Page 5 of 7
The Journal of Organic Chemistry
brine, dried over MgSO
was purified by flash chromatography on silica gel (hexane/EtOAc =
/1) to afford 5 (2.31 g, 4.89 mmol, 98%) as an orange amorphous: IR
CDCl ); 3407 (O–H), 2240 (C≡C), 1357 (O=S=O), 1165 (O=S=O);
H NMR (500 MHz, CDCl ) δ: 1.41 (d, J = 6.9 Hz, 3H), 2.00 (d, J =
.2 Hz, 1H), 2.40 (s, 3H), 3.08 (t, J = 7.7 Hz, 2H), 3.57-3.66 (m, 2H),
4
. After concentration in vacuo, the residue
To a solution of 7 (62.7 mg, 0.1 mmol) in DCM (1.0 mL) was added
(S)-DTBM-SEGPHOS(AuCl) (8.2 mg, 5 mol%) and NaBArF (8.9
1
2
3
4
5
6
7
8
9
2
2
(
1
mg, 10 mol%) at room temperature. After stirring for 24 h, the
reaction mixture was concentrated in vacuo. The residue was purified
by flash chromatography on silica gel (hexane/EtOAc = 3/1) to afford
8 (18.0 mg, 0.038 mmol 32%, 72% ee) as a yellow amorphous solid
[HPLC, Chiralcel-OD-H column eluting under condition with 65% i-
3
3
5
4.57-4.62 (m, 1H), 5.21 (s, 2H), 6.89 (s, 1H), 7.09 (m, 3H), 7.16 (t, J
= 7.7 Hz, 1H), 7.23-7.29 (m, 6H), 7.54 (d, J = 7.4 Hz, 1H), 7.71 (d, J
1
PrOH/n-hexane over 30 min at 0.80 mL/min, t = 17.66 min (minor
1
3
1
isomer), t = 25.44 min (major isomer)]].
=
8.0 Hz, 2H); C{ H} NMR (125 MHz, CDCl
3
) δ: 21.6, 24.2, 24.3,
2
4
1
1
9.8, 51.7, 58.4, 73.0, 77.5, 109.7, 110.6, 118.7, 119.2, 121.8, 126.6,
26.8 (2C), 127.5 (2C), 127.6, 127.8, 128.7 (2C), 129.6 (2C), 134.6,
36.5, 137.7, 144.5; HRMS (ESI) calcd for C28H N O S (MH )
29 2 3
4. Formal Synthesis of Vindorosine
+
+
NTs
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
473.1893, found 473.1887.
N-[2-(1-Benzyl-1H-indol-3-yl)ethyl]-4-methyl-N-{3-
(triisopropylsilyl)oxy]but-3-en-1-yn-1-yl}benzenesulfonamide (7).
To a solution of 5 (5.57 g, 11.8 mmol) in dry CH Cl (118 mL) was
added manganese dioxide (30.5 g, 353 mmol) at room temperature.
After stirring for 6 h, the reaction mixture was filtered through celite.
The filtrate was concentrated in vacuo to afford the corresponding
ketone 6. This material was used for the next reaction without further
purification because of its instability toward silica gel. To a solution
O
N
[
H
H
2
2
S3
(
6aS,11bS)-3-Tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-
d]carbazol-5(6H)-one (S3). A mixture of 8 (91.0 mg, 0.193 mmol)
and Pd(OH) /C (ca. 50% wt on carbon, 53 mg) in i-PrOH (1.0 mL)
was stirred under hydrogen atmosphere at rt for 12 h. The resulting
suspension was filtered through a celite pad and the pad was washed
with EtOAc. The filtrate was concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (CHCl
to afford S3 (21 mg, 0.055 mmol, 29%, 65% brsm) as a white solid:
mp 232–237 °C; IR (CDCl ): 1612 (C=O), 1360 (O=S=O), 1166
O=S=O); H NMR (500 MHz, CDCl ) δ: 1.98-2.07 (m, 2H), 2.23
dd, J = 16.0, 10.0 Hz, 1H), 2.50 (s, 3H), 2.54 (dd, J = 16.5, 6.5 Hz,
H), 3.76-3.82 (m, 2H), 3.93 (dd, J = 9.5, 6.5 Hz, 1H), 4.03-4.06 (m,
H), 6.02 (d, J = 7.5 Hz, 1H), 6.33 (s, 1H), 6.49-6.52 (m, 1H), 6.72
(d, J = 8.0 Hz, 1H), 7.07 (ddd, J = 7.5, 7.5, 1.5 Hz, 1H), 7.43 (d, J =
8.0 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H); C NMR{ H} (125 MHz,
CDCl ) δ: 21.7, 35.4, 40.8, 48.6, 54.8, 63.8, 106.5, 111.7, 119.7,
22.3, 127.3 (2C), 129.1, 129.8, 130.3 (2C), 134.7, 145.5, 147.5,
2
3 2 2
of the crude 6 and Et N (4.11 mL, 29.5 mmol) in dry CH Cl (118
mL) was added TIPSOTf (3.96 mL, 14.7 mmol) dropwise at −78 °C
under argon, and the reaction mixture was allowed to warm up to
room temperature. After stirring for 2 h, the reaction mixture was
3
/MeOH = 20/1)
3
diluted with sat. NH
organic extracts were washed with water and brine, dried over
Na SO . After concentration in vacuo, the residue was purified by
flash chromatography on NH silica gel (hexane/EtOAc = 12/1) to
afford 7 (7.21 g, 11.5 mmol, ca. 98%; including a small amount of
TIPSOH) as a pale yellow oil; IR (CDCl ): 2229 (C ≡ C), 1369
O=S=O), 1167 (O=S=O); H NMR (500 MHz, CDCl ) δ: 1.09 (d, J =
.5 Hz, 18H), 1.18-1.26 (m, 3H), 2.41 (s, 3H), 3.10 (t, J = 8.1 Hz,
4 2 2
Cl and extracted with CH Cl . The combined
1
(
(
1
1
3
2
4
2
3
1
3
1
1
(
3
3
7
1
1
2H), 3.64 (t, J = 7.8 Hz, 2H), 4.63 (s, 1H), 4.72 (s, 1H), 5.24 (s, 2H),
.92 (s, 1H), 7.08-7.12 (m, 3H), 7.17 (t, J = 7.0 Hz, 1H), 7.23-7.31
+
+
21 2 3
59.2, 196.2; HRMS (ESI) calcd for C21H N O S (MH ) 381.1267,
found 381.1266.
6
(
m, 6H), 7.55 (d, J = 7.5 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H); 13C{ H}
NMR (125 MHz, CDCl ) δ: 12.5 (3C), 17.9 (6C), 21.6, 24.3, 49.9,
2.0, 69.1, 79.8, 102.6, 109.7, 110.6, 118.7, 119.2, 121.9, 126.4,
126.8 (2C), 127.5 (2C), 127.6, 127.8, 128.7 (2C), 129.7 (2C), 134.7,
1
3
(
6aS,11bS)-7-Methyl-3-tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-
d]carbazol-5(6H)-one (11). A mixture of S3 (21.0 mg, 0.055 mmol)
and 37% HCHO aq. (170 µL) in CH Cl : MeOH (10 : 1) was added
to NaBH CN (14 mg, 0.221 mmol) at 0 °C. The reaction mixture was
adjusted to pH 3 and stirred for 1.5 h. The reaction mixture was
diluted with NaHCO and extracted with CH Cl . The combined
organic extracts were washed with brine, dried over Na SO . After
concentration in vacuo, the residue was purified by flash
chromatography on silica gel (CHCl /MeOH = 40/1) to afford 11 (22
5
2
2
+
47 2 3
136.5, 137.4, 139.6, 144.5; HRMS (ESI) calcd for C37H N O SSi
3
+
(MH ) 627.3071, found 627.3071.
3
2
2
3
. Gold-Catalyzed Cascade Cyclization
2
4
(6aR*,11bR*)-7-Benzyl-3-tosyl-2,3,6a,7-tetrahydro-1H-
pyrrolo[2,3-d]carbazol-5(6H)-one (8). To a solution of 7 (62.7 mg,
.1 mmol) in DCE (1 mL) was added IPrAuCl (3.1 mg, 5 mol%),
AgSbF (1.7 mg, 5 mol%) and i-PrOH (77 µL, 1.0 mmol) at room
3
mg, 0.055 mmol, quant.) as a white solid: [HPLC, Cosmosil CHiRAL
5B column eluting under condition with 55% i-PrOH/n-hexane over
0
6
3
0 min at 0.80 mL/min, t
1
= 17.84 min (minor isomer), t
): 1616 (C=O), 1357
O=S=O), 1168 (O=S=O); H NMR (500 MHz, DMSO-d ) δ: 1.75
dd, J = 17.0, 9.5 Hz, 1H), 1.86 (dd, J = 12.0, 5.0 Hz, 1H), 2.10-2.28
2
= 19.18 min
temperature. After stirring for 6 h, TBAF (ca. 1 M in THF, 150 µL,
0.15 mmol) was added. After stirring for 30 min at room temperature,
the reaction mixture was concentrated in vacuo. The residue was
purified by flash chromatography on silica gel (hexane/EtOAc = 3/1)
(
(
(
major isomer)]: mp 174–177 °C; IR (CDCl
3
1
6
(m, 1H), 2.45-2.48 (m, 4H), 2.67 (s, 3H), 3.70-3.76 (m, 1H), 4.01 (dd,
J = 10.0, 6.0 Hz, 1H), 4.07 (dd, J = 10.0, 8.0 Hz, 1H), 5.85 (d, J = 7.5
Hz, 1H), 5.93 (s, 1H), 6.40 (ddd, J = 7.0, 7.0, 1.0 Hz, 1H), 6.56 (d, J =
.0 Hz, 1H), 7.08 (ddd, J = 7.5, 7.5, 1.0 Hz, 1H), 7.57 (d, J = 8.0 Hz,
6
H), 7.96 (d, J = 8.5 Hz, 2H); C{ H} NMR (125 MHz, DMSO-d )
δ: 21.1, 31.4, 34.59, 34.62, 48.8, 53.4, 68.3, 105.5, 108.7, 117.9,
121.2, 127.2 (2C), 129.0, 130.6 (3C), 134.1, 145.8, 149.0, 159.4,
95.2; HRMS (ESI) calcd for C22
95.1425. The spectral date were in good agreement with those
to afford 8 (43.0 mg, 0.091 mmol, 91%) as a yellow solid: mp 180–
1
1
82 °C; IR (CDCl
NMR (500 MHz, CDCl
2.10-2.15 (m, 2H), 2.49 (s, 3H), 2.51 (dd, J = 16.6, 6.3 Hz, 1H), 3.76
dd, J = 10.3, 5.7 Hz, 1H), 3.80 (td, J = 10.9, 5.3 Hz, 1H), 3.96 (d, J =
3
): 1620 (C=O), 1360 (O=S=O), 1168 (O=S=O); H
3
) δ: 1.98 (ddd, J = 11.7, 11.7, 8.2 Hz, 1H),
8
2
13
1
(
1
1
4.9 Hz, 1H), 4.04 (dd, J = 10.0, 8.3 Hz, 1H), 4.43 (d, J = 14.9 Hz,
H), 6.02 (d, J = 6.9 Hz, 1H), 6.29 (s, 1H), 6.46 (m, 2H), 7.06-7.10
+
+
1
3
23 2 3
H N O S (MH ) 395.1424, found
(
m, 1H), 7.27-7.30 (m, 1H), 7.32-7.37 (m, 4H), 7.41 (d, J = 8.0 Hz,
1
3
1
2H), 7.88 (d, J = 8.6 Hz, 2H); C{ H} NMR (125 MHz, CDCl
3
) δ:
9d
previously reported.
2
1
1
C
1.6, 35.2, 35.4, 48.7, 48.9, 53.8, 67.4, 106.5, 109.1, 118.7, 122.0,
27.2 (2C), 127.6, 127.8 (2C), 128.7 (2C), 129.1, 130.3 (2C), 130.5,
34.6, 136.9, 145.5, 148.1, 159.4, 196.4; HRMS (ESI) calcd for
(6aS,11bS,E)-7-Benzyl-N-[(R)-2-(methoxymethyl)pyrrolidin-1-yl]-
3
-tosyl-2,3,6a,7-tetrahydro-1H-pyrrolo[2,3-d]carbazol-5(6H)-
imine (10). A mixture of 8 (100.0 mg, 0.21 mmol) and (R)-1-amino-
-(methoxymethyl)pyrrolidine 9 (56 µL, 0.043 mmol) in toluene (1.0
mL) was stirred at 95 °C for 24 h. The reaction mixture was
concentrated in vacuo. The residue was purified by flash
+
+
28
27 2 3
H N O S (MH ) 471.1737, found 471.1738.
2
Asymmetric Reaction Using DTBM-SEGPHOS(AuCl)
2
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