Synthesis of the Carbon Framework of Scholarisine A
FULL PAPER
1
3
Acetate 20: Ac
2
O (14 mL) was added to a solution of 19 (1.21 g, mixture)
Cl (25 mL)
3
(m), 7.59 ppm (m), 1H}; C NMR (125 MHz, CDCl ): d=21.39, 21.57,
and DMAP (60.3 mg 493 mmol) in pyridine (24 mL) and CH
2
2
22.28, 23.48, 27.27, 28.13, 29.31, 30.26, 34.09, 35.37, 35.63, 38.08, 40.55,
41.00, 46.31, 46.34, 60.21, 60.45, 73.39, 74.96, 107.28, 107.98, 109.17,
109.20, 117.63, 117.90, 119.32, 119.35, 120.97, 121.03, 125.82, 125.86,
127.28, 127.79, 128.17, 128.71, 128.72, 136.36, 136.47, 136.79, 137.13,
at ꢀ788C. The mixture was stirred for 3 h and warmed to room tempera-
ture. The solvents were removed under reduced pressure with toluene.
The crude product was purified by silica-gel column chromatography
ꢀ
1
(
AcOEt/n-hexane=3:97) to afford 20 (1.12 g, 2 steps 56%) as a colorless
138.16, 138.19, 170. 62, 170.66 ppm; IR (Zn-Se): n˜ =3423 (br), 1730 cm
;
:
1
+
oil. H NMR (500 MHz, CDCl
3
): d=0.00–0.02 (m, 6H), {0.87 (s), 0.88
MS (EI): m/z: 391 [M ]; HRMS (EI): m/z: calcd for C25
H
29NO
3
+
(
s), 9H}, 1.26–1.76 (m, 4H), {1.85 (s), 1.94 (s), 3H}, 2.22–2.32 (m, 1H),
391.2146 [M ]; found: 391.2145.
2
1
.99–3.20 (m, 2H), 3.46–3.60 (m, 2H), 4.85- 5.02 (m, 2H), 5.16–5.25 (m,
H), 5.30–5.63 (m, 3H), 5.39 (s, 2H), {6.72 (dd, J=18.0, 10.9 Hz), 6.72
Carboxylic acid 5: IBX (3.66 g, 13.1 mmol) was added to a solution of 23
2.55 g, 6.51 mmol) in DMSO (45 mL). The mixture was stirred at room
(
(
dd, J=17.9, 11.9 Hz), 1H}, 6.98 (d, J=7.3 Hz, 2H), 7.08–7.30 (m, 6H),
temperature for 2 h, then the reaction was quenched with pH 7 buffer.
The mixture was filtered through Celite and extracted with CH Cl . The
1
3
7
.68 ppm (d, J=7.4 Hz, 1H); C NMR (CDCl
3
, 125 MHz): d=ꢀ5.35,
2
2
ꢀ
5.33, 14.17, 18.24, 21.18, 21.23, 25.91, 25.93, 29.80, 30. 21, 36.95, 37.66,
combined organic layers were concentrated under reduced pressure. The
residue was dissolved in CH Cl again and the solution was washed with
3
1
1
1
7.81, 38.18, 39.16, 39.58, 47.33, 47.34, 60.61, 60.76, 61.93, 72.75, 73.20,
09.44, 110.44, 110.57, 114.71, 115.77, 118.60, 118.64, 119.45, 119.62,
19.67, 122.40, 125.81, 127.14, 127.15, 128.36, 128.38, 128.71, 135.20,
35.22, 137.30, 137.33, 138.01, 138.02, 141.16, 141.97, 170.32, 170.43 ppm;
2
2
H O. The organic layer was dried over Na SO and concentrated under
2
2
4
reduced pressure to afford 24 (2.32 g, mixture). The crude product was
used for the next reaction without further purification.
ꢀ
1
+
IR (Zn-Se): n˜ =1736 cm ; MS (EI): m/z: 531 [M ]; HRMS (EI): m/z:
calcd for C33
NaOH (898 mg, 22.4 mmol) in EtOH/H
solution of the above aldehyde 24 and AgNO
2
O=9:1 (20 mL) was added to a
(1.52 g, 8.95 mmol) in
+
45 3
H O NSi: 531.3169 [M ]; found: 531.3149.
3
Alkene 21: A solution of second-generation Grubbs catalyst (555 mg,
EtOH/H O=9:1 (30 mL) and THF (17 mL) was added at 08C. The mix-
2
6
1
5.4 mmol) in toluene (10 mL) was added to a solution of 20 (5.69 g,
0.7 mmol) in toluene (500 mL). The mixture was stirred with heating at
ture was stirred for 1 h at 08C. Brine and Et O were added and the
2
whole solution was acidified with 2m aqueous HCl (!pH 1) and extract-
reflux for 13 h and the solvent was removed under reduced pressure. The
crude product was purified by silica-gel column chromatography
ed with Et O. The combined organic layers were dried over Na SO and
2
2
4
concentrated under reduced pressure to afford 25 (2.42 g, mixture). The
(
AcOEt/n-hexane=4:96) to afford 21 (5.26 g, 96%) as a pale yellow oil.
crude product was used for the next reaction without further purification.
1
H NMR (500 MHz, CDCl
(
3
(
7
7
1
6
1
1
1
3
): d={ꢀ0.03 (s), ꢀ0.02 (s), 6H}, {0.80 (s), 0.82
K
2
CO
in MeOH (57 mL) and THF (34 mL). The reaction mixture was stirred at
08C for 2 h and the solvent was removed under reduced pressure.
CH Cl and water were added and the mixture was acidified with 2m
3
(4.12 g, 29.8 mmol) was added to a solution of 25 (2.42 g, mixture)
s), 9H}, 1.56–1.97 (m, 4H), {2.00 (s), 2.09 (s), 3H}, 2.20–3.10 (m,2H),
.21–3.57 (m, 3H), {4.95 (m), 5.45 (m), 1H}, 5.30 (m, 2H), {5.73 (m), 5.89
m), 1H}, {6.34 (d, J=11.2 Hz), 6.37 (d, J=11.2 Hz), 1H}, 6.99 (d, J=
.4 Hz, 2H), 7.08–7.25 (m, 6H), {7.52 (d, J=7.9 Hz), 7.67 ppm (d, J=
5
2
2
aqueous HCl (to pH 1). The organic layer was separated and the aqueous
layer was extracted with AcOEt. The combined organic layers were
washed with brine, dried over Na SO , and concentrated under reduced
2 4
1
3
.2 Hz), 1H}; C NMR (CDCl
3
, 125 MHz): d=ꢀ5.37, ꢀ5.32, 14.19, 18.18,
8.19, 21.04, 21.45, 21.57, 25.81, 25.85, 38.11, 41.19, 46.87, 47.16, 60.38,
0.88, 61.10, 73.23, 109.15, 109.24, 117.39, 118.43, 118.83, 119.33, 119.50,
21.98, 122.12, 126.04, 126.13, 127.24, 127.27, 128.18, 128.65, 128.67,
35.38, 136.69, 136.76, 137.91, 137.94, 170.58, 171.13 ppm; IR (Zn-Se): n˜ =
pressure. The crude product was purified by silica-gel column chromatog-
raphy (AcOEt/n-hexane=1:3 (+0.5% AcOH)) to afford 5 (2.16 g, 3
1
steps 91%) as a yellow amorphous solid. H NMR (500 MHz, CDCl
3
):
ꢀ
1
+
730 cm
;
MS (EI): m/z: 503 [M ]; HRMS (EI): m/z: calcd for
NSi: 503.2856 [M ]; found: 503.2848.
d=1.24–1.36 (m, 1H), 1.42–1.70 (m, 3H), 2.08–2.26 (m, 3H), {2.76–3.02
m), 3.10 (m), 3.28 (m), 4H}, {3.94 (m), 4.24 (m), 1H}, 5.32 (d, J=
17.2 Hz, 1H), 5.35 (d, J=17.2 Hz, 1H), 6.96 (m, 2H), 7.11–7.16 (m, 2H),
+
C
31
H
41
O
3
(
Cyclooctane 22: PtO
5.26 g, 10.4 mmol) in MeOH (150 mL) and benzene (50 mL). Hydrogen
was admitted through a balloon and the reaction mixture was stirred for
2 h. The catalyst was removed by filtration through Celite, and the sol-
2
(474 mg, 2.09 mmol) was added to a solution of 21
1
3
(
3
7.20–7.29 (m, 4H), 7.59–7.66 ppm (m, 1H); C NMR (125 MHz, CDCl ):
d=22.28, 23.19, 27.71, 30.28, 30.32, 31.97, 33.65, 35.23, 39.22, 41.82, 42.29,
42.60, 46.29, 46.33, 70.02, 72.43, 107.71, 108.94, 109.17, 109.24, 117.80,
117.98, 119.38, 119.41, 121.03, 121.07, 125.80, 125.86, 127.30, 128.00,
128.17, 128.72, 136.38, 136.40, 136.49, 136.63, 138.16, 138.19, 177.89,
2
vent was removed under reduced pressure. The crude product was puri-
fied by silica-gel column chromatography (AcOEt/n-hexane=5:95) to
afford 22 (5.27 g, mixture) as a colorless oil. H NMR (500 MHz, CDCl
1
ꢀ1
):
178.13 ppm; IR (Zn-Se): n˜ =3362 (br), 1705 cm ; MS (FAB): m/z: 363
3
+
+
d={ꢀ0.04 (s), ꢀ0.03 (s), 0.01 (s), 6 H}, {0.79 (s), 0.85 (s), 9H}, 1.20–1.86
m, 7H), {1.99 (s), 2.11 (s), 3H}, 2.73–3.30 (m, 4H), 3.45–3.58 (m, 2H),
4.82 (m), 5.26 (m), 1H}, {5.30 (d, J=17.6 Hz), 5.34 (d, 17.5 Hz), 2H},
[M ]; HRMS (EI): m/z: calcd for C23
H
25NO
3
: 363.1835 [M ]; found:
(
{
6
7
363.1832.
Hydroxycarboxylic acid 26: Compound 5 (1.42 g, 3.91 mmol) was added
.97 (d, J=7.8 Hz, 2H), 7.07–7.14 (m, 2H), 7.18–7.29 (m, 4H), {7.51 (m),
to a solution of Na (931 mg, 40.5 mmol) in liq. NH (ca. 20 mL) in THF
3
1
3
.58 ppm (m), 1H}; C NMR (CDCl
3
,
125 MHz): d=ꢀ5.40, ꢀ5.32,
(14 mL) at ꢀ788C. The mixture was stirred at ꢀ788C for 3.5 h. The reac-
ꢀ
5.28, 18.13, 18.25, 21.46, 21.58, 22.46, 23.63, 25.81, 25.89, 27.39, 29.02.,
tion was quenched with solid NH Cl and the whole was warmed up to
4
2
7
1
1
1
9.13, 30.12, 34.02, 38.39, 41.11, 41.49, 46.33, 46.34, 60.81, 61.19, 73.11,
4.66, 107.36, 107.88, 109.09, 109.13, 117.68, 118.01, 119.28, 119.31, 120.91,
20.97, 125.85, 125.88, 127.27, 127.92, 128.35, 128.72, 128.73, 136.35,
36.49, 136.89, 137.14, 138.18, 138.25, 170.34, 170.80 ppm; IR (Zn-Se): n˜ =
room temperature. Then, H O and Et O were added and the mixture was
2
2
acidified with 6m HCl (!pH 1), then extracted with AcOEt. The com-
bined organic layers were dried over Na SO and concentrated under re-
2
4
duced pressure. The crude product was purified by silica-gel column
chromatography (AcOEt/n-hexane=9:1 (0.5% of AcOH was added)) to
afford 26 (3.77 g, 96%) as a white amorphous solid.
ꢀ
1
+
731 cm
;
MS (EI): m/z: 505 [M ]; HRMS (EI): m/z: calcd for
+
C
31
H
43
O
3
NSi: 505.3012 [M ]; found: 505.3026.
Alcohol 23: HF·pyridine (7:3, 3 mL) was added to a solution of 22
5.27 g, mixture) and pyridine (10 mL) in THF (120 mL) at room temper-
ature. The reaction mixture was stirred for 11 h, then the reaction was
quenched with saturated aq. CuSO and the aqueous layer was extracted
with Et O. The combined organic layers were washed with brine, dried
over Na SO , and concentrated in vacuo. The crude mixture was purified
by silica-gel column chromatography (AcOEt/hexane=1:9) to afford 23
cis and trans isomers of 26 were partially separated by silica-gel column
(
chromatography (MeOH/CHCl /AcOH=10:200:1). cis-26: white amor-
3
1
phous solid. H NMR (500 MHz, CDCl ): d=1.39–1.56 (m, 2H), 1.58–
3
4
1.68 (m, 2H), 1.70 (m, 1H), 1.80 (m, 1H), 2.29 (d, J=7.3 Hz, 2H), 2.83
(m, 1H), 2.92 (m, 1H), 2.96 (dd, J=14.7, 6.9 Hz, 1H), 3.16 (dd, J=14.7,
3.4 Hz, 1H), 3.95 (m, 1H), 7.11 (dt, J=7.1, 1.1 Hz, 1H), 7.12 (dt, J=7.2,
1.3 Hz, 1H), 7.28 (dd, J=7.2, 1.1 Hz, 1H), 7.57 (dd, J=7.1, 1.3 Hz, 1H),
2
2
4
1
13
(
2.55 g, 2 steps 62%) as a white amorphous solid. H NMR (500 MHz,
CDCl ): d=1.20–1.89 (m, 7H), {2.02 (s), 2.09 (s), 3H}, 2.76–2.88 (m, 1H),
2.90–3.02 (m), 3.12 (dd, J=14.7, 4.1 Hz), 3.24 (dd, J=14.7, 7.8 Hz), 3.28
7.89 (brs, 1H); C NMR (125 MHz, CDCl ): d=24.94, 30.90, 31.08,
3
3
34.44, 41.48, 42.82, 72.42, 107.09, 110.46, 117.75, 119.54, 121.11, 129.10,
ꢀ
1
{
135.02, 135.34, 177.55; IR (Zn-Se): n˜ =3392 (br), 1704 cm ; MS (EI): m/
+
+
(
2
dd, J=14.7, 2.6 Hz), 3H}, {4.78 (m), 5.29 (m), 1H}, 5.34 (d, J=17.2 Hz,
H), 6.98 (d, J=7.1 Hz, 2H), 7.09–7.16 (m, 4H), 7.20–7.30 (m, 4H), {7.53
z: 273 [M ]; HRMS (EI): m/z: calcd for C16
found: 273.1359. trans-26: white amorphous solid. H NMR (500 MHz,
H
19NO
3
: 273.1365 [M ];
1
Chem. Eur. J. 2013, 19, 4255 – 4261
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4259