LETTER
Enantioselective Synthesis of (+)-Aphanorphine
2821
H
H
In summary, we have succeeded in the enantioselective
synthesis of (+)-aphanorphine by employing a samarium
diiodide promoted carbon–nitrogen bond-cleavage reac-
tion to construct the benzazepinone ring system as a key
reaction. The synthetic strategy developed here required
relatively short reaction sequences, and would be applica-
ble to the synthesis of its related derivatives in optically
pure forms.
OH
i
O
O
ii
NHBoc
HN
MeO
MeO
MeO
2
3
H
O
H
O
iii
iv, v
N
N
MeO
O
H
O
Bt
CO Et
CO2Et
2
4
Bt = benzotriazoyl
5
Acknowledgment
H
H
This work was supported in part by a grant from the Ministry of
Education, Culture, Sports, Science and Technology of Japan.
OH
NH HCl
OR
vi
NH
MeO
MeO
CO2H
CO2Me
References
6
7 R = H
R = TBS
vii
8
(
1) Gulavita, N.; Hori, A.; Shimizu, Y.; Laszlo, P.; Clardy, J.
Tetrahedron Lett. 1988, 29, 4381.
Scheme 1 Reagents and conditions: (i) NaH, THF, reflux (100%);
ii) OHCCO Et, benzotriazole, PTSA, toluene, reflux (84%); (iii)
TiCl , MeCN, 60 °C (76%); (iv) 2 N NaOH aq, EtOH, reflux; (v) 3 N
HCl aq; (vi) SOCl , MeOH, reflux (88% from 5); (vii) TBSCl, imida-
zole, DMF, r.t. (97%).
(
2) Honda, T.; Yamamoto, A.; Cui, Y.; Tsubuki, M. J. Chem.
Soc., Perkin Trans. 1 1992, 531.
(
2
4
(
(
3) Hallinan, K. O.; Honda, T. Tetrahedron 1995, 51, 12211.
4) (a) Takano, S.; Inomata, K.; Sato, T.; Takahashi, M.;
Ogasawara, K. J. Chem. Soc., Chem. Commun. 1990, 290.
2
(b) Hulme, A. N.; Henry, S. S.; Meyers, A. I. J. Org. Chem.
1
995, 60, 1265. (c) Meyers, A. I.; Schmidt, W.; Santiago, B.
mesylate 12 with potassium tert-butoxide in THF fur-
nished the tricyclic compound 13, in 77% yield from 11.
Heterocycles 1995, 40, 525. (d) Fadel, A.; Arzel, P.
Tetrahedron: Asymmetry 1995, 6, 893. (e) Node, M.;
Imazato, H.; Kurosaki, R.; Kawano, Y.; Inoue, T.; Nishide,
K.; Fuji, K. Heterocycles 1996, 42, 811. (f) Shiotani, S.;
Okada, H.; Nakamata, K.; Yamamoto, T.; Sekino, F.
Heterocycles 1996, 43, 1031. (g) Fadel, A.; Arzel, P.
Tetrahedron: Asymmetry 1997, 8, 371. (h) Shimizu, M.;
Kamikubo, T.; Ogasawara, K. Heterocycles 1997, 46, 21.
(i) Tanaka, K.; Taniguchi, T.; Ogasawara, K. Tetrahedron
Lett. 2001, 42, 1049. (j) Tamura, O.; Yanagimachi, T.;
Kobayashi, T.; Ishibashi, H. Org. Lett. 2001, 3, 2427.
Finally, reduction of the amide 1310 with lithium alumi-
num hydride in refluxing THF afforded (–)-8-O-methyl-
aphanorphine (14). The spectroscopic data of 14 including
3
0
specific optical rotation {[a]
–9.72 (c 0.67, CHCl3);
D
4
q
27
lit. [a] –7.40 (c 0.35, CHCl )} were identical to those
D
3
4
q
reported in the literature.
Since (–)-14 was already converted to (+)-aphanorphine
4
q
by a simple demethylation, this synthesis constitutes its
total synthesis (Scheme 2).
(
(
k) Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3, 3923.
l) ElAzab, A. S.; Taniguchi, T.; Ogasawara, K.
Heterocycles 2002, 56, 39. (m) Taylor, S. K.; Ivanovic, M.;
Simons, L. J.; Davis, M. M. Tetrahedron: Asymmetry 2003,
14, 743. (n) Kita, Y.; Futamura, J.; Ohba, Y.; Sawama, Y.;
Genesh, J. K.; Fujioka, H. J. Org. Chem. 2003, 68, 5917.
(o) Zhai, H.; Luo, S.; Ye, C.; Ma, Y. J. Org. Chem. 2003, 68,
8268. (p) Tamura, O.; Yanagimachi, T.; Ishibashi, H.
Tetrahedron: Asymmetry 2003, 14, 3033. (q) Synthesis of
(+)-aphanorphine, see: Takano, S.; Inomata, K.; Sato, T.;
Ogasawara, K. J. Chem. Soc., Chem. Commun. 1989, 1591.
H
OTBS
OTBS
i
ii
NH
O
NH
MeO
MeO
MeO
MeO
CO2Me
8
9
OR
OMs
iv
v
NMe
NMe
(5) Honda, T.; Ishikawa, F. Chem. Commun. 1999, 1065.
(6) (a) Honda, T.; Kimura, M. Org. Lett. 2000, 2, 3925.
O
O
Me
Me
(
b) Katoh, M.; Matsune, R.; Nagase, H.; Honda, T.
1
1
0 R = TBS
1 R = H
12
iii
Tetrahedron Lett. 2004, 45, 6221. (c) Honda, T.; Takahashi,
R.; Namiki, H. J. Org. Chem. 2005, 70, 499. (d) Katoh, M.;
Mizutani, H.; Honda, T. Tetrahedron Lett. 2005, 46, 5161.
7) (a) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V.
Chem. Rev. 1998, 98, 409. (b) Katritzky, A. R.; Cobo-
Domingo, J.; Yang, B.; Steel, P. J. Tetrahedron: Asymmetry
1999, 10, 255. (c) Koepler, O.; Laschat, S.; Baro, A.;
Fischer, P.; Miehlich, B.; Hotfilder, M.; le Viseur, C. Eur. J.
Org. Chem. 2004, 3611.
H
H
(
ref.
NMe
NMe vi
ent-1
MeO
MeO
Me
Me
14
O
13
Scheme 2 Reagents and conditions: (i) SmI , THF–HMPA, MeOH,
(8) Jurczak, J.; Gryko, D.; Kobrzycka, E.; Gruza, H.;
Prokopowicz, P. Tetrahedron 1998, 54, 6051.
(9) Preparation and Spectroscopic Data of Compound 9.
To a stirred solution of 8 (1.00 g, 2.74 mmol) in THF (15
2
0
0
°C to r.t. (59%); (ii) NaH, MeI, DMF, 0 °C (98%); (iii) TBAF, THF,
°C (99%); (iv) MsCl, TEA, CH Cl , –78 °C (98%); (v) t-BuOK,
2
2
THF, reflux (79%); (vi) LiAlH , THF, reflux (87%).
4
mL) was added a solution of SmI (0.2 M in THF, 68.5 mL,
2
13.7 mmol) containing HMPA (2.38 mL, 13.7 mmol) and
Synlett 2005, No. 18, 2820–2822 © Thieme Stuttgart · New York