Synthesis of (-)-aphanorphine using aryl radical cyclization.

Article abstract of DOI:10.1021/ol015818j

[structure: see text] The synthesis of (-)-aphanorphine was achieved by using Bu(3)SnH-mediated aryl radical cyclization of 1-benzyloxycarbonyl-2-(2-bromo-4-methoxyphenylmethyl)-2-methoxycarbonyl-4-(phenylthiomethylene)pyrrolidine, leading to exclusive fo

Full text of DOI:10.1021/ol015818j

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2427-2429
Synthesis of (−)-Aphanorphine Using
Aryl Radical Cyclization
Osamu Tamura, Takehiko Yanagimachi, Tetsuya Kobayashi, and
Hiroyuki Ishibashi*
Faculty of Pharmaceutical Sciences, Kanazawa UniVersity,
Takara-machi, Kanazawa 920-0934, Japan
isibasi@dbs.p.kanazawa-u.ac.jp
Received March 9, 2001
ABSTRACT
The synthesis of (−)-aphanorphine was achieved by using Bu3SnH-mediated aryl radical cyclization of 1-benzyloxycarbonyl-2-(2-bromo-4-
methoxyphenylmethyl)-2-methoxycarbonyl-4-(phenylthiomethylene)pyrrolidine, leading to exclusive formation of the 6-exo cyclization product.
(-)-Aphanorphine (1) is an alkaloid isolated from the
freshwater blue-green alga Aphanizomenon flos-aquae. One
of the structural characteristics of the alkaloid is its posses-
sion of a quaternary carbon at the benzylic position.1 We
recently reported sulfur-directed exo-selective aryl radical
cyclization onto methylenecycloalkanes, which provides an
excellent method for the construction of benzylic quaternary
centers.2 For example, while treatment of 2a with Bu3SnH
in the presence of AIBN causes aryl radical cyclization to
give 6-endo product 3,3 reaction of 2b leads to exclusive
formation of 5-exo cyclization product 4 (Scheme 1). We
describe here the total synthesis of 1 based on this method-
ology for construction of the quaternary carbon of 1.
The key transformation of our synthetic planning of 1 is
6-exo aryl radical cyclization of B generated from C, leading
to tricyclic compound A, which possesses structural char-
acteristics of 1 (Scheme 2).
Scheme 2
Scheme 1
To examine this aryl radical cyclization, model radical
precursor 10a was prepared from commercially available
trans-4-hydroxy-L-proline (5) (Scheme 3). Thus, acid-
10.1021/ol015818j CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/07/2001

precursor 10a in 73% yield.8 To investigate the effect of the
phenylthio group in the radical cyclization, radical precursor
11 having no substituent at the olefin terminus was also
prepared from 9a by employing Tebbe reagent9 even in low
yield.10
Scheme 3a
The crucial radical cyclization was next examined (Scheme
4). On treatment of 10a with Bu3SnH in the presence of
Scheme 4a
a Key: (a) see, ref 4; (b) LHMDS, 2-bromobenzyl bromide, THF
for 7a; LHMDS, 2-bromo-4-methoxybenzyl bromide, THF for 7b;
(c) TBAF, THF; (d) PCC, CH2Cl2; (e) PhSCH2P(O)Ph2, BuLi,
CeCl3, THF, then NaH, THF; (f) Tebbe reagent, THF.
catalyzed esterification of 5, protection of the amino group
with benzyl chloroformate, and silylation of the hydroxyl
group provided fully protected amino acid 6.4 The lithium
enolate of 6 was alkylated with 2-bromobenzyl bromide to
give a 4:1 inseparable mixture of 7a and its diastereomer in
96% yield.5,6 Treatment of the mixture with TBAF followed
by oxidation of the resulting alcohol 8a afforded ketone 9a
in 97% yield. Horner-Wittig reaction of 9a with the lithium
a Key: (a) Bu3SnH, AIBN, benzene, reflux. 13a, 71%; 14, 20%;
15, 17%.
AIBN in boiling benzene, aryl radical cyclization proceeded
smoothly, leading to exclusive formation of 6-exo cyclization
product 13a in 71% yield. In contrast, treatment of 11 with
Bu3SnH under similar conditions gave 6-exo cyclization
product 14 and olefin 15 in 20% and 17% yields, respec-
tively. Olefin 15 might result from a 1,5-hydrogen shift of
intermediary radical D. These results clearly show that the
phenylthio group of 10a is essential for efficient 6-exo
cyclization, probably as a result of its radical-stabilization
ability in radical E.
7
salt of PhSCH2P(O)Ph2 in the presence of CeCl3 followed
by treatment of the adduct with NaH afforded radical
(1) For isolation of 1, see: (a) Gulavita, N.; Hori, A.; Shimizu, Y.; Laszlo,
P.; Clardy, J. Tetrahedron Lett. 1988, 29, 4381. For synthesis or synthetic
studies of 1, see: (b) Takano, S.; Inomata, K.; Sato, T.; Ogasawara, K. J.
Chem. Soc., Chem. Commun. 1989, 1591. (c) Takano, S.; Inomata, K.; Sato,
T.; Takahashi, M.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1990,
290. (d) Honda, T.; Yamamoto, A.; Cui, Y.; Tsubuki, M. J. Chem. Soc.,
Perkin Trans. 1 1992, 531. (e) Hulme, A. N.; Henry, S. S.; Meyers, A. I.
J. Org. Chem. 1995, 60, 1265. (f) Meyers, A. I.; Schmidt, W.; Santiago, B.
Heterocycles 1995, 40, 525. (g) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry
1995, 6, 893. (h) Hallinan, K. O.; Honda, T. Tetrahedron 1995, 51, 12211.
(i) Node, M.; Imazato, H.; Kurosaki, R.; Kawano, Y.; Inoue, T.; Nishide,
K.; Fuji, K. Heterocycles 1996, 42, 811. (j) Shiotani, S.; Okada, H.;
Nakamata, K.; Yamamoto, T.; Sekino, F. Heterocycles 1996, 43, 1031. (k)
Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1997, 8, 371. (l) Shimizu,
M.; Kamikubo, T.; Ogasawara, K. Heterocycles 1997, 46, 21.
(2) (a) Ishibashi, H.; Kobayashi, T.; Takamasu, D. Synlett 1999, 1286.
(b) Ishibashi, H.; Kobayashi, T.; Nakashima, S.; Tamura, O. J. Org. Chem.
2000, 65, 9022.
With these results of model experiments in hand, we turned
our attention to the total synthesis of (-)-aphanorphine (1).
Alkylation of the lithium enolate of 6 with 2-bromo-4-
methoxybenzyl bromide11 gave a 4:1 mixture of 7b and its
diastereomer in 91% yield. After desilylation, recrystalliza-
tion from n-hexane-Et2O afforded alcohol 8b in diastereo-
merically pure form in 68% yield. Alcohol 8b was led to
radical precursor 10b by the same procedure as that used
(3) Pal, S.; Mukhopadhyaya, J. K.; Ghatak, U. R. J. Org. Chem. 1994,
59, 2687.
(4) Mayer, S. C.; Ramanjulu, J.; Vera, M. D.; Pfizenmayer, A. J.; Joullie´,
M. M. J. Org. Chem. 1994, 59, 5192.
(5) Nagumo, S.; Mizukami, M.; Akutsu, N.; Nishida, A.; Kawahara, N.
Tetrahedron Lett. 1999, 40, 3209.
(6) The stereochemistry of the major isomer 7a was established by three-
step transformation into 12 in 57% yield. See ref 5.
(8) Without CeCl3, the reaction gave only a trace amount of 10a, probably
as a result of facile enolization of ketone 9a.
(9) For a review, see: Kelly, S. E. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon: Oxford, 1991;
Vol. 1, p 743.
(10) Neither Wittig reaction with Ph3PdCH2 nor Peterson reaction with
TMSCH2Li took place.
(11) Ghosh, A. K.; Mukhopadhyaya, J. K.; Ghatak, U. R. J. Chem. Soc.,
Perkin Trans. 1 1997, 2747.
(7) Grayson, J. I.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1977, 2263.
2428
Org. Lett., Vol. 3, No. 16, 2001

for 10a (Scheme 3). Treatment of 10b with Bu3SnH and
AIBN in boiling benzene also caused clean 6-exo radical
cyclization to afford the desired tricyclic compound 13b in
76% yield (Scheme 5). Alkaline hydrolysis of the ester group
of 13b gave carboxylic acid 16 in quantitative yield.
Condensation of 16 with 2-mercaptopyridine N-oxide fol-
lowed by treatment of the resulting thiohydroxamate ester
17 with Bu3SnH in the presence of AIBN induced Barton
decarboxylation,12 affording 18 in 52% yield. Heating 18
with Raney nickel in methanol caused simultaneously
desulfurization, deprotection of the benzyloxycarbonyl group,
and reductive methylation13 of the resulting secondary amine
19 to furnish known O-methyl aphanorphine (20) in 65%
yield, [R]20 +9.4 (c 0.30, CHCl3) {lit.1c [R]29 +8.46 (c
D
D
Scheme 5a
0.35, CHCl3), lit.1j [R]21 +10.4 (c 1.24, CHCl3)}. Finally,
D
synthesis of (-)-aphanorphine (1) was accomplished by
demethylation using BBr3,1c,j mp 200-210 °C (lit.1c mp 215-
222 °C, lit.1j mp 223-228 °C), [R]20D -23.6 (c 0.20, MeOH)
{lit.1j [R]23 -24.0 (c 0.33, MeOH)}.
D
In conclusion, we have successfully applied sulfur-
directed aryl radical cyclization to the total synthesis of
(-)-aphanorphine (1). This synthesis clearly demonstrates
the value of this cyclization for the construction of a benzylic
quaternary center in a considerably complex molecule.
Further applications of this cyclization are currently under
investigation.
Acknowledgment. We are grateful to Prof. K. Ogasawara
1
(Tohoku University) for providing H and 13C spectra of
(-)-aphanorphine. We also thank Dr. S. Nagumo (Hokkaido
College of Pharmacy) for kind discussion on the alkylation
of trans-4-hydroxy-L-proline derivatives.
Supporting Information Available: Experimental pro-
cedures for compounds 7b, 8b, 9b, 10b, 13b, 18, 20, and 1.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL015818J
(12) Barton, D. H. R.; Motherwell, W. B. Heterocycles 1984, 21, 1. See
also: Campbell, J. A.; Rapoport, H. J. Org. Chem. 1996, 61, 6313.
(13) For reductive methylation of a secondary amine with Raney nickel
in methanol, see: Franc¸ois, D.; Lallemand, M.-C.; Selkti, M.; Tomas, A.;
Kunesch, N.; Husson, H.-P. Angew. Chem., Int. Ed. 1998, 37, 104. See
also: He, X.-S.; Brossi, A. J. Heterocycl. Chem. 1991, 28, 1741.
a Key: (a) Bu3SnH, AIBN, benzene, reflux, 76%; (b) 5 N NaOH,
MeOH, reflux, quant.; (c) 2-mercaptopyridine N-oxide, EDC,
DMAP, benzene, rt, then Bu3SnH, AIBN, reflux, 52%; (d) Raney
Ni (W-2), MeOH, reflux, 65%; (e) ref 1c,j.
Org. Lett., Vol. 3, No. 16, 2001
2429