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

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+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)


4 Å MS, -40 oC, 3 h

94%

(2.1:1)


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.


EtOAc 1:1). m.p. 131.0-131.5 °C. [α]D20 -74.7


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.

S11


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


material 6α (45.0 mg, 0.062 mmol, 1.0 equiv),


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.

S12

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

S13

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.


EtOAc 1:1). m.p. 160.0-161.0 °C. [α]D20 -51.6


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),

S14

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


material 11α (74.0 mg, 0.094 mmol, 1.0 equiv)


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

S15

(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


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


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.

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),

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


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,

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)

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.


EtOAc 1:1). m.p. 161.0-161.8 °C. [α]D20 +102.9


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.


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.

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

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


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,

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

1H NMR (400 MHz, CDCl3) spectrum of 1a

13C NMR (100 MHz, CDCl3) spectrum of 1a

1H NMR (400 MHz, CDCl3) spectrum of Digitoxigenin

1H NMR (400 MHz, CDCl3) spectrum of 2α

13C NMR (100 MHz, CDCl3) spectrum of 2α

HSQC spectrum of 2α in CDCl3

1H NMR (400 MHz, CDCl3) spectrum of 2β

13C NMR (100 MHz, CDCl3) spectrum of 2β

HSQC spectrum of 2β in CDCl3

1H NMR (400 MHz, CDCl3) spectrum of 3

13C NMR (100 MHz, CDCl3) spectrum of 3

1H NMR (400 MHz, CD3OD) spectrum of 5β

13C NMR (100 MHz, CD3OD) spectrum of 5β

1H- 1H COSY NMR (400 MHz, CDCl3) spectrum of 6α

1H- 1H COSY NMR (400 MHz, CDCl3) spectrum of 6β

1H- 1H COSY NMR (400 MHz, CDCl3) spectrum of 7α

1H NMR (400 MHz, CDCl3) spectrum of 10

1H NMR (400 MHz, CD3OD) spectrum of 12α

13C NMR (100 MHz, CD3OD) spectrum of 12α

1H- 1H COSY NMR (400 MHz, CD3OD) spectrum of 12β

HSQC spectrum of 12β in CD3OD

1H NMR (400 MHz, CDCl3) spectrum of S2

13C NMR (100 MHz, CDCl3) spectrum of S2

HSQC spectrum of S2 in CDCl3

1H- 1H COSY NMR (400 MHz, CD3OD) spectrum of 14β

1H- 1H COSY NMR (400 MHz, CDCl3) spectrum of S3

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