Copyright WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001. Supporting Information for Angew. Chem. Int. Ed. Z17260

Convergent Synthesis of Digitoxin: Stereoselective Synthesis and Glycosylation of the Digoxin Trisaccharide Glycal

Frank E. McDonald* and K. Subba Reddy

Experimental procedures and characterization for compounds 7, 8, 9, 11, 12, 13, 15, 16β β , 16α α, 1

General:

1H NMR spectra were measured in CDCl at 300 MHz on a 3

Varian Mercury 300 NMR spectrometer, at 400 MHz on an INOVA 400 NMR

spectrometer,

or

at

600

MHz

on

an

INOVA

600

NMR

spectrometer, and were referenced to residual CHCl3 (7.26 ppm). 13C NMR spectra were recorded at 75 MHz or 100 MHz on these instruments, and were referenced with the 77.0 ppm resonance of CDCl3. IR.

Infrared spectra were recorded on Mattson Genesis II FT-

Mass spectra (EI) or high-resolution mass spectra (EI) were

measured at 70 eV on VG-70S instrument.

High-resolution FAB

mass spectra were recorded on Jeol SX102 at 6kV-Xe using 3nitrobenzylalcohol,

in

some

cases

1

with

addition

of

LiI

as

a

matrix.

Melting

points

were

determined

with

melting point apparatus and are uncorrected.

a

Fisher-Johns

Optical rotations

were measured at 23oC (concentration in g / 100 mL) using a Perkin-Elmer

241

performed

Atlantic

by

MC

polarimeter. Microlab,

Elemental

Inc.

in

analyses

Norcross,

were

GA.

All

reactions were conducted in oven-dried (125oC) or flame-dried glassware under atmospheres of dry nitrogen. reactions

were

distilled

from

sodium

Ether and THF for

benzophenone

ketyl;

methylene chloride and triethylamine were distilled from CaH2; DMF

was

used

(Aldrich).

without

purification

from

Sure-Seal

bottles

All reagents were purchased from Aldrich Chemical

Co. and used without further purification unless noted.

Flash

chromatography was performed with silica gel (40 microns; 32-63 µ) purchased from Scientific Adsorbents, Inc.

Alkynyl glycoside 8: Me

OBz

H Me

HO Me TBSO

O

TBSO

Me

5a

TBSO

1 mol% Ph3 P-HBr toluene

TBSO

OR'

4a

O

TBSO DIBAL CH2 Cl2 , -78 oC

2

O OTBS 7 R' = Bz 8 R' = H

H

A mixture of glycal 4a (1.79 g, 5 mmol) and alkynol acceptor 5a (1.74 g, 5 mmol) was azeotropically dried (2 x toluene). Ph3P-HBr (17

mg,

0.05

mmol,

1

mol%)

was

introduced

toluene (10 mL) under argon atmosphere. was allowed to stir for 6 h at rt.

followed

by

dry

The resulting mixture

The reaction mixture was

quenched with sat. NaHCO3 solution (5 ml), diluted with EtOAc (400 mL), washed with H2O (1 x 25 mL), brine (2 x 25 mL), dried (Na2SO4), and concentrated under reduced pressure to give crude reaction mixture (β:α, 97:3, determined by The

desired

β-anomer

was

separated

by

1

H NMR integration). silica

gel

column

chromatography (eluent, hexanes:EtOAc, 98:2 to 95:5) to afford the glycoside 7 (3.100 g, 88%). m.p. = 78-80oC; [α]23D +14.9 (CHCl3, c, 2.04); IR (KBr) 3303, 2931, 1713, 1276, 1252, 1118, 885, 839 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.05-8.03 (m, 2H), 7.57 - 7.51 (m, 1H), 7.44 - 7.38 (m, 2H), 5.66 (dq, J = 6.5, 2.7 Hz, 1H), 5.11 (dd, J = 9.5, 2.1 Hz, 1H), 4.78 (dd, J = 3.3, 2.1 Hz, 1H), 4.02 (app. t, J = 3.1 Hz, 1H), 3.99 (app. dd, J = 3.9, 2.1 Hz, 1H), 3.84 (app dq, J = 6.3, 2.4 Hz, 1H), 3.23 (dd, J = 9.0, 2.4 Hz, 1H), 2.45 (d, J = 2.4 Hz, 1H), 2.04 and 2.00 (ddd, J = 13.2, 4.2, 2.1 Hz, 1H,), 1.72, 1.68, and 1.64 (ddd, J = 13.3, 3.9, 2.1 Hz, 1H), 1.42 (d, J = 6.6 Hz, 3H), 1.13 (d, J = 6.3 Hz, 3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.83 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.07 (s, 3H),

3

0.05 (s, 6H), 0.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δ

165.4,

132.6, 130.6, 129.5, 128.1, 98.6, 82.8, 82.0, 75.3, 73.9, 71.4, 69.9,

69.3,

65.3,

39.9,

26.2,

25.9,

25.8,

18.5,

18.3,

18.2,

18.1,

15.9,

-3.3,

-4.1,

-4.5,

-4.6,

-4.8,

-4.9;

HRMS

(FAB+)

Calcd

for

C37H66O7Si3Li

[(M+Li)+]

713.4276,

Found

713.4271;

Anal. Calcd for C37H66O7Si3: C, 62.84; H, 9.41. Found: C, 62.73; H, 9.41. The glycoside 7 (3.100 g, 4.38 mmol) was dissolved in dry CH2Cl2 (25 mL) and cooled to -78oC.

The above solution was treated

slowly with DIBAL-H (11 mL, 11 mmol, 1M solution in CH2Cl2) for a period of 30 min.

The reaction mixture was then quenched with

cold (-70oC) EtOAc (10 mL) and was stirred for an additional 30 min.

The mixture was then poured into a cold solution of 1M aq.

HCl (300 mL).

Extractive work up (EtOAc / H2O) and silica gel

chromatography

(hexanes:EtOAc,

95:5

glycoside 8 (2.617 g, 99% yield).

to

9:1)

afforded

alkynyl

[α]23D + 47.7 (CHCl3, c,

1.66); IR (neat) 3465, 3311, 2931, 1463, 1254, 837 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.02 (dd, J = 9.8, 2.0 Hz, 1H), 4.67 (dd, J = 4.2, 2.4 Hz, 1H), 4.03 (app. q, J = 6.4 Hz, 1H), 3.99 (dd, br, J = 5.2, 1.6 Hz, 1H), 3.89 (dq, J = 7.4, 2.8 Hz, 1H), 3.62 (dd, J = 5.8, 4.0 Hz, 1H), 3.21 (dd, J = 9.0, 2.4 Hz, 1H), 2.49 (d, J = 2.4 Hz, 1H), 1.97 and 1.94 (ddd, J = 13.2, 4.0, 2.0 Hz, 1H),

4

1.73, 1.70 and 1.67 (ddd, J = 12.2, 3.6, 2.0 Hz, 1H), 1.21 (d, J = 6.4 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 18H), 0.15 (s, 3H), 0.12 (s, 3H), 0.07 (s, 3H), 0.06 (s, 6H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 98.65, 84.79, 83.59, 75.12, 74.30, 69.95, 69.71, 67.36, 65.25, 39.19, 26.10, 25.89, 25.79, 18.69, 18.56, 18.23, 18.19, 18,13, -4.59,

-4.98;

609.4014,

(FAB+)

HRMS

Found:

59.75; H, 10.36.

609.4034;

Calcd.

for

Anal.

-3.38, -4.19, -4.51,

C30H62O6Si3Li

Calcd.

for

[(M+Li)+]

C30H62O6Si3,

C,

Found C, 59.84; H, 10.26.

Disaccharide glycal 11: Me

OH

Me O

TBSO

10 - 25 mol% W(CO)6

H

DABCO, THF 65o C, hν (350 nm)

O OTBS

TBSO

Me

8

Me

O

RO RO

Bu4 NF, THF

TBSO 9 R = TBS 10 R = H 11 R = Ac

A.

With 25 mol% W(CO)6:

O

O

Ac 2O, Et 3N, cat. DMAP, CH 2Cl 2

An oven-dried 50 mL Schlenk flask was

fitted with a reflux condenser and magnetic stir bar, under an argon

atmosphere,

and

was

charged

with

tungsten

hexacarbonyl

(176 mg, 0.5 mmol, dried under vacuum), alkynyl alcohol 8 (1.204 g, 2 mmol, azeotropically dried twice from toluene), sublimed DABCO (672 mg, 6 mmol) and freshly distilled anhydrous THF (6

5

mL).

The resulting solution was irradiated for 5 h at 350 nm

(Rayonet

photoreactor)

without

external

cooling,

so

that

the

reaction temperature reached the boiling point of THF (approx. 65oC). Volatile components were removed under reduced pressure, and the product was purified by silica gel chromatography using an

eluent

mixture

of

hexanes-triethylamine-Et20

(98:1:1)

to

afford 9 (1.150 g, 96%, which contained approximately 10-12% of an

exocyclic

isomer

which

was

not

easily

separated

at

this

stage). Compound 9 (1.050 g, 1.74 mmol) was dissolved in THF (10 mL) and then solid tetrabutylammonium fluoride - hydrate (4.087 g, 15.66 mmol) was added at room temperature.

After stirring for 2 h

(short reaction time required for selective removal of only two silyl

ethers),

aqueous

workup

(EtOAc

/

H2O),

separation

of

organic layers, and solvent removal under reduced pressure gave the disaccharide diol 10.

The crude diol 10 was acylated with

Et3N (1.5 mL), DMAP (10 mg), Ac2O (1.5 mL) and CH2Cl2 (20 mL), at room temperature for 18 h to afford the pure disaccharide glycal 11

(0.705

g,

88%

yield,

2

steps)

after

silica

gel

column

chromatography (hexanes: EtOAc: Et3N, 90: 9:1). B.

With 10 mol% W(CO)6

The procedure is essentially the same as procedure A except 10 mol% W(CO)6 was utilized.

Thus a mixture of alkynol 8 (2.388 g,

3.97 mmol), W(CO)6 (140 mg, 0.397 mmol), DABCO (889 mg, 7.94

6

mmol)

and

THF

(12

mL)

was

irradiated

under

argon

for

6

h.

Solvent was removed under reduced pressure to give crude product 9,

which

upon

desilylation

and

acylation

as

described

above

afforded white crystalline disaccharide 11 after chromatography (1.326 g, 73% yield).

m.p. 73–75oC; [α]D23 +164 (CHCl3, C,

1.05); IR (KBr) 2934, 1756, 1645, 1372, 1248, 1080, 1019, 834 cm-1; 1H NMR (600 MHz, CDCl3): δ 6.28 (app. d, J = 6.0 Hz, 1H), 5.44 (app. q, J = 3.0 Hz, 1H), 4.86 (dd, J = 9.6, 1.8 Hz, 1H), 4.77 (app. t, J = 6.0 Hz, 1H), 4.51 (dd, J = 9.6, 3.0 Hz, 1H), 4.22 (dd, J = 5.7, 3.0 Hz, 1H), 4.12 (app. sextet, J = 6.0 Hz, 1H), 3.87 (app, dq, J = 9.6, 2.4 Hz, 1H), 3.45 (dd, J = 10.2, 3.6 Hz, 1H), 2.10 (s, 3H), 2.05 and 2.02 (ddd, J = 5.6, 3.2, 2.8 Hz, 1H), 2.00 (s, 3H), 1.90, 1.88 and 1.85 (ddd, J = 7.6, 4.4, 2.8 Hz, 1H), 1.29 (d, J = 9.6 Hz, 3H), 1.17 (d, J = 9.0 Hz, 3H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H).

13C NMR (100 MHz,

CDCl3): δ 170.1, 169.9, 144.8, 102.8, 99.5, 80.9, 72.7, 69.0, 67.5, 67.4, 63.9, 35.7, 25.9, 20.9, 20.8, 18.3, 17.9, 17.4, 4.2,

-4.6.

465.2496,

HRMS

found

(FAB+)

465.2494.

Calcd. Anal.

for

Calcd.

57.62, H, 8.35; found C, 57.69, H, 8.33.

7

C22H38Si2O8Li for

[(M+Li)+]

C22H38Si2O8,

C,

Glycoside 12: Me

H

HO

Me

Me

O

AcO

OBz

O AcO

5a

TBSO

O

mixture

O

O AcO

H

O OTBS

TBSO 12

11

A

OBz

Me

O

AcO

1 mol% Ph3 P-HBr toluene

TBSO

Me

Me

of

disaccharide

glycal

11

(870

mg,

1.9

mmol)

and

alkynol acceptor 5a (662 mg, 1.9 mmol) was azeotropically dried (2 x toluene). followed

by

Ph3P-HBr (7 mg, 0.02 mmol, 1 mol%) was introduced

dry

toluene

(5

mL)

under

argon

atmosphere.

resulting mixture was stirred for 18 h at rt.

The

The reaction

mixture was quenched with sat. NaHCO3 solution (5 mL), diluted with EtOAc (250 mL), washed with H2O (1 x 25 mL), brine (2 x 25 mL), dried

(Na2SO4), and concentrated under reduced pressure to

give crude reaction mixture (β:α, >99:1, determined by integration).

1

H NMR

The product was purified by silica gel column

chromatography to afford the glycoside 12 (1.088 g, 71% yield) as

a

colorless

oil,

solid upon standing.

which

solidified

m.p. 66–68oC;

to

a

[α]D23

crystalline +21.4

white

(CHCl3,

C,

0.75); IR (neat) 2931, 1750, 1720, 1250, 1087, 777 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.03 – 8.02 (m, 2H), 7.55 – 7.52 (m, 1H), 7.43 – 7.39 (m, 2H), 5.65 (dq, J = 6.4, 2.8 Hz, 1H), 5.43 (app. q, J = 3.2 Hz, 1H), 5.08 (dd, J = 9.4, 2.0 Hz, 1H), 4.51 (dd, J

8

= 10.2, 2.8 Hz, 1H), 4.27 (br, d, J = 1.6 Hz, 1H), 4.00 (app. t, J = 3.2 Hz, 1H), 3.88 (app. sextet, J = 6.4 Hz, 1H), 3.81 (app. sextet, J = 2.8 Hz, 1H), 3.12 (dd, J = 9.6, 2.4 Hz, 1H), 2.45 (d, J = 2.4 Hz, 1H), 2.11 (s, 3H), 2.00 (s, 3H), 1.98 (dd, J = 5.6, 2.4 Hz, 1H), 1.95 (dd, J = 3.0, 2.4 Hz, 1H ), 1.86, 1.84 and 1.81 (ddd, J = 7.6, 4.4, 2.8 Hz, 1H), 1.72, 1.69 and 1.66 (ddd, J = 5.6, 3.6, 2.4 Hz, 1H), 1.41 (d, J = 6.0 Hz, 3H), 1.17 (d, J = 6.0 Hz, 3H), 1.14 (d, J = 6.4 Hz, 3H), 0.91 (s, 9H), 0.83 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.053 (s, 3H), 0.037 (s, 3H).

13C NMR (100 MHz, CDCl ): δ 170.1, 169.9, 165.6, 132.7, 3

130.6, 129.6, 128.2, 99.6, 98.9, 82.7, 82.2, 73.9, 72.7, 71.4, 69.2,

67.4,

67.4,

65.2,

39.7,

35.8,

25.7,

25.7,

18.2, 18.1, 17.9, 17.9, 15.7, -4.2, -5.0, -5.3. Calcd. Anal.

for

[(M+Li)+]

C41H66Si2O12Li

Calcd.

for

C41H66Si2O12,

C,

813.4253, 61.01,

H,

60.80, H, 8.22.

Alkynyl triol 13: Me

Me O

RO

O

O RO

DIBAL CH2 Cl2 , -78 oC

OR'

Me O OTBS

TBSO 12 R = Ac, R' = Bz 13 R = R' = H

9

H

20.9,

20.8,

HRMS (FAB+)

found

813.4235;

8.24;

found

C,

The glycoside 12 (1.00 g, 1.24 mmol) was dissolved in dry CH2Cl2 (50 mL) and cooled to –78oC. The above solution was treated slowly with DIBAL-H (6.2 mL, 6.2 mmol, 1M solution in CH2Cl2) for a period of 1 h.

The reaction mixture was then quenched with

cold (-70oC) EtOAc (5 mL), and was stirred for an additional 30 min.

The mixture was then poured into a cold solution of 1M aq.

HCl (200 mL). chromatography

Extractive workup (EtOAc / H2O) and silica gel (hexanes:EtOAc,

4:1

triol 13 (0.752 g, 98% yield).

to

1:1)

afforded

alkynyl

m.p. 62 – 64oC; [α]D23 +39.5

(CHCl3, C, 1.03); IR (KBr) 3420, 2932, 1630, 1468, 1401, 1168, 1082, 837 cm-1; 1H NMR (600 MHz, CDCl3): δ 5.00 (dd, J = 9.6, 1.2 Hz, 1H), 4.83 (dd, J = 9.6, 1.2 Hz, 1H), 4.69 (dd, J = 4.8, 2.4 Hz, 1H), 4.28 (br, d, J = 1.8 Hz, 1H), 4.09 (br, J = 1.8 Hz, 1H), 4.03 (app. sextet, J = 5.4 Hz, 1H), 3.67 (app. dq, J = 6.0, 3.0 Hz, 1H), 3.61 (dd, J = 5.4, 4.2 Hz, 1H), 3.25 (app. sextet, J = 3.6 Hz, 1H), 3.10 (dd, J = 9.6, 2.4 Hz, 1H), 2.99 (br, d, J = 5.4 Hz, 1H), 2.49 (d, J = 1.6 Hz, 1H), 2.31 (br. s, 1H), 2.11 and 2.09 (app. dd, J = 3.6, 1.6 Hz, 1H), 2.07 (br. s, 1H), 1.89 and 1.87 (app. dd, J = 3.2, 1.2 Hz, 1H), 1.73 – 1.67 (m, 2H), 1.62 (br. s, 1H), 1.25 (d, J = 4.4, 3H), 1.21 (d, J = 4.0, 3H), 1.19 (d, J = 4.4 Hz, 3H), 0.90 (s, 9H), 0.87 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H).

10

13C NMR (100

MHz, CDCl3): δ 99.4, 98.8, 84.6, 83.5, 82.3, 74.4,73.0, 69.2, 68.8,

68.1,

68.1,

67.5,

65.2,

38.9,

37.8,

[(M+Li)+]

C30H58Si2O9Li

625.3779,

25.7,

18.6,

HRMS (FAB+) Calcd.

18.2, 18.1, 17.9, -4.3, -4.8, -5.1, -5.4. for

25.8,

found

625.3783;

Anal.

Calcd. for C30H58Si2O9, C, 58.22, H, 9.45; found C, 57.78, H, 9.36. Trisaccharide glycal 15: Me

Me

O

O HO

H

Me

O

HO

OH

O OTBS

TBSO 13

25 mol% W(CO)6 DABCO, THF 65o C, hν (350 nm) Me

Me

O

RO RO

procedure

is

disaccharide 11.

O

O

TBSO

TBSO 14 R = H

Ac 2O, Et 3N, cat. DMAP, CH 2Cl 2

The

Me

O

O

15 R = Ac

essentially

the

same

as

described

for

Thus a mixture of alkynol 13 (360 mg, 0.58

mmol), W(CO)6 (51 mg, 0.15 mmol), DABCO (202 mg, 1.8 mmol) and THF (3.6 mL) was irradiated under argon for 6 h.

Solvent was

removed under reduced pressure to give a crude product which was passed

through

a

silica

gel

pad

(washing

hexanes : EtOAc, 4 : 1 to 1 : 1).

11

with

a

mixture

of

Solvent was removed under

reduced pressure to give crude trisaccharide diol 14.

The diol

14 was acylated with Et3N (2 mL), DMAP (20 mg), Ac2O (2 mL) and CH2Cl2 (10 mL) at rt for 3 h.

The product was purified by basic

silica gel chromatography (eluent hexanes:EtOAc:Et3N, 95:4:1 to 9:8:2) to afford trisaccharide glycal 15 (330 mg, 81% yield). m.p. 65–70oC; [α]D23 +89 (CHCl3, C, 0.85); IR (KBr) 2955, 2932, 1752, 1642, 1247, 1086 cm-1; 1H NMR (400 MHz, CDCl3): δ 6.28 (d, J = 6.0 Hz, 1H), 5.44 (app. q, J = 3.2 Hz, 1H), 4.91 (dd, J = 9.2, 1.6 Hz, 1H), 4.81 (dd, J = 9.2, 1.6 Hz, 1H), 4.77 (app. t, J = 5.6 Hz, 1H), 4.51 (dd, J = 10.0, 3.2 Hz, 1H), 4.28 (br. S, 1H), 4.19 (dd, J = 5.6, 3.2 Hz, 1H), 4.09 (app. sextet, J = 4.0 Hz, 1H), 3.81 (app. dq, J = 6.4, 3.2 Hz, 1H), 3.44 (dd, J = 10.0, 3.6 Hz, 1H), 3.08 (dd, J = 9.6, 2.4 Hz, 1H), 2.11 (s, 3H), 2.00 (s, 3H), 2.02 – 2.96 (m, 1H), 1.92 and 1.89 (ddd, J = 5.6, 3.6, 1.6 Hz, 1H), 1.87, 1.84 and 1.81 (ddd, J = 7.6, 4.4, 3.2 Hz, 1H), 1.68, 1.66 and 1.63 (ddd, J = 5.6, 4.0, 2.4 Hz, 1H), 1.27 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.0 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.09 (s, 6H), 0.06 (s, 3H), 0.05 (s, 3H), 13C NMR (100 MHz, CDCl3): δ 170.1, 169.9, 144.8, 102.8, 99.7, 99.6, 83.1, 80.5, 72.7, 69.3, 69.2, 67.9, 67.5,

67.4,

64.1,

39.4,

35.9,

25.9,

18.1,

17.9,

17.2,

-4.2,

-4.7,

12

-5.4.

25.7,

20.9,

HRMS

(FAB+)

20.8,

18.3,

Calcd.

for

C34H62Si2O11Li [(M+Li)+] 709.3991, found 709.4022; Anal. Calcd. for C34H62Si2O11, C, 58.09, H, 8.89; found C, 57.82, H, 8.84.

Glycosylation of trisaccharide 15 with (+)-digitoxigenin (2). Me

Me

O

AcO AcO

Me

O

O

O

O

TBSO

TBSO

15

Me Me

1 mol% Ph3 P-HBr CHCl3

H

H (2 ) digitoxigenin

H H

HO

O

O

OH

Me Me Me AcO

Me

O O

AcO

Me

O O

TBSO

H

O O

H

OH

H

TBSO

Me Me

O

AcO

O

O AcO

Me

TBSO 16α

H

O H

O O TBS

13

O

O

+ Me

H

H

16β

Me

O

O

H

O

H

H

OH

H

A

25

mL

Schlenk

flask

was

charged

with

a

mixture

of

trisaccharide glycal 15 (55 mg, 78 µmol, dried azeotropically from toluene) and (+)-digitoxigenin (2, 30 mg, 78 µmol).

Ph3P-

HBr (1-2 mg) was introduced followed by dry chloroform (3 mL) under argon atmosphere. stir for 1 h at rt.

The resulting mixture was allowed to The reaction mixture was quenched with

saturated NaHCO3 solution (1 mL), diluted with CH2Cl2 (100 mL), washed with H2O (1 x 10 mL), brine (2 x 10 mL), dried (Na2SO4), and concentrated under reduced pressure to give crude reaction mixture as a 3 : 2 anomeric mixture (β : α, determined by integration).

1

H NMR

The products were separated by careful silica gel

column chromatography (eluent: CHCl3: MeOH, 99.9: 0.1 to 99: 1) to afford the desired beta-glycoside 16β β (14 mg, 16%, slower moving

compound

by

TLC),

the

alpha-epimer

16α α

(18

mg,

21%,

faster moving compound by TLC), and mixture fractions of 16α α and 16β β (38 mg, 45%), for 82% combined yield of products 16α α

and

16β β. Data for 16β β : m.p. 130-132oC; [α]D23 +33.4 (CHCl3, C, 0.93); IR (neat) 3490, 2932, 2886, 2857, 1780, 1750, 1627, 1449, 1368, 1169, 1086, 1049, 1025, 993, 837, 757 cm-1; 1H NMR (400 MHz, CDCl3): δ 5.87 (s, 1H), 5.44 (app. q, J = 3.2 Hz, 1H), 5.01 and

14

4.97 (A of AB of CH2-, J = 18.4, 1.6 Hz, 1H), 4.92 and 4.90 (app. dd, J = 7.6, 1.6 Hz, 1H), 4.86 and 4.83 (app. dd, J = 10.4, 1.6 Hz, 1H), 4.83 and 4.78 (B of AB of CH2-, J = 18.0, 1.6 Hz, 1H), 4.83 and 4.80 (app. dd, J = 9.6, 1.2 Hz, 1H), 4.52 and 4.49 (dd, J = 10.4, 3.2 Hz, 1H), 4.26 (br. s, 2H), 4.02 (br. s, 1H), 3.89 (app. sextet, J = 6.4 Hz, 1H), 3.85 – 3.78 (app. sextet, J = 3.2 Hz, 2H), 3.13 and 3.11 (dd, J = 9.6, 2.8 Hz, 1H), 3.08 and 3.05 (dd, J = 9.6, 2.4 Hz, 1H), 2.78 (m, 1H), 1.88 to 1.20 (m, 25H), 2.11 (s, 3H), 2.01 (s, 3H), 1.25 to 1.21 (m, 2H), 1.18 (d, J = 3.2 Hz, 3H), 1.17 (d, J = 2.8 Hz, 3H), 1.16 (d, J = 1.6 Hz, 3H), 0.92 (s, 3H), 0.88 (s, 9H), 0.86 (s, 12H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H). 174.5,

170.07,

169.96,

117.68,

13C NMR (100 MHz, CDCl ): δ 3

99.92,

99.73,

85.65,

83.07,

82.52, 73.41, 72.71, 72.20, 69.50, 69.19, 68.41, 67.90, 67.48, 67.38, 50.89, 49.57, 41.88, 40.16, 40.06, 39.57, 36.26, 35.89, 35.72, 35.18, 33.14, 30.16, 29.71, 26.88, 26.69, 26.59, 25.86, 25.74, 23.63, 21.41, 21.15, 20.99, 20.77, 18.16, 18.09, 17.90, 17.84, 15.76, -4.11, -4.18, -5.41, -5.51.

HRMS (FAB+) Calcd.

for C57H96Si2O15Li [(M+Li)+] 1083.6448, found: 1083.6478; Anal. Calcd. for C57H96Si2O15, C, 63.53, H, 8.98; found C, 61.99, H, 8.78. Data for 16α α: m.p. 110-112oC; [α]23D + 81.4 (CHCl3, C, 0.66); IR (neat) 3483, 2930, 2895, 2856, 1780, 1750, 1622, 1449, 1369, 15

1248, 1227, 1171, 1142, 1127, 1087, 1050, 1025, 990, 907, 838, 775 cm-1; 1H NMR (400 MHz, CDCl3): δ 5.87 (s, 1H), 5.43 (app. q, J = 2.8 Hz, 1H), 5.02 and 4.97 (A of AB of CH2-, J = 16.4, 1.6 Hz, 1H), 4.89 (app. br. d, J = 8.4 Hz, 1H), 4.83 and 4.79 (app. br, d, J = 11.6 Hz, 1H), 4,79 (br. s, 1H),

4.83 and 4.78 (B of

AB of CH2-, J = 18.0, 2.0 Hz, 1H), 4.52 and 4.49 (dd, J = 9.6, 2.8 Hz, 1H), 4.26 (br. s, 2H), 4.18 (br. s, 1H), 4.16 (app. sextet, J = 6.4 Hz, 1H), 3.92 – 3.87 (app. pentet, J = 6.4 Hz, 2H), 3.86 (br. s, 1H), 3.81 (app. sextet, J = 3.6 Hz, 1H), 3.17 and 3.14 (dd, J = 9.2, 2.4 Hz, 1H), 3.08 and 3.05 (dd, J = 9.6, 2.4 Hz, 1H), 2.78 (app. t, J = 6 Hz, 1H), 2.19 to 1.20 (m, 19H), 2.11 (s, 3H), 2.01 (s, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.16 (d, J = 6.4 Hz, 3H), 1.12 (d, J = 6.0 Hz, 3H), 0.90 (s, 9H), 0.89 (s, 3H), 0.87 (s, 9H), 0.86 (s, 3H), 0.07 (s, 3H), 0.06 (s, 6H), 0.04 (s, 3H).

13C NMR (100 MHz, CDCl ): δ 174.61, 3

170.10,

117.64,

170.01,

99.81,

99.49,

94.49,

85.68,

174.53, 83.14,

82.26, 73.41, 72.70, 71.11, 69.18, 68.01, 67.80, 67.46, 67.34, 61.88, 50.91, 49.57, 41.86, 40.05, 39.44, 37.83, 36.26, 35.87, 35.57, 35.11, 33.17, 32.13, 30.06, 26.83, 26.47, 25.98, 25.75, 24.06, 23.50, 21.28, 21.12, 21.02, 20.78, 18.33, 18.16, 18.09, 17.45, 15.76, -4.19, -4.21, -5.06, -5.40.

HRMS (FAB+) Calcd.

for C57H96Si2O15Li [(M+Li)+] 1083.6448, found: 1083.6489.

16

Anal.

Calcd. for C57H96Si2O15, C, 63.53, H, 8.98; found C, 62.20, H, 8.79.

Synthesis of (+)-Digitoxin (1): O

O Me Me

Me

Me

O

AcO AcO

Me

O

O TBSO

H H

O

O

O

H

OH

H

TBSO

β 16β Me Me Me

O

AcO AcO

Me

O

O

O

H

OH

H

HO

NaOMe, MeOH

Me Me

Me

O HO

Me

O

O

O HO

1, (+)-digitoxin

17

H H

O

O HO

O

O

β 17β

HO

H

H H

O

O HO

Me

O

O NH4 F - HF, DMF / NMP, 70o C

Me

H

H

H

OH

H

A mixture of 16β β (45 mg, 42 µmol, produced in a larger scale run using conditions from entry 3 in table) and NH4F-HF (340 mg, 5.97 mmol) was dispersed in a mixture of anhydrous DMF (4 mL) and Nmethylpyrrolidine (NMP, 4 mL).

The resulting mixture was kept

at 70oC while stirring the contents for 5 days under argon.

The

solvent was removed under reduced pressure, and the residue was dissolved in CH2Cl2 / H2O (100 mL / 10 mL). The organic layer was washed with H2O (2 x 10 mL), brine (1 x 10 mL), dried (Na2SO4) and concentrated under reduced pressure to afford crude product, which upon silica gel column chromatography (eluent CHCl3:MeOH, 99:1 to 98:2) afforded 17β β (14 mg, 40% yield). Data for 17β β:

H NMR (400 MHz, CDCl3): δ 5.87 (br, s, 1H), 5.45

1

(app. br, d, J = 2.8 Hz, 1H), 5.01 and 4.96 (A of AB of CH2-, J = 18 Hz, 1H), 4.91 and 4.89 (app. br, d, J = 9.6 Hz, 1H), 4.88 and 4.87 (app. dd, J = 2.4 Hz, 1H), 4.85 and 4.84 (dd, J = 2.8 Hz, 1H), 4.83 and 4.78 (B of AB of CH2-, J = 18.0 Hz, 1H), 4.25 (app. br, d, J = 11.2 Hz, 2H), 4.02 (br, s, 1H), 3.96 (sextet, J = 3.2 Hz, 1H), 3.84 (sextet, J = 3.2 Hz, 1H), 3.76 (sextet, J = 2.8 Hz, J = 2.8 Hz, 1H), 3.26 and 3.23 (app. dd, J = 9.2, 2.8 Hz, 1H), 3.03 (br, s, 1H), 2.85 (br, s, 1H), 2.77 (app. br, m, 1H), 2.15-2.04 (series of m, 3H), 2.12 (s, 3H), 2.01 (s, 3H), 1.951.84 (series of m, 3H), 1.73-1.38 (series of m, 24H), 1.22 (d, J

18

= 6.4 Hz, 6H), 1.19 (d, J = 6.0 Hz, 3H), 0.91 (s, 3H), 0.86 (s, 3H). A sample of 17β β (10 mg, 12 µmol) was dissolved in anhydrous MeOH (2 mL) and treated with solid NaOMe (2 mg, 37 µmol) at rt for 16 h under argon. to

give

crude

The solvent was removed under reduced pressure product,

which

upon

silica

gel

chromatography

(eluent: CHCl3:MeOH, 98:2 to 95:5) afforded pure digitoxin (1, 9 mg,

100%).

synthetic

m.p.

236-237

digitoxin,

+

oC;

lit[1]:

19.33

(CHCl3,

240oC C,

(dec.). 0.15);

[α]D23 [α]D23

commercial digitoxin [Aldrich], + 20.47 (CHCl3, C, 0.15).

of of IR

(neat) 3455, 2928, 2856, 1738, 1620, 1450, 1379, 1164, 1129, 1069, 1013, 910, 732 cm-1; 1H NMR (400 MHz, CDCl3): δ 5.87 (s, 1H), 5.01 and 4.97 (A of AB of CH2-, J = 18.4, 1.6 Hz, 1H), 4.92 and 4.90 (app. dd, J = 7.2, 2.0 Hz, 1H), 4.89 and 4.88 (app. dd, J = 7.6, 1.6 Hz, 1H), 4.87 and 4.84 (dd, J = 10.0, 1.6 Hz, 1H), 4.83 and 4.78 (B of AB of CH2-, J = 18.0, 2.0 Hz, 1H), 4.24 (app. br, t, J = 2.8 Hz, 2H), 4.12 (br, s, 1H), 4.02 (br. s, 1H), 3.85-3.73 (m, 3H), 3.29 (br, d, J = 10.0 Hz, 1H), 3.25 and 3.22 (app. dd, J = 9.6, 3.2 Hz, 1H), 3.21 and 3.19 (app. dd, J = 10.0, 2.8 Hz, 1H), 3.04 (br, s, 1H, OH), 2.97 (br, s, 1H, OH), 2.77 (br, dd, J = 8.8, 5.6 Hz, 1H), 2.35 (app. br, t, J =3.2 Hz, 1H), 2.17-2.03 (m, 5H), 1.9-1.83 (m, 2H), 1.78-1.35 (series of m, 22H), 1.28 (d, J = 6.4 Hz, 3H), 1.22 (d, J = 6.0 Hz, 6H),

19

13C NMR (100 MHz, CDCl ): δ 174.63, 3

0.91 (s, 3H), 0.86 (s, 3H).

174.58 and 174.53 (two-bond coupling to H22)[2], 117.64, 98.22, 98.15, 95.31, 85.64, 82.52, 82.15, 73.44, 72.65, 72.50, 69.46, 68.23, 68.04, 66.42, 66.33, 50.89, 49.57, 41.80, 40.04, 37.76, 37.09, 36.66, 36.18, 35.70, 35.14, 33.12, 30.15, 29.68, 26.84, HRMS (FAB+)

26.62, 26.51, 23.58, 21.38, 21.11, 18.14, 15.75.

Calcd. for C41H64O13Li [(M+Li)+] 771.4507, found: 771.4515.

References

[1]

Aldrich

Handbook

of

Fine

Chemicals

and

Laboratory

Equipment, p. 598, 2000 – 2001 catalog. [2]

This coupling has previously been observed.

(a) H. T. A.

Cheung, L. Brown, J. Boutagy, R. Thomas, J. Chem. Soc., Perkin Trans. 1 1981, 1773. the

published

(b) Our synthetic compound 1 also matches

tabulated

13

C

NMR

spectrum

of

digitoxin:

T.

Drakenberg, P. Brodelius, D. D. McIntyre, H. J. Vogel, Can. J. Chem. 1990, 68, 272.

20