C-1'), 85.7(C-14), 73.7 (C-
21), 72.2 (C-3), 70.8 (C-4'), 64.4 (C-5'), 51.0 (C-17), 49.8 (C-13), 48.4 (C-3'), 42.0,
40.2, 36.8, 35.9, 35.5, 33.3, 31.0, 29.6, 27.1, 26.9, 26.8, 24.0(C-19), 21.6, 21.4,
18.2(C-6'), 16.0(C-18). HRMS calc. for C29H46NO6 [M+H] +: 504.3320, found:
504.3328.
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Preparation of 7β
According to the General Procedure C,
starting material 6β (28.0 mg, 0.038 mmol, 1.0
equiv) and LiOH (5.5 mg, 0.23 mmol, 6.0
equiv) in MeOH (3.0 ml), H2O (0.8 mL) was
stirred at room temperament for 2 h to give
deacetylated product (11.6 mg, 47%) as white
solid with 25% recovery of 6β after
purification by silica gel chromatography
(petroleum-EtOAc 1:1). According to the General Procedure D, above deacetylated
product (11.6 mg, 0.017 mmol, 1.0 equiv), K2CO3 (18.5 mg, 0.13 mmol, 8.0 equiv)
and methyl 2-sulfanylacetate (9.0 µL, 0.10 mmol, 6.0 equiv) in CH3CN was stirred
for 24 h to afford 7β (6.5 mg, 79%) as white solid after purification by silica gel
column chromatograph (petroleum-EtOAc 1:1→DCM:MeOH 10:1). Analytical data
for 7β: Rf = 0.25 (DCM:MeOH 10:1). m.p. 178.5-179.0 °C. [α]D20 31.8 (c, 0.33 in
MeOH). 1H NMR (400MHz CD3OD): δ 5.90 (s, 1H, H-22), 5.04 (dd, J = 1.2, 18.4 Hz,
H-21a), 4.96-4.93 (m, 2H, H-21b, H-1', overlapped with H2O peak), 4.04 (s, 1H, H-3),
3.76-3.69 (m, 1H, H-5'), 3.34-3.29 (m, 2H, H-3', H-4', overlapped with deuterated
solvent peak), 2.85-2.82 (m, 1H, H-17), 2.23-2.14 (m, 2H), 1.97-1.84 (m, 4H), 1.80-
1.60 (m, 7H), 1.51-1.43 (m, 6H), 1.38-1.28 (m, 8H), 0.94 (s, 3H, H-19), 0.88 (s, 3H,
H-18). 13C NMR (100 MHz, CD3OD): δ 177.1(C-23), 175.9(C-20), 116.4(C-22),
94.8(C-1'), 85.1(C-14), 74.0(C-21), 72.7(C-3), 71.9(C-4'), 69.6(C-5'), 50.7(C-17),
49.7(C-13), 48.8(C-3'), 41.3, 39.6, 36.6, 35.5, 34.9, 32.0, 31.7, 29.8, 26.7, 26.5, 23.8,
22.9(C-19), 21.1, 21.0, 17.5(C-6'), 15.0(C-18). HRMS calc. for C29H46NO6 [M+H]+:
504.3320, found: 504.3333.
7. Scheme 4:Synthesis of C12 acetylated digoxigenin 10 [4]
To a solution of digoxin (800 mg, 1.02 mmol) in pyridine
(4 mL) at rt was added Ac2O (4 mL). After stirring at 80 oC for 12 h, the reaction was quenched with MeOH (4
mL), and the resulting mixture was concentrated under
reduced pressure. The residue was diluted with EtOAc,
and the organic phase, after being washed with 1 N HCl,
saturated NaHCO3 and water, respectively, was dried
over Na2SO4 and then concentrated in vacuo. The residue
was purified by silica gel column chromatograph (petroleum-EtOAc 1:2) to give the
digoxin pentacetate 9 (980 mg, 96%) as a light yellow solid, Compound 9 (980 mg, 0.98
mmol) in a mixed solvent of MeOH (84 mL) and H2SO4 (0.1 N, 84 mL) was kept at 70 oC
for 7 h. The mixture was neutralized with Et3N and concentrated under reduced
pressure. The residue was diluted with EtOAc, and the organic phase, after being
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washed with saturated NaHCO3, water and brine, was dried over Na2SO4 and then
concentrated in vacuo. The residue was purified by silica gel column chromatograph
(Et2O/EtOAc 5:1→petroleum-EtOAc 1:1) to give product 10 (348 mg, 80%) as a
white solid. The 1H NMR was consistent with reference [4]. m.p. 271.0-272.0 °C.
[α]D20 +45.7 (c, 1.0 in CHCl3). 1H NMR (400MHz CDCl3) for compound 10: δ 5.82 (s,
1H, H-22), 4.86 (dd, J = 1.2, 18.0 Hz, 1H, H-21a), 4.75 (dd, J = 1.2, 18.0 Hz, 1H, H-
21b), 4.59 (dd, J = 4.0, 12.0 Hz, 1H, H-12), 4.11 (s, 1H, H-3), 2.89-2.85 (m, 1H, H-
17), 2.15-2.09 (m, 1H), 2.07 (s, 3H, Ac), 2.02-1.85 (m, 4H), 1.81-1.63 (m, 6H), 1.59-
1.43 (m, 6H), 1.36-1.23 (m, 4H), 0.93 (s, 3H, H-19), 0.86 (s, 3H, H-18).
8. Scheme 4:Synthesis of L-3-aminosugar analogues of digoxin
Preparation of 11α and11β
According to General Procedure A, donor 1c (126.0 mg, 0.23 mmol, 1.5 equiv) and
acceptor 10 (65.0 mg, 0.15 mmol, 1.0 equiv) and Ph3PAuNTf2 (11.0 mg, 0.015 mmol,
0.1 equiv) in dry DCM (0.2 ml) was reacted to provide 11α (73.0 mg, 62%) and 11β
(41.0 mg, 34%), both are white solids.
Analytical data for 11α: Rf = 0.25 (petroleum-
EtOAc 1:1). m.p. 160.0-161.0 °C. [α]D20 -51.6
(c, 2.46 in CHCl3). 1H NMR (400MHz CDCl3):
δ 8.31 (d, J = 8.4 Hz, 2H, -Ph), 7.97 (d, J = 8.4
Hz, 2H, -Ph), 6.57 (d, J = 8.8 Hz, 1H, -NH),
5.83 (s, 1H, H-22), 4.87 (d, J = 2.4 Hz, 1H, H-
1'), 4.86 (d, J = 18.0 Hz, 1H, H-21a), 4.76 (d,
J= 18.0 Hz, 1H, H-21b), 4.60 (dd, J = 3.2, 11.2
Hz, 1H, H-12), 4.33 (dd, J = 3.6, 10.4 Hz, 1H,
H-4'), 4.04-3.98 (m, 1H, H-5'), 3.95-3.90 (m, 2H, H-3, H-3'), 2.89-2.86 (m, 1H, H-17),
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2.18-2.13 (m, 1H), 2.09 (s, 3H, Ac), 2.03 (s, 3H, Ac), 1.98-1.55 (m, 15H), 1.44-1.22
(m, 6H), 1.17 (dd, J = 6.0, 3H, H-6'), 1.00 (s, 3H, H-19), 0.89 (s, 3H, H-18). 13C NMR
(100 MHz, CDCl3): δ 174.5(C-23), 173.5(C-20), 171.1(C=O), 170.7(C=O), 150.1(Ph),
147.4(Ph), 128.1(2C, Ph), 124.6(2C, Ph), 118.2(C-22), 95.7(C-1'), 85.9(C-14),
77.4(C-12), 73.6(C-3), 73.5(C-21), 72.7(C-4'), 62.6(C-5'), 54.2(C-13), 48.9(C-3'),
46.1(C-17), 41.6, 37.3, 35.5(C-2'), 34.0, 33.3, 32.6, 31.3, 30.2, 27.4, 26.9, 26.7,
24.1(C-19), 21.8, 21.5, 21.2, 17.6(C-6'), 10.6(C-18). HRMS calc. for
C39H52N2NaO13S [M+Na] +: 811.3082, found: 811.3102.
Analytical data for 11β: Rf = 0.20
(petroleum-EtOAc 1:1). m.p. 167.0-168.0 °C.
[α]D20 14.5 (c, 1.28 in CHCl3). 1H NMR
(400MHz CDCl3): δ 8.35 (d, J = 8.8 Hz, 2H,
-Ph), 8.04 (d, J = 8.8 Hz, 2H, -Ph), 5.83 (s,
1H, H-22), 5.14 (d, J = 6.0 Hz, 1H, -NH),
4.87 (d, J = 18.0 Hz, 1H, H-21a), 4.76 (d, J =
18.0 Hz, 1H, H-21b), 4.74 (dd, J = 2.0, 6.8
Hz, 1H, H-1'), 4.59 (dd, J = 4.0, 12.0 Hz, 1H, H-12), 4.49 (dd, J = 3.6, 7.6 Hz, 1H, H-
4'), 3.95-3.92 (m, 2H, H-3, H-3'), 3.81-3.74 (m, 1H, H-5'), 2.89-2.86 (m, 1H, H-17),
2.17-2.11 (m, 1H), 2.09 (s, 3H, -OAc), 2.00-1.91 (m, 3H), 1.92(s, 3H, -OAc), 1.86-
1.70 (m, 5H), 1.68-1.54 (m, 7H), 1.35-1.18 (m, 6H), 1.19 (d, J = 6.0 Hz, 3H, H-6'),
0.89 (s, 3H), 0.87 (s, 3H, H-18). 13C NMR (100 MHz, CDCl3): δ 174.6 (C-23), 173.7
(C-20), 171.1 (C=O), 169.8 (C=O), 150.4 (Ph), 146.2 (Ph), 128.5 (2C, Ph), 124.7 (2C,
Ph), 118.2 (C-22), 95.0 (C-1'), 86.0 (C-14), 77.4 (C-12), 73.5 (C-21), 72.7 (C-4'), 72.6
(C-3), 69.0 (C-5'), 54.2 (C-13), 49.2 (C-3'), 46.2 (C-17), 41.6, 36.5, 35.8 (C-2'), 35.3,
33.3, 32.6, 32.0, 30.1, 27.4, 26.6, 26.5, 24.1, 23.7 (C-19), 21.7, 21.5 (COCH3), 21.0
(COCH3), 18.7 (C-6'), 10.5 (C-18). HRMS calc. for C39H52N2NaO13S [M+Na] +:
811.3082, found: 811.3077.
Preparation of 12α
According to the General Procedure C, starting
material 11α (74.0 mg, 0.094 mmol, 1.0 equiv)
and LiOH (6.8 mg, 0.28 mmol, 3.0 equiv) in
MeOH (3.7 ml), H2O (1.0 ml) was stirred at room
temperament for 4 h to give deacetylated product
(38.3 mg, 58%) as white solid after purification
by silica gel chromatography (petroleum-EtOAc
1:2). According to the General Procedure D,
above deacetylated product (36.0 mg, 0.05 mmol,
1.0 equiv), K2CO3 (56.0 mg, 0.4 mmol, 8.0 equiv)
and methyl 2-sulfanylacetate (27.5 µL, 0.31 mmol, 6.0 equiv) in CH3CN was stirred
at room temperament for 24 h to yield 12α (22.5 mg, 85%) as white solid after
purification by silica gel column chromatograph (petroleum-EtOAc 1:1→DCM:
MeOH 10:1). It should be noted that 12α was unstable, it was decomposed upon
standing even kept at low temperature. Analytical data for 12α: Rf = 0.25 (DCM:
MeOH 10:1). 1H NMR (400MHz CD3OD): δ 5.91 (s, 1H, H-22), 4.98 (dd, J = 1.6,
18.0 Hz, H-21a), 4.98-4.93 (m, 2H, H-21b, H-1'), 4.00 (s, 1H, H-3), 3.85-3.78 (m, 1H,
H-5'), 3.42-3.33(m, 4H, H-12, H-3', H-4', H-17), 2.19-2.11 (m, 1H), 2.03-1.87 (m,
6H), 1.84-1.78 (m, 2H), 1.76-1.60 (m, 9H),1.52-1.42 (m, 2H), 1.30-1.29 (m, 2H), 1.25
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(d, J = 6.0 Hz, 3H, H-6'), 0.99 (s, 3H, H-19), 0.79 (s, 3H, H-18). 13C NMR (100 MHz,
CD3OD): δ 177.1(C-23), 175.9(C-20), 116.3(C-22), 93.9(C-1'), 85.4(C-14), 74.2(C-
12), 74.1(C-21), 72.1(C-3), 70.0(C-4'), 63.5(C-5'), 55.9(C-13), 49.2(C-3'), 45.6(C-17),
40.8(C-8), 36.8(C-5), 34.9, 32.5, 32.2, 32.1, 30.6, 29.4, 28.7, 27.0, 26.4, 26.0, 22.9(C-
19), 21.4, 16.8(C-6'), 8.5(C-18). HRMS calc. for C29H46NO7 [M+H] +: 520.3269,
found: 520.3286.
Preparation of 12β
According to the General Procedure C,
starting material 11β (34.7 mg, 0.045 mmol,
1.0 equiv) and LiOH (3.2 mg, 0.13 mmol, 3.0
equiv) in MeOH (1.8 ml), H2O (0.5 ml) was
stirred at room temperament for 4 h to afford
deacetylated product (14.5 mg, 47%) as white
solid after purification by silica gel
chromatography (petroleum-EtOAc 1:2→1:3).
According to the General Procedure D, above deacetylated product (14.0 mg, 0.02
mmol, 1.0 equiv), K2CO3 (22.0 mg, 0.16 mmol, 8.0 equiv) and methyl 2-
sulfanylacetate (11.0 µL, 0.12 mmol, 6.0 equiv) in CH3CN was stirred for 24 h to
yield 12β (7.4 mg, 72%) as white solid after purification by silica gel column
chromatograph (petroleum-EtOAc 1:1→DCM:MeOH 10:1). It should be noted that
12β was also unstable, it was decomposed upon standing even kept at low
temperature. Analytical data for 12β: Rf = 0.20 (DCM:MeOH 10:1). 1H NMR
(400MHz CD3OD): δ 5.91 (s, 1H, H-22), 4.98 (dd, J = 1.6, 18.4 Hz, H-21a), 4.94 (dd,
J = 2.0, 8.4 Hz, 1H, H-1'), 4.93 (dd, J = 1.6, 18.4 Hz, 1H, H-21b), 4.05 (s, 1H, H-3),
3.75-3.70 (m, 1H, H-5'), 3.46 (dd, J = 4.4, 8.4 Hz, 1H, H-3'), 3.41-3.37 (m, 2H, H-12,
H-4'), 3.35-3.30 (m, 1H, H-17), 2.19-2.11 (m, 1H), 2.02-1.81 (m, 7H), 1.80-1.59 (m,
8H), 1.55-1.29 (m, 6H), 1.27 (d, J = 6.0 Hz, 3H, H-6'), 0.95 (s, 3H, H-19), 0.79 (s, 3H,
H-18). 13C NMR (100 MHz, CD3OD): δ 177.1(C-23), 175.9(C-20), 116.3(C-22),
94.5(C-1'), 85.4(C-14), 74.3(C-12), 74.1(C-21), 72.6(C-3), 70.5(C-4'), 70.1(C-5'),
55.9(C-13), 48.8(C-3'), 45.7(C-17), 40.8, 36.6, 35.0, 34.8(C-2'), 32.2, 32.1, 31.6, 29.9,
29.4, 27.0, 26.4, 23.7, 22.8(C-19), 21.3, 17.6(C-6'), 8.5(C-18). HRMS calc. for
C29H46NO7 [M+H] +: 520.3269, found: 520.3271.
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S16
9. Scheme 5:Synthesis of N-acetyl L-3-aminosugar analogues of digoxin
General procedure E for acetyl migration reaction
To a solution of 4-nitrobenzenesulfonamide (1.0 equiv) in deoxygenated dry CH3CN
(c = 0.02 mol/L) was added K2CO3 (8.0 equiv) and PhSH (6.0 equiv). After stirring at
room temperament for 16 h, the mixture was filtered and concentrated in vacuo. The
residue was purified by silica gel column chromatograph to give the acetyl migrated
product.
Preparation of 13α
According to the General Procedure E, 11α
(161 mg, 0.20 mmol, 1.0 equiv), K2CO3 (225 mg,
1.63 mmol, 8.0 equiv) and PhSH (126 µL, 1.23
mmol, 6.0 equiv) in CH3CN was stirred for 16 h
to afford 13α (100 mg, 81%) as white solid after
purification by silica gel column chromatograph
(DCM-MeOH 50:1). Analytical data for 13α: Rf =
0.40 (DCM:MeOH 15:1). m.p. 144.0-145.0 °C.
[α]D20 +20.6 (c, 1.74 in CHCl3). 1H NMR
(400MHz CDCl3): δ 7.35 (d, J = 7.2 Hz, 1H, -NH), 5.83 (s, 1H, H-22), 4.91 (d, J =
2.8 Hz, 1H, H-1'), 4.86 (d, J = 18.0 Hz, 1H, H-21a), 4.75 (d, J = 18.0 Hz, 1H, H-21b),
4.59 (dd, J = 4.0, 12.0 Hz, 1H, H-12), 4.41-4.39 (m, 1H, H-3'), 3.97 (s, 1H, H-3), 3.82
(s, 1H, -OH), 3.78-3.71 (m, 1H, H-5'), 3.41 (br d, J = 9.6 Hz, 1H, H-4'), 2.89-2.85 (m,
1H, H-17), 2.15-2.11 (m, 1H), 2.07 (s, 3H, -OAc), 2.04-1.79 (m, 6H), 2.00 (s, 3H, -
OAc), 1.76-1.60 (m, 11H), 1.43-1.26 (m, 4H), 1.22 (d, J = 6.0 Hz, 3H, H-6'), 0.94 (s,
3H, H-19), 0.87 (s, 3H, H-18). 13C NMR (100 MHz, CDCl3): δ 174.5(C-23), 173.6(C-
20), 172.8(C=O), 171.0 (C=O), 118.2(C-22), 95.6(C-1'), 85.9(C-14), 77.4(C-12),
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S17
74.6(C-4'), 73.5(C-21), 73.0(C-3), 65.1(C-5'), 54.2(C-13), 48.1(C-3'), 46.1(C-17),
41.5, 37.4, 35.5, 33.8, 33.3, 32.5, 31.4, 30.3, 27.4, 26.9, 26.6, 26.6, 24.1(C-19),
23.6(COCH3), 21.8, 21.4(COCH3), 17.6(C-6'), 10.8(C-18). HRMS calc. for
C33H49NNaO9 [M+Na] +: 626.3300, found: 626.3295.
Preparation of 14α
According to the General Procedure C, 13α
(70.9 mg, 0.12 mmol, 1.0 equiv) and LiOH (8.5
mg, 0.36 mmol, 3.0 equiv) in MeOH (4.4 ml),
H2O (1.1 ml) was stirred at room temperament
for 40 min to give 14α (42.2 mg, 64%) as white
solid after purification by silica gel
chromatography (DCM-MeOH 30:1). Analytical
data for 14α: Rf = 0.20 (DCM-MeOH 20:1). m.p.
157.0-158.0 °C. [α]D20 -1.7 (c, 2.72 in CHCl3). 1H
NMR (400MHz CDCl3): δ 7.36 (d, J = 7.2 Hz, 1H, -NH), 5.91 (s, 1H, H-22), 4.91 (d,
J = 2.4 Hz, 1H, H-1'), 4.88 (d, J = 18.4 Hz, 1H, H-21a), 4.79 (d, J = 18.4 Hz, 1H, H-
21b), 4.39 (br s, 1H, H-3'), 3.96 (s, 1H, H-3), 3.91 (s, 1H, -OH), 3.78-3.71 (m, 1H, H-
5'), 3.42-3.35 (m, 2H, H-12, H-4'), 3.32-3.28 (m, 1H, H-17), 2.17-2.03 (m, 3H), 2.01
(s, 3H, -Ac), 1.94-1.82 (m, 5H), 1.76-1.56 (m, 10H), 1.42-1.27 (m, 5H), 1.22 (d, J =
6.4 Hz, 3H, H-6'), 0.95 (s, 3H, H-19), 0.78 (s, 3H, H-18). 13C NMR (100 MHz,
CDCl3): δ 175.1(C-23), 175.0(C-20), 172.8(C=O), 117.8(C-22), 95.6(C-1'), 85.9(C-
14), 75.0(C-12), 74.5(C-4'), 74.0(C-21), 73.0(C-3), 65.1(C-5'), 55.8(C-13), 48.1(C-3'),
45.8(C-17), 41.5, 37.4, 35.3, 33.8, 33.3, 32.7, 31.4, 30.4, 30.2, 27.6, 26.9, 26.7,
24.3(C-19), 23.6(COCH3), 21.8, 17.6(C-6'), 9.2(C-18). HRMS calc. for C31H47NNaO8
[M+Na] +: 584.3194, found: 584.3184.
Preparation of S2
According to the General Procedure E, 11β
(85.9 mg, 0.11 mmol, 1.0 equiv), K2CO3 (121.0
mg, 0.88 mmol, 8.0 equiv) and PhSH (67 µL, 0.66
mmol, 6.0 equiv) in CH3CN was stirred for 16 h
to provide S2 (47.3 mg, 72%) as white solid after
purification by silica gel column chromatograph
(DCM-MeOH 30:1). Analytical data for S1: Rf
=0.2 (DCM:MeOH 30:1). m.p. 153.0-154.0 °C. [α]D20 +58.7 (c, 1.12 in CHCl3). 1H
NMR (400MHz CDCl3): δ 5.91 (br s, 1H, -NH), 5.82 (s, 1H, H-22), 4.87 (d, J = 18.0
Hz, H-21a), 4.76 (d, J = 18.0 Hz, 1H, H-21b), 4.70 (dd, J = 2.0, 7.6 Hz, 1H, H-1'),
4.59 (dd, J = 4.0, 12.4 Hz, 1H, H-12), 4.42 -4.37 (m, 1H, H-3'), 4.01 (s, 1H, H-3),
3.65-3.58 (m, 1H, H-5'), 3.52 (dd, J = 3.6, 7.2 Hz, 1H, H-4'), 3.16 (br s, 1H, -OH),
2.89-2.85 (m, 1H, H-17), 2.17-2.11 (m, 1H), 2.08 (s, 3H, -Ac), 2.03 (s, 3H,- Ac), 1.99-
1.90 (m, 3H), 1.88-1.65 (m, 10H), 1.57-1.38 (m, 5H), 1.30 (d, J = 6.0 Hz, 3H, H-6'),
1.25-1.18 (m, 3H), 0.90 (s, 3H, H-19), 0.86 (s, 3H, H-18). 13C NMR (100 MHz,
CDCl3): δ 174.6(C-23), 173.7(C-20), 172.2(C=O), 171.1(C=O), 118.2(C-22), 95.4(C-
1'), 86.0(C-14), 77.8(C-12), 73.5(C-21), 72.7(C-3), 72.3(C-4'), 71.5(C-5'), 54.2(C-13),
47.7(C-3'), 46.2(C-17), 41.6, 36.4, 35.3, 34.9, 33.3, 32.6, 32.1, 30.2, 27.4, 26.6, 26.5,
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S18
24.3, 23.7(COCH3), 23.6(C-19), 21.7, 21.5(COCH3), 18.7(C-6'), 10.6(C-18). HRMS
calc. for HRMS calc. for C33H49NNaO9 [M+Na] +: 626.3300, found: 626.3276.
Preparation of 14β
According to the General Procedure C, S2
(32.2 mg, 0.053 mmol, 1.0 equiv) and LiOH
(3.8 mg, 0.16 mmol, 3.0 equiv) in MeOH (2.1
ml), H2O (0.5 ml) was stirred at room
temperament for 1 h to yield 14β (15.0 mg,
50%) as white solid after purification by silica
gel chromatography (DCM-MeOH 20:1).
Analytical data for 14β: Rf = 0.20 (DCM-
MeOH 20:1). m.p. 166.0-167.0 °C. [α]D20 +22.7 (c, 1.5 in MeOH). 1H NMR (400MHz
CD3OD): δ 5.91 (s, 1H, H-22), 4.98 (dd, J = 1.2, 18.4 Hz, 1H, H-21a), 4.93-4.87 (m,
1H, H-21b, overlapped with H2O peak), 4.84 (dd, J = 2.0, 8.4 Hz, 1H, H-1'), 4.36-
4.33 (m, 1H, H-3'), 4.04 (s, 1H, H-3), 3.74-3.68 (m, 1H, H-5'), 3.41-3.33 (m, 3H, H-
12, H-4', H-17), 2.18-2.11 (m, 1H), 2.01 (s, 3H, -Ac), 1.99-1.88 (m, 5H), 1.78-1.68 (m,
5H), 1.66-1.59 (m, 3H), 1.54-1.46 (m, 3H), 1.40-1.20 (m, 5H), 1.27 (d, J = 6.0 Hz, 3H,
H-6'), 0.95 (s, 3H, H-19), 0.79 (s, 3H, H-18). 13C NMR (100 MHz, CD3OD): δ
177.1(C-23), 175.9(C-20), 172.6(C=O), 116.3(C-22), 95.5(C-1'), 85.4(C-14), 74.3(C-
12), 74.1(C-21), 72.5(C-3), 71.2(C-4'), 70.8(C-5'), 55.9(C-13), 47.5(C-3'), 45.7(C-17),
40.8, 36.6, 35.2, 34.8, 32.2, 32.1, 31.6, 29.8, 29.4, 27.9, 26.4, 23.7, 22.8(C-19),
21.3(COCH3), 17.7(C-6'), 8.5(C-18). HRMS calc. for C31H47NNaO8 [M+Na] +:
584.3194, found: 584.3188.
10. Scheme 6:Synthesis of N-acetylated D-3-aminosugar analogues of digoxin
Preparation of 15α and15β. According to the General Procedure A, donor 1b
(200.0 mg, 0.36 mmol, 1.5 equiv) and acceptor 10 (103.0 mg, 0.24 mmol, 1.0 equiv)
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S19
and Ph3PAuNTf2 (17.6 mg, 0.024 mmol, 0.1 equiv) in dry DCM (0.6 ml) was reacted
to afford 15α (109.0 mg, 58%) and 15β (68.0 mg, 36%), both are white solids.
Analytical data for 15α: Rf = 0.25 (petroleum-
EtOAc 1:1). m.p. 161.0-161.8 °C. [α]D20 +102.9
(c, 3.07 in CHCl3). 1H NMR (400MHz CDCl3):
δ 8.32 (d, J = 8.8 Hz, 2H, Ph), 7.98 (d, J = 8.8
Hz, 2H, Ph), 6.59 (d, J = 8.8 Hz, 1H, -NH), 5.84
(s, 1H, H-22), 4.87 (dd, J = 1.2, 18.0 Hz, 1H, H-
21a), 4.86 (d, J = 4.4 Hz, 1H, H-1'), 4.76 (dd, J
= 1.2, 18.0 Hz, 1H, 21b), 4.59 (dd, J = 4.0, 11.6
Hz, 1H, H-12), 4.32 (dd, J = 3.6, 10.4 Hz, 1H, H-4'), 4.04-3.98 (m, 1H, H-5'), 3.96 (s,
1H, H-3), 3.93-3.89 (m, 1H, H-3'), 2.90-2.86 (m, 1H, H-17), 2.18-2.13 (m, 1H), 2.09
(s, 3H, Ac), 2.06 (s, 3H, Ac), 2.02-1.90 (m, 4H), 1.87-1.64 (m, 7H), 1.53-1.25 (m,
10H), 1.17 (d, J = 6.0 Hz, 3H, H-6'), 1.01 (s, 3H, H-19), 0.89 (s, 3H, H-18). 13C NMR
(100 MHz, CDCl3): δ 174.5(C-23), 173.5(C-20), 171.1(C=O), 170.8(C=O), 150.1(Ph),
147.3(Ph), 128.1(2C, Ph), 124.7(2C, Ph), 118.3(C-22), 95.8(C-1'), 85.8(C-14),
77.4(C-12), 73.6(C-21), 73.5(C-4'), 72.7(C-3), 62.6(C-5'), 54.1(C-13), 48.9(C-3'),
46.1(C-17), 41.6, 38.1, 35.5(C-2'), 33.9, 33.3, 32.6, 32.4, 30.7, 29.9, 27.4, 26.8, 26.5,
24.8, 24.1(C-19), 21.7, 21.5(COCH3), 21.2(COCH3), 17.6(C-6'), 10.6(C-18). HRMS
calc. for C39H52N2NaO13S [M+Na] +: 811.3082, found: 811.3091.
Analytical data for 15β: Rf = 0.20 (petroleum-
EtOAc 1:1). m.p. 168.0-169.0 °C. [α]D20
+40.1 (c, 0.69 in CHCl3). 1H NMR (400MHz
CDCl3): δ 8.36 (d, J = 8.8 Hz, 2H, Ph), 8.03
(d, J = 8.8 Hz, 2H, Ph), 5.83 (s, 1H, H-22),
5.03 (br s, 1H, -NH), 4.87 (dd, J = 1.2, 18.0
Hz, 1H, H-21a), 4.77 (d, J = 2.0, 7.2 Hz, 1H,
H-1'), 4.75 (dd, J = 1.2, 18.0 Hz, 1H, 21b),
4.59 (dd, J = 4.0, 11.6 Hz, 1H, H-12), 4.49
(dd, J = 3.6, 8.0 Hz, 1H, H-4'), 3.94-3.89 (m, 2H, H-3', H-3), 3.80-3.74 (m, 1H, H-5'),
2.89-2.85 (m, 1H, H-17), 2.16-2.11 (m, 1H), 2.07 (s, 3H, Ac), 2.06-1.94 (m, 4H), 1.91
(s, 3H, Ac),1.86-1.64 (m, 7H), 1.57-1.50 (m, 4H), 1.48-1.28 (m, 6H), 1.19 (d, J = 6.4
Hz, 3H, H-6'), 0.90 (s, 3H, H-19), 0.87 (s, 3H, H-18). 13C NMR (100 MHz, CDCl3): δ
174.6 (C-23), 173.6 (C-20), 171.1 (C=O), 169.8 (C=O), 150.4 (Ph), 146.0 (Ph), 128.6
(2C, Ph), 124.7 (2C, Ph), 118.2 (C-22), 95.4 (C-1'), 86.0 (C-14), 77.4 (C-12), 73.5 (C-
21), 72.9 (C-4'), 72.7 (C-3), 69.1 (C-5'), 54.2 (C-13), 49.1 (C-3'), 46.1 (C-17), 41.6,
36.6, 35.8 (C-2'), 35.4, 33.3, 32.6, 30.3, 29.9, 27.4, 26.6, 26.5, 23.7 (C-19), 21.8, 21.5
(COCH3), 21.0 (COCH3), 18.8 (C-6'), 10.5 (C-18). HRMS calc. for C39H52N2NaO13S
[M+Na] +: 811.3082, found: 811.3079.
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S20
Preparation of S3
According to the General Procedure E, 15α (84.0 mg,
0.11 mmol, 1.0 equiv), K2CO3 (118.0 mg, 0.85 mmol, 8.0
equiv) and PhSH (66 µL, 0.64 mmol, 6.0 equiv) in
CH3CN was stirred at room temperament for 16 h to give
S3 (42.5 mg, 71%) as white solid after purification by
silica gel column chromatograph (petroleum-EtOAc
1:1→1:3). Analytical data for S3: Rf = 0.40 (petroleum-acetone 1:1). m.p. 145.0-
146.0 °C. [α]D20 +37.9 (c, 0.86 in CHCl3). 1H NMR (400MHz CDCl3): δ 7.37 (d, J =
7.2 Hz, 1H, -NH), 5.83 (s, 1H, H-22), 4.91 (d, J = 3.2 Hz, 1H, H-1'), 4.86 (dd, J = 1.2,
18.0 Hz, 1H, H-21a), 4.76 (dd, J = 1.2, 18.0 Hz, 1H, H-21b), 4.59 (dd, J = 4.0, 12.0
Hz, 1H, H-12), 4.42-4.38 (m, 1H, H-3'), 3.98 (s, 1H, H-3), 3.86 (s, 1H, -OH), 3.74 (dq,
J = 6.4, 9.6 Hz, 1H, H-5'), 3.42 (dd, J = 3.2, 9.6 Hz, H-4'), 2.89-2.85 (m, 1H, H-17),
2.16-2.11 (m, 1H), 2.07 (s, 3H, -Ac), 2.04-2.02 (m, 1H), 1.99 (s, 3H, -Ac), 1.96-1.86
(m, 5H), 1.82-1.64 (m, 10H), 1.61-1.55 (m, 2H), 1.51-1.46 (m, 3H), 1.22 (d, J = 6.4
Hz, 3H, H-6'), 0.95 (s, 3H, H-19), 0.87 (s, 3H, H-18). 13C NMR (100 MHz, CDCl3): δ
174.5(C-23), 173.6(C-20), 172.8(C=O), 171.0(C=O), 118.2(C-22), 95.7(C-1'),
85.9(C-14), 77.4(C-12), 74.7(C-4'), 73.5(C-21), 73.0(C-3), 65.1(C-5'), 54.2(C-13),
48.2(C-3'), 46.1(C-17), 41.5, 38.3, 35.5, 33.8, 33.3, 32.5, 30.9, 29.9, 27.4, 26.8, 26.6,
24.8, 24.2(C-19), 23.6(COCH3), 21.7, 21.5(COCH3), 17.6(C-6'), 10.6(C-18). HRMS
calc. for C33H49NNaO9 [M+Na] +: 626.3300, found: 626.3350.
Preparation of 16α
According to the General Procedure C, S3
(13.0 mg, 0.02 mmol, 1.0 equiv) and LiOH (1.5
mg, 0.065 mmol, 3.0 equiv) in MeOH (0.87 ml),
H2O (0.2 ml) was stirred at room temperament
for 1 h to yield 16α (6.3 mg, 51%) as white solid
after purification by silica gel chromatography
(DCM-acetone 1.5:1). Analytical data for 16α:
Rf = 0.20 (petroleum-acetone 1:1). m.p. 148.0-
149.0 °C. [α]D20 +13.5 (c, 0.57 in CHCl3). 1H NMR (400MHz CDCl3): δ 7.37 (d, J =
7.2 Hz, 1H, -NH), 5.92 (s, 1H, H-22), 4.92 (d, J = 3.2 Hz, 1H, H-1'), 4.88 (d, J = 18.0
Hz, 1H, H-21a), 4.79 (dd, J = 1.2, 18.0 Hz, 1H, H-21b), 4.43-4.39 (m, 1H, H-3'), 3.99
(s, 1H, H-3), 3.84 (s, 1H, -OH), 3.78-3.71 (m, 1H, H-5'), 3.44-3.36 (m, 2H, H-12, H-
4'), 3.32-3.29 (m, 1H, H-17), 2.16-2.10 (m, 1H), 2.05-2.02 (m, 1H), 2.00 (s, 3H, -Ac),
1.94-1.82 (m, 5H), 1.78-1.63 (m, 6H), 1.54-1.27 (m, 10H), 1.23 (d, J = 6.0 Hz, 3H, H-
6'), 0.96 (s, 3H, H-19), 0.79 (s, 3H, H-18). 13C NMR (100 MHz, CDCl3): δ
174.8(C=O), 174.5(C-20), 172.8(C=O), 118.0(C-22), 95.6(C-1'), 86.0(C-14), 75.2(C-
12), 74.7(C-21), 73.8(C-4'), 72.8(C-3), 65.2(C-5'), 55.7(C-13), 48.2(C-3'), 45.8(C-17),
41.6, 38.3, 35.4, 33.8 (C-2'), 33.4, 32.7, 32.5, 30.9, 30.5, 27.6, 26.8, 24.7, 24.3(C-19),
23.6(COCH3), 21.8, 17.6(C-6'), 9.1(C-18). HRMS calc. for C31H47NNaO8 [M+Na] +:
584.3194, found: 584.3196.
Preparation of S4
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S21
According to the General Procedure E, 15β
(68.0 mg, 0.086 mmol, 1.0 equiv), K2CO3
(95.0 mg, 0.69 mmol, 8.0 equiv) and PhSH (54
µL, 0.52 mmol, 6.0 equiv) in CH3CN was
stirred at room temperament for 16 h to
provide S3 (36.4 mg, 70%) as white solid after
purification by silica gel column
chromatograph (EtOAc). Analytical data for
S4: Rf = 0.30 (petroleum-acetone 1:1). m.p.
154.0-155.0 °C. [α]D20 +8.4 (c, 0.95 in CHCl3). 1H NMR (400MHz CDCl3): δ 5.93-
5.82 (m, 2H, -NH, H-22), 4.86 (d, J = 18.4 Hz, 1H, H-21a), 4.74 (d, J = 18.4 Hz, 1H,
H-21b), 4.71 (dd, J = 2.0, 7.6 Hz, 1H, H-1'), 4.60 (dd, J = 4.0 Hz, 12.0 Hz, 1H, H-12),
4.39 (br s, 1H, H-3'), 3.99 (s, 1H, H-3), 3.65-3.59 (m, 1H, H-5'), 3.54-3.52 (m, 1H, H-
4'), 3.05 (br s, 1H, -OH), 2.89-2.85 (m, 1H, H-17), 2.18-2.10 (m, 1H), 2.07 (s, 3H, -
Ac), 2.03 (s, 3H, -Ac), 1.96-1.65 (m, 12H), 1.57-1.35 (m, 6H), 1.30 (d, J = 6.4 Hz, 3H,
H-6'), 1.25-1.19 (m, 3H), 0.90 (s, 3H, H-19), 0.86 (s, 3H, H-18). 13C NMR (100 MHz,
CDCl3): δ 174.6(C-23), 173.8(C-20), 172.1(C=O), 171.0(C=O), 118.2(C-22), 95.7(C-
1'), 86.0(C-14), 77.4(C-12), 73.6(C-4'), 72.6(C-21), 72.6(C-3), 71.6(C-5'), 54.2(C-13),
47.5(C-3'), 46.1(C-17), 41.6, 36.5, 35.4, 34.8, 33.3, 32.6, 30.3, 30.0, 27.4, 26.7, 26.6,
26.6, 23.7, 21.8, 21.5, 18.8(C-6'), 10.5(C-18). HRMS calc. for C33H49NNaO9 [M+Na]
+: 626.3300, found: 626.3273.
Preparation of 16β
According to the General Procedure C,
S4 (28.0 mg, 0.046 mmol, 1.0 equiv) and
LiOH (3.4 mg, 0.14 mmol, 3.0 equiv) in
MeOH (2.0 ml), H2O (0.5 ml) was stirred at
room temperament for 1 h to give 16β
(13.5 mg, 52%) as white solid after
purification by silica gel chromatography
(DCM-MeOH 20:1). Analytical data for
16β: Rf = 0.20 (DCM-MeOH 15:1). m.p.
162-163 °C. [α]D20 -16.3 (c, 0.4 in CHCl3). 1H NMR (400MHz CDCl3): δ 5.92 (s, 1H,
H-22), 5.80 (d, J = 6.4 Hz, 1H, -NH), 4.88 (d, J = 18.0 Hz, 1H, H-21a), 4.79 (d, J =
18.0 Hz, 1H, H-21b), 4.72 (dd, J = 2.4, 7.2 Hz, 1H, H-1'), 4.43-4.38 (m, 1H, H-3'),
4.00 (s, 1H, H-3), 3.66-3.54 (m, 1H, H-5'), 3.54 (b rs, 1H, H-4'), 3.37-3.28 (m, 2H, H-
12, H-17), 2.15-2.08 (m, 1H), 2.04 (s, 3H, -Ac), 1.99-1.83 (m, 5H), 1.77-1.66 (m, 8H),
1.54-1.41 (m, 6H), 1.31 (d, J = 6.4 Hz, 3H, H-6'), 1.23-1.18 (m, 3H), 0.91 (s, 3H, H-
19), 0.78 (s, 3H, H-18). 13C NMR (100 MHz, CDCl3): δ 174.9(C-23), 174.7(C-20),
172.1(C=O), 117.9(C-22), 95.5(C-1'), 86.1(C-14), 75.3(C-12), 73.9(C-21), 72.7(C-4'),
72.4(C-3), 71.7(C-5'), 55.7(C-13), 47.4(C-3'), 45.8(C-17), 41.7, 36.5, 35.2, 34.8(C-2'),
33.4, 32.8, 30.5, 30.3, 29.9, 27.6, 26.7, 26.7, 23.8(C-19), 23.7(COCH3), 21.9, 18.8(C-
6'), 9.1(C-18). HRMS calc. for C31H47NNaO8 [M+Na] +: 584.3194, found: 584.3196.
11. References
[1] Zeng, J; Sun, G; Yao, W; Zhu; Y, Wang, R; Cai, L; Liu, K; Zhang, Q; Liu, X; Wan,
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S22
Q. Angew. Chem. Int. Ed. 2017, 56, 5227 –5231.
[2] Hutchinson, C; Shekhani, M; Prudent, J. PCT Int. Appl, 2010017480, 11 Feb 2010.
[3] Gilbert, S; Fred, W; Hee, Y; Richard, C; Isaacs; Shino, M. J. Am. Chem. Soc. 1996,
118, 10660-10661.
[4] Zhang, J; Shi, H; Ma, Y; Yu, B. Chem. Commun. 2012, 48, 8679–8681.
12. NMR Spectra
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1H NMR (400 MHz, CDCl3) spectrum of 1a
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13C NMR (100 MHz, CDCl3) spectrum of 1a
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1H NMR (400 MHz, CDCl3) spectrum of Digitoxigenin
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1H NMR (400 MHz, CDCl3) spectrum of 2α
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13C NMR (100 MHz, CDCl3) spectrum of 2α
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HSQC spectrum of 2α in CDCl3
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1H NMR (400 MHz, CDCl3) spectrum of 2β
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13C NMR (100 MHz, CDCl3) spectrum of 2β
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HSQC spectrum of 2β in CDCl3
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1H NMR (400 MHz, CDCl3) spectrum of 3
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13C NMR (100 MHz, CDCl3) spectrum of 3
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1H NMR (400 MHz, CDCl3) spectrum of 5α
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13C NMR (100 MHz, CDCl3) spectrum of 5α
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HSQC spectrum of 5α in CDCl3
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1H NMR (400 MHz, CD3OD) spectrum of 5β
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13C NMR (100 MHz, CD3OD) spectrum of 5β
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1H NMR (400 MHz, CDCl3) spectrum of 6α
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13C NMR (100 MHz, CDCl3) spectrum of 6α
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1H- 1H COSY NMR (400 MHz, CDCl3) spectrum of 6α
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HSQC spectrum of 6α in CDCl3
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1H NMR (400 MHz, CDCl3) spectrum of 6β
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13C NMR (100 MHz, CDCl3) spectrum of 6β
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1H- 1H COSY NMR (400 MHz, CDCl3) spectrum of 6β
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HSQC spectrum of 6β in CDCl3
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1H NMR (400 MHz, CDCl3) spectrum of 7α
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13C NMR (100 MHz, CDCl3) spectrum of 7α
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1H- 1H COSY NMR (400 MHz, CDCl3) spectrum of 7α
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HSQC spectrum of 7α in CDCl3
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1H NMR (400 MHz, CD3OD) spectrum of 7β
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13C NMR (100 MHz, CD3OD) spectrum of 7β
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1H NMR (400 MHz, CDCl3) spectrum of 10
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1H NMR (400 MHz, CDCl3) spectrum of 11α
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13C NMR (100 MHz, CDCl3) spectrum of 11α
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HSQC spectrum of 11α in CDCl3
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1H NMR (400 MHz, CDCl3) spectrum of 11β
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13C NMR (100 MHz, CDCl3) spectrum of 11β
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1H- 1H COSY NMR (400 MHz, CDCl3) spectrum of 11β
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HSQC spectrum of 11β in CDCl3
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1H NMR (400 MHz, CD3OD) spectrum of 12α
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13C NMR (100 MHz, CD3OD) spectrum of 12α
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1H NMR (400 MHz, CD3OD) spectrum of 12β
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13C NMR (100 MHz, CD3OD) spectrum of 12β
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1H- 1H COSY NMR (400 MHz, CD3OD) spectrum of 12β
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HSQC spectrum of 12β in CD3OD
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1H NMR (400 MHz, CDCl3) spectrum of 13α
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13C NMR (100 MHz, CDCl3) spectrum of 13α
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HSQC spectrum of 13α in CDCl3
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1H NMR (400 MHz, CDCl3) spectrum of 14α
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13C NMR (100 MHz, CDCl3) spectrum of 14α
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HSQC spectrum of 14α in CDCl3
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1H NMR (400 MHz, CDCl3) spectrum of S2
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13C NMR (100 MHz, CDCl3) spectrum of S2
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HSQC spectrum of S2 in CDCl3
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1H NMR (400 MHz, CD3OD) spectrum of 14β
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13C NMR (100 MHz, CD3OD) spectrum of 14β
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1H- 1H COSY NMR (400 MHz, CD3OD) spectrum of 14β
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HSQC spectrum of 14β in CDCl3
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1H NMR (400 MHz, CDCl3) spectrum of 15α
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13C NMR (100 MHz, CDCl3) spectrum of 15α
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1H NMR (400 MHz, CDCl3) spectrum of 15β
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13C NMR (100 MHz, CDCl3) spectrum of 15β
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1H- 1H COSY NMR (400 MHz, CDCl3) spectrum of 15β
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1H NMR (400 MHz, CDCl3) spectrum of S3
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13C NMR (100 MHz, CDCl3) spectrum of S3
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1H- 1H COSY NMR (400 MHz, CDCl3) spectrum of S3
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1H NMR (400 MHz, CDCl3) spectrum of 16α
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13C NMR (100 MHz, CDCl3) spectrum of 16α
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1H NMR (400 MHz, CDCl3) spectrum of S4
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13C NMR (100 MHz, CDCl3) spectrum of S4
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1H NMR (400 MHz, CDCl3) spectrum of 16β
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13C NMR (100 MHz, CDCl3) spectrum of 16β
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1H- 1H COSY NMR (400 MHz, CDCl3) spectrum of 16β
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HSQC spectrum of 16β in CDCl3