5
92
Synthesis
Q. Dou, Z. Jiang
Paper
Method 2: TCCA (225 mg, 0.95 mmol) dissolved in acetone (10 mL)
was added dropwise to a stirred solution of 2 (1.00 g, 2.45 mmol) in
freshly distilled pyridine (0.225 mL, 2.85 mmol) and acetone (15 mL)
at 0 °C, followed by gentle heating to r.t. over 40 min. The reaction
was then quenched with sat. aq Na SO (15 mL) and the volatiles were
evaporated under reduced pressure. After extraction of the residue
with EtOAc (15 mL), the separated aqueous layer was extracted with
EtOAc (10 mL). The combined organic solutions were washed with aq
min under N2 atmosphere and then allowed to stir at r.t. for 15 min
prior to dilution with Et O (10 mL). The course of the reaction was
2
monitored by TLC. The mixture was evaporated under reduced pres-
sure to leave a light yellow solid, which was dissolved in EtOAc (15
mL) and the EtOAc layer was washed with brine (2 × 20 mL). The
EtOAc solution was dried (Na SO ) and concentrated. After the crude
2
3
2
4
product was recrystallized from ethanol twice, chromatography of
the residue on silica gel (eluent: EtOAc–CH Cl –PE, 1:1:6) gave 5 as a
2
2
1
M HCl (2 × 10 mL), sat. aq NaHCO (3 × 25 mL) and brine (2 × 20 mL),
white solid; yield: 0.96 g (87%); mp 210–211 °C (EtOH); [α]D25 –18.3
3
dried (Na SO ), and concentrated. The product was purified by silica
(c 1 g/100 mL CH Cl ).
2
4
2
2
gel column chromatography (eluent: EtOAc–PE, 1:5) to afford 3 as
IR (KBr): 3389 (N–H), 1743 and 1690 (C=O), 1127 (C–O), 710 and 650
cm (C–H).
2
5
white crystals; yield: 753 mg (76%); mp 133–135 °C (EtOH); [α]D
7.1 (c 1 g/100 mL CH Cl ).
–1
–
2
2
1
H NMR (400 MHz, CDCl /TMS): δ = 0.64 (3 H, s, 18-H), 0.90 (3 H, d,
3
IR (KBr): 3330 (O–H), 1743 and 1690 (C=O), 1123 cm–1 (C–O).
J = 6.4 Hz, 21-H), 0.96 (3 H, d, J = 6.4 Hz, 19-H), 2.04 (3 H, s), 2.43 (3 H,
s), 3.66 (3 H, s), 5.14 (1 H, m, 3α-H), 7.31 (2 H, d, J = 7.8 Hz), 7.84 (2 H,
1
H NMR (400 MHz, CDCl /TMS): δ = 0.70 (3 H, s, 18-H), 0.94 (3 H, d,
3
J = 6.4 Hz, 21-H), 1.03 (3 H, s, 19-H), 3.69 (3 H, s), 4.13 (1 H, m, 3α-H).
d, J = 7.8 Hz).
13
13
C NMR (100 MHz, CDCl /TMS): δ = 12.04, 18.26, 21.09, 22.84, 24.15,
C NMR (100 MHz, CDCl /TMS): δ = 12.01, 14.22, 18.25, 21.07, 21.44,
3
3
2
3
8.06, 30.94, 31.04, 34.36, 34.56, 35.31, 36.04, 36.21, 37.05, 37.09,
9.83, 40.27, 42.84, 50.18, 51.48, 55.94, 56.12, 67.62, 174.66, 212.71.
21.64, 22.81, 22.96, 28.06, 30.93, 30.97, 31.05, 34.39, 34.45, 35.31,
36.50, 39.76, 42.85, 45.42, 46.70, 51.53, 55.91, 56.05, 56.13, 70.75,
128.00, 128.10, 129.52, 129.57, 135.46, 143.93, 161.99, 170.48,
HRMS (ESI): m/z [M + Na]+ calcd for C25H40O Na: 427.2819; found:
4
174.70.
427.2814.
+
HRMS (ESI): m/z [M + Na] calcd for C34H50N O SNa: 637.3282; found:
2
6
637.3273.
Methyl 3α-Acetoxy-6-oxocholan-24-oate (4)
Method 1: Compound 3 (1.50 g, 3.71 mmol) dissolved in anhydrous
Methyl 3α-Acetoxychol-6-en-24-oate (6)
CH Cl (50 mL) was reacted with Ac O (0.42 mL, 4.45 mmol) in the
2
2
2
presence of Na CO (39.21 mg, 0.37 mmol). The mixture was allowed
A magnetically stirred solution of 5 (1.30 g, 2.12 mmol) in freshly dis-
tilled toluene (100 mL) was treated dropwise with a solution of LiH in
freshly distilled toluene (20 mL) over 10 min at 60 °C, and TMEDA
(0.22 mL) was then added dropwise. The suspension was warmed to
2
3
to stand for 8 h at r.t. and diluted with sat. aq NaHCO3 (10 mL). The
organic layer was then separated and the aqueous phase was extract-
ed with an additional amount of CH Cl (15 mL). The combined ex-
2
2
tracts were successively washed with aq 1 M HCl (2 × 15 mL), sat. aq
NaHCO3 (3 × 25 mL), and brine (2 × 25 mL). The organic layer was
dried (Na SO ) and filtered. The filtrate was evaporated under re-
90 °C at reflux under N atmosphere. The process of the reaction was
monitored by TLC. After stirring for 18 h, the reaction was quenched
2
with sat. aq NH Cl (12 mL) and filtered through a Celite pad. The fil-
2
4
4
duced pressure to leave 4 as a pale yellow solid, which was used in the
next step without purification; yield: 1.59 g (96%).
trate was evaporated under reduced pressure and extracted with
EtOAc (25 mL). The combined organic extracts were washed with sat.
aq NaHCO (2 × 25 mL) and brine (20 mL), dried (Na SO ) and filtered.
Method 2: To a stirred solution of 3 (300 mg, 0.74 mmol) in anhydrous
3
2
4
Evaporation of the solvent gave a brown oil, which was purified chro-
matographically on a silica gel column (eluent: EtOAc–CH Cl –PE,
CH Cl (15 mL) was added sequentially dropwise AcCl (0.06 mL, 0.81
2
2
mmol) and Et N (0.10 mL, 0.72 mmol). The mixture was stirred at r.t.
2
2
3
1
:5:50) to give the pure product 6 as a white solid; yield: 528 mg
overnight. After removal of volatiles, the mixture was acidified with
aq 1 M HCl (2 × 15 mL), basified with sat. aq NaHCO3 (2 × 10 mL),
washed with brine (20 mL), and filtered. The solid residue was puri-
fied on a silica gel column (4 cm × 5 cm) using EtOAc–PE (1:3) to af-
ford 4 as a pale yellow solid; yield: 231.0 mg (86%); mp 183–185 °C
25
(74%); mp 120–123 °C (EtOH); [α]D +3.1 (c, 1 g/100 mL CH Cl ).
2 2
IR (KBr): 3299 (C=C), 1743 and 1700 (C=O), 1127 cm–1 (C–O).
1
H NMR (400 MHz, CDCl /TMS): δ = 0.67 (3 H, s, 18-H), 0.92 (3 H, d,
3
J = 6.4 Hz, 21-H), 1.02 (3 H, s, 19-H), 2.07 (3 H, s), 3.67 (3 H, s), 5.14 (1
H, m, 3α-H), 5.68 (1 H, m, 6-H), 5.78 (1 H, m, 7-H).
25
(
EtOH); [α]D –9.4 (c 1 g/100 mL CH Cl ).
2 2
IR (KBr): 1770, 1743 and 1690 (C=O), 1123 cm–1 (C–O).
13
C NMR (100 MHz, CDCl /TMS): δ = 11.96, 18.28, 21.40, 21.45, 22.25,
3
1
H NMR (400 MHz, CDCl /TMS): δ = 0.70 (3 H, s, 18-H), 0.94 (3 H, d,
22.83, 24.15, 28.07, 31.00, 31.05, 32.79, 33.81, 34.63, 35.26, 35.32,
39.99, 40.25, 42.85, 46.98, 51.49, 55.87, 55.91, 71.86, 125.11, 128.13,
170.58, 174.76.
3
J = 6.4 Hz, 21-H), 1.09 (3 H, s, 19-H), 2.03 (3 H, s), 3.69 (3 H, s), 5.19 (1
H, m, 3α-H).
13
HRMS (ESI): m/z [M + Na]+ calcd for C27H42O Na: 453.2975; found:
C NMR (100 MHz, CDCl /TMS): δ = 12.02, 18.26, 21.03, 21.20, 22.63,
3
4
2
3
1
4.05, 28.04, 30.91, 30.93, 31.02, 34.43, 35.29, 36.31, 36.77, 36.85,
6.89, 39.78, 40.32, 42.88, 47.09, 51.45, 55.92, 56.12, 70.56, 170.24,
74.58, 211.85.
453.2946.
Methyl 3α-Acetoxy-6,7-epoxycholan-24-oate (7)
HRMS (ESI): m/z [M + Na]+ calcd for C27H42O : 469.2924; found:
5
m-CPBA (3-chloroperbenzoic acid, 324 mg, 1.88 mmol) dissolved in
469.2915.
anhydrous CH Cl (10 mL) was added dropwise at 0 °C to a stirred
2
2
solution of 6 (675 mg, 1.57 mmol) in anhydrous CH Cl (15 mL) over
2
2
Methyl 3α-Acetoxy-6-[2-[(4-methylphenyl)sulfonyl]hydrazinyl-
idene]cholan-24-oate (5)
15 min. The reaction mixture was allowed to reach 35 °C and stirred
for 1 h and the course of reaction was monitored by TLC. The reaction
was quenched with sat. aq Na SO (20 mL) and evaporated under re-
p-Toluenesulfonyl hydrazone (0.40 g, 2.15 mmol) was added in five
portions to a stirred solution of 4 (0.80 g, 1.79 mmol) in anhydrous
EtOH (15 mL) over 10 min. The mixture was heated at reflux for 45
2
3
duced pressure prior to extraction with Et O (20 mL). The combined
2
organic phases were washed with sat. aq Na SO (20 mL), sat. aq
2
3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 588–594