An effective route to (-)-aphanorphine using D-tyrosine as a chiral building block

Article abstract of DOI:10.1055/s-2006-958931

A stereoselective approach toward a naturally occurring alkaloid, (-)-aphanorphine, has been achieved via a series of reactions from Boc-D-tyrosine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-958931

PAPER
55
An Effective Route to (–)-Aphanorphine Using D-Tyrosine as a Chiral Building
Block
S
ynthesis of (–)-Aphan
i
orphin
n
e
from
D
-TyrosineLi,*a Peijie Zhou,a Hans F. Rothb
a
Department of Neurosciences, Georgetown University Medical Center, 4000 Reservoir Road NW, Washington DC 20057, USA
Fax +1(202)6870617; E-mail: ml258@georgetown.edu
b
Orgchem Technologies, Inc, 2201 W. Campbell Dr, Chicago, IL 60612, USA
Received 1 August 2006
(–)-aphanorphine (1). Honda’s group employed a samari-
um diiodide promoted reductive carbon–nitrogen bond
cleavage to provide a benzazepinone as a key intermedi-
ate. Gallagher and co-workers3 successfully applied a lac-
tam methodology by using cyclic sulfamidates as lactam
precursors.9 As part of our long-term drug discovery pro-
gram employing chiral pool substrates, we have recently
launched an asymmetric synthesis of (–)-aphanorphine
(1) and its analogues. Herein, we wish to report an alter-
native synthesis of 1, which complements Honda’s strate-
gy, by using commercially available Boc-D-tyrosine as
the starting material.
Abstract: A stereoselective approach toward a naturally occurring
alkaloid, (–)-aphanorphine, has been achieved via a series of reac-
tions from Boc-D-tyrosine.
Keywords: aphanorphine, rhodium 1,3-dicarbonyl carbenoid, C–H
insertion, intra-annular chirality transfer, thioketal
Aphanorphine (1) is a tricyclic alkaloid featuring a 3-benz-
azepine skeleton, which bears a striking similarity to the
synthetic analgesic pentazocine (2) (Figure 1).1 The first
isolation of 1 was reported by Clardy and co-workers2 in
1988 from the freshwater blue-green alga Aphanizomenon
flosaquae along with other neurotoxins, such as saxitoxin
and neosaxitoxin.
As outlined in the retrosynthetic analysis, our approach
toward (–)-aphanorphine (1) relied on a substrate-con-
trolled asymmetric alkylation of ester 3 to establish the
benzylic quaternary carbon center. The 3-benzapine skel-
eton of 3 could be constructed via a rhodium 1,3-dicarbo-
nyl carbenoid-mediated C–H insertion to generate the
C(1)–C(9a) bond. This called for a 1,3-dicarbonyl precur-
sor 4, which in turn could be prepared from commercially
available Boc-D-tyrosine 5 (Scheme 1).
H
H
4
N
N
3
1
9a
HO
HO
2
(–)-aphanorphin (1)
pentazocine (2)
NH2
CO2H
H
NMe
H
NBoc
HO
HO
D-tyrosine
MeO
O
Figure 1 (–)-Aphanorphin (1), pentazocine (2) and D-tyrosine
TMSEO
O
H
(–)-aphanorphin (1)
3
Due to its significant bioactivity and highly rigid struc-
ture, the narcotic aphanorphine (1) has received signifi-
cant attention and diverse synthetic strategies toward 1
have been developed by different research teams.3 A for-
mal synthesis of 1 was realized by Fadel and Arzel in
1997,4 using an enzyme-catalyzed asymmetrization as a
key step. Later, Ishibashi and co-workers5 reported a
Bu3SnH-mediated aryl radical cyclization to establish the
scaffold of (–)-aphanorphine (1) with high selectivity. In
2001 and 2003, Funk6 and Zhai7 published their synthetic
endeavors, respectively. In constructing the A/B fused
ring system, both groups employed a Lewis acid catalyzed
intramolecular electrophilic ring cyclization. Most re-
cently, Honda8 and Gallagher3 reported their entries to
H
NHBoc
NBoc
O
CO2H
HO
MeO
N2
Boc-D-tyrosine (5)
TMSEO
O
4
Scheme 1 Retrosynthetic analysis of aphanorphine (1)
The implementation of this strategy is delineated in
Scheme 2. Boc-D-tyrosine 5 was coupled with N,O-di-
methylhydroxylamine hydrochloride to give the corre-
sponding Weinreb amide 6 in 87% yield without any
noticeable racemization (1H NMR).10 Further methylation
of the amine as well as the side chain was performed ac-
cording to the procedures reported by Gesson.11 However,
obvious isomerization (9:1) was observed as evidenced
from 1H NMR spectrum and hence slightly modified reac-
SYNTHESIS 2007, No. 1, pp 0055–0060
x
x
.
x
x
.2
0
0
6
Advanced online publication: 12.12.2006
DOI: 10.1055/s-2006-958931; Art ID: M04806SS
© Georg Thieme Verlag Stuttgart · New York

56
M. Li et al.
PAPER
tion conditions (– 20 °C, 16 h) were applied to circumvent termediate 9. The transformation of 9 to a 2-diazo-1,3-di-
the strong base-induced racemization. Consequently, in- carbonate proceeded uneventfully in mild conditions,14
termediate 7 was obtained in a moderate 75% yield with a giving the desired compound 4 as a sole product. Howev-
negligible racemization ratio of 98:2 as indicated by er, use of excess p-toluenesulfonyl azide made the purifi-
chiral-phase HPLC.12 On treatment with an excess cation of 4 extremely difficult and that would inevitably
amount of 8, which was prepared according to the proto- contaminate the desired product. Therefore, somewhat
cols reported by Shioiri and co-workers,13 compound 7 less than the stoichiometric amount of p-toluenesulfonyl
was cleanly converted into the desired 1,3-dicarbonyl in- azide was employed in performing this reaction.14
H
H
H
NBoc
OMe
NHBoc
NHBoc
b
a
OMe
N
CO2H
MeO
O
N
HO
O
HO
Boc-D-tyrosine (5)
7
6
c, 8
H
H
O
H
NBoc
NBoc
O
NBoc
O
d
e
MeO
O
O
MeO
N2
MeO
TMSEO
TMSEO
TMSEO
O
3
4
9
f, 11
H
H
H
NBoc
O
N
H
g
h
N
O
MeO
MeO
O
MeO
OH
TMSEO
O
O
O
13
12
10a (1S,4R) : 10b (1R,4R) 12:1
i
H
H
H
j
k
N
N
NMe
SMe
SMe
MeO
MeO
HO
O
14
(–)-aphanorphin (1)
15
Si
TMSE =
Br
Br
N+
N+
O
O
O
N
N
Si
O
8
11
Scheme 2 Reagents and conditions: (a) DCC, DMAP, N,O-dimethylhydroxylamine hydrochloride, CH2Cl2, r.t., 87%; (b) NaH, MeI, DMF,
–20 °C, 75%; (c) LDA, 8, THF, –78 °C to 25 °C, 97%; (d) DIPEA, TsN3, CH2Cl2, r.t., 88%; (e) Rh2(OAc)4, CF3CONH2, CH2Cl2, r.t., 78%; (f)
aq 50% KOH, MeI, 11, toluene, –40 °C, 90%; (g) CF3CO2H, CH2Cl2, r.t.; (h) BEP, DIPEA, –20 °C to r.t., 93% in two steps; (i) MeSH, Me3SiCl,
CHCl3, r.t., 86%; (j) LiAlH4, THF, r.t. to reflux, 83%; (k) BBr3, CH2Cl2, –20 °C to 0 °C, 88%.
Synthesis 2007, No. 1, 55–60 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-Aphanorphine from D-Tyrosine
57
With 4 in hand, we then investigated the construction of was recovered. Further optimization led to the utilization
the A/B fused rings. Considering the high activity of the of the least bulky methanethiol,23 which successfully con-
rhodium 1,3-dicarbonyl carbenoid,15 we explored the verted the ketone 13 to the corresponding thioketal 14 in
means to direct the reaction towards the formation of de- 86% yield. Employing a known protocol,3,24 ensuing re-
sired C–H insertion product 3. Exposure of 4 to rhodium duction and deprotection proceeded completely in a con-
diacetate furnished 3 in 54% yield along with a minor sistent manner to deliver the target (–)-aphanorphine
product identified as an azulene derivative (24%).16 As an (1), whose spectral data were identical to those previously
optimization, we explored the carbenoid-induced cycliza- reported.2
tion by employing rhodium trifluoroacetamide as the cat-
In summary, an alternative total synthesis of (–)-aphanor-
phine (1) was accomplished using D-tyrosine as a chiral
alyst, which has been successfully used by Moody and co-
workers17 in their synthetic endeavors towards diazon-
building block. This synthesis featured a rhodium car-
amide A. Similarly to Moody’s result, the more active
benoid-mediated C–H insertion and an asymmetric phase-
transfer methylation as key steps. It merits comment that
rhodium trifluoroacetamide facilitated the cyclization of 4
by enhancing the yield and shortening the reaction time as
by switching from D-tyrosine to L-tyrosine, the enantio-
well. The desired 3 was obtained in 78% yield, which
mer of (–)-aphanorphine (1) could also be obtained in an
could suffice the amount requirement for further modifi-
optically pure form.
cation.
The next task was the stereoselective introduction of a
Chemicals were purchased from Aldrich or Acros Chemical Corpo-
methyl group onto the C1 of ring B via the alkylation of
1,3-dicarbonate 3. As outlined in our retrosynthetic strat-
egy, we hypothesized that the chiral amine function at C4
would serve to direct the asymmetric alkylation. The me-
thylation of 3 proceeded to deliver the methylated diaste-
reomers in a total 93% yield by employing NaH and MeI
at fairly low temperature (–40 °C). Further flash chro-
matographic purification gave the desired (1S,4R)-10a
and the unwanted (1R,4R)-10b in a ratio of 73:27, which
was unsatisfactory. Further optimization involved lower-
ing the reaction temperature as well as the utilization of
chiral ligand such as (–)-sparteine.18 However, no signifi-
cant improvement was observed for the enantioselectivity
of establishing the quaternary carbon center. To overcome
this problem, we employed a phase-transfer alkylation in
the presence of a catalytic amount of cinchona-derived
ammonium salt 11, which has been developed and suc-
cessfully used for synthesis of both natural and non-natu-
ral products.19 This method greatly enhanced the
stereoselectivity of the methylation by affording the de-
sired compound 10a and its diastereomer 10b in a ratio of
12:1 (based on isolated yield).
ration and used without further purification. Solvents were distilled
before use: CH2Cl2 was distilled from CaH2 and THF was distilled
from sodium wire. All reactions were performed under inert atmo-
sphere (argon or N2) unless otherwise noted. NMR spectra were re-
corded with a Varian Unity INOVA 300 at 300 MHz (1H), 75 MHz
1
(13C) at 25 °C. H chemical shifts (d) were reported in ppm with
Me4Si (d = 0.00) or CDCl3 (d = 7.26) as internal standards. 13C
chemical shifts were reported with CDCl3 (d = 77.00) or Me4Si
(d = 0.00) as internal standards. Optical rotations were recorded at
r.t. TLC was performed on Merck silica gel 60 F254 glass plates.
Flash column chromatography was performed using Merck silica
gel (35–75 mesh).
tert-Butyl (R)-3-(4-Hydroxyphenyl)-1-[methoxy(methyl)ami-
no]-1-oxopropan-2-ylcarbamate (6)
To a solution of commercially available Boc-D-tyrosine (4.8 g, 17.0
mmol) in CH2Cl2 (12 mL), was added N,O-dimethylhydroxylamine
hydrochloride (2.0 g, 20.5 mmol) and DCC (4.2 g, 20.5 mmol). The
solution was cooled to 0 °C, and DMAP (150 mg) and Et3N (8.5
mL) were added. The mixture was allowed to warm up to r.t. and
stirred for 4 h. The resulting light brown solution was poured into
ice-water (30 mL) and extracted with EtOAc (3 × 30 mL). The or-
ganic layers were combined and washed successively with H2O
(3 × 20 mL) and brine (3 × 20 mL). After drying (Na2SO4), the sol-
vent was removed under reduced pressure, and the residue was pu-
rified by flash column chromatography (Rf 0.25, MeOH–CH2Cl2,
1:100) to afford compound 6 as an off-white solid; yield: 4.8 g
(87%).
1H NMR (300 MHz, CDCl3): d = 1.46 (s, 9 H), 2.05 (s, 3 H), 3.33
(s, 3 H), 3.45 (m, 2 H), 4.93 (t, J = 9.3 Hz, 1 H), 6.68 (d, J = 8.5 Hz,
2 H), 6.92 (d, J = 8.3 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 28.96, 29.01, 33.53, 55.37, 56.22,
70.64, 125.38, 127.29, 129.99, 137.78, 158.96, 173.95.
Intermediate 10a was further subjected to trifluoroacetic
acid to effect the concurrent removal of both the Boc and
TMSE groups,20 giving 12 as a key precursor for ensuing
B/C ring conjugation. The establishment of the (–)-apha-
norphine skeleton was accomplished in 95% yield by em-
ploying 2-bromo-1-ethylpyridinium tetrafluoroborate
(BEP) as a coupling reagent, which has been widely used
in peptide bond formation.21 The desired intramolecular
coupling compound 13 was obtained as a sole product
while the unwanted intermolecular amide bond formation
was not observed.
HRMS: m/z calcd for C16H24N2O5: 324.1685; found: 324.1688.
tert-Butyl (R)-1-[Methoxy(methyl)amino]-3-(4-methoxyphe-
nyl)-1-oxopropan-2-yl(methyl)carbamate (7)
To a solution of compound 6 (4.5 g, 14.0 mmol) in DMF (40 mL)
at –20 °C (dry ice-MeCN cold bath), was added NaH (1.2 g, 60% in
mineral oil, 30 mmol) in small portions. After the H2 evolution had
ceased, MeI (5.7 g, 40 mmol) was added dropwise. The mixture was
allowed to stir at the same temperature for 3 h before crushed ice (5
g) was added. The mixture was extracted with EtOAc (3 × 30 mL)
and the organic layers were combined and washed successively
with H2O (3 × 20 mL) and brine (3 × 20 mL). After drying
At the final stage of the total synthesis, we designed a con-
comitant reduction of the amide and ketone, which called
for a thioketal precursor. However, even though the con-
ventional reagents 1,3-propanedithiol and 1,2-ethane-
dithiol were used for the thioketal construction,22 possibly
due to the steric hindrance of substrate 13, the yield was
unsatisfactory (27–41%) and most of starting material
Synthesis 2007, No. 1, 55–60 © Thieme Stuttgart · New York

58
M. Li et al.
PAPER
(Na2SO4), the solvent was removed on a rotary evaporator, and the
crude product was purified by flash column chromatography
(Rf 0.35, hexanes–EtOAc–Et3N, 10:4:1) to afford the title com-
pound 7 as a colorless solid; yield: 3.7 g (75%); [a]D –7.2 (c =
0.55, CHCl3).
filtrates were combined and concentrated under reduced pressure to
afford a pale brown residue as the crude product. After flash column
chromatographic purification (Rf 0.35, CH2Cl2–EtOAc–Et3N,
10:2:1), the desired compound 3 was obtained as an off-white syrup
which solidified slowly at r.t.; yield: 700 mg (78%).
25
1H NMR (300 MHz, CDCl3): d = 1.46 (s, 9 H), 2.13 (s, 3 H), 2.30
(s, 3 H), 3.35 (s, 3 H), 3.39 (s, 3 H), 3.46 (m, 2 H), 4.89 (t, J = 9.0
Hz, 1 H), 6.66 (d, J = 8.5 Hz, 2 H), 6.92 (d, J = 8.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 28.96, 29.10, 33.63, 37.32, 55.37,
56.22, 58.65, 71.10, 125.39, 128.64, 129.99, 134.06, 158.58,
173.88.
1H NMR (300 MHz, CDCl3): d = 0.03 (s, 9 H), 1.05 (t, J = 6.8 Hz,
2 H), 1.46 (s, 9 H), 2.26, 2.27 (s, 3H), 3.33 (s, 3 H), 3.43–3.46 (m,
2 H), 4.15 (t, J = 6.6 Hz, 2 H), 4.99 (t, J = 9.0 Hz, 1 H), 5.35 (s, 1
H), 6.67 (dd, J = 8.0, 3.2 Hz, 1 H), 6.72 (d, J = 2.9 Hz, 1 H), 7.03
(d, J = 8.0 Hz, 1 H).
2-(Trimethylsilyl)ethyl (1S,3R)-3-[tert-Butoxycarbonyl(meth-
yl)amino]-7-methoxy-2-oxo-1,2,3,4-tetrahydronaphthalene-1-
carboxylate (10a) and 2-(Trimethylsilyl)ethyl (1R,3R)-3-[tert-
Butoxycarbonyl(methyl)amino]-7-methoxy-2-oxo-1,2,3,4-tet-
rahydronaphthalene-1-carboxylate (10b)
HRMS: m/z calcd for C18H28N2O5: 352.1998; found: 352.1996.
2-(Trimethylsilyl)ethyl (4R)-4-[tert-Butoxycarbonyl(meth-
yl)amino]-5-(4-methoxyphenyl)-3-oxopentanoate (9)
To a solution of 2-trimethylsilylethyl acetate (8; 2.4 g, 15 mmol) in
THF (30 mL) at –78 °C, was added LDA (1.0 M in THF, 15.0 mL,
15 mmol) dropwise. The resulting pale yellow solution was stirred
at the same temperature for 30 min and a solution of compound 7
(3.52 g, 10 mmol) in THF (20 mL) was added dropwise via syringe.
The mixture was allowed to warm up slowly to r.t. and stirred for 6
h. Using an ice bath, the mixture was cooled to 0 °C and quenched
by adding sat. aq NH4Cl (15 mL). Most of the solvent was removed
under reduced pressure and the residue was extracted with EtOAc
(3 × 50 mL). The organic layers were then combined and washed
with brine (3 × 30 mL) and dried (Na2SO4). After concentration un-
der reduced pressure, the crude product obtained was purified by
flash column chromatography (Rf 0.38, hexanes–EtOAc–Et3N,
6:2:1) to afford the title compound 9 as a colorless solid; yield: 4.38
g (97%); [a]D25 –3.3 (c = 0.30, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.04 (s, 9 H), 1.03 (t, J = 6.9 Hz,
2 H), 1.48 (s, 9 H), 2.26 (s, 3 H), 3.35 (s, 3 H), 3.41–3.46 (m, 4 H),
4.10 (t, J = 6.9 Hz, 2 H), 4.93 (t, J = 9.2 Hz, 1 H), 6.67 (d, J = 8.8
Hz, 2 H), 6.90 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 9.66, 12.03, 28.99, 29.72, 32.78,
37.35, 55.02, 56.53, 58.88, 70.27, 75.36, 126.67, 128.96, 128.98,
133.09, 159.25, 171.24, 175.43.
To a solution of compound 3 (613 mg, 1.36 mmol) in toluene (10
mL), was added chiral ligand 11 (83 mg, 0.16 mmol) and MeI (400
mg, 2.72 mmol). The suspension was cooled to –40 °C (dry ice-
CCl4 cold bath). With vigorous stirring, aq KOH (2.0 mL, 17.2
mmol) was added dropwise and the resulting pale yellow solution
was allowed to stir at the same temperature till all the starting mate-
rial had been consumed (5 h). The suspension was allowed to warm
up to r.t. and diluted with EtOAc (30 mL), washed successively
with sat. aq NH4Cl (3 × 15 mL) and brine (3 × 15 mL) and dried
(Na2SO4). After concentration and flash chromatographic purifica-
tion (Rf 0.36 for 10a, Rf 0.33 for 10b, CH2Cl2–EtOAc–Et3N,
10:2:1), the desired product 10a was obtained as a colorless solid,
along with its diastereomer 10b.
Compound 10a
Yield: 523 mg (83%); [a]D25 +8.2 (c = 0.15, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.05 (s, 9 H), 1.06 (t, J = 7.2 Hz,
2 H), 1.45 (s, 3 H), 1.50 (s, 9 H), 2.36 (s, 3 H), 3.26–3.28 (m, 2 H),
3.43 (s, 3 H), 4.08 (t, J = 7.3 Hz, 2 H), 4.83 (t, J = 7.8 Hz, 1 H), 6.66
(dd, J = 8.2, 3.2 Hz, 1 H), 6.70 (d, J = 2.9 Hz, 1 H), 7.02 (d, J = 8.2
Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 8.73, 12.00, 22.65, 23.24, 41.05,
42.83, 43.15, 57.06, 57.58, 62.17, 71.00, 109.62, 109.96, 128.38,
135.65, 146.88, 152.23, 159.63, 168.65, 171.34.
HRMS: m/z calcd for C23H37NO6Si: 451.2389; found: 451.2393.
2-(Trimethylsilyl)ethyl (4R)-4-[tert-Butoxycarbonyl(meth-
yl)amino]-2-diazo-5-(4-methoxyphenyl)-3-oxopentanoate (4)
To a solution of compound 9 (3.6 g, 8.0 mmol) in anhyd CH2Cl2 (20
mL), was added successively TsN3 (1.5 g, 7.6 mmol) and DIPEA
(15 mL). The mixture was allowed to stir at r.t. for 2 h and filtered
through a short silica gel column. The column was washed with
CH2Cl2 (2 × 20 mL) and the filtrates were combined, and concen-
trated under reduced pressure to give a pale brown crude product.
The residue was further purified by flash column chromatography
(Rf 0.33, hexanes–EtOAc–Et3N, 6:2:1) to afford compound 4 as a
pale brown syrup; yield: 3.3 g (88%). Unconsumed compound 9
(293 mg) was recovered.
HRMS: m/z calcd for C24H37NO6Si: 463.2390; found: 463.2389.
Compound 10b
Yield: 43 mg (7%); [a]D25 +16.7 (c = 0.12, CHCl3).
1H NMR (300 MHz, CDCl3): d = 0.05 (s, 9 H), 1.05 (t, J = 6.7 Hz,
2 H), 1.46 (s, 3 H), 1.48 (s, 9 H), 2.28 (s, 3 H), 3.36 (s, 3 H), 3.35–
3.38 (m, 2 H), 4.15 (t, J = 6.9 Hz, 2 H), 4.58 (t, J = 9.0 Hz, 1 H),
6.68 (dd, J = 8.0, 3.0 Hz, 1 H), 6.76 (d, J = 3.0 Hz, 1 H), 6.99 (d,
J = 8.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 8.76, 12.05, 23.18, 25.03, 42.04,
42.11, 47.33, 58.28, 63.52, 72.80, 109.00, 111.99, 126.12, 134.32,
147.88, 151.99, 159.96, 166.83, 170.52.
1H NMR (300 MHz, CDCl3): d = 0.03 (s, 9 H), 1.05 (t, J = 6.7 Hz,
2 H), 1.46 (s, 9 H), 2.26 (s, 3 H), 3.33 (s, 3 H), 3.43–3.45 (m, 2 H),
4.13 (t, J = 6.8 Hz, 2 H), 4.99 (t, J = 9.5 Hz, 1 H), 6.68 (d, J = 8.8
Hz, 2 H), 6.93 (d, J = 8.8 Hz, 2 H).
Compound 13
To a solution of 10 (269 mg, 0.58 mmol) in anhyd CH2Cl2 (5.0 mL),
was added CF3CO2H (0.6 mL) and the mixture was allowed to stir
at r.t. overnight. The solvent was removed under reduced pressure
to give a light brown syrup. The residue was dissolved in toluene
(20 mL) and subjected to azeotropic distillation to give crude 12
(148.8 mg). Under argon, crude 12 (148.8 mg) was dissolved in an-
hyd CH2Cl2 (5.0 mL) and BEP18 (159 mg, 0.58 mmol) was added.
The mixture was cooled to –20 °C and DIPEA (1.2 mL) was added
dropwise. The resulting yellow solution was allowed to warm up to
r.t. slowly and stirred for 3 h. After concentration under reduced
pressure and flash chromatographic purification (Rf 0.35, CHCl3–
2-(Trimethylsilyl)ethyl (3R)-3-[tert-Butoxycarbonyl(meth-
yl)amino]-7-methoxy-2-oxo-1,2,3,4-tetrahydronaphthalene-1-
carboxylate (3)
To a solution of compound 4 (956 mg, 2.0 mmol) in anhyd CH2Cl2
(10 mL) at r.t., was added successively trifluoroacetamide (0.1 mL)
and Rh2(OAc)4 (40 mg, 0.18 mmol). The mixture was allowed to
stir at r.t. until all the starting material 4 had been consumed (ap-
proximately 3 h). The mixture was filtered through a short silica gel
column and the column was washed with CH2Cl2 (2 × 10 mL). The
Synthesis 2007, No. 1, 55–60 © Thieme Stuttgart · New York

PAPER
Synthesis of (–)-Aphanorphine from D-Tyrosine
59
MeOH, 40:1), compound 13 was obtained as an off-white amor-
phous solid; yield: 132 mg (93% for two steps); [a]D25+15.5 (c =
0.25, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.49 (s, 3 H), 2.56 (s, 3 H), 2.72
(d, J = 9.6 Hz, 1 H), 2.79 (s, 1 H), 3.66 (m, 1 H), 3.80 (s, 3 H), 6.69
(dd, J = 8.0, 2.8 Hz, 1 H), 6.70 (d, J = 2.8 Hz, 1 H), 7.09 (d, J = 8.0
Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 42.23, 42.69, 43.15, 55.38, 61.35,
70.89, 109.12, 111.26, 125.50, 130.27, 147.83, 156.92, 166.83,
168.56.
1H NMR (300 MHz, CD3OD): d = 1.43 (s, 3 H), 1.86 (d, J = 10.8
Hz, 1 H), 2.02 (dd, J = 11.0, 5.8 Hz, 1 H), 2.48 (s, 3 H), 2.73 (d,
J = 9.2 Hz, 1 H), 2.83 (d, J = 16.6 Hz, 1 H), 2.87 (d, J = 9.2 Hz, 1
H), 3.03 (d, J = 16.6 Hz, 1 H), 3.43 (q, J = 2.8 Hz, 1 H), 6.52 (d,
J = 2.3 Hz, 1 H), 6.65 (d, J = 2.3 Hz, 1 H), 6.91 (dd, J = 8.2, 2.2 Hz,
1 H).
13C NMR (75 MHz, CDCl3): d = 21.61, 36.53, 42.10, 42.74, 44.22,
63.55, 72.61, 110.92, 114.58, 125.26, 131.23, 148.57, 156.55.
References
Compound 14
(1) For a review of the synthesis of pentazocine(2) and related
benzomorphans, see: Palmer, D. C.; Strauss, M. J. Chem.
Rev. 1977, 77, 1.
(2) Gulavita, N.; Hori, A.; Shimizu, Y.; Laszlo, P.; Clardy, J.
Tetrahedron Lett. 1988, 29, 4381.
(3) For a detailed literature on the synthesis of 1, see: Bower, J.
F.; Szeto, P.; Gallagher, T. Chem. Commun. 2005, 5793; and
references cited therein.
(4) (a) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1997, 8,
371. (b) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1995,
6, 893.
(5) (a) Tamura, O.; Yanagimachi, T.; Ishibashi, H. Tetrahedron:
Asymmetry 2003, 14, 3033. (b) Tamura, O.; Yanagimachi,
T.; Kobayashi, T.; Ishibashi, H. Org. Lett. 2001, 3, 2427.
(6) Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3, 3923.
(7) (a) Zhai, H.; Luo, S.; Ye, C.; Ma, Y. J. Org. Chem. 2003, 68,
8268. (b) Hu, H.; Zhai, H. Synlett 2003, 2129.
(8) Katoh, M.; Inoue, H.; Suzuki, A.; Honda, T. Synlett 2005,
2820.
To a solution of compound 13 (120 mg, 0.49 mmol) in anhyd CHCl3
(5 mL), was added MeSH (150 mg, 3.1 mmol). The solution was
cooled to 0 °C and TMSCl (336 mg, 3.1 mmol) was added drop-
wise. The mixture was allowed to warm up slowly to r.t. and stirred
overnight. Et3N (2.0 mL) was then added and the solvent was re-
moved on a rotary evaporator to afford a pale brown syrup. The res-
idue was purified by flash column chromatography (Rf 0.28,
CHCl3–MeOH, 40:1) to give compound 14 as a colorless syrup;
yield: 136 mg (86%); [a]D25 +3.9 (c = 0.20, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.43 (s, 3 H), 2.28 (2 s, 6 H), 2.50
(s, 3 H), 2.73 (br s, 1 H), 2.76 (br s, 1 H), 3.39 (m, 1 H), 3.83 (s, 3
H), 6.71 (dd, J = 7.8, 2.8 Hz, 1 H), 6.72 (d, J = 2.8 Hz, 1 H), 7.07
(d, J = 8.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 40.04, 42.33, 43.96, 46.87, 46.88,
60.00, 62.03, 72.82, 100.02, 115.35, 124.60, 126.56, 130.03,
135.70, 137.25, 159.39.
HRMS: m/z calcd for C16H21NO2S2: 323.1013; found: 323.1009.
(9) Bower, J. F.; Svenda, J.; Williams, A. J.; Charmant, J. P. H.;
Lawrence, R. M.; Szeto, P.; Gallagher, T. Org. Lett. 2004, 6,
4727; and references cited therein.
(10) For examples of Weinreb amide formation, see: (a)Ruiz,J.;
Sotomayor, N.; Lete, E. Org. Lett. 2003, 5, 1115. (b)Davis,
F. A.; Prasad, K. R.; Nolt, M. B.; Wu, Y. Org. Lett. 2003, 5,
925. (c) Conrad, R. M.; Grogan, M. J.; Bertozzi, C. R. Org.
Lett. 2002, 4, 1359.
(11) (a) Bouazza, F.; Renoux, B.; Bachmann, C.; Gesson, J.-P.
Org. Lett. 2003, 5, 4049. (b) Johnson, C. R.; Senanayake, C.
H. J. Org. Chem. 1989, 54, 736.
(12) Chiralcel OD-H column (100 × 4.6 mm), hexanes–i-PrOH
(10: 90), 1.0 mL/min, 23 °C, l = 276 nm, retention time 6.9
min (D-7) and 7.7 min (L-7).
(13) (a) Sasaki, S.; Hamada, Y.; Shioiri, T. Synlett 1999, 453.
(b) Walkup, R. D.; Boatman, P. D.; Kane, R. R.;
Cunningham, R. T. Tetrahedron Lett. 1991, 32, 3937.
(14) Regitz, M.; Rüter, J.; Liedhegener, A. Org. Synth. Coll. Vol.
VI; Wiley: New York, 1988, 388; and references cited
therein.
(15) (a) Jiang, N.; Li, C.-J. Chem. Commun. 2004, 394. (b) Zhu,
S.-Z.; He, P. Curr. Org. Chem. 2004, 8, 97. For a review,
see: (c) Marchard, A. P.; Macbrockway, N. Chem. Rev.
1974, 74, 431.
Compound 15
To a solution of compound 14 (120 mg, 0.37 mmol) in THF (5 mL)
at r.t., was added a suspension of LiAlH4 (72 mg, 1.90 mmol) in
THF (1 mL). The mixture was allowed to reflux until the starting
material had been consumed (8 h). The mixture was allowed to cool
to r.t. and powdered Na2SO4·10H2O (300 mg) was added in small
portions. After H2 evolution had ceased, the solid was filtered
through a pad of Celite and washed with THF (3 × 10 mL). The fil-
trates were combined and concentrated under reduced pressure. The
resulting residue was purified by flash column chromatography
(Rf 0.36, CHCl3–MeOH–Et3N, 50:1:1) to give compound 15 as a
colorless syrup; yield: 64 mg (83%); [a]D25 +10.2 (c = 0.25, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.46 (s, 3 H), 1.85 (d, J = 10.2 Hz,
1 H), 2.00 (dd, J = 9.6, 6.0 Hz, 1 H), 2.46 (s, 3 H), 2.71 (d, J = 9.2
Hz, 1 H), 2.77 (br s, 1 H), 2.78–2.90 (m, 2 H), 3.38 (m, 1 H), 3.79
(s, 3 H), 6.68 (dd, J = 8.2, 2.7 Hz, 1 H), 6.78 (d, J = 2.7 Hz, 1 H),
7.02 (d, J = 8.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.32, 34.90, 41.23, 41.62, 43.18,
55.35, 61.31, 70.82, 109.15, 111.23, 125.52, 130.23, 147.80,
157.93.
Aphanorphine (1)
To a solution of compound 15 (50 mg, 0.23 mmol) in CH2Cl2 (2
mL) at –20 °C (dry ice-MeCN cold bath), was added BBr3 (1.0 M
CH2Cl2 solution, 0.55 mL, 0.55 mmol). After stirring for 2 h at –20
°C, the mixture was allowed to warm up slowly to 0 °C and stirred
for another 2 h at the same temperature. MeOH (2.0 mL) was added
dropwise and the resulting light brown solution was stirred at 0 °C
for 30 min before Et3N (5.0 mL) was added. After stirring for anoth-
er 30 min, the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography to afford 1;
yield: 41 mg (88%); [a]D25 –20.2 (c = 0.15, MeOH).
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(19) For reviews, see: (a) Maruoka, K.; Ooi, T. Chem. Rev. 2003,
103, 3013. (b) Nelson, A. Angew. Chem. Int. Ed. 1999, 38,
1583.
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