Unexpected domino ring closure: highly stereoselective construction of a tetracyclic indole alkaloid ring system

Article abstract of DOI:10.1016/j.tetlet.2008.10.005

An unexpected highly stereoselective domino ring closure gave the tetracyclic indole alkaloid IV-2 in good yield in one hydrogenation step. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2008.10.005

Tetrahedron Letters 49 (2008) 7184–7186
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpected domino ring closure: highly stereoselective construction
of a tetracyclic indole alkaloid ring system
*
Jian Xiao, Teck-Peng Loh
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
An unexpected highly stereoselective domino ring closure gave the tetracyclic indole alkaloid IV-2 in
good yield in one hydrogenation step.
Received 4 August 2008
Revised 21 September 2008
Accepted 1 October 2008
Available online 7 October 2008
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
The discovery of an efficient method to construct polycyclic
rigid ring systems present in natural products with excellent regi-
oselectivity and diastereoselectivity is an important goal for both
academic and industrial researchers.1 Domino or cascade reactions
allow the formation of rigid ring systems in one pot which avoids
isolation of intermediates in multistep syntheses of complex
molecular targets. However, the development of a highly stereo-
selective domino reaction for the construction of indole polycyclic
rings is still a challenge and remains difficult.2
The tetrahydropyrrolo[2,3-b]indole skeleton I is a key structural
component of many indole alkaloids exhibiting a diverse range of
biological activity.3 The tetrahydroimidazo[1,2-a]indole system II
is also found in many natural products such as tryptoquivalines,
asperlicins, fiscalins, fumiquinazolines and kapakahines.4 Tetra-
cyclic [6,5,5,5] ring system III can be considered as a combination
of tetrahydropyrrolo[2,3-b]indole I and tetrahydroimidazo[1,2-
a]indole II (Scheme 1). The presence of these heterocyclic systems
in natural products stimulates interest in the structural manipula-
tion of these new compounds. As such, the synthesis of tetracyclic
[6,5,5,5] ring system III and [6,5,5,6] ring system IV is of interest,
and recently, Herranz reported an acid-promoted cyclization of
tryptophan-based a-amino nitriles to synthesize ring system III,
the structure of which was determined by 2D NMR.5
There is only one example in the literature for the synthesis of a
tetracyclic [6,5,5,6] ring system IV. Compound IV-1 was synthe-
sized by phosphoryl chloride-mediated cyclization of the conden-
sation product of tryptamine with diketene; however, IV-1 could
not be functionalized for structural manipulation (Fig. 1).6
During the course of our synthetic efforts aimed at developing a
novel rigid chiral ligand for asymmetric catalysis, we identified an
unexpected domino ring closure process which provided an easy
and stereoselective access to the tetracyclic [6,5,5,6] ring system
IV-2. Herein, we present the synthesis of IV-2, the structure of
which has been confirmed by X-ray analysis.
Starting from commercially available (L)-tryptophan methyl es-
ter 1, initial protection of the ammonium nitrogen atom with ben-
zyl chloroformate in the presence of sodium bicarbonate, followed
by acid-catalyzed ring closure afforded the hexahydro[2,3-b]pyrro-
loindole 3 in an overall yield of 60% as an endo/exo mixture of iso-
mers. Subsequent acetylation of 3 with 5 equiv of acetyl chloride in
the presence of Et3N and DMAP failed to yield the desired acetyl-
ation product 5; however, the unexpected Claisen condensation
product 4 was obtained.7 When l and 2 equiv of acetyl chloride
were employed, compound 4 was also obtained as the major prod-
uct in 41% and 71% yields, respectively. Even when we decreased
the reaction temperature, slowed down the addition rate and
reduced the amount of acetyl chloride, compound 4 was still
N
N
I
N
N
N
N
R
H
H
N
N
N
II
N
III
IV
O
CH3
N
H
N
H
H3C
IV-1
O
Scheme 1. Tetracyclic ring systems III and IV.
R = CO2CH3, CH2OH, CO2H
IV-2
* Corresponding author. Tel.: +65 6316 8899; fax: +65 6791 1961.
E-mail address: teckpeng@ntu.edu.sg (T.-P. Loh).
Figure 1. Tetracyclic [6,5,5,6] ring IV-1 and IV-2.
0040-4039/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.005

J. Xiao, T.-P. Loh / Tetrahedron Letters 49 (2008) 7184–7186
7185
H
elucidate its precise structure, a crystal suitable for X-ray analysis
was grown by slow evaporation from a mixture of CH2Cl2 and hex-
ane. As shown in Figure 1, a new six-membered ring D was formed
which was fused to the two heterocyclic rings, A and B. The methyl
ester group preferred the endo-conformation.
The proposed mechanism for the formation of 6 involved two
steps, (1) deprotection of the benzyl carbamate in the presence
of Pd/C and H2 to afford intermediate 7 and (2) reductive amina-
H
CbzCl
CO2CH3
CO2CH3
TFA
CH2Cl2, H2O, NaHCO3
0 oC-RT, 2 h
2 d
NHCO2CH2Ph
NH3Cl
N
H
N
H
Yield 60%
Yield 98%
2
1
H
H
H
CO2CH3
CO2CH2Ph
CH3COCl
N
N
CO2CH3
CO2CH2Ph
Et3N, DMAP, CH2Cl2
0 oC-RT, 2 h
N
N
O
O
H
H
3
tion where the amine attacks the c-carbonyl group to give 8 which
Yield 78%
undergoes reduction to afford the final product 6 (Scheme 3).
Chemical functionalization of compound 6 was next explored in
order to further manipulate the tetracyclic ring system. An initial
attempt to carry out a Grignard addition to the carboxylate group
failed due to the rigid scaffold of the ring system. However, reduc-
tion of 6 with LiBH4 was performed successfully in THF to yield the
chiral alcohol 9 as a single isomer which can be further manipu-
lated (Scheme 4).
4
Ac2O
Pd/C, H2
MeOH, RT,12 h
Yield 60%
Et3N, DMAP, CH2Cl2
0 oC-RT, 2 h
Yield 86%
H
H
H
To test the generality of this new finding, commercially avail-
CO2CH3
CO2CH2Ph
CO2CH3
N
able N -carbobenzyloxy-L-tryptophan 10 was first treated with
a
N
N
N
benzyl alcohol using DCC coupling to afford 11, which underwent
acid-catalyzed ring closure to provide the hexahydro[2,3-b]pyrrolo
indole 12. Reaction of 12 with excess acetyl chloride and Et3N pro-
vided 13 in 70% yield. Finally, hydrogenation gave the chiral tetra-
cyclic acid 14 as a single isomer in 78% yield (Scheme 5).
In summary, an unexpected highly stereoselective domino ring
closure process led to an easy, clean and efficient synthesis of a tet-
racyclic indole alkaloid ring system. Structural manipulation of
H
O
CH3
6
O
5
only 1 isomer
Scheme 2. Synthesis of tetracyclic ring product 6.
obtained as the major product (Scheme 2). However, compound 5
could be acquired by the use of acetic anhydride and Et3N. Treat-
ment of 5 with acetyl chloride in the presence of base failed to
yield 4. The 1H NMR spectrum of 4 was slightly complex due to
the existence of rotamers. A single crystal was grown from an
ether/hexane (1:1) mixture and its structure was confirmed
(Fig. 2).
As demonstrated by the crystal structure, compound 4 adopted
an envelope-like conformation. It was clear that the methyl ester
group was directly under the phenyl ring, and other orientations
were blocked by the bulky benzyloxy group. The rigid and crowded
nature could account for the reason why we met with failure when
we tried to carry out a Grignard addition to the methyl ester.8
Thus deprotecting the benzyloxy group is essential for the suc-
cess of this transformation. In the next step, deprotection followed
by filtration to remove Pd/C gave a colourless crystalline solid in
good yield.9 The 1H NMR spectrum showed that the signal of the
carbamate CH3 group protons was shifted significantly from d
2.33 to d 1.41 compared to the corresponding signal in 4. To
H
H
CO2CH3
Pd/C, H2
CO2CH3
N
N
H
N
N
MeOH, RT, 12 h
Yield 60%
O
O
CO2CH2Ph
H
6
CH3
O
4
H
H
CO2CH3
CO2CH3
N
N
H
H
N
N
O
O
H
8
CH3
O
7
Scheme 3. Proposed mechanism.
Figure 2. ORTEP drawing of molecule 4 and 6.

7186
J. Xiao, T.-P. Loh / Tetrahedron Letters 49 (2008) 7184–7186
H
H
Further chemical
manipulation
CO2CH3
LiBH4
CH2OH
N
N
N
N
H
6
THF, RT, 2 h
Yield 86 %
H
9
CH3
O
CH3
O
Scheme 4. Chemical manipulation of 6.
H
H
CO2H
PhCH2OH
CO2CH2Ph
TFA
DCC, DMAP, CH2Cl2
2 d
NHCO2CH2Ph
NHCO2CH2Ph
N
N
H
0 oC-RT, 2 h
Yield 96 %
H
Yield 60 %
10
11
H
H
H
CO2CH2Ph
CH3COCl
CO2CH2Ph
N
N
N
N
H
O
O
DCC, DMAP, CH2Cl2
0 oC-RT, 2 h
CO2CH2Ph
H
CO2CH2Ph
Yield 70 %
12
13
H
Pd/C, H2
CO2H
MeOH, RT, 12 h
Yield 78 %
N
N
H
CH3
14
O
only 1 isomer
Scheme 5. Synthesis of tetracyclic acid 14.
6. Jackson, A. H.; Shannon, P. V.; Wilkins, R. D. J. J. Chem. Soc., Chem. Commun. 1987,
653–654.
these new compounds provided other versatile building blocks.
Further modification and application of this reaction to synthesize
other ring systems is ongoing in our lab.
7. Compound 4: 1H NMR (300 MHz, CDCl3): d 7.97 (d, 1H, J = 9.8 Hz), 7.43–7.22 (m,
6H), 7.22–7.16 (m, 1H), 7.13–7.04 (m, 1H), 6.15 (d, 1H, J = 9.8 Hz), 5.12 (s, 2H),
4.86(d, 1H, J = 16.0 Hz), 4.58 (d, 1H, J = 12.2 Hz), 4.19-3.99 (m, 2H), 3.06 (s, 3H),
2.75–2.70 (m, 1H), 2.61–2.50 (m, 1H), 2.33 (s, 2H), 2.12–1.95 (m, 1H). 13C NMR
(75 MHz, CDCl3): d 203.7, 171.3, 167.8, 154.4, 144.2, 142.7, 135.8, 131.3, 128.6,
127.6, 125.1, 123.6, 119.2, 77.9, 67.3, 59.8, 52.4, 45.7, 33.3, 31.0. IR(KBr): cmÀ1
3032, 2951, 2250, 1712, 1600, 1109, 912, 754, 732, 700; HRMS (m/z)
calcd: 436.1629; found: 436.1630 (M+). Crystal data for 4: C24 H24 N2 O6,
M = 436.45, crystal dimensions 30 Â 0.30 Â 0.20 mm3, orthorhombic. space
group P2(1)2(1)2(1) a = 10.0800(3) Å, b = 11.1128(3) Å, c = 19.7964(6) Å.
V = 2217.53(11) Å3, Z = 4, Dcalcd = 1.307 Mg/m3, independent reflections 6785
Acknowledgements
We thank Dr. Yong-Xin Li for X-ray analyses. We gratefully
acknowledge Nanyang Technological University and the Ministry
of Education Academic Research Fund Tier 2 (No. T207B1220RS)
for funding this research.
(R(int) = 0.0305) F(000) = 920, final R1 = 0.0420, wR2 = 0.1094 and
data) = 0.0555, Rw = 0.1203, CCDC number 624126.
R (all
References and notes
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and their application for enantioselective reduction of ketones. Xiao, J.; Loh,
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9. General procedure for this domino ring cyclization to synthesize tetracyclic system 6:
(2S,3aR,8aR)-1-Benzyl 2-methyl 8-(3-oxobutanoyl)-3,3a,8,8a-tetrahydropyr-
rolo[2,3-b]indole-1,2(2H)-dicarboxylate 4 (300 mg, 0.69 mmol) was dissolved
in 2 ml of methanol and 10% Pd/C (75 mg, 0.069 mmol) was added. The mixture
was stirred overnight at room temperature under a H2 balloon. After filtration
through Celite and evaporation, the residue was purified by column
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chromatography to afford product
6 (170 mg, 60%) as a crystalline solid.
Compound 6 1H NMR (300 MHz, CDCl3): d 7.89 (d, 1H, J = 7.8 Hz), 7.17 (d, 2H,
J = 7.8 Hz), 7.03–6.98 (td, 1H, J = 0.9, 7.6 Hz), 5.37 (d, 1H, J = 7.6 Hz), 3.99 (dd, 1H,
J = 2.3, 8.4 Hz), 3.90–3.72 (m, 2H), 3.36 (s, 3H), 2.76–2.51 (m, 2H), 2.31–2.12 (m,
2H), 1.41 (d, 3H, J = 1.6 Hz). 13C NMR (75 MHz, CDCl3): d 174.5, 168.6, 142.8,
132.7, 128.1, 124.1, 124.0, 116.6, 83.0, 60.3, 52.1, 48.9, 43.7, 37.8, 37.7, 19.3.
IR(KBr): cmÀ1 2926, 1717, 1655, 1479, 1396, 1252, 1065, 772, 719; HRMS (m/z)
calcd: 286.1312; found: 286.1305 (M+). Crystal Data for 6: C16H18N2O3,
M = 286.32, colorless prism, 0.45 Â 0.30 Â 0.20 mm3, trigonal, space group
P3(2), a = 7.62510(10) Å, b = 7.62510(10) Å, c = 20.5405(6) Å, V = 1034.27(4) Å3,
Z = 3, Dcalcd = 1.379 Mg/m3, reflections collected 17517, independent reflections
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2644; (b) González-Vera, J. A.; García-López, M. T.; Herranz, R. J. Org. Chem. 2005,
70, 8971–8976.
4080 (Rint = 0.0244), final
R [I > 2r(I)] = 0.0317, R (all data) = 0.0332, Rw =
0.0842, CCDC number 671820.