Total syntheses of dichotomines A-D and the stereochemical revision of dichotomines B-D

Article abstract of DOI:10.1002/ejoc.201200235

New asymmetric total syntheses of (-)-dichotomines A-D (1-4) starting from L-tryptophan methyl ester and 2,3-O-isopropylidene-D-glyceraldehyde are described. The absolute configuration of the stereogenic center of (-)-dichotomine A (1) was reconfirmed as (S), on the basis of the X-ray crystallographic analysis of the conjugate (i.e., 17) of its methyl ester (i.e., 16) with (S)-N-tosylproline, whereas the absolute configurations of the stereogenic centers of (-)-dichotomines B-D (2-4) were revised as (R). Copyright

Full text of DOI:10.1002/ejoc.201200235

Job/Unit: O20235
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FULL PAPER
DOI: 10.1002/ejoc.201200235
Total Syntheses of Dichotomines A–D and the Stereochemical Revision of
Dichotomines B–D
Qiang Zhang,[a] Jing Dong,[a] Xiao-Xin Shi,*[a] and Xia Lu[a]
Keywords: Total synthesis / Asymmetric synthesis / Nitrogen heterocycles / Alkaloids / Configuration determination
New asymmetric total syntheses of (–)-dichotomines A–D (1–
4) starting from -tryptophan methyl ester and 2,3-O-isoprop-
ylidene- -glyceraldehyde are described. The absolute con-
figuration of the stereogenic center of (–)-dichotomine A (1)
was reconfirmed as (S), on the basis of the X-ray crystallo-
graphic analysis of the conjugate (i.e., 17) of its methyl ester
(i.e., 16) with (S)-N-tosylproline, whereas the absolute con-
figurations of the stereogenic centers of (–)-dichotomines B–
D (2–4) were revised as (R).
L
D
proaches for dichotomines A–D and their derivatives.
Herein, we disclose new asymmetric total syntheses for all
of the four alkaloids dichotomines A–D, starting from l-
tryptophan methyl ester and the readily available 2,3-O-iso-
propylidene-d-glyceraldehyde.
Introduction
Dichotomines A, B, C, and D (Figure 1, 1–4), four new
β-carboline-type alkaloids, were first isolated by Yoshikawa
and his colleagues in 2004[1] from the roots of Stellaria
dichotoma L. var. lanceolata Bunge (Chinese name “Yin
Chai Hu”), which are used in China as a folk medicine for
the treating fevers.[2] Dichotomines A–D have shown antial-
lergic effects on the passive cutaneous anaphylaxis reaction
in the ear and inhibitory activity on the release of β-
hexosaminidase in RBL-2H3 cells. Dichotomine C has also
shown inhibitory activity on the release of antigen-IgE-me-
diated TNF-α and IL-4 in RBL-2H3 cells.[1] To date, only
dichotomine C has been synthesized, performed by Hibino
and co-workers,[3] however, the other three alkaloids dicho-
tomines A, B, and D have not been synthesized. Consider-
ing their various interesting physiological activities, we have
been recently engaged in developing new synthetic ap-
Results and Discussion
In the retrosynthetic analysis shown in Scheme 1, we
speculate that dichotomine A (1) could be obtained from
iodide 5 after dehalogenation at the terminal position (C-
15) of the side chain and hydrolysis of the ester group. Di-
chotomines B–D (2–4) and compound 5 could be derived
from compound 6. We also speculate that compound 6
could be derived from intermediate 7 through a chiral inver-
sion at the inner position (C-14) of the side chain, and 7
could be derived from tetrahydro-β-carboline intermediate
8 through an aromatization reaction. Intermediate 8 could
be eventually obtained from a Pictet–Spengler reaction[4] of
l-tryptophan methyl ester with readily available 2,3-O-iso-
propylidene-d-glyceraldehyde.[5]
As depicted in Scheme 2, our synthetic efforts began with
the Pictet–Spengler reaction of l-tryptophan methyl ester[6]
with 2,3-O-isopropylidene-d-glyceraldehyde (1.5 equiv.) in
the presence of trifluoroacetic acid (TFA, 3 equiv.) in ethyl
acetate. Tetrahydro-β-carboline 8 was obtained as a dia-
stereomeric mixture of two epimers (cis/trans, 55:45) in a
94% combined yield. The mixture was used directly in the
next step without the separation of the two epimers.
The reaction of compound 8 with p-toluenesulfonyl
chloride (1.0 equiv.) and powdered potassium carbonate
(3.0 equiv.) in the presence of a catalytic amount of pyridine
(0.3 equiv.) in dichloromethane afforded N-tosyltetrahydro-
β-carboline (9) also as a diastereomeric mixture of two epi-
mers (cis/trans, 55:45) in a 97% combined yield. When com-
pound 9 in anhydrous dimethyl sulfoxide was treated with
Figure 1. Structure of dichotomines A–D.
[a] Department of Pharmaceutical Engineering, School of
Pharmacy, East China University of Science and Technology,
130 Mei-Long Road, Shanghai 200237, P. R. China
Fax: +86-216-4252052
E-mail: xxshi@ecust.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200235.
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Q. Zhang, J. Dong, X.-X. Shi, X. Lu
FULL PAPER
Scheme 1. Retrosynthetic analysis of dichotomines A–D (1–4).
an excess amount of powdered potassium carbonate obtained in 93% yield through the transesterification of di-
(5.0 equiv.) and then stirred overnight at room temperature, chotomine C (3) with butanol and potassium carbonate
a tandem β-elimination[7] and oxidative aromatization un- (0.2 equiv.) as the catalyst.
der air (O2)[8] furnished β-carboline 10 in 88% yield. Expos-
Finally, dichotomine A (1) was obtained through a five-
ing compound 10 to aqueous concentrated hydrochloric step sequence of transformations as portrayed in Scheme 4.
acid in tetrahydrofuran at room temperature resulted in the The key intermediate 6 was first exposed to methanesulf-
removal of the acetonide moiety to produce diol 7 in 91% onyl chloride (2.0 equiv.) in dichloromethane in the pres-
yield.
ence of triethylamine (3.0 equiv.) to give mesylate 14 in 94%
The regioselective protection of the primary hydroxy of yield, which was then transformed into iodide 5 in 82%
diol 7 by using triphenylmethyl chloride (TrCl, 1.3 equiv.) yield by means of a nucleophilic substitution of 14 with
in the presence of triethylamine (2.0 equiv.) in dichloro- sodium iodide (5.0 equiv.) in refluxing acetone. The dehalo-
methane afforded secondary alcohol 11 in 89% yield. A chi- genation of iodide 5 at the terminal position (C-15) of the
ral inversion at the C-14 position was then achieved by side chain was achieved by reductive hydrogenolysis with
treatment of secondary alcohol 11 successively with meth- Pd/C (10%, w/w) as a catalyst, providing compound 15 in
anesulfonyl chloride (2.5 equiv.) and benzoic acid (BzOH, a nearly quantitative yield. The methanolysis of benzoate
5.0 equiv.) in presence of diisopropylethylamine (4.0 equiv.) 15 by heating the reaction mixture to reflux in the presence
in chloroform. Although intermediate 12 could not be iso- of triethylamine (3.0 equiv.) afforded alcohol 16 in 92%
lated, because of its instability, benzoate 13 was obtained yield. For the conclusion of the synthesis, the hydrolysis of
in 67% yield over the two steps with inversion to the (R) 16 by treatment with sodium hydroxide (3.0 equiv.) in aque-
configuration (Walden inversion).[9]
ous methanol furnished dichotomine A (1) in 93% yield.
The removal of the triphenylmethyl group with concen-
Upon measuring the optical rotations, all of the four di-
trated hydrochloric acid in aqueous acetonitrile (CH3CN/ chotomines A–D (1–4) obtained through the above total
H2O, 10:1) produced primary alcohol 6 in 86% yield. The syntheses were found to be levorotatory. Although the abso-
methanolysis of compound 6 in refluxing methanol in the lute configurations of (–)-dichotomines A–D (1–4), isolated
presence of triethylamine (3.0 equiv.) afforded dichotom- from the plant source, were determined by using Mosher’s
ine C (3) in 94% yield.
method in Yoshikawa’s report[1] to have the (S) configura-
Next, dichotomines B (2) and D (4) were readily ob- tion, herein we reconfirm the absolute configurations of
tained from dichotomine C (3) after hydrolysis or transes- (–)-dichotomines A–D (1–4) by means of the X-ray crystal-
terification reactions, respectively, as shown in Scheme 3. lographic analysis of a conjugate (i.e., 17) of dichotomine A
Dichotomine B (2) was obtained in 90% yield upon the methyl ester (16) with (S)-N-tosylproline.
treatment of dichotomine C (3) first with sodium hydroxide
As depicted in Scheme 5, the treatment of compound 16
(3.0 equiv.) in aqueous methanol (CH3OH/H2O, 10:1) and with triethylamine (2.0 equiv.) and (S)-1-tosylpyrrolidine-2-
then with acetic acid (6.0 equiv.). Dichotomine D (4) was carbonyl chloride (1.5 equiv.), which was readily prepared
2
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Total Syntheses of Dichotomines A–D
Scheme 2. Synthesis of dichotomine C (3).
(S)-N-tosylproline subunit was coupled with compound 16
and used as an internal reference for X-ray single crystal
analysis of compound 17. According to the ORTEP draw-
ing of compound 17 as shown in Figure 2, the absolute con-
figuration of the stereogenic center at the C-14 position of
compound 17 was unequivocally determined as (S), and
hence, the stereogenic centers of both dichotomine A (1)
and its methyl ester 16 should also have the (S) absolute
configuration.
Compounds 16 and 17 were derived from the same key
intermediate 6, and no change in the stereogenic center (C-
14) was involved in these transformations as shown in
Schemes 2 to 4. This means that compounds 16 and 17 as
well as the four (–)-dichotomines A–D (1–4) should possess
the same relative configuration at their C-14 positions.
However, dichotomine A (1) possesses an (S) absolute con-
figuration, whereas dichotomines B–D (2–4) possess the (R)
Scheme 3. Syntheses of dichotomines B (2) and D (4).
from the reaction of (S)-N-tosylproline[10] and thionyl absolute configuration because of the rearrangement in the
chloride prior to use, provided 17 in 85% yield. Here, the sequence of the substituents to assign the configuration of
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Q. Zhang, J. Dong, X.-X. Shi, X. Lu
FULL PAPER
Scheme 4. Synthesis of dichotomine A (1).
Conclusions
In conclusion, new asymmetric total syntheses of (–)-di-
chotomines A–D (1–4) starting from l-tryptophan methyl
ester and 2,3-O-isopropylidene-d-glyceraldehyde were
achieved. From these total syntheses, dichotomines A–D
(1–4) were obtained in 9–13 steps and in 24%, 32%, 35%,
and 33% overall yields, respectively. The absolute configu-
ration of the stereogenic center of (–)-dichotomine A (1)
was reconfirmed as (S), on the basis of the X-ray crystallo-
graphic analysis of a conjugate (i.e., 17) of (–)-dichotom-
ine A methyl ester (16) with (S)-N-tosylproline. However,
the absolute configurations of the stereogenic center in (–)-
dichotomines B–D (2–4) were revised as (R).
Scheme 5. Preparation of compound 17 from compound 16.
Experimental Section
1
General Methods: The H and 13C NMR spectroscopic data were
recorded with a Bruker AM-400 instrument at 400 MHz or
100 MHz. The chemical shifts are given on the delta scale as parts
per million (ppm) with tetramethylsilane (TMS) as the internal
standard. The IR spectroscopic data were recorded with a Nicolet
Magna IR-550 spectrometer. The mass spectrometry data were re-
corded with HP5989A equipment. The optical rotations of chiral
compounds were measured with a WZZ-1S polarimeter at room
temperature, and the column chromatography was performed on
silica gel (Qingdao Chemical Factory). All of the reagents and sol-
vents were analytically pure and used as such without further puri-
fication. l-tryptophan methyl ester and 2,3-O-isopropylidene-d-
glyceraldehyde were prepared according to known procedures.[7,5]
Figure 2. ORTEP drawing of compound 17.
the stereogenic center (C-14). In Yoshikawa’s report,[1]
structures of dichotomines B–D (2–4) were correct, but
their absolute configurations were incorrectly designated as
(S). In Hinbino’s report,[3] both the structures and absolute
configurations of dichotomines B–D (2–4) were incorrect.
Methyl
hydro-1H-pyrido[3,4-b]indole-3-carboxylate
methyl ester (15.02 g, 68.82 mmol) was dissolved in ethyl acetate
(3S)-1-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2,3,4,9-tetra-
(8): l-Tryptophan
4
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Total Syntheses of Dichotomines A–D
(150 mL), and the solution was cooled to 0 °C with an ice bath.
After 2,3-O-isopropylidene-d-glyceraldehyde (13.43 g,
1 H, indole NH), 7.74 (d, J = 8.2 Hz, 2 H, Ar in Ts), 7.39 (d, J =
7.8 Hz, 1 H, 5-H), 7.30 (d, J = 7.8 Hz, 1 H, 8-H), 7.10–7.18 (m, 3
H, Ar), 7.06 (dd, J = 7.8 Hz, J = 7.3 Hz, 1 H, 7-H), 4.76 (d, J =
9.1 Hz, 1 H, 14-H), 4.17–4.27 (m, 1 H, 1-H), 4.01–4.12 (m, 2 H,
15-H), 3.91 (s, 3 H, COOCH3), 3.51–3.67 (m, 1 H, 3-H), 3.14 (dd,
1
2
103.20 mmol) was added, trifluoroacetic acid (23.53 g,
206.36 mmol) was added dropwise within 30 min. The stirring was
continued at 0 °C for 4 h, and then TLC showed that the reaction
was complete. The reaction mixture was quenched by the addition
of an aqueous solution of potassium carbonate until pH 9–10, and
then the mixture was transferred to a separatory funnel. The or-
ganic layer was separated and washed with brine. The organic solu-
tion was dried with anhydrous MgSO4. The solvent was evaporated
under vacuum to give a crude oil which was purified by flash
chromatography (EtOAc/hexane, 1:3) to produce compound 8
(21.35 g, 64.62 mmol) as an epimeric mixture (cis/trans, 55:45) in a
combined yield of 94%. Data for cis epimer: m.p. 86.7–87.5 °C;
2
1
2
1J = 16.2 Hz, J = 12.0 Hz, 1 H, 4-H), 2.94 (dd, J = 16.2 Hz, J
= 4.0 Hz, 1 H, 4-HЈ), 2.28 (s, 3 H, ArCH3), 1.52 (s, 3 H, CCH3),
1.32 (s, 3 H CCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.9
(COOMe), 144.5 (Ar), 136.6 (Ar), 136.4 (Ar), 130.9 (Ar), 129.5
(Ar), 127.9 (Ar), 126.4 (Ar), 122.4 (Ar), 119.6 (Ar), 118.3 (Ar),
111.2 (Ar), 110.4 (Ar), 109.4 [C(CH3)2], 67.7 (C-14), 57.6 (C-15),
57.4 (C-3), 53.5 (C-1), 52.8 (COOCH3), 27.0 (C-4), 25.4 [C(CH3)2],
22.8 [C(CH3)2], 21.6 (ArCH3) ppm. HRMS (ESI): calcd. for
C25H29N2O6S [M + H]+ 485.1746; found 485.1748. IR (KBr film):
1
[α]2D0 = –66.1 (c = 0.5, CHCl3). H NMR (400 MHz, CDCl3): δ =
ν = 3410 (N–H), 2986, 2929, 1745 (C=O), 1598, 1492, 1334, 1271,
˜
8.43 (s, 1 H, indole NH), 7.49 (d, J = 7.7 Hz, 1 H, 5-H), 7.34 (d, 1222, 1159, 1068, 848, 744, 670, 581 cm–1. Data for trans epimer:
1
2
J = 7.8 Hz, 1 H, 8-H), 7.16 (dd, J = 7.7 Hz, J = 7.3 Hz, 1 H, 6-
m.p. 155.6–156.6 °C; [α]2D0 = +147.7 (c = 1.3, CHCl3). 1H NMR
1
2
H), 7.09 (dd, J = 7.8 Hz, J = 7.3 Hz, 1 H, 7-H), 4.09–4.19 (m, 3 (400 MHz, CDCl3): δ = 8.39 (s, 1 H, indole NH), 7.77 (d, J =
H, 14-H and 15-H), 4.00–4.06 (m, 1 H, 1-H), 3.83 (dd, 1J = 7.1 Hz, 8.2 Hz, 2 H, Ar in Ts), 7.47 (d, J = 7.6 Hz, 1 H, 5-H), 7.32 (d, J =
2J = 5.1 Hz, 1 H, 3-H), 3.72 (s, 3 H, COOCH3), 3.09 (dd, 1J =
7.7 Hz, 1 H, 8-H), 7.27 (d, J = 8.2 Hz, 2 H, Ar in Ts), 7.21 (dd, J
1
15.3 Hz, 2J = 5.0 Hz, 1 H, 4-H), 2.93 (dd, 1J = 15.2 Hz, 2J = 7.2 Hz,
= 7.6 Hz, 2J = 7.2 Hz, 1 H, 6-H), 7.12 (dd, 1J = 7.7 Hz, 2J = 7.2 Hz,
1 H, 4-HЈ), 2.19 (br. s, 1 H, 2-H), 1.57 (s, 3 H, CCH3), 1.37 (s, 3 1 H, 7-H), 5.34–5.38 (m, 1 H, 14-H), 5.16 (d, J = 5.9 Hz, 1 H, 1-
1
2
H, CCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.2 (CO-
OMe), 136.1 (Ar), 133.4 (Ar), 126.7 (Ar), 121.9 (Ar), 119.3 (Ar),
118.1 (Ar), 111.1 (Ar), 109.9 (Ar), 107.5 [C(CH3)2], 78.6 (C-14),
H), 4.96–5.03 (m, 1 H, 15-H), 4.01 (dd, J = 8.7 Hz, J = 7.1 Hz,
1 H, 15-HЈ), 3.70 (s, 3 H, COOCH3), 3.42 (d, J = 15.5 Hz, 1 H, 3-
1
2
H), 3.18 (dd, J = 8.7 Hz, J = 6.6 Hz, 1 H, 4-H), 2.58–2.70 (m, 1
68.1 (C-15), 53.4 (C-1), 52.7 (C-3), 52.2 (COOCH3), 27.1 (C-4), H, 4-HЈ), 2.39 (s, 3 H, ArCH3), 1.66 (s, 3 H, CCH3), 1.45 (s, 3 H,
25.4 (CCH3), 25.3 (CCH3) ppm. HRMS (ESI): calcd. for
CCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.2 (COOMe),
C18H23N2O4 [M + H]+ 331.1658; found 331.1665. IR (KBr film): 144.1 (Ar), 136.6 (Ar), 136.1 (Ar), 130.1 (Ar), 127.5 (Ar), 127.0
ν = 3376 (N–H), 2985, 2953, 1711 (C=O), 1445, 1373, 1212, 1154,
(Ar), 125.9 (Ar), 122.6 (Ar), 119.6 (Ar), 118.3 (Ar), 111.2 (Ar),
˜
1053, 865, 744 cm–1. Data for trans epimer: m.p. 86.7–87.5 °C; 108.2 (Ar), 107.0 [C(CH3)2], 79.8 (C-14), 65.6 (C-15), 53.9 (C-1),
[α]2D0 = –12.3 (c = 0.5, CHCl3). H NMR (400 MHz, CDCl3): δ =
53.8 (C-3), 52.9 (COOCH3), 26.7 (C-4), 23.6 [C(CH3)2], 21.6
1
8.41 (s, 1 H, indole NH), 7.51 (d, J = 7.7 Hz, 1 H, 5-H), 7.31 (d, [C(CH3)2], 21.5 (ArCH3) ppm. HRMS (ESI): calcd. for
J = 8.0 Hz, 1 H, 8-H), 7.14–7.21 (m, 1 H, 6-H), 7.06–7.14 (m, 1 H,
C25H29N2O6S [M + H]+ 485.1746; found 485.1748. IR (KBr film):
ν = 3457 (N–H), 2984, 2925, 1742 (C=O), 1598, 1454, 1340, 1210,
7-H), 4.58–4.68 (m, 1 H, 14-H), 4.44–4.50 (m, 1 H, 15-H), 3.99–
˜
4.11 (m, 1 H, 15-HЈ), 3.82 (s, 3 H, COOCH3), 3.71–3.79 (m, 1 H, 1163, 1038, 847, 745, 664, 571 cm–1.
1-H), 3.53 (t, J = 8.1 Hz, 1 H, 3-H), 3.12–3.19 (m,1 H, 4-H), 2.75–
2.87 (m, 1 H, 4-HЈ), 2.34 (br. s, 1 H, 2-H), 1.56 (s, 3 H, CCH3),
1.41 (s, 3 H, CCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.2
(COOMe), 135.9 (Ar), 131.5 (Ar), 126.6 (Ar), 121.9 (Ar), 119.4
(Ar), 118.0 (Ar), 111.0 (Ar), 109.7 (Ar), 109.3 [C(CH3)2], 77.4 (C-
14), 65.8 (C-15), 56.2 (C-1), 53.4 (C-3), 52.3 (COOCH3), 26.4 (C-
4), 25.4 (CCH3), 24.6 (CCH3) ppm. HRMS (ESI): calcd. for
C18H23N2O4 [M + H]+ 331.1658; found 331.1665. IR (KBr film):
Methyl
(S)-1-(2,2-Dimethyl-1,3-dioxolan-4-yl)-9H-pyrido[3,4-b]-
indole-3-carboxylate (10): Powdered potassium carbonate (21.56 g,
156.00 mmol) was added to a solution of compound 9 (15.00 g,
30.96 mmol) in anhydrous DMSO (dimethyl sulfoxide, 75 mL). The
suspension was then stirred at room temperature for 8 h (over-
night), and the reaction was monitored by TLC. When the reaction
was complete, the mixture was diluted with ethyl acetate (300 mL),
and then water (350 mL) was added. The mixture was transferred
to a separatory funnel, and the two layers were separated. The
aqueous solution was extracted with ethyl acetate (2ϫ90 mL), and
the combined extracts were dried with anhydrous MgSO4. Evapo-
ration of the solvent gave a crude oil that was purified by flash
chromatography (EtOAc/hexane, 1:6) to furnish compound 10
(8.90 g, 27.27 mmol, 88%) as a yellow oil. [α]2D0 = +13.9 (c = 0.9,
ν = 3379 (N–H), 2985, 2923, 1725 (C=O), 1688, 1460, 1434, 1360,
˜
1246, 1218, 1159, 1087, 1007, 743 cm–1.
Methyl (3S)-1-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-tosyl-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (9): Compound 8
(21.34 g, 64.59 mmol) and pyridine (1.53 g, 19.34 mmol) were dis-
solved in dichloromethane (150 mL), and the solution was cooled
to 0 °C with an ice bath. Powdered potassium carbonate (26.97 g,
195.14 mmol) was added, and then p-toluenesulfonyl chloride
(12.44 g, 65.25 mmol) was added in portions over 30 min. The ice
bath was removed, and the mixture was stirred at room tempera-
ture for 3 h. Water (75 mL) was added, and the mixture was trans-
ferred to a separatory funnel. The organic phase was separated and
washed successively with an aqueous solution of HCl (1 n, 60 mL),
water (40 mL), and brine (40 mL). After the organic solution was
dried with anhydrous MgSO4, the solvent was removed under vac-
uum to give a crude solid which was purified by flash chromatog-
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 9.52 (br. s, 1 H, indole
NH), 8.84 (s, 1 H, 4-H), 8.19 (d, J = 7.9 Hz, 1 H, 5-H), 7.55–7.65
(m, 2 H, 7-H and 8-H), 7.32–7.40 (m, 1 H, 6-H), 5.74 (t, J = 6.6 Hz,
1 H, 14-H), 4.68 (dd, 1J = 8.6 Hz, 2J = 6.6 Hz, 1 H, 15-H), 4.39
(dd, 1J = 8.6 Hz, 2J = 6.6 Hz, 1 H, 15-HЈ), 4.04 (s, 3 H, COOCH3),
1.62 [s, 3 H, C(CH3)2], 1.58 [s, 3 H, C(CH3)2] ppm. 13C NMR
(100 MHz, CDCl3): δ = 166.5 (COOMe), 142.6 (C-1), 140.4 (C-3),
136.8 (Ar), 134.9 (Ar), 129.8 (Ar), 129.0 (Ar), 121.8 (Ar), 121.4
(Ar), 120.9 (Ar), 117.4 (Ar), 112.0 (Ar), 110.7 [C(CH3)2], 78.8 (C-
14), 69.3 (C-15), 52.6 (COOCH3), 26.3 [C(CH3)2], 25.0
[C(CH3)2] ppm. HRMS (ESI): calcd. for C18H19N2O4 [M + H]+
raphy (EtOAc/hexane, 1:4) to afford compound
9 (30.33 g,
62.59 mmol) as an epimeric mixture (cis/trans, 55:45) in a combined
yield of 97%. Data for cis epimer: m.p. 155.6–156.6 °C; [α]2D0
=
327.1345; found 327.1344. IR (neat): ν = 3410 (N–H), 2991, 1698
˜
1
–66.5 (c = 1.3, CHCl3). H NMR (400 MHz, CDCl3): δ = 8.18 (s, (C=O), 1628, 1435, 1349, 1264, 1213, 1136, 1055, 862, 752 cm–1.
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Pages: 10
Q. Zhang, J. Dong, X.-X. Shi, X. Lu
FULL PAPER
Methyl (S)-1-(1,2-Dihydroxyethyl)-9H-pyrido[3,4-b]indole-3-carb-
oxylate (7): To a solution of compound 10 (8.90 g, 27.27 mmol) in
tetrahydrofuran (80 mL) were added water (1 mL) and concen-
trated hydrochloric acid (2 mL). The resulting solution was stirred
at room temperature, and the reaction was monitored by TLC. Af-
ter the stirring was continued at room temperature for approxi-
mately 3 h, the reaction was complete. The solution was concen-
trated under vacuum to remove the THF, and the residue was parti-
tioned between ethyl acetate (80 mL) and an aqueous solution of
K2CO3 (10%, w/w, 40 mL). The aqueous phase was then extracted
with ethyl acetate (2ϫ50 mL). The organic extracts were combined
and dried with anhydrous Na2SO4. Evaporation of the solvent un-
der vacuum gave the crude product as a yellow solid. Recrystalli-
zation of the yellow solid in methanol afforded compound 7
0 °C with an ice bath. Methanesulfonyl chloride (4.66 g,
40.68 mmol) was added, and then DIPEA (N,N-diisopropylethyl-
amine, 8.39 g, 64.92 mmol) was added dropwise at 0 °C over
15 min. After the addition of the reagents, TLC showed that the
reaction was complete. Then, the reaction mixture was immediately
quenched by the addition of an aqueous solution of potassium carb-
onate (15%, w/v, 40 mL). The organic phase was separated, dried
with anhydrous MgSO4, and filtered. To the organic solution was
added benzoic acid (9.92 g, 81.23 mmol). The mixture was then
heated and stirred at 50 °C for 4 h. The reaction solvent was con-
centrated under vacuum, and the residue was partitioned between
ethyl acetate (100 mL) and an aqueous solution of potassium car-
bonate (15%, w/w, 75 mL). The organic layer was separated,
washed with brine (10 mL), and dried with anhydrous MgSO4. Af-
(7.10 g, 24.80 mmol, 91%) as yellow crystals; m.p. 198.2–199.4 °C. ter removal of the solvent, the crude product was purified by
1
[α]2D0 = +17.4 (c = 0.5, MeOH). H NMR (400 MHz, [D6]DMSO):
chromatography (EtOAc/hexane, 1:5) to give compound 13 (6.89 g,
δ = 13.17 (s, 1 H, indole NH), 9.07 (s, 1 H, 4-H), 8.48 (d, J = 10.89 mmol, 67%) as a pale yellow solid; m.p. 120.3–121.9 °C.
1
8.0 Hz, 1 H, 5-H), 7.85 (d, J = 8.2 Hz, 1 H, 8-H), 7.74 (dd, J =
[α]2D0 = +6.1 (c = 1.9, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
2
1
2
8.2 Hz, J = 7.4 Hz, 1 H, 7-H), 7.41 (dd, J = 8.0 Hz, J = 7.4 Hz, 9.51 (s, 1 H, indole NH), 8.86 (s, 1 H, 4-H), 8.18 (d, J = 7.9 Hz, 1
1 H, 6-H), 5.79 (t, J = 4.9 Hz, 1 H, 14-H), 4.08 (s, 3 H, COOCH3), H, 5-H), 8.12 (d, J = 7.4 Hz, 2 H, Ar in Bz), 7.52–7.62 (m, 2 H,
3.97–4.17 (m, 2 H, 15-H) ppm. 13C NMR (100 MHz, [D6]DMSO): Ar), 7.48 (dd, J = 7.8 Hz, J = 7.4 Hz, 2 H, Ar in Bz), 7.31–7.40
1
2
δ = 161.6 (COOMe), 144.8 (C-1), 143.1 (C-3), 133.3 (Ar), 131.1 (m, 3 H, Ar), 7.22–7.30 (m, 5 H, Ar), 7.09–7.18 (m, 9 H, Ar), 6.70
(Ar), 130.9 (Ar), 127.7 (Ar), 123.0 (Ar), 121.8 (Ar), 119.8 (Ar),
117.8 (Ar), 113.2 (Ar), 70.5 (C-14), 64.6 (C-15), 53.4 (CO-
(t, J = 3.9 Hz, 1 H, 14-H), 4.09 (d, J = 3.9 Hz, 2 H, 15-H), 4.02
(s, 3 H, COOCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.6
OCH3) ppm. HRMS (ESI): calcd. for C15H15N2O4 [M + H]+ (COOMe), 166.2 (PhCOO), 143.3 (C-1), 140.6 (C-3), 140.5 (Ar),
287.1032; found 287.1030. IR (KBr film): ν = 3257 (N–H), 3169 137.2 (Ar), 136.2 (Ar), 133.6 (Ar), 130.0 (Ar), 129.9 (Ar), 129.8
˜
(O–H), 2957, 1720 (C=O), 1626, 1520, 1434, 1360, 1272, 1078, 966, (Ar), 129.0 (Ar), 128.7 (Ar), 128.0 (Ar), 127.2 (Ar), 121.9 (Ar),
768 cm–1.
121.6 (Ar), 121.0 (Ar), 118.1 (Ar), 112.1 (Ar), 87.5 [C(Ph)3], 76.7
(C-14), 65.1 (C-15), 52.7 (COOCH3) ppm. HRMS (ESI): calcd. for
Methyl (S)-1-[1-Hydroxy-2-(trityloxy)ethyl]-9H-pyrido[3,4-b]indole-
3-carboxylate (11): Compound 7 (7.05 g, 24.63 mmol) and triethyl-
amine (4.98 g, 49.21 mmol) were dissolved in dichloromethane
(70 mL), and the solution was cooled to 0 °C by an ice bath. Tri-
phenylmethyl chloride (8.94 g, 32.07 mmol) was added in three por-
tions over 20 min. The ice bath was removed, and the mixture was
then stirred at room temperature, as the reaction was monitored by
TLC. After the stirring was continued for approximately 5 h, the
reaction was complete. Additional dichloromethane (100 mL) and
an aqueous potassium carbonate solution (10%, w/w, 50 mL) were
added, and the mixture was transferred to a separatory funnel. The
two layers were separated, and the aqueous phase was extracted
with dichloromethane (2ϫ30 mL). The extracts were combined
and dried with anhydrous MgSO4, and then the solvent was evapo-
rated to give the crude product as off-white crystals, which were
collected on a Büchner funnel and rinsed with a mixed solvent
(ethyl acetate/hexane, 1:4) to furnish compound 11 (11.59 g,
21.93 mmol, 89%); m.p. 205.4–206.2 °C. [α]2D0 = +9.4 (c = 1.1,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 9.91 (s, 1 H, indole
C41H32N2O5 [M]+ 632.2311; found 632.2328. IR (KBr film): ν =
˜
3335 (N–H), 3058, 2948, 1716 (C=O), 1626, 1598, 1493, 1449, 1350,
1262, 1108, 746, 707 cm–1.
Methyl (R)-[1-(Benzoyloxy)-2-hydroxyethyl]-9H-pyrido[3,4-b]indole-
3-carboxylate (6): To
a solution of compound 13 (5.80 g,
9.17 mmol) in acetonitrile (30 mL) and water (3 mL) was added
concentrated hydrochloric acid (2 mL). The mixture was stirred at
room temperature, and the reaction was monitored by TLC. After
stirring for approximately 4 h, the reaction was complete. The reac-
tion solution was diluted with ethyl acetate (70 mL), and an aque-
ous solution of potassium carbonate (15%, w/w, 30 mL) was
added. The organic phase was separated and washed with brine
(10 mL). The aqueous phase was then extracted with ethyl acetate
(2ϫ30 mL). The organic extracts were combined and dried with
anhydrous Na2SO4. Evaporation of the solvents under vacuum
gave the crude product which was purified by chromatography
(EtOAc/hexane, 1:4) to give compound 6 (3.08 g, 7.89 mmol, 86%);
m.p. 101.4–102.6 °C. [α]2D0 = –5.3 (c = 1.6, CHCl3). 1H NMR
NH), 8.76 (s, 1 H, 4-H), 8.14 (d, J = 7.8 Hz, 1 H, 5-H), 7.53 (dd, (400 MHz, [D6]DMSO): δ = 11.88 (s, 1 H, indole NH), 8.92 (s, 1
2
1J = 7.8 Hz, J = 7.5 Hz, 1 H, 6-H), 7.32–7.40 (m, 6 H, Ar), 7.21–
H, 4-H), 8.41 (d, J = 7.9 Hz, 1 H, 5-H), 7.88 (d, J = 7.8 Hz, 2 H,
7.27 (m, 10 H, Ar), 7.19 (d, J = 8.2 Hz, 1 H, 8-H), 5.42 (t, J = Ar in Bz), 7.84 (d, J = 8.2 Hz, 1 H, 8-H), 7.56–7.67 (m, 2 H, Ar),
1
2
1
5.7 Hz, 1 H, 14-H), 4.70 (br. s, 1 H, OH), 4.00 (s, 3 H, COOCH3),
3.82 (dd, 1J = 9.6 Hz, 2J = 5.7 Hz, 1 H, 15-H), 3.56 (dd, 1J =
9.6 Hz, 2J = 5.7 Hz, 1 H, 15-HЈ) ppm. 13C NMR (100 MHz,
CDCl3): δ = 166.6 (COOMe), 143.9 (C-1), 143.3 (C-3), 140.5 (Ar),
135.7 (Ar), 135.3 (Ar), 129.3 (Ar), 128.9 (Ar), 128.6 (Ar), 128.0
(Ar), 127.3 (Ar), 121.7 (Ar), 121.4 (Ar), 120.7 (Ar), 117.2 (Ar),
112.0 (Ar), 87.8 (CPh3), 73.2 (C-14), 67.9 (C-15), 52.6 (CO-
OCH3) ppm. HRMS (ESI): calcd. for C34H28N2O4 [M]+ 528.2049;
7.41 (dd, J = 7.8 Hz, J = 7.7 Hz, 2 H, Ar in Bz), 7.33 (dd, J =
2
7.6 Hz, J = 7.3 Hz, 1 H, Ar), 6.51 (d, J = 4.9 Hz, 1 H, OH), 5.57
1
2
(dd, J = 10.6 Hz, J = 4.7 Hz, 1 H, 14-H), 4.74–4.84 (m, 2 H, 15-
H), 3.94 (s, 3 H, COOCH3) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 166.0 (COOMe), 165.7 (PhCOO), 144.3 (C-1), 141.1
(C-3), 135.3 (Ar), 135.1 (Ar), 133.2 (Ar), 129.6 (Ar), 129.2 (Ar),
128.5 (Ar), 128.4 (Ar), 121.8 (Ar), 120.6 (Ar), 120.1 (Ar), 117.0
(Ar), 112.8 (Ar), 71.7 (C-14), 67.8 (C-15), 51.9 (COOCH3) ppm.
found 528.2051. IR (KBr film): ν = 3422 (N–H, O–H), 3055, 2918, HRMS (ESI): calcd. for C22H18N2O5 [M]+ 390.1216; found
˜
1719 (C=O), 1626, 1492, 1430, 1343, 1255, 1086, 745, 707 cm–1.
390.1215. IR (KBr film): ν = 3372 (N–H, O–H), 2950, 1718 (C=O),
˜
1626, 1498, 1434, 1350, 1263, 1111, 746, 712 cm–1.
Methyl (R)-[1-(Benzoyloxy)-2-(trityloxy)ethyl]-9H-pyrido[3,4-b]-
indole-3-carboxylate (13): Compound 11 (8.59 g, 16.25 mmol) was
dissolved in a chloroform (80 mL), and the solution was cooled to
Methyl (R)-1-(1,2-Dihydroxyethyl)-9H-pyrido[3,4-b]indole-3-carb-
oxylate (3): To a solution of compound 6 (1.08 g, 2.77 mmol) in
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20235
/KAP1
Date: 02-05-12 10:59:41
Pages: 10
Total Syntheses of Dichotomines A–D
absolute methanol (10 mL) was added triethylamine (0.84 g, solvent (EtOAc/hexane, 1:1). Filtration and rinsing with a small
8.30 mmol). The mixture was then heated to reflux and stirred at
this temperature for 5 h, and then TLC showed that the reaction
was complete. The removal of the solvent under vacuum gave the
crude product as an off-white solid which was collected on a
Büchner funnel and rinsed with small amount of ethyl acetate (2ϫ)
to furnish dichotomine C (0.745 g, 2.60 mmol, 94%); m.p. 196.7–
199.1 °C, ref.[3] m.p. 196–198 °C. [α]2D0 = –17.2 (c = 0.6, MeOH),
amount of ethyl acetate afforded dichotomine B (0.436 g,
1.60 mmol, 90%); m.p. 287.1–288.9 °C. [α]2D0 = –18.6 (c = 1.0,
MeOH), ref.[1] [α]2D7 = –19.0 (c = 1.00, MeOH). 1H NMR
(400 MHz, [D6]DMSO): δ = 11.83 (s, 1 H, indole NH), 8.86 (s, 1
H, 4-H), 8.39 (d, J = 7.6 Hz, 1 H, 5-H), 7.76 (d, J = 7.8 Hz, 1 H,
8-H), 7.60 (dd, J = 7.8 Hz, J = 7.4 Hz, 1 H, 7-H), 7.30 (dd, J =
7.6 Hz, 1J = 7.4 Hz, 1 H, 6-H), 5.19 (t, J = 5.6 Hz, 1 H, 14-H),
3.82–3.92 (m, 2 H, 15-H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 166.6 (COOH), 145.2 (C-1), 141.0 (C-3), 135.6 (Ar), 134.9 (Ar),
128.5 (Ar), 121.9 (Ar), 120.7 (Ar), 120.0 (Ar), 116.0 (Ar), 112.6
(Ar), 73.6 (C-14), 65.4 (C-15) ppm. HRMS (ESI): calcd. for
1
2
1
ref.[1] [α]2D7 = –16.6 (c = 0.50, MeOH). H NMR (400 MHz, [D6]-
1
DMSO): δ = 11.64 (s, 1 H, indole NH), 8.83 (s, 1 H, 4-H), 8.37 (d,
1
J = 7.9 Hz, 1 H, 5-H), 7.76 (d, J = 8.0 Hz, 1 H, 8-H), 7.58 (dd, J
= 8.0 Hz, 2J = 7.2 Hz, 1 H, 7-H), 7.29 (dd, 1J = 7.9 Hz, 2J = 7.2 Hz,
1 H, 6-H), 5.90–5.93 (m, 1 H, 14-H), 5.10 (br. s, 1 H, OH), 4.84 C14H13N2O4 [M + H]+ 273.9875; found 273.0872. IR (KBr film):
(br. s, 1 H, OH), 3.91 (s, 3 H, COOCH3), 3.75–4.00 (m, 2 H, 15-
H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 161.6 (COOMe),
144.8 (C-1), 143.1 (C-3), 133.3 (Ar), 131.1 (Ar), 130.9 (Ar), 127.7
(Ar), 123.0 (Ar), 121.8 (Ar), 119.8 (Ar), 117.8 (Ar), 113.2 (Ar), 70.5
(C-14), 64.6 (C-15), 53.4 (COOCH3) ppm. HRMS (ESI): calcd. for
C15H15N2O4 [M + H]+ 287.1032; found 287.1030. IR (KBr film):
ν = 3254 (N–H, O–H), 3069, 2962, 2906, 1651 (C=O), 1628, 1599,
˜
1361, 1221, 1121, 1059, 899, 767 cm–1.
Methyl
(R)-[1-(Benzoyloxy)-2-(methylsulfonyloxy)ethyl]-9H-pyr-
(4.01 g,
ido[3,4-b]indole-3-carboxylate (14): Compound
6
10.27 mmol) was dissolved in dichloromethane (40 mL), and the
solution was cooled to 0 °C by an ice bath. Methanesulfonyl chlor-
ide (2.35 g, 20.51 mmol) was added, and then triethylamine (3.12 g,
30.83 mmol) was added dropwise over 10 min. After the addition
was finished, TLC showed that the reaction was complete. The re-
action was then immediately quenched by the addition of water
(20 mL), and the mixture was transferred to a separatory funnel.
The organic phase was separated and washed with an aqueous po-
tassium carbonate solution to pH 8. The organic solution was dried
with anhydrous MgSO4 and concentrated to dryness to give a crude
product which was purified by flash chromatography (EtOAc/hex-
ane, 1:3) to produce compound 14 (4.52 g, 9.65 mmol, 94%); m.p.
142.1–143.3 °C. [α]2D0 = +9.0 (c = 0.7, CHCl3). 1H NMR (400 MHz,
[D6]DMSO): δ = 12.34 (s, 1 H, indole NH), 8.98 (s, 1 H, 4-H), 8.43
(d, J = 7.6 Hz, 1 H, 5-H), 8.10 (d, J = 8.1 Hz, 2 H, Ar in Bz), 7.77
ν = 3169 (N–H, O–H), 3059, 2957, 1720 (C=O), 1626, 1434, 1360,
˜
1078, 966, 768 cm–1.
Butyl
(R)-1-(1,2-Dihydroxyethyl)-9H-pyrido[3,4-b]indole-3-carb-
oxylate (4): To a solution of compound 3 (0.74 g, 2.58 mmol) in n-
butanol (10 mL) was added a catalytic amount of potassium car-
bonate (72 mg, 0.52 mmol). The resulting mixture was heated to
reflux and stirred for approximately 4 h. After TLC showed that
the reaction was complete, the reaction solution was concentrated
under vacuum to remove the n-butanol, and the residue was dis-
solved in ethyl acetate (10 mL). The resulting mixture was then
filtered through a thin layer of Celite to remove the catalytic
amount of potassium carbonate. The solvent was evaporated to
dryness, and the residue was triturated with a mixed solvent (meth-
anol/water, 2:1). After suction filtration and drying under vacuum,
1
(d, J = 8.0 Hz, 1 H, 8-H), 7.62–7.71 (m, 2 H, Ar), 7.55 (dd, J =
dichotomine D (0.79 g, 2.41 mmol, 93%) was obtained; m.p. 199.5– 8.1 Hz, 2J = 7.5 Hz, 2 H, Ar in Bz), 7.35 (dd, 1J = 7.6 Hz, 2J =
200.2 °C. [α]2D0 = –2.2 (c = 0.8, CHCl3), ref.[1] [α]2D7 = –1.8 (c = 0.75,
7.2 Hz, 1 H, 6-H), 6.82 (dd, J = 8.2 Hz, J = 3.8 Hz, 1 H, 14-H),
5.14 (dd, 1J = 11.0 Hz, 2J = 8.2 Hz, 1 H, 15-H), 4.92 (dd, 1J =
11.0 Hz, 2J = 3.8 Hz, 1 H, 15-HЈ), 3.91 (s, 3 H, COOCH3), 3.32 (s,
3 H, SO2CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 165.6
(PhCOO), 165.2 (COOCH3), 141.2 (C-1), 137.8 (C-3), 136.2 (Ar),
1
2
1
CHCl3). H NMR (400 MHz, [D6]DMSO): δ = 8.80 (s, 1 H, 4-H),
8.36 (d, J = 7.6 Hz, 1 H, 5-H), 7.75 (d, J = 7.8 Hz, 1 H, 8-H), 7.57
1
2
1
2
(dd, J = 7.8 Hz, J = 7.3 Hz, 1 H, 7-H), 7.28 (dd, J = 7.6 Hz, J
= 7.3 Hz, 1 H, 6-H), 5.08 (t, J = 7.2 Hz, 1 H, 14-H), 4.30–4.38 [m,
2 H, COOCH2(CH2)2CH3], 3.79–3.94 (m, 2 H, 15-H), 1.68–1.81 135.2 (Ar), 133.8 (Ar), 129.6 (Ar), 129.2 (Ar), 129.1 (Ar), 128.9
(m, 2 H, CO2CH2CH2CH2CH3), 1.39–1.54 [m, 2 H, CO2(CH2)2- (Ar), 128.8 (Ar), 122.2 (Ar), 120.9 (Ar), 120.6 (Ar), 118.2 (Ar),
CH2CH3], 0.97 [t, J = 7.4 Hz, 3 H, CO2(CH2)3CH3] ppm. 13C
112.5 (Ar), 71.8 (C-14), 69.0 (C-15), 52.1 (COOCH3), 37.0
NMR (100 MHz, [D6]DMSO): δ = 165.5 (COOBu), 146.1 (C-1), (SO2CH3) ppm. HRMS (ESI): calcd. for C23H21N2O7S [M + H]+
141.3 (C-3), 135.3 (Ar), 135.1 (Ar), 128.2 (Ar), 128.1 (Ar), 121.7
(Ar), 120.7 (Ar), 119.8 (Ar), 116.5 (Ar), 112.9 (Ar), 74.7 (C-14),
65.3 (C-15), 64.2 [CO2CH2(CH2)2CH3], 30.4 (CO2CH2CH2-
CH2CH3), 18.8 [CO2(CH2)2CH2CH3], 13.6 [CO2(CH2)3CH3] ppm.
HRMS (ESI): calcd. for C18H21N2O4 [M + H]+ 329.1501; found
469.1069; found 469.1071. IR (KBr film): ν = 3374 (N–H), 3031,
˜
2936, 1726 (C=O), 1702 (C=O), 1625, 1599, 1436, 1356, 1268, 1174,
1113, 965, 715 cm–1.
Methyl (R)-[1-(Benzoyloxy)-2-iodoethyl]-9H-pyrido[3,4-b]indole-3-
carboxylate (5): To a solution of compound 14 (4.02 g, 8.58 mmol)
in acetone (30 mL) was added sodium iodide (6.44 g, 42.96 mmol).
The suspension was then heated at reflux and stirred under argon
overnight. After the reaction was cooled to room temperature, the
solvent was removed by distillation under vacuum, and the residue
was partitioned between ethyl acetate (80 mL) and an aqueous
solution of sodium sulfite (10%, w/w, 30 mL). The organic phase
was separated and dried with anhydrous MgSO4. After removal of
the solvent, the crude product was purified by flash chromatog-
raphy (EtOAc/hexane, 1:3) to give compound 5 (3.52 g, 7.04 mmol,
82%) as a white solid; m.p. 187.3–188.1 °C. [α]2D0 = +10.1 (c = 0.5,
329.1502. IR (KBr film): ν = 3381 (N–H), 3241 (O–H), 2953, 1698
˜
(C=O), 1625, 1568, 1465, 1374, 1346, 1247, 1043, 751 cm–1.
(R)-1-(1,2-Dihydroxyethyl)-9H-pyrido[3,4-b]indole-3-carboxylic
Acid (2): To a solution of compound 3 (0.51 g, 1.78 mmol) in meth-
anol (6 mL) was added a solution of sodium hydroxide (0.215 g,
5.38 mmol) in water (0.6 mL). The mixture was warmed to 60 °C,
and the stirring was continued at 60 °C for 4 h. After the reaction
solution was cooled to room temperature, acetic acid (0.64 g,
10.66 mmol) was added dropwise. After the stirring was continued
at room temperature for 3 h, the solvent was evaporated to dryness
under vacuum, and the residue was triturated with absolute meth-
anol (15 mL). The mixture was passed through a thin layer of Celite
(2 cm), and the pad of Celite was washed with absolute methanol
(2ϫ). The eluents were combined and concentrated under vacuum
to give the crude solid product which was triturated with a mixed
1
CHCl3). H NMR (400 MHz, [D6]DMSO): δ = 12.33 (s, 1 H, in-
dole NH), 8.93–8.98 (m, 1 H, Ar), 8.40–8.44 (m, 1 H, 5-H and 4-
H), 8.06–8.10 (m, 2 H, Ar), 7.46–7.80 (m, 5 H, Ar), 7.32–7.36 (m,
1 H, Ar), 6.64–6.70 (m, 1 H, 14-H), 3.93–3.97 (m, 2 H, 15-H), 3.90
(s, 3 H, COOCH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20235
/KAP1
Date: 02-05-12 10:59:41
Pages: 10
Q. Zhang, J. Dong, X.-X. Shi, X. Lu
165.6 (PhCOO), 165.0 (COOCH3), 141.2 (C-1), 139.9 (C-3), 136.1 (1.37 g, 22.81 mmol) was added dropwise. After the stirring was
FULL PAPER
(Ar), 134.9 (Ar), 133.7 (Ar), 129.5 (Ar), 129.1 (Ar), 129.0 (Ar),
128.8 (Ar), 122.2 (Ar), 120.8 (Ar), 120.5 (Ar), 117.9 (Ar), 112.5
(Ar), 74.1 (C-14), 52.1 (COOCH3), 5.0 (C-15) ppm. HRMS (ESI):
calcd. for C22H18IN2O4 [M + H]+ 501.0311; found 501.0313. IR
continued at room temperature for 3 h, the solvent was evaporated
to dryness under vacuum, and the residue was triturated with abso-
lute methanol (15 mL). The mixture was passed through a thin
layer of Celite (2 cm), and the pad of Celite was washed with abso-
(KBr film): ν = 3393 (N–H), 2922, 2852, 1730 (C=O), 1705 (C=O), lute methanol (2ϫ). The eluents were combined and concentrated
˜
1625, 1597, 1432, 1349, 1263, 1111, 747, 712 cm–1.
under vacuum to give the crude solid product which was triturated
with a mixed solvent (EtOAc/hexane = 1:1). Filtration and rinsing
with a small amount of ethyl acetate afforded dichotomine A
(0.91 g, 3.55 mmol, 93%) as off-white crystals; m.p. 267.3–
267.7 °C. [α]2D0 = –10.1 (c = 1.2, MeOH), ref.[1] [α]2D7 = –9.7 (c =
0.85, MeOH). 1H NMR (400 MHz, [D6]DMSO): δ = 11.86 (s, 1 H,
indole NH), 8.89 (s, 1 H, 4-H), 8.40 (d, J = 7.9 Hz, 1 H, 5-H), 7.80
Methyl (S)-1-[1-(Benzoyloxy)ethyl]-9H-pyrido[3,4-b]indole-3-carb-
oxylate (15): A solution of compound 5 (3.02 g, 6.04 mmol) in ethyl
acetate (35 mL) was placed in a three-necked round-bottomed
flask, which was equipped with a magnetic stir bar, a gas inlet, and
an outlet. The Pd/C catalyst (10%, 300 mg) was added, and the
flask was then purged several times with hydrogen gas. The reaction
mixture was vigorously stirred under an atmosphere of hydrogen
gas at room temperature for 10 h. After the reaction was complete,
the mixture was passed through a thin layer of Celite to remove
the catalyst. Evaporation of solvent under vacuum gave a pale yel-
low solid which was washed several times with a mixed solvent
(ethyl acetate/hexane, 1:2) to afford compound 15 (2.19 g,
5.85 mmol, 97%) as an off-white solid; m.p. 201.2–203.7 °C. [α]2D0
1
2
(d, J = 8.0 Hz, 1 H, 8-H), 7.61 (dd, J = 7.5 Hz, J = 8.0 Hz, 1 H,
1
2
7-H), 7.27–7.38 (dd, J = 7.9 Hz, J = 7.5 Hz, 1 H, 6-H), 5.36 (q,
J = 6.5 Hz, 1 H, 14-H), 1.63 (d, J = 6.5 Hz, 3 H, 15-H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 172.0 (COOH), 153.2 (C-1),
146.3 (C-3), 141.0 (Ar), 139.0 (Ar), 133.8 (Ar), 133.6 (Ar), 127.0
(Ar), 126.1 (Ar), 125.2 (Ar), 121.3 (Ar), 118.0 (Ar), 73.9 (C-14),
28.3 (C-15) ppm. HRMS (ESI): calcd. for C14H13N2O3 [M + H]+
257.0926; found 257.0920. IR (KBr film): ν = 3242 (N–H, O–H),
˜
1
= –20.2 (c = 0.2, CHCl3). H NMR (400 MHz, CDCl3): δ = 9.54
2921, 2851, 1706 (C=O), 1645, 1595, 1448, 1358, 1122, 1056, 896,
(s, 1 H, indole NH), 8.86 (s, 1 H, 4-H), 8.17 (d, J = 7.9 Hz, 1 H,
5-H), 8.08 (d, J = 7.7 Hz, 2 H, Ar in Bz), 7.52–7.63 (m, 3 H, Ar),
758 cm–1.
2
7.43 (dd, 1J = 7.8 Hz, J = 7.7 Hz, 2 H, Ar in Bz), 7.31–7.38 (m, 1
Methyl {(S)-1-[(S)-1-Tosylpyrrolidine-2-carbonyloxy]ethyl}-9H-pyr-
ido[3,4-b]indole-3-carboxylate (17): To a solution of compound 16
(0.50 g, 1.85 mmol) in dichloromethane (8 mL) was added (S)-1-
tosylpyrrolidine-2-carbonyl chloride (0.80 g, 2.78 mmol). After the
solution was cooled to 0 °C with an ice bath, a solution of triethyl-
amine (0.37 g, 3.66 mmol) in dichloromethane (5 mL) was added
dropwise over 10 min. After the addition was finished, the ice bath
was removed, and the solution was stirred at room temperature for
3 h. An aqueous solution of potassium carbonate (10%, w/w,
10 mL) was added, and the mixture was transferred to a separatory
funnel. The organic phase was separated and washed successively
with water (5 mL) and brine (5 mL). After the organic solution
was dried with anhydrous MgSO4, the solvent was removed under
vacuum to give the crude solid product which was purified by flash
chromatography (EtOAc/hexane, 1:6) to afford compound 17
(0.82 g, 1.57 mmol, 85%) as an off-white solid; m.p. 267.3–
267.7 °C. [α]2D0 = –101 (c = 0.42, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 10.44 (s, 1 H, indole NH), 8.80 (s, 1 H, 4-H), 8.11 (d,
J = 7.8 Hz, 1 H, 5-H), 7.66–7.776 (m, 3 H, Ar), 7.50 (dd, 1J =
H, 6-H), 6.81 (q, J = 6.6 Hz, 1 H, 14-H), 4.06 (s, 3 H, COOCH3),
2.02 (d, J = 6.6 Hz, 3 H, 15-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 166.9 (PhCOO), 166.6 (COOCH3), 142.0 (C-1), 140.6 (C-3),
137.1 (Ar), 135.4 (Ar), 133.5 (Ar), 130.2 (Ar), 129.8 (Ar), 129.7
(Ar), 129.1 (Ar), 128.6 (Ar), 121.8 (Ar), 121.7 (Ar), 121.1 (Ar),
118.0 (Ar), 112.2 (Ar), 72.3 (C-14), 52.7 (COOCH3), 18.6 (C-
15) ppm. HRMS (ESI): calcd. for C22H19N2O4 [M + H]+ 375.1345;
found 375.1342. IR (KBr film): ν = 3389 (N–H), 3063, 2927, 1704
˜
(C=O), 1626, 1597, 1435, 1354, 1260, 1115, 1061, 744, 714 cm–1.
Methyl (S)-1-(1-Hydroxyethyl)-9H-pyrido[3,4-b]indole-3-carboxyl-
ate (16): To a solution of compound 15 (2.01 g, 5.37 mmol) in abso-
lute methanol (20 mL) was added triethylamine (1.63 g,
16.11 mmol). The mixture was heated to reflux and stirred at this
temperature for 4 h, and then TLC showed that the reaction was
complete. The removal of the solvent under vacuum gave the crude
product as an off-white solid which was triturated with a mixed
solvent (EtOAc/hexane, 1:1). Filtration of the mixture and drying
the solid furnished compound 16 (1.33 g, 4.92 mmol, 92%); m.p.
2
7.6 Hz, J = 7.5 Hz, 1 H, 8-H), 7.20–7.30 (m, 3 H, 7-H, 6-H, and
Ar), 6.44 (q, J = 6.1 Hz, 1 H, 14-H), 4.26 (d, J = 7.7 Hz, 1 H,
137.3–138.7 °C. [α]2D0
=
–67.7 (c = 0.7, MeOH). 1H NMR
(400 MHz, [D6]DMSO): δ = 11.71 (s, 1 H, indole NH), 8.87 (s, 1
H, 4-H), 8.35 (d, J = 7.7 Hz, 1 H, 5-H), 7.83 (d, J = 8.0 Hz, 1 H,
OCOCHN), 3.98 (s,
3 H, COOCH3), 3.48–3.60 (m, 1 H,
NCHHCH2CH2), 3.20 (dd, 1J = 15.5 Hz, 2J = 8.7 Hz, 1 H,
NCHHCH2CH2), 2.37 (s, 3 H, ArCH3), 2.06–2.15 (m, 1 H,
NCH2CHHCH2), 1.90–2.02 (m, 1 H, NCH2CHHCH2), 1.80 (d, J
1
2
1
8-H), 7.56 (dd, J = 8.0 Hz, J = 7.5 Hz, 1 H, 7-H), 7.28 (dd, J =
7.7 Hz, 2J = 7.5 Hz, 1 H, 6-H), 5.95 (d, J = 3.7 Hz, 1 H, OH), 5.34
(q, J = 6.6 Hz, 1 H, 14-H), 3.94 (s, 3 H, COOCH3), 1.65 (d, J =
6.6 Hz, 3 H, 15-H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
166.1 (COOCH3), 148.7 (C-1), 141.0 (C-3), 135.1 (Ar), 134.0 (Ar),
128.4 (Ar), 128.3 (Ar), 121.6 (Ar), 120.7 (Ar), 119.9 (Ar), 116.6
(Ar), 112.8 (Ar), 69.8 (C-14), 51.8 (COOCH3), 22.6 (C-15) ppm.
HRMS (ESI): calcd. for C15H15N2O3 [M + H]+ 271.1083; found
= 6.1 Hz, 3 H, 15-H), 1.51–1.67 (m, 2 H, NCH2CH2CH2) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 170.2 (COOCH), 166.7 (COOCH3),
144.5 (C-1), 142.9 (C-3), 141.4 (Ar), 136.3 (Ar), 134.3 (Ar), 133.4
(C-10), 130.1 (Ar), 129.0 (Ar), 127.6 (Ar), 121.4 (Ar), 121.3 (Ar),
120.7 (Ar), 117.7 (Ar), 112.9 (Ar), 76.2 (C-14), 61.0 (OCOCH),
52.7 (NCH2), 49.3 (COOCH3), 29.6 (NCHCH2CH2), 24.8
(NCH2CH2CH2), 21.6 (ArCH3), 19.8 (C-15) ppm. HRMS (ESI):
calcd. for C27H28N3O6S [M + H]+ 522.1699; found 522.1698. IR
271.1077. IR (KBr film): ν = 3344 (N–H), 3263 (O–H), 2968, 2926,
˜
1715 (C=O), 1625, 1566, 1497, 1434, 1310, 1261, 1014, 758,
742 cm–1.
(KBr film): ν = 3373 (N–H), 2923, 1733 (C=O), 1625, 1596, 1497,
˜
1453, 1346, 1245, 1156, 1098, 816, 745, 665, 592 cm–1.
(S)-1-(1-Hydroxyethyl)-9H-pyrido[3,4-b]indole-3-carboxylic
Acid
(1): To a solution of compound 16 (1.03 g, 3.81 mmol) in methanol
(10 mL) was added a solution of sodium hydroxide (0.46 g,
11.50 mmol) in water (0.6 mL). The mixture was warmed to 60 °C,
and the stirring was continued at this temperature for 4 h. After
the reaction solution was cooled to room temperature, acetic acid
CCDC-855428 (for 17) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20235
/KAP1
Date: 02-05-12 10:59:41
Pages: 10
Total Syntheses of Dichotomines A–D
Angew. Chem. 2011, 123, 8692–8719; Angew. Chem. Int. Ed.
2011, 50, 8538–8564; d) X.-X. Shi, S.-L. Liu, W. Xu, Y.-L. Xu,
Tetrahedron: Asymmetry 2008, 19, 435–442.
Supporting Information (see footnote on the first page of this arti-
cle): Crystal data and structure refinement for compound 17; 1H
and 13C NMR spectra for compounds 1–11 and 13–17.
[5] C. R. Schmid, J. D. Bryant, M. Dowlatzedah, J. L. Phillips,
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Kitahara, T. Toma, J. Shimokawa, T. Fukuyama, Org. Lett.
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Acknowledgments
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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Received: February 28, 2012
Published Online: ᭿
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Job/Unit: O20235
/KAP1
Date: 02-05-12 10:59:41
Pages: 10
Q. Zhang, J. Dong, X.-X. Shi, X. Lu
FULL PAPER
Total Synthesis
Q. Zhang, J. Dong, X.-X. Shi,*
X. Lu .............................................. 1–10
Total Syntheses of Dichotomines A–D and
the Stereochemical Revision of Dichotom-
ines B–D
Keywords: Total synthesis / Asymmetric
synthesis / Nitrogen heterocycles / Alk-
aloids / Configuration determination
New asymmetric total syntheses of (–)-di-
chotomines A–D (1–4) starting from l-
tryptophan methyl ester and 2,3-O-iso-
stereogenic center of (–)-dichotomine A (1)
was reconfirmed as (S), whereas the absol-
ute configurations of the stereogenic cen-
ters of (–)-dichotomines B–D (2–4) were re-
vised as (R).
propylidene-d-glyceraldehyde
are
de-
scribed. The absolute configuration of the
10
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