Synthesis of (±)-aphanorphine: a new approach to tricyclic 3-benzazepine scaffold using two radical C-C bond-forming reactions

Article abstract of DOI:10.1016/j.tetlet.2008.05.058

An expeditious approach to (±)-aphanorphine has been established using readily available starting materials. The present synthesis relies on the direct assembly between N-methylpyrrolidone (NMP) and 2-bromoanisaldehyde, which takes place through Et₃B/air-mediated transformation of the α-nitrogen-substituted sp³C-H bond, and features a new design concept for the synthesis of the tricyclic 3-benzazepine skeleton.

Full text of DOI:10.1016/j.tetlet.2008.05.058

Tetrahedron Letters 49 (2008) 4473–4475
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of ( )-aphanorphine: a new approach to tricyclic 3-benzazepine
scaffold using two radical C–C bond-forming reactions
a
b
b
a,
Takehiko Yoshimitsu a, , Chie Atsumi , Emiko Iimori , Hiroto Nagaoka , Tetsuaki Tanaka
*
*
a Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
b Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An expeditious approach to ( )-aphanorphine has been established using readily available starting mate-
Received 21 April 2008
Revised 10 May 2008
Accepted 13 May 2008
Available online 16 May 2008
rials. The present synthesis relies on the direct assembly between N-methylpyrrolidone (NMP) and
2-bromoanisaldehyde, which takes place through Et3B/air-mediated transformation of the
a-nitrogen-
substituted sp3C–H bond, and features a new design concept for the synthesis of the tricyclic 3-benzaze-
pine skeleton.
Ó 2008 Elsevier Ltd. All rights reserved.
(ꢀ)-Aphanorphine (1), a unique tricyclic 3-benzazepine alkaloid
isolated from the freshwater blue-green alga Aphanizomenon flos-
aquae, has attracted considerable attention over the past two dec-
ades because of the biological interest stemming from its structural
similarity to benzomorphane analgesics such as pentazocine (Fig.
1).1 Accordingly, many synthetic approaches to this natural prod-
uct have appeared in the literature, showing various concepts for
the construction of the tricyclic 3-benzazepine skeleton.2
cyclization of alkenylated pyrrolidinone scaffolds, suggested the
relevance of our strategic interpretations.
We describe here a new concise approach to ( )-aphanorphine
(1) that features two strategic radical C–C bond-forming reactions
on NMP, involving sp3C–H hydroxyalkylation and Bu3SnH-medi-
ated cyclization, the latter of which has been employed as a key
bond-forming reaction in Gallagher’s synthesis.2v,z
Our synthesis started with readily available NMP (5), employing
radical sp3C–H bond transformation chemistry (Scheme 2).5–7
Thus, lactam 5 was directly hydroxybenzylated with 2-bromoanis-
aldehyde (4)8 using Et3B/air9 at room temperature to afford desired
compound 3a/b as an inseparable diastereomixture, slightly favor-
ing the production of erythro-type adduct 3a, along with regio-
isomer 3c in 64% combined yield (3a:3b:3c = 5:3:1) (Fig. 2).10
The hydroxyalkylation took place predominantly at the methylene
position alpha to the nitrogen atom, thereby enabling the direct
installation of the arylmethyl motif at the 5-position of NMP (5).
The benzylic hydroxyl group of each of compounds 3a/b was
easily removed by treatment with Et3SiH in the presence of
BF3ꢁOEt2 to provide 5-benzylated pyrrolidone 6 in 94% yield.
Although the methylenation of compound 6, in an attempt to deli-
ver key 3-methylenepyrrolidone 2, was unfruitful under various
conditions,11 pyrrolidone 6 could eventually be converted in three
steps into pyrrolidone 2 via the following sequence: compound 6
was initially subjected to LiHMDS and then to diethyl carbonate
to effect ethoxycarbonylation, giving ester 7 in 85% yield. Reduc-
tion of ester 7 with NaBH4 in the presence of CaCl2 provided
alcohol 8 (95%), which, by subsequent dehydration reaction using
N,N0-dicyclohexylcarbodiimide (DCC) and CuI in refluxing chloro-
benzene, was efficiently transformed into olefin 2 (84%).12 Since
olefin 2 has already been utilized as an intermediate in Gallagher’s
The prospect that aphanorphine (1) serves as a potential lead
compound for the discovery of new analgesics has prompted us
to devise an expeditious route to this class of compounds, which,
hopefully, would be applicable to the synthesis of
a wide
range of tricyclic 3-benzazepine derivatives. In this context, we
envisaged that the Et3B/air-mediated hydroxyalkylation reaction
of N-methylpyrrolidone (NMP) with aldehyde 4, recently devised
in this laboratory,3,4 would provide 5-benzylated pyrrolidinone 3
that constitutes an ideal intermediate for aphanorphine (1) synthe-
sis (Scheme 1). Recent reports from the laboratories of Ishibashi2n,q
and Gallagher,2v,z who have shown that the quaternary stereocen-
ter of (ꢀ)-aphanorphine (1) could be constructed by the radical
HO
HO
NCH3
N
H
H
(-)-aphanorphine (1)
pentazocine
Figure 1.
* Corresponding authors. Tel.: +81 6 6879 8213; fax: +81 6 6879 8214 (T.Y.); tel.: +81 6 6879 8210; fax: +81 6 6879 8214 (T.T.).
E-mail addresses: yoshimit@phs.osaka-u.ac.jp (T. Yoshimitsu), t-tanaka@phs.osaka-u.ac.jp (T. Tanaka).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.058

4474
T. Yoshimitsu et al. / Tetrahedron Letters 49 (2008) 4473–4475
Br
OCH3
Br
OCH3
radical
O
OMe
cyclization
O
N
H3CO
O
N
O
HO
N
refs. 2v,z
NCH3
NCH3
CH3 OH
CH3
OH
3a
OH
Br
3b
3c
H
H
Br
2
3a:3b:3c = 5:3:1
radical sp3C-H
( })-1
hydroxyalkylation
Figure 2. Hydroxyalkylation products.
O
Et3B, air
H3CO
OCH3
tocol for the radical annulation reaction, 3-methylenepyrrolidone 2
was further converted into tricyclic lactam 9: a diluted solution of
pyrrolidone 2, Bu3SnH, and 1,10-azobis(cyclohexylcarbonitrile)
(ACCN)13 in toluene was heated at reflux for a short period (ca.
5 min) to yield annulated compound 9 (61%) accompanied by
isomerized internal alkene 10 (34%). The previously reported
two-step transformation process from this compound 9, involving
LAH reduction and BBr3-mediated demethylation, enabled us to ac-
cess final target molecule 1. The 1H NMR, 13C NMR, IR, and analyt-
ical data obtained for compounds 2, 9, and 1 were in full agreement
with those reported in the literature.14
In conclusion, we have established a new expeditious route to
( )-aphanorphine (1), which relies on the radical-based direct
assembly between N-methylpyrrolidone (NMP) (5) and 2-bromo-
anisaldehyde (4). The present synthesis provides a new concept
for the construction of the tricyclic 3-benzazepine skeleton from
readily available NMP, which would be applicable to the short syn-
theses of a diverse array of aphanorphine derivatives simply by
switching starting aldehydes. Further work along this line, which
would allow us to discover new potent analgesics, is avidly being
undertaken in this laboratory.
NCH3
H
O
N
Br
CH3
H
Br
OH
OHC
NMP (5)
3
4
Scheme 1. Bridgehead annulation approach to ( )-aphanorphine (1) using two
radical C–C bond-forming reactions.
O
Et3B, air
H3CO
NCH3
O
N
Br
OCH3
H
CH3
Br
OH
OHC
5
4
3a/3b
rt
57% (ds=5:3) + 3c 7%
.
BF3 OEt2
Et3SiH
ClCH2CH2Cl
reflux
94%
O
O
(EtO)2CO
LiHMDS
EtO2C
Br
H3CO
H3CO
NCH3
Acknowledgment
NCH3
THF
rt
H
H
This work was supported by a Grant-in-Aid [KAKENHI KIBAN
KENKYU (C) No. 19590006] from the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan.
Br
6
85%
7
MeOH
rt
95%
NaBH4
CaCl2
References and notes
O
1. Gulavita, N.; Hori, A.; Shimizu, Y.; Laszlo, P.; Clardy, J. Tetrahedron Lett. 1988, 29,
4381–4384.
O
HO
Br
H3CO
2. Total and formal syntheses: (a) Takano, S.; Inomata, K.; Sato, T.; Ogasawara, K.
J. Chem. Soc., Chem. Commun. 1989, 1591–1592; (b) Takano, S.; Inomata, K.;
Sato, T.; Takahashi, M.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1990, 290–
292; (c) Honda, T.; Yamamoto, A.; Cui, Y.; Tsubuki, M. J. Chem. Soc., Perkin Trans.
1 1992, 531–532; (d) Meyers, A. I.; Schmidt, W.; Santiago, B. Heterocycles 1995,
40, 525–529; (e) Hulme, A. N.; Henry, S. S.; Meyers, A. I. J. Org. Chem. 1995, 60,
1265–1270; (f) Hallinan, K. O.; Honda, T. Tetrahedron 1995, 51, 12211–12216;
(g) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1995, 6, 893–900; (h) Node, M.;
Imazato, H.; Kurosaki, R.; Kawano, Y.; Inoue, T.; Nishide, K.; Fuji, K. Heterocycles
1996, 42, 811–819; (i) Shiotani, S.; Okada, H.; Nakamata, K.; Yamamoto, T.;
Sekino, F. Heterocycles 1996, 43, 1031–1047; (j) Shimizu, M.; Kamikubo, T.;
Ogasawara, K. Heterocycles 1997, 46, 21–26; (k) Fadel, A.; Arzel, P. Tetrahedron:
Asymmetry 1997, 8, 283–291; (l) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry
1997, 8, 371–374; (m) Tanaka, K.; Taniguchi, T.; Ogasawara, K. Tetrahedron Lett.
2001, 42, 1049–1052; (n) Tamura, O.; Yanagimachi, T.; Kobayashi, T.; Ishibashi,
H. Org. Lett. 2001, 3, 2427–2429; (o) Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3,
3923–3925; (p) ElAzab, A. S.; Taniguchi, T.; Ogasawara, K. Heterocycles 2002,
56, 39–43; (q) Tamura, O.; Yanagimachi, T.; Ishibashi, H. Tetrahedron:
Asymmetry 2003, 14, 3033–3041; (r) Zhai, H.; Luo, S.; Ye, C.; Ma, Y. J. Org.
Chem. 2003, 68, 8268–8271; (s) Taylor, S. K.; Ivanovic, M.; Simons, L. J.; Davis,
M. M. Tetrahedron: Asymmetry 2003, 14, 743–747; (t) Kita, Y.; Futamura, J.;
Ohba, Y.; Sawama, Y.; Ganesh, J. K.; Fujioka, H. J. Org. Chem. 2003, 68, 5917–
5924; (u) Hu, H.; Zhai, H. Synlett 2003, 2129–2130; (v) Bower, J. F.; Szeto, P.;
Gallagher, T. Chem. Commun. 2005, 5793–5795; (w) Katoh, M.; Inoue, H.;
Suzuki, A.; Honda, T. Synlett 2005, 2820–2822; (x) Li, M.; Zhou, P.; Roth, H. F.
Synthesis 2007, 55–60; (y) Ma, Z.; Zhai, H. Synlett 2007, 161–163; (z) Bower, J.
F.; Szeto, P.; Gallagher, T. Org. Biomol. Chem. 2007, 5, 143–150; (0a) Ma, Z.; Hu,
H.; Xiong, W.; Zhai, H. Tetrahedron 2007, 63, 7523–7531; (0b) Grainger, R. S.;
Welsh, E. J. Angew. Chem., Int. Ed. 2007, 46, 5377–5380.
H3CO
DCC, CuI
NCH3
NCH3
PhCl
reflux
84%
H
H
Br
2
8
Bu3SnH
ACCN
toluene
reflux
O
HO
1) LAH
2) BBr3
H3CO
NCH3
NCH3
H
( })-aphanorphine (1)
H
O
61%
9
38% in 2 steps
from 9
H3CO
NCH3
H
34%
10
Scheme 2. Total synthesis of ( )-aphanorphine (1).
3. (a) Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Am. Chem. Soc. 2005, 127, 11610–
11611; For reviews, see: (b) Yoshimitsu, T.; Nagaoka, H.; Tanaka, T. J. Synth. Org.
Chem. Jpn. 2007, 65, 665–675; (c) Yoshimitsu, T. Farumashia 2007, 43, 219–223.
total synthesis, this constitutes the formal synthesis of ( )-apha-
norphine (1).2v,z Following a slight modification of Gallagher’s pro-

T. Yoshimitsu et al. / Tetrahedron Letters 49 (2008) 4473–4475
4475
4. Radical sp3 C–H carbamoylation: Yoshimitsu, T.; Matsuda, K.; Nagaoka, H.;
Tsukamoto, K.; Tanaka, T. Org. Lett. 2007, 9, 5115–5118.
14. Spectral data of compound 3a (major isomer): colorless needles of mp 156–
157 °C (EtOAc–CH2Cl2); IR (neat)
3299, 2931, 1662 cmꢀ1 1H NMR (300 MHz,
m
;
5. Reviews of alpha-aminoalkyl radical chemistry: (a) Aurrecoechea, J. M.; Suero,
R. ARKIVOC 2004, 10–35; (b) Hart, D. In Radicals in Organic Synthesis; Renaud, P.,
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 279–302; (c)
Renaud, P.; Giraud, L. Synthesis 1996, 913–926.
6. Pertinent reviews of alpha-functionalization of nitrogen compounds, see: (a)
Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069–1084; (b) Griesbeck, A. G.;
Hoffmann, N.; Warzecha, K.-d. Acc. Chem. Res. 2007, 40, 128–140; (c) Hoffmann,
N.; Bertrand, S.; Marinkovic, S.; Pesch, J. Pure Appl. Chem. 2006, 78, 2227–2246;
(d) Ishii, Y.; Sakaguchi, S. Bull. Chem. Soc. Jpn. 2004, 77, 909–920; (e) Beak, P.;
Johnson, T. A.; Kim, D. D.; Lim, S. H. Top. Organomet. Chem. 2003, 5, 139; (f)
Doye, S. Angew. Chem., Int. Ed. 2001, 40, 3351.
CDCl3) d 1.60–1.71 (m, 1H), 2.02–2.12 (m, 1H), 2.22 (ddd, 1H, J = 16.8, 10.4,
4.1 Hz), 2.52 (dt, 1H, J = 15.7, 9.5 Hz), 3.00 (s, 3H), 3.80 (s, 3H), 3.77–3.87 (m,
1H), 5.30 (s, 1H), 5.35 (d, 1H, J = 1.7 Hz), 6.91 (dd, 1H, J = 8.6, 2.5 Hz), 7.08 (d,
1H, J = 2.5 Hz), 7.56 (d, 1H, J = 8.6 Hz); 13C NMR (75 MHz, CDCl3) d 17.0, 28.0,
30.8, 55.5, 63.7, 69.5, 113.5, 117.9, 121.5, 128.9, 131.2, 159.5, 176.5; MS m/z:
314 (MH+); HRMS (FAB) calcd for C13H17O3N79Br (MH+): 314.0392, found:
314.0384. m/z: 316 (MH+); HRMS (FAB) calcd for C13H17O3N81Br (MH+):
316.0372, found: 316.0369. Compound 6: colorless solid of mp 77–78 °C; IR
(neat) m ;
2927, 1662 cmꢀ1 1H NMR (300 MHz, CDCl3) d1.73–1.82 (m, 1H), 1.84–
2.05 (m, 1H), 2.21–2.46 (m, 2H), 2.57 (dd, 1H, J = 13.5, 9.2 Hz), 2.89 (s, 3H), 3.24
(dd, 1H, J = 13.4, 4.3 Hz), 3.79 (s, 3H), 3.75–3.89 (m, 1H), 6.82 (dd, 1H, J = 8.4,
2.6 Hz), 7.09 (d, 1H, J = 8.4 Hz), 7.13 (d, 1H, J = 2.6 Hz); 13C NMR (75 MHz,
CDCl3) d 23.2, 28.0, 29.5, 38.2, 55.4, 59.8, 113.6, 118.1, 124.7, 128.3, 131.6,
158.9, 174.9; MS m/z: 298 (MH+); HRMS (FAB) calcd for C13H17O2N79Br (MH+)
298.0443, found: 298.0421. m/z: 300 (MH+); HRMS (FAB) calcd for
7. For recent exmaples of C–C bond formations via alpha-nitrogen-substituted sp3
C–H transformation, see: (a) Hartwig, J. F.; Seth, B. H. J. Am. Chem. Soc. 2007,
129, 6690; (b) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103,
8928; (c) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen, C.-y. J.
Am. Chem. Soc. 2006, 128, 3538–3539; (d) Pastine, S. J.; Gribkov, D. V.; Sames, D.
Am. Chem. Soc. 2006, 128, 14220–14221; (e) Catino, A. J.; Nichols, J. M.; Nettles,
B. J.; Doyle, M. P. J. Am. Chem. Soc. 2006, 128, 5648–5649; (f) Matsuo, J.; Tanaki,
Y.; Ishibashi, H. Org. Lett. 2006, 8, 4371–4374; (g) Li, Z.; Li, C.-J. J. Am. Chem. Soc.
2005, 127, 3672–3673; (h) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 15, 3173–3176;
(i) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810–11811; (j) Li, Z.; Li, C.-J. Org.
Lett. 2004, 6, 4997–4999; (k) DeBoef, B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc.
2004, 126, 6556–6557; (l) Murahashi, S.-i.; Komiya, N.; Terai, H.; Nakase, T. J.
Am. Chem. Soc. 2003, 125, 15312–15313; (m) Davies, H. M. L.; Venkataramani,
C.; Hansen, T.; Hopper, D. W. J. Am. Chem. Soc. 2003, 125, 6462–6468; (n)
Davies, H. M. L.; Venkataramani, C. Angew. Chem., Int. Ed. 2002, 41, 2197–2199;
(o) Suga, S.; Suzuki, S.; Yoshida, J. J. Am. Chem. Soc. 2002, 124, 30–31; (p)
Yoshida, J.; Suga, S.; Suzuki, S.; Kinomura, N.; Yamamoto, A.; Fujiwara, K. J. Am.
Chem. Soc. 1999, 121, 9546–9549; (q) Chatani, N.; Asaumi, T.; Yorimitsu, S.;
Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001, 123, 10935–10941; (r)
Chatani, N.; Fukuyama, T.; Tatamidani, H.; Kakiuchi, F.; Murai, S. J. Org. Chem.
2000, 65, 4039–4047; (s) Marinkovic, S.; Hoffmann, N. Chem. Commun. 2001,
1576–1578.
C
13H17O2N81Br (MH+) 300.0423, found: 300.0411. Compound
diastereomixture): pale yellow oil; IR (neat)
7
(ca. 1:1
m
2927, 1738, 1693 cmꢀ1 1H
;
NMR (300 MHz CDCl3) d 1.28 (t, 1.5H, J = 7.2 Hz), 1.33 (t, 1.5H, J = 7.2 Hz), 2.00–
2.22 (m, 1.5H), 2.36 (dt, 0.5H, J = 13.2, 8.1 Hz), 2.57 (dd, 0.5H,J = 13.6, 9.0 Hz),
2.68 (dd, 0.5H, J = 13.3, 10.2 Hz), 2.92 (s, 1.5H), 2.94 (s, 1.5H), 3.25 (dd, 0.5H,
J = 13.6, 4.4 Hz), 3.35–3.43 (m, 1.5H), 3.79 (s, 3H), 3.80–3.95 (m, 1H), 4.16–4.30
(m, 2H), 6.80–6.84 (m, 1H), 7.06–7.27 (m, 2H); MS m/z: 370 (MH+); HRMS
(FAB) calcd for C16H21O4N79Br(MH+): 370.0654, found: 370.0631, m/z: 372
(MH+); HRMS (FAB) calcd for C16H21O4N81Br (MH+): 372.0634, found:
372.0612. Compound 8 (ca. 1:1 diastereomixture): pale yellow oil; IR (neat)
m
3396, 2927, 1670 cmꢀ1 1H NMR (300 MHz CDCl3) d 1.44–1.81 (m, 1H), 1.89–
;
2.08 (m, 1H), 2.47–2.71 (m, 2H), 2.89–2.93 (s ꢂ 2, 3H), 3.16–3.46 (m, 2H), 3.53–
3.85 (m, 2H), 3.79 (s, 3H), 6.82 (m, 1H), 7.07–7.20 (m, 2H); MS m/z: 328 (MH+);
HRMS (FAB) calcd for C14H19O3N79Br (MH+): 327.0470; found: 328.0531, m/z:
330 (MH+); HRMS (FAB) calcd for C14H19O3N81Br (MH+): 329.0450; found:
330.0506. Compound 2 (Refs. 2v and 2z): colorless oil; IR (neat)
m 2931,
1693 cmꢀ1 1H NMR (300 MHz CDCl3) d 2.46–2.53 (m, 2H), 2.68 (dddd, 1H,
;
J = 17.9, 8.0, 2.8, 2.8 Hz), 3.01 (s, 3H), 3.30 (dd, 1H, J = 13.5, 4.1 Hz), 3.80 (s, 3H),
3.83–3.88 (m, 1H), 5.97 (t, 1H, J = 2.6 Hz), 5.29 (s, 1H), 6.83 (dd, 1H, J = 8.4,
2.6 Hz), 7.09 (d, 1H, J = 8.4 Hz), 7.13 (d, 1H, J = 2.6 Hz); 13C NMR (68 MHz,
CDCl3) d 28.8, 30.4, 39.3, 55.6, 56.9, 113.7, 115.3, 118.3, 124.8, 128.1, 131.7,
138.9, 159.2, 168.2. Compound 9 (Refs. 2o, 2v, and 2z): colorless solid of mp
8. (a) Lear, Y.; Durst, T. Can. J. Chem. 1997, 75, 817; (b) Comins, D. L.; Brown, J. D. J.
Org. Chem. 1984, 49, 1078–1083.
9. (a) Ollivier, C.; Renaud, P. . P. Chem. Rev. 2001, 101, 3415–3434; (b) Yorimitsu,
H.; Oshima, K. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, Germany, 2001; Vol. 1, pp 11–27; (c) O’Mahony, G.
Synlett 2004, 572–573; (d) Yamamoto, Y. (original commentary); Yoshimitsu, T.
(first update); Wood, J. L.; Schacherer, L. N. (second update) In e-EROS
Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A.; Fuchs, P. L.; Wipf,
P.; Crich, D. Eds.; Wiley, 2007.
142–143 °C; IR (neat)
m ;
2936, 1686 cmꢀ1 1H NMR (300 MHz CDCl3) d 1.55 (s,
3H), 2.03 (d, 1H, J = 10.6 Hz), 2.18 (dd, 1H, J = 10.6, 5.5 Hz), 2.83 (s, 3H), 2.92–
2.94 (m, 2H), 3.78 (s, 3H), 3.82–3.86 (m, 1H), 6.73 (dd, 1H, J = 8.4, 2.5 Hz), 6.99
(d, 1H, J = 8.4 Hz); 13C NMR (68 MHz, CDCl3) d 17.5, 27.6, 30.0, 40.7, 45.2, 54.9,
55.3, 110.1, 112.8, 124.4, 130.7, 141.5, 158.1, 177.1. O-Methylaphanorphine
10. The stereochemistry of major compound 3a was established by chemical
(Refs. 2o, 2v, and 2z): colorless oil; IR (neatl) m ;
2934, 1493 cmꢀ1 1H NMR
correlation: Bu3SnH/AIBN-mediated reduction of major 3a provided
a
(300 MHz CDCl3) d 1.48 (s, 3H), 1.86 (d, 1H, J = 11.0 Hz), 2.02 (ddd, 1H, J = 11.0,
5.5, 1.0 Hz), 2.47 (s, 3H), 2.77 (d, 1H, J = 9.5 Hz), 2.83 (dd, 1H, J = 9.5, 1.3 Hz),
2.85 (dd, 1H, J = 16.5,3.1 Hz), 3.02 (d, 1H, J = 16.5 Hz), 3.42–3.44 (m, 1H), 3.78
(s, 3H), 6.69 (dd, 1H, J = 8.5, 2.4 Hz), 6.78 (d, 1H, J = 2.4 Hz), 7.02 (d, 1H,
J = 7.9 Hz); 13C NMR (68 MHz, CDCl3) d 21.5, 35.7, 41.5, 41,7, 43.2, 55.2, 61.2,
71.3, 109.4, 110.8, 126.1, 130.2, 148.1, 157.7. ( )-Aphanorphine (1) (Refs. 2n,
debrominated alcohol that was identical to the authentic material whose
structure was unambiguously elucidated by X-ray analysis.
11. For instance, an attempt to methylenate lactam 6 by a three-step procedure
involving (1) ethoxylation, (2) hydroxymethylation with paraformaldehyde,
and (3) deacylation was unsuccessful in our hands: Rigolet, S.; Melot, J. M.;
Vebrel, J.; Chiaroni, A.; Riche, C. J. Chem. Soc., Perkin Trans. 1 2000, 1095–
1103.
12. (a) Klutchko, S.; Hoefle, M. L. J. Med. Chem. 1981, 24, 104–109; (b) Yang, J.;
Cohn, S. T.; Romo, D. Org. Lett. 2000, 6, 763–766.
13. Superiority of ACCN compared to AIBN, for example, see: Keck, G. E.; Burnett,
D. A. J. Org. Chem. 1987, 52, 2960–2962.
2o, and 2x): colorless solid of mp 210–215 °C; IR (neat)
m ;
2928, 1576 cmꢀ1 1H
NMR (300 MHz CD3OD) d 1.45 (s, 3H), 1.84 (d, 1H,J = 11.0 Hz), 2.00 (ddd, 1H,
J = 11.0, 5.8, 1.3 Hz), 2.42 (s, 3H), 2.64 (d, 1H, J = 9.6 Hz), 2.82–2.89 (m, 2H), 3.00
(d, 1H, J = 16.6 Hz), 3.40 (q, 1H, J = 2.6 Hz), 6.56 (dd, 1H, J = 8.2, 2.5 Hz), 6.67 (d,
1H, J = 2.5 Hz), 6.89 (d, 1H, J = 8.2 Hz); 13C NMR (68 MHz, CD3OD) d 21.5, 36.5,
41.9, 42.8, 44.3, 64.0, 72.6, 110.9, 114.6, 124.8, 131.3, 148.1, 156.7.