An efficient and general method for the stereodivergent syntheses of tadalafil-like tetracyclic compounds

Article abstract of DOI:10.1002/ejoc.200901378

A clean and general DBU-catalyzed epimerization at C-12a position of the tadalafil-like tetracyclic compounds has been fully studied. In addition, by using this clean epimerization as the key step, four stereomers of 6-d ₁-tadalafil were stereodivergently synthesized from, both L- and D-tryptophan methyl ester hydrochlorides and deuterated piperonal.

Full text of DOI:10.1002/ejoc.200901378

FULL PAPER
DOI: 10.1002/ejoc.200901378
An Efficient and General Method for the Stereodivergent Syntheses of
Tadalafil-Like Tetracyclic Compounds
Sen Xiao,[a] Xiao-Xin Shi,*[a] Feng Ni,[a] Jing Xing,[a] Jing-Jing Yan,[a] and Shi-Ling Liu[a]
Keywords: Nitrogen heterocycles / Epimerization / Tadalafil analogue / Stereodivergent synthesis
A clean and general DBU-catalyzed epimerization at C-12a
position of the tadalafil-like tetracyclic compounds has been
fully studied. In addition, by using this clean epimerization
as the key step, four stereomers of 6-d1-tadalafil were stereo-
divergently synthesized from both and -tryptophan
methyl ester hydrochlorides and deuterated piperonal.
L-
D
tuted tadalafil-like tetracyclic compound 2 can be easily
synthesized according to a known two-step procedure
(Scheme 1).[1b] But synthesis of trans (6S,12aR)- or
(6R,12aS)-tetracyclic compound 3 (Scheme 2) remains to be
investigated. We have just observed an excellent transforma-
tion of tadalafil into 12a-epi-tadalafil (6R,12aS-stereomer)
via DBU-catalyzed epimerization at C-12a position.[7] If
this epimerization could be successfully applied to a variety
of tetracyclic compound 2, all four stereomers of tadalafil-
like tetracyclic compounds could thus be stereodivergently
synthesized from both - and -tryptophan (Scheme 2).
Introduction
In the recent years, the syntheses of tadalafil (Cialis®,
IC351) and its analogues have aroused much interest from
synthetic and medicinal chemists,[1] because it is a cGMP
specific Type V phosphodiesterase (PDE5) inhibitor, and
this kind of compounds could be used for the treatment of
cardiovascular disease[2] and erectile dysfunction
(ED).[1d,1e,3]
Although tadalafil and its analogues possess two stereo-
genic chiral centers at C-6 and C-12a positions in the tetra-
cyclic scaffold, and have four stereomers with (6R,12aR),
(6R,12aS), (6S,12aS) and (6S,12aR)-configurations, respec-
tively, researches seemed to be focused on the (6R,12aR)-
stereomer, while the three other stereomers were less investi-
gated. However, many similar tetracyclic compounds, that
possess different configurations of both chiral centers, ex-
hibited various other biological activities,[4] or can be used
as intermediates in the pharmaceutical syntheses.[5] There-
fore, highly stereoselective syntheses of all four stereomers
of tadalafil-like compounds are of considerable significance.
Scheme 1. Preparation of compound 2 from 1,3-disubstituted-tetra-
hydro-β-carboline 1.
Results and Discussion
By using cis (1S,3S)- or (1R,3R)-1,3-disubstituted-tetra-
hydro-β-carboline 1 as starting material, which can be
stereospecifically prepared from the Pictet–Spengler reac-
tion of -tryptophan methyl ester hydrochloride or -tryp-
tophan methyl ester hydrochloride with various aldehydes
via a CIAT (crystallization-induced asymmetric transfor-
mation) process,[6] cis (6S,12aS)- or (6R,12aR)-2,6-disubsti-
In order to gain a better insight into the base-catalyzed
epimerization and to investigate the scope and limitation of
the epimerization, all twenty tetracyclic compounds 2a–2t
were prepared from (1S,3S)-1,3-disubstituted-tetrahydro-β-
carbolines 1 (Scheme 1), and were exposed to 0.5 equiv. of
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) in a mixed sol-
vent of DMSO and ethanol (DMSO/EtOH = 1:5) at reflux.
The results are summarized in Table 1. It can be seen that
all the twenty cis tetracyclic compounds 2a–2t were success-
fully epimerized under this condition to afford trans
(6S,12aR)-2,6-disubstituted tetracyclic compounds 3a–3t in
excellent yields (Table 1, entries 1–20). Other bases such as
NaOH, NaOEt and K2CO3 can also be used for the epi-
merization, but DBU gave the best yields.
[a] Department of Pharmaceutical Engineering, School of Phar-
macy, East China University of Science and Technology,
130 Mei-Long Road, Shanghai 200237, P. R. Republic of China
Fax: +86-021-64251033
E-mail: xxshi@ecust.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901378.
Eur. J. Org. Chem. 2010, 1711–1716
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Xiao, X.-X. Shi, F. Ni, J. Xing, J.-J. Yan, S.-L. Liu
FULL PAPER
Table 2. The reversed epimerization at C-12a position of compound
3 to form compound 2.
Entry
3
Base (equiv.) Conditions[a]
DBU (2) 80 °C, 12 h
NaOH (0.5) 50 °C, 8 h
2
% Yield[b]
1
2
3
4
5
6
7
8
3a
3a
3a
3b
3b
3j
2a
2a
2a
2b
2b
2j
0
0
0
0
0
0
0
0
NaOEt (1)
DBU (2)
NaOEt (1)
DBU (2)
DBU (2)
DBU (2)
70 °C, 8 h
80 °C, 12 h
70 °C, 8 h
80 °C, 12 h
80 °C, 12 h
80 °C, 12 h
3m
3r
2m
2r
[a] In the mixed solvent of DMSO and EtOH (1:5). [b] 91–98% of
compounds 3a, 3b, 3j, 3m and 3r were recovered.
Scheme 2. Stereodivergent syntheses of all four stereomers of tadal-
afil and its analogues from both - and -tryptophan.
Table 1. The base-catalyzed epimerization at C-12a position of
compound 2 to form compound 3.[a]
.
Entry
2
R1
R2
3
% Yield[b]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
3,4-(OCH2O)-C6H3 Et
3,4-(OCH2O)-C6H3 Me
3,4-(OCH2O)-C6H3 nBu
3,4-(OCH2O)-C6H3 Bn
3,4-(OCH2O)-C6H3 2-HE[c]
3,4-(OCH2O)-C6H3 iPr
3a
3b
3c
3d
3e
3f
3g
3h
3i
98
98
96
97
95
95
97
96
96
97
98
98
97
95
96
96
97
94
95
96
Me
Me
Me
Me
Me
Et
nBu
Bn
9
10
11
12
13
14
15
16
17
18
19
20
2j
2k
2l
3j
3k
3l
3,4,5-(OMe)3-C6H2 Me
3,4,5-(OMe)3-C6H2 Et
2m
2n
2o
2p
2q
2r
2s
2t
n-Hex
n-Hex
Ph
Me
Bn
Et
3m
3n
3o
3p
3q
3r
3s
3t
Scheme 3. A plausible mechanism for the base-catalyzed epimeri-
zation.
Ph
Bn
Me
iPr
Bn
iPr
2-OMe-C6H4
2-OMe-C6H4
2-OEt-C6H4
2-Cl-C6H4
As can also be seen from Scheme 3, the epimerization
seems to be reversible, because the enolate I-A can also be
formed from the reaction of compound 3 with a base. But
why did we not observe any evidence of the backward epi-
merization from compound 3 to compound 2 (Table 2)?
This is probably due to the fact that there is a large energy
[a] Condition: 0.5 equiv. of DBU, refluxing (80 °C) for 3 h in the
mixed solvent of DMSO and EtOH (1:5). [b] Isolated yield. [c] 2-
Hydroxyethyl.
It is worthy to note that the base-catalyzed epimerization barrier between compounds 3 and 2, and compound 3 is
at C-3 position of 1,2,3-trisubstituted-tetrahydro-β-carbol- much more stable than compound 2. Comparison between
ines was reversible and gave a mixture of epimers in equilib- the conformations of compounds 2 and 3 may support this
rium,[8] but here the epimerization of compounds 2a–2t was assumption. As shown in Scheme 4, compound 2 has a
complete and gave compounds 3a–3t in almost quantitative more strained and less stable conformation in which the
yields. Moreover, when compounds 3a, 3b, 3j, 3m and 3r fused tetrahydro-β-carboline and piperazine have cis chair–
were treated with weak or strong bases in a mixture of sol- chair junction, thermodynamic instability of compound 2
vents (DMSO and ethanol, 1:5) under different conditions might be due to repulsion between a carbonyl group (C-1)
(Table 2, Entries 1–8), no reversed epimerization was ob- and the indole ring; while compound 3 has a less strained
served at all.
and more stable conformation in which the fused tetra-
The base-catalyzed epimerization probably occurs via hydro-β-carboline and piperazine have trans chair–chair
two steps (Scheme 3), the first step being the reaction of junction.
compound 2 with a base to form an enolate anion I-A, and
The cis structure of compounds 2a–2t and trans structure
the second step a protonation of the enolate I-A to form of compounds 3a–3t can be unequivocally determined by
compound 3. Protonation on the Si face of sp2-hybrid C- 2D NMR technique and NOE (nuclear Overhauser effect)
1
12a of enolate I-A produces compound 3, while protonation analysis. For example, in the H–1H NOESY spectra of cis
on the Re face of sp2-hybrid C-12a of enolate I-A regener- compound 2b (Figure 1), the proton at C-6 and the proton
ates compound 2. Another enolate I-B is likely formed un- at C-12a have an obvious correlation spot, meaning that H-
1
der the same basic condition, but it does not change com- 6 and H-12a have cis relationship; while in H-1H NOESY
pound 2 after protonation.
spectra of trans compound 3b (Figure 2), the proton at C-
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Eur. J. Org. Chem. 2010, 1711–1716

Stereodivergent Syntheses of Tadalafil-Like Tetracyclic Compounds
Scheme 4. Conformations of compounds 2 and 3.
12a does not correlate with the proton at C-6, but it corre-
lates with the two neighboring protons on the aromatic ring
at C-6 position, meaning that H-6 and H-12a have trans
relationship.
1
Figure 2. H-1H NOESY spectra and NOE of trans compound 3b.
same sequence. Four stereomers of 6-d1-tadalafil can thus
be stereodivergently synthesized from both - and -trypto-
phan methyl ester hydrochlorides.
1
Figure 1. H-1H NOESY spectra and NOE of cis compound 2b.
The clean epimerization described above provides a good
and general method for stereodivergent syntheses of tadal-
afil-like tetracyclic compounds. For example, as depicted in
Scheme 5, when we started with -tryptophan methyl ester
hydrochloride and the deuterated piperonal 4, which was
prepared as described in Scheme 6 via deprotection of a
deuterated dithiane 5, we could first obtain 1,3-disubsti-
tuted tetrahydro-β-carboline (1S,3S)-6. The ent-6-d1-tadal-
afil (6S,12aS)-7 was then obtained by following the two
steps shown in Scheme 1, and 6-epi-6-d1-tadalafil
(6S,12aS)-7 was finally obtained via the base-catalyzed epi-
merization. If we started with -tryptophan methyl ester
Scheme 5. Stereodivergent syntheses of four stereomers of 6-d1-tad-
alafil from both - and -tryptophan methyl ester hydrochlorides.
Four deuterated compounds (6R,12aR)-7, (6R,12aS)-7,
hydrochloride, d1-tadalafil (6R,12aR)-7 and 12a-epi-6-d1- (6S,12aS)-7 and (6S,12aR)-7 may be quite useful for drug
tadalafil (6R,12aS)-7 could be obtained after following the metabolism studies,[9] because they are optically pure, and
Eur. J. Org. Chem. 2010, 1711–1716
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1713

S. Xiao, X.-X. Shi, F. Ni, J. Xing, J.-J. Yan, S.-L. Liu
FULL PAPER
7.7 Hz, 1 H), 11.05 (br. s, 1 H, NH on the indole ring) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 164.28, 162.57, 147.68, 147.30,
136.31, 132.91, 130.41, 125.97, 121.79, 121.68, 118.91, 118.13,
111.34, 108.43, 108.16, 107.58, 101.28, 52.16, 50.93, 48.38, 40.13,
26.65, 11.47 ppm. MS (EI): m/z (%) = 404 (21) [M+ + 1], 403 (100)
[M+], 402 (7), 386 (2), 374 (2), 330 (1), 318 (4), 317 (5), 289 (7),
282 (10), 264 (6), 263 (33), 262 (30), 233 (10), 205 (4), 204 (7), 169
Scheme 6. Preparation of the deuterated piperonal 4.
(4), 135 (1), 115 (1), 102 (1). IR (KBr): ν = 3316, 2980, 2960, 1663,
˜
1490, 1461, 1328, 1242, 1159, 1039, 744 cm–1. C23H21N3O4
(403.44): calcd. C 68.47, H 5.25, N 10.42; found C 68.19, H 5.14,
N 10.48.
percentages of deuterium-labeling at C-6 position for each
compound are higher than 99%.
Preparation of the Deuterated Dithiane 5: 2-(1,3-Benzodioxol-5-yl)-
1,3-dithiane (2.40 g, 9.99 mmol) was dissolved in absolute tetra-
hydrofuran (40 mL), the solution was then cooled to –78 °C under
N2 with a dry-ice bath. A solution of nBuLi (1.6 , 9.5 mL,
15.20 mmol) in cyclohexane was injected into the cooled solution
via syringe. The reaction temperature was kept in the range of –78
to –40 °C, and the mixture was stirred at this temperature for about
5 h. Heavy water (1 mL) was quickly added into the flask, and the
reaction mixture was warmed to room temperature. Solvents were
removed by a rotavapor under vacuum, the residue was then parti-
tioned between ethyl acetate (45 mL) and water (15 mL). The or-
ganic phase was separated and washed with brine (10 mL). After
drying over anhydrous MgSO4, ethyl acetate was removed by distil-
lation under vacuum to give a crude oil which was purified by flash
chromatography (eluent: EtOAc/hexane = 1:6) to produce 2-(1,3-
benzodioxol-5-yl)-2-deuterio-1,3-dithiane (5) (2.27 g, 9.41 mmol) in
Conclusions
In summary, a clean and general base-catalyzed epi-
merization at C-12a position of the cis tetracyclic com-
pounds 2a–2t was fully studied, and trans compounds 3a–
3t were obtained in excellent yields by performing the epi-
merization in a mixed solvent of DMSO and ethanol (1:5)
at reflux in the presence of 0.5 equiv. of DBU. A plausible
mechanism for the epimerization was discussed, it was re-
vealed that the epimerization of cis compound 2 into trans
compound 3 was clean and complete, and none of reverse
epimerization from trans compound 3 to cis compounds 2
was detected. The wide scope of the epimerization of cis
compound 2 into trans compound 3 provides an efficient
and general method for stereodivergent syntheses of tadal-
afil-like tetracyclic compounds from both - and -trypto-
phan.
1
94% yield, m.p. 84–85 °C. H NMR (500 MHz, CDCl3): δ = 1.84–
1.97 (m, 1 H), 2.12–2.20 (m, 1 H), 2.89 (dt, J1 = 13.8, J2 = 3.7 Hz,
2 H), 3.04 (dt, J1 = 14.4, J2 = 2.0 Hz, 2 H), 5.95 (s, 2 H), 6.76 (d,
J = 8.0 Hz, 1 H), 6.94 (dd, J1 = 8.0, J2 = 1.5 Hz, 1 H), 6.98 (d, J
= 1.5 Hz, 1 H) ppm. MS: m/z (%) = 243 (7) [M+ + 2], 242 (10) [M+
+ 1], 241 (77) [M+], 208 (2), 197 (4), 176 (4), 169 (5), 168 (12), 167
(100), 166 (11), 165 (37), 162 (6), 149 (3), 136 (9), 135 (5), 132 (5),
Experimental Section
General Methods: H NMR and 13C NMR spectra were acquired
123 (5), 107 (2), 77 (1). IR (KBr): ν = 2889, 1606, 1501, 1486, 1439,
˜
1
1354, 1279, 1247, 1102, 1042, 940, 875, 816, 806, 738 cm–1. HRMS
(EI): calcd. for C11H11DO2S2: 241.0341; found 241.0343.
on Bruker AM-500, chemical shifts were given on the δ scale as
parts per million (ppm) with tetramethylsilane (TMS) as the in-
ternal standard. IR spectra were recorded on Nicolet Magna IR-
550. Mass spectra were recorded on HP5989A. Column
chromatography was performed on silica gel (Qingdao Ocean
Chemical Corp.). Optical rotations of chiral compounds were mea-
sured on WZZ-1S automatic polarimeter at room temperature.
Preparation of the Deuterated Piperonal 4: To a solution of com-
pound 5 (2.20 g, 9.12 mmol) in THF (25 mL), was added periodic
acid (3.12 g, 13.69 mmol) in portions. After stirring was continued
at room temperature for 10 min, the reaction mixture was cooled
to 0 °C with a ice bath. Ethyl acetate (80 mL) and an aqueous
solution of sodium sulfite (10%, w/v, 60 mL) were added. After a
vigorous stirring was continued for 10 min, the organic phase was
separated and washed with an aqueous solution of sodium sulfite
(10%, w/v, 30 mL) once more. Concentration of the organic solu-
tion under vacuum gave a crude product which was purified by
flash chromatography (eluent: EtOAc/hexane = 1:5) to afford the
deuterated piperonal 4 (1.28 g, 8.47 mmol) in 93% yield, m.p. 36–
37 °C. 1H NMR (500 MHz, CDCl3): δ = 6.09 (s, 2 H), 6.94 (d, J =
General Procedure for the Base-Catalyzed Epimerization at C-12a
of 2: To a solution of DBU (0.38 g, 2.50 mmol) in a mixed solvent
of DMSO (3 mL) and ethanol (15 mL), was added compound 2a
(2.02 g, 5.00 mmol). The mixture was stirred and heated at reflux,
and then the stirring was continued at reflux for about 3 h. After
the reaction was complete, ethanol was removed by distillation un-
der reduced pressure. The residue was cooled to room temperature,
water (20 mL) was then slowly added while a vigorous stirring was
continued, and off-white solid precipitated. The solid was collected
on a Büchner funnel and rinsed with water. After drying in warm
air, the crude product was purified by flash chromatography (elu-
ent: CHCl3/EtOAc = 4:1) to give compound 3a (1.98 g, 4.91 mmol)
in 98% yield, m.p. 267–268 °C. [α]2D0 = +278.9 (c = 0.2, CHCl3). 1H
NMR (500 MHz, [D6]DMSO): δ = 1.07 (t, J = 7.2 Hz, 3 H), 2.96
7.9 Hz, 1 H), 7.35 (d, J = 1.2 Hz, 1 H), 7.42 (dd, J1 = 7.9, J2
=
1.2 Hz, 1 H) ppm. MS: m/z (%) = 152 (10) [M+ + 1], 151 (100)
[M+], 150 (46), 149 (98), 122 (6), 121 (23), 91 (6), 65 (6), 64 (5), 63
(6), 62 (3), 53 (2). IR (KBr): ν = 2999, 2920, 2110, 1663, 1621,
˜
1601, 1494, 1449, 1262, 1102, 1036, 926, 806, 619 cm–1. HRMS
(EI): calcd. for C8H5DO3: 151.0380; found 151.0381.
(dd, J1 = 14.3, J2 = 12.0 Hz, 1 H), 3.22–3.32 (m, 2 H), 3.36–3.48 Preparation of (1S,3S)-6: To a solution of the deuterated piperonal
(m, 1 H), 4.04 (d, J = 17.7 Hz, 1 H), 4.08 (dd, J1 = 12.7, J2
=
4 (1.28 g, 8.47 mmol) in nitromethane (20 mL), was added -tryp-
4.0 Hz, 1 H), 4.28 (d, J = 17.7 Hz, 1 H), 6.01 (d, J = 4.0 Hz, 2 H),
tophan methyl ester hydrochloride (2.00 g, 7.85 mmol). The sus-
6.62 (d, J = 8.0 Hz, 1 H), 6.77 (s, 1 H), 6.83 (s, 1 H), 6.88 (d, J = pension was heated and stirred at reflux for about 4 h. Then the
8.0 Hz, 1 H), 7.02 (dd, J1 = 7.3, J2 = 7.7 Hz, 1 H), 7.11 (dd, J1 =
7.3, J2 = 8.0 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.52 (d, J =
mixture was cooled to room temperature. A pale yellow solid was
collected on a Büchner funnel by suction and rinsed with a small
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Stereodivergent Syntheses of Tadalafil-Like Tetracyclic Compounds
amount of nitromethane. The solid was then partitioned between
ethyl acetate (50 mL) and an aqueous solution of potassium car-
bonate (1.60 g, 11.58 mmol) in water (20 mL). The organic layer
was separated and dried with anhydrous MgSO4. Evaporation of
the solvent under a vacuum gave a crude oil which was purified by
chromatography (eluent: EtOAc/hexane = 1:4) to afford (1S,3S)-6
(2.65 g, 7.54 mmol) as white crystals in 96% yield, m.p. 90–92 °C.
(20 mL) was slowly added while stirring, an off-white solid precipi-
tated. The off-white solid was collected on a Büchner funnel and
rinsed with water. The crude solid was purified by flash chromatog-
raphy (eluent: CHCl3/EtOAc = 4:1) to afford compound (6S,12aR)-
7 (1.08 g, 2.77 mmol) in 98 % yield. Off-white solid, m.p. 295–
297 °C. [α]2D0 = +300.0 (c = 0.2, CHCl3). 1H NMR (500 MHz, [D6]-
DMSO): δ = 2.84 (s, 3 H), 2.95 (dd, J1 = 15.3, J2 = 11.8 Hz, 1 H),
3.25 (dd, J1 = 15.3, J2 = 4.2 Hz, 1 H), 4.03 (d, J = 17.6 Hz, 1 H),
1
[α]2D0 = –21.0 (c = 1.0, CHCl3). H NMR (500 MHz, CDCl3): δ =
2.99 (dd, J1 = 15.0, J2 = 11.2 Hz, 1 H), 3.21 (dd, J1 = 15.0, J2 = 4.07 (dd, J1 = 11.8, J2 = 4.2 Hz, 1 H), 4.24 (d, J = 17.6 Hz, 1 H),
4.1 Hz, 1 H), 3.82 (s, 3 H), 3.96 (dd, J1 = 11.1, J2 = 4.1 Hz, 1 H),
5.95 (s, 2 H), 6.80 (d, J = 7.9 Hz, 1 H), 6.82 (d, J = 1.3 Hz, 1 H),
6.88 (dd, J1 = 7.9, J2 = 1.3 Hz, 1 H), 7.10–7.17 (m, 2 H), 7.23 (d,
J = 7.7 Hz, 1 H), 7.47 (br. s, 1 H, NH on the indole ring), 7.53 (d,
J1 = 7.5 Hz, 1 H) ppm. MS (EI): m/z (%) = 352 (19) [M+ + 1], 351
6.00 (d, J = 6.8 Hz, 2 H), 6.60 (dd, J1 = 8.0, J2 = 1.2 Hz, 1 H),
6.76 (d, J = 1.2 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 7.01 (dd, J1 =
7.7, J2 = 7.4 Hz, 1 H), 7.10 (dd, J1 = 7.4, J2 = 7.9 Hz, 1 H), 7.31
(d, J = 7.9 Hz, 1 H), 7.50 (d, J = 7.7 Hz, 1 H), 11.07 (br. s, 1 H,
NH on the indole ring) ppm. MS (EI): m/z (%) = 391 (26) [M+
+
(100) [M+], 350 (13), 349 (13), 336 (12), 334 (6), 333 (14), 293 (9), 1], 390 (100) [M+], 389 (12), 361 (3), 319 (5), 318 (7), 290 (10), 269
292 (46), 291 (6), 290 (10), 289 (13), 277 (6), 274 (9), 265 (15), 264 (8), 268 (10), 265 (8), 264 (39), 263 (41), 262 (9), 234 (15), 233 (7),
(56), 263 (48), 249 (4), 235 (7), 234 (16), 233 (9), 230 (12), 207 (7), 206 (8), 205 (13), 170 (6), 115 (2), 102 (1). IR (KBr): ν = 3421,
˜
206 (14), 205 (24), 170 (16), 148 (6), 145 (11), 117 (3), 103 (3), 77
2945, 1658, 1489, 1437, 1402, 1317, 1246, 1039, 741 cm–1. HRMS
(EI): calcd. for C22H18DN3O4: 390.1438; found 390.1432.
(1). IR (KBr): ν = 3370, 2950, 1732, 1487, 1437, 1278, 1245, 1038,
˜
742 cm–1. HRMS (EI): calcd. for C20H17DN2O4: 351.1329; found
351.1330.
(6R,12aR)-6-(1,3-Benzodioxol-5-yl)-6-deuterio-2,3,6,7,12,12a-hexa-
hydro-2-methyl-pyrazino[1Ј,2Ј:1,6]pyrido[3,4-b]indole-1,4-dione
(6S,12aS)-6-(1,3-Benzodioxol-5-yl)-6-deuterio-2,3,6,7,12,12a-hexa- (6R,12aR)-7: Compound (6R,12aR)-7 was prepared in 82% yield
hydro-2-methyl-pyrazino[1Ј,2Ј:1,6]pyrido[3,4-b]indole-1,4-dione
(6S,12aS)-7: To a solution of compound (1S,3S)-6 (2.20 g,
6.26 mmol) in ethyl acetate (60 mL), was added powder of potas-
sium carbonate (3.03 g, 21.92 mmol). The suspension was stirred
and cooled to 0 oC with an ice-bath, and then a solution of chlo-
roacetyl chloride (1.06 g, 9.39 mmol) in dichloromethane (5 mL)
was added dropwise over 30 min. After the addition was finished,
stirring was continued for about 2 h. The reaction was then
quenched by adding water (30 mL). The organic layer was sepa-
rated and washed with brine (10 mL), and then the organic solution
was dried with anhydrous MgSO4. Removal of the solvent under a
vacuum gave pale yellow solid which was dissolved in DMF
(25 mL), and an aqueous solution of methylamine (3.24 g, 30% w/
w, 31.30 mmol). The mixture was then stirred overnight at room
temperature. Water (125 mL) was added dropwise over 30 min, and
white solid precipitated during the addition. The white solid was
collected on a Büchner funnel and rinsed with water. The crude
solid was purified by flash chromatography (eluent: CHCl3/EtOAc
= 4:1) to give compound (6S,12aS)-7 (2.08 g, 5.33 mmol) as an off-
white solid in 85% yield, m.p. 298–299 °C. [α]2D0 = –66.8 (c = 0.3,
from -tryptophan through the same sequential procedures as that
for (6S,12aS)-7. Off-white solid, m.p. 295–296 °C. [α]2D0 = +69.9 (c
= 0.4, CHCl3). Characterization data of (6R,12aR)-7 is identical
with that of (6S,12aS)-7.
(6R,12aS)-6-(1,3-Benzodioxol-5-yl)-6-deuterio-2,3,6,7,12,12a-hexa-
hydro-2-methyl-pyrazino[1Ј,2Ј:1,6]pyrido[3,4-b]indole-1,4-dione
(6R,12aS)-7: Compound (6R,12aS)-7 was prepared from
(6R,12aR)-7 in 98% yield according to the same procedure as that
for (6S,12aR)-7. Off-white solid, m.p. 293–294 °C. [α]2D0 = –295.1 (c
= 0.3, CHCl3). Characterization data is identical with that of
(6S,12aR)-7.
Supporting Information (see footnote on the first page of this arti-
1
cle): Characterization data of compounds 3b–3t; H NMR spectra
of compounds 3a–3t, 4, 5, (1S,3S)-6, (1R,3R)-6, (6S,12aS)-7 and
(6S,12aR)-7; 13C NMR spectra of compounds 3a, 3f, 3h, 3i, 3o,
and 3q–3t.
Acknowledgments
1
CHCl3). H NMR (500 MHz, [D6]DMSO): δ = 2.92 (s, 3 H), 2.96
We thank the National Natural Science Foundation of China (No.
20972048) and Shanghai Educational Development Foundation
(Dawn Program, No. 03SG27) for the financial support of this
work.
(dd, J1 = 15.8, J2 = 11.7 Hz, 1 H), 3.51 (dd, J1 = 15.8, J2 = 4.5 Hz,
1 H), 3.94 (d, J = 17.0 Hz, 1 H), 4.17 (d, J = 17.0 Hz, 1 H), 4.39
(dd, J1 = 11.7, J2 = 4.5 Hz, 1 H), 5.91 (s, 2 H), 6.77 (s, 2 H), 6.86
(s, 1 H), 6.99 (dd, J1 = 7.7, J2 = 7.3 Hz, 1 H), 7.05 (dd, J1 = 7.8,
J2 = 7.3 Hz, 1 H), 7.29 (d, J = 7.8 Hz, 1 H), 7.54 (d, J = 7.7 Hz, 1
H), 11.03 (br. s, 1 H, NH on the indole ring) ppm. MS (EI): m/z
(%) = 391 (20) [M+ + 1], 390 (100) [M+], 389 (7), 319 (3), 318 (5),
290 (5), 275 (3), 269 (11), 268 (6), 265 (6), 264 (32), 263 (36), 262
(7), 235 (3), 234 (11), 233 (5), 206 (6), 205 (11), 204 (3), 170 (8),
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(6S,12aR)-6-(1,3-Benzodioxol-5-yl)-6-deuterio-2,3,6,7,12,12a-hexa-
hydro-2-methyl-pyrazino[1Ј,2Ј:1,6]pyrido[3,4-b]indole-1,4-dione
(6S,12aR)-7: To a solution of DBU (215 mg, 1.41 mmol) in a mixed
solvent of DMSO (2 mL) and ethanol (10 mL), was added com-
pound (6S,12aS)-7 (1.10 g, 2.82 mmol). The mixture was stirred
and heated to reflux. Stirring was then continued at reflux tempera-
ture for about 3 h. Ethanol was removed by distillation under a
vacuum, the residue was then cooled to room temperature. Water
Eur. J. Org. Chem. 2010, 1711–1716
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: November 28, 2009
Published Online: February 11, 2010
1716
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1711–1716