Novel asymmetric total syntheses of (R)-(-)-pyridindolol, (R)-(-)-pyridindolol K1, and (R)-(-)-pyridindolol K2 via a mild one-pot aromatization of N-tosyl-tetrahydro-β-carboline with (S)-2,3-O- isopropylidene-l-glyceraldehyde as the source of chirality

Article abstract of DOI:10.1016/j.tetasy.2013.04.009

Novel total syntheses of (R)-(-)-pyridindolol 1, (R)-(-)-pyridindolol K1 2, and (R)-(-)-pyridindolol K2 3 are described. By using l-tryptophan methyl ester and (S)-2,3-O-isopropylidene-l-glyceraldehyde as the starting materials, (R)-(-)-pyridindolol 1, (R)-(-)-pyridindolol K1 2, and (R)-(-)-pyridindolol K2 3 were synthesized in 5-7 steps in 66%, 41%, and 55% overall yields, respectively. The characteristic step of the total syntheses is a mild one-pot aromatization of N-tosyl-1,2,3,4-tetrahydro-β-carboline (N-Ts-THBC), which was obtained via Pictet-Spengler reaction of l-tryptophan methyl ester with (S)-2,3-O-isopropylidene-l-glyceraldehyde, and subsequent N-tosylation.

Full text of DOI:10.1016/j.tetasy.2013.04.009

Tetrahedron: Asymmetry 24 (2013) 633–637
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Novel asymmetric total syntheses of (R)-(ꢀ)-pyridindolol,
(R)-(ꢀ)-pyridindolol K1, and (R)-(ꢀ)-pyridindolol K2 via a mild one-pot
aromatization of N-tosyl-tetrahydro-b-carboline with
(S)-2,3-O-isopropylidene-L-glyceraldehyde as the source of chirality
⇑
Qiang Zhang, Zhen Fan, Jing Dong, Xiao-Xin Shi , Xia Lu
Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, 130 Mei-Long Road, Shanghai 200237, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 March 2013
Accepted 10 April 2013
Novel total syntheses of (R)-(ꢀ)-pyridindolol 1, (R)-(ꢀ)-pyridindolol K1 2, and (R)-(ꢀ)-pyridindolol K2 3
are described. By using L-tryptophan methyl ester and (S)-2,3-O-isopropylidene-L-glyceraldehyde as the
starting materials, (R)-(ꢀ)-pyridindolol 1, (R)-(ꢀ)-pyridindolol K1 2, and (R)-(ꢀ)-pyridindolol K2 3 were
synthesized in 5–7 steps in 66%, 41%, and 55% overall yields, respectively. The characteristic step of the
total syntheses is a mild one-pot aromatization of N-tosyl-1,2,3,4-tetrahydro-b-carboline (N-Ts-THBC),
which was obtained via Pictet–Spengler reaction of
L-tryptophan methyl ester with (S)-2,3-O-isopropyl-
idene- -glyceraldehyde, and subsequent N-tosylation.
L
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Cook et al. reported the first total synthesis of racemic pyridin-
dolol 1 and (S)-(+)-pyridindolol 1.7 Pandit et al. also reported a no-
vel approach to racemic pyridindolol 1.8,9 The first total syntheses
of (R)-(ꢀ)-pyridindolol K2 3 and its enantiomer were performed by
Hibino et al.10 By using the same strategy, Hibino et al. also per-
formed the total syntheses of (R)-(ꢀ)-pyridindolol 1, (R)-(ꢀ)-pyrid-
indolol K1 2, and (R)-(ꢀ)-pyridindolol K2 3.11
Pyridindolol 1 (Fig. 1) was first isolated from Streptomyces
alboverticillatus by Umezawa et al.;1 its structure and the (R)-abso-
lute configuration were also determined via X-ray crystallographic
analysis by Umezawa et al. later in the same year.2 Pyridindolol K1
2 and pyridindolol K2 3, together with pyridindolol 1, were
isolated from the culture broth of Streptomyces sp. K93-0711 by
Omura et al. in 1997.3 Biological studies have revealed that
pyridindolol 1 is a specific inhibitor of bovine liver b-galactosidase
under acidic conditions (optimal pH 4.0),1,4 and also inhibits the
activity of both bovin brain and heart PDE1’s.5,6 Pyridindolol K2 3
has shown an activity, which inhibits the adhesion of HL-60 cells
to a LPS-activated HUVES monolayer.3
In all of the aforementioned reported syntheses7–11 of the three
pyridindolols 1–3, thekey point shouldbe the strategyfor construct-
ing the b-carboline nucleus. Hibino et al. used a thermal electrocyc-
lization reaction to build the desired b-carboline nucleus.10,11 Cook7
and Pandit8 employed a two-step strategy to construct the b-carbo-
line nucleus, which involved a Pictet–Spengler reaction to form the
1,2,3,4-tetrahydro-b-carboline (THBCs) and the subsequent aroma-
tization of these intermediates via Pd/C-catalyzed dehydrogenation
or DDQ-mediated oxidation. However, Hibino’s thermal-electrocyc-
lization-based strategy required many steps,10,11 while Cook’s and
Pandit’s two-step strategy7,8 suffered from racemization of the ste-
16
3
OR1
4
5
6
12 11
9
pyridindolol 1: R1 = R2 = H
pyridindolol K1 2: R1 = R2 = Ac
pyridindolol K2 3: R1 = Ac, R2 = H
2
N
1
reogenic center of the L-acetonide moiety due to the harsh condi-
7
10
13
N
8
tions of the Pd/C-catalyzed dehydrogenation of THBCs, or suffered
from low yields during the DDQ-mediated oxidation of THBCs. Re-
cently, we have developed a very mild and efficient method for con-
structing the b-carboline nucleus.12 By applying this method, we
were able to efficiently and practically synthesize (R)-(ꢀ)-pyridin-
dolol 1, (R)-(ꢀ)-pyridindolol K1 2, and (R)-(ꢀ)-pyridindolol K2 3
(R)
H
14
OH
OR2
15
Figure 1. Structures of the three targeted b-carboline alkaloids.
starting from the readily available L
-tryptophan methyl ester13 and
(S)-2,3-O-isopropylidene-L
-glyceraldehyde;14,15 herein we report
⇑
Corresponding author. Tel.: +862164252052.
E-mail address: xxshi@ecust.edu.cn (X.-X. Shi).
our results in detail.
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.04.009

634
Q. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 633–637
Table 1
2. Results and discussion
Optimization of the reaction conditions for the one-pot conversion of N-Ts-THBC 5
into compound 6
As shown in Scheme 1, our synthetic efforts began with the Pic-
Yielda (%)
tet–Spengler reaction16,17 of -tryptophan methyl ester13 with (S)-
L
Entry
Solvent
Base (equiv)
Temperature (°C)
Time (h)
2,3-O-isopropylidene-
from
-ascorbic acid according to the literature.14,15 When
phan methyl ester was treated with (S)-2,3-O-isopropylidene-
L
-glyceraldehyde, which can be prepared
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
DMSOb
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMFe
DMF
None
NaHCO3 (5)
Et3N (5)
80
80
80
60
60
25
25
25
25
25
25
25
25
25
25
25
25
25
12
12
12
10
10
10
10
10
10
10
10
20
20
20
20
20
20
20
0
21
41
45
51
80
68
87
70
66
74
<5
<5
42
10
8
L
L
-trypto-
L-
Pyridine (3)
DMAPc (3)c
DBUd (3)
Na2CO3 (5)
K2CO3 (5)
DBU (3)
Na2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
glyceraldehyde (1.5 equiv.) and trifluoroacetic acid (3.0 equiv) at
0 °C in ethyl acetate, 1,2,3,4-tetrahydro-b-carboline (THBC) 4 was
obtained as a diastereomeric mixture of two epimers (cis/trans,
35:65) in 94% combined yield. The epimeric mixture of compound
4 could be used as such for the next step. Compound 4 was then
treated with p-toluenesulfonyl chloride (1.0 equiv), fine powdered
potassium carbonate (3.0 equiv) and pyridine (0.3 equiv) at 0 °C to
room temperature in dichloromethane, as a result, N-tosyl-1,2,3,4-
tetrahydro-b-carboline (N-Ts-THBC) 5 was obtained as a diastereo-
meric mixture of two epimers (cis/trans, 35:65) in 97% combined
yield. The epimeric mixture of N-Ts-THBC 5 could also be used as
such for the subsequent mild one-pot aromatization. When N-Ts-
DMF
CH2Cl2
CHCl3
MeCN
THF
EtOAc
MeOH
i-PrOH
31
43
THBC
5 was treated with powdered potassium carbonate
a
b
c
Isolated yield of compound 6.
Dimethyl sulfoxide.
4-Dimethylaminopyridine.
1,8-Diazabicyclo[5,4,0]undec-7-ene.
N,N-Dimethylformamide.
(5.0 equiv) at room temperature in anhydrous dimethyl sulfoxide
(DMSO) under an atmosphere of air, the desired b-carboline 6
was obtained in 87% yield. Although both THBC 4 and N-Ts-THBC
5 existed as mixtures of the corresponding epimers, isolation of
the epimers was not necessary, since the stereogenic centers are
lost during the conversion of N-Ts-THBC 5 into compound 6.
In order to determine the optimized reaction conditions for the
conversion of N-Ts-THBC 5 into compound 6, we attempted the
above one-pot conversion under various conditions; the results
are summarized in Table 1. As can be seen from Table 1, the
conversion did not occur in the absence of a base (entry 1), and fine
d
e
powdered K2CO3 served as the best base for the reaction in DMSO
(entry 8). Various solvents were also checked for this reaction (en-
tries 9–18), when the one-pot conversion was performed in DMSO
or N,N-dimethylformamide (DMF) at room temperature, the de-
sired compound 6 could be obtained in good yields (entries
COOMe
COOMe
3
3
COOMe
NH
N
1
Ts
1
b
c
a
NH2
N
H
N
H
94%
97%
87%
O
O
N
H
O
O
L-tryptophan methyl ester
4
5
CH2OH
COOMe
CH2OH
N
N
N
e
d
N
N
H
N
H
H
91%
92%
OH
O
O
OH
pyridindolol 1
O
O
6
7
f
90%
CH2OAc
CH2OAc
CH2OAc
N
N
N
h
g
N
H
N
84%
N
H
75%
H
O
OH
OH
OAc
pyridindolol K1 2
O
OH
pyridindolol K2 3
8
Scheme 1. Total syntheses of pyridindolols 1–3. Reagents and conditions: (a) 1.5 equiv of (S)-2,3-O-isopropylidene-L-glyceraldehyde, 3.0 equiv of trifluoroacetic acid, 0 °C for
5 h in EtOAc; (b) 1.0 equiv of p-toluenesulfonyl chloride, 0.3 equiv of pyridine, 3.0 equiv of powdered K2CO3, 0 °C to rt for 6 h in CH2Cl2; (c) 5.0 equiv of powdered K2CO3, rt for
10 h in DMSO; (d) 5.0 equiv of diisobutylaluminum hydride (DIBAL-H), 0 °C for 6 h in CH2Cl2; (e) aqueous concentrated HCl (12 mol Lꢀ1), 0 °C for 2 h in THF; (f) 1.5 equiv of
acetyl chloride, 3.0 equiv of triethylamine, 0 °C for 0.5 h in CH2Cl2; (g) aqueous concentrated HCl (12 mol Lꢀ1), rt for 1.5 h in THF; (h) 1.1 equiv of acetyl chloride, 2.0 equiv of
diisopropylethylamine (DIPEA), 0 °C for 15 min in CH2Cl2.

Q. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 633–637
635
6–11), whereas the one-pot conversion was very slow at room
temperature in several other solvents such as dichloromethane,
chloroform, acetonitrile, tetrahydrofuran, ethyl acetate, methanol,
and isopropanol, affording the desired product 6 in only low yields
(entries 12–18).
apparatus. Column chromatography was performed on silica gel
(Qingdao Qcean Chemical Corp.). All reagents and solvents were
analytically pure, and were used as such after being received from
the commercial suppliers. The starting compound
methyl ester was prepared from -tryptophan according to the liter-
ature.13 The starting compound (S)-2,3-O-isopropylidene-
-glycer-
-ascorbic acid according to the
L-tryptophan
L
With the desired compound 6 in hand, we next attempted to
convert ester 6 into the primary alcohol 7. Several reducing agents
such as potassium borohydride (KBH4), sodium borohydride
(NaBH4), lithium aluminum hydride (LiAlH4), and diisobutylalumi-
num hydride (DIBAL-H) were examined. We found that KBH4 did
not work at all in all of the tested solvents such as methanol, etha-
nol, THF, DMSO, and DMF. However, the ester group of compound 6
could be efficiently reduced by NaBH4 in DMSO at room tempera-
ture, or LiAlH4 in THF at reflux, or DIBAL-H in CH2Cl2 at 0 °C, afford-
ing the desired product 7 in 77%, 83%, or 92% yield, respectively.
Primary alcohol 7 is a key intermediate for the syntheses of the
targeted (R)-(ꢀ)-pyridindolols 1–3; it can be readily converted into
(R)-(ꢀ)-pyridindolol 1, (R)-(ꢀ)-pyridindolol K1 2, and (R)-(ꢀ)-
pyridindolol K2 3 as follows. When compound 7 was exposed to
aqueous concentrated HCl (12 mol Lꢀ1) at 0 °C in THF, the aceto-
nide moiety was removed smoothly to afford (R)-(ꢀ)-pyridindolol
1 in 91% yield. When compound 7 was treated with acetyl chloride
(1.5 equiv) and triethylamine (3.0 equiv) at 0 °C in dichlorometh-
ane, compound 8 was obtained efficiently in 90% yield. Compound
8 was then exposed to aqueous concentrated HCl (12 mol Lꢀ1) at
room temperature in THF, and (R)-(ꢀ)-pyridindolol K2 3 was ob-
tained in 84% yield. Finally, when (R)-(ꢀ)-pyridindolol K2 3 was
treated with acetyl chloride (1.1 equiv) and diisopropylethylamine
(DIPEA, 2.0 equiv) at 0 °C in CH2Cl2, selective acetylation of the less
hindered terminal primary hydroxyl group occurred smoothly to
afford (R)-(ꢀ)-pyridindolol K1 2 in 75% yield. The characterization
data of the three (R)-(ꢀ)-pyridindolols 1–3 obtained from the
above total syntheses were identical to those of the previously re-
ported ones.11
L
aldehyde was prepared from
literature.14,15
L
4.2. Methyl (3S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1,2,3,4-
tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 4
L
-Tryptophan methyl ester (5.010 g, 22.96 mmol) was dissolved
in ethyl acetate (40 mL), and the solution was cooled to 0 °C with
an ice bath. After (S)-2,3-O-isopropylidene- -glyceraldehyde
L
(4.480 g, 34.42 mmol) was added, trifluoroacetic acid (7.840 g,
68.76 mmol) was slowly added within 10 min. After the addition
was finished, the stirring was continued for 5 h at 0 °C. After TLC
showed the reaction was complete, the reaction was quenched
by adding an aqueous solution of potassium carbonate until pH
9–10, after which the mixture was then transferred into a separa-
tory funnel. Two phases were separated and the aqueous phase
was extracted twice with ethyl acetate (2 ꢁ 20 mL). The organic
extracts were combined and washed with brine (20 mL). The or-
ganic solution was dried over anhydrous MgSO4. The solvent was
evaporated under vacuum to give a crude oil, which was purified
by flash chromatography (eluent: EtOAc/hexane = 1:4) to produce
compound 4 (7.130 g, 21.58 mmol) as an epimeric mixture in
94% combined yield (cis/trans = 35:65). For the cis-epimer:
½
a 2D0
ꢂ
¼ ꢀ23:9 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3) d 8.58 (br
s, 1H, NH in indole ring), 7.53 (d, J = 7.7 Hz, 1H, H-5), 7.36 (d,
J = 7.7 Hz, 1H, H-8), 7.20 (t, J = 7.7 Hz, 1H, H-7), 7.13 (t, J = 7.7 Hz,
1H, H-6), 4.75–4.72 (m, 1H, H-14), 4.46–4.40 (m, 1H, H-15),
4.10–4.06 (m, 1H, H-150), 3.99 (t, J = 5.5 Hz, 1H, H-1), 3.75 (s, 3H,
OCH3), 3.67 (dd, J1 = 7.2 Hz, J2 = 7.6 Hz, 1H, H-3), 3.35 (br s, 1H,
H-2), 3.20–3.14 (m, 2H, H-4 and H-40), 1.46 (s, 3H, CH3), 1.41 (s,
3H, CH3). 13C NMR (100 MHz, CDCl3) d 173.38, 136.13, 129.90,
126.49, 122.13, 119.48, 118.13, 111.08, 109.33, 108.29, 77.75,
66.16, 53.27, 52.38, 51.15, 26.43, 25.15, 24.13. HRMS (ESI) m/z
calcd for C18H23N2O4 [M+H]+: 331.1658, found: 331.1665. IR (KBr
film) 3379 (N–H), 2985, 2923, 1725 (C@O), 1688, 1460, 1434,
1360, 1246, 1218, 1159, 1087, 1007, 743 cmꢀ1. For the trans-epi-
3. Conclusion
In conclusion, novel asymmetric total syntheses of (R)-(ꢀ)-
pyridindolol 1, (R)-(ꢀ)-pyridindolol K1 2, and (R)-(ꢀ)-pyridindolol
K2 3 starting from readily available L-tryptophan methyl ester and
(S)-2,3-O-isopropylidene-L-glyceraldehyde were performed. (R)-
(ꢀ)-Pyridindolol 1 was synthesized via 5 steps in 66% overall yield,
(R)-(ꢀ)-pyridindolol K1 2 was synthesized via 7 steps in 41% over-
all yield, and (R)-(ꢀ)-pyridindolol K2 3 was synthesized via 6 steps
in 55% overall yield. In addition, the one-pot conversion of N-Ts-
THBC 5 into compound 6 as the key step for the above total synthe-
ses was studied in detail, in order to determine the optimized reac-
tion conditions; the best yield of compound 6 could be obtained in
DMSO with K2CO3 as the base.
mer: ½a 2D0
ꢂ
¼ ꢀ14:2 (c 0.7, CHCl3). 1H NMR (400 MHz, CDCl3) d
8.71 (br s, 1H, NH in indole ring), 7.50 (d, J = 7.8 Hz, 1H, H-5),
7.38 (d, J = 7.8 Hz, 1H, H-8), 7.19 (t, J = 7.8 Hz, 1H, H-7), 7.11 (t,
J = 7.8 Hz, 1H, H-6), 4.23ꢀ4.13 (m, 4H, H-1, H-14 and H-15),
3.84ꢀ3.81 (m, 1H, H-3), 3.83 (s, 3H, OCH3), 3.16 (d, J = 15.1 Hz,
1H, H-4), 2.84 (dd, J1 = 15.1 Hz, J2 = 12.4 Hz, 1H, H-40), 2.28 (br s,
1H, H-2), 1.57 (s, 3H, CH3), 1.45 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3) d 173.41, 135.94, 133.63, 126.62, 122.01, 119.45, 118.08,
111.12, 109.97, 107.86, 78.90, 67.56, 56.16, 55.61, 52.31, 26.95,
25.62, 25.53. HRMS (ESI) m/z calcd for C18H23N2O4 [M+H]+:
331.1658, found: 331.1665. IR (KBr film) 3442 (N–H), 2984,
4. Experimental
4.1. General
2955, 1747 (C@O), 1464, 1373, 1268, 1159, 1061, 857, 729 cmꢀ1
.
1H and 13C NMR spectra were acquired on a Bruker AM-400
instrument at 400 MHz or 100 MHz. Chemical shifts are given on
the delta scale as parts per million (ppm) with tetramethylsilane
(TMS) as the internal standard by assigning the TMS resonance in
the 1H NMR spectrum as 0.00 ppm and the CDCl3 resonance in
the 13C NMR spectrum as 77.23 ppm. All coupling constants (J val-
ues) are reported in Hertz (Hz). IR spectra were recorded on a Nico-
let Magna IR-550 spectrometer. Mass spectra were recorded on
HP5989A equipment. Optical rotations of the chiral compounds
were measured on a WZZ-1S polarimeter at room temperature.
Melting points were determined on a Mel-TEMP II melting point
4.3. Methyl (3S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-tosyl-
1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate 5
Compound 4 (6.930 g, 20.98 mmol) and pyridine (0.500 g,
6.321 mmol) were dissolved in dichloromethane (60 mL), and the
solution was cooled to 0 °C with an ice bath. Powdered potassium
carbonate (8.700 g, 62.95 mmol) was then added, after which
p-toluenesulfonyl chloride (4.000 g, 20.98 mmol) was added in
portions over 10 min. After the addition was finished, the ice-bath
was removed, and the mixture was stirred at room temperature for
6 h. After the reaction was complete (checked by TLC), water

636
Q. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 633–637
(40 mL) was added, and the mixture was transferred into a separ-
atory funnel. Two phases were separated, and the aqueous phase
was extracted twice with dichloromethane (2 ꢁ 20 mL). The organ-
ic extracts were combined, and washed successively with HCl
aqueous solution (1 mol/L, 20 mL) and water (15 mL). After the or-
ganic solution was dried over anhydrous MgSO4, the solvent was
removed under vacuum to give a crude solid, which was purified
by flash chromatography (eluent: EtOAc/hexane = 1:4) to afford
compound 5 (9.870 g, 20.37 mmol) as an epimeric mixture in
97% combined yield. (cis/trans = 35:65). For the cis-epimer: mp
134.87, 129.83, 129.03, 121.79, 121.39, 120.87, 117.42, 111.98,
110.67, 78.82, 69.30, 52.65, 26.32, 25.02. HRMS (ESI) m/z calcd
for C18H19N2O4 [M+H]+: 327.1345, found: 327.1343. IR (neat)
3410 (N–H), 2991, 1698 (C@O), 1628, 1435, 1349, 1264, 1213,
1136, 1055, 862, 752 cmꢀ1
.
4.5. (R)-(1-(2,2-Dimethyl-1,3-dioxolan-4-yl)-9H-pyrido[3,4-b]
indol-3-yl)methanol 7
Compound 6 (2.693 g, 8.252 mmol) was dissolved in dichloro-
methane (50 mL), and the resulting solution was cooled to 0 °C with
an ice bath. A solution of DIBAL-H in toluene (2 mol Lꢀ1, 20.5 mL,
41.00 mmol) was injected over 5 min with syringe. The mixture
was then stirred at 0 °C for about 6 h, and monitored by TLC. After
the reaction was complete, an aqueous solution of NH3ꢃH2O
(3 mol Lꢀ1, 30 mL) was added. The mixture was then stirred vigor-
ously for 10 min, and then transferred into a separatory funnel.
Two phases were separated, and the aqueous phase was then ex-
tracted twice with dichloromethane (2 ꢁ 25 mL). The organic
extracts were combined, and dried over anhydrous MgSO4. Evapora-
tion of the solvent under vacuum gave the crude product as a yellow
solid, which was purified by flash chromatography (eluent: EtOAc/
CH2Cl2 = 1:10) to give pure compound 7 (2.265 g, 7.592 mmol) as a
121.6–122.6 °C. ½a D20
ꢂ
¼ ꢀ26:2 (c 1.4, CHCl3). 1H NMR (400 MHz,
CDCl3) d 8.26 (s, 1H, NH in indole ring), 7.75 (d, J = 8.3 Hz, 2H, both
orth-H in Ts), 7.45 (d, J = 8.2 Hz, 1H, H-5), 7.28ꢀ7.23 (m, 3H, H-8
and both meta-H in Ts), 7.16 (t, J = 8.2 Hz, 1H, H-7), 7.09 (t,
J = 8.2 Hz, 1H, H-6), 5.39 (d, J = 5.0 Hz, 1H, H-1), 4.90 (dd, J1 = 6.1,
J2 = 4.8 Hz, 1H, H-3), 4.85–4.79 (m, 1H, H-14), 3.65 (s, 3H, OCH3),
3.47 (dd, J1 = 12.8 Hz, J2 = 6.5 Hz, 1H, H-15), 3.35–3.30 (m, 2H, H-
150 and H-4), 3.07 (dd, J1 = 14.8, J2 = 4.8 Hz, 1H, H-40), 2.38 (s, 3H,
CH3 in Ts), 1.262 (s, 3H, CH3), 1.265 (s, 3H, CH3). 13C NMR
(100 MHz, CDCl3)
d 171.13, 144.17, 137.59, 136.25, 129.66,
129.43, 127.23, 126.24, 122.30, 119.57, 118.23, 111.04, 109.72,
108.45, 76.49, 65.09, 58.17, 54.53, 52.59, 25.85, 25.18, 23.95,
21.55. HRMS (ESI) m/z calcd for C25H29N2O6S [M+H]+: 485.1746,
found: 485.1748. IR (KBr film) 3457 (N–H), 2984, 2925, 1742
(C@O), 1598, 1454, 1340, 1210, 1163, 1038, 847, 745, 664,
pale yellow oil in 92% yield. ½a D20
ꢂ
¼ ꢀ5:0 (c 0.4, CHCl3). 1H NMR
(400 MHz, CDCl3) d 9.19 (s, 1H, NH in indole ring), 8.06 (d,
J = 7.9 Hz, 1H, H-5), 7.81 (s, 1H, H-4), 7.55–7.50 (m, 2H, H-7 and H-
8), 7.25 (t, J = 7.9 Hz, 1H, H-6), 5.58 (dd, J1 = 6.9 Hz, J2 = 6.7 Hz, 1H,
H-14), 4.88 (s, 2H, H-16), 4.57 (dd, J1 = 8.5 Hz, J2 = 6.9 Hz, 1H, H-
15), 4.33 (dd, J1 = 8.5, J2 = 6.7 Hz, 1H, H-150), 1.56 (s, 3H, CH3), 1.55
(s, 3H, CH3). 13C NMR (100 MHz, CDCl3) d 148.25, 141.92, 141.32,
133.23, 131.59, 129.29, 122.31, 121.61, 120.50, 112.22, 111.44,
111.17, 79.25, 69.87, 65.37, 26.94, 25.96. HRMS (ESI) m/z calcd for
571 cmꢀ1
.
For the trans-epimer: mp 111.5–112.8 °C.
½
a 2D0
ꢂ
¼
þ141:6 (c 0.3, CHCl3). 1H NMR (400 MHz, CDCl3) d 8.54 (s, 1H,
NH in indole ring), 7.65 (d, J = 8.2 Hz, 2H, both orth-H in Ts),
7.40–7.34 (m, 2H, H-5 and H-8), 7.19–7.14 (m, 3H, H-7 and both
meta-H in Ts), 7.06 (t, J = 7.6 Hz, 1H, H-6), 5.15 (d, J = 8.6 Hz, 1H,
H-1), 4.97 (d, J = 6.0 Hz, 1H, H-3), 4.65 (dd, J1 = 9.0, J2 = 5.9 Hz,
1H, H-15), 4.42–4.13 (m, 2H, H-14 and H-150), 3.65 (s, 3H, OCH3),
3.22 (d, J = 15.0 Hz, 1H, H-4), 2.34 (s, 3H, CH3 in Ts), 2.31 (dd,
J1 = 15.0, J2 = 6.0 Hz, 1H, H-40), 1.65 (s, 3H, CH3), 1.42 (s, 3H, CH3).
13C NMR (100 MHz, CDCl3) d 171.10, 144.23, 136.78, 136.24,
130.46, 130.03, 126.99, 126.23, 122.39, 119.38, 118.38, 111.18,
110.25, 105.28, 78.79, 67.30, 54.81, 53.97, 52.79, 27.24, 25.84,
21.54, 20.68. HRMS (ESI) m/z calcd for C25H29N2O6S [M+H]+:
485.1746, found: 485.1748. IR (KBr film) 3385 (N–H), 2984,
2929, 1733 (C@O), 1597, 1450, 1347, 1256, 1211, 1164, 1056,
C
17H18N2O3 [M]+: 298.1317, found: 298.1313. IR (KBr film) 3463
(N–H, O–H), 2985, 2876, 1628, 1570, 1471, 1373, 1245, 1216,
1152, 1066, 857, 787, 636, 572 cmꢀ1
.
4.6. (R)-(–)-Pyridindolol 1
Compound 7 (0.630 g, 2.112 mmol) was dissolved in tetrahy-
drofuran (8 mL), and then the solution was cooled to 0 °C with
894, 742, 664, 580 cmꢀ1
.
an ice bath. Aqueous concentrated hydrochloric acid (12 mol Lꢀ1
,
0.2 mL) was then added. After the mixture was stirred at 0 °C for
2 h, the reaction was complete. The reaction solution was concen-
trated under vacuum to remove THF, and the residue was then par-
titioned between ethyl acetate (25 mL) and aqueous K2CO3 (10%
w/w, 10 mL). The mixture was transferred into a separatory funnel,
and two phases were separated. The aqueous phase was then ex-
tracted twice with ethyl acetate (2 ꢁ 10 mL). The organic extracts
were combined and dried over anhydrous Na2SO4. Evaporation of
the solvent under vacuum gave the crude product as a yellow solid.
Recrystallization of the yellow solid from methanol afforded (R)-
(ꢀ)-pyridindolol 1 (0.496 g, 1.920 mmol) as white solid in 91%
4.4. Methyl (R)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)-9H-pyrido
[3,4-b]indole-3- carboxylate 6
Powdered potassium carbonate (14.07 g, 101.8 mmol) was
added to a solution of compound 5 (9.870 g, 20.37 mmol) in anhy-
drous DMSO (40 mL). The suspension was then stirred for 10 h at
room temperature. The reaction was monitored by TLC. After the
reaction was complete, the mixture was diluted with ethyl acetate
(200 mL), and water (200 mL) was also added. The mixture was
transferred into a separatory funnel, and the two layers were sep-
arated. The aqueous solution was extracted twice with ethyl ace-
tate (2 ꢁ 60 mL), and the extracts were then combined and dried
over anhydrous MgSO4. Evaporation of the solvent gave a crude
oil, which was purified by flash chromatography (eluent: EtOAc/
CH2Cl2 = 1:20) to furnish compound 6 (5.782 g, 17.72 mmol) as a
yield. Mp 166.6–167.6 °C (lit.11 165–168 °C). ½a 2D0
¼ ꢀ46:7 (c 0.5,
ꢂ
MeOH) {lit.11
½
a 2D5
ꢂ
¼ ꢀ41 (c 0.1, MeOH)}. 1H NMR (400 MHz,
DMSO-d6) d 12.70 (s, 1H, NH in indole ring), 8.65 (s, 1H, H-4),
8.48 (d, J = 7.8 Hz, 1H, H-5), 7.85–7.74 (m, 2H, H-7 and H-8), 7.40
(t, J = 7.8 Hz, 1H, H-6), 5.66 (t, J = 5.2 Hz, 1H, H-14), 4.99 (s, 2H, both
H-16), 3.99 (dd, J1 = 11.1, J2 = 5.2 Hz, 1H, H-15), 3.91 (dd, J1 = 11.1,
J2 = 5.2 Hz, 1H, H-150). 13C NMR (100 MHz, DMSO-d6) d 144.42,
143.47, 141.95, 133.93, 131.94, 131.82, 123.70, 121.57, 119.69,
113.99, 113.49, 70.30, 65.04, 59.93. HRMS (ESI) m/z calcd for
pale yellow oil in 87% yield. ½a D20
ꢂ
¼ ꢀ14:2 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3) d 9.52 (br s, 1H, NH in indole ring), 8.84 (s, 1H,
H-4), 8.19 (d, J = 7.9 Hz, 1H, H-5), 7.65ꢀ7.55 (m, 2H, H-7 and H-
8), 7.40ꢀ7.33 (m, 1H, H-6), 5.74 (t, J = 6.6 Hz, 1H, H-14), 4.68 (dd,
J1 = 8.6 Hz, J2 = 6.6 Hz, 1H, H-15), 4.39 (dd, J1 = 8.6 Hz, J2 = 6.6 Hz,
1H, H-150), 4.04 (s, 3H, OCH3), 1.62 (s, 3H, CH3), 1.58 (s, 3H, CH3).
13C NMR (100 MHz, CDCl3) d 166.51, 142.64, 140.36, 136.78,
C
14H14N2O3 [M]+: 258.1004, found: 258.1007. IR (KBr film) 3421
(N–H, O–H), 2961, 2923, 1628, 1564, 1458, 1398, 1261, 1094,
1022, 906, 801, 742, 650, 492 cmꢀ1
.

Q. Zhang et al. / Tetrahedron: Asymmetry 24 (2013) 633–637
637
4.7. (R)-(1-(2,2-Dimethyl-1,3-dioxolan-4-yl)-9H-pyrido[3,4-b]
4.9. (R)-(–)-Pyridindolol K1 2
indol-3-yl)methyl acetate 8
Compound 3 (0.967 g, 3.220 mmol) was dissolved in a dichloro-
methane (20 mL), and the solution was cooled to 0 °C with an ice
bath. Acetyl chloride (0.280 g, 3.567 mmol) was added, and then
DIPEA (0.830 g, 6.422 mmol) was added dropwise at 0 °C over
15 min. TLC showed the reaction was complete immediately after
the addition was finished. The reaction was then quenched by add-
ing an aqueous solution of potassium carbonate (10% w/w, 10 mL).
The organic layer was separated, and the aqueous phase was ex-
tracted twice with dichloromethane (2 ꢁ 10 mL). The organic ex-
tracts were combined and dried over anhydrous MgSO4. After
removal of the solvent, the crude product was purified by flash
chromatography (eluent: EtOAc/hexane = 1:4) to give (R)-(ꢀ)-
pyridindolol K1 2 (0.830 g, 2.424 mmol) as a pale yellow solid in
Compound 7 (1.270 g, 4.257 mmol) was dissolved in a dichloro-
methane (15 mL), and the solution was cooled to 0 °C with an ice
bath. Acetyl chloride (0.500 g, 6.370 mmol) was added, and then
a solution of triethylamine (1.290 g, 12.75 mmol) in dichlorometh-
ane (10 mL) was dropwise added at 0 °C over 0.5 h. After the addi-
tion was complete, the reaction was then immediately quenched
by adding an aqueous solution of potassium carbonate (10% w/w,
10 mL). The organic layer was separated, washed with brine
(10 mL), and dried over anhydrous MgSO4. After removal of the sol-
vent, the crude product was then purified by flash chromatography
(eluent: EtOAc/hexane = 1:5) to give compound
8
(1.305 g,
3.836 mmol) as a colorless oil in 90% yield. ½a D20
ꢂ
¼ ꢀ9:3 (c 0.6,
CHCl3). 1H NMR (400 MHz, CDCl3) d 9.30 (s, 1H, NH in indole ring),
8.14 (d, J = 7.9 Hz, 1H, H-5), 7.98 (s, 1H, H-4), 7.59–7.52 (m, 2H, H-7
and H-8), 7.30 (t, J = 7.9 Hz, 1H, H-6), 5.65 (t, J = 6.8 Hz, 1H, H-14),
5.38 (ab peaks, Jab = Jba = 12.2 Hz, 2H, both H-16), 4.64 (dd, J1 = 8.5,
J2 = 6.8 Hz, 1H, H-15), 4.41 (dd, J1 = 8.5, J2 = 6.8 Hz, 1H, H-150), 2.19
(s, 3H, CH3 in Ac), 1.61 (s, 3H, CH3), 1,60 (s, 3H, CH3). 13C NMR
75% yield. Mp 125.5–126.5 °C (lit.11 124–125 °C). ½a 2D0
¼ ꢀ13:6 (c
ꢂ
0.2, MeOH) {lit.11
½
a 2D5
ꢂ
¼ ꢀ14 (c 0.2, MeOH)}. 1H NMR (400 MHz,
CDCl3) d 9.78 (s, 1H, NH in indole ring), 8.13 (d, J = 7.9 Hz, 1H, H-
5), 7.99 (s, 1H, H-4), 7.61–7.57 (m, 2H, H-7 and H-8), 7.32–7.26
(m, 1H, H-6), 5.43 (dd, J1 = 7.5, J2 = 1.7 Hz, 1H, H-15), 5.37 (s, 2H,
both H-16), 4.86 (dd, J1 = 11.0, J2 = 1.7 Hz, 1H, H-150), 4.18 (dd,
J1 = 11.0, J2 = 7.5 Hz, 1H, H-14), 2.21 (s, 3H, CH3), 2.18 (s, 3H,
(100 MHz, CDCl3)
d 170.98, 143.75, 142.26, 140.46, 132.77,
130.51, 128.64, 121.72, 121.12, 120.03, 113.37, 111.69, 110.54,
CH3). 13C NMR (100 MHz, CDCl3)
d 173.59, 171.63, 143.82,
78.83, 69.33, 67.75, 26.38, 25.28, 21.16. HRMS (ESI) m/z calcd for
C
141.52, 140.88, 133.11, 131.10, 129.57, 122.45, 121.82, 121.00,
114.44, 112.66, 72.26, 70.91, 68.03, 21.8, 21.79. HRMS (ESI) m/z
calcd for C18H18N2O5 [M]+: 342.1216, found: 342.1210. IR (KBr
film) 3373 (N–H), 3106, 2922, 1741, 1658, 1494, 1363, 1248,
19H20N2O4 [M]+: 340.1423, found: 340.1418. IR (KBr film) 3403
(N–H), 2985, 2933, 1735 (C@O), 1627, 1495, 1367, 1245, 1107,
1066, 963, 858, 747, 635, 455 cmꢀ1
.
1152, 1074, 988, 862, 745, 625, 480 cmꢀ1
.
4.8. (R)-(–)-Pyridindolol K2 3
Acknowledgments
To a solution of compound 8 (1.300 g, 3.819 mmol) in tetrahy-
drofuran (10 mL), aqueous concentrated hydrochloric acid
(12 mol/L, 0.2 mL) was added. The resulting solution was stirred
at room temperature, and the reaction then monitored by TLC.
After stirring was continued at room temperature for around
1.5 h, the reaction was complete. The reaction solution was con-
centrated under vacuum, and the residue was partitioned between
ethyl acetate (20 mL) and an aqueous solution of potassium car-
bonate (10% w/w, 10 mL). The two phases were separated, and
the aqueous phase was extracted twice with ethyl acetate
(2 ꢁ 10 mL). The organic extracts were combined, washed with
brine (10 mL), and dried over anhydrous Na2SO4. After removal
of the solvent, the crude product was purified by flash chromatog-
raphy (eluent: EtOAc/CHCl3 = 1:4) to give (R)-(ꢀ)-pyridindolol K2 3
(0.968 g, 3.213 mmol) as white crystals in 84% yield. Mp 121.3–
We are grateful to the National Natural Science Foundation of
China (NSFC) (Grant number 20972048) and the Shanghai Educa-
tional Development Foundation (Grant number 03SG27) for the
financial support of this work.
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123.3 °C (lit.11 123–124 °C). ½a 2D0
ꢂ
¼ ꢀ32:5 (c 0.3, MeOH) (lit.11
½
a 2D3
ꢂ
¼ ꢀ33 (c 0.2, MeOH)). 1H NMR (400 MHz, DMSO-d6) d 11.28
(s, 1H, NH in indole ring), 8.24 (d, J = 7.8 Hz, 1H, H-5), 8.08 (s, 1H,
H-4), 7.70 (d, J = 7.8 Hz, 1H, H-8), 7.54 (t, J = 7.8 Hz, 1H, H-7),
7.23 (t, J = 7.8 Hz, 1H, H-6), 5.81 (t, J = 4.6 Hz, 1H, H-14), 5.27 (s,
2H, both H-16), 5.07 (dd, J1 = 8.6 Hz, J2 = 4.6 Hz, 1H, H-15), 4.81
(dd, J1 = 8.6 Hz, J2 = 4.6 Hz, 1H, H-150), 2.14 (s, 3H, CH3CO). 13C
NMR (100 MHz, DMSO-d6) d 170.81, 145.96, 142.89, 141.37,
133.34, 129.32, 128.47, 121.95, 120.77, 119.61, 112.94, 112.91,
75.27, 67.60, 65.77, 21.33. HRMS (ESI) m/z calcd for C16H16N2O4
[M]+: 300.1110, found: 300.1118. IR (KBr film) 3385 (N–H, O–H),
2957, 2923, 1740, 1628, 1494, 1362, 1249, 1146, 1055, 997, 868,
13. Orme, M. W.; Martinelli, M. J.; Doecke, C. W.; Pawlak, J. M.; Chelius, E. C. World
Patent WO 04/011463, 2004; Chem. Abstr. 2004, 140, 146170.
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16. Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030.
17. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797.
732, 660, 536 cmꢀ1
.