Formal asymmetric synthesis of (-)-aphanorphine via ring-closing metathesis reaction

Article abstract of DOI:10.1055/s-0028-1083498

We have developed an asymmetric route to (-)-aphanorphine from O-Me-D-tyrosine methyl ester hydrochloride salt, available from D-tyrosine in four steps. The tricyclic framework of (-)-aphanorphine was assembled stereoselectively by intramolecular Friedel-

Full text of DOI:10.1055/s-0028-1083498

LETTER
2821
Formal Asymmetric Synthesis of (–)-Aphanorphine via Ring-Closing
Metathesis Reaction
A
ccess to (–)-Aph
i
a
norphi
a
ne from
D
-
o
Tyrosine via
b
Ring-Closin
a
g
M
etathesi
o
s
Yang,a,b Bin Cheng,b Zhong Li,*a Hongbin Zhai*b
a
Shanghai Key Laboratory of Chemical Biology, Institute of Pesticides and Pharmaceuticals, School of Pharmacy,
East China University of Science and Technology, Shanghai 200237, P. R. of China
b
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. of China
E-mail: zhaih@mail.sioc.ac.cn
Received 15 July 2008
tion of bicycle 2. In turn, the formation of trisubstituted
alkene 2 would involve ring-closing metathesis (RCM) of
diene 3. The precursors 3 can be generated efficiently
from D-tyrosine as a chiral pool.
Abstract: We have developed an asymmetric route to (–)-aphanor-
phine from O-Me-D-tyrosine methyl ester hydrochloride salt, avail-
able from D-tyrosine in four steps. The tricyclic framework of (–)-
aphanorphine was assembled stereoselectively by intramolecular
Friedel–Crafts reaction of the corresponding bicyclic precursor,
which was in turn generated via ring-closing metathesis reaction.
Herein we wish to report an enantiocontrolled formal syn-
thesis of (–)-aphanorphine from commercially available
starting materials, which involves ring-closing metathesis
(RCM) as a key reaction. As shown in Scheme 2, the as-
sembly of (–)-aphanorphine (1) commenced from O-Me-
D-tyrosine methyl ester hydrochloride salt (4),7 available
from D-tyrosine in high overall yield (92%) within four
scalable steps including (i) esterification, (ii) Boc protec-
tion of the amino group, (iii) methylation of phenolic hy-
droxyl group, and (iv) removal of the Boc group.
Tosylation of 4 (TsCl, Et3N, CH2Cl2)5e followed by alkyl-
ation (methallyl chloride, K2CO3, n-Bu4NI, DMF) cleanly
afforded tertiary sulfonamide 5 in 84% yield (2 steps). Re-
duction of methyl ester 5 with LiAlH4 in THF at 0 °C pro-
duced primary alcohol 6 in excellent yield (92%). Swern
oxidation8 of 6 followed by Wittig reaction (MePPh3Br,
KHMDS, THF) gave 1,6-diene 3 in 94% combined yield
over the two steps, which set the stage for RCM reaction.
Upon treatment with Grubbs second-generation catalyst9
(7, 7.6 mol%) in CH2Cl2 at reflux for 7 hours, diene 3 (16
mM) was smoothly converted in 86% yield to the 2,5-di-
hydropyrrole derivative 2, in which ring C was in place.
Similar to the cases that we reported previously, the for-
mation of ring B could potentially be achieved by Friedel–
Crafts alkylative cyclization onto the phenyl ring.5a,b,e Ex-
posure of 2 with AlCl3 in CH2Cl2 at room temperature for
24 hours effected the desirable intramolecular Friedel–
Crafts reaction. Consequently, sulfonamide 810 was stere-
Key words: aphanorphine, asymmetric synthesis, ring-closing
metathesis reaction, tyrosine
(–)-Aphanorphine (1, Scheme 1), a 3-benzazepine alka-
loid with a quaternary benzylic stereocenter isolated from
the freshwater blue-green alga Aphanizomenon
flosaquae,1 bears close structural similarity to (–)-
pentazocine2 and to natural analgesics such as morphine3
and eptazocine4 as well. Due to its potential pharmacolog-
ical activities, the synthesis of aphanorphine [in all forms:
(–)-, (+)-, and ( )-] has received considerable attention
from both our group5 and other laboratories.6 Starting
with highly symmetric 1,4-disubstituted (rather than 1,3-
disubstituted or 1,2,4-trisubstituted) benzenes as the
source of ring A, our previous syntheses featured (i) for-
mation of ring B via a Friedel–Crafts alkylative cycliza-
tion of tertiary alcohols5a–5d or a gem-disubstituted olefin5e
and (ii) stereospecific introduction5 of the benzylic qua-
ternary carbon center that was concomitantly realized.
The present retrosynthetic analysis is outlined in
Scheme 1. The tricyclic framework of 1 could be accessed
stereoselectively by intramolecular Friedel–Crafts reac-
Ts
H
N
Me Friedel–Crafts
13
oselectively formed in 89% yield. The 1H and C NMR
N
HO
spectroscopic data of 8 were in accord with those recorded
in literature.5a,b Thus, a new chiral-pool-based formal
enantiospecific synthesis of (–)-aphanorphine (1) has
been completed, since 8 could be further transformed to 1
in three known steps (desulfonylation, N-methylation,
and 8-O-demethylation).5a
MeO
Me
(–)-aphanorphine (1)
2
Ts
N
NH2
CO2H
RCM
HO
MeO
In summary, we have developed an efficient asymmetric
route to (–)-aphanorphine from O-Me-D-tyrosine methyl
ester hydrochloride salt, available from D-tyrosine in four
steps. The tricyclic framework of (–)-aphanorphine was
assembled stereoselectively by intramolecular Friedel–
Crafts reaction of the corresponding bicyclic precursor,
which was in turn generated via RCM reaction.
3
D-Tyr
Scheme 1
SYNLETT 2008, No. 18, pp 2821–2822
1
4
.1
1
.2
0
0
8
Advanced online publication: 15.10.2008
DOI: 10.1055/s-0028-1083498; Art ID: U07508ST
© Georg Thieme Verlag Stuttgart · New York

2822
X. Yang et al.
LETTER
N.; Henry, S. S.; Meyers, A. I. J. Org. Chem. 1995, 60,
Ts
N
PMB
NH2⋅HCl a) TsCl, Et3N, CH2Cl2, 93%
1265. (c) Hallinan, K. O.; Honda, T. Tetrahedron 1995, 51,
12211. (d) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry
1995, 6, 893. (e) Meyers, A. I.; Schmidt, W.; Santiago, B.
Heterocycles 1995, 40, 525. (f) Node, M.; Imazato, H.;
Kurosaki, R.; Kawano, Y.; Inoue, T.; Nishide, K.; Fuji, K.
Heterocycles 1996, 42, 811. (g) Shiotani, S.; Okada, H.;
Nakamata, K.; Yamamoto, T.; Sekino, F. Heterocycles
1996, 43, 1031. (h) Shimizu, M.; Kamikubo, T.; Ogasawara,
K. Heterocycles 1997, 46, 21. (i) Fadel, A.; Arzel, P.
Tetrahedron: Asymmetry 1997, 8, 371. (j) Tamura, O.;
Yanagimachi, T.; Kobayashi, T.; Ishibashi, H. Org. Lett.
2001, 3, 2427. (k) Tanaka, K.; Taniguchi, T.; Ogasawara, K.
Tetrahedron Lett. 2001, 42, 1049. (l) ElAzab, A. S.;
Taniguchi, T.; Ogasawara, K. Heterocycles 2002, 56, 39.
(m) Tamura, O.; Yanagimachi, T.; Ishibashi, H.
PMB
b) CH2=C(Me)CH2Cl
K2CO3, TBAI, DMF, 90%
CO2Me
CO2Me
4
5
Ts
Ts
a) Swern
b) Wittig
LAH
THF, 0 °C
PMB
HO
N
PMB
N
94%
92%
3
6
Ts
AlCl3
CH2Cl2
Grubbs II (7)
CH2Cl2, ∆
N
MeO
89%
86%
Tetrahedron: Asymmetry 2003, 14, 3033. (n) Taylor, S. K.;
Ivanovic, M.; Simons, L. J.; Davis, M. M. Tetrahedron:
Asymmetry 2003, 14, 743. (o) Kita, Y.; Futamura, J.; Ohba,
Y.; Sawama, Y.; Ganesh, J. K.; Fujioka, H. J. Org. Chem.
2003, 68, 5917. (p) Bower, J. F.; Szeto, P.; Gallagher, T.
Chem. Commun. 2005, 5793. (q) Katoh, M.; Inoue, H.;
Suzuki, A.; Honda, T. Synlett 2005, 2820. (r) Li, M.; Zhou,
P.; Roth, H. F. Synthesis 2007, 55. (s) Bower, J. F.; Szeto,
P.; Gallagher, T. Org. Biomol. Chem. 2007, 5, 143.
(t) Grainger, R. S.; Welsh, E. J. Angew. Chem. Int. Ed. 2007,
46, 5377. For the synthesis of ( )-aphanorphine, see:
(u) Honda, T.; Yamamoto, A.; Cui, Y.; Tsubuki, M. J. Chem.
Soc., Perkin Trans. 1 1992, 531. (v) Fuchs, J. R.; Funk,
R. L. Org. Lett. 2001, 3, 3923 . For the synthesis of (+)-
aphanorphine, see: (w) Takano, S.; Inomata, K.; Sato, T.;
Ogasawara, K. J. Chem. Soc., Chem. Commun. 1989, 1591.
(7) For the synthesis of O-Me-D-tyrosine methyl ester
hydrochloride salt(4), see: Hulme, A. N.; Rosser, E. M. Org.
Lett. 2002, 4, 265.
2
H
MesN
Cl
NMes
3 steps
(ref. 5a)
Ts
N
1
Ru
PCy3
MeO
Cl
Ph
8
7
Scheme 2
Acknowledgment
Financial support was provided by the grants from NSFC
(90713007; 20772141; 20625204; 20632030) and MOST_863
(2006AA09Z405;2006AA09Z446).
(8) For Swern oxidation, see: Anthory, J. M.; Debra, S. B.;
Daniel, S. J. Org. Chem. 1979, 44, 4148.
(9) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
References and Notes
(1) Gulavita, N.; Hori, A.; Shimizu, Y.; Laszlo, P.; Clardy, J.
Tetrahedron Lett. 1988, 29, 4381.
(2) Palmer, D. C.; Strauss, M. J. Chem. Rev. 1977, 77, 1.
(3) For a recent review, see: Zezula, J.; Hudlicky, T. Synlett
2005, 388.
(4) Taylor, S. K.; Ivanovic, M.; Simons, L. J.; Davis, M. M.
Tetrahedron: Asymmetry 2003, 14, 743; and references cited
therein.
(5) (a) Zhai, H.; Luo, S.; Ye, C.; Ma, Y. J. Org. Chem. 2003, 68,
8268. (b) Hu, H.; Zhai, H. Synlett 2003, 2129. (c) Ma, Z.;
Zhai, H. Synlett 2007, 161. (d) Ma, Z.; Hu, H.; Xiong, W.;
Zhai, H. Tetrahedron 2007, 63, 7523. (e) Yang, X.; Li, Z.;
Zhai, H. Org. Lett. 2008, 10, 2457.
(10) Compound 8: white solid; mp 136–138 °C (Lit.5a 137–138
°C); [a]D25 –16.9 (c 0.89, CHCl3) {Lit.5a [a]D20 –13.4 (c 0.97,
CHCl3); Lit.5b [a]D20 –14.3 (c 0.93, CHCl3)}. 1H NMR (300
MHz, CDCl3): d = 1.41 (s, 3 H), 1.41–1.49 (m, 1 H), 1.79 (d,
J = 11.1 Hz, 1 H), 2.43 (s, 3 H), 2.91–3.16 (m, 2 H), 3.03 (d,
J = 8.4 Hz, 1 H), 3.41 (d, J = 8.7 Hz, 1 H), 3.80 (s, 3 H), 4.40
(t, J = 3.3 Hz, 1 H), 6.74 (dd, J = 8.4, 2.4 Hz, 1 H), 6.79 (d,
J = 2.7 Hz, 1 H), 6.99 (d, J = 8.1 Hz, 1 H), 7.30 (d, J = 8.1
Hz, 2 H), 7.71 (d, J = 8.1 Hz, 2 H). 13C NMR (75.47 MHz,
CDCl3): d = 20.8, 21.6, 38.3, 41.8, 42.4, 55.4, 58.0, 63.1,
110.3, 111.9, 125.5, 127.3, 129.8, 130.6, 135.9, 143.4,
145.1, 158.2. ESI-MS: m/z = 380 [M + Na], 358 [M + H].
ESI-HRMS: m/z calcd for C20H23NO3S + H: 358.1477;
found: 358.1473. ESI-HRMS: m/z calcd for C22H23NO3S +
Na: 380.1296; found: 380.1308.
(6) For synthesis of (–)-aphanorphine, see: (a) Takano, S.;
Inomata, K.; Sato, T.; Takahashi, M.; Ogasawara, K.
J. Chem. Soc., Chem. Commun. 1990, 290. (b) Hulme, A.
Synlett 2008, No. 18, 2821–2822 © Thieme Stuttgart · New York

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