Diastereoselective syntheses of indoloquinolizidines by a pictet-spengler/lactamization cascade

Article abstract of DOI:10.1021/ol101922h

An expedient diastereoselective synthesis of highly functionalized indolo[2,3-α]quinolizidines adopting a cis H2/H12b geometry has been realized by a Pictet-Spengler/lactamization cascade sequence. The absolute stereochemistry at C2, C3, and C12b was gove

Full text of DOI:10.1021/ol101922h

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5366-5369
Diastereoselective Syntheses of
Indoloquinolizidines by a
Pictet-Spengler/Lactamization Cascade
Huihui Fang,† Xiaoyu Wu,*,† Linlin Nie,† Xiaoyang Dai,† Jie Chen,† Weiguo Cao,*,†
and Gang Zhao*,‡
Department of Chemistry, Shanghai UniVersity, 99 Shangda Road,
Shanghai 200444, China, and Key Laboratory of Synthetic Organic Chemistry of
Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, China
wuxy@shu.edu.cn; wgcao@mail.shu.edu.cn; zhaog@mail.sioc.ac.cn
Received August 16, 2010
ABSTRACT
An expedient diastereoselective synthesis of highly functionalized indolo[2,3-r]quinolizidines adopting a cis H2/H12b geometry has been
realized by a Pictet-Spengler/lactamization cascade sequence. The absolute stereochemistry at C2, C3, and C12b was governed by the
originally created chirality of the Michael adduct through organocatalyzed conjugate addition of dialkyl malonates to r,ꢀ-unsaturated aldehydes.
The indolo[2,3-R]quinolizidine ring system is of great interest
and significance since this structural subunit is found in
numerous natural alkaloids. The stereochemical diversity and
structural complexity of such natural products have rendered
them interesting synthetic targets.1
requires multistep functional group transformations and
laborious protecting group operations. Therefore, more
efficient diastereoselective methods to access these com-
pounds would be highly desired. In addition, although
numerous asymmetric catalytic syntheses of indoloquino-
lizidines have been developed recently,3,4 relatively few
utilized a cascade strategy.4
Conventionally, optically pure indoloquinolizidines are
prepared from the chiral pool.2 However, this strategy often
† Shanghai University.
(3) Examples of quinolizidine syntheses by asymmetric catalysis: (a)
Santos, L. S.; Pilli, R. A.; Rawal, V. H. J. Org. Chem. 2004, 69, 1283. (b)
Frisch, K.; Landa, A.; Saaby, S.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2005, 44, 6058. (c) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2006, 128,
9646. (d) Szawkalo, J.; Czarnocki, S. J.; Zawadzka, A.; Wojtasiewicz, K.;
Leniewski, A.; Maurin, J. K.; Czarnocki, Z.; Drabowicz, J. Tetrahedron:
Asymmetry 2007, 18, 406. (e) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404. (f) Mergott, D. J.;
Zuend, S. J.; Jacobsen, E. N. Org. Lett. 2008, 10, 745. (g) Jana, C. K.;
Studer, A. Chem.sEur. J. 2008, 14, 6326. (h) Itoh, T.; Yokoya, M.;
Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2006, 8, 1533. (i) Muratore,
M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon,
D. J. J. Am. Chem. Soc. 2009, 131, 10796. (j) Jakubec, P.; Helliwell, M.;
Dixon, D. J. Org. Lett. 2008, 10, 4267. (k) Jiang, J.; Qing, J.; Gong, L. Z.
‡ Shanghai Institute of Organic Chemistry.
(1) (a) The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.;
Academic Press: New York, 1998; Vol 50. (b) Sza´ntay, C.; Honty, K. In
The Chemistry of Heterocyclic Compounds; Saxton, J. E., Ed.; Wiley: New
York, 1994; Vol. 25, pp 161-216. (c) Baxter, E. W.; Mariano, P. S. In
Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.;
Springer: New York, 1992; Vol 8, pp 197-319.
(2) For selected examples of quinolizidine syntheses based on starting
materials from the chiral pool, see: (a) Martin, S. F.; Chen, K. X.; Eary,
C. T. Org. Lett. 1999, 1, 79. (b) Yu, S.; Berner, O. M.; Cook, J. M. J. Am.
Chem. Soc. 2000, 122, 7827. (c) Deiters, A.; Chen, K.; Eary, C. T.; Martin,
S. F. J. Am. Chem. Soc. 2003, 125, 4541. (d) Amat, M.; Pe´rez, M.; Managlia,
A. T.; Casamitjana, N.; Bosch, J. Org. Lett. 2005, 7, 3653. (e) Stork, G.;
Tang, P. C.; Casey, M.; Goodman, B.; Toyota, M. J. Am. Chem. Soc. 2005,
127, 16255. (f) Amat, M.; Santos, M. M. M.; Bassas, O.; Llor, N.; Escolano,
C.; Go´mez-Esque´, A.; Molins, E.; Allin, S. M.; McKee, V.; Bosch, J. J.
Org. Chem. 2007, 72, 5193. (g) Ma, J.; Yin, W. Y.; Zhou, H.; Cook, J. M.
Org. Lett. 2007, 9, 3491.
Chem.sEur. J. 2009, 15, 7031
.
(4) (a) Franze´n, J.; Fisher, A. Angew. Chem., Int. Ed. 2009, 48, 787.
(b) Zhang, W.; Franze´n, J. AdV. Synth. Catal. 2010, 352, 499. (c) Wu, X. Y.;
Dai, X. Y.; Nie, L. L.; Fang, H. H.; Chen, J.; Ren, Z. J.; Cao, W. G.; Zhao,
G. Chem. Commun. 2010, 46, 2733
.
10.1021/ol101922h  2010 American Chemical Society
Published on Web 11/09/2010

Recently, we and Franze´n et al. reported an efficient
synthesis of highly functionalized indoloquinolizidines by
organocatalyzed5 enantioselective cascade reactions between
R,ꢀ-unsaturated aldehydes and active methylene compounds.6
Good to excellent yields and excellent enantioselectivities
have been achieved. The relative stereochemistry of the major
isomers was revealed to be a trans H2/H12b geometry
(Scheme 1).4 Among the challenges to be addressed in the
Scheme 1
.
Organocatalyzed Asymmetric Syntheses of Highly
Substituted Indoloquinolizidines
Figure 1. Concept of the Pictet-Spengler/lactamization cascade.
configuration with respect to C2 in the δ-lactam ring.4a,b
Although numerous examples of substrate control of C12b
chirality have been reported,2f,8 to our knowledge using 7
or similar substrates as the source of chirality has yet to be
reported.
To test the feasibility of this cascade, a model reaction
between tryptamine 6a and conjugate adduct 7a was examined
under a broad set of conditions (Table 1). A careful screen of
syntheses of natural alkaloids containing indoloquinolizidine
motifs is the control of C2 and C12b chirality, which usually
prefers the cis H2/H12b diastereomer.1,2 Herein we describe
a new development of our work leading to indolo[2,3-R]-
quinolizidines with cis H2/H12b conformation. This method
employs an efficient cascade reaction of two components:
tryptamines 6 and conjugate adducts 7. Aldehydes 7 were
obtained from an asymmetric organocatalyzed Michael
addition of dialkyl malonates to R,ꢀ-unsaturated aldehydes
(Figure 1).6a
Table 1. Screen of Reaction Conditionsa
Our proposed cascade is shown in Figure 1. The acid-
promoted Pictet-Spengler reaction of tryptamine 6 and alde-
hyde 7 leads to the amine intermediate 8 as a mixture of
diastereomers,7 which undergoes lactamization to afford mul-
tiring compound 3 and/or 9. Undoubtedly, the chiral-labile
stereocenter C3 should adopt the thermodynamically stable trans
entry
acid
solvent [7a], mM yield %b ee %c
1
2
3
4
5
6
7
8
PhCO2H
AcOH
TFA
4-NO2-C6H4CO2H
3,5-(NO2)2C6H3CO2H toluene
toluene
toluene
toluene
toluene
60
60
60
60
60
60
60
60
20
10
10
10
10
10
10
10
10
23
34
53
48
39
37
29
33
68
81
90
62
68
-
93
96
97
95
95
91
90
93
97
97
98
98
96
-
TfOH
TsOH
HCl
toluene
toluene
toluene
toluene
toluene
DCM
(5) For selected reviews on organocatalysis, see: (a) Acc. Chem. Res.
2004, 37 (8), special issue on organocatalysis. (b) Berkessel, A.; Gro¨ger,
H. Asymmetric Organocatalysis; VCH: Weinheim, Germany, 2004. (c)
Chem. ReV. 2007, 107 (12), special issue on organocatalysis. (d) Dalko,
P. I. EnantioselectiVe Organocatalysis; Wiley-VCH: Weinheim, 2007. (e)
Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int.
Ed. 2008, 47, 6138. (f) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. ReV.
2009, 38, 2178. (g) Grondal, C.; Jeanty, M.; Enders, D. Nature Chem. 2010,
2, 167.
9
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
10
11
12
13
14
15
16
CHCl3
THF
DMSO
DMF
(6) (a) Brandau, S.; Landa, A.; Franze´n, J.; Marigo, M.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2006, 45, 4305. (b) Carlone, A.; Cabrera, S.; Marigo,
M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 1101. (c) Carlone,
A.; Marigo, M.; North, C.; Landa, A.; Jørgensen, K. A. Chem. Commun.
2006, 4928. (d) Rueping, M.; Sugiono, E.; Merino, E. Chem.sEur. J. 2008,
14, 6329. (e) Rueping, M.; Kuenkel, A.; Tato, F.; Bats, J. W. Angew. Chem.,
Int. Ed. 2009, 48, 3699. (f) Zu, L. S.; Li, H.; Xie, H.-X.; Wang, J.; Jiang,
W.; Tang, Y.; Wang, W. Angew. Chem., Int. Ed. 2007, 46, 3732.
(7) For examples of catalyed asymmetric Pictet-Spengler reactions: (a)
Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086. (b)
Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.; van Maarseveen,
J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46, 7485. (c) Sewgobind,
N. V.; Wanner, M. J.; Ingemann, S.; de Gelder, R.; van Maarseveen, J. H.;
Hiemstra, H. J. Org. Chem. 2008, 73, 6405. (d) Klausen, R. S.; Jacobsen,
E. N. Org. Lett. 2009, 11, 887. (e) Also see ref 3f and ref 3i.
-
-
EtOH
-
-
17d TFA
DCM
-
-
a General conditions of reaction 1: 1a (1.5 equiv), 10a (1 equiv), and
catalyst (0.1 equiv) in EtOH (0.2 M) at 0 °C for 48 h. General conditions
of reaction 2: crude 7a (1 equiv), 6a (1.5 equiv), and acid (1 equiv) at 50
°C. b Yield referred to isolated pure product. c Enantiomeric excess was
determined by chiral HPLC analysis. d Reaction run at 20 °C.
acids (entries 1-8) revealed that TFA afforded the product in
a moderate yield (entry 3). Although the enantiomeric excess
Org. Lett., Vol. 12, No. 23, 2010
5367

of the product was somewhat independent of the acid chosen,
acids other than TFA led to lower yields. To our delight, the
yields were substantially improved by lowering the substrate
concentration to 10 mM in toluene (entry 10).9 A brief screen
of solvents revealed that the reaction was quite solvent depend-
ent. DCM proved to be the best (entry 11).
ring, providing the products in good yields and excellent
enantioselectivities as single diastereoisomers (entries 1-6).
Styrenyl-substituted aldehydes 7h-i and aliphatic-substituted
aldehydes 7j-l also gave only one diastereomer and excellent
enantioselectivities (entries 7-11); however, the yields of
products 9h-l were much lower than those of the aromatic
analogues.
Chloroform and THF provided the product with good
yield, albeit inferior to DCM (entries 12 and 13). In more
polar solvents, such as DMSO, DMF, and EtOH, no or trace
formation of the product was detected (entries 14-16). No
product was observed when the temperature was lowered to
20 °C (entry 17).
To further illustrate the power of this diastereoselective
cascade reaction, the substituted tryptamines 6b-c and
conjugate adducts 7m-p arising from diethyl malonate and
dibenzyl malonate were also examined. The results are listed
in Table 3. Except in the case of entry 7, all of the substrates
The cis H2/H12b configuration was determined by com-
1
parison of the H NMR spectrum of 9a with the previous
work of Franze´n et al.4b To our pleasure, no trans diaste-
reoisomer was observed; this was confirmed by HPLC and
TLC tests of the product 9a with a trans sample obtained
by Franze´n’s method.
Table 3. Further Expansion of Substrate Scope
After the optimized reaction conditions were obtained
(entry 11, Table 1), the scope of this cascade reaction was
next examined. We first investigated the one-pot cascade
sequence employing tryptamine 6a and aldehydes 7b-l
obtained from asymmetric conjugate addition of dimethyl
malonate 10a to the corresponding R,ꢀ-unsaturated aldehydes
1b-l. As shown in Table 2, the cascade reaction proceeded
entry
R1, 6
R2, R3
C6H5, Me
4-Br-C6H4, Me
4-F-C6H4, Me
7
9
yield % ee %
1
2
3
4
5
6
7
8
9
Br, 6b
Br, 6b
Br, 6b
MeO, 6c C6H5, Me
MeO, 6c 4-F-C6H4, Me
H, 6a
Br, 6b
H, 6a
H, 6a
7a 9m
7b 9n
7c 9o
7a 9p
7c 9q
7m 9r
7m 9s
7n 9t
86
62
79
75
78
52
27
65
42
52
99
96
99
98
98
98
99
77
87
97
C6H5, Et
C6H5, Et
4-Br-C6H4, Et
2-Br-C6H4CHdCH, Et 7o 9u
C6H5, Bn 7p 9v
Table 2. Cascade Reaction of Tryptamine 6a and Aldehydes 7b-la
10 H, 6a
yield %b
ee %c
employed afforded the products in moderate to good yields.
Conjugate adducts arising from diethyl malonate or dibenzyl
malonate generally led to lower yields as compared to those
from dimethyl malonate (entries 1-5 vs entries 6-10).
The collective results shown above (Tables 2 and 3) indicated
that this cascade sequence could tolerate a broad spectrum of
substrates. On the basis of the fact that cis H2/H12b relative
configuration and highly substituted indolo[2,3-R]quinolizidine
diastereoisomer were obtained, this method should be useful
in both library syntheses and total syntheses alike.
entry
R
7
9
1
2
3
4
5
6
7
8
4-Br-C6H4
4-F-C6H4
7b
7c
7d
7e
7f
7g
7h
7i
9b
9c
9d
9e
9f
9g
9h
9i
64
85
67
73
85
72
43
54
42
41
41
97
98
98
97
95
96
98
92
88
93
93
2,4-(Cl)2-C6H3
4-Me-C6H4
2-MeO-C6H4
4-MeO-C6H4
2-Br-C6H4CHdCH
4-F-C6H4CHdCH
Me
9
10
11
7j
7k
7l
9j
9k
9l
Et
n-Pr
The relative configuration of the cyclized product 9h was
unambiguously determined to be 2S, 3S, and 12bR by single-
crystal X-ray diffraction analysis (Figure 2). The stereo-
chemistry at C2 of 9h originated from 7h by asymmetric
conjugate addition of dimethyl malonate to unsaturated
aldehyde 1h catalyzed by (S)-prolinol TMS ether. The
selective formation of C3 and C12b stereochemistry was
induced by C2 chirality during the lactamization procedure.
a See footnote a in Table 1. b Yield referred to isolated pure product.
c Enantiomeric excess was determined by chiral HPLC analysis.
well for aromatic-substituted aldehydes 7b-g bearing electron-
donating or electron-withdrawing substituents on the aryl
(8) For selected examples of substrate-controlled selective formation of
quinolizidines: (a) Allin, S. M.; Vaidya, D. G.; James, S. L.; Allard, J. E.;
Smith, T. A. D.; McKee, V.; Martin, W. P. Tetrahedron Lett. 2002, 43,
3661. (b) Allin, S. M.; Thomas, C. I.; Doyle, K.; Elsegood, M. R. J. J.
Org. Chem. 2005, 70, 357. (c) Allin, S. M.; Thomas, C. I.; Allard, J. E.;
Doyle, K.; Elsegood, M. R. J. Eur. J. Org. Chem. 2005, 4179. (d) Allin,
S. M.; Duffy, L. J.; Page, P. C. B.; McKee, V.; Edgar, M.; McKenzie,
M. J.; Amat, M.; Bassas, O.; Santos, M. M. M.; Bosch, J. Tetrahedron
Lett. 2006, 47, 5713. (e) Amat, M.; Santos, M. M. M.; Go´mez, A. M.;
Jokic, D.; Molins, E.; Bosch, J. Org. Lett. 2007, 9, 2907.
The excellent diastereoselectivities in all of the cascade
reactions are notable and deserve further comment.10 It is
well documented that the stereogenic center formed in the
(9) For examples of asymmetric Pictect-Spengler cyclization in low
substrate concentration, see: ref 3e and ref 3i.
5368
Org. Lett., Vol. 12, No. 23, 2010

Figure 2. X-ray structure of 9h.
Figure 3. Proposed transition states in lactamization.
Pictet-Spengler reaction is subject to epimerization.11 No
epimerization was observed when pure 9a or the C12 epimer
of 9a was treated with TFA at 50 °C in DCM.12 It is plausible
that the diastereoselectivity of the overall cascade reaction
is determined by the differential rates of lactamization of
intermediate 8a and 8a′ (Figure 3). The exclusive formation
of 9a was reasonable since far less steric interaction presents
in TS1 with all the substituents around the newly formed
lactam ring adopting equatorial placement. This result is in
accordance with the observed product structure. TS2 and TS3
are disfavored due to the presence of significant steric
interaction.
indolo[2,3-R]quinolizidines. The highly functionalized prod-
ucts were obtained as single diastereomers from a broad
spectrum of readily available reagents in moderate to good
yields and good to excellent enantioselectivities. The H2/
H12b relative configuration of the products was determined
to be cis, which is commonly adopted by a number of natural
alkaloids. Further investigation to extend the applicability
of this reaction to a broader range of substrates and apply
this method in total syntheses of natural alkaloids is currently
underway in our laboratory.
In summary, we have developed an operationally simple
diastereoselective cascade sequence for the preparation of
Acknowledgment. The generous financial support from
National Science Foundation of China (No. 20802043) and
the Foundations of Education Commision of Shanghai
Municipality (Nos. J50102) are gratefully acknowledged.
Manuscript revision by Dr. He-gui Gong at Shanghai
University is also gratefully acknowledged.
(10) The relative configuration of 9g and 9r was also confirmed by
comparison of 1H NMR spectra with known compounds reported in ref 4b.
The stereochemistry of other products was assigned by analogy.
(11) (a) Cox, E. D.; Hamaker, L. K.; Li, J.; Yu, P.; Czerwinski, K. M.;
Deng, L.; Bennett, D. W.; Cook, J. M. J. Org. Chem. 1997, 62, 44. (b)
Jiang, W. Q.; Sui, Z. H.; Chen., X. Tetrahedron Lett. 2002, 43, 8941. (c)
Han, D. M.; Fo¨rsterling, F. H.; Deschamps, J. R.; Parrish, D.; Liu, X. X.;
Yin, W. Y.; Huang, S. M.; Cook, J. M. J. Nat. Prod. 2007, 70, 75. (d) Shi,
X. X.; Liu, S. L.; Xu, W.; Xu, Y. L. Tetrahedron: Asymmetry 2008, 19,
435. (e) Van Linn, M. L.; Cook, J. M. J. Org. Chem. 2010, 75, 3587.
(12) It is reported that harsh conditions (refluxing in TFA) were required
to epimerize C12b chirality of 9a: (a) Lounasmaa, M.; Berner, M.; Brunner,
M.; Suomalainen, H.; Tolvanen, A. Tetrahedron 1998, 54, 10205. (b) Also
see ref 4b.
Supporting Information Available: General experimental
conditions, NMR spectra, and HPLC analysis of the products;
CIF of 9h. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL101922H
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