New asymmetric transformation of optically active allene-1,3-dicarboxylate and its application to the formal asymmetric synthesis of (-)-epibatidine

Article abstract of DOI:10.1039/a806477f

A new efficient synthesis of di-(-)-L-menthyl (R)-allene-1,3-dicarboxylate [(R)-1] involving asymmetric transformation through epimerization-crystallization with the assistance of a catalytic amount of Et₃N was developed; the highly endo-select

Full text of DOI:10.1039/a806477f

New asymmetric transformation of optically active allene-1,3-dicarboxylate
and its application to the formal asymmetric synthesis of (2)-epibatidine
Manabu Node,* Kiyoharu Nishide, Toshio Fujiwara and Shogo Ichihashi
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, 607-8414, Japan. E-mail: node@mb.kyoto-phu.ac.jp
Received (in Cambridge, UK) 17th August 1998, Accepted 23rd September 1998
O
A new efficient synthesis of di-(2)- -menthyl (R)-allene-
L
RO2C
CO2R
1,3-dicarboxylate [(R)-1] involving asymmetric transforma-
tion through epimerization–crystallization with the assis-
tance of a catalytic amount of Et3N was developed; the
highly endo-selective asymmetric Diels–Alder reaction of
(R)-1 with N-Boc-pyrrole for the asymmetric synthesis
of 7-tert-butoxycarbonyl-7-azabicyclo[2.2.1]heptan-2-one
[(2)-6], a synthetic intermediate of (2)-epibatidine, is
described.
2
R = (–)-L-menthyl
i
RO2C
H
RO2C
H
H
CO2R
H
+
•
•
CO2R
(S)-1
(R)-1
5 : 4
ii
Allene-1,3-dicarboxylates are useful for [4 + 2] cycloaddition as
dienophiles.1 Kanematsu and his colleagues have reported the
highly diastereoselective Diels–Alder reaction of cyclopenta-
diene with optically active dimenthyl allene-1,3-dicarboxylate
1, which was prepared by optical resolution using crystalliza-
Asymmetric
Transformation
RO2C
CO2R
H
•
tion from a diastereomeric mixture of di-(2)- -menthyl allene-
L
H
1,3-dicarboxylates.2 Naruse and his colleagues recently re-
ported the enantiomeric enrichment of allene-1,3-
dicarboxylates by a chiral organoeuropium reagent.3 For the
synthesis of optically active allene, the former method using
optical resolution provides a low yield ( < 25%), and the latter
method has major drawbacks, i.e. the need for an equimolar
amount of expensive Eu(hfc)3, and the partial decomposition of
the substrate due to the long reaction times needed. Therefore,
a more efficient method for the preparation of optically active
allene-1,3-dicarboxylate is required. Although several crystal-
lization-induced asymmetric transformations by racemization
have been reported,4 the asymmetric transformation of dissym-
metric compounds such as allenes has not been examined. We
report here a new efficient synthesis of optically active allene-
1,3-dicarboxylate by asymmetric transformation through epi-
merization–crystallization with the assistance of a catalytic
amount of Et3N, and its application to the formal total synthesis
of (2)-epibatidine using the Diels–Alder reaction as a key
step.
(R)-1
Scheme 1 Reagents and conditions: i, DMC, Et3N, CH2Cl2, room temp.,
86%; ii, Et3N (0.01 equiv.), pentane, crystallization (33), 90%.
by the above asymmetric transformation using (+)-
D
-menthol as
a chiral auxiliary.
Next, we applied di-(2)- -menthyl (R)-allene-1,3-dicarbox-
L
ylate (R)-1 to an asymmetric synthesis of (2)-epibatidine,
which was isolated from the skin of the Ecuadorian poison frog
Epipedobates tricolor, and possesses a unique 7-azabicyclo-
[2.2.1]heptane skeleton and a potent non-opioid analgesic
effect.7 There have been only a few reports8 on the asymmetric
synthesis of (2)-epibatidine, although there have been many
reports on its total synthesis.9,10 We planned the asymmetric
synthesis of a synthetic intermediate for (2)-epibatidine using
the Diels–Alder reaction of 1 according to Kanematsu et al.,2a
as shown in Scheme 3.
The Diels–Alder reaction of (±)-dimethyl allene-1,3-di-
carboxylate with N-Boc-pyrrole (10 equiv.) gave almost
equimolar amounts of the endo and exo adducts, both at a low
temperature with the assistance of a Lewis acid [AlCl3 (1.2
equiv.), CH2Cl2, 278 °C, 12 h, 73%], and at a high
temperature9d [toluene, 90 °C, 12 h, 89%]. On the other hand,
Since allene-1,3-dicarboxylate is an excellent Michael ac-
ceptor,5 the epimerization of optically active allene-1,3-di-
carboxylate, which was prepared from di-
L
- or - -menthyl
D
acetone-1,3-dicarboxylate by a new method6 using 2-chloro-
1,3-dimethylimidazolinium chloride (DMC), as shown in
Scheme 1, was examined in the presence of a catalytic amount
of Et3N.
we found that the same reaction of di- -(2)-menthyl allene-
L
1,3-dicarboxylate (R)-1 with N-Boc-pyrrole and AlCl3 in
CH2Cl2 at 278 °C for 13 h gave the endo adduct (2)-3 as a sole
product in 86% yield. The absolute stereochemistry of the endo
Thus, an optically pure di-(2)- -menthyl (R)-allene-1,3-di-
L
carboxylate [(R)-1]2 was treated with Et3N (0.1 equiv.) in an
NMR tube to give a diastereomeric mixture of 1 (R:S = 4:5)
within 30 min. This experiment shows that these diastereomers
are in equilibrium in the presence of a catalytic amount of Et3N,
as shown in Scheme 2. This result suggests that crystallization-
induced asymmetric transformation of 1 would be possible,
since the R diastereomer formed good crystals.2a
O–
RO2C
H
RO2C
H
+Et3N
–Et3N
OR
CO2R
H
•
•
Et3N+
H
(R)-1
R = (–)-L-Menthyl
To crystallize the R diastereomer, a pentane solution of a
+Et3N –Et3N
diastereomeric mixture (R:S = 4:5) of di-(2)- -menthyl allene-
L
1,3-dicarboxylate 1 and 0.01 equiv. of Et3N was kept below
220 °C for 2 days. After removal of the mother liquid, the
precipitated crystals were washed with cooled pentane. This
crystallization procedure of the mother liquid was repeated
twice. Colorless crystalline (R)-1 was obtained in 90% yield
( > 98% de). Similarly, the enantiomer (S)-1 was also obtained
RO2C
H
H
•
CO2R
(S)-1
Scheme 2
Chem. Commun., 1998, 2363–2364
2363

Boc
tertiary amine, and a quite efficient synthesis of (2)-6 from di-
(2)- -menthyl acetone-1,3-dicarboxylate.
N
H
RO2C
H
L
i
CO2R
H
+
•
CO2R
N
H
Notes and references
Boc
(R)-1
CO2R
1 For examples: K. A. Parker and S. M. Ruder, J. Am. Chem. Soc., 1989,
111, 5948; M. Yoshida, Y. Hidaka, Y. Nawata, J. M. Rudziñski, E.
Osawa and K. Kanematsu, J. Am. Chem. Soc., 1988, 110, 1232.
2 (a) I. Ikeda, K. Honda, E. Osawa, M. Shiro, M. Aso and K. Kanematsu,
J. Org. Chem., 1996, 61, 2031; (b) M. Aso, I. Ikeda, T. Kawabe, M.
Shiro and K. Kanematsu, Tetrahedron Lett., 1992, 33, 5787; (c) I. Ikeda,
A. Gondo, M. Shiro and K. Kanematsu, Heterocycles, 1993, 36,
2669.
R = (–)-L-Menthyl
(–)-3
ii
Boc
N
Boc
Boc
N
N
H
iv
iii
O
O
CO2R
H
CO2R
(–)-5
(–)-6
CO2R
3 Y. Naruse, H. Watanabe, Y. Ishiyama and T. Yoshida, J. Org. Chem.,
1997, 62, 3862; Y. Naruse, H. Watanabe and S. Inagaki, Tetrahedron:
Asymmetry, 1992, 3, 603.
(–)-4
Ref. 10
4 W.-C. Shieh, J. A. Carlson and G. M. Zaunius, J. Org. Chem., 1997, 62,
8271; J. D. Armstrong, III, K. K. Eng, J. L. Keller, R. M. Purick, F. W.
Hartner, Jr., W.-B. Choi, D. Askin and R. P. Volante, Tetrahedron Lett.,
1994, 35, 3239; S. K. Boyer, R. A. Pfund, R. E. Portmann, G. H.
Sedelmeier and H. F. Wetter, Helv. Chim. Acta, 1988, 71, 337; P. J.
Reider, P. Davis, D. L. Hughes and E. J. J. Grabowski, J. Org. Chem.,
1987, 52, 955; T. Sohda, K. Mizuno and Y. Kawamatsu, Chem. Pharm.
Bull., 1984, 32, 4460; S. Shibata, H. Matsushita, H. Kaneko, M.
Noguchi, M. Saburi and S. Yoshikawa, Heterocycles, 1981, 16, 1901;
J. C. Clark, G. H. Phillipps and M. R. Steer, J. Chem. Soc., Perkin Trans.
1, 1976, 475; M. K. Hargreaves and M. A. Khan, J. Chem. Soc., Perkin
Trans. 1, 1973, 1204.
H
Cl
N
N
H
(–)-Epibatidine
Scheme 3 Reagents and conditions: i, AlCl3, CH2Cl2, 278 °C, 13 h, 86%;
ii, 10% Pd/C, H2, EtOAc, room temp., 99%; iii, O3, PPh3, CH2Cl2, 278 °C,
52%; iv, 10% HCl, heat, then Boc2O, Et3N, CH2Cl2, room temp., 55%.
5 M. E. Jung, Comprehensive Organic Synthesis, ed. B. M. Trost and I.
Fleming, Pergamon, Oxford, 1991, vol. 4, pp. 53–58.
6 M. Node, T. Fujiwara, S. Ichihashi and K. Nishide, Tetrahedron Lett.,
1998, 39, 6331.
7 T. F. Spande, H. M. Garraffo, M. W. Edwards, H. J. C. Yeh, L. Pannell
and J. W. Daly, J. Am. Chem. Soc., 1992, 114, 3475.
8 Asymmetric synthesis of (2)-epibatidine, see: S. Aoyagi, R. Tanaka, M.
Naruse and C. Kibayashi, Tetrahedron Lett., 1998, 39, 4513; C. D.
Jones, N. S. Simpkins and G. M. P. Giblin, Tetrahedron Lett., 1998, 39,
1023; H. Kosugi, M. Abe, R. Hatsuda, H. Uda and M. Kato, Chem.
Commun., 1997, 1857; B. M. Trost and G. R. Cook, Tetrahedron Lett.,
1996, 37, 7485.
adduct (2)-3 was elucidated by an X-ray crystallographic
analysis.
The observed significant difference in endo/exo selectivity
between the dimethyl ester and the di- -(2)-menthyl ester
L
could be explained on the basis of steric repulsion between the
N-Boc group of the diene and the methyl or menthyl group in
the dienophile 1, based on an X-ray crystallographic analy-
sis.2a
The endo adduct (2)-3 was subsequently converted into a
synthetic intermediate (2)-610 for (2)-epibatidine. Thus,
regioselective hydrogenation of non-conjugated olefin on (2)-3
with 10% Pd/C gave the dihydro derivative (2)-4 quantita-
tively. After ozonolysis of the remaining double bond, the
obtained b-keto ester 5 was subjected to hydrolysis, decarbox-
ylation, and N-tert-butoxycarbonylation (reprotection of the
deprotected secondary amine) to give (2)-6 in moderate yield;
9 For recent synthetic studies on epibatidine, see (a) N. S. Sirisoma and
C. R. Johnson, Tetrahedron Lett., 1998, 39, 2059; (b) M. Ikeda, Y.
Kugo, Y. Kondo, T. Yamazaki and T. Sato, J. Chem. Soc., Perkin Trans.
1, 1997, 3339; (c) G. M. P. Giblin, C. D. Jones and N. S. Simpkins,
Synlett, 1997, 589; (d) N. P. Pavri and M. L. Trudell, Tetrahedron Lett.,
1997, 38, 7993; (e) S. Singh and G. P. Basmadjian, Tetrahedron Lett.,
1997, 38, 6829. Also see the references cited therein.
10 (a) D. L. J. Clive and V. S. C. Yeh, Tetrahedron Lett., 1998, 39, 4789;
(b) S. R. Fletcher, R. Baker, M. S. Chambers, R. H, Herbert, S. C.
Hobbs, S. R. Thomas, H. M. Verrier, A. P. Watt and R. G. Ball, J. Org.
Chem., 1994, 59, 1771; (c) A. Hernández, M. Marcos and H. Rapoport,
J. Org. Chem., 1995, 60, 2683; (d) J. A. Campbell and H. Rapoport,
J. Org. Chem., 1996, 61, 6313; (e) E. Albertini, A. Barco, S. Benetti, C.
De Risi, G. P. Pollini and V. Zanirato, Tetrahedron, 1997, 53, 17
177.
17
its specific rotation {[a]D 274.5 (c 1.02, CHCl3), lit.10a
26
[a]D 275.1 (c 1.56, CHCl3)} and spectroscopic data were
identical to those in the literature.10 This transformation
constitutes a formal asymmetric synthesis of (2)-epibatidine.
In conclusion, we have developed the first asymmetric
transformation of dissymmetric allene-1,3-dicarboxylate
through epimerization based on addition–elimination with a
Communication 8/06477F
2364
Chem Commun., 1998