Synthesis of polycyclic alkaloid-type compounds by an N -acyliminium Pictet-Spengler/diels-alder sequence

Article abstract of DOI:10.1055/s-0030-1258057

A range of structurally diverse penta- and hexacyclic alkaloid-type compounds have been prepared in a two-step procedure from readily available starting materials. A flexible N-acyliminium Pictet-Spengler reaction employing electron-rich -arylethyl-amines, cinnamaldehyde derivatives, and alkynoyl chlorides sets the stage for an intramolecular Diels-Alder cycloaddition. The complex and diverse polycyclic alkaloid-like compounds are easily obtained in reasonable to excellent yield in a reliable and efficient reaction sequence. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258057

LETTER
2485
Synthesis of Polycyclic Alkaloid-Type Compounds by an N-Acyliminium
Pictet–Spengler/Diels–Alder Sequence
S
ynthesis of Po
e
lycyclic
A
l
l
kaloid-
c
T
ype
C
om
p
o
ounds Ruijter,* Jaime Garcia-Hartjes, Frank Hoffmann, Loek T. M. van Wandelen, Frans J. J. de Kanter, Elwin
Janssen, Romano V. A. Orru
Department of Chemistry & Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam,
The Netherlands
Fax +31(20)5987488; E-mail: E.Ruijter@few.vu.nl
Received 16 June 2010
groups react to give an intermolecular cycloaddition prod-
uct; the remaining two functional groups then undergo a
proximity-induced intramolecular cycloaddition reaction
to give a polycyclic product (Figure 1). This strategy al-
Abstract: A range of structurally diverse penta- and hexacyclic al-
kaloid-type compounds have been prepared in a two-step procedure
from readily available starting materials. A flexible N-acyliminium
Pictet–Spengler reaction employing electron-rich b-arylethyl-
amines, cinnamaldehyde derivatives, and alkynoyl chlorides sets lows the rapid generation of both diversity and complexi-
the stage for an intramolecular Diels–Alder cycloaddition. The
ty. Essential for diversity generation are broad substrate
complex and diverse polycyclic alkaloid-like compounds are easily
tolerance and considerable possibility for diversification.
obtained in reasonable to excellent yield in a reliable and efficient
reaction sequence.
selective
cyclization
Key words: alkaloids, polycycles, N-acyliminium Pictet–Spengler
Reactions, Diels–Alder reactions, microwave irradiation
FG3
FG4
FG3
FG4
FG1
FG2
FG1
FG2
One of the major challenges of modern-day organic chem-
istry is the development of synthetic methodology that al-
lows the discovery of novel potent and highly selective
small-molecule modulators of cellular processes. It is in-
creasingly recognized that compound collections from
combinatorial chemistry efforts typically suffer from lack
of diversity. Whereas combinatorial chemistry has thus
far focused primarily on structurally simple nitrogen-
based aromatic heterocycles, natural products often fea-
ture polycyclic and/or macrocyclic structures,1 thereby
covering a much larger portion of biological activity
space.2 Consequently, natural products have often been
proposed as starting points for the development of com-
pound libraries.3 The lesson to be learned from nature is
that diversification of scaffolds rather than slight variation
of substituents increases the probability of novel lead
identification. In this context, Schreiber introduced the
concept of diversity-oriented synthesis (DOS).4 Cascade
and tandem reactions5 and in particular multicomponent
reactions6 have become essentials tools in the realization
of DOS.
proximity-
induced
FG3
FG4
FG1
cyclization
FG2
Figure 1 Double cyclization approach towards polycyclic scaffolds
During our initial studies, the N-acyliminium Pictet–
Spengler (NAIPS) reaction proved an ideal primary cy-
clization reaction both in terms of substrate tolerance and
diversity and complexity generation (three new bonds and
one new ring system are formed).7 An additional advan-
tage of this reaction is the recent development of a catalyt-
ic asymmetric version.8 The efficiency of the NAIPS
reaction is illustrated by the synthesis of the phosphodi-
esterase V inhibitor tadalafil (Cialis).9 The reaction allows
incorporation of an alkyne moiety in, for example, the
acid chloride component. Since many secondary cycliza-
tion reactions based on this alkyne can be envisioned and
the NAIPS reaction is compatible with a broad range of al-
dehydes, many diverse scaffolds may be constructed us-
ing this approach. Although some isolated examples of
combination of the NAIPS reaction and intramolecular
Diels–Alder (IMDA) reaction have been reported,10 the
scope of this strategy has not been fully exploited. We en-
visioned that 1-styryl-2-alkynoyl-functionalized tetrahy-
droisoquinolines and tetrahydro-b-carbolines accessible
by NAIPS reaction of cinnamaldehyde derivatives and
alkynoyl chlorides would readily undergo IMDA cy-
cloaddition upon heating. IMDA reactions between elec-
tron-deficient alkynes and styryl moieties leading to
deconjugated dihydronaphthalenes have been reported in
the literature11 and are either followed by oxidation to
The development of novel synthetic concepts is of vital
importance for the construction of natural product-like
compounds and libraries thereof. To this end, we intro-
duce a diversity-oriented synthetic approach to diverse-
scaffold polycyclic compounds. The strategy is based on
a double cycloaddition approach involving two bifunc-
tional components, carefully selected in such a way that
under specific reaction conditions only two functional
SYNLETT 2010, No. 16, pp 2485–2489
x
x
.x
x
.2
0
1
0
Advanced online publication: 19.08.2010
DOI: 10.1055/s-0030-1258057; Art ID: G20010ST
© Georg Thieme Verlag Stuttgart · New York

2486
E. Ruijter et al.
LETTER
naphthalenes11a or rearrangement to conjugated dihy- dehyde 3d (entry 4), whereas the corresponding product
dronaphthalenes.11b,c
5d was not formed in the reaction with 1. Apparently, the
indole ring is more nucleophilic than the dimethoxyphe-
nyl ring.
In order to maximize reaction efficiency, we set out to de-
velop a one-pot, three-component coupling protocol for
the NAIPS reaction based on a procedure reported by
Wang and Ganesan.12 To avoid undesired side reactions
(most notably, amide formation between the amine and
acid chloride inputs) we investigated several dehydrating
agents to ensure quantitative imine formation prior to ad-
dition of the acid chloride component. Although the use of
both Na2SO4 and molecular sieves afforded the desired
NAIPS products in reasonable to good yield, the use of tri-
methyl orthoformate led to the cleanest reaction and most
reproducible results.
Table 2 N-Acyliminium Pictet–Spengler Reaction of Tryptamine
(2), Cinnamaldehydes 3a–e, and Phenylpropiolyl Chloride (4)a
O
Cl
N
O
N
H
4
+
NH2
O
N
H
R1
2
Thus, 3,4-dimethoxyphenethylamine (1) was reacted with
commercially available cinnamaldehydes 3a–e and
known aldehyde 3f.13 The in situ generated imines were
then reacted with phenylpropiolyl chloride (4). The result-
ing N-acyliminium ions immediately cyclized to give tet-
rahydroisoquinolines 5 in reasonable to very good yield
(Table 1). The only exception was the reaction with 4-
dimethylaminocinnamaldehyde (3d, entry 4). In this case,
the desired product was not formed at all. Plausibly, the
intermediate N-acyliminium ion was too unreactive in this
case due to delocalization of the positive charge.
6
R1
3
Entry
R1
H
Product
6a
Yield (%)
1
2
3
4
5
66
56
52
23
61
2-MeO
6b
3-MeO, 4-OAc
4-Me2N
6c
6d
Table 1 N-Acyliminium Pictet–Spengler Reaction of 3,4-Dimeth-
oxyphenethylamine (1), Cinnamaldehydes 3a–f, and Phenylpropiolyl
Chloride (4)a
2-O2N
6e
a Conditions: 2, 3, HC(OMe)3, r.t., 3 h; then 4, CH2Cl2, 0 °C, 30 min.
O
MeO
With ten diverse NAIPS14 products in hand, we set out to
investigate the IMDA15 reaction to give the polycyclic al-
kaloid-type compounds 7–10. The tautomerized products
7 and 9 were assigned the trans-fused structures shown
below (Tables 3 and 4) based on the spatial constraints
imposed by the primary cyclization reactions and the
Woodward–Hoffmann rules. Preliminary experiments
showed that traditional heating (toluene, reflux) typically
led to slow conversion accompanied by the formation of
brightly colored side products. Therefore, we decided to
apply microwave heating to achieve higher conversions
and suppress side reactions. A rapid optimization of reac-
tion time and temperature showed that heating to 170 °C
for 15 minutes provided the best results.
Cl
N
O
MeO
4
MeO
MeO
+
NH2
O
R1
1
5
R1
3
Entry
R1
H
Product
Yield (%)
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
85
43
47
0
2-MeO
Thus, microwave heating of tetrahydroisoquinolines 5 led
to the formation of alkaloid-type pentacycles 7 and 8.16 In
the absence of electron-withdrawing substituents on the
styryl moiety, the IMDA reaction proceeded in modest
conversion (Table 3, entries 1 and 2) to afford an insepa-
rable mixture of 7a and 8a, and 7b and 8b, respectively.
Due to the formation of regioisomers of both 7c and 8c,
yield and product ratio could not be adequately assessed
for IMDA of 5c (entry 3). The microwave-assisted IMDA
of electron-deficient compounds 5e and 5f proceeded
smoothly to give the cyclization products in good to ex-
cellent yield, with a strong preference for the formation of
rearranged products 7e and 7f (entries 4 and 5).
3-MeO, 4-AcO
4-Me2N
2-O2N
72
79
2-F3C
a Conditions: 1, 3, HC(OMe)3, r.t., 3 h; then 4, CH2Cl2, 0 °C, 30 min.
Similarly, tryptamine (2) was reacted with cinnamalde-
hydes 3a–e and phenylpropiolyl chloride (4) to give tet-
rahydro-b-carbolines 6 in modest to good yield (Table 2).
Interestingly, the desired product 6d was formed using al-
Synlett 2010, No. 16, 2485–2489 © Thieme Stuttgart · New York

LETTER
Synthesis of Polycyclic Alkaloid-Type Compounds
2487
Table 3 Intramolecular Diels–Alder Reaction of Tetrahydroisoquinolines 5a–fa
MeO
MeO
MeO
MeO
MeO
MeO
N
O
N
O
H
H
N
MW
O
+
toluene
R1
R1
5
7
8
R1
Entry
R1
Product
7/8a
Ratio 7/8
5.5:1
Conv. (%)
29
1
2
3
4
5
H
2-MeO
7/8b
7/8c
1:3
quant.
n.d.b
b
3-MeO, 4-AcO
2-O2N
–
7/8e
5:1
quant.
quant.
2-F3C
7/8f
10:1
a Conditions: MW, toluene, 170 °C, 15 min.
b The formation of a mixture of regioisomers made accurate assessment of yield and product ratio impossible in this case.
The microwave-assisted IMDA of tetrahydro-b-carbo-
lines 6 typically proved more efficient (Table 4). Al-
though the reaction with dimethylamino-functionalized
6c did not afford any cyclization product (entry 4), the
majority of these compounds were readily converted to in-
separable mixture of hexacycles 9 and 10 (entries 1, 2, and
5).
Table 4 Intramolecular Diels–Alder Reaction of Tetrahydro-b-
carbolines 6a–ea
N
N
H
O
H
H
In an attempt to provide selective access to both the rear-
ranged (7 and 9) and oxidized products (8 and 10), we per-
formed the IMDA reaction either under inert atmosphere
or in the presence of a dehydrogenation agent (e.g., S, Pd/
C), respectively. Although the product ratios changed
somewhat in favor of the desired product in both cases,
full selectivity towards either product was not observed.
The highest selectivity was observed under standard mi-
crowave conditions for compounds carrying electron-
poor styryl moieties (5e and 5f), which gave almost exclu-
sively the rearranged products 7e17 and 7f. Interestingly,
these products were quantitatively converted to the corre-
sponding naphthalenes 8e18 and 8f upon treatment with
DDQ (Scheme 1). Unfortunately, however, treatment of
7a–c, 9a–c and 9e led to oxidative decomposition.
N
O
R1
N
H
9
+
MW
toluene
R1
N
N
H
O
6
R1
10
Entry
R1
H
Product
9/10a
9/10b
9/10c
9/10d
9/10e
Ratio 9/10
2:3
Conv. (%)
1
2
3
4
5
90
80
MeO
MeO
MeO
MeO
2-MeO
1:2
N
N
O
O
b
b
H
3-MeO, 4-AcO
4-Me2N
–
–
H
DDQ
CHCl3
–
0
R1
R1
2-O2N
>10:1
90
a Conditions: MW, toluene, 170 °C, 15 min.
7e R = NO2
7f R = CF3
8e R = NO2 (quant)
8f R = CF3 (quant)
b The formation of a mixture of regioisomers made accurate assess-
ment of yield and product ratio impossible in this case.
Scheme 1 DDQ-mediated oxidation of 7e–f
In summary, N-acyliminium Pictet–Spengler reaction of
3,4-dimethoxyphenethylamine or tryptamine, cinnamal-
dehyde derivatives, and alkynoyl chlorides followed by
intramolecular Diels–Alder reaction afford penta- and
Synlett 2010, No. 16, 2485–2489 © Thieme Stuttgart · New York

2488
E. Ruijter et al.
LETTER
(8) For catalytic asymmetric Pictet–Spengler-type reactions,
hexacyclic alkaloid-type compounds in an efficient two-
step sequence. The products are typically mixtures of tau-
tomerized and oxidized cyclization products. When elec-
tron-deficient cinnamaldehyde derivatives were used, the
secondary cyclization afforded primarily the tautomerized
products, which could subsequently be oxidized to the ar-
omatic compounds by treatment with DDQ. The short and
efficient synthetic sequence and the variability of the
products make this approach very promising for the con-
struction of arrays of natural product-like compounds
with potential biological activity.
see: (a) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc.
2006, 128, 1086. (b) Mergott, D. J.; Zuend, S. J.; Jacobsen,
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(9) Revell, K. D.; Srinivasan, N.; Ganesan, A. Synlett 2004,
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(10) (a) Paulvannan, K.; Hale, R.; Mesis, R.; Chen, T.
Tetrahedron Lett. 2002, 43, 203. (b) Fokas, D.; Yu, L.;
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Acknowledgment
We thank Dr. M. T. Smoluch (VU University Amsterdam) for
(HR)MS measurements.
References and Notes
(1) (a) Henkel, T.; Brunne, R. M.; Müller, H.; Reichel, F.
Angew. Chem. Int. Ed. 1999, 35, 643. (b) Lee, M.-L.;
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(13) Keskin, H.; Miller, R. E.; Nord, F. F. J. Org. Chem. 1952, 16,
199.
(14) Standard Procedure for NAIPS Reaction
Tryptamine or 3,4-dimethoxyphenethylamine (1 or 2, 2.00
mmol) and the appropriate cinnamaldehyde derivative (3a–
f, 2.10 mmol) were dissolved in HC(OMe)3 (10 mL) and
stirred for 3 h at r.t. The volatiles were removed in vacuo,
and the residue was dissolved in anhyd CH2Cl2 (15 mL) and
cooled to 0 °C. Phenylpropiolyl chloride (4, 2.10 mmol) was
added, and the mixture was stirred for 30 min at 0 °C. The
reaction was quenched by addition of sat. aq NaHCO3. The
organic phase was separated, dried (Na2SO4), filtered, and
concentrated in vacuo. The crude product was purified by
flash chromatography.
(2) Lipinski, C.; Hopkins, A. Nature (London) 2004, 432, 955.
(3) For example, see: (a) Dobson, C. M. Nature (London) 2004,
432, 824. (b) Clardy, J.; Walsh, C. Nature (London) 2004,
432, 829. (c) Wessjohann, L. A.; Ruijter, E. Top. Curr.
Chem. 2004, 243, 137. (d) Ortholand, J.-Y.; Ganesan, A.
Curr. Opin. Chem. Biol. 2004, 8, 271. (e) Boldi, A. M.
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Biol. 2005, 9, 266. (j) Arya, P.; Quevillon, S.; Joseph, R.;
Wei, C.-Q.; Gan, Z.; Parisien, M.; Sesmilo, E.; Reddy, P. T.;
Chen, Z.-X.; Durieux, P.; Laforce, D.; Campeau, L.-C.;
Khadem, S.; Couve-Bonnaire, S.; Kumar, R.; Sharma, U.;
Leek, D. M.; Daroszewska, M.; Barnes, M. L. Pure Appl.
Chem. 2005, 77, 163. (k) Koch, M. A.; Schuffenhauer, A.;
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Waldmann, H. Proc. Natl. Acad. Sci. U.S.A. 2005, 102,
17272.
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Chem. Soc. 2004, 126, 14095. (d) Burke, M. D.; Schreiber,
S. L. Angew. Chem. Int. Ed. 2004, 43, 46.
(5) For a review, see: Tietze, L. F. Chem. Rev. 1996, 96, 115.
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Ed. 2000, 39, 3168. (b) Zhu, J. Eur. J. Org. Chem. 2003,
1133. (c) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471.
(d) Dömling, A. Chem. Rev. 2006, 106, 17.
(15) Standard Procedure for Microwave-Assisted IMDA
Reaction
Compound 5 or 6 (10 or 500 mg) were dissolved in toluene
(5 mL) and heated to 170 °C for 15 min using a CEM
Discover microwave reactor. The product was either
analyzed directly by 1H NMR (in case of quantitative
conversion/10 mg scale) or purified by flash
chromatography (500 mg scale).
(16) Procedure for DDQ Oxidation of 7 to 8
Compound 7e or 7f (1.0 equiv) was dissolved in CH2Cl2 and
DDQ (2.0 equiv) was added. The mixture was stirred for 1 h
at r.t., concentrated in vacuo, and purified by flash
chromatography to afford 8e and 8f, respectively.
(17) Data for Compound 7e
Rf = 0.26 (EtOAc–cyclohexane = 4:1). 1H NMR (500 MHz):
d = 7.79 (dd, J = 8.1, 1.1 Hz, 1 H), 7.39–7.22 (m, 6 H), 7.16
(d, J = 8.1 Hz, 1 H), 6.73 (s, 1 H), 6.60 (s, 1 H), 4.54 (d,
J = 2.6 Hz, 1 H), 4.34 (ddd, J = 13.0, 6.0, 1.8 Hz, 1 H), 3.98–
3.93 (m, 1 H), 3.87 (s, 3 H), 3.79 (s, 3 H), 3.12 (dd, J = 16.4,
16.1 Hz, 1 H), 3.04 (td, J = 12.5, 4.5 Hz, 1 H), 2.91–2.87 (m,
2 H), 2.67 (dd, J = 15.8, 2.2 Hz, 1 H). 13C NMR (126 MHz):
d = 164.1, 149.4, 148.4, 148.3, 138.83, 138.81, 134.6, 132.4,
131.6, 129.5, 128.3, 128.0 (2 C), 127.9, 127.4, 126.0, 124.2,
111.9, 107.3, 60.9, 56.2, 55.9, 41.0, 37.4, 29.8, 28.3. IR
(neat): n = 2932, 2835, 2245, 1678, 1516, 1416, 1358, 1254,
1227, 1115, 910, 725, 698 cm–1. ESI-HRMS (+): m/z calcd.
for C28H25N2O5+ [M + H]+: 469.1758; found: 469.1741.
(18) Data for Compound 8e
(7) For recent DOS approaches involving N-acyliminium
chemistry, see: (a) Sunderhaus, J. D.; Dockendorff, C.;
Martin, S. F. Org. Lett. 2007, 9, 4223. (b) Sunderhaus, J.
D.; Dockendorff, C.; Martin, S. F. Tetrahedron 2009, 65,
6454. (c) Karpov, A. S.; Rominger, F.; Müller, T. J. J. Org.
Biomol. Chem. 2005, 3, 4382.
Rf = 0.73 (EtOAc–cyclohexane = 1:1). 1H NMR (250 MHz):
d = 8.35 (dd, J = 1.1, 7.7 Hz, 1 H), 8.05 (d, J = 8.6 Hz, 1 H),
Synlett 2010, No. 16, 2485–2489 © Thieme Stuttgart · New York

LETTER
7.68 (s,1 H), 7.55–7.48 (m, 5 H), 7.36–7.28 (m, 3 H), 6.60 (s,
Synthesis of Polycyclic Alkaloid-Type Compounds
2489
129.3, 128.1, 127.8, 127.7, 127.2, 125.8, 124.0, 111.8,
1 H), 4.43 (ddd, J = 2.0, 6.3, 12.7 Hz, 1 H), 4.09 (s, 3 H),
3.86 (s, 3 H), 3.54 (dt, J = 4.7, 12.7 Hz, 1 H), 3.02 (m, 1 H),
2.71 (ddd, J = 2.0, 4.7, 16.6 Hz, 1 H). 13C NMR (101 MHz):
d = 163.9, 149.3, 148.3, 148.2, 138.7, 134.5, 132.2, 131.4,
107.3, 60.7, 60.2, 56.0, 55.8, 40.8, 37.2, 29.7, 28.2, 14.0.
IR (neat): n = 2924, 2851, 1701, 1516, 1258, 1099, 1026,
760, 729, 702 cm–1.
Synlett 2010, No. 16, 2485–2489 © Thieme Stuttgart · New York