Synthesis of (-)-aphanorphine using a sulfur-directed aryl radical cyclization

Article abstract of DOI:10.1016/S0957-4166(03)00530-5

Treatment of radical precursor 15a having a vinyl sulfide moiety with Bu₃SnH in the presence of AIBN in boiling benzene afforded exclusively the 6-exo cyclization product 16a, whereas similar treatment of the exo-methylene compound 15b gave a mixture of the 6-exo cyclization product 16b and the endo-olefin product 17 formed by a 1,5-hydrogen shift. Based on these findings, the synthesis of (-)-aphanorphine was achieved using a sulfur-directed 6-exo-selective aryl radical cyclization of 22.

Full text of DOI:10.1016/S0957-4166(03)00530-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3033–3041
Synthesis of (−)-aphanorphine using a sulfur-directed aryl radical
cyclization
Osamu Tamura, Takehiko Yanagimachi and Hiroyuki Ishibashi*
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan
Received 16 April 2003; accepted 25 April 2003
Abstract—Treatment of radical precursor 15a having a vinyl sulfide moiety with Bu3SnH in the presence of AIBN in boiling
benzene afforded exclusively the 6-exo cyclization product 16a, whereas similar treatment of the exo-methylene compound 15b
gave a mixture of the 6-exo cyclization product 16b and the endo-olefin product 17 formed by a 1,5-hydrogen shift. Based on these
findings, the synthesis of (−)-aphanorphine was achieved using a sulfur-directed 6-exo-selective aryl radical cyclization of 22.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
tion of benzylic quaternary centers. Recently, we
reported a total synthesis of 1 using this methodology
for the formation of a carbonꢀcarbon bond (path b in
Scheme 1),8 and we present a full account of this work
herein.
(−)-Aphanorphine 1 is an alkaloid isolated from the
freshwater blue–green alga Aphanizomenon flos-aquae.1
Since the structural features of 1 are closely related to
those of analgesics such as pentazocine and eptazocine,
significant attention has been focused on the synthesis
of 1 (Fig. 1).2–5
All reported syntheses of 1 involve carbonꢀnitrogen
bond formation (path a) to construct an aphanorphine
skeleton from either intermediate 2 or 3 which already
has the asymmetric quaternary center (Scheme 1). For-
mation of an aziridine from 2 followed by reductive
cleavage of the benzylic position,2,3a,b amino-
mercuration3c or halocyclization4 of 2, and N-alkyla-
tion of 33d have been used for carbonꢀnitrogen bond
formation. An alternative strategy for the synthesis of 1
involves carbonꢀcarbon bond formation (path b),
which builds the aphanorphine skeleton with construc-
tion of the benzylic quaternary carbon.
Figure 1.
We have previously reported6 that treatment of 4a with
Bu3SnH in the presence of AIBN generated aryl radical
5 (R=H), which underwent cyclization to give the
6-endo product 6,7 whereas a similar reaction of 4b
having a phenylthio group at the terminus of the
alkenic bond lead to exclusive formation of the 5-exo
cyclization product 7 (Scheme 2). This sulfur-directed
exo-selective aryl radical cyclization onto methylenecy-
cloalkanes provided an excellent method for construc-
* Corresponding author. E-mail: isibasi@mail.p.kanazawa-u.ac.jp
Scheme 1.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00530-5

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O. Tamura et al. / Tetrahedron: Asymmetry 14 (2003) 3033–3041
Without separation, the mixture of 11a and 11b was
treated with TBAF, and a mixture of alcohols 12a and
12b was obtained in 94% yield. The cis-stereochemistry
between the methoxycarbonyl group and the hydroxyl
group of the major isomer 12a was determined on the
basis of chemical transformation. Alkaline-hydrolysis
of the mixture of 12a and 12b followed by treatment
with diphenylphosphoryl azide (DPPA) and triethyl-
amine gave lactone 13 in 52% yield (Scheme 4).
The next task was introduction of
a phenylth-
iomethylene group onto the pyrrolidine ring of 12 via
ketone 14. Oxidation of alcohol 12 (4:1 diastereomeric
mixture) with PCC gave ketone 14. Although the oxida-
tion proceeded without any difficulty, Horner reaction
of ketone 14, unexpectedly, was not easy (Scheme 5,
Table 1). Treatment of 14 with lithium salt of
Ph2P(O)CH2SPh11 gave only a small quantity of
phenylthiomethylene compound 15a (entry 1). A simi-
lar treatment of 14 with HMPA gave a slightly
improved yield (entry 2). The best result was obtained
by sequential treatments of 14 with the lithium salt of
Scheme 2.
12
Ph2P(O)CH2SPh in the presence of CeCl3 followed by
NaH, and this method gave radical precursor 15a in
73% yield from ketone 14 (entry 3). A similar difficulty
was encountered in the preparation of compound 15b
having no substituent at the olefin terminus. Neither
Wittig reaction of 14 with Ph3PꢁCH2 nor Peterson
reaction with TMSCH2Li gave 15b, and only the Tebbe
reagent13 afforded 15b although in low yield (entry 4).
With radical precursors 15a and 15b in hand, we next
examined their radical cyclization. Vinyl sulfide 15a, on
Scheme 3.
2. Results and discussion
Our plan for the synthesis of 1 involving carbon–car-
bon bond formation (Scheme 1) by sulfur-directed aryl
radical cyclization is as follows. 6-exo Cyclization of
aryl radical B generated from bromide C would provide
tricyclic compound A, which possesses the structural
characteristics of 1. The requisite stereochemistry of the
2-position of C could be formed by alkylation of 4-
hydroxy- -proline derivative D from a less-hindered
L
side (Scheme 3).
Our investigation began by alkylation of fully protected
amino acid 99 obtained from commercially available
trans-4-hydroxy- -proline 8 with 2-bromobenzyl bro-
L
mide 10. Enolization of 9 with LHMDS followed by
treatment with bromide 10 gave alkylation products
11a and 11b as a 4:1 inseparable mixture in 96% yield.10
Scheme 4.

O. Tamura et al. / Tetrahedron: Asymmetry 14 (2003) 3033–3041
3035
Scheme 5.
treatment with 1.5 equiv. of Bu3SnH and a catalytic
amount of AIBN in boiling benzene, exclusively
afforded 6-exo aryl radical cyclization product 16a in
71% yield. The 13C NMR spectrum of 16a exhibited
two sets of signals at l 46.1, 46.9 and l 66.9, 67.3 ppm,
which were indicative of the two quaternary carbon
atoms of 16a as rotamers (Scheme 6).
Scheme 6.
In contrast, a similar treatment of exo-methylene com-
pound 15b with Bu3SnH and AIBN gave a complex
mixture of products, from which the 6-exo cyclization
product 16b (20%) and endo olefin 17 (17%) were
isolated. Olefin 17 might result from a 1,5-hydrogen
shift of the initially formed aryl radical F followed by a
reduction with Bu3SnH at a less-hindered position of
allyl radical G (Scheme 7). The radical reactions of 15a
and 15b clearly showed that the phenylthio group of
15a was essential for efficient 6-exo cyclization, proba-
bly as a result of radical-stabilization ability in radical
E (Scheme 6).
With these results of model experiments in hand, we
turned our attention to the total synthesis of (−)-
aphanorphine 1. First, radical precursor 21 was pre-
pared from 9 by a synthetic route similar to that for
15a. Alkylation of ester 9 with 2-bromo-4-methoxyben-
zyl bromide 1814 in the presence of LHMDS gave a 4:1
mixture of 19a and 19b in 91% yield. Without separa-
tion, desilylation with TBAF followed by recrystalliza-
tion of the resulting 4:1 mixture of alcohols from
hexane–ethyl acetate furnished diastereomerically pure
alcohol 20 in 68% yield from 19. Oxidation of alcohol
20 followed by phenylthiomethylenation of the result-
ing ketone 21 by a protocol similar to that used for 15a
afforded vinyl sulfide 22 in 78% yield from 20. As
expected, the key radical cyclization of 22 with Bu3SnH
and AIBN proceeded smoothly to give tricyclic com-
pound 23 in 76% yield (Scheme 8).
Scheme 7.
To synthesize aphanorphine from compound 23,
removal of the methoxycarbonyl group at the bridge
head position is required. For this purpose, we first
attempted reduction of the ester group to a formyl
group, which might be removed by decarbonylation
with Wilkinson catalyst.15 However, reduction of 23
with DIBAL-H did not occur, probably for a steric
reason (Scheme 9).
To solve this problem, the Barton decarboxylation
protocol16 was next examined. Alkaline hydrolysis of
ester 23 gave carboxylic acid 24. Condensation of acid
24 with N-hydroxy-2-thiopyridone gave thiohyroxam-
ate 25, which was heated with Bu3SnH and AIBN to
Table 1. Vinyl sulfide formation and methylenation of ketones 14
Entry
Conditions
Product
Yield (%)
1
2
3
4
Ph2P(O)CH2SPh (3 equiv.), BuLi (3 equiv.), THF
Ph2P(O)CH2SPh (3 equiv.), BuLi (3 equiv.), THF, HMPA
Ph2P(O)CH2SPh (3 equiv.), BuLi (3 equiv.), CeCl3, THF, then NaH, THF
Tebbe reagent
15a
15a
15a
15b
7
20
73
28

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O. Tamura et al. / Tetrahedron: Asymmetry 14 (2003) 3033–3041
afford decarboxylated compound 26 in 52% yield
from 23. When compound 26 was treated with Raney
nickel in boiling methanol, O-methylaphanorphine 29
was obtained in 65% yield. Formation of 29 can be
explained by a three-step sequence involving deprotec-
tion of the benzyloxycarbonyl group, desulfurization,
and reductive methylation of the resulting amine 27
via iminium ion 28, which was generated from amine
27 with formaldehyde derived from methanol.17
Finally, synthesis of (−)-aphanorphine 1 was accom-
plished by demethylation of 29 by the previously
reported method3d (Scheme 10).
3. Conclusions
Synthesis of (−)-aphanorphine was accomplished by
the use of sulfur-directed aryl radical cyclization. In
this synthesis, the phenylthio group plays an impor-
Scheme 10.
tant role not only for efficient radical cyclization but
also for availability of radical precursors. This synthe-
sis clearly demonstrates the value of sulfur-directed
aryl radical cyclization for the construction of a ben-
zylic quaternary center in a considerably complex
molecule.
4. Experimental
4.1. General
Melting points are uncorrected. IR spectra were
recorded with a Shimazu FTIR-8100 spectrophotome-
Scheme 8.
1
ter for solutions in CHCl3. H and 13C NMR spectra
were measured on a JEOL JNM-EX 270 or a JEOL
JNM-GSX 500 spectrometer. l Values quoted are rel-
ative to tetramethylsilane. High resolution mass spec-
tra (HRMS) were obtained with a JEOL JMS-SX 102
instrument. Column chromatography was performed
on silica gel 60 PF254 (Nacalai Tesque) under
pressure.
Scheme 9.

O. Tamura et al. / Tetrahedron: Asymmetry 14 (2003) 3033–3041
3037
4.2. (4R)-1-Benzyloxycarbonyl-2-[(2-bromophenyl)-
methyl]-2-methoxycarbonyl-4-(tert-butyldimethylsily-
loxy)pyrrolidine, 11
extracted with CHCl3. The organic phase was washed
with brine, dried (MgSO4), and concentrated under
reduced pressure to give crude carboxylic acid (117 mg)
as an oil. This material was used for the next step
without purification. To a solution of the carboxylic
acid (83 mg) in THF (8 mL) were added diphenylphos-
phoryl azide (526 mg, 1.91 mmol) and Et3N (351 mg,
3.44 mmol) at rt, and the mixture was stirred for 2 h at
the same temperature. A saturated solution of NaHCO3
(30 mL) was added to the mixture, and the whole was
extracted with AcOEt. The organic phase was washed
with brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel with hexane–AcOEt (4:1)
to give 13 (41.2 mg, 52%) as an oil. [h]2D4 −51.5 (c 0.43,
CHCl3); IR (CHCl3) 1792, 1701 cm−1. Rotamers of 13
To a stirred solution of 99 (1.71 g, 4.34 mmol) in THF
(7 mL) was added dropwise a 1.0 M solution of
LiN(SiMe3)2 in THF (5.21 mL, 5.21 mmol) at −20°C.
After 2 h, a solution of 2-bromobenzyl bromide (1.30 g,
5.21 mmol) in THF (4 mL) was added to the mixture at
−20°C, and then the mixture was stirred at rt for 3 h.
The mixture was diluted with a saturated solution of
NH4Cl, and extracted with AcOEt. The organic phase
was washed with brine, dried (MgSO4), and concen-
trated under reduced pressure. The residue was sub-
jected to column chromatography on silica gel with
hexane–AcOEt (10:1) to give an inseparable 4:1 mixture
of 11a and 11b (2.34 g, 96%). IR (CHCl3) 1740, 1700
cm−1. Rotamers of both 11a and 11b were observed by
1
were observed by the H NMR due to the benzyloxy-
1
carbonyl group H NMR (270 MHz, CDCl3) l 1.91
1
1
the H NMR due to their benzyloxycarbonyl group; H
NMR (270 MHz, CDCl3) l (−0.17) to (−0.02) (6H, m),
0.87 (s), 0.88 (s), 0.92 (s), 0.93 (s, total 9H), 1.97–2.25
(1H, m), 2.25–2.85 (1H, m), 3.22–3.42 (1H×4/5, m),
3.35–3.72 (4H, m), 3.63 (s), 3.79 (s), 3.88 (s), 3.90 (s,
total 3H), 4.43–4.65 (1H×1/5, m), 5.05–5.45 (2H, m),
6.57–7.44 (9H, m). Anal. calcd for C27H36BrNO5Si: C,
57.65; H, 6.45; N, 2.49. Found: C, 57.57; H, 6.47; N,
2.35.
(1H×1/2, br d, J=10.9 Hz), 2.13 (1H×1/2, br d, J=10.9
Hz), 2.37–2.61 (1H, m), 3.34–3.98 (4H, m), 4.20–4.35
(1H, m), 5.14 (1H×1/2, d, J=12.5 Hz), 5.33 (1H×1/2, d,
J=12.5 Hz), 5.13–5.20 (1H, m), 6.84–7.55 (9H, m);
HRMS calcd for C20H1879BrO4N 415.0419, found
415.0414.
4.5. 1-Benzyloxycarbonyl-2-[(2-bromophenyl)methyl)]-2-
methoxycarbonyl-4-oxopyrrolidine, 14
4.3. (4R)-1-Benzyloxycarbonyl-2-[(2-bromophenyl)-
To a stirred solution of 12a (1.58 g, 3.52 mmol) in
CH2Cl2 (10 mL) were added PCC (1.52 g, 7.03 mmol)
and Florisil® (3 g) at rt. After 10 h, the mixture was
diluted with Et2O and filtered through a pad of silica
gel, and the filtrate was concentrated under reduced
pressure. The residue was purified by column chro-
matography on silica gel with hexane–AcOEt (4:1) to
give 14 (1.49 g, 97%) as a colorless oil. IR (CHCl3):
1767, 1748, 1707 cm−1. Rotamers of 14 were observed
methyl]-4-hydroxy-2-(methoxycarbonyl)pyrrolidine, 12
To a stirred solution of 11 (1.91 g, 3.39 mmol) in THF
(12 mL) was added dropwise a 1.0 M solution of
tetrabutylammonium fluoride in THF (3.73 mL, 3.73
mmol) at rt. After 2 h, the mixture was diluted with
water and extracted with AcOEt. The organic phase
was washed with brine, dried (MgSO4), and concen-
trated under reduced pressure. The residue was sub-
jected to column chromatography on silica gel with
hexane–AcOEt (4:1) to give an inseparable 4:1 mixture
of 12a and 12b (1.43 g, 94%). IR (CHCl3) 3021, 1740,
1698 cm−1. Rotamers of both 12a and 12b were
1
by the H NMR due to the benzyloxycarbonyl group
1H NMR (270 MHz, CDCl3) l 2.75 (1H, d, J=9.1 Hz),
2.95 (1H, d, J=9.1 Hz), 3.29–3.94 (4H, m), 3.67 (3H×1/
2, s), 3.81 (3H×1/2, s), 5.17 (1H, d, J=12.2 Hz), 5.32
(1H, d, J=12.2 Hz), 6.96 (1H, br s), 7.09 (2H, br s),
7.36–7.40 (5H, m), 7.52–7.54 (1H, m). Anal. calcd for
C21H20BrNO5: C, 56.52; H, 4.52; N, 3.14. Found: C,
56.62; H, 4.64; N, 3.10.
1
observed by the H NMR due to their benzyloxycar-
1
bonyl group; H NMR (270 MHz, CDCl3) l 1.57 (1H,
br s), 2.05–2.30 (2H, m), 2.77–2.93 (1H, m), 3.48–3.82
(4H+1H×4/5, m), 3.53 (s), 3.69 (s), 3.75 (s), 3.87 (s,
total 3H), 4.30 (1H×1/5, quin, J=6.4 Hz), 5.07 (d,
J=11.3 Hz), 5.12 (d, J=12.5 Hz), 5.14 (d, J=12.5 Hz),
5.16 (d, J=11.9 Hz), 5.23 (d, J=11.3 Hz), 5.25 (d,
J=11.9 Hz), 5.28 (d, J=12.5 Hz), 5.34 (d, J=12.5 Hz,
total 2H), 6.83–6.89 (1H, m), 6.95–7.22 (2H, m), 7.34–
7.44 (5H, m), 7.51–7.56 (1H, m). Anal. calcd for
C21H22BrNO5: C, 56.26; H, 4.95; N, 3.12. Found: C,
56.09; H, 5.02; N, 3.20.
4.6. 1-Benzyloxycarbonyl-2-[(2-bromophenyl)methyl]-2-
methoxycarbonyl-4-(phenythiomethylene)pyrrolidine, 15a
(Table 1, entry 3)
A suspension of anhydrous CeCl3 (966 mg, 3.92 mmol)
in THF (18 mL) was stirred vigorously for 2 h at rt,
and then cooled to −78°C. To the suspension was
added a solution of PhSCHLiP(O)Ph2 [prepared by
treatment of a solution of PhSCH2P(O)Ph2 (1.09 g, 3.36
mmol) in THF (11 mL) with a 1.6 M solution of BuLi
in hexane (2.1 mL, 3.36 mmol) at −78°C] at −78°C for
20 min. After 30 min, a solution of 14 (500 mg, 1.12
mmol) in THF (10 mL) was added to the mixture at
−78°C, and then the mixture was allowed to warm to rt.
4.4. Benzyl (1R,4R)-2-Aza-1-[(2-bromophenyl)methyl]-5-
oxa-6-oxobicyclo[2.2.1]heptane-2-carboxylate, 13
A mixture of 12 (114 mg, 0.254 mmol), 5N NaOH (3
mL), and methanol (3 mL) was heated at reflux for 2 h.
After cooling, water (20 mL) was added to the mixture,
which was washed with Et2O. The aqueous phase was
acidified to pH 1–2 with 5N HCl, and the whole was
After stirring at rt for
3
h, N,N,N%,N%-tetra-
methylethylenediamine (455 mg, 3.92 mmol) was added

3038
O. Tamura et al. / Tetrahedron: Asymmetry 14 (2003) 3033–3041
to the mixture, and the mixture was stirred for 30 min.
The mixture was diluted with a saturated solution of
NaHCO3 (50 mL), and the whole was extracted with
CHCl3. The organic phase was dried (MgSO4) and
concentrated under reduced pressure to give a crude
adduct of 14 with PhSCH2P(O)Ph2 as a pale yellow oil.
The oil was dissolved in THF (10 mL). To the stirred
solution was added NaH (60% dispersion, 161 mg, 6.72
mmol) at rt. After 3 h, the mixture was diluted with a
saturated solution of NH4Cl, and the whole was
extracted with AcOEt. The organic phase was washed
with brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel with hexane–AcOEt (4:1)
to afford 15a (449 mg, 73%) as a mixture of geometrical
isomers. IR (CHCl3) 1742, 1701, 1584 cm−1. Rotamers
of 15a were observed by the 1H NMR due to the
ture was further heated at reflux for 3 h. After cooling,
the mixture was concentrated under reduced pressure.
The residue was dissolved in Et2O (40 mL), and the
solution was vigorously stirred with an 8% solution of
KF overnight. The organic phase was separated, and
the aqueous phase was further extracted with Et2O. The
organic phases were combined, washed with brine,
dried (MgSO4), and concentrated under reduced pres-
sure. The residue was purified by column chromatogra-
phy on silica gel with hexane–AcOEt (4:1) to give 16a
(235 mg, 71%) as a colorless oil. IR (CHCl3) 1744, 1700
1
cm−1. Rotamers of 16a were observed by the H NMR
1
and 13C NMR due to the benzyloxycarbonyl group. H
NMR (270 MHz, CDCl3) l 2.28 (1H, br d, J=10.9
Hz), 2.43 (1H×1/2, br d, J=10.9 Hz), 2.44 (1H×1/2, dd,
J=10.9, 2.1 Hz), 3.34–3.79 (6H, m), 3.44 (3H×1/2, s),
3.81 (3H×1/2, s), 4.94 (1H×1/2, d, J=12.5 Hz), 4.95
(1H×1/2, d, J=12.2 Hz), 5.10 (1H×1/2, d, J=12.5 Hz),
5.21 (1H×1/2, d, J=12.2 Hz), 7.12–7.39 (14H, m); 13C
NMR (125.7 MHz, CDCl3) l 36.7, 37.8, 38.6, 38.7,
44.1, 45.2, 46.1, 46.9, 52.3, 52.6, 60.4, 61.1, 65.6, 65.9,
66.9, 67.3, 123.8, 124.0, 126.2, 126.4, 127.5, 127.6,
127.8, 128.1, 128.2, 125.4, 128.5, 128.6, 128.7, 129.1,
129.5, 129.6, 129.8, 130.1, 130.7, 133.8, 134.2, 136.1,
136.4, 136.9, 139.8, 140.1, 153.5, 172.3, 172.5. Anal.
calcd for C28H28NO4S: C, 71.01; H, 5.75; N, 2.96.
Found C, 70.73; H, 5.92; N, 2.96.
1
benzyloxycarbonyl group. H NMR (270 MHz, CDCl3)
l 2.82 (1H, br d, J=18.6 Hz), 3.16 (1H×3/5, br d,
J=18.6 Hz), 3.18 (1H×2/5, br d, J=18.6 Hz), 3.48
(3H×2/5, s), 3.79 (3H×3/5, s), 3.51–4.29 (4H, m), 5.14
(1H×3/5, d, J=12.5 Hz), 5.19 (1H×2/5, d, J=12.2 Hz),
5.28 (1H×2/5, d, J=12.2 Hz), 5.30 (1H×3/5, d, J=12.5
Hz), 5.74 (1H×3/5, br s), 5.78 (1H×2/5, br s), 6.90–7.50
(14H, m). Anal. calcd for C28H26BrNO4S: C, 60.87; H,
4.74; N, 2.54. Found: C, 60.74; H, 4.80; N, 2.66.
4.7. 1-Benzyloxycarbonyl-2-[(2-bromophenyl)methyl]-2-
methoxycarbonyl-4-(methylene)pyrrolidine, 15b (Table
1, entry 4)
4.9. (1S*,4S*)-3-Benzyloxycarbonyl-4-methoxycarbonyl-
1-methyl-2,3,4,5-tetrahydro-1,4-methano-3-benzazepine,
16b and 1-benzyloxycarbonyl-2-benzyl-2-methoxycar-
bonyl-4-methyl-3-pyrroline, 17
To a stirred solution of 14 (120 mg, 0.269 mmol) in
THF (1 mL) was added a 0.5 M solution of m-chloro-m-
methylene[bis(cyclopentadi-
Using a procedure similar to that described above for
16a, compound 15b (42 mg, 0.095 mmol) was treated
with Bu3SnH (33 mg, 0.113 mmol) and AIBN (2.0 mg,
11 mmol) in boiling benzene (14 mL). After work-up,
the crude material was chromatographed on silica gel
with hexane–AcOEt (4:1). The first fraction gave 17
(5.9 mg, 17%), and the second fraction gave 16b (6.9
mg, 20%). 16b: IR (CHCl3) 1740, 1700 cm−1. Rotamers
of 16b were observed by the 1H NMR due to the
enyl)titanium]dimethylalminum (Tebbe reagent) in
toluene (0.54 mL, 0.27 mmol) at −20°C. The mixture
was stirred at −20°C for 20 min, then at rt for 3 h. An
aqueous 10% solution of NaOH (0.5 mL) and Et2O (30
mL) were added to the mixture. The mixture was
filtered through a pad of Celite®, and the filtrate was
dried (MgSO4) and concentrated under reduced pres-
sure. The residue was purified by column chromatogra-
phy on silica gel with hexane–AcOEt (4:1) to give 15b
(32.9 mg, 28%) as a colorless oil. IR (CHCl3) 1740,
1
benzyloxycarbonyl group. H NMR (270 MHz, CDCl3)
l 1.55 (3H×1/2, s), 1.56 (3H×1/2, s), 2.13 (1H, dd,
J=10.9, 9.6 Hz), 2.27 (1H, br d, J=10.9 Hz), 3.41–3.56
(4H, m), 3.45 (3H×1/2, s), 3.82 (3H×1/2, s), 4.93 (1H×1/
2, d, J=12.5 Hz), 4.96 (1H×1/2, d, J=12.2 Hz), 5.10
(1H×1/2, d, J=12.5 Hz), 5.21 (1H×1/2, d, J=12.2 Hz),
7.13–7.40 (9H, m); HRMS calcd for C22H23NO4
365.1627, found 365.1324. 17: IR (CHCl3) 1738, 1705
1
1700 cm−1. Rotamers of 15b were observed by the H
1
NMR due to the benzyloxycarbonyl group. H NMR
(270 MHz, CDCl3) l 2.75 (1H, br d, J=15.5 Hz), 2.94
(1H, d, J=15.5 Hz), 3.53–3.70 (3H, m), 3.48 (3H×1/3,
s), 3.78 (3H×2/3, s), 4.08–4.18 (1H, m), 4.55 (2H×1/3,
br s), 4.65 (2H×2/3, br s), 5.07 (1H×1/3, d, J=12.0 Hz),
5.14 (1H×2/3, d, J=12.5 Hz), 5.27 (1H×1/3, d, J=12.0
Hz), 5.30 (1H×2/3, d, J=12.5 Hz), 6.90–6.94 (1H, m),
6.99–7.14 (2H, m), 7.32–7.49 (6H, m); HRMS calcd for
C22H2279BrO4N 443.0732, found 443.0750.
1
cm−1. Rotamers of 17 were observed by the H NMR
due to the benzyloxycarbonyl group. 1H NMR (270
MHz, CDCl3) l 2.17 (3H, s), 3.14–3.20 (2H, m), 3.48–
4.20 (2H, m), 3.51 (3H×1/3, s), 3.76 (3H×2/3, s), 5.10–
5.25 (3H, m), 6.94–6.98 (2H, br d, J=9.6 Hz), 7.10–
7.40 (8H, m); HRMS calcd for C22H23NO4 365.1628,
found 365.1638.
4.8. (1S*,4R*)-3-Benzyloxycarbonyl-4-methoxycar-
bonyl-1-(phenylthio)methyl-2,3,4,5-tetrahydro-1,4-meth-
ano-3-benzazepine, 16a
4.10. (4R)-1-Benzyloxycarbonyl-2-[(2-bromo-4-
methoxyphenyl)methyl]-4-(tert-butyldimethylsilyloxy)-2-
(methoxycarbonyl)pyrrolidine, 19
To a solution of 15a (384 mg, 0.695 mmol) in refluxing
benzene (70 mL) was added dropwise a solution of
Bu3SnH (303 mg, 1.04 mmol) and AIBN (80 mg, 0.45
mmol) in benzene (30 mL) over 40 min, and the mix-
Using a procedure similar to that described above for

O. Tamura et al. / Tetrahedron: Asymmetry 14 (2003) 3033–3041
3039
1
11, a solution of 9 (5.75 g, 14.6 mmol) in THF (60 mL)
was treated with a 1.0 M solution of LiN(SiMe3)2 in
THF (17.5 mL, 17.5 mmol) followed by a solution of
2-bromo-4-methoxybenzyl bromide (18, 4.91 g, 17.5
mmol) in THF (15 mL). After work-up, the crude
material was subjected to column chromatography on
silica gel with hexane–AcOEt (4:1) to give an insepara-
ble 4:1 mixture of 19a and 19b (7.86 g, 91%). IR
(CHCl3): 1740, 1698 cm−1. Rotamers of both 19a and
carbonyl group; H NMR (270 MHz, CDCl3) l 2.74
(1H, d, J=18.5 Hz), 2.95 (1H, d, J=18.5 Hz), 3.29–
3.94 (4H, m), 3.57 (3H×1/2, s), 3.80 (3H×1/2, s), 3.76
(3H, s), 5.16 (1H, d, J=12.2 Hz), 5.31 (1H, d, J=12.2
Hz), 6.63 (1H, br d, J=9.6 Hz), 6.82 (1H, br d, J=6.8
Hz), 7.05 (1H, br s), 7.37–7.40 (5H, m). Anal. calcd for
C22H22BrNO6: C, 55.48; H, 4.66; N, 2.94. Found: C,
55.23; H, 4.67; N, 2.89.
1
19b were observed by the H NMR due to their benzyl-
4.13. (S)-1-Benzyloxycarbonyl-2-(2-bromo-4-methoxy-
phenyl)methyl-2-methoxycarbonyl-4-(pheny-
thiomethylene)pyrrolidine, 22
oxycarbonyl group; 1H NMR (270 MHz, CDCl3) l
−0.13 to 0.12 (6H, m), 0.75 (s), 0.76 (s), 0.79 (s, total
9H), 1.96–2.23 (1H, m), 2.42–2.67 (1H, m), 3.16–3.26
(1H×4/5, m), 3.36–3.63 (4H, m), 3.50 (s), 3.74 (s), 3.76
(s), 3.77 (s, total 6H), 4.41–4.51 (1H×1/5, m), 4.94–5.33
(2H, m), 6.57–7.44 (8H, m). Anal. calcd for
C28H38BrNO6Si: C, 56.75; H, 6.46; N, 2.36. Found: C,
56.95; H, 6.59; N, 2.33.
Using a procedure similar to that described above for
15a, compound 21 (1.30 g, 2.73 mmol) was treated with
CeCl3 (2.35 g, 9.55 mmol) and PhSCHLiP(O)Ph2 [pre-
pared from PhSCH2P(O)Ph2 (2.66 mg, 8.19 mmol) and
a 1.6 M solution of BuLi in hexane (5.15 mL, 8.19
mmol)] in THF (57 mL). After work-up, the crude
material was exposed to NaH (60% dispersion, 800 mg,
20 mmol) at rt in THF (50 mL). After work-up, the
crude product was purified by column chromatography
on silica gel with hexane–AcOEt (4:1) to afford 22 (1.27
g, 80%) as an inseparable mixture of geometrical iso-
mers. IR (CHCl3) 1738, 1701, 1605 cm−1; Two rotamers
of 22 were observed by the 1H NMR due to the
4.11. (2R,4R)-1-Benzyloxycarbonyl-2-(2-bromo-4-
methoxyphenyl)methyl-4-hydroxy-2-(methoxycarbonyl)-
pyrrolidine, 20
Using a procedure similar to that described above for
12, a solution of 19 (579 mg, 0.98 mmol) in THF (5
mL) was treated with a 1.0 M solution of tetra-
butylammonium fluoride in THF (1.1 mL, 1.1 mmol).
After work-up, the crude material was chro-
matographed on silica gel with hexane–AcOEt (4:1) to
give a 4:1 mixture of 20 and its diastereomer (451 mg,
97%). The mixture was further purified by recrystalliza-
tion from hexane–Et2O to afford 20 (318 mg, 68% from
19) in diastereomerically pure form. Mp 53–55°C; [h]D23
−154.6 (c 0.50, CHCl3); IR (CHCl3) 3021, 1744, 1698
cm−1. Two rotamers (3:2) of 20 were observed by the
1H NMR due to the benzyloxycarbonyl group; 1H
NMR (270 MHz, CDCl3) l 2.10 (1H, br d, J=14.5
Hz), 2.22 (1H×3/5, dd, J=14.5, 4.6 Hz), 2.27 (1H×2/5,
dd, J=14.5, 5.3 Hz), 2.83 (1H×3/5, dd, J=11.9, 4.3
Hz), 2.92 (1×2/5, dd, J=11.9, 4.3 Hz), 3.44–3.81 (6H,
m), 3.54 (3H×2/5, s), 3.76 (3H×3/5, s), 3.77 (3H×2/5, s),
3.87 (3H×3/5, s), 5.11 (1H×3/5, d, J=12.5 Hz), 5.17
(1H×2/5, d, J=11.9 Hz), 5.26 (1H×2/5, d, J=11.9 Hz),
5.34 (1H×3/5, d, J=12.2 Hz), 6.58 (1H×3/5, dd, J=8.6,
2.6 Hz), 6.72–6.87 (1H+1H×2/5, m), 7.07 (1H×3/5, d,
J=2.6 Hz), 7.09 (1H×2/5, d, J=2.3 Hz), 7.20–7.50 (4H,
m). Anal. calcd for C22H24BrNO6: C, 55.24; H, 5.06; N,
2.93. Found: C, 55.09; H, 5.17; N, 2.93.
1
benzyloxycarbonyl group; H NMR (270 MHz, CDCl3)
l 2.79 (1H, d, J=16.8 Hz), 3.16 (1H, dd, J=16.8, 5.6
Hz), 3.44–4.29 (4H, m), 3.47 (3H×1/2, s), 3.65 (3×1/2,
s), 3.68 (3H×1/2, s), 3.78 (3H×1/2, s), 5.11 (1H×1/2, d,
J=12.2 Hz), 5.14 (1H×1/2, d, J=12.5 Hz), 5.28 (1H×1/
2, d, J=12.2 Hz), 5.11 (1H×1/2, d, J=12.5 Hz), 5.77
(1H, br d, J=7.6 Hz), 6.60 (1H×1/2, dd, J=8.6, 2.6
Hz), 6.70 (1H×1/2, dd, J=8.6, 2.6 Hz), 6.76 (1H×1/2,
d, J=8.6 Hz), 6.94 (1H×1/2, d, J=8.6 Hz), 7.07 (1H, d,
J=8.6 Hz), 6.97–7.42 (10H, m). Anal. calcd for
C29H28BrNO5S: C, 59.80; H, 4.84; N, 2.40. Found: C,
60.10; H, 4.83; N, 2.20.
4.14. (1S,4R)-3-Benzyloxycarbonyl-8-methoxy-4-
methoxycarbonyl-1-phenylthiomethyl-2,3,4,5-tetrahydro-
1,4-methano-3-benzazepine, 23
Using a procedure similar to that described above for
16a, compound 22 (1.30 g, 2.23 mmol) was treated with
Bu3SnH (974 mg, 3.35 mmol) and AIBN (80 mg, 0.45
mmol) in benzene (250 mL). After work-up, the crude
product was purified by column chromatography on
silica gel with hexane-AcOEt (4:1) to give 23 (855 mg,
76%) as a colorless oil. [h]2D5 −77.6 (c 0.60, CHCl3); IR
(CHCl3) 1741, 1698 cm−1; Two rotamers (1:1) of 23
4.12. (R)-1-Benzyloxycarbonyl-2-(2-bromo-4-
methoxyphenyl)methyl-2-methoxycarbonyl-4-oxopyrro-
lidine, 21
1
were observed by the H NMR due to the benzyloxy-
1
carbonyl group; H NMR (270 MHz, CDCl3) l 2.26
(1H, br d, J=10.9 Hz), 2.41 (1H, m), 3.36–3.79 (6H,
m), 3.44 (3H×1/2, s), 3.77 (3H, s), 3.80 (3H×1/2, s), 4.94
(1H×1/2, d, J=12.5 Hz), 4.96 (1H×1/2, d, J=12.5 Hz),
5.10 (1H×1/2, d, J=12.5 Hz), 5.20 (1H×1/2, d, J=12.5
Hz), 6.77 (1H×1/2, dd, J=8.2, 2.6 Hz), 6.79 (1H×1/2,
dd, J=8.3, 2.6 Hz), 6.86 (1H, d, J=2.3 Hz), 7.05
(1H×1/2, d, J=8.3 Hz), 7.11 (1H×1/2, d, J=8.6 Hz),
7.18–7.38 (10H, m). Anal. calcd for C29H29NO5S: C,
69.16; H, 5.80; N, 2.78. Found: C, 68.89; H, 5.93; N,
2.60.
Using a procedure similar to that described above for
14, a solution of 20 (82.0 mg, 0.172 mmol) in CH2Cl2
(0.8 mL) was treated with PCC (100 mg, 0.344 mmol)
and Florisil® (200 mg). After work-up, the crude mate-
rial was purified by column chromatography on silica
gel with hexane–AcOEt (4:1) to give 21 (97.4 mg, 97%)
as a colorless oil. [h]2D3 −85.2 (c 1.12, CHCl3); IR
(CHCl3) 1767, 1748, 1707 cm−1. Two rotamers of 21
1
were observed by the H NMR due to the benzyloxy-

3040
O. Tamura et al. / Tetrahedron: Asymmetry 14 (2003) 3033–3041
4.15.
(1S,4R)-3-Benzyloxycarbonyl-8-methoxy-1-
mg, 65%) as a colorless oil. [h]2D3 +9.39 (c 0.30, CHCl3),
{lit.3a [h]2D9 +8.5 (c 0.35, CHCl3), lit.3d [h]2D1 +10.4 (c
1.24, CHCl3)}; 1H NMR (270 MHz, CHCl3) l 1.47
(3H, s), 1.84 (1H, d, J=10.9 Hz), 2.00 (1H, dd, J=9.6,
5.9 Hz), 2.46 (3H, s), 2.71 (1H, d, J=8.8 Hz), 2.78–2.91
(3H, m), 3.38 (1H, m), 3.78 (3H, s), 6.68 (1H, dd,
J=8.3, 2.6 Hz), 6.78 (1H, d, J=2.6 Hz), 7.02 (1H, d,
J=8.3 Hz); 13C NMR (67.8 MHz, CDCl3) l 21.3, 34.9,
41.2, 41.6, 43.1, 55.3, 61.3, 70.8, 109.1, 111.2, 125.5,
phenylthiomethyl-2,3,4,5-tetrahydro-1,4-methano-3-benz-
azepine, 26
A solution of 23 (1.23 g, 2.44 mmol) in 5N aqueous
NaOH–MeOH (2:1, 15 mL) was heated at reflux for 2
h. The mixture was diluted with water (40 mL) and
washed with Et2O. The aqueous phase was acidified to
pH 1–2 and extracted with CHCl3. The organic phase
was washed with brine, dried (MgSO4), and concen-
trated under reduced pressure to give crude carboxylic
1
130.2, 147.8, 157.9. These H and 13C NMR spectral
data are identical with those reported.3d
1
acid 24 (1.20 g, quant.) as a pale yellow oil. H NMR
(270 MHz, CDCl3) l 2.34 (1H, d, J=11.2 Hz), 2.52
(1H, d, J=11.2 Hz), 3.34–3.80 (6H, m), 3.77 (3H, s),
4.99 (1H, br d, J=12.5 Hz), 5.12 (1H, dd, J=12.2, 8.9
Hz), 6.76–6.88 (2H, m), 7.03 (1H×1/2, d, J=8.3 Hz),
7.11 (1H×1/2, d, J=8.6 Hz), 7.20–7.39 (10H, m). One
proton of carboxylic acid was not observed in this
spectrum. This compound was used immediately for the
next step without further purification. To a stirred
solution of the crude acid 24 (1.13 g, 2.30 mmol) in
benzene (30 mL) was added a solution of 2-mercap-
topyridine N-oxide (350 mg, 2.76 mmol), DMAP (421
4.17. (−)-Aphanorphine, 1
According to the reported method,3a,d compound 29
was converted to 1, mp 200–210°C (lit.3a mp 215–
222°C). [h]2D1 −23.6 (c 0.20, MeOH) {lit.3d [h]2D3 −24.0 (c
1
0.33, MeOH)}; H NMR (270 MHz, CD3OD) l 1.44
(3H, s), 1.86 (1H, d, J=10.9 Hz), 2.02 (1H, dd, J=
10.9, 5.6 Hz), 2.48 (3H, s), 2.73 (1H, d, J=9.2 Hz), 2.83
(1H, br d, J=16.5 Hz), 2.87 (1H, d, J=9.2 Hz), 3.03
(1H, d, J=16.5 Hz), 3.42 (1H, quin, J=2.6 Hz), 6.91
(1H, dd, J=8.3, 2.3 Hz), 6.65 (1H, d, J=2.3 Hz), 6.52
(1H, d, J=8.3 Hz); 13C NMR (67.8 MHz, CD3OD) l
21.6, 36.5, 42.1, 42.7, 44.2, 63.5, 72.6, 110.9, 114.5,
125.2, 131.2, 148.5, 156.5. These 1H and 13C NMR
spectral data are identical with those provided by Pro-
fessor Ogasawara.
mg,
3.45
mmol),
and
1-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide hydrochloride (EDC, 660
mg, 3.45 mmol) in benzene (10 mL) at rt. After 30 min,
to the mixture was added a solution of Bu3SnH (2.00 g,
6.87 mmol) and AIBN (110 mg, 0.67 mmol) in benzene
(150 mL), and then the mixture was heated at reflux for
3 h. After cooling, the mixture was concentrated under
reduced pressure. The residue was dissolved in Et2O (40
mL), and then the solution was vigorously stirred with
an 8% solution of KF (30 mL) overnight. The organic
phase was separated, and the aqueous phase was fur-
ther extracted with Et2O. The organic phases were
combined, washed with brine, dried (MgSO4) and con-
centrated under reduce pressure. The residue was
purified by column chromatography on silica gel with
hexane-AcOEt (4:1) to afford 26 (530 mg, 52%) as a
colorless oil. [h]D25 −95.6 (c 0.76, CHCl3); IR (CHCl3)
1693 cm−1. Two rotamers (1:1) of 26 were observed by
Acknowledgements
We are grateful to Professor K. Ogasawara (Tohoku
1
University) for providing H and 13C NMR spectra of
(−)-aphanorphine.
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