Enantioselective intramolecular α-amidoalkylation reaction in the synthesis of pyrrolo[2,1-a]isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2012.02.057

BINOL-derived chiral Br?nsted acids are capable of carrying out the intramolecular α-amidoalkylation of a tertiary N-acyliminium ions when a methoxylated benzene ring is used as internal π nucleophile. The reaction can be applied to the synthesis of pyrro

Full text of DOI:10.1016/j.tetlet.2012.02.057

Tetrahedron Letters 53 (2012) 2157–2159
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Tetrahedron Letters
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Enantioselective intramolecular
of pyrrolo[2,1-a]isoquinolines
a-amidoalkylation reaction in the synthesis
⇑
Asier Gómez-SanJuan, Nuria Sotomayor, Esther Lete
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco/Euskal Herriko Unibertsitatea UPV/EHU, Apdo. 644, 48080 Bilbao, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
BINOL-derived chiral Brønsted acids are capable of carrying out the intramolecular
a tertiary N-acyliminium ions when a methoxylated benzene ring is used as internal
reaction can be applied to the synthesis of pyrrolo[2,1-a]isoquinolines and use of the sterically congested
acid 3e is determinant to obtain good levels of enantioselection.
Ó 2012 Elsevier Ltd. All rights reserved.
a
-amidoalkylation of
nucleophile. The
Received 19 January 2012
Revised 7 February 2012
Accepted 13 February 2012
Available online 18 February 2012
p
Keywords:
N-Acyliminium ions
a-Amidoalkylation
Brønsted Acids
Asymmetric catalysis
Enantiomerically pure nitrogen heterocycles are ubiquitous
structures in natural products and pharmaceuticals. In this context,
the enantioselective construction of the isoquinoline unit continues
to be an intensely investigated field.1 The asymmetric intramolecu-
nificant progress in this area has been marked by the development
of organocatalytic approaches, using chiral Brønsted acids (mainly
BINOL derived phosphoric acids)7 and hydrogen bond donors
(mainly ureas and thioureas).8 Thus, examples of intermolecular
lar
a
-amidoalkylation reaction of aromatics and heteroaromatics
a-amidoalkylation of heteroaromatic systems with N-acyliminium
has become a powerful approach for the synthesis of substituted
and fused isoquinoline systems.2 Since these reactions are highly
diastereoselective,3 many efficient synthesis have been reported
to date based either in the use chiral substrates or chiral auxiliaries.
In this context, our group has also demonstrated the synthetic
ions formed in situ from cyclic hydroxylactams to form tertiary9 or
quaternary stereogenic centers have been reported.10 However,
despite the excellent enantioselectivity achieved, some limitations
remain. Most importantly, the intramolecular
a-amidoalkylation
reactions are still limited to a few examples and specifically with
electron-rich heteroaromatic rings. Enantioselective tertiary N-
acyliminium ion cyclization under BINOL derived phosphoric acids
catalysis has been reported, starting from tryptamines and enol lac-
tones or ketoesters and keto acids.11 The scope of the reaction has
been shown to be broad, allowing the synthesis of fused b-carboline
skeletons in good overall yields and excellent enantioselectivities.12
The intramolecular reaction using chiral proton donors
(thioureas) also provides excellent yields and enantioselectivities,
but requires electron rich heteroaromatic systems, as indoles or
pyrroles.13 This procedure has failed when N-acyliminium ions
tethered to electron rich methoxy substituted aromatic rings
(N-phenethyl hydroxylactams) were used, obtaining pyrroloiso-
quinolines with low conversions (0–40%) and 0% ee.
application of highly stereoselective intramolecular
ation reactions of -hydroxylactams derived from N-phenethyli-
a-amidoalkyl-
a
mides for the synthesis of enantiopure 5,10b-disubstituted
tetrahydropyrrolo[2,1-a]isoquinolines or 10bR-substituted 5,6-
dihydrotetrahydropyrrolo[2,1-a]isoquinolines. In the first case,
the stereochemical control was achieved starting form imides de-
rived form L
-DOPA,4 while in the second approach the strategy im-
plied the use of a 2-exo-hydroxy-10-bornylsulfinyl group as a chiral
auxiliary.5 Therefore, our next goal was to perform the reactions in
an enantioselective fashion. Herein we describe our preliminary re-
sults in an enantioselective Friedel–Crafts reaction of
lactams 2 derived form N-phenethylimides 1, catalyzed by chiral
a-hydroxy-
phosphoric acids 3, obtaining optically active pyrroloisoquinolines
4 substituted in the
a
position to the nitrogen atom (Scheme 1).
We reasoned that chiral BINOL derived phosphoric acids could
be more active in the case of using benzene derivatives as internal
The first enantioselective versions of
a-amidoalkylation reac-
tions were carried out using copper-based catalysts,6 though a sig-
p-nucleophiles, thus allowing higher conversions. Therefore, we
began our investigation on -amidoalkylation reaction selecting
a
three different imides 1a–c. MeLi addition to these imides leads
to the N-phenethyl hydroxylactams 2a–c, that can be efficiently
cyclized to the corresponding fused isoquinolines upon treatment
⇑
Corresponding author. Tel.: +34 946012576; fax: +34 946012748.
E-mail address: esther.lete@ehu.es (E. Lete).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.057

2158
A. Gómez-SanJuan et al. / Tetrahedron Letters 53 (2012) 2157–2159
Table 2
CH3O
CH3O
CH3O
CH3O
MeLi
Optimization of reaction conditions for 2c
OH
O
N
O
O
N
THF, –78 ºC
O
O
O
P
H3C
*
OH
O
CH3O
CH3O
2
CH3O
CH3O
1
3a-e (20 mol %)
OH
N
N
O
solvent, reflux
O
N
O
N
a
O
N
O
O
H3C
H3C
O
O
H3C
4c
4c Yielda (%) eeb (%)
O
H3C
2c
P
*
S
OH
O
3a-e
b
c
Entry Solvent
Catalyst 3 (20 mol %) Time
*
O
O
CH3O
CH3O
1
2
3
CH3CN
CH3CN
CH3CN/
H2O
3a
3a
3a
6 h
72
48
93
2
4
<1
CH3O
CH3O
P
24 hc
5 h
O
O
O
N
O
N
H3C
H3C
4
5
6
7
8
9
CH2Cl2
CH2Cl2
THF
3a
3a
3a
3a
3b
3b
6 h
76
68
—
6
4
—
<1
2
24 hc
2 days
6 h
4
I
R
EtOH
35
CH3CN
CH3CN/
H2O
CH2Cl2
Toluene
CH3CN
CH3CN/
H2O
6 days 49
3a: R = H
3b: R = SiPh
O
24 h
56
2
O
O
3
P
OH
3c: R = 3,5 -(CF3)3-C6H3
3d: R = 9-Anthryl
10
11
12
13
3b
3b
3c
3c
6 days
6 days
5 h
—
—
84
73
—
—
<1
<1
3e: R = 2,4,6-(i-Pr)3-C6H2
R
5 h
(R)-3
14
15
16
17
CH2Cl2
Toluene
CH3CN
CH3CN/
H2O
CH2Cl2
Toluene
CH3CN
CH2Cl2
Toluene
Toluene
Toluene
3c
3c
3d
3d
5 h
5 h
3 days 46
24 h 56
67
64
<1
26
6
Scheme 1. Brønsted acid catalyzed intramolecular
a
-amidoalkylation.
with a Brønsted acid as TFA.14 The use of a chiral phosphoric acid
would lead to enantioenriched isoquinolines 4 through the forma-
tion of an N-acyliminium intermediate/chiral conjugate base ion
pair as I (Scheme 1).
< 1
18
19
20
21
22
23
24
3d
3d
3e
4 days 10
4 days 37
2 days 80
50
50
16
—
74
76
74
3e
2 days
—
Our initial survey using phosphoric acid 3a (10 mol %) as catalyst
identified 5-hydroxy-5-methylpyrrolidin-2-one 2c as a promising
lead. Thus, treatment of hydroxylactams 2a,b with 10 mol % of 3a
in toluene at reflux produces the formation of the N-acyliminium
intermediate, but no cyclization occurs, isolating the corresponding
enamide after work-up (Table 1, entries 1,2). However, cyclization
took place efficiently with hyroxylactam 2c, obtaining pyrroloiso-
quinoline 4c, though with a poor enantioselectivity (12% ee, Table
1, entry 3). The use of higher catalyst loading (20 mol %, entry 4)
enhanced the reaction rate, which was completed within 6 h, with
similar ee. The reactions were considerably slower at room temper-
ature with no improvement of enantioselectivity (Table 1, entry 5).
The reaction conditions were optimized using various solvents
and temperatures, using 20 mol % of catalyst 3a, for shorter reac-
tion times (Table 2). The reaction yields improved significantly
using more polar solvents as dichloromethane acetonitrile, or ace-
tonitrile/water (10%) though 4c was obtained almost in racemic
form in all cases (Table 2, entries 1, 3, 4). No significant improve-
ment of enantioselectivity was observed at room temperature (en-
tries 2, 5). The reaction did not proceed at all in THF (entry 6), and
3e
4 days 23
4 days 10
4 days 31
3ed
3ee
a
b
c
Yield of isolated product.
Determined by CSP HPLC.
The reaction was carried out at room temperature.
10 mol % of 3e was used.
d
e
30 mol % of 3e was used.
no enantioselection was observed using EtOH (entry 7). Under sim-
ilar conditions, catalyst 3b proved to be less reactive (entries 8–
11), observing no reaction in toluene or dichloromethane even
after 6 days. On the other hand, catalyst 3c was the most active,
producing pyrroloisoquinoline 4c in good yields in just 5 h, but al-
most racemic (entries 12–15). Only a small improvement of the ee
was observed using toluene as solvent (entry 15, 26% ee). The ste-
rically congested catalyst 3d was less reactive in all solvents,
though a significant increase of enantioselectivity to 50% ee was
observed using toluene, with a moderate yield (entry 19). Finally,
the best enantioselectivity (74% ee) was obtained with 20 mol %
of catalyst 3e in toluene.
Table 1
The absolute configuration of 4c was assigned as R by correla-
tion with related pyrroloisoquinoline structures previously pre-
pared in enantiomerically pure form by our group5 and others.15
As has been shown, there is a strong influence of the structure
of the phosphoric acid on the rate, and most importantly, on the
enantioselectivity of the reaction. Thus, the substituents on posi-
tions 3 and 3’ modulate the chiral environment in which the reac-
tion takes place, through the formation of an N-acyliminium
intermediate/chiral conjugate base ion pair as I (Scheme 1).7 This
concept has been invoked to explain the enantioselection in both
inter- and intramolecular N-acyliminium reactions,7,16 The related
enantioselective alkylation of imines and acylimines catalyzed by
BINOL-phosphoric acids has been studied quite extensively,7 and
Preliminary evaluation of lactams 2a–c
Entry
Substrate
3a (mol %)
T
4 Yielda (%)
eeb (%)
f
1
2
3
4
5
2a
2b
2c
2c
2c
10
10
10
20
20
Refluxc
Refluxc
Refluxc
Refluxd
50 °Ce
—
—
12
10
8
f
64
65
34
a
b
c
d
e
f
Yield of isolated product.
Determined by CSP HPLC.
Reaction time: 24 h.
Reaction time: 6 h.
Reaction time: 5 days.
The corresponding enamide was isolated.

A. Gómez-SanJuan et al. / Tetrahedron Letters 53 (2012) 2157–2159
2159
4. (a) García, E.; Arrasate, S.; Lete, E.; Sotomayor, N. J. Org. Chem. 2005, 70, 10368–
10374; (b) García, E.; Arrasate, S.; Ardeo, A.; Lete, E.; Sotomayor, N. Tetrahedron
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D.; Onomura, O. J. Organomet. Chem. 2007, 692, 654–663.
a model to explain the stereochemical outcome of these reactions
has been reported recently.17
In summary, it has been shown that BINOL-derived chiral
Brønsted acids are capable of carrying out the intramolecular
a
-amidoalkylation of a tertiary N-acyliminium ions derived from
an 5-hydroxy-5-methylpyrrolidin-2-one, when an methoxylated
benzene ring is used as internal
nucleophile.18 These preliminary
p
results are interesting because, as indicated above, this procedure
failed when thiourea catalysts were used, and required electron
rich heteroaromatic systems, as indoles or pyrroles.13 In our case,
the use of the sterically congested acid 3e is determinant to obtain
good levels of enantioselection, and contrasts with the results
obtained by Dixon11,12 with b-carbolines, where the best results
were obtained with 3b, the less reactive acid for this system. These
results illustrate the subtle balance of interactions in an intermedi-
ate such as I that control both the enantioselectivity and the reac-
tivity itself. Work along these lines is in progress.
7. (a) Terada, M. Chem. Commun. 2008, 4097–4112; (b) Kampen, D.; Reisenger, C.
M.; List, B. Top. Curr. Chem. 2010, 291, 395–456; (c) Schenker, S.; Zamfir, A.;
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Nachtsheim, B. J.; Ieawsuwan, W.; Atodiresei, I. Angew. Chem., Int. Ed. 2011, 50,
6706–6720.
8. (a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743; (b) Sohtome,
Y.; Nagasawa, K. Synlett 2010, 1–22.
9. (a) Yu, X.; Lu, A.; Wang, Y.; Wu, G.; Song, H.; Zhou, Z.; Tang, C. Eur. J. Org. Chem.
2011, 892–897; (b) Xie, Y.; Zhao, Y.; Qian, B.; Yang, L.; Xia, C.; Huang, H. Angew.
Chem., Int. Ed. 2011, 50, 5682–5686.
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3060–3066; (b) Rueping, M.; Nachtsheim, B. Synlett 2010, 119–122.
11. Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon, D.
J. J. Am. Chem. Soc. 2009, 131, 10796–10797.
12. Holloway, C. A.; Muratore, M. E.; Storer, R. I.; Dixon, D. J. Org. Lett. 2010, 12,
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Acknowledgments
13. Raheem, I. T.; Thiara, P. S.; Jacobsen, E. N. Org Lett. 2008, 10, 1577–1580.
14. Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M. J.; Lete, E. J. Org. Chem. 1997,
62, 2080–2092.
We wish to thank the Ministerio de Ciencia e Innovación
(CTQ2009-07733), and Universidad del País Vasco (UFI 11/22) for
their financial support. Technical and human support provided
by SGIker (UPV/EHU, MICINN, GV/EJ, ERDF and ESF) is gratefully
acknowledged.
15. (a) Amat, M.; Elias, V.; Llor, N.; Subrizi, F.; Molins, E.; Bosch, J. Eur. J. Org. Chem.
2010, 4017–4026; (b) Allin, S. M.; Gaskell, S. N.; Towler, J. M. R.; Bulman Page,
P. C.; Saha, B.; McKenzie, M. J.; Martin, W. P. J. Org. Chem. 2007, 72, 8972–8975;
(c) Kawai, N.; Matsuda, M.; Uenishi, J. Tetrahedron 2011, 67, 8648–8653.
16. Representaitive examples (a) Terada, M.; Machioka, K.; Sorimachi, K. Angew.
Chem., Int. Ed. 2009, 48, 2553–2556; (b) Rueping, M.; Lin, M.-Y. Chem. Eur. J.
2010, 16, 4169–4172; (c) Li, G.; Kaplan, M. J.; Wojtas, L.; Antilla, J. C. Org. Lett.
2010, 12, 1960–1963; (d) Xie, Y.; Zhao, Y.; Qian, B.; Yang, L.; Xia, C.; Huang, H.
Supplementary data
Angew. Chem., Int. Ed. 2011, 50, 5682–5686. See also Refs..10–12
17. Simón, L.; Goodman, J. M. J. Org. Chem. 2011, 76, 1775–1788.
.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.057. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
18. (R)-(+)-8,9-dimethoxy-10b-methyl-1,5,6,10b-tetrahydropyrrolo[2,1-
a]isoquinolin-3[2H]-one (4c): To a solution of the succinimide 1c (48.4 mg,
0.18 mmol) in dry THF (5 mL), MeLi (0.42 mL of a 0.97 M solution, 0.40 mmol)
was added at –78 °C. The resulting mixture was stirred at this temperature for
6 h, and was quenched by the addition of saturated aqueous NH4Cl solution
(5 mL). The mixture was and allowed to warm to rt, and the organic layer was
separated. The aqueous phase was extracted with CH2Cl2 (3 ꢀ 10 mL). The
combined organic extracts were dried (Na2SO4) and concentrated in vacuo to
afford hydroxy lactam 2c.14 Without further purification, 2c was dissolved in
dry toluene (25 mL), and acid 3e (26 mg, 0.03 mmol) was added. The resulting
mixture was refluxed for 4 days. The solvent was removed, and the
pyrroloisoquinoline 4c was obtained after chromatographic purification
References and notes
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Drug Discov. Devel. 2010, 13, 669–684; (c) Stockigt, J.; Antonchick, A. P.; Wu, F.-
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Yazici, A.; Pyne, S. G. Synthesis 2009, 513–541; (e) Martínez-Estibalez, U.;
Gómez-SanJuan, A.; García-Calvo, O.; Lete, E.; Sotomayor, N. Eur. J. Org. Chem.
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(alumina, AcOEt) (11 mg, 23%):
enantiomeric excess was determined by HPLC to be 74%. [Chiralcel OD, 5%
½
a 2D0
ꢁ
:
+130.1 (c = 0.5, CHCl3); The
hexane: 2-propanol, 1 mL/min, tr (R) = 49.6 min (87%), tr (S) = 57.1 min (13%)];
IR (film) 1685 cmꢂ1 1H NMR (CDCl3); 1.50 (s, 3H), 2.04–2.10 (m, 1H), 2.32-2.44
;
(m, 2H), 2.57–2.67 (m, 2H), 2.84–2.91 (m, 1H), 3.29 (td, J = 13.0, 4.5 Hz, 1H), 3.84
(s, 3H), 3.86 (s, 3H), 4.28 (ddd, J = 12.2, 6.2, 1.8 Hz, 1H), 6.56 (s, 1H), 6.63 (s, 1H);
13C NMR (CDCl3). 27.0, 27.6, 30.0, 34.4, 36.0, 55.2, 55.9, 64.6, 107.9, 116.8, 125.5,
133.3, 147.7, 147.9, 175.7; MS (EI) m/z (rel. intensity) 261 (M+, 8), 246 (100), 230
(14), 202 (9), 185 (4), 172 (4), 123 (6), 117 (4), 91 (5), 77 (8). Anal. Calcd
forC15H19NO3: C, 68.94, H, 7.33, N, 5.36. Found: C, 69.14, H, 7.09, N, 5.07.
3. For reviews, see Ref..2 For representative examples from our group, see: (a)
Osante, I.; Collado, M. I.; Lete, E.; Sotomayor, N. Eur. J. Org. Chem. 2001, 1267–
1277; (b) Ardeo, A.; García, E.; Arrasate, S.; Lete, E.; Sotomayor, N. Tetrahedron
Lett. 2003, 44, 8445–8448; Abdullah, M. N.; Arrasate, S.; Lete, E.; Sotomayor, N.
Tetrahedron 2008, 64, 1323–1332.