Organocatalytic approach to benzofused nitrogen-containing heterocycles: Enantioselective total synthesis of (+)-angustureine

Article abstract of DOI:10.1002/chem.200801480

A study was conducted to demonstrate an organocatalytic approach to benzofused nitrogen-containing heterocycles. he study also demonstrated enantioselective total synthesis of (+)-angustureine. It reported the easy an d enantioselective preparation of tet

Full text of DOI:10.1002/chem.200801480

DOI: 10.1002/chem.200801480
Organocatalytic Approach to BenzofusedNitrogen-Containing Heterocycles:
Enantioselective Total Synthesis of (+)-Angustureine
Santos Fustero,*[a, b] Javier Moscardó,[a] Diego JimØnez,[a]
[a]
María Dolores PØrez-Carrión,[b] María Sµnchez-Roselló,[a] andCarlos del Pozo
Pyrrolidine and piperidine benzofused heterocyclic ring
systems have become attractive targets in organic and me-
dicinal chemistry. These families of compounds are extreme-
ly valuable scaffolds due to their widespread occurrence in
Nature, diverse biological activity, and interesting chemical
properties.[1] Therefore, the development of new strategies
for the generation of these heterocyclic frameworks, espe-
cially in a chiral nonracemic form, is of great interest in or-
ganic synthesis.
Regarding the piperidine family, strategies for the catalyt-
ic enantioselective preparation of tetrahydroquinolines are
mainly based either on the asymmetric hydrogenation of the
corresponding aromatic quinoline derivatives by using chiral
metal catalysts[2] or, more recently, chiral Brønsted acids;[3]
or alternatively an enantioselective aza-Diels–Alder reac-
tion.[4] In the same way, one of the common strategies used
to access enantiomerically enriched tetrahydroisoquinolines
is based on the asymmetric transfer hydrogenation of isoqui-
noline and dihydroisoquinoline skeletons.[5] However, proba-
bly the most popular method used to access these deriva-
tives relies on the addition of nucleophilic carbon species to
the C=N bond of dihydroisoquinolines.[6] In the pyrrolidine
benzofused family, the indoline core is the most important
substructure, and their synthesis is nowadays the subject of
intensive research. In recent years, several reports for the
enantioselective formation of indolines have appeared in
the literature.[7] However, the construction of the isoindoline
core is clearly underdeveloped and only one method for its
catalytic enantioselective preparation has been reported
very recently.[8]
The addition of nitrogen-centered nucleophiles to a,b-un-
saturated systems, that is, the so-called aza-Michael reaction,
À
is one of the simplest and most direct ways to create C N
bonds. The intramolecular version is particularly relevant
because it allows the direct generation of nitrogen-contain-
ing heterocycles. Despite its synthetic potential, examples of
the enantioselective version of this intramolecular reaction[9]
are very scarce and all rely on the use of organocatalysts.
One of these examples described the organocatalytic synthe-
sis of tetrahydroisoquinolines by using amides as nitrogen
nucleophiles, although with poor enantiocontrol.[10] Very re-
cently, the synthesis of pyrazolo–indole compounds was per-
formed by using the indole nitrogen as a nucleophile in the
presence of a cinchonidine-derived catalyst.[11] The third ex-
ample of an organocatalytic intramolecular aza-Michael re-
action (IMAMR) reported to date was developed by our re-
search group,[12] and allowed for the generation of several
five- and six-membered heterocycles with excellent enantio-
selectivities by using carbamates as nitrogen nucleophiles.[13]
We envisioned the possibility of performing this organocata-
lytic IMAMR on ortho-substituted anilines and benzyl-
amines that have a pendant a,b-unsaturated moiety. Herein
[a]Prof. Dr. S. Fustero, J. Moscardó, Dr. D. JimØnez,
Dr. M. Sµnchez-Roselló, Dr. C. del Pozo
Departamento de Química Orgµnica
Universidad de Valencia
we report the easy and enantioselective preparation of tetra-
hydroquinolines, tetrahydroisoquinolines, indolines, and iso-
indolines by following the aforementioned transformation.
The common synthetic strategy for the synthesis of these
four valuable heterocyclic derivatives is depicted in
Scheme 1. Our approach started with a cross metathesis
(CM) reaction of the terminal alkenylic chain of ortho-sub-
stituted N-protected anilines and benzylamines with acrolein
to afford the corresponding a,b-unsaturated derivatives that,
in turn, were subjected to an organocatalytic IMAMR and
subsequent aldehyde reduction. The starting N-protected
amines 1–4 (Table 1) were prepared according to procedures
46100-Burjassot, Valencia (Spain)
Fax : (+34)963-544-939
E-mail: santos.fustero@uv.es
[b]Prof. Dr. S. Fustero, M. D. PØrez-Carrión
Laboratorio de MolØculas Orgµnicas
Centro de Investigación Príncipe Felipe
46013-Valencia (Spain)
E-mail: sfustero@cipf.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801480.
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Chem. Eur. J. 2008, 14, 9868 – 9872

COMMUNICATION
Table 2. Optimization of the reaction conditions.
Entry Catalyst Solvent T [8C]
t [h] 10a[a] [%] ee[b] [%]
1
2
3
4
5
6
7
8
I
I
I
I
I
I
II
III
CHCl3
CHCl3
CHCl3
CHCl3
toluene
THF
0
À20
À30
À40
0
1
12
12
12
48
78
70
72
56
45
trace
68
82
92
98
>99
78
–
>99
54
Scheme 1. The synthetic strategy. PG=Protecting group.
Table 1. Preparation of starting N-protected amines 5–8.
À40 to RT 24
CHCl3
CHCl3
À30
16
12
À30
72
[a]Isolated yields. [b]Determined by chiral HPLC (see the Supporting
Information).
Entry
Substrate
n
m
PG[a]
Product
Yield[b] [%]
(0.2 equiv) as the cocatalyst. The reaction took 1 h to run to
completion, affording the desired isoindoline 10a in 78%
yield and 82% enantiomeric excess (ee) after aldehyde re-
duction (Table 2, entry 1). With this encouraging result, the
next reaction was carried out at À208C to give 10a in 70%
yield and 92% ee after 12 h (Table 2, entry 2). To our de-
light, when the temperature was lowered to À308C, the
product was obtained in 72% yield with an excellent 98%
ee (Table 2, entry 3). Lower temperatures (À408C) led to
complete selectivity (>99% ee) although the yield was
slightly inferior. Other solvents, such as toluene, made the
process less efficient because 10a was obtained after 48 h in
45% yield and the ee dropped to 78%. In THF the process
did not take place even after the reaction mixture was
warmed up to room temperature (Table 2, entries 5 and 6).
It is worth noting that catalyst II also afforded the final
product with an excellent 99% ee at À308C (Table 2,
entry 7). However, under the same reaction conditions cata-
lyst III afforded isoindoline 10a in a modest 54% ee
(Table 2, entry 8). Therefore, optimized conditions were
found to involve exposure of substrate 5a to either catalyst
I or II in the presence of benzoic acid in CHCl3 at À308C,
which made the preparation of isoindoline (+)-10a in good
yield and excellent ee possible (Table 2, entries 3 and 7).
To explore the effects of nitrogen substitution on enantio-
selectivity, substrates 5a–d, which have carbamates, sulfon-
1
2
3
4
5
6
7
1a
1b
1c
1d
2
0
0
0
0
1
1
2
1
1
1
1
0
1
0
Cbz
Boc
Ts
5a
5b
5c
5d
6
60
70
65
35
50
60
73
Ac
Cbz
Cbz
Cbz
3
4
7
8
[a]PG abbreviations: Cbz =benzyloxycarbonyl, Boc=tert-butyloxycar-
bonyl, Ts=tosyl, Ac=acetyl. [b]Isolated yields.
previously described in the literature (see the Supporting In-
formation).
Michael acceptors (5–8) for the organocatalytic conjugate
addition were assembled by a CM reaction between com-
pounds 1–4 and acrolein, catalyzed by second-generation
Hoveyda–Grubbs catalyst 9 Cl2(IMes)Ru=CH(o-iPrOC6H4).
A
The reaction proceeded at room temperature in dichlorome-
thane, giving rise to the desired aminoaldehydes 5–8 as
stable products in all cases and in moderate to good yields
(Table 1).
With a,b-unsaturated aldehydes 5–8 in hand, the first step
of our study was the optimization of the cyclization process
in terms of the reaction conditions and catalyst employed.
We decided to examine the process on N-Cbz benzylamine
5a as a model substrate. Diarylprolinols I and II and imida-
zolidinone III were chosen as catalysts for the organocata-
lytic process.[14] The screening process to identify the opti-
mum conditions is summarized in Table 2.
A
synthesized. When the Boc protecting group was used (i.e.,
5b), the process took place with a similar yield but with a
slight decrease in the ee compared to 5a (Table 3, entries 1,2
vs. 3,4). The use of tosylamide 5c as the starting material
followed the same trend, giving rise to isoindoline 10c in
good yield and ee with catalysts I and II (Table 3, entries 5
and 6). Finally, the use of acetamide 5d as the nitrogen nu-
cleophile in the IMAMR produced a dramatic decrease of
the yield and rendered 10d with modest ee (Table 3, en-
tries 7 and 8).
The first attempt was performed at 08C with catalyst I
(20 mol%) in CHCl3, in the presence of benzoic acid
With these results in hand, it became apparent that the
decrease of the nucleophilicity of the nitrogen source in the
IMAMR resulted in lower yields and ee values of the final
Chem. Eur. J. 2008, 14, 9868 – 9872
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9869

S. Fustero et al.
Table 3. Influence of the nitrogen-protecting group in the IMAMR.
ion (99% ee; Table 4, entries 3 and 4). Finally, when the or-
ganocatalytic protocol was performed on aniline derivative
8, tetrahydroquinoline (+)-13 was formed in up to 92% ee
(Table 4, entries 5 and 6).
It is worth noting that the IMAMR with benzylamines 5
and 7 led to slightly better ee values than aniline derivatives
6 and 8. This difference between both types of substrates
would be rationalized again in terms of nitrogen nucleophi-
licity because benzylamines possess a more nucleophilic car-
bamate and afford the corresponding bicyclic derivatives
with nearly complete selectivity.
The application of the present method to the enantiose-
lective synthesis of biologically active tetrahydroquinoline
alkaloid Angustureine[15] proved its utility.[16] Therefore,
after the organocatalytic aza-Michael reaction on compound
8, under the aforementioned conditions, aldehyde 14 was
obtained in 68% yield. Wittig reaction with propyltriphenyl-
phosphonium bromide, followed by carbamate reduction
with LiAlH4 and palladium-catalyzed hydrogenation, afford-
ed the desired natural product (S)-(+)-15 in a very simple
manner (Scheme 2). Additionally, oxidation of aldehyde 14
and further esterification with trimethylsilyldiazomethane
gave rise to tetrahydroquinoline b-amino acid derivative
(+)-16 (Scheme 2).
Entry
5
PG
Catalyst
10
Yield [%]
ee[a] [%]
1
2
3
4
5
6
7
8
5a
5a
5b
5b
5c
5c
5d
5d
Cbz
Cbz
Boc
Boc
Ts
Ts
Ac
Ac
I
II
I
II
I
II
I
10a
10a
10b
10b
10c
10c
10d
10d
72
68
72
68
61
63
36
28
98
99
94
91
94
91
64
58
II
[a]Determined by chiral HPLC (see the Supporting Information).
products. Thus, conjugate addition with acetyl amides is
much slower (if compared with carbamates and tosyl
amides), and alternative reaction pathways promoted by
protons liberated during the process (Brønsted acid cataly-
sis) apparently became more important. This is a nonselec-
tive process that competes with the iminium activation by
the organocatalyst, which translates into the decrease of the
selectivity in the overall process.
The extension of this protocol to the synthesis of several
enantiomerically enriched benzofused heterocycles was ex-
amined next. Thus, when aniline derivative 6 was subjected
to the optimized conditions, indoline (+)-11 was obtained in
good yield and excellent ee (93% and 92% with catalysts I
and II, respectively; Table 4, entries 1 and 2). When benzyl-
A
droisoquinoline (+)-12 in a complete enantioselective fash-
Table 4. Enantioselective synthesis of indolines, tetrahydroisoquinolines,
and tetrahydroquinolines.
Entry
n
m
Substrate Catalyst Alcohol
Yield
[%]
ee[a]
[%]
1
2
1
1
0
0
6
6
I
II
70
67
93
92
Scheme 2. Enantioselective synthesis of (+)-Angustureine 15.
The synthesis of (S)-(+)-Angustureine allowed us to indi-
rectly determine the absolute configuration of tetrahydro-
quinoline 13. The newly created stereocenter was thus deter-
mined to be R, which is in agreement with the commonly
accepted mechanism to rationalize organocatalytic processes
through iminium activation. Once the iminium ion is formed
in its preferred E conformation (Scheme 3, intermediate A),
the attack on the nitrogen source that gives rise to enamine
intermediate B (Scheme 3) takes place from the bottom side
(Re face) of the diene moiety because the upper side is
shielded by the pyrrolidine substituent.[17]
3
4
1
1
1
1
7
7
I
II
67
63
99
99
5
6
2
2
0
0
8
8
I
II
70[b]
60[b]
92
91
[a]Determined by chiral HPLC (see the Supporting Information).
[b]The formation of tetrahydroquinoline ( +)-13 was slower than the
rest, and it was necessary to extend the reaction time to 24 h to obtain
the yields shown in the table.
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Enantioselective Total Synthesis of (+)-Angustureine
COMMUNICATION
lowships, M.S.-R. for a postdoctoral contract, and C.P. for a Ramón y
Cajal contract.
Keywords: aza-Michael
reaction
·
cyclization
·
enantioselectivity · heterocycles · homogeneous catalysis
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Scheme 3. The stereochemical outcome of the IMAMR on substrates 5–
8.
In conclusion, we have developed an efficient and simple
method for the enantioselective synthesis of indolines, isoin-
dolines, tetrahydroquinolines, and tetrahydroisoquinolines
by means of an organocatalytic IMAMR of the correspond-
ing aniline and benzylamine derivatives. The process took
place with good yields and excellent ee values if diarylproli-
nols I and II were used as catalysts. The application of this
method to the synthesis of the alkaloid (+)-Angustureine
has also been presented. An investigation into further appli-
cations of this methodology is currently underway.
Experimental Section
Synthesis of adducts 10–13: In a flame-dried, 10 mL, round-bottomed
flask, unsaturated aldehydes 5–8 (1 equiv) were dissolved in dry chloro-
form (0.1m) and the solution was cooled to À308C. A mixture of catalyst
I or II (20 mol%) and benzoic acid (0.2 equiv) in chloroform was added
to this solution, and the resulting solution was stirred at this temperature
for 12 h (except for substrate 8, which was maintained for 24 h). The mix-
ture was then diluted with methanol and NaBH4 (3 equiv) was added
portionwise. The mixture was allowed to reach 08C and, after 30 min at
this temperature, the reaction was quenched with saturated NH4Cl and
extracted with dichloromethane (3”10 mL). The organic extracts were
washed with brine, dried over anhydrous Na2SO4, and concentrated to
dryness under vacuum. After flash chromatography over silica gel with
mixtures of hexane/ethyl acetate as the eluent, the corresponding alco-
hols 10–13 were obtained as colorless oils. The enantiomeric ratios were
determined by using HPLC analysis with a Chiracel IC column (25”
0.46 cm).
Representative example: (1S)-N-Benzyloxycarbonyl-1-(2-hydroxyethyl)-
isoindoline (+)-10a was isolated by following the aforementioned proce-
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dure and using flash chromatography with hexanes/ethyl acetate 3:1 as
the eluent to give a colorless oil (72% yield, 98% ee with catalyst I;
68% yield, 99% ee with catalyst II). The ee was determined by using
HPLC analysis with a Chiralpack IC column (eluent: hexane/isopropanol
87:13); flow rate=1.1 mLminÀ1, tmajor =36.9 min, tminor =39.2 min. [a]2D5
=
+21.0 (c=1.0 in CHCl3); 1H NMR (300 MHz): d=1.60–1.69 (m, 1H),
2.16–2.27 (m, 1H), 3.70 (brs, 2H), 3.96 (brs, 1H), 4.63 (d, J=14.9 Hz,
1H), 4.91 (d, J=14.9 Hz, 1H), 5.22 (s, 2H), 5.38 (d, J=10.0 Hz, 1H),
7.21–7.40 ppm (m, 9H); 13C NMR (75 MHz): d=40.4 (CH2), 51.8 (CH2),
59.0 (CH2), 60.6 (CH), 67.5 (CH2), 122.4 (CH), 127.6 (2 CH), 128.0 (CH),
128.2 (CH), 128.6 (CH), 135.8 (C), 136.3 (C), 141.3 (C), 156.6 ppm (C);
HMRS (EI+): m/z calcd for C18H19NO3 [M+]: 297.1365; found:
297.1360.
Acknowledgements
We thank the Ministerio de Educación y Ciencia (CTQ2007-61462) and
the Generalitat Valenciana (GV/2007/013), Spain, for their financial sup-
port. J.M., M.D.P.-C., and D.J. express their thanks for predoctoral fel-
Chem. Eur. J. 2008, 14, 9868 – 9872
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9871

S. Fustero et al.
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Jiang, E. N. Duesler, W. Wang, Org. Lett. 2007, 9, 965; for examples
with azides as nitrogen nucleophiles, see: g) T. E. Horstmann, D. J.
Guerin, S. C. Miller, Angew. Chem. 2000, 112, 3781; Angew. Chem.
Int. Ed. 2000, 39, 3635; h) D. J. Guerin, S. C. Miller, J. Am. Chem.
Soc. 2002, 124, 2134; for examples with hydrazones as nitrogen nu-
cleophiles, see: i) D. Perdicchia, K. A. Jørgensen, J. Org. Chem.
2007, 72, 3565; for examples with nitrogen heterocycles as nucleo-
philes, see: j) P. DinØr, M. Nielsen, M. Marigo, K. A. Jørgensen,
Angew. Chem. 2007, 119, 2029; Angew. Chem. Int. Ed. 2007, 46,
1983; k) J. Wang, H. Li, L. Zu, W. Wang, Org. Lett. 2006, 8, 1391;
[13]Very recently, the same strategy with very few variants has been re-
ported in the literature, see: E. C. Carlson, L. K. Rathbone, H.
Yang, N. D. Collett, R. G. Carter, J. Org. Chem. 2008, 73, 5155.
[14]For a recent review of the use of diarylprolinols in organocatalysis,
see: A. Mielgo, C. Palomo, Chem. Asian J. 2008, 3, 922.
[15]C. Theeraladonon, M. Arisawa, M. Nakagawa, A. Nishida, Tetrahe-
dron: Asymmetry 2005, 16, 827, and references cited therein.
[16]Only one example of enantioselective organocatalytic synthesis by
means of chiral Brønsted acids has been described before, see
ref. [3a]. Other metal-catalyzed enantioselective syntheses of Angus-
tureine have also been described, see: a) reference [2a]; b) refer-
ence [2b]; c) N. T. Patil, H. Wu, Y. Yamamoto, J. Org. Chem. 2007,
72, 6577.
[17]Identical stereochemical evolution in the formation of heterocycles
10–12 can be assumed (see ref. [14]). In the case of 10, the absolute
configuration of the stereocenter was S because the priority of sub-
stituents is reversed.
Received: July 21, 2008
Published online: October 1, 2008
9872
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