Efficient and highly selective synthesis of enantiopure cis-or trans-3,4-disubstituted 1,2,3,4-tetrahydroisoquinolines

Article abstract of DOI:10.1021/ol901388e

Image Presented An efficient synthesis of enantiopure 3,4-disubstituted 1,2,3,4-tetrahydroisoquinolines, by treatment of readily available (2R, 1′S)- or (2S, 1′S)-2-(1-aminoalkyl)epoxides with H ₃PO₄·BF₃ complex, under mil

Full text of DOI:10.1021/ol901388e

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3750-3753
Efficient and Highly Selective Synthesis
of Enantiopure cis- or trans-3,4-
Disubstituted 1,2,3,4-
Tetrahydroisoquinolines
Jose´ M. Concello´n,* Paula Tuya, Virginia del Solar, Santiago Garc´ıa-Granda, and
M. Rosario D´ıaz
Departamento de Qu´ımica Orga´nica e Inorga´nica, and Departamento de Qu´ımica
F´ısica y Anal´ıtica, UniVersidad de OViedo, Julia´n ClaVer´ıa 8, 33071 OViedo, Spain
jmcg@unioVi.es
Received June 19, 2009
ABSTRACT
An efficient synthesis of enantiopure 3,4-disubstituted 1,2,3,4-tetrahydroisoquinolines, by treatment of readily available (2R,1′S)- or (2S,1′S)-
2-(1-aminoalkyl)epoxides with H3PO4·BF3 complex, under mild reaction conditions, is reported. Both enantiopure diastereoisomers (3S,4S)-
and (3S,4R)-3-alkyl-4-hydroxymethyl-1,2,3,4-tetrahydroisoquinolines were available starting from the suitable syn- or anti-aminoepoxide,
respectively. A mechanism based on an intramolecular Friedel-Crafts-type reaction has been proposed to explain these results.
Tetrahydroisoquinolines (THIQs) are important organic
compounds due to their widespread occurrence in nature1
and pharmacological applications.2 Indeed, the use of THIQs
as calcium antagonists,3 antibacterial4 and antitumor antibiot-
ics,5 or in cardiovascular diseases6 has been described. A
typical example of a THIQ with therapeutic properties is
1-methyltetrahydroisoquinoline, a simple compound with
activity against endogenous Parkinson’s disease.7 Conse-
quently, much attention has been focused toward the
(3) Dong, H.; Sheng, J. Z.; Wong, T. M. Br. J. Pharmacol. 1993, 109,
113–119.
(1) (a) Bentley, K. W. Nat. Prod. Rep. 2003, 20, 342–365. (b) Scott,
J. D.; Williams, R. M. Chem. ReV. 2002, 102, 1669–1730. (c) Rozwadowska,
M. D. Heterocycles 1994, 39, 903–931. (d) Chrzanowska, M.; Rozwad-
owska, M. D. Chem. ReV. 2004, 104, 3341–3370. (e) Vicario, J. L.; Bad´ıa,
D.; Carrillo, L.; Etxebarria, J. Curr. Org. Chem. 2003, 7, 1775–1792.
(2) (a) Herbert, R. B. In The Chemistry and Biology of Isoquinoline
Alkaloids; Philipson, J. D., Roberts, M. F., Zenk, M. H., Eds.; Springer-
Verlag: Berlin, 1985; p 213. (b) Samma, M. In Isoquinoline Alcaloids,
Chemistry and pharmacology; Academic Press: New York, 1972.
(4) Chandrasekhar, S.; Mohanty, P. K.; Harikishan, K.; Sasmal, P. K.
Org. Lett. 1999, 1, 877–878.
(5) Scott, J. D.; Williams, R. M. Chem. ReV. 2002, 102, 1669–1730.
(6) Dong, H,; Lee, C. M.; Huang, W. L.; Peng, S. X. Br. J. Pharmacol.
1992, 107, 262–268.
(7) Ishiwata, K.; Koyanagi, Y.; Abe, K.; Kawamura, K.; Taguchi, K.;
Saitoh, T.; Toda, J.; Senda, M.; Sano, T. J. Neurochem. 2001, 79, 868–
876.
10.1021/ol901388e CCC: $40.75
Published on Web 07/23/2009
 2009 American Chemical Society

development of efficient syntheses of a range of substituted
tetrahydroisoquinolines.
ity.13 As part of our interest in the development of new
synthetic applications of the these enantiopure amino ep-
oxides, our objective in this paper is to describe a novel and
efficient transformation of (2R,1′S)- or (2S,1′S)-2-(1-ami-
noalkyl) epoxides into enantiopure cis- and trans-3,4-
disubstituted 1,2,3,4-tetrahydroisoquinolines, respectively.
These transformations were promoted by boron trifluoride
phosphoric acid complex (H3PO4.BF3).
Traditionally, tetrahydroisoquinolines were synthesized
using the ring closure of iminium intermediates via the
Pictet-Spengler8 or Bischler-Napieralski reactions.9 Other
methods are also known for the synthesis of 1-substituted
1,2,3,4-tetrahydroisoquinolines in racemic and enantiopure
forms. However, although enantiopure 3- and/or 4-substituted
tetrahydroisoquinolines are of considerable interest due to
their biological activity and as naturally occurring alkaloids,10
the reported methods for the synthesis of enantiopure 3,4-
disubstituted tetrahydroisoquinolines with high diastereose-
lectivity are scarce.11 In addition the reported syntheses
present some drawbacks, such as the high number of reaction
steps required,11a,d the production of some intermediate
compound as mixture of diastereoisomers11d or the poor
generality of the THIQs prepared.11b,c,e Taking into account
these previously described syntheses, development of new
methods for the synthesis of enantiopure 3,4-disubstituted
1,2,3,4-tetrahydroisoquinolines from readily available starting
compounds is of considerable interest.
Previously, we reported the synthesis of both enantiopure
(2R,1′S)- or (2S,1′S)-2-(1-aminoalkyl) epoxides by the total
stereoselective reduction of enantiopure R-amino-R′-chloro
ketones with LiAlH4 or by a highly stereoselective addition
reaction of iodomethyllithium to chiral 2-amino aldehydes,
respectively.12 More recently, we have developed various
transformations of the former aminoepoxides to obtain
several enantiopure compounds with total or high selectiv-
Our first attempt to obtain THIQs were performed using
the syn-aminoepoxide derived from alanine [(2R,1′S)-2-(1-
dibenzylaminoethyl)epoxide] 1a as the starting material
model. The treatment of 1a was performed under the reaction
conditions shown in Table 1. While no THIQ 2a was
Table 1. Reaction Conditions Tested to Transform the
Aminoepoxide 1a into the Tetrahydroisoquinoline 2a
entry solvent Lewis acid T (°C) reaction time (h) yield (%)a
1
2
3
4
5
6
7
CH2Cl2 BF3·OEt2
rt
6
2
4
6
8
4
6
-
50
78
92
77
80b
81
CH2Cl2 H3PO4·BF3 rt
CH2Cl2 H3PO4·BF3 rt
CH2Cl2 H3PO4·BF3 rt
CH2Cl2 H3PO4·BF3
CH2Cl2 H3PO4·BF3 reflux
0
PhMe H3PO4·BF3 rt
a Isolated yield after column chromatography based on the starting amino
epoxide 1a. b Mixture of cis/trans diastereoisomers (8.1) was obtained.
(8) Cox, A. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797–1842.
(9) For example, see: Morimoto, T.; Suzuki, N.; Achiwa, K. Tetrahe-
dron: Asymmetry 1998, 9, 183–187.
obtained with BF3·OEt2, the use of H3PO4·BF3 complex
allowed access to 2a in all cases. Analysis of results shown
in Table 1, indicates that the best result was obtained by
treatment of a solution of 1a in CH2Cl2 with 3 equivalents
of H3PO4·BF3 at room temperature for 6 h. After usual
workup, (3S,4S)-2-benzyl-3-methyl-4-hydroxymethyl 1,2,3,4-
tetrahydroiso-quinoline 2a was obtained with complete
selectivity (only one isomer was detected in the crude
reaction products) and in high yield (92%).
(10) Mondeshka, D. M.; Stensland, B.; Angelova, I.; Ivanov, C. B.;
Atanosova, R. Acta Chem. Scand. 1994, 48, 689–698. (b) Rinehart, K. L.;
Holt, T. G.; Frege, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.;
Martin, D. G. J. Org. Chem. 1990, 55, 4512–4517. (c) Wright, A. E.; Forleo,
P. A.; Gumahandana, G. P.; Gunasekera, S. P.; Koehn, F. E.; McConnell,
O. J. J. Org. Chem. 1990, 55, 4508–4512. (d) Davidson, R. S. Tetrahedron
Lett. 1992, 33, 3721–3724.
(11) For leading references, see: (a) Davies, F. A.; Andemichael, Y. W.
J. Org. Chem. 1999, 64, 8627–8634. (b) Tellitu, I.; Bad´ıa, D.; Dom´ınguez,
E.; Garc´ıa, F. J. Tetrahedron: Asymmetry 1994, 5, 1567–1578. (c) Carrillo,
L.; Bad´ıa, D.; Dom´ınguez, E.; Ortega, F.; Tellitu, I. Tetrahedron: Asymmetry
1998, 9, 151–155. (d) Vicario, J. L.; Bad´ıa, D.; Dom´ınguez, E.; Carrillo,
L. J. Org. Chem. 1999, 64, 4610–4616. (e) Pedrosa, R.; Andre´s, C.; Iglesias,
J. M.; Obeso, M. A. Tetrahedron 2001, 57, 4005–4014. (f) Kawabata, T.;
Majumdar, S.; Tsubaki, K.; Monguchi, D. Org. Biomol. Chem. 2005, 3,
1609–1611. (g) Kawabata, T.; Matsuda, S.; Kawakami, S.; Monguchi, D.;
Moriyama, K. J. Am. Chem. Soc. 2006, 128, 15394–15395.
To establish the generality and limitations of this trans-
formation, the reaction was also performed utilizing other
syn-amino epoxides 1b-d. Thus, under the same reaction
conditions, enantiopure cis-3,4-substituted tetrahydroiso-
quinolines 2b and 2c were obtained from aminoepoxides 1b
and 1c. In both cases the transformation took place with total
regio- and stereoselectivity, as is shown in Scheme 1 and
(12) (a) Barluenga, J.; Baragan˜a, B.; Alonso, A.; Concello´n, J. M.
J. Chem. Soc., Chem. Commun. 1994, 969–970. (b) Barluenga, J.; Baragan˜a,
B.; Alonso, A.; Concello´n, J. M. J. Org. Chem. 1995, 60, 6696–6699. (c)
Concello´n, J. M.; Bernad, P. L.; Pe´rez-Andre´s, J. A. J. Org. Chem. 1997,
62, 8902–8906. (d) Concello´n, J. M.; Cuervo, H.; Ferna´ndez-Fano, R.
Tetrahedron 2001, 57, 8983–8987.
(13) (a) Concello´n, J. M.; Bernad, P. L.; del Solar, V.; Garc´ıa-Granda,
S.; D´ıaz, M. R. AdV. Synth. Catal. 2008, 477–481. (b) Concello´n, J. M.;
Rivero, I. A.; Rodr´ıguez-Solla, H.; Concello´n, C.; Espan˜a, E.; Garc´ıa-
Granda, S.; D´ıaz, M. R. J. Org. Chem. 2008, 73, 6048–6051. (c) Concello´n,
J. M.; del Solar, V.; Garc´ıa-Granda, S.; D´ıaz, M. R. J. Org. Chem. 2007,
72, 7567–7573. (d) Concello´n, J. M.; del Solar, V.; Su´arez, J. R.; Blanco,
E. G. Tetrahedron 2007, 63, 2805–2810. (e) Concello´n, J. M.; Bernad, P. L.;
del Solar, V.; Sua´rez, J. R.; Garc´ıa-Granda, S.; D´ıaz, M. R. J. Org. Chem.
2006, 71, 6420–6426. (f) Concello´n, J. M.; Sua´rez, J. R.; del Solar, V.
Org. Lett. 2006, 8, 349–351. (g) Concello´n, J. M.; Sua´rez, J. R.; del Solar,
V. J. Org. Chem. 2005, 70, 7447–7450. (h) Concello´n, J. M.; Sua´rez, J. R.;
del Solar, V.; Llavona, R. J. Org. Chem. 2005, 70, 10348–103453. (i)
Concello´n, J. M.; Riego, E.; Sua´rez, J. R.; Garc´ıa-Granda, S.; D´ıaz, M. R.
Org. Lett. 2004, 6, 4499–4501.
Scheme 1
.
Synthesis of Enantiopure cis-3,4-Disubstituted
1,2,3,4-Tetrahydroisoquinolines 2
Org. Lett., Vol. 11, No. 16, 2009
3751

Table 2. Synthesis of Enantiopure 3,4-Disubstituted
1,2,3,4-Tetrahydroisoquinolines 2 or 6 and
Tetrahydronaphthalene 3
Scheme 3
.
Proposed Mechanism to Obtain THIQs 2 or
Tetrahydronaphthalene 3
starting
entry compound
R
product
dra
>98:2
>98:2
>98:2
>98:2
90:10 (91:9)
90:10 (92:8)
yield (%)b
1
2
3
4
5
6
1a
1b
1c
1d
5b
5d
Me
2a
2b
2cc
3
6b
6d
90
96
98
87
82
90
i-Bu
HOCH2
Bn
i-Bu
Bn
a Relation determined by 1H NMR analysis of the crude products; dr of
the starting aminoepoxides 5 is given in parentheses. b Isolated yield after
column chromatography based on the starting amino epoxide 1 or 5.
c Compound 2c was obtained as its O-debenzylated derivative.
Table 2. In the case of reaction of 1c, O-deprotection took
place under the reaction conditions and the O-debenzylated
THIQ 2c was obtained. Remarkably, this Friedel-Crafts-
type reaction was mediated by H3PO4·BF3 complex under
very mild conditions. To the best of our knowledge,
applications in organic synthesis of this complex have
scarcely been reported to date. Thus, this transformation is
the first example reported, in which H3PO4·BF3 promotes the
synthesis of an enantiopure organic compound.
heterocycle. Thus, the regiochemistry of the ring-opening
of oxirane could be governed by the size of the generated
heterocycle, the formation of six-membered ring being
favored over a seven membered-ring. The ring-opening took
place with complete inversion of its absolute configuration.
After the final hydrolysis of the reaction mixture, the THIQ
2 was obtained with complete selectivity and in nearly
quantitative yield (Scheme 3). This proposed stereochemical
course is supported by the absolute configuration of the C-4
atom of the obtained THIQ (see below). When the reaction
was performed from 1d, a different intramolecular Friedel-
Crafts-type reaction took place. In this case, the electrophilic
substitution took place on the ω-phenyl group of the
aminoepoxide 1d, instead of the phenyl group of the
dibenzylamino group. In addition, the regiochemistry of
the ring-opening of the oxirane also changed and the reaction
took place on the less substituted carbon atom instead of
the most substituted, since the formation of a six membered-
ring (instead of five) could be favored (Scheme 3).
However, when the reaction was performed on the syn-
aminoepoxide, derived from phenylalanine 1d, a chiral
tetrahydronaphthalene 3 (Scheme 2 and Table 2) instead of
Scheme 2. Synthesis of Enantiopure Tetrahydronaphthalene 3
the expected tetrahydroisoquinoline was obtained. The
structure and absolute configuration of compound 3 (as
depicted in Scheme 2) were established unambiguously by
single-crystal X-ray analysis.14
To test this hypothesis and to prove the utility of the
method to obtain the other trans-diastereoisomer with high
enantiomeric purity, we synthesized the anti-aminoepoxides
5c and 5d, which were subsequently treated with H3PO4·BF3
under the same reaction conditions (CH2Cl2, room temper-
ature, 6 h). Thus, from 5d the corresponding enantiopure
tetrahydroisoquinoline 6d was obtained in high yield and
with complete selectivity (Scheme 4 and Table 2). Therefore,
the synthesis of THIQ instead of the tetrahydronaphthalene,
could demonstrate that the electrophilic substitution reaction
took place on the phenyl group closer to the oxirane ring,
which in turn depended on the relative configuration of the
aminoepoxide derived from phenylalanine.
The synthesis of products 2 and 3 can be explained by
assuming that in both cases an intramolecular Friedel-Crafts-
type reaction took place (Scheme 3). Initially, H3PO4 and
BF3 were released from the complex. Then, the coordination
of the oxygen with the BF3 or a proton (released in turn
from H3PO4) weakened the C-O bond generating electro-
philic species 4. The electrophilic aromatic substitu-
tion reaction took place by reaction of the more substituted
carbon atom of the oxirane ring and the ortho-carbon of a
phenyl of the dibenzylamino group affording a six-membered
(14) CCDC 732703 contains the supplementary crystallographic data
for compound 3. These data can be obtained free of charge via: www.
ccdc.cam.ac.uk/conts/retrieving.html (or the Cambridge Data Center, 12
Union Road, Cambridge CB21EZ, UK; fax (+44)1223-336-033, or e-mail
deposit@ccdc.cam.ac.uk).
As was expected, the reaction from anti-aminoepoxide 5b,
with only one type of phenyl group, afforded the corre-
3752
Org. Lett., Vol. 11, No. 16, 2009

of 1H and 13C NMR data and HMBC and HSQC experiments
on compounds 2 and 6. The absolute configurations were
established on the basis of NOESY experiments of com-
pounds 2b and 6b.15 NOESY experiments on compound 2b
shown a cis arrangement of Hb,c and Hh protons. Moreover,
the NOE interactions of Hg with Hh, and Hb with Hd, in the
case of the trans-isomer 6b would also support the config-
uration of compound 2b due to the absence of NOE
interactions between Hb,c and Hh in compound 6b. The
absolute configuration of the other compounds 2 and 6 was
established based on their corresponding spectral data and
by analogy to the results of the NOESY experiments of
THIQs 2b and 6b.
In conclusion, a H3PO4·BF3-mediated synthesis of enan-
tiopure cis- or trans-3,4-disubstituted 1,2,3,4-tetrahydroiso-
quinolines, under mild reaction conditions from the readily
available (2R,1′S)- and (2S,1′S)-2-(1-aminoalkyl)epoxides 1
or 5 is reported. This protocol constitutes the first example
in which H3PO4·BF3 is reported to promote the synthesis of
enantiopure compounds. A mechanism, via an intramolecular
Friedel-Crafts type reaction, is proposed to explain the
synthesis of enantiopure 3,4-disubstituted THIQ, which are
not trivial to access in enantiopure form. Studies directed
toward fully delineating the factors involved in these
transformations, the generality of the reaction and the
development of other synthetic applications of the H3PO4·BF3
complex are currently under investigation in our laboratory.
Scheme 4
.
Synthesis of Enantiopure trans-3,4-Disubstituted
1,2,3,4-Tetrahydroisoquinolines 6
sponding THIQ 6b, in an enantiopure manner (Scheme 4
and Table 2). Therefore, the two diastereoisomers (cis and
trans) were available in enantiopure form by this method.
In addition, no important differences were observed in the
yields of THIQ 6b and in the course of reaction from 5b in
comparison with that described from syn-aminoepoxide 1b.
The total regio- and stereoselectivity of the ring-opening
of epoxides was established by H and 13C NMR analyses
1
(300 MHz) of the crude reaction products, showing the
presence of a single isomer in the crude reaction from amino
epoxides 1. In contrast, starting from amino epoxides 5b or
5d, the THIQs 6 were obtained as a diastereoisomeric
mixture in the same relationship to that of the starting amino
epoxides 5.9 Thus, these results constitute indirect evidence
of the stereospecificity of the ring-opening of amino epoxides
1 or 5 by the phenyl group being promoted by H3PO4·BF3.
In addition the absence of diastereoisomers in the crude
reaction constituted evidence of the enantiomeric purity of
THIQs 2 and 6 (Figure 1).
Acknowledgment. We thank the Ministerio de Ciencia e
Innovacio´n (MICINN CTQ2007-61132 and MAT-2006-
01997) and Principado de Asturias (FICYT IB08-08) for
financial support and J.M.C. thanks his wife Carmen Ferna´n-
dez-Flo´rez for her time. P.T. thanks MICINN for a predoc-
toral fellowship. We also thank Euan C. Goddard (CRL,
University of Oxford) for his revision of English.
Supporting Information Available: General procedure,
1
CIF for compound 3, spectroscopic data, and copies of H
and 13C NMR spectra for THIQs 2 and 6, and tetrahy-
dronaphthalene 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
Figure 1. NOE Effect observed on compounds 2b and 6b.
OL901388E
(15) Since the stereochemistry of the CHN carbon is fixed in the starting
material, the determination of relative congifuration by nOe effect has also
been utilised as a proof for the elucidation of the absolute stereochemistry
of compounds 2 and 6.
The structures of THIQs 2 and 6 shown in Schemes 1, 3,
and 4 were assigned on the basis of the corresponding data
Org. Lett., Vol. 11, No. 16, 2009
3753