ChemMedChem
10.1002/cmdc.201900068
FULL PAPER
-
acetate = 3/1, R
f
= 0.26) to give 24 as colorless solid (1.3 g, 3.3 mmol,
[M-H] calcd for C15
17
H O
6
: 293.1031, found: 293.1019; HPLC (method 1):
ꢄꢅ
6
CH
8 % yield). Melting point: 134 °C; specific rotation: ꢀꢁꢂ ꢃ = -40.5 (4.2,
R
t = 16.9 min, purity 94.0 %.
1
2 2
Cl
); H NMR (CDCl
CH ), 4.37 (d, J = 4.6 Hz, 1H, 4-H), 4.61 (d, J = 3.5 Hz,
Ph,
3 3 3
): ꢈ [ppm] = 1.28 (s, 3H, CH ), 1.47 (s, 3H, CH ),
3
1
3
7
H
.85 (s, 3H, CO
2
3
Methyl
[(trifluoromethyl)sulfonyl]oxy}phenyl)tetrahydrofuro[3,4-
d][1,3]dioxole-4-carboxylate (27): Under N atmosphere, triethylamine
1.5 mL, 110 mg, 1.1 mmol) was added to a solution of 26 (110 mg, 0.37
mmol) in dry dichloromethane (20 mL) and the mixture was cooled to
20 °C. Then a 1 M solution of trifluoromethanesulfonic anhydride in
(3aS,4R,6S,6aS)-2,2-dimethyl-6-(4-
H, 6-H), 4.77 (dd, J = 5.9/3.5 Hz, 1H, 6a-H), 5.02 – 5.11 (m, 3H, OCH
a-H), 6.95 – 7.00 (m, 2H, 3''-H4-(benzyloxy)phenyl, 5''-H4-(benzyloxy)phenyl), 7.29 –
.48 (m, 7H, 2''-H4-(benzyloxy)phenyl, 6''-H4-(benzyloxy)phenyl, 2'-Hphenyl, 3'-Hphenyl, 4'-
2
{
2
(
13
phenyl, 5'-Hphenyl, 6'-Hphenyl); C NMR (CDCl
3
): ꢈ [ppm] = 25.0 (1C,
3
C(CH )
2
), 25.8 (1C, C(CH
3
)
2
), 52.2 (1C, CO
2
CH ), 70.1 (1C, OCH Ph),
3
2
-
8
0.7 (1C, C-4), 81.8 (1C, C-6a), 82.0 (1C, C-3a), 83.3 (1C, C-6), 113.4 (1C,
dichloromethane (0.6 mL, 0.6 mmol) was added dropwise and the reaction
mixture was stirred for 30 min at -20 °C. Afterwards, a saturated aqueous
solution of sodium bicarbonate was added and the mixture was extracted
with dichloromethane (3×). The combined organic layers were dried
C(CH
3
)
2
), 114.5 (2C, C-3''4-(benzyloxy)phenyl, C-5''4-(benzyloxy)phenyl), 127.1 (1C, C-
1
1
5
''4-(benzyloxy)phenyl), 127.7 (2C, C-2'phenyl, C-6'phenyl), 128.1 (1C, C-4'phenyl),
28.7 (2C, C-2''4-(benzyloxy)phenyl, C-6''4-(benzyloxy)phenyl), 129.2 (2C, C-3'phenyl, C-
'
phenyl), 137.2 (1C, C-1'phenyl), 158.9 (1C, C-4''4-(benzyloxy)phenyl), 167.9 (1C,
(
Na
purified by flash column chromatography (Ø = 3 cm, h = 15 cm, V = 30 mL,
petroleum ether/ethyl acetate = 2/1, R = 0.63) to give 27 as colorless oil
2 4
SO ), filtered, and the solvent was removed in vacuo. The residue was
-1
2 3
CO CH ); IR (neat): ꢆꢇ [cm ] = 2992, 2956, 2898, 2875, 1759, 1613, 1515,
1454, 1385, 1255, 1221, 1204, 1171, 1126, 1095, 1026, 856, 829, 817,
f
]+ calcd for C22
ꢄꢅ
736, 550, 518, 463; LCMS (m/z): [M+NH
4
H28NO : 402.1911,
6
(130 mg, 0.30 mmol, 82 % yield). Specific rotation: ꢀꢁꢂ ꢃ = -5.6 (6.4,
found: 402.1935; HPLC (method 1): t
R
= 22.3 min, purity 99.7 %.
1
2 2
CH Cl ); H NMR (DMSO-d
6 3
): ꢈ [ppm] = 1.29 (s, 3H, CH ), 1.41 (s, 3H,
3
CH ), 3.68 (s, 3H, CO
2
CH ), 4.72 (d, J = 5.1 Hz, 1H, 4-H), 4.92 (dd, J =
3
Methyl
(3aS,4R,6S,6aS)-6-[4-(benzyloxy)phenyl]-2,2-
(25):
6.1/2.2 Hz, 1H, 6a-H), 5.08 – 5.12 (m, 1H, 3a-H), 5.25 – 5.27 (m, 1H, 6-H),
7.48 – 7.53 (m, 2H, 3'-Hphenyl, 5'-Hphenyl), 7.53 – 7.58 (m, 2H, 2'-Hphenyl, 6'-
dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylate
Erbium(III) trifluoromethanesulfonate (100 mg, 0.16 mmol) was added to a
solution of 24 (1.2 g, 3.1 mmol) in dry ACN (10 mL). The reaction mixture
was heated under microwave irradiation for 30 min at 120 °C and 200 W.
Then a saturated aqueous solution of sodium bicarbonate was added. The
mixture was extracted with ethyl acetate (3×) and the combined organic
H
phenyl); 13C NMR (DMSO-d
C(CH ), 51.6 (1C, CO CH
C-6), 85.7 (1C, C-6a), 113.0 (1C, C(CH
121.6 (2C, C-3'phenyl, C-5'phenyl), 128.2 (2C, C-2'phenyl, C-6'phenyl), 139.2 (1C,
6
): ꢈ [ppm] = 25.0 (1C, C(CH
), 79.7 (1C, C-4), 81.2 (1C, C-3a), 83.7 (1C,
), 118.2 (q, J = 322 Hz, 1C, CF ),
3 2
) ), 26.1 (1C,
3
)
2
2
3
3
)
2
3
-1
C-1'phenyl), 148.5 (1C, C-4'phenyl), 168.0 (1C, CO
2991, 2955, 1762, 1501, 1421, 1375, 1205, 1137, 1103, 883, 607, 528;
HRMS (m/z): [M+Na]+ calcd for
NaO S: 449.0488, found:
2 3
CH ); IR (neat): ꢆꢇ [cm ] =
layers were dried (Na
The residue was purified by flash column chromatography (Ø = 5 cm, h =
5 cm, V = 65 mL, cyclohexane/ethyl acetate = 2/1, R = 0.53) to give 25
as colorless solid (320 mg, 0.83 mmol, 26 % yield). Melting point: 102 °C;
2 4
SO ), filtered, and the solvent was removed in vacuo.
C H F
16 17 3
8
1
f
449.0494; HPLC (method 1): t
R
= 24.0 min, purity 97.2 %.
ꢄꢅ
); 1H NMR (DMSO-d
CH ), 4.63 (d, J =
specific rotation: ꢀꢁꢂ ꢃ = -2.8 (5.3, CH
2
Cl
), 3.67 (s, 3H, CO
.1 Hz, 1H, 4-H), 4.88 (dd, J = 6.1/2.1 Hz, 1H, 6a-H), 5.07 – 5.15 (m, 4H,
a-H, 6-H, OCH
2
6
): ꢈ [ppm]
Methyl
(2R,3S,4R,5S)-3,4-dihydroxy-5-(4-
=
5
3
1.28 (s, 3H, CH
3
), 1.40 (s, 3H, CH
3
2
3
{
[(trifluoromethyl)sulfonyl]oxy}phenyl)tetrahydrofuran-2-
carboxylate (28): p-Toluenesulfonic acid monohydrate (22 mg,
.11 mmol) was added to a solution of 27 (490 mg, 1.1 mmol) in methanol
10 mL). The mixture was heated under microwave irradiation for 30 min
2
Ph), 6.98 – 7.03 (m, 2H, 3''-H4-(benzyloxy)phenyl, 5''-H4-
0
(
(
benzyloxy)phenyl), 7.23 – 7.29 (m, 2H, 2''-H4-(benzyloxy)phenyl, 6''-H4-(benzyloxy)phenyl),
7
–
.29 – 7.35 (m, 1H, 4'-Hphenyl), 7.35 – 7.42 (m, 2H, 3'-Hphenyl, 5'-Hphenyl), 7.42
7.47 (m, 2H, 2'-Hphenyl, 6'-Hphenyl); 13C NMR (DMSO-d
): ꢈ [ppm] = 25.0
), 26.1 (1C, C(CH ), 51.5 (1C, CO CH ), 69.2 (1C, OCH Ph),
9.3 (1C, C-4), 81.3 (1C, C-3a), 84.1 (1C, C-6), 85.5 (1C, C-6a), 112.8 (1C,
at 120 °C and 100 W. Afterwards, the solvent was removed in vacuo and
the residue was purified by flash column chromatography (Ø = 3 cm, h =
6
(1C, C(CH
3
)
2
3
)
2
2
3
2
15 cm, V = 30 mL, petroleum ether/ethyl acetate = 1/2, R
f
= 0.32) to give
7
28 as colorless solid (420 g, 1.1 mmol, 94% yield). Melting point: 114 °C;
ꢄꢅ
1
3
C(CH )
2
), 114.9 (2C, C-3''4-(benzyloxy)phenyl, C-5''4-(benzyloxy)phenyl), 127.5 (2C, C-
''4-(benzyloxy)phenyl, C-6''4-(benzyloxy)phenyl), 127.6 (2C, C-2'phenyl, C-6'phenyl), 127.8
1C, C-4'phenyl), 128.5 (2C, C-3'phenyl C-5'phenyl), 130.2 (1C, C-1''4-
benzyloxy)phenyl), 137.1 (1C, C-1'phenyl), 157.9 (1C, C-4''4-(benzyloxy)phenyl), 168.2
specific rotation: ꢀꢁꢂ ꢃ = -8.7 (4.5, methanol); H NMR (DMSO-d
6
): ꢈ [ppm]
), 3.74 – 3.81 (m, 1H, 4-H), 4.30 (q, J = 4.5 Hz, 1H,
-H), 4.75 (d, J = 9.1 Hz, 1H, 5-H), 4.93 (d, J = 4.4 Hz, 1H, 2-H), 5.28 (d,
2
(
=
3
2 3
3.66 (s, 3H, CO CH
,
(
J = 8.2 Hz, 1H, C-4-OH), 5.51 (d, J = 4.6 Hz, 1H, C-3-OH), 7.46 – 7.51 (m,
H, 3'-Hphenyl, 5'-Hphenyl), 7.53 – 7.58 (m, 2H, 2'-Hphenyl, 6'-Hphenyl); 13C NMR
-1
(
1C, CO
380, 1248, 1206, 1176, 1066, 1043, 976, 948, 856, 824, 732; HRMS
m/z): [M+Na]+ calcd for C22
: 407.1465, found: 407.1465; HPLC
method 1): t = 24.1 min, purity 98.1 %.
2 3
CH ); IR (neat): ꢆꢇ [cm ] = 2934, 2918, 2850, 1731, 1612, 1514,
2
1
(DMSO-d ): ꢈ [ppm] = 51.3 (1C, CO CH ), 72.0 (1C, C-3), 78.4 (1C, C-4),
6
2
3
(
(
H24NaO
6
80.2 (1C, C-2), 80.7 (1C, C-5), 118.2 (q, J = 320 Hz, 1C, CF ), 121.2 (2C,
3
R
C-3'phenyl, C-5'phenyl), 128.2 (2C, C-2'phenyl, C-6'phenyl), 141.8 (1C, C-1'phenyl),
-1
1
48.5 (1C, C-4'phenyl), 169.8 (1C, CO
2939, 2867, 1755, 1727, 1501, 1418, 1199, 1129, 1102, 1081, 1058, 1014,
887, 833, 602, 532; HRMS (m/z): [M+Na]+ calcd for C13
NaO S:
409.0175, found: 409.0133; HPLC (method 1): t = 19.3 min, purity 97.8 %.
2 3
CH ); IR (neat): ꢆꢇ [cm ] = 3532, 3396,
Methyl
(3aS,4R,6S,6aS)-6-(4-hydroxyphenyl)-2,2-
(26):
dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylate
H F
13 3
8
Palladium on activated charcoal (10 % Pd, 67 mg) was added to a solution
R
of 25 (670 mg, 1.7 mmol) in dry methanol (50 mL) and the mixture was
2
stirred overnight under H atmosphere. Afterwards, the mixture was filtered
through Celite® 545 and the solvent was removed in vacuo. The residue
was purified by flash column chromatography (Ø = 3 cm, h = 15 cm, V =
Methyl
(2R,3S,4R,5S)-3,4-dihydroxy-5-(4-{[4-
(morpholinomethyl)phenyl]ethynyl}phenyl)tetrahydrofuran-2-
2
carboxylate (29): Under N atmosphere, copper(I) iodide (40 mg, 0.21
3
0 mL, petroleum ether/ethyl acetate = 2/1, R
f
= 0.31) to give 26 as
mmol), tetrakis(triphenylphosphine)palladium(0) (130 mg, 0.11 mmol) and
triethylamine (1.0 mL, 760 mg, 7.5 mmol) were added to a solution of 28
(420 mg, 1.1 mmol) in dry ACN (50 mL). Then a solution of 4-
colorless solid (410 mg, 1.4 mmol, 80 % yield). Melting point: 168 °C;
ꢄꢅ
specific rotation: ꢀꢁꢂ ꢃ = -16.0 (5.3, methanol); 1H NMR (DMSO-d
ppm] = 1.27 (s, 3H, CH ), 1.39 (s, 3H, CH ), 3.66 (s, 3H, CO CH ), 4.60
d, J = 5.2 Hz, 1H, 4-H), 4.86 (dd, J = 6.1/2.1 Hz, 1H, 6a-H), 5.05 – 5.08
m, 1H, 6-H), 5.08 – 5.13 (m, 1H, 3a-H), 6.71 – 6.78 (m, 2H, 3'-Hphenyl, 5'-
phenyl), 7.09 – 7.16 (m, 2H, 2'-Hphenyl, 6'-Hphenyl), 9.46 (s, 1H, OH); 13C NMR
DMSO-d ): ꢈ [ppm] = 25.0 (1C, C(CH ), 26.1 (1C, C(CH ), 51.5 (1C,
), 79.2 (1C, C-4), 81.3 (1C, C-3a), 84.3 (1C, C-6), 85.4 (1C, C-6a),
), 115.2 (2C, C-3'phenyl, C-5'phenyl), 127.5 (2C, C-2'phenyl
C-6'phenyl), 128.1 (1C, C-1'phenyl), 157.0 (1C, C-4'phenyl), 168.3 (1C, CO CH );
IR (neat): ꢆꢇ [cm ] = 3376, 2946, 1744, 1614, 1593, 1521, 1441, 1371,
231, 1183, 1107, 1073, 1048, 851, 838, 784, 597 529, 516; HRMS (m/z):
6
): ꢈ
[
(
(
H
(
3
3
2
3
(morpholinomethyl)phenylacetylene (430 mg, 2.1 mmol) in dry ACN (5 mL)
was added dropwise over a period of 30 min at ambient temperature and
the reaction mixture was heated to reflux overnight. Afterwards, the solvent
was removed in vacuo and the residue was purified by flash column
6
3
)
2
3 2
)
2 2
chromatography (Ø = 3 cm, h = 15 cm, V = 30 mL, CH Cl /methanol = 19/1,
2 3
CO CH
R
f
= 0.38) to give 29 as colorless solid (150 mg, 0.35 mmol, 33% yield).
ꢄꢅ
1
112.7 (1C, C(CH
3
)
2
,
Melting point: 169 °C; specific rotation: ꢀꢁꢂ ꢃ = -7.1 (4.5, ethyl acetate); H
NMR (DMSO-d ): ꢈ [ppm] = 2.30 – 2.41 (m, 4H, NCH CH ), 3.49 (s, 2H,
PhCH N), 3.55 – 3.61 (m, 4H, NCH CH ), 3.66 (s, 3H, CO CH ), 3.75 –
.83 (m, 1H, 4-H), 4.30 (q, J = 4.5 Hz, 1H, 3-H), 4.72 (d, J = 9.0 Hz, 1H, 5-
2
3
6
2
2
-1
2
2
2
2
3
1
3
9
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