An Efficient Synthesis of (1R,4S)-1-Methyl-8-methoxy-3-(4-toluenesulfonyl)- 2,3,4,5-tetrahydro-1,4-methano-3-benzazepine. A Formal Synthesis of (-)-Aphanorphine

Article abstract of DOI:10.1055/s-2003-42102

We report a highly efficient synthesis of (1R,4S)-1-methyl-8-methoxy-3-(4- toluenesulfonyl)-2,3,4,5-tetrahydro-1,4-methano-3-benzazepine in six steps from 5. The present work constitutes a new formal synthesis of marine alkaloid (-)-aphanorphine.

Full text of DOI:10.1055/s-2003-42102

LETTER
2129
An Efficient Synthesis of (1R,4S)-1-Methyl-8-methoxy-3-(4-toluenesulfonyl)-
2,3,4,5-tetrahydro-1,4-methano-3-benzazepine. A Formal Synthesis of (–)-
Aphanorphine
A
F
ormal Synthesi
a
s
of (–)-Ap
n
hanorphine wei Hu, Hongbin Zhai*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China
E-mail: zhaih@mail.sioc.ac.cn
Received 23 August 2003
H
H
Abstract: We report a highly efficient synthesis of (1R,4S)-1-meth-
3
N
A
B
1
Me
yl-8-methoxy-3-(4-toluenesulfonyl)-2,3,4,5-tetrahydro-1,4-metha-
no-3-benzazepine in six steps from 5. The present work constitutes
a new formal synthesis of marine alkaloid (–)-aphanorphine.
8
N
Ts
12
HO
C
MeO
Ref.4l,4q
Me
Me
1: (-)-aphanorphine
2
Key words: aphanorphine, benzazepine, Friedel–Crafts alkylation,
marine alkaloid, synthesis
Ts
H
H
HO2C
N
N
(–)-Aphanorphine (1, Scheme 1) was isolated by Shimizu
and Clardy in 1988 from the freshwater blue-green alga
Aphanizomenon flos-aquae.1 This tricyclic 3-benzazepine
derivative possesses a benzylic quaternary carbon and is
structurally analogous to another two naturally occurring
alkaloids, morphine2 and eptazocine.3 The presence of a
methylene bridge (C10) between stereogenic carbon cen-
ters C1 and C4 endows 1 with a rigid conformation. Due
to its structural novelty and potential analgesic property,
the syntheses of (–)-, (+)-, or ( )-aphanorphine, or the key
intermediates have stimulated considerable interest from
the synthetic community.4 In the majority of the previous
syntheses ring B was constructed prior to ring C; however,
there were three exceptions. Funk4n proved that rings B
and C could be simultaneously generated from a sub-
stituted e-lactam by an intramolecular mesylate displace-
ment. Ishibashi’s strategy4m involved the final formation
of ring B via an aryl radical cyclization. Recently, our
laboratory4q disclosed a formal asymmetric synthesis of 1
featuring the formation of ring B at the final stage by
Lewis acid-promoted Friedel–Crafts alkylative cycli-
zation of 2-arylmethyl-4-methyl-4-pyrrolidinol (corre-
sponding to 3 in Scheme 1), which was derived by a facile
reaction sequence including asymmetric Roush methally-
lation and intramolecular endo epoxy displacement, etc.4q
MeO
Me
OH
HO
4
3
Scheme 1
adversely affected the overall synthetic efficiency in
terms of atom economy and stereoselectivity.
Thus we embarked on a novel expeditious synthesis of 2,
an advanced intermediate for aphanorphine synthesis, as
outlined in Scheme 2. By an established four-step process
(esterification, N-tosylation, O-silylation, and reduction),
(2S,4R)-4-hydroxyproline (4) could be efficaciously con-
verted to fully protected alcohol 5 in 72% yield.5 Swern
oxidation6 of 5 led to an aldehyde, which, without tedious
purification, was directly alkylated with 4-methoxyphe-
nylmagnesium bromide7 to provide the chain extension
products 6 as a pair of diastereomeric alcohols (91%,
dr = 3:2). Being equally useful, the two isomers were not
separated. Upon treatment of 6 with triethylsilane8 in the
presence of BF3·OEt2 in dichloromethane at 0 °C, PMB-
substituted pyrrolidinol 7 was attainable in high yield
(95%), as a result of benzylic reductive dehydroxylation
with concomitant O-desilylation. Under typical Swern
conditions,6 alcohol 7 was oxidized to afford pyrrolidino-
ne 8 in 88% yield. Nucleophilic addition9 of methylmag-
nesium iodide to ketone 8 in diethyl ether produced the
tertiary alcohols 3a/3b (apparently equally utilizable,
80%). The diastereomeric ratio was measured by 1H NMR
integral analysis to be 4:1, presumably favoring 3a (ac-
cording to steric hindrance considerations). By following
the same protocol4q developed in this laboratory previous-
ly, AlCl3-promoted Friedel–Crafts alkylative cyclization
of alcohols 3a/3b was effected to furnish the desired inter-
mediate 210 as colorless needles (64%). The sample ob-
tained from the abovementioned sequence was
determined by HPLC analysis (Chiralpak AD column
(250 × 4.6 mm), UV detector 254 nm, eluent hexanes/2-
(2S,4R)-4-Hydroxyproline (4) was envisaged as an appro-
priate starting point to secure the key intermediates for
aphanorphine synthesis, such as 3 and eventually 2, as de-
lineated in Scheme 1. If successful, the current ‘chiral
pool’ strategy would constitute a new formal synthesis of
(–)-aphanorphine. Although we were not the first to ‘ex-
tract’ the chiron from 4 in synthesizing 1, the previous
approach4m made use of an initial enolate benzylation of a
derivative of 4 and decarboxylation at a later stage, which
SYNLETT 2003, No. 14, pp 2129–2130
0
6
.1
1
.2
0
0
3
Advanced online publication: 29.10.2003
DOI: 10.1055/s-2003-42102; Art ID: U16903ST
© Georg Thieme Verlag Stuttgart · New York

2130
H. Hu, H. Zhai
LETTER
PMP
H
PMP
H
References
Ts
Ts
Ts
a, b
c
N
N
N
4 steps
HO
HO
(1) Gulavita, N.; Hori, A.; Shimizu, Y.; Laszlo, P.; Clardy, J.
Tetrahedron Lett. 1988, 29, 4381.
4
91%
OTBS
95%
72%5
(2) Palmer, D. C.; Strauss, M. J. Chem. Rev. 1977, 77, 1.
(3) Shiotani, S.; Kometani, T.; Mitsuhashi, K.; Nozawa, T.;
Kurobe, A.; Fitsukaichi, O. J. Med. Chem. 1976, 19, 803.
(4) (a) Takano, S.; Inomata, K.; Sato, T.; Ogasawara, K. J.
Chem. Soc., Chem. Commun. 1989, 1591. (b) Takano, S.;
Inomata, K.; Sato, T.; Takahashi, M.; Ogasawara, K. J.
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Perkin Trans. 1 1992, 531. (d) Hume, A. N.; Henry, S. S.;
Meyers, A. I. J. Org. Chem. 1995, 60, 1265. (e) Meyers, A.
I.; Schmidt, W.; Santiago, B. Heterocycles 1995, 40, 525.
(f) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1995, 6,
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12211. (h) Node, M.; Imazato, H.; Kurosaki, R.; Kawano,
Y.; Inoue, T.; Nishide, K. Heterocycles 1996, 42, 811.
(i) Shiotani, S.; Okada, H.; Nakamata, K.; Yamamoto, T.;
Sekino, F. Heterocycles 1996, 43, 1031. (j) Fadel, A.;
Arzel, P. Tetrahedron: Asymmetry 1997, 8, 283. (k) Fadel,
A.; Arzel, P. Tetrahedron: Asymmetry 1997, 8, 371.
(l) Shimizu, M.; Kamikubo, T.; Ogasawara, K. Heterocycles
1997, 46, 21. (m) Tamura, O.; Yangimachi, T.; Kobayashi,
T.; Ishibashi, H. Org. Lett. 2001, 3, 2427. (n) Fuchs, J. R.;
Funk, R. L. Org. Lett. 2001, 3, 3923. (o) Tanaka, K.;
Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42,
1049. (p) El Azab, A. S.; Taniguchi, T.; Ogasawara, K.
Heterocycles 2002, 56, 39. (q) Zhai, H.; Luo, S.; Ye, C.; Ma,
Y. J. Org. Chem. 2003, 68, ASAP; MS No. JO0348726.
(5) For the preparation of compound 5, see: (a) Han, G.;
LaPorte, M. G.; Folmer, J. J.; Werner, K. M.; Weinreb, S. M.
J. Org. Chem. 2000, 65, 6293. (b) Westwood, N. B.;
Walker, R. T. Tetrahedron 1998, 54, 13391.
OTBS
OH
Ts
5
6
7
88%
d
PMP
H
Ts
PMP
H
H
N
N
e
N
Ts
f
R1
80%
MeO
up to 64%
R2
O
Me
3a: R1 = Me, R2 = OH
3b: R1 = OH, R2 = Me
2
8
Scheme 2 Reagents and conditions: a) Swern oxidation; b) PMP–
MgBr, THF, –78 °C; 0 °C; c) Et3SiH, BF3·OEt2, DCM, 0 °C; d)
Swern oxidation; e) MeMgI, Et2O, –78 °C; –25 °C; f) AlCl3, DCM,
r.t. PMP = p-methoxyphenyl.
propanol (4:1), flow rate 0.7 mL/min) to be in high enan-
tiopurity (99.8% ee), indicating that essentially no
epimerization ever took place. The [a]D20 of 2 was found
to be –14.2 (c 0.93, CHCl3) {lit.4q [a]D –13.4 (c 0.969,
20
CHCl3)}. Other spectroscopic data of 2 were also in
agreement with those disclosed in the literature.4q
In summary, we have accomplished an efficient synthesis
of (1R,4S)-1-methyl-8-methoxy-3-(4-toluenesulfonyl)-
2,3,4,5-tetrahydro-1,4-methano-3-benzazepine (2) in six
steps from a known building block 5. The present work
can be considered as a new formal synthesis of marine
alkaloid (–)-aphanorphine, since 2 could further be ma-
nipulated to give 1 in three steps (desulfurization,4q N-me-
thylation,4q and 8-O-demethylation4l). The prominent
features of our synthesis include (i) preserving both C2
chirality and C6 atom of 4 (cf Ishibashi’s strategy4m), (ii)
concomitant benzylic reductive dehydroxylation and O-
desilylation in the formation of 7, and (iii) simultaneous
construction of ring B and the quaternary carbon center
(C1) in 2 via an intramolecular Friedel–Crafts reaction.
Finally, it is noteworthy that both epimers of 3 and of 6
were equivalently useful for their subsequent transforma-
tions, respectively.
(6) For Swern oxidation, see: Anthory, J. M.; Debra, S. B.;
Daniel, S. J. Org. Chem. 1979, 44, 4148.
(7) Steele, M.; Watkinson, M.; Whiting, A. J. Chem. Soc.,
Perkin Trans. 1 2001, 588.
(8) For reduction with triethylsilane, see: (a) Orfanopoulos, M.;
Smonou, I. Synth. Commun. 1988, 18, 833. (b) Smonou, I.;
Orfanopoulos, M. Tetrahedron Lett. 1988, 29, 5793.
(9) For methylation of similar pyrrolidinones, see: (a) Blanco,
M.-J.; Sardina, F. J. J. Org. Chem. 1998, 63, 3411.
(b) Moulines, J.; Bats, J.-P.; Hautefaye, P.; Nuhrich, A.;
Lamidey, A.-M. Tetrahedron Lett. 1993, 34, 2315.
(10) Compound 2, a colorless solid: mp 137–138 °C; 99.8% ee;
[a]D20 –13.4 (c 0.969, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 1.41 (s, 3 H, CH3), 1.46 (ddd, J = 11.1, 6.3, 1.5 Hz, 1 H,
0.5CH2), 1.79 (d, J = 11.1 Hz, 1 H, 0.5CH2), 2.43 (s, 3 H,
benzylic CH3), 2.93 (dd, J = 16.6, 2.8 Hz, 1 H, 0.5 CH2),
3.02 (d, J = 8.7 Hz, 1 H, 0.5 CH2), 3.12 (d, J = 16.8 Hz, 1 H,
0.5 CH2), 3.40 (dd, J = 8.6, 1.4 Hz, 1 H, 0.5 CH2), 3.79 (s, 3
H, OCH3), 4.39–4.45 (m, 1 H. NCH), 6.72 (dd, J = 8.6, 2.8
Hz, 1 H, CH), 6.78 (d, J = 2.1 Hz, 1 H, CH), 6.98 (d, J = 8.1
Hz, 1 H, CH), 7.28 (d, J = 8.1 Hz, 2 H, 2 CH), 7.69 (d,
J = 8.4 Hz, 2 H, 2 CH). 13C NMR (75 MHz, CDCl3): d =
20.7, 21.5, 38.2, 41.7, 42.3, 55.3, 57.8, 62.9, 110.0, 111.7,
125.2, 127.1, 129.6, 130.4, 135.6, 143.1, 144.9, 157.9. MS
(EI): 357 (18) [M+], 202 (15), 173 (100). Anal. Calcd for
C20H23NO3S: C, 67.20; H, 6.49; N, 3.92. Found: C, 67.18; H,
6.55; N, 3.80.
Acknowledgment
We thank Chinese Academy of Sciences (‘Hundreds of Talent’ Pro-
gram), STCSM (‘Venus’ Program), and National Natural Science
Foundation of China for financial support.
Synlett 2003, No. 14, 2129–2130 © Thieme Stuttgart · New York