Short stereoselective synthesis of (+)-crispine A via an N-sulfinyl Pictet-Spengler reaction

Article abstract of DOI:10.1016/j.tetlet.2013.01.121

We report the highly stereoselective synthesis of (R)-(+)-crispine A from the (R)-N-sulfinyl amine 1 by using a one-pot process involving the Pictet-Spengler reaction with 4-chlorobutanal, removal of the sulfinyl group by protonolysis of the N-S bond and in situ cyclization, with a 55% overall yield.

Full text of DOI:10.1016/j.tetlet.2013.01.121

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Short stereoselective synthesis of (+)-crispine A via an N-sulfinyl
Pictet–Spengler reaction
Rubén Sánchez-Obregón a, , Benjamín Ortiz a, Virginia M. Mastranzo a, Francisco Yuste a,b
,
⇑
José Luis García Ruano b,
⇑
a Instituto de Química, Universidad Nacional Autónoma de México, Coyoacán, 04510 México D.F., México
b Departamento de Química Orgánica, Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the highly stereoselective synthesis of (R)-(+)-crispine A from the (R)-N-sulfinyl amine 1 by
using a one-pot process involving the Pictet–Spengler reaction with 4-chlorobutanal, removal of the sul-
finyl group by protonolysis of the N–S bond and in situ cyclization, with a 55% overall yield.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 17 December 2012
Revised 22 January 2013
Accepted 28 January 2013
Available online xxxx
Keywords:
(R)-(+)-Crispine A
Pictet–Spengler reaction
N-Sulfinyl amines
Remote stereocontrol
N-desulfinylation
Alkoxy and hydroxy tetrahydroisoquinolines bearing a stereo-
center at C-1 are the structural motif of many natural alkaloids
with interesting biological properties. Representative natural prod-
ucts include compounds with a simple alkyl group at C-1, such as
(+)-salsolidine and (+)-carnegine, as well as others bearing an addi-
tional five-membered ring (pyrroloisoquinoline alkaloids), such as
(ꢀ)-trolline and (+)-crispine A (Fig. 1).
chemical methods.8 Most of these procedures involve the use of
long sequences for preparing the starting materials required by
the corresponding methodology, thus resulting in a moderate effi-
ciency. A similar problem is detected in methods based on en-
zyme-catalyzed kinetic resolution.9
So far only two reported papers specifically describe the synthe-
sis of (+)-crispine A. The first one10 is based on the application of
the highly diastereoselective N-acyliminium cyclization reaction11
to the case of the crispine A, and has similar problems to those pre-
viously indicated. The second and most direct so far reported
method involves the Pictet–Spengler reaction of 4-chloro-1,1-dim-
ethoxybutane with the commercially available but expensive (R)-
amino ester indicated in Scheme 1. It affords (+)-crispine A in a
one-pot sequence of Pictet–Spengler reaction followed by
decarboxylation.12
The main advantage of this procedure is the clever use of the
Pictet–Spengler reaction, that allows the bis-cyclization affording
the skeleton of (+)-crispine A in only one-step. However, its main
drawbacks are the moderate control of the stereoselectivity ex-
erted by the amino ester moiety (63% de) and the low yield
(39%) of the two-step procedure required for decarboxylation.
From these results we reasoned that the use of another easily
removable and more efficient chiral auxiliary as stereocontroller,
could provide a better method for obtaining (R)-(+)-crispine
A. Taking into account that the sulfinamine group had been suc-
cessfully used in the preparation of tetrahydro-b-carbolines13a
and 1-alkyl tetrahydroisoquinolines13b by Pictet–Spengler reac-
tion, we have investigated the role of this group in a similar
Among them, (+)-crispine A emerged as a target of great interest
due to its high cytotoxic activity against various human cancer cell
lines.1,2 It was firstly isolated in 2002 from Cardus crispus by Zhao
and co-workers.2 The pharmacological interest of (+)-crispine A
has prompted many groups to develop in its asymmetric synthesis
over the last ten years. Many of the reported papers are not specif-
ically oriented toward the synthesis of crispine A, but its prepara-
tion is reported as an example illustrating the validity of different
synthetic methodologies. This is the case of catalytic hydrogena-
tion methods applied to cyclic enamines3 or iminium salts,4 asym-
metric allylation of cyclic imines,5 and Bi(OTf)3-catalyzed
intramolecular 1,3-chirality transfer reactions.6
The enantioselective deprotonation of N-Boc pyrrolidine fol-
lowed by Pd-catalyzed
a
-arylation7 was also illustrated with a
synthesis of (+)-crispine A, which, in turn, has been also described
from chiral 1-cyanotetrahydroisoquinolines, obtained by electro-
⇑
Corresponding authors.
E-mail addresses: rubens@unam.mx (Rubén Sánchez-Obregón), joseluis.garcia.
ruano@uam.es (José Luis García Ruano).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.121
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2
R. Sánchez-Obregón et al. / Tetrahedron Letters xxx (2013) xxx–xxx
MeO
MeO
MeO
MeO
MeO
MeO
NH
N
N
N
O
MeO
MeO
(R)-(+)-Salsolidine
(R)-(+)-Carnegine
(S)-(-)-Trolline
(R)-(+)-Crispine A
Figure 1. Examples of tetrahydroisoquinoline-derived natural products.
CH(OMe)2
MeO
MeO
CO2Me
MeO
MeO
MeO
MeO
CO2Me
Cl
two-steps
39%
N
N
NH2
TFA
82%
(R)-(+)-Crispine A
63% de
Scheme 1. Synthesis of (+)-crispine A via Pictet–Spengler reaction.12
OR'
Cl
OR
(CH2)3
R=R'=Me
MeO
MeO
MeO
MeO
n-BuLi, THF, -78 °C
R-R'=(CH2
)
2
NH2 (S)-Menthyl p-toluenesulfinate
NH
p-Tol
TFA, -78 ˚C
S
85%
O
1
[α]D +77.6 (c = 0.51, acetone); 94.5% ee
Scheme 2. Synthesis and unsuccessful reactions of the N-sulfinyl amine 1.
sequence to that shown in Scheme 1. In this Letter we describe the
results obtained in this study, demonstrating that the sulfinamine
allows the complete control of the stereoselectivity in the Pictet–
Spengler reaction and is more easily removed than the CO2Me
group, thus providing a more efficient method for the asymmetric
synthesis of (R)-(+)-crispine A.
chiral HPLC) was identical to that of the starting material 1, which
indicated that it was not affected under the used reaction condi-
tions. Removal of the p-tolylsulfinyl chiral auxiliary group was
accomplished in 88% yield using concentrated HCl in ethanol at
0 °C to produce exclusively (R)-(+)-crispine A17 by cyclization
in situ of the resulting aminochloro derivative (Scheme 3).
The absolute configuration of the obtained crispine was
unequivocally established as (R) by comparison of its specific rota-
tion with that reported in the literature for this enantiomer.12
It also allowed us to assign the same configuration to the ben-
zylic carbon of intermediate 2.
The role of the sulfinyl group in the stereoselectivity control of
the Pictet–Spengler reaction can be rationalized by assuming that
the approach of the nucleophilic ring to the iminium intermediate
(formed by the reaction of the aldehyde with the amine) adopting
its presumably most stable conformation (that minimizing the
strong dipolar repulsions of the S–O and C@N+ bonds) should take
place to the pro-R face of the iminium, in order to avoid the strong
steric interactions with the p-tolyl group oriented toward the pro-S
face (Scheme 4).
Unfortunately the use of BF3ꢁOEt2 instead of TFA as the catalyst
did not allow the in situ desulfinylation and subsequent cyclization
resulting in the formation of (+)-crispine A in only one-step from 1.
However, we explored the conversion of sulfinamide 1 into 3 via a
one-pot process involving asymmetric Pictet–Spengler reaction/
hydrolysis/cyclization (Scheme 5). To our delight, this two-step
one-pot procedure directly connecting the starting sulfinamide 1
with (R)-(+)-crispine A took place in 55% overall yield.17
The shortest reported routes to (R)-crispine A are the three-step
sequence (54% overall yield) from the known but hard to prepare
methyl 2-(2-bromo-4,5-dimethoxyphenyl)acetate7 and the three-
step sequence (32% overall yield) from commercially available
The synthesis of (R)-N-p-tolylsulfinyl 2-(3,4-dimethoxy)phenyl
ethylamine (1), used as the precursor of our sequence, was per-
formed following the procedure reported by us,14 consisting in
the reaction of the 3,4-dimethoxyphenylethylamine with n-butyl-
lithium (2 equiv) at ꢀ78 °C and the quick addition of the resulting
anion to (S)-menthyl p-toluenesulfinate (Scheme 2). Under these
conditions, the N-sulfinyl derivative 1 was obtained in 85% yield15
(94.5% ee by chiral HPLC). Then, Pictet–Spengler reaction of 1 with
different aldehyde surrogates was studied under a variety of
conditions. First, we checked the conditions indicated in Scheme 1,
consisting in the use of 4-chloro-1,1-dimethoxybutane as the
coupling partner and protic acids (trifluoroacetic, acetic, or
p-toluenesulfonic acids) as catalysts at low temperatures (ꢀ78 to
0 °C). In general, application of these reaction conditions resulted
in the recovery of the starting material or hydrolysis of the nitro-
gen–sulfur bond of sulfinamide 1 (Scheme 2). Similar results were
obtained starting from the cyclic acetal 2-(3-chloropropyl)-1,
3-dioxolane.
Then, we turned our attention to the use of Lewis acids. When
sulfinamide 1 reacted under Pictet–Spengler conditions with the
cyclic and acyclic acetals using BF3ꢁOEt2 as the catalyst no cyclized
products could be isolated. However, the use of 4-chlorobutanal
(4 equiv) in dry CH2Cl2 at ꢀ78 °C, using 2.2 equiv of BF3ꢁEt2O as
the catalyst afforded, after 2 h, a 90:10 diastereoisomeric mixture
(as determined by 1H NMR spectroscopic analysis of the crude)
of the expected Pictet–Spengler product. A better result was ob-
served by performing the reaction at ꢀ90 °C (Scheme 3), because
only one diastereoisomer of compound 2 (>98% de) was obtained
in 57% yield.16 The optical purity of this compound (94.8% ee by
but
expensive
(R)-(ꢀ)-methyl
2-amino-3-(3,4-dimethoxy-
phenyl)propanoate.12 Our approach proceeds in a two-step one-
pot process (55% yield) starting from the N-sulfinyl derivative 1,
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R. Sánchez-Obregón et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
MeO
MeO
MeO
Cl-(CH2)3-CHO
p-Tol
NH
p-Tol
BF3.OEt2, -90 °C, 3 h
57%
N
S
MeO
S
O
O
Cl
1 (94.5% ee)
2 (94.8% ee)
HCl, EtOH
oC, 5 min
88%
0
MeO
MeO
MeO
MeO
N
NH
3 (R)-(+)-Crispine A
[α]D +90.0 (c = 1.05, CHCl3)
Cl
Lit.12 [α]D +90.0 (c = 1.0, CHCl3)
Scheme 3. A two-step synthesis of 3 from the N-sulfinyl amine 1.
MeO
MeO
Ar
HN
Tol
O
N
S
R
S
O
1
H
Tol
TolOS
N
MeO
MeO
N
R
O
R
H
S
R
N
R
SOTol
Cl
Tol
H
OMe
H
2
OMe
OMe
OMe
Scheme 4. Mechanistic proposal for explaining the stereochemical results.
1.
OHC
Cl
MeO
MeO
MeO
MeO
BF3.OEt2, CH2Cl2, -90º C, 3 h
2. Et3N
3. HCl, EtOH, 0º C, 5 min
N
p-Tol
NH
S
55% overall yield
O
1
(R)-(+)-Crispine A
Scheme 5. One-pot synthesis of (R)-(+)-crispine A (3) from 1.
or in a three-step sequence (43% overall yield) starting from com-
mercially available and cheap 3,4-dimethoxy phenethylamine.
In summary, we have reported the highly stereoselective
synthesis of (R)-(+)-crispine A from the N-sulfinyl amine 1 by
using a one-pot process involving the Pictet–Spengler reaction
with 4-chlorobutanal, removal of the sulfinyl group by
protonolysis of the N–S bond and cyclization, with a 55% overall
yield.
(AVANCAT CS2009/PPQ-1634) is gratefully acknowledged. FY
thanks Conacyt-México and DGAPA-UNAM for
fellowship.
a sabbatical
Supplementary data
Supplementary data (1H NMR and 13C NMR spectra and CSP-
HPLC data for compounds 1–3) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.01.121.
Acknowledgments
References and notes
We thank M. I. Chávez, E. García-Ríos, E. Huerta, R. Patiño, M. A.
Peña, F. J. Pérez, B. Quiroz, H. Ríos and L. Velasco for their technical
assistance. We also thank Dra Ana M. Martín Castro for reviewing
the manuscript. Financial support from DGAPA-UNAM (Proyecto
IN206910), Spanish Government (CTQ-2012-35957), and CAM
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3. Hou, G.-H.; Xie, J.-H.; Yan, P.-C.; Zhou, Q.-L. J. Am. Chem. Soc. 2009, 131, 1366–
1367.
Please cite this article in press as: Sánchez-Obregón, R.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.01.121

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R. Sánchez-Obregón et al. / Tetrahedron Letters xxx (2013) xxx–xxx
4. (a) Szawkalo, J.; Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.; Drabowicz, J.;
mixture was stirred at ꢀ90 °C for 3 h. Then, Et3N (0.247 g, 2.44 mmol, 2 equiv)
was added. The volatiles were evaporated to provide a crude residue that was
judged to be a >98:2 mixture of diastereoisomers by 1H NMR analysis. The
residue was purified by flash chromatography over silica gel eluting with
hexane/ethyl acetate 60:40 to give the major diastereoisomer 2 as a colorless
Czarnocki, Z. Tetrahedron: Asymmetry 2005, 16, 3619–3621; (b) Szawkalo, J.;
Czarnocki, S. J.; Zawadzka, A.; Wojtasiewicz, K.; Leniewski, A.; Maurin, J. K.;
Czarnocki, Z.; Drabowicz, J. Tetrahedron: Asymmetry 2007, 18, 406–413.
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P. J. Org. Chem. 2011, 76, 5936–5953.
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J.-P. J. Org. Chem. 2011, 76, 9720–9732.
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J.; Martin, W. P. J. Org. Chem. 2007, 72, 8972–8975.
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Elsegood, M. R. J. J. Chem. Soc., Perkin Trans. 1 2001, 3029–3036.
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oil (0.283 g, 57%). [a] +56.4 (c 1.07, CHCl3), [a]
+78.2 (c 1.05, acetone). 1H
D
D
NMR (CDCl3, 300 MHz): d 1.50–1.60 (m, 1H), 1.70–1.93 (m, 3H), 2.42 (s, 3H),
2.53–2.64 (m, 1H), 2.80–2.94 (m, 1H), 3.36 (t, J = 6 Hz, 2H), 3.40–3.51 (m, 1H),
3.56–3.64 (m, 1H), 3.83 (s, 3H), 3.84 (s, 3H), 4.37 (dd, J = 3.3 and 9.0 Hz, 1H),
6.52 (s, 1H), 6.53 (s, 1H), 7.29 and 7.54 (AA0BB0 system, 4H). 13C NMR (CDCl3,
75 MHz): d 21.33, 28.10, 29.39, 34.13, 40.42, 44.62, 55.00, 55.79, 55.87, 109.29,
111.61, 125.34, 126.10, 129.40, 129.83, 140.71, 141.40, 147.45, 147.74. MS-FAB
m/z 408 (33, M++1), 330 (98), 314 (19), 268 (94), 205 (43), 191 (100), 154 (78),
136 (75), 89 (49), 77 (57). The enantiomeric purity was determined by HPLC
(Chiralpak IA, heptane/ethanol/triethylamine: 90:10:0.1, 1.0 mL/min, tR
(major) 21.1–21.7 min, tR (minor) 27.0–28.4 min: 94.8% ee.
17. (R)-(+)-Crispine A (3): To a stirred solution of 2 (0.432 g, 1.06 mmol, 1 equiv) in
EtOH (15 mL) cooled at 0 °C concentrated HCl (0.4 mL, 4.9 mmol, 4.6 equiv)
was added. The resulting mixture was stirred at 0 °C for 5 min, then a saturated
aqueous K2CO3 (6 mL) was added and the mixture was extracted with ethyl
acetate (4 ꢂ 20 mL). The combined organic extracts were dried with sodium
sulfate and evaporated. The residue was purified by flash chromatography over
silica gel using ethyl acetate/methanol/triethylamine 85:14:1 as the eluent to
14. Garcia Ruano, J. L.; Alonso, R.; Zarzuelo, M. M.; Noheda, P. Tetrahedron:
Asymmetry 1995, 6, 1133–1142.
give (R)-(+)-crispine A (3) as a colorless oil that solidifies on standing (0.217 g,
6
88%), mp 55–57 °C (lit. mp 53–55 °C), [
a
]
+90.0 (c 1.05, CHCl3), [lit.12
[a]
D
D
15. Compound 1: To
a
stirred solution of N-(3,4-dimethoxy)phenethylamine
+90.0 (c 1.0, CHCl3)]. A sample was crystallized from acetone–hexane, mp 82–
(1.81 g, 10 mmol) in dry THF (40 mL) cooled at ꢀ78 °C a solution 2.1 M of n-
BuLi in hexanes (20 mmol, 2 equiv) was added. The resulting mixture was
stirred at ꢀ78 °C for 15 min and then added very quickly to a solution of (S)-
menthyl p-toluenesulfinate (2.94 g, 10 mmol, 1 equiv) in THF (22 mL). The
reaction mixture was allowed to warm to room temperature and stirred 1 h.
Then it was quenched with a saturated aqueous solution of NH4Cl (50 mL) and
extracted with CH2Cl2 (3 ꢂ 50 mL). The organic layers were washed with water
(3 ꢂ 40 mL), dried with sodium sulfate and concentrated. The residue was
purified by flash chromatography over silica gel eluting with hexane/ethyl
84 °C (lit. mp 86–88 °C), [
a]
D + 90.5 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): d
1.65–1.78 (m, 1H), 1.79–2.02 (m, 2H), 2.26–2.37 (m, 1H), 2.51–2.77 (m, 3H),
2.96–3.12 (m, 2H), 3.14–3.22 (m, 1H), 3.41 (t, J = 8.1 Hz, 1H), 3.84 (s, 3H), 3.85
(s, 3H), 6.57 (s, 1H), 6.61 (s, 1H). 13C NMR (CDCl3, 75 MHz): d 22.22, 28.03,
30.47, 48.34, 53.12, 55.89, 56.00, 62.93, 108.98, 111.44, 126.27, 131.06, 147.27,
147.38. The enantiomeric purity was determined by HPLC (chiralcel OJ,
heptane/ethanol/triethylamine: 95/5/0.2, 0.8 mL/min, tR (minor) 11.7 min, tR
(major) 12.7–12.9 min: 94.8% ee.
One-pot process: To a stirred solution of 1 (0.520 g, 1.63 mmol, 1 equiv) and 4-
chlorobutanal (0.692 g, 6.52 mmol, 4 equiv) in dry CH2Cl2 (25 mL) cooled at
ꢀ90 °C, BF3ꢁEt2O (0.509 g, 3.58 mmol, 2.2 equiv) was added and the resulting
mixture was stirred at ꢀ78 °C for 3 h. Then, Et3N (0.362 g, 3.58 mmol,
2.2 equiv) was added and the volatiles were evaporated. The residue was
dissolved in EtOH (25 mL), cooled at 0 °C and concentrated HCl (0.66 mL,
8.02 mmol, 4.92 equiv) was added. The resulting mixture was stirred at 0 °C for
5 min, then a saturated aqueous K2CO3 (10 mL) was added and the mixture
was extracted with ethyl acetate (4 ꢂ 25 mL). The combined organic extracts
were dried with sodium sulfate and evaporated. The residue was purified by
flash chromatography over silica gel using ethyl acetate/methanol/
triethylamine 85:14:1 as the eluent to give (R)-(+)-crispine A (3) as a white
acetate 40:60 to produce 1 as a pale yellow oil (2.71 g, 85%), [
a]D +77.6 (c 0.51,
acetone) [lit.13 D + 66.9 (c 0.50, acetone)]. 1H NMR (CDCl3, 300 MHz): d 2.40
[a]
(s, 3H), 2.76 (t, J = 6.9 Hz, 2H), 3.01–3.12 (m, 1H), 3.30–3.40 (m, 1H), 3.84 (s,
3H), 3.85 (s, 3H), 4.09 (m, 1H), 6.65 (d, J = 1.8 Hz, 1H), 6.70 (dd, J = 2.1 and
8.1 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 7.28 and 7.53 (AA0BB0 system, 4H). 13C NMR
(CDCl3, 75 MHz): d 21.27, 36.40, 42.27, 55.78, 55.90, 111.31, 111.96, 120.77,
125.89, 129.48, 130.87, 141.07, 141.16, 147.71, 148.99. The enantiomeric
purity was determined by HPLC (Chiralpak IA, hexane/ethanol/triethylamine:
80:20:0.1, 1.0 mL/min, tR (major) 9.2–9.4 min, tR (minor) 12.4–12.7 min: 94.5%
ee.
16. Compound 2: To a stirred solution of 1 (0.391 g, 1.22 mmol, 1 equiv) and 4-
chlorobutanal (0.518 g, 4.88 mmol, 4 equiv) in dry CH2Cl2 (15 mL) cooled at
ꢀ78 °C BF3ꢁEt2O (0.381 g, 2.68 mmol, 2.2 equiv) was added and the resulting
solid (0.207 g, 55%), mp 54–56 °C, [a] +89.2 (c 1.0, CHCl3).
D
Please cite this article in press as: Sánchez-Obregón, R.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.01.121