A facile asymmetric route to (-)-aphanorphine

Article abstract of DOI:10.1021/jo0348726

8O-Methylaphanorphine was synthesized from 4-methoxyphenylacetaldehyde in 36% overall yield and in nine steps, featuring the formation of ring B via a Friedel-Crafts alkylative cyclization with the concomitant stereospecific introduction of the benzylic q

Full text of DOI:10.1021/jo0348726

SCHEME 1
A F a cile Asym m etr ic Rou te to
(-)-Ap h a n or p h in e
Hongbin Zhai,*,† Shengjun Luo,†,‡ Chengfeng Ye,† and
Yongxiang Ma‡
Laboratory of Modern Synthetic Organic Chemistry and
State Key Laboratory of Bio-Organic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China, and
Department of Chemistry, Lanzhou University,
Lanzhou, Gansu 730000, China
zhaih@mail.sioc.ac.cn
Received J une 22, 2003
As a part of our long-term marine natural product
program, we recently launched an original asymmetric
total synthesis of (-)-aphanorphine (1). In our own
synthetic strategy, we envisioned that ring B of the
tricycle could be effectively constructed with the con-
comitant stereospecific introduction of the benzylic qua-
ternary carbon center, by an intramolecular Friedel-
Crafts alkylation4 of pyrrolidinol 2 (Scheme 1). Chiral
homoallylic alcohol 4, presumably obtainable from 4-meth-
oxyphenylacetaldehyde5 (5, a highly symmetric 1,4-
disubstituted benzene) by Roush methallylation,6 could
be converted to epoxy amine 3 and then to tertiary alcohol
2, in which rings A and C were both set. If successful,
our synthetic studies should provide a general efficient
method for rapid assembly of aphanorphine analogues
and of other related alkaloids.
Our enantioselective synthesis of (-)-aphanorphine (1)
is delineated in Scheme 2. Roush reaction6 of 55 with the
enantiopure diisopinocampheyl(methallyl)borane reagent
in ether [prepared from methallylmagnesium chloride7
and commercially available (+)-DIP-chloride] furnished
in 85% yield (R)-homoallylic alcohol 4 as a colorless oil
(95.4% ee, as determined by HPLC analysis: Chiralpak
AS column (250 × 4.6 mm), UV detector 254 nm, eluent
hexanes/2-propanol (4:1), flow rate 0.7 mL/min). Stereo-
selective epoxidation8 with TBHP in the presence of 2
mol % of VO(acac)2 in dichloromethane at room temper-
ature produced epoxy alcohols 6a /6b (96%, dr 2:1) as an
inseparable mixture. Surprisingly, reaction of 4 with
m-CPBA gave 6a /6b in an approximately 1:1 ratio, which
was not sufficiently acceptable for our purpose. To
eventually form the pyrrolidine ring, the attempt to
convert the hydroxyls of 6a /6b to suitable nitrogen-based
nucleophilic functional groups was then executed. Dis-
placement of the sulfonates of 6a /6b with NaN3 or
MeNH2 resulted mainly in an elimination product. Reac-
tion of 6a /6b with (BOC)NHTs9 under typical Mit-
sunobu10 conditions (PPh3, DEAD, THF) led to an amide
Abstr a ct: 8O-Methylaphanorphine was synthesized from
4-methoxyphenylacetaldehyde in 36% overall yield and in
nine steps, featuring the formation of ring B via a Friedel-
Crafts alkylative cyclization with the concomitant stereospe-
cific introduction of the benzylic quaternary carbon center.
The current work constitutes an efficient enantioselective
formal synthesis of 3-benzazepine marine alkaloid (-)-
aphanorphine.
(-)-Aphanorphine (1) is a tricyclic 3-benzazepine al-
kaloid isolated by Shimizu and Clardy in 1988 from the
freshwater blue-green alga Aphanizomenon flos-aquae.1
It has spawned a virtual explosion of synthetic interest2
due to its unique structure resembling benzomorphane
analgesics such as pentazocine.3 The potential pharma-
cological activity should endow aphanorphine and its
analogues with great value as lead compounds in new
drug development. In all previous syntheses of 1, ring B
was constructed prior to ring C with the following two
exceptions: the strategy presented by Ishibashi and co-
workers2b involved the final formation of ring B via an
aryl radical cyclization, and Funk and co-workers2a
discovered that rings B and C could be simultaneously
generated from a substituted ꢀ-lactam by an intramo-
lecular mesylate displacement. Remarkably, the majority
of the known syntheses of 1 started from either 1,3-
disubstituted or 1,2,4-trisubstituted benzenes, but not
from those with 1,4-disubstitution, i.e., more highly
symmetric molecules.
* Corresponding author.
(4) Shapiro, B. L.; Shapiro, M. J . J . Org. Chem. 1976, 41, 1522.
(5) (a) Eicher, T.; Wobido, M.; Speicher, A. J . Prakt. Chem. 1996,
338, 706. (b) Firouzabadi, H.; Sharifi, A. Synthesis 1992, 10, 999.
(6) (a) Roush, W. R.; Halterman, R. L. J . Am. Chem. Soc. 1986, 108,
294. (b) Reddy, M. V. R.; Yucel, A. J .; Ramachandran, P. V. J . Org.
Chem. 2001, 66, 2512.
(7) Taber, D. F.; Christos, T. E.; Rahimizadeh, M.; Chen, B. J . Org.
Chem. 2001, 66, 5911.
(8) For stereoselective epoxidation of alkenols, see: Gruttadauria,
M.; Meo, P. L.; Noto, R. Tetrahedron 1999, 55, 14097.
(9) Neustadt, B. R. Tetrahedron Lett. 1994, 35, 379.
(10) Henry, J . R.; Marcin, L. R.; McIntosh, M. C.Tetrahedron Lett.
1989, 30, 5709.
† Shanghai Institute of Organic Chemistry.
‡ Lanzhou University.
(1) Gulavita, N.; Hori, A.; Shimizu, Y.; Laszlo, P.; Clardy, J .
Tetrahedron Lett. 1988, 29, 4381.
(2) For most recent synthesis or synthetic studies, see: (a) Fuchs,
J . R.; Funk, R. L. Org. Lett. 2001, 3, 3923. (b) Tamura, O.; Yangimachi,
T.; Kobayashi, T.; Ishibashi, H. Org. Lett. 2001, 3, 2427. (c) Tanaka,
K.; Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 1049.
(d) ElAzab, A. S.; Taniguchi, T.; Ogasawara, K. Heterocycles 2002, 56,
39. For a list of earlier synthesis or synthetic studies, see the references
cited in ref 2a.
(3) Palmer, D. C.; Strauss, M. J . Chem. Rev. 1977, 77, 1.
10.1021/jo0348726 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/13/2003
8268
J . Org. Chem. 2003, 68, 8268-8271

SCHEME 2a
remained unreacted under the same condition. Under
harsher conditions (e.g., at higher reaction temperatures
when using different solvents), a cyclization product could
not be isolated and the starting material could not be
recovered. Although 8b could not be utilized directly to
synthesize 9, it could be recycled by a two-step sequence
(oxygen extrusion followed by epoxidation) to afford the
8a /8b mixture. The intramolecular Friedel-Crafts alkyl-
ative cyclization4 of N-tosylpyrrolidine 9 was then vigor-
ously investigated. Treating 9 with PPA17 (at 72, 90 or
100 °C) or 85% H2SO418 (at 0 °C) failed to form the desired
cyclization product. Gratifyingly, agitating 9 with excess
19
AlCl3 in dichloromethane at room temperature for 12
h effected the expected transformation to provide 10 (88%
yield, 99.7-100% ee20), in which the tricyclic framework
of aphanorphine 1 had been established. Finally, (+)-8O-
methylaphanorphine 12 was afforded by reductive de-
sulfurization21 with Red-Al in refluxing xylene (96%)
followed by N-methylation22 with formaldehyde and
NaBH3CN in MeOH at room temperature (98%). The
[R]20 of 12 was found to be +8.7 (c 1.06, CHCl3) [lit.23
D
[R]28 +8.1 (c 1.2, CHCl3) [lit.2b [R]20 +9.4 (c 0.30,
D
D
CHCl3)]]. Other spectroscopic data of 12 were also in
accord with those disclosed in the literature.1,2,23 De-
methylation of 12 with BBr3 in dichloromethane has been
reported to give tricyclic 3-benzazepine alkaloid (-)-
aphanorphine (1) in 86% yield.23
In summary, we have accomplished a formal asym-
metric synthesis of marine alkaloid (-)-aphanorphine (1).
8-O-methylaphanorphine 12 was synthesized from 5 in
nine steps and in 36% overall yield. The present synthesis
has the following features. (i) A highly symmetric 1,4-
disubstituted (rather than 1,3-disubstituted or 1,2,4-
trisubstituted) benzene was utilized as the source of ring
A. (2R)-1-(4-Methoxyphenyl)-4-methyl-4-penten-2-ol 4
was efficiently synthesized in an enantioselective manner
by Roush reaction. (ii) Our unique strategy of sequential
cyclizations secured high synthetic efficiency: base-
promoted cyclization (via an intramolecular endo epoxy
displacement) formed 2-arylmethyl-4-methyl-4-pyrroli-
dinol 9, setting the stage for a Lewis acid-effected
Friedel-Crafts alkylative cyclization, during which the
stereospecific introduction of the benzylic quaternary
carbon center was concomitantly realized.
a
Conditions: (a) methallyl-MgCl, (+)-DIP-Cl, ether, -78 °C, 1
h; rt, 4 h; 5, ether, -78 °C, 4 h; rt 1 h; 3 M NaOH, 30% H2O2,
reflux, 1 h; (b) VO(acac)2, TBHP, DCM, 0 °C, 10 min; rt, 7.5 h; (c)
HN3, PPh3, DEAD, PhH, 0 °C; rt 30 min; (d) Lindlar catalyst, H2,
anhyd EtOH, rt, 8.5 h; (e) TsCl, TEA, Et2O, rt, 1.5 h; (f) NaH,
PhH, reflux, 18 h; (g) AlCl3, DCM, rt, 12 h; (h) Red-Al, xylene,
reflux, 1 h; (i) HCHO, NaBH3CN, MeOH, rt, 12 h. PMB )
p-methoxybenzyl.
in only 36% yield; moreover, deprotecting the BOC was
comparably unsatisfactory. Replacement of (BOC)NHTs
with (CBZ)NHTs11 yielded nothing but the elimination
product. To our delight, by treating 6a /6b with HN3,12
PPh3, and DEAD in benzene, azides 7a /7b were obtained
in high yield (92%).13 Selective azido hydrogenation
(while keeping the epoxy groups intact) was realized with
the Lindlar catalysis14 (1 atm of H2, anhydrous EtOH,
room temperature). The homoallylic amines thus ob-
tained were immediately exposed to p-toluenesulfonyl
chloride and triethylamine in ether at room temperature
to produce in excellent yield (98%) the expected sulfona-
mides 8a (65%) and 8b (33%), which were easily separ-
able by silica gel chromatography.15
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. NMR
spectra were recorded in CDCl3 or CD3OD (1H at 300 MHz and
13C at 75 MHz) using TMS as the internal standard. Column
(16) For intramolecular epoxy displacement, see: LaLonde, R. T.;
Muhammad, N.; Wong, C. F.; Sturiale, E. R. J . Org. Chem. 1980, 45,
3664.
(17) Shiotani, S.; Okada, H.; Yamamoto, T.; Nakamata, K.; Adachi,
J .; Nakamoto, H. Heterocycles 1996, 43, 113.
(18) Bogert, M. T.; Davidson, D. J . Am. Chem. Soc. 1934, 56, 185.
(19) Chandrasekhar, S.; Reddy, M. V. Tetrahedron 2000, 56, 1111.
(20) Determined by HPLC analysis: Chiralpak AD column (250 ×
4.6 mm), UV detector 254 nm, eluent hexanes/2-propanol (4: 1), flow
rate 0.7 mL/min.
On reflux with excess sodium hydride in benzene, 8a
was smoothly converted to 9 in 88% yield by forming the
pyrrolidine ring through an intramolecular endo-epoxy
displacement.16 It is noteworthy that the isomer 8b
(11) Moore, J . D.; Harned, A. M.; Henle, J .; Flynn, D. L.; Hanson,
P. R. Org. Lett. 2002, 4, 1847.
(12) Wolff, H. Org. React. 1946, 3, 307.
(13) For conversion of alcohols to azides by Mitsunobu reaction,
see: Pearson, W. H.; Hembre, E. J . J . Org. Chem. 1996, 61, 5546.
(14) For azide reduction with Lindlar catalyst in the presence of
epoxides, see: Block, O.; Klein, G.; Altenbach, H. J .; Braner, D. J . J .
Org. Chem. 2000, 65, 716.
(15) For amine sulfonylation, see: Dauban, P.; Ferry, S.; Faure, H.;
Ruat, M.; Dodd, R. H. Bioorg. Med. Chem. Lett. 2000, 10, 2001.
(21) For reductive desulfurization, see: Negash, K.; Nichols, D. E.;
Watts, V. J .; Mailman, R. B. J . Med. Chem. 1997, 40, 2140.
(22) For N-methylation by reductive amination, see: Abdel-Magid,
A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J .
Org. Chem. 1996, 61, 3849.
(23) Shimizu, M.; Kamikubo, T.; Ogasawara, K. Heterocycles 1997,
46, 21.
J . Org. Chem, Vol. 68, No. 21, 2003 8269

chromatography was performed on silica gel. Dichloromethane,
DMF, and diisopropylamine were distilled over calcium hydride
under N2. Ether, THF, benzene, toluene, and xylene were
distilled over sodium benzophenone ketyl under N2. Ethanol was
distilled over magnesium under N2.
(2R)-1-(4-Meth oxyp h en yl)-4-m eth yl-4-p en ten -2-ol (4). To
a dry 100-mL three-necked round-bottomed flask equipped with
a thermometer and a dropping funnel were added Mg turnings
(4.80 g, 197 mmol), iodine (a grain), and anhydrous ether (25
mL). To this mixture was added dropwise a solution of 3-chloro-
2-methylpropene (90%, 4.30 mL, 39.3 mmol) in dry ether (20
mL) over 60 min while maintaining the temperature at 0 °C.
The mixture was stirred at 0 °C for 1 h and at rt for 1.5 h and
allowed to stand for several hours until the upper layer became
clear. The upper clear ether solution contained methallylmag-
nesium chloride (0.46 M by titration).
To a 25-mL round-bottomed flask containing (+)-DIP-Cl (238
mg, 0.742 mmol) and dry ether (3 mL) at -78 °C was added the
above Grignard reagent (0.46 M, 1.46 mL, 0.672 mmol). The
mixture was stirred at -78 °C for 1 h and at rt for 4 h and cooled
back to -78 °C. A solution of (4-methoxyphenyl)acetaldehyde
(100.5 mg, 0.669 mmol) in ether (2 mL) was slowly added to the
above mixture at -78 °C. The mixture was stirred at -78 °C
for 4 h and at rt for 1 h, quenched with aqueous NaOH solution
(3 M, 0.25 mL, 0.75 mmol) and 30% H2O2 (0.25 mL, 2.4 mmol),
refluxed for 1 h, and cooled to rt. The two layers were separated,
and the aqueous layer was extracted with ethyl acetate for three
times. The organic layers were combined, washed with brine,
dried (MgSO4), filtered, and concentrated. The residue was
chromatographed (EtOAc/hexanes, 1:20) to furnish alcohol 4 (117
mg, 85%). An analytical sample was obtained by converting the
above-mentioned alcohol 4 (which could be used directly for the
next reaction) to the TBS ether (TBSCl, imidazole, DMF, rt, 16
h), chromatographic separation (EtOAc/hexanes, 1:100) and
desilylation (TBAF, THF, rt, 24 h) to remove a tiny amount of
colorless oil: 1H NMR (CDCl3, 300 MHz) diastereomers, 2:1, δ
1.26 (s, 1H, 0.33CH3), 1.36 (s, 2H, 0.67CH3), 1.51-1.73 (m, 1H,
0.5CH2), 1.77-1.93 (m, 1H, 0.5CH2), 2.58-2.70 (m, 2H, oxiranyl
CH2), 2.78-2.83 (m, 2H, benzylic CH2), 3.50-3.56 (m, 0.33H,
0.33N3CH), 3.59-3.70 (m, 0.67H, 0.67N3CH), 3.80 (s, 3H, OCH3),
6.86 (d, J ) 8.1 Hz, 2H, 2CH), 7.13 (d, J ) 8.4 Hz, 2H, 2CH).
Anal. Calcd for C13H17NO2: C, 63.14; H, 6.93; N, 16.99. Found:
C, 63.10; H, 6.94; N, 17.15.
(2R,4R)-N-[(1-(4-Met h oxyp h en yl)-4-m et h yl-4,5-ep oxy)-
p en tyl]-4-tolu en esu lfon a m id e (8a ) a n d (2R,4S)-N-[(1-(4-
Me t h oxyp h e n yl)-4-m e t h yl-4,5-e p oxy)p e n t yl]-4-t olu e n e -
su lfon a m id e (8b). A solution of 7a /7b (34.0 mg, 0.137 mmol)
in dry EtOH (2 mL) was stirred with Lindlar catalyst (Pd/CaCO3/
Pb, 5% Pd, 11 mg) under H2 (1 atm) at rt for 8.5 h and filtered
(through folded filters). The solid bed was washed with EtOH,
and the filtrate was concentrated to give the crude amines, which
could be used directly for the next reaction. An analytical sample
of the diastereomeric amines was obtained by column chromato-
graph (CH2Cl2/MeOH/Et3N, 100:2:1) as a colorless oil: 1H NMR
(CDCl3, 300 MHz) diastereomers, 2:1, δ 1.34 (s, 2H, 0.67CH3),
1.36 (s, 1H, 0.33CH3), 1.37-1.55 (m, 1H, 0.5CH2), 1.70-2.10 (m,
3H, NH2 + 0.5CH2), 2.40-2.80 (m, 4H, oxiranyl CH2 + benzylic
CH2), 3.03-3.15 (m, 0.33H, 0.33NCH), 3.15-3.28 (m, 0.67H,
0.67NCH), 3.79 (s, 3H, OCH3), 6.85 (d, J ) 8.0 Hz, 2H, 2CH),
7.11 (d, J ) 8.0 Hz, 2H, 2CH).
To a solution of the above-mentioned crude amines in dry Et2O
(1 mL) were added Et3N (0.10 mL, 0.72 mmol) and TsCl (52 mg,
0.27 mmol, in one portion). The mixture was stirred at rt for
1.5 h, quenched with saturated aqueous NaHCO3, and extracted
three times with EtOAc. The organic layers were combined, dried
(MgSO4), filtered, and concentrated. The residue was chromato-
graphed (EtOAc/hexanes, 1:5) to give 8a (33.5 mg, 65%) as a
colorless crystal and 8b (17 mg, 33%) as a colorless oil.
1
8a : mp 102-103 °C; [R]20 -22.2 (c 0.911, CHCl3); H NMR
D
(CDCl3, 300 MHz): δ 1.21 (s, 3H, CH3), 1.59 (dd, J ) 14.4, 8.5
Hz, 1H, 0.5 CH2), 1.77 (dd, J ) 14.4, 5.3 Hz, 1H, 0.5 CH2), 2.41
(s, 3H, benzylic CH3), 2.47 (d, J ) 4.5 Hz, 1H, 0.5CH2 (oxiranyl)),
2.52 (d, J ) 4.5 Hz, 1H, 0.5CH2 (oxiranyl)), 2.62-2.75 (m, 2H,
benzylic CH2), 3.48-3.57 (m, 1H, NCH), 3.77 (s, 3H, OCH3), 4.91
(d, J ) 7.4 Hz, 1H, NH), 6.72 (d, J ) 8.4 Hz, 2H, 2CH), 6.91 (d,
J ) 8.4 Hz, 2H, 2CH), 7.24 (d, J ) 8.1 Hz, 2H, 2CH), 7.65 (d, J
) 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ 20.9, 21.4, 40.5,
41.2, 52.7, 53.8, 55.1, 55.4, 113.8, 126.9, 128.5, 129.5, 130.4,
137.5, 143.2, 158.3; MS (EI) 375 (M+, 2), 358 (M - 17, 1), 254
(80), 91 (100). Anal. Calcd for C20H25NO4S: C, 63.97; H, 6.71;
N, 3.73. Found: C, 64.23; H, 6.70; N, 3.61.
the pinenol impurity. 4: colorless oil: 95.4% ee (determined by
1
HPLC analysis); [R]20 -19.8 (c 1.17, CHCl3); H NMR (CDCl3,
D
300 MHz): δ 1.74 (s, 3H, CH3), 1.91 (br s, 1H, OH), 2.10-2.26
(m, 2H, CH2), 2.64-2.77 (m, 2H, benzylic CH2), 3.77 (s, 3H,
OCH3), 3.87-3.93 (m, 1H, OCH), 4.87 (d, J ) 0.8 Hz, 1H, 0.5CH2
(vinyl)), 4.80 (d, J ) 0.8 Hz, 1H, 0.5CH2 (vinyl)), 6.84 (d, J ) 8.6
Hz, 2H, 2CH), 7.14 (d, J ) 8.6 Hz, 2H, 2CH); 13C NMR (CDCl3,
75 MHz) δ 22.3, 42.5, 45.2, 55.0, 69.8, 113.2, 113.7, 130.2, 130.4,
142.6, 158.0; MS (EI) 134 (100), 121 (47), 57 (21). Anal. Calcd
for C13H18O2: C, 75.69; H, 8.80. Found: C, 75.59; H, 8.55.
(2S)-1-(4-Met h oxyp h en yl)-3-(1-m et h yloxir a n yl)-2-p r o-
p a n ol (6a /6b). To a solution of 4 (1.13 g, 5.48 mmol) in
anhydrous dichloromethane (45 mL) at 0 °C were added VO-
(acac)2 (29 mg, 0.11 mmol) and then TBHP (4.15 M in toluene,
2.64 mL, 11.0 mmol, dropwise). The reaction mixture was stirred
at 0 °C for 10 min, allowed to warm to rt, stirred for further 7.5
h, quenched with saturated aqueous sodium thiosulfate solution,
and extracted with EtOAc. The organic layers were combined,
washed with water and brine successively, dried (MgSO4),
filtered, and concentrated. The residue was purified by column
chromatography (EtOAc/hexanes, 1:6) to give a mixture of
oxiranes 6a /6b (1.17 g, 96%) as a colorless oil: 1H NMR (CDCl3,
300 MHz) diastereomers, 2:1, δ 1.37 (s, 2H, 0.67CH3), 1.38 (s,
1H, 0.33CH3), 1.50-1.97 (m, 3H, CH2 + OH), 2.50-2.94 (m, 4H,
oxiranyl CH2 + benzylic CH2), 3.81 (s, 3H, OCH3), 3.82-3.88
(m, 0.33H, 0.33OCH), 4.05-4.14 (m, 0.67H, 0.67OCH), 6.87 (d,
J ) 8.7 Hz, 2H, 2CH), 7.15 (d, J ) 8.7 Hz, 2H, 2CH); MS (EI)
222 (M+, 2), 204 (9), 150 (20), 121 (100). Anal. Calcd for
C13H18O3: C, 70.24; H, 8.16. Found: C, 69.80; H, 7.88.
8b: 1H NMR (CDCl3, 300 MHz) δ 0.80 (s, 3H, CH3), 1.20-
1.35 (m, 1H, 0.5CH2), 1.80 (dd, J ) 14.7, 4.1 Hz, 1H, 0.5 CH2),
2.40 (s, 3H, benzylic CH3), 2.42 (d, J ) 4.8 Hz, 1H, 0.5CH2
(oxiranyl)), 2.45 (d, J ) 4.7 Hz, 1H, 0.5CH2 (oxiranyl)), 2.69 (dd,
J ) 13.8, 7.9 Hz, 1H, 0.5CH2 (benzylic)), 2.94 (dd, J ) 13.8, 4.5
Hz, 1H, 0.5CH2 (benzylic)), 3.40-3.51 (m, 1H, NCH), 3.76 (s,
3H, OCH3), 5.32 (d, J ) 4.3 Hz, 1H, NH), 6.77 (d, J ) 8.5 Hz,
2H, 2CH), 7.01 (d, J ) 8.4 Hz, 2H, 2CH), 7.28 (d, J ) 8.1 Hz,
2H, 2CH), 7.79 (d, J ) 8.1 Hz, 2H, 2CH); 13C NMR (CDCl3, 75
MHz) δ 19.6, 21.4, 39.7, 41.2, 53.0, 53.1, 55.1, 55.3, 113.7, 127.3,
129.1, 129.5, 130.4, 137.0, 143.2, 158.2.
(2R,4S)-4-H yd r oxy-2-(4-m et h oxyb en zyl)-4-m et h yl-1-(4-
tolu en esu lfon yl)p yr r olid in e (9). To a suspension of NaH (60%
in mineral oil, 34 mg, 0.85 mmol) in dry benzene (3 mL) was
added a solution of 8a (40.0 mg, 0.106 mmol) in benzene (2 mL)
under N2. The mixture was refluxed for 18 h, cooled to rt, poured
into crushed ice, and adjusted to pH 4.0 with 25% H2SO4. The
benzene layer was separated, and the aqueous phase was
extracted repeatedly with CH2Cl2. The organic extracts were
combined, dried (MgSO4), filtered, and concentrated. The residue
was chromatographed (EtOAc/hexanes, 1:4) to provide the
cyclization product 9 (35 mg, 88%) as colorless crystals: mp 105-
107 °C; [R]20D -63.6 (c 0.759, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 1.09 (s, 3H, CH3), 1.58 (dd, J ) 13.6, 9.2 Hz, 1H, 0.5CH2), 1.82
(ddd, J ) 13.6, 3.6, 1.2 Hz, 1H, 0.5CH2), 2.44 (s, 3H, benzylic
CH3), 3.04 (d, J ) 10.2 Hz, 1H, 0.5CH2N), 3.11 (dd, J ) 13.4,
9.4 Hz, 1H, 0.5CH2 (benzylic)), 3.24 (dd, J ) 13.4, 4.0 Hz, 1H,
0.5CH2 (benzylic)), 3.41 (dd, J ) 10.5, 1.2 Hz, 1H, 0.5CH2N),
(2R)-2-Azid o-1-(4-m eth oxyp h en yl)-3-(1-m eth yloxir a n yl)-
p r op a n e (7a /7b). Hydrazoic acid (2.29 M in benzene, 0.17 mL,
0.39 mmol) was added to a solution of epoxy alcohol 6a /6b (44
mg, 0.20 mmol) and triphenylphosphine (78 mg, 0.30 mmol) in
benzene (1 mL). The resultant mixture was cooled to 0 °C, and
DEAD (40% in toluene, 0.14 mL, 0.31 mmol) was added in a
dropwise fashion. The solution was allowed to slowly warm to
rt. After 0.5 h, the mixture was concentrated and the crude
product was purified by column chromatography (EtOAc/hex-
anes, 1:40) to give a mixture of azides 7a /7b (45 mg, 92%) as a
8270 J . Org. Chem., Vol. 68, No. 21, 2003

3.74-3.84 (m, 1H, NCH), 3.79 (s, 3H, OCH3), 6.86 (d, J ) 8.7
Hz, 2H, 2CH), 7.21 (d, J ) 8.4 Hz, 2H, 2CH), 7.35 (d, J ) 8.4
Hz, 2H, 2CH), 7.77 (d, J ) 8.1 Hz, 2H, 2CH); 13C NMR (CDCl3,
75 MHz) δ 21.5, 25.4, 41.2, 43.1, 55.2, 61.5, 61.6, 76.0, 113.9,
127.6, 129.7, 130.0, 130.9, 133.7, 143.7, 158.2; MS (EI) 358 (M
-17, 3), 254 (43), 91 (100). Anal. Calcd for C20H25NO4S: C, 63.97;
H, 6.71; N, 3.73. Found: C, 63.83; H, 6.76; N, 3.73.
NCH), 6.80 (d, J ) 8.1 Hz, 1H, CH), 6.84 (s, 1H, CH), 7.08 (d, J
) 8.1 Hz, 1H, CH); 13CNMR (MeOH-d4, 75 MHz) δ 20.1, 35.7,
42.1, 43.3, 55.8, 58.5, 61.0, 110.5, 114.2, 123.5, 131.7, 145.4,
160.2. Anal. Calcd for C13H17NO‚HCl‚1/2H2O: C, 62.77; H, 7.70;
N, 5.63. Found: C, 62.66; H, 7.98; N, 5.58.
(+)-8O-Meth yla p h a n or p h in e (12). A mixture of amine 11
(114 mg, 0.561 mmol), aqueous HCHO solution (37%, 0.50 mL,
6.71 mmol), and NaCNBH3 (95%, 371 mg, 5.61 mmol) in
methanol (8 mL) was stirred overnight at rt. After evaporation
of the volatiles, the residue was partitioned between 5% HCl
and ether, and the two layers were separated. The aqueous layer
was washed one more time with ether, and the organic phase
was discarded. The aqueous phase was made basic with con-
centrated NH4OH, extracted with CH2Cl2/IPA (3:1), dried (Mg-
SO4), filtered, and concentrated. The residue was chromato-
graphed (CH2Cl2/MeOH/Et3N, 100:2:1) to give aphanorphine
(1R,4S)-1-Meth yl-8-m eth oxy-3-(4-tosyl)-2,3,4,5-tetr ah ydr o-
1,4-m eth a n o-3-ben za zep in e (10). Aluminum chloride (2.24 g,
16.8 mmol) was added to a solution of 9 (0.63 g, 1.68 mmol) in
dry CH2Cl2 (30 mL). The mixture was stirred at rt for 12 h,
poured into saturated aqueous NaHCO3 solution, and extracted
with CH2Cl2. The combined organic layers were washed with
water and brine successively, dried (MgSO4), filtered, and
concentrated. The residue was chromatographed (EtOAc/hexane,
1:10) to give, after one recrystallization, tricycle 10 (525 mg, 88%)
as a colorless solid: mp 137-138 °C; 100% ee (determined by
HPLC analysis); [R]20D -13.4 (c 0.969, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 1.41 (s, 3H, CH3), 1.46 (ddd, J ) 11.1, 6.3, 1.5 Hz,
1H, 0.5CH2), 1.79 (d, J ) 11.1 Hz, 1H, 0.5CH2), 2.43 (s, 3H,
benzylic CH3), 2.93 (dd, J ) 16.6, 2.8 Hz, 1H, 0.5CH2), 3.02 (d,
J ) 8.7 Hz, 1H, 0.5CH2), 3.12 (d, J ) 16.8 Hz, 1H, 0.5CH2), 3.40
(dd, J ) 8.6, 1.4 Hz, 1H, 0.5CH2), 3.79 (s, 3H, OCH3), 4.39-4.45
(m, 1H. NCH), 6.72 (dd, J ) 8.6, 2.8 Hz, 1H, CH), 6.78 (d, J )
2.1 Hz, 1H, CH),6.98 (d, J ) 8.1 Hz, 1H, CH), 7.28 (d, J ) 8.1
Hz, 2H, 2CH), 7.69 (d, J ) 8.4 Hz, 2H, 2CH); 13C NMR (CDCl3,
75 MHz): δ 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
methyl ether 12 (120 mg, 98%) as a colorless oil: [R]20 +8.7 (c
D
1.06, CHCl3); 1H NMR (CDCl3, 300 Hz) δ 1.48 (s, 3H, CH3), 1.86
(d, J ) 10.8 Hz, 1H, 0.5CH2), 2.01 (ddd, J ) 11.0, 5.7, 1.6 Hz,
1H, 0.5CH2), 2.47 (s, 3H, NCH3), 2.72 (d, J ) 9.3 Hz, 1H,
0.5CH2), 2.81-2.84 (m, 1H, 0.5CH2), 2.86-2.89 (m, 1H, 0.5CH2),
3.02 (d, J ) 16.5 Hz, 1H, 0.5CH2), 3.37-3.43 (m, 1H, NCH), 3.79
(s, 3H, OCH3), 6.70 (dd, J ) 8.2, 2.6 Hz, 1H, CH), 6.79 (d, J )
2.7 Hz, 1H, CH), 7.03 (d, J ) 8.1, Hz, 1H, CH). The HCl salt of
12: mp 206-208 °C; 1H NMR (MeOH-d4, 300 MHz) δ 1.51 (s,
3H, CH3), 2.07 (dd, J ) 12.6, 1.2 Hz, 1H, 0.5CH2), 2.36 (dd, J )
12.8, 6.2 Hz, 1H, 0.5CH2), 2.88 (s, 3H, NCH3), 3.06 (d, J ) 11.4
Hz, 1H, 0.5CH2), 3.14-3.20 (m, 2H, CH2), 3.49 (d, J ) 11.1 Hz,
1H, 0.5CH2), 3.69 (s, 3H, OCH3), 4.08-4.16 (m, 1H, NCH), 6.76
(d, J ) 9.0 Hz, 1H, CH), 6.77 (s, 1H, CH), 7.04 (d, J ) 9.0, Hz,
1H, CH); 13C NMR (MeOH-d4, 75 MHz) δ 20.1, 35.0, 40.5, 43.3,
44.6, 55.8, 68.3, 71.9, 110.6, 114.4, 123.1, 131.7, 145.0, 160.3.
Anal. Calcd for C14H19NO‚HCl‚1/3H2O: C, 64.73; H, 8.02; N, 5.39.
Found: C, 64.71; H, 7.76; N, 5.23.
(EI) 357 (M+, 18), 202 (15), 173 (100). Anal. Calcd for C20H23
-
NO3S: C, 67.20; H, 6.49; N, 3.92. Found: C, 67.18; H, 6.55; N,
3.80.
(1R,4S)-1-Meth yl-8-m eth oxy-2,3,4,5-tetr a h yd r o-1,4-m eth -
a n o-3-ben za zep in e (11). To a solution of 10 (103 mg, 0.288
mmol) in xylene (3 mL) was added Red-Al (sodium bis(2-
methoxyethoxy)aluminum hydride in toluene, 65%, 0.32 mL,
1.07 mmol). The resultant mixture was heated at reflux for 1 h,
cooled to rt, and poured onto wet Na2SO4. After filtration and
washing with CH2Cl2/IPA (3:1), the filtrate was dried (MgSO4)
and concentrated. The residue was chromatographed (CH2Cl2/
Ack n ow led gm en t. We thank the National Natural
Science Foundation of China, Chinese Academy of
Sciences (“Hundreds of Talent” Program), and the
Science & Technology Commission of Shanghai Munici-
pality (“Venus” Program) for providing financial sup-
port.
MeOH/Et3N, 80:2:1) to give 11 (56 mg, 96%) as a colorless oil:
1
[R]20 -54.6 (c 0.471, CHCl3); H NMR (CDCl3, 300 Hz) δ 1.49
D
(s, 3H, CH3), 1.85 (d, J ) 11.2 Hz, 1H, 0.5CH2), 1.92 (ddd, J )
11.2, 5.5, 1.0 Hz, 1H, 0.5CH2), 2.37 (br s, 1H, NH), 2.73 (d, J )
16.9 Hz, 1H, 0.5CH2), 2.90 (d, J ) 10.0 Hz, 1H, 0.5CH2), 3.02
(dd, J ) 10.2, 0.8 Hz, 1H, 0.5CH2), 3.09 (dd, J ) 16.8, 2.7 Hz,
1H, 0.5CH2), 3.75-3.90 (m, 1H, NCH), 3.79 (s, 3H, OCH3), 6.71
(dd, J ) 8.3, 2.6 Hz, 1H, CH), 6.83 (d, J ) 2.6 Hz, 1H, CH), 7.02
(d, J ) 8.3 Hz, 1H, CH). The HCl salt of 11: mp 240-241 °C;
1H NMR (MeOH-d4, 300 MHz) δ 1.58 (s, 3H, CH3), 2.14 (s, 2H,
CH2), 3.05-3.33 (m, 4H, 2CH2), 3.75 (s, 3H, OCH3), 4.34 (s, 1H,
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
4, 6a /6b, 7a /7b, and their hydrogenation products, 8a ,b, 9-11,
11‚HCl, 12, and 12‚HCl as well as 13C NMR spectra of 4, 8a ,b,
9, 10, 11‚HCl, and 12‚HCl. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0348726
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