Organocatalyzed enantioselective one-pot three-component access to indoloquinolizidines by a Michael addition-Pictet-Spengler sequence

Article abstract of DOI:10.1039/c001512a

The enantioselective three-component Michael addition-Pictet-Spengler sequence of β-ketoesters 1, α,β-unsaturated aldehydes 2 and tryptamines 4 represents a facile and rapid one-pot access to highly substituted indoloquinolizidines in moderate to excellent yields and good to excellent enantioselectivities.

Full text of DOI:10.1039/c001512a

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Organocatalyzed enantioselective one-pot three-component access to
indoloquinolizidines by a Michael addition–Pictet–Spengler sequencew
Xiaoyu Wu,*a Xiaoyang Dai,a Linlin Nie,a Huihui Fang,a Jie Chen,a Zhongjiao Ren,a
Weiguo Cao*a and Gang Zhao*b
Received (in Cambridge, UK) 25th January 2010, Accepted 25th February 2010
First published as an Advance Article on the web 19th March 2010
DOI: 10.1039/c001512a
The enantioselective three-component Michael addition–Pictet–
Spengler sequence of b-ketoesters 1, a,b-unsaturated aldehydes
2 and tryptamines 4 represents a facile and rapid one-pot access
to highly substituted indoloquinolizidines in moderate to excellent
yields and good to excellent enantioselectivities.
Indoloquinolizidines are important structural subunits found
in numerous natural alkaloids. Their structural diversity and
stereochemical complexity have rendered them interesting
synthetic targets.1
Traditionally optically pure indoloquinolizidines are
prepared from a chiral pool.2 However, this strategy often
requires multi-step functional group transformations and
laborious protecting group manipulations. On the other hand,
few examples employing highly efficient asymmetric catalytic
approaches to indoloquinolizidines have been documented
Fig. 1 Concept of Michael addition–Pictet–Spengler sequences.
recently,4 although much success has been achieved for the
synthesis of quinolizidine analogs.3 Some of these reports
adopted organocatalyst-mediated enantioselective protocols.5
intermediary hemiacetals with tryptamine in the presence of an
acid additive (Fig. 1). The formation of indoloquinolizidine via
an imminium ion intermediate by Pictet–Spengler cyclization
is well-documented in the literature.4,7 With many points
of diversity present in the reaction products, this cascade
sequence would be easily expanded to combinatorial library
generation and target synthesis. Herein we present our
findings.
Of particular interest is the prolinol ether catalyzed one-pot
cascading reaction demonstrated by Franzen and Fisher,4a
wherein a well-established strategy of conjugate addition of
1,3-dicarbonyl to a,b-unsaturated aldehydes was utilized.6
The asymmetric conjugate addition of activated amides to
a,b-unsaturated aldehydes provided indoloquinolizidines in
good yields, moderate diastereoselectivities and high enantio-
selectivities. Nevertheless, a,b-unsaturated aldehydes with
aliphatic substituents were not included. The development of
new stereoselective and efficient procedures that accommodate
a wide scope of substrates to indoloquinolizidines is still highly
desired.
Proof of concept studies were required to determine the
feasibility of the cascade (Table 1). The organocatalytic
conjugate addition between b-ketoester 1a and cinnamic
1
aldehyde 2a was conducted at 10 C using A as a catalyst,
benzoic acid as an additive and toluene as solvent. After full
conversion of b-ketoester 1a as monitored by TLC the
reaction mixture was diluted with toluene, followed by the
addition of tryptamine and a stoichiometric amount of
benzoic acid. The mixture was heated at 50 1C for 24 h. The
desired indoloquinolizidine 3a was isolated as a single
diastereomer in moderate yield and good enantioselectivity
(entry 1). A brief screening of different solvents revealed
toluene to be the best one in terms of yield and enantio-
selectivity (entries 2–5). The stereochemistry was determined
in the Michael addition step. Solvents other than toluene
resulted in lower enantioselectivity, indicating that the
diastereomers formed in the first step partially racemized
under the heating reaction conditions in the presence of acid.8
When the temperature of the first step was decreased to
À15 1C, compound 3a was obtained in 79% yield and 92%
ee using A as a catalyst (entry 6). With catalyst B the cascade
In our search for new and powerful one-pot cascade
sequences for synthesis of indoloquinolizidines, we speculated
that cyclic hemiacetal products from secondary amine catalyzed
conjugate addition of b-ketoesters to a,b-unsaturated aldehydes
could be further transformed to indoloquinolizidine by treating
a Department of Chemistry, Shanghai University, 99 Shangda Rd,
Shanghai 200444, People’s Republic of China.
E-mail: wuxy@shu.edu.cn, wgcao@mail.shu.edu.cn;
Fax: (+86)-21-6683-4856
b Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of
China. E-mail: zhaog@mail.sioc.ac.cn; Fax: (+86)-21-6416-6128
w Electronic supplementary information (ESI) available: Synthesis
and characterization of compounds and additional details of catalytic
experiments. CCDC 763310. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c001512a
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Table 1 Catalyst and solvent screeninga
products with enantioselectivities ranging from 88%–95% ee.
Indoloquinolizidines with alkyl substituents frequently occur
as intermediates in the total synthesis of indole-containing
alkaloids.2 It was thus remarkable to observe that the present
catalytic process was also applicable to crotonaldehyde and
2-hexenaldehyde (entries 7, 8). Ethyl trans-4-oxo-2-butenoate
was also tested. However only moderate enantioselectivities
are obtained (entries 9, 10).
To further illustrate the power of this novel cascade reaction,
a small combinatorial library of indoloquinolizidines were
prepared in good to excellent yields and excellent enantio-
selectivities (Table 3). Less nucleophilic 5-bromo tryptamine 4c
with an electron withdrawing bromo at the 5-position also
afforded the cyclization products (entries 3, 4), albeit in
somewhat lower yield as compared with those of 4a and 4b.
All the b-ketoesters 1a–e tested worked well, delivering the
desired products efficiently and stereoselectively.
Entry
Cat
Solvent
Yield (%)b
ee (%)c
1e
2e
3e
4e
5e
6f
7e
A
A
A
A
A
A
B
Toluene
CHCl3
CH3CN
THF
DMF
Toluene
Toluene
65
68
42
81
67
55
—
—
92
92
d
—
—
d
79
78
a
General conditions: (step 1) b-ketoester 1 (0.1 mmol), aldehyde 2a
(0.2 mmol), Cat. (10 mol%), BzOH (10 mol%) in toluene (0.2 mL);
(step 2) Solvent (2 mL), tryptamine 4a (0.2 mmol) and BzOH
The relative configurations of the isolated diastereomers
were assigned on the basis of NMR studies of compound 3j,
confirmed by the X-ray crystal structure of 3a.9 The absolute
configuration of 3a is determined to be 2S,12bS based on
previous work by Jørgensen,6d Franzen4a and Rovis.8
The diastereoselectivity in the substrate controlled formation
of 12b-position chirality could be rationalized by the transition
states depicted in Fig. 2. Diastereomer 3a formed exclusively
due to less steric interaction between the equatorial b proton
and the indole moiety in TS1, as compared to that between the
axial a proton and the indole moiety in TS2.
It should be noted that indoloquinolizidine 3i prepared by
the above-mentioned method can be further transformed
to 5 easily by reduction of the enamine double bond and
rearrangement (Scheme 1).10 This transformation led to core
structures en route to a number of indole-based natural
alkaloids.1,2
b
(0.2 mmol). Yield referred to chromatographically pure product.
c
d
Enantiomeric excess was determined by chiral HPLC analysis. No
e
formation of desired product observed. Step 1 carried out at
f
10 1C. Step 1 carried out at À15 1C.
sequences afforded 3a in almost identical yield (78%) and
enantioselectivity (92%) (entry 7). It should be noted catalyst
B required a longer reaction time to secure full conversion in
the first step at 10 1C due to greater steric hindrance on the
aryl parts of B.
Next, the scope of this three-component one-pot cascade
Michael–Pictet–Spengler reaction was examined. As shown in
Table 2, a series of a,b-unsaturated aldehydes 2 with different
substituents together with 1a and tryptamine 4a were
employed. Aromatic, aliphatic and alkoxyl carbonyl substituted
a,b-unsaturated aldehydes all served as appropriate substrates,
providing diverse indoloquinolizidines in moderate to excellent
yields. Aldehydes with aromatic substituents delivered the
Table 3 Further expanding of substrate scopea
Table 2 a,b-unsaturated aldehyde scopea
Entry
Cat
R
Product
Yield (%)b
ee (%)c
Entry
Cat
1
2
4
Product
Yield (%)b
ee (%)c
1d,e
2e
3e
4f
A
A
A
B
B
B
B
B
A
B
Ph
3a
3b
3c
3c
3d
3e
3f
3g
3h
3h
81
76
81
91
86
93
56
68
58
59
92
93
89
93
95
88
81
85
67
69
1e
2d
3e
4d
5d
6d
7d
8e
9d
10e
B
A
B
A
A
A
A
B
A
B
1a
1a
1a
1a
1b
1c
1d
1d
1e
1d
2a
2b
2a
2b
2a
2a
2a
2a
2a
2c
4b
4b
4c
4c
4a
4a
4a
4a
4a
4a
3i
3j
3k
3l
3m
3n
3o
3o
3p
3q
70
93
67
57
95
95
95
73
92
51
94
93
94
92
92
96
87
96
94
80
p-Br-C6H4
p-NO2-C6H4
p-NO2-C6H4
2,4-Cl2-C6H3
3-furanyl
Me
n-Pr
CO2Et
CO2Et
5f
6f
7f
8f
9e
10f
a
b
See footnote a, Table 1. Yields referred to chromatographically
a
b
See footnote a, Table 1. Yields referred to chromatographically
c
pure product. Enantiomeric excess was determined by chiral HPLC
d
analysis. Conducted using 1 mmol 1a. Step 1 carried out at
c
pure product. Enantiomeric excess was determined by chiral HPLC
e
d
e
f
analysis. Step 1 carried out at À15 1C. Step 1 carried out at 10 1C.
À15 1C. Step 1 carried out at 10 1C.
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Fig. 2 Transition states in Pictet–Spengler cyclization.
Scheme 1 Further transformations of indoloquinolizidines.
In conclusion, we have developed an operationally simple
method for the preparation of indoloquinolizidines through
a one-pot three-component cascade asymmetric catalytic
process. The highly functionalized products are obtained from
readily available reagents in moderate to excellent yields
and good to excellent enantioselectivities. This method is
potentially useful in combinatorial library construction and
the synthesis of natural alkaloids.
The generous financial support from the National Natural
Science Foundation of China (No. 20802043) and the
Foundations of Education Commission of Shanghai Municipality
(No. J50102) is gratefully acknowledged. Manuscript revision
by Dr He-gui Gong is also gratefully acknowledged.
8 An apparent epimerization reaction was also observed by Rovis
and co-workers in a secondary amine and carbene catalyzed
cascade sequence: S. P. Lathrop and T. Rovis, J. Am. Chem.
Soc., 2009, 131, 13628.
Notes and references
9 See supporting information for details.
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Biological Perspectives, ed. S. W. Pelletier, Springer, New York,
1992, vol. 8, p. 197.
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P. G. Humphreys, L. E. Oveman and A. D. Wrobleski, J. Am.
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Chem. Commun., 2010, 46, 2733–2735 | 2735