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,
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Scheme 1
.
Synthesis of Enantiopure cis-3,4-Disubstituted
1,2,3,4-Tetrahydroisoquinolines 2
Org. Lett., Vol. 11, No. 16, 2009
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