An enantioselective approach to (-)-aphanorphine featuring a stereoselective oxidative amidation

Article abstract of DOI:10.1039/c3ra44037k

A formal enantioselective synthesis of (-)-aphanorphine (91% ee), that culminates with the preparation of (+)-O-methyl aphanorphine, was achieved. The methodology involves the diastereoselective synthesis of a key 3,5-disubstituted pyrrolidinone intermediate by the intramolecular oxidative amidation of a suitably functionalized α-hydroxy pentenoic acid derivative. A late-stage N-formyl protection, which functions as a latent N-methyl group, is utilized as a simple alternative to a protecting group switch and subsequent N-methylation strategy implemented in all other syntheses of aphanorphine related to the present approach. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra44037k

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An enantioselective approach to (2)-aphanorphine
featuring a stereoselective oxidative amidation3
Cite this: RSC Advances, 2013, 3,
19127
Sunil V. Pansare* and Kaivalya G. Kulkarni
A formal enantioselective synthesis of (2)-aphanorphine (91% ee), that culminates with the preparation of
(+)-O-methyl aphanorphine, was achieved. The methodology involves the diastereoselective synthesis of a
key 3,5-disubstituted pyrrolidinone intermediate by the intramolecular oxidative amidation of a suitably
functionalized a-hydroxy pentenoic acid derivative. A late-stage N-formyl protection, which functions as a
latent N-methyl group, is utilized as a simple alternative to a protecting group switch and subsequent
N-methylation strategy implemented in all other syntheses of aphanorphine related to the present
approach.
Received 21st May 2013,
Accepted 6th August 2013
DOI: 10.1039/c3ra44037k
www.rsc.org/advances
Aphanorphine (1)1 is an alkaloid that shares structural
features with the analgesic benzomorphan alkaloids eptazo-
cine (3), pentazocine (4) and morphine (5, Fig. 1). This
structural resemblance and the synthetically intriguing 3-ben-
zazepine ring system and quaternary stereocenter have all
contributed to significant interest in the synthesis of apha-
norphine,2–4 which continues to be a popular target for
showcasing new methodology leading to the benzazepine
motif. We describe here a synthesis of (+)-O-methyl aphanor-
phine (2), an immediate synthetic precursor of (2)-aphanor-
phine.
Our interest in aphanorphine stems from our studies on
the enantioselective synthesis and applications of a-alkyl
a-hydroxy acid derivatives as intermediates to biologically
relevant motifs and natural products.5 We therefore envisaged
an a-hydroxy acid based route to aphanorphine as detailed in
Scheme 1. The strategy utilizes a stereoselective, intramole-
cular C–N bond formation as a pivotal step in the synthesis of
a key pyrrolidine intermediate. A cyclative Friedel–Crafts
alkylation in this pyrrolidine is used, as in previous aphanor-
phine syntheses,2a,3a,4f for constructing the bridged benzaze-
pine motif in aphanorphine. The precursor of the pyrrolidine
is obtained by a cross metathesis reaction of an enantiomeri-
cally enriched a-hydroxy pentenoic acid derivative which, in
turn, is obtained by asymmetric allylation of a chiral pyruvate
(Scheme 1).
N-methyl pyrrolidinones are natural products6 or motifs in
bioactive molecules,7 and the present study could potentially
provide methodology for their synthesis as well; and 2) the
starting material for the pyrrolidinone based approach, the
a-hydroxy N-methyl amide (R)-85f (Scheme 2) is directly
obtained by our asymmetric allylation protocol5f employing
an ephedrine-derived chiral pyruvamide. Furthermore, the
intramolecular Friedel–Crafts alkylation (Scheme 1) of the
N-methyl pyrrolidine, obtained from the pyrrolidinone, could
potentially provide the aphanorphine framework. Our studies
therefore commenced with (R)-8 (92% ee) which was prepared
by the asymmetric allylation of an ephedrine and pyruvic acid-
derived morpholinone 6 as shown in Scheme 2.5f
We reasoned that a simple halolactamization of 8 would
provide the functionalized pyrrolidinone 9 (Scheme 3) which
could be elaborated further to provide the target benzazepine
motif. Towards this goal, the halolactamization of 8 was
examined under a variety of conditions that are reported to
Initially, we chose to explore the synthesis of a suitably
substituted N-methyl pyrrolidinone as a precursor to the
functionalized pyrrolidine motif in aphanorphine. The moti-
vation for this approach was twofold: 1) several substituted
Department of Chemistry, Memorial University, St. John’s, Newfoundland, Canada
A1B 3X7. E-mail: spansare@mun.ca
Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 (2)-Aphanorphine (1), (+)-O-methylaphanorphine (2), (2)-eptazocine (3),
(2)-pentazocine (4) and (2)-morphine (5).
3
c3ra44037k
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Scheme 1
promote lactamization of secondary amides (I2/NaHCO3,8a
NIS/NaOH,8b ICl,8c NBS,8d BuLi/I2,8e and bromonium bis(colli-
dine)perchlorate8f). None of these attempts provided any
halolactam. This may be due, in part, to competing halolacto-
nization as evidenced by the formation of small amounts of
the halolactone. In addition, the halohydrin resulting from
halolactone hydrolysis was also observed in some of these
reactions. Similarly, intramolecular amidomercuration/halo-
genation9 protocols (Hg(OAc)2, KI, I2 or Hg(OAc)2, KBr) were
Scheme 3
the trans pentenoic acid 10. Amidation of 10 with methylamine
provided 11. However, reactions of 11 under a variety of
halolactamization conditions, including the Knapp procedure,
lead to complex mixtures which rarely contained a trace of the
required lactam 12 (Scheme 3). Consequently, the direct
halolactamization of 8 or 11 as a route to an advanced,
pyrrolidine precursor to aphanorphine was not pursued
further.
Clearly, an alternative to halolactamization was necessary.
We decided to explore the possibility of a nitrenium ion
mediated construction of the key pyrrolidine intermediate14
and chose to use a N-methoxy amide for this purpose.15
Towards this end, conventional amidation of the acid 10 with
methoxyamine provided the corresponding N-methoxyamide
13 (Scheme 4). Oxidative ring closure of the crude
N-methoxyamide employing bis(trifluoroacetoxy)iodoben-
zene16 and in situ hydrolysis of the resulting benzylic
trifluoroacetate15 generated the hydroxypyrrolidinone 14 as a
5 : 1 mixture of diastereomers. At this stage, it was unclear if
the diastereomers of 14 were a consequence of indiscriminate
C–N bond formation or due to unselective capture of the
intermediate benzylic cation by trifluoroacetate. However,
subsequent reduction of 14 with triethylsilane yielded the
pyrrolidinone 15 as a single diastereomer. This indicated that
also unsuccessful. Nonetheless, iodolactamization10 of
8
employing the conditions of Knapp10h (treatment of 8 with
TMSOTf, which presumably forms the O-silylimidate, followed
by addition of iodine) provided 9 in good yield (84%) but with
poor diastereoselectivity (dr = 1.6 : 1, Scheme 3).
It is noteworthy that the direct halolactamization of 5-aryl-
4-pentenamides is not reported, and the iodolactamization of
the corresponding thioimidates follows the 5-exo mode.11 We
were therefore curious about the direct iodolactamization of
11 (Scheme 3). To examine this possibility, 8 was converted to
the acid12 which was subjected to a Grubbs II catalyst
mediated cross-metathesis13 with 4-vinyl anisole to provide
Scheme 4
Scheme 2
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for 19. This also confirmed the absolute configuration of 15,
and hence that of 17, to be as shown. We now proceeded to
complete the synthesis of (+)-O-methyl aphanorphine from 17.
Treatment of 17 with acetic formic anhydride provided the
N-formyl derivative, an intramolecular Friedel–Crafts cycliza-
tion (AlCl3, Scheme 6) of which efficiently provided the
benzomorphan 20. Reduction of the formamide in 20 with
LAH provided (+)-O-methyl aphanorphine (2). The conversion
of 2 to (2)-aphanorphine (1) by O-demethylation with BBr3 is
known,3a,19 so the present synthesis of 2 also constitutes a
formal synthesis of 1.
In conclusion, a synthesis of (+)-O-methyl aphanorphine
(91% ee) was achieved from the readily available a-hydroxy
acid derivative 8 in 10 steps and 7.1% overall yield. This
constitutes a formal synthesis of (2)-aphanorphine (91% ee). A
highly stereoselective intramolecular oxamidation was
employed to construct the key pyrrolidine precursor to the
benzazepine framework of the target. Notably, a N-formyl
protecting group serves as a N-methyl surrogate in this
synthesis. This avoids the more conventional approach
employed in related aphanorphine syntheses that rely on
N-deprotection, after the intramolecular Friedel Crafts cycliza-
tion, followed by N-methylation. Since the N-deprotection step
usually requires forcing conditions (detosylation3a,4f (Red-Al in
refluxing xylene) or debenzoylation2a,4l (50% aq. NaOH or
KOH, ethanol, reflux, 24 h), the N-formylation approach
provides a convenient alternative that eliminates a late-stage
step in the synthesis. We are currently investigating applica-
tions of the methodology described here in the synthesis of
other, pyrrolidinone- and pyrrolidine-containing, natural
products.
Scheme 5
the crucial C–N bond formation step was highly stereoselec-
tive.17 The high diastereoselectivity for the formation of 15
contrasts the modest diastereoselectivity (1.8 : 1) observed for
the iodine(III) mediated intramolecular amidohydroxylation of
N-para-methoxyphenyl-2-benzyl-4-pentenamides.18 While it is
reasonable to assume that the stereocenter in 13 plays some
role in the stereoselective C–N bond formation, the exact
reasons for this significant difference in stereoselectivity are
unclear at present.
With the pyrrolidinone 15 in hand, the synthesis of the
target was in sight. Reduction of the N–O bond in 15 with
Mo(CO)6 provided lactam 16 (Scheme 5) which was reduced
with LAH to provide the key pyrrolidine 17. N-Tosylation of 17
provided 18.
The stereochemistry of the oxamidation step, and hence the
absolute configuration of the pyrrolidinone 15, was first
established by conversion of the tosylamide 18 to the
benzomorphan derivative (2)-19 (91% ee, Scheme 6) which
has previously been converted to (2)-aphanorphine.
Comparison of the optical rotation of 19 ([a]2D5 218.9 (c 0.9,
CHCl3)) with the reported2b value for (1R,4S)-19 ([a]2D5 216.9 (c
0.89, CHCl3)) confirmed the shown absolute stereochemistry
15
Experimental section
General experimental methods
All commercially available reagents were used without
purification. All reactions requiring anhydrous conditions
were performed under an atmosphere of dry nitrogen using
oven dried glassware. Dichloromethane and tetrahydrofuran
were distilled from CaH2 and sodium/benzophenone respec-
tively. Commercial precoated silica gel plates were used for
TLC. Silica gel for column chromatography was 230–400 mesh.
All melting points are uncorrected. Optical rotations were
measured at the sodium D line on a digital polarimeter at
ambient temperature.
(R)-2-Hydroxy-N,2-dimethylpent-4-enamide (8)5f
This was prepared according to the literature procedure.5f
Reaction of 1R,2S ephedrine hydrochloride with pyruvoyl
chloride provided the morpholinone 65f which was allylated
to provide 7.5f Dissolving metal reduction of 7 provided 8.5f
1
Spectroscopic data for 6, 7 and 8 (IR, H NMR, 13C NMR) is in
agreement with reported data.5f The enantiomeric excess of 8
(92%) was determined by chiral HPLC analysis; Chiralpak AS-
H, hexanes–2-propanol 93 : 7, 254 nm, t1 = 12.4 min (minor), t2
Scheme 6
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= 14.6 min (major), Ee: 92%. In repeated preparations, 8 was
acid (8a)12 as a pale yellow gum. This was used in the next step
obtained in 92–96% ee.
without further purification.
1
IR (neat): 3362, 2980, 1719, 1635, 1227, 1163, 919 cm21; H
(3R)-3-Hydroxy-5-(iodomethyl)-1,3-dimethylpyrrolidin-2-one
(9)
NMR (300 MHz, CDCl3): d 5.85–5.74 (m, 1H, CH), 5.22 (br s,
1H, CHLCH2), 5.18–5.17 (br d, 1H, J = 5.0, CHLCH2), 2.64–2.57
(dd, 1H, J = 7.1, 13.8, CH2CH), 2.48–2.40 (dd, 1H, J = 7.5, 13.8,
CH2CH), 1.50 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 180.6
(CLO), 131.8 (CHLCH2), 120.0 (CHLCH2), 74.4 (C-CO2H), 44.4
(CH2CH), 25.4 (CH3); MS (APCI, neg.): m/z 128.9 (M-1) (APCI,
neg.): m/z 128.9 (M-1); [a]2D5 211.1 (c 1, EtOH); lit.12 [a]2D5 25.2 (c
1, EtOH) for material with 42% ee).
To a solution of the above acid (300 mg, 2.30 mmol) in
CH2Cl2 (4 mL) under nitrogen was added a solution of the
Grubbs second generation catalyst (39.0 mg, 0.046 mmol) in
CH2Cl2 (4 mL) followed by the addition of 4-vinyl anisole (0.6
mL, 4.60 mmol). The solution was heated to reflux 7 h, cooled
to ambient temperature and the solvent was evaporated under
reduced pressure to obtain a brown solid. This was dissolved
in EtOAc (5 mL) and the solution was extracted with saturated,
aqueous NaHCO3 (2 6 5 mL). The combined bicarbonate
extracts were cooled and acidified to pH 2 with conc. HCl. The
acidic solution was extracted with EtOAc (3 6 15 mL) and the
combined organic layers were dried (Na2SO4) and concen-
trated under reduced pressure to provide 380 mg (70%) of 10
as a white solid. This was pure by 1H NMR and was used
without further purification. An analytical sample was
obtained by flash chromatography on silica gel (EtOAc–
hexanes, 1 : 1).
To a solution of R-8 (92% ee, 0.27 g, 1.91 mmol) in CH2Cl2 (6
mL) at 0 uC, was added freshly distilled triethylamine (0.58 mL,
4.21 mmol) and freshly distilled trimethylsilyltriflate (0.78 mL,
4.21 mmol). The resulting brown solution was warmed to
room temperature and stirred for 45 min. The mixture was
cooled to 0 uC and a solution of iodine (1.07g, 4.21 mmol) in
CH2Cl2 (19 mL) was added. The mixture was stirred at room
temperature for 20 h and a saturated solution of sodium
bicarbonate (25 mL) was added. The mixture was stirred for 30
min and the phases were separated. The aqueous phase was
extracted with CH2Cl2 (2 6 30 mL), the combined organic
phases were washed with saturated, aqueous sodium thiosul-
fate (15 mL), dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by flash chromatography
on silica gel (EtOAc–hexanes, 8 : 2) to provide the iodolactam 9
(light brown solid, 430 mg, 84%) as a 1.6 : 1 mixture of
diastereomers.
IR (neat): 3316, 2361, 1682, 1254 cm21; H NMR (500 MHz,
1
CDCl3): Major diastereomer: d 3.48–3.35 (m, 2H), 3.33–3.27 (m,
1H), 2.84 (s, 3H), 2.36–2.32 (dd, 1H, J = 7.7, 14.0), 1.83–1.79
(dd, 1H, J = 5.5, 14.0), 1.51 (s, 3H); minor diastereomer: d 3.48–
3.35 (m, 2H), 3.33–3.27 (m, 1H), 2.87 (s, 3H), 2.29–2.25 (dd, 1H,
J = 7.0, 13.3), 2.02–1.98 (dd, 1H, J = 6.1, 13.3), 1.40 (s, 3H); 13C
NMR (75 MHz, CDCl3): Major diastereomer: d 177.1, 73.8, 56.6,
40.9, 28.0, 25.2, 8.6; minor diastereomer: d 175.1, 73.9, 56.1,
40.2, 27.8, 20.7, 10.6; MS (APCI, pos.): m/z 270.0 (M + 1);
HRMS: m/z 268.9915 (268.9913 calculated for C7H12INO2 (M+)).
Mp: 169–170 uC; IR (neat): 3434, 2932, 1720, 1509, 1274,
1247, 1202, 1150, 1103, 1027, 961 cm21; H NMR (300 MHz,
1
CDCl3): d 7.29 (d, 2H, J = 8.7), 6.83 (d, 2H, J = 8.7), 6.46 (d, 1H, J
= 15.7), 6.09–5.98 (m, 1H), 3.80 (s, 3H), 2.75–2.70 (dd, 1H, J =
7.2, 14.0), 2.58–2.51 (dd, 1H, J = 7.8, 14.0), 1.52 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 180.7, 159.1, 134.2, 129.8, 127.5,
120.7, 114.0, 74.8, 55.3, 43.6, 25.3; MS (APCI, pos.): m/z 236
(M+); HRMS (CI, TOF): m/z 236.1046 (236.1049 calc. for
(R)-E-2-Hydroxy-5-(4-methoxyphenyl)-2-methylpent-4-enoic
acid (10)
To a solution of the amide 8 (405 mg, 2.83 mmol) in THF–
water (1 : 1, 14 mL) at ambient temperature was added iodine
(1.69 g, 6.60 mmol) and the solution was stirred in the dark for
12 h. The solution was then extracted with ethyl acetate (3 6
20 mL), the combined extracts were washed with saturated
aqueous sodium thiosulfate solution, dried (Na2SO4) and
concentrated under reduced pressure to provide 610 mg of a
yellow gum. This was dissolved in THF–water (1 : 1, 12 mL)
and zinc (480 mg, 7.4 mmol) was added. The vigorously stirred
mixture was heated at 50 uC for 4 h, cooled to room
temperature and the THF was removed under reduced
pressure. The residue was cooled to 0 uC, aqueous HCl (4N,
10 mL) was added and the mixture was stirred until all of the
solids dissolved. The resulting acidic solution was extracted
with EtOAc (3 6 50 mL) and the combined extracts were dried
(Na2SO4) and concentrated under reduced pressure. The
residue was dissolved in EtOAc (10 mL) and the solution was
extracted with saturated aqueous NaHCO3 (2 6 10 mL). The
combined aqueous extracts were cooled to 0 uC, acidified with
concentrated aqueous HCl and the resulting clear solution was
extracted with EtOAc (3 6 30 mL). The combined extracts were
dried (Na2SO4) and concentrated. The residue was dissolved in
EtOAc and the solution was filtered through a pad of silica gel
to provide 220 mg (60%) of (R)-2-hydroxy-2-methyl-4-pentenoic
C
13H16O4 (M+)); [a]D25 29.5 (c 0.5, CHCl3).
(R)-E-2-Hydroxy-5-(4-methoxyphenyl)-N,2-dimethylpent-4-
enamide (11)
To a stirred solution of the acid 10 (0.12 g, 0.51 mmol) in THF
at 0 uC, was added 1-ethyl-3-(3-dimethylaminopropyl)carbodii-
mide (EDCI) hydrochloride (145 mg, 0.76 mmol), ethyl
cyanoglyoxylate-2-oxime (0.10 g, 0.76 mmol) and a solution
of methylamine (2.0 M in THF, 0.50 mL, 1.01 mmol). The
mixture was stirred at 0 uC for 24 h and then at ambient
temperature for 8 h. Aqueous hydrochloric acid (10 mL, 1.0 M)
was added and the mixture was stirred for 5 min. The THF was
removed under reduced pressure and the aqueous phase was
extracted with CH2Cl2 (2 6 15 mL). The combined extracts
were washed with saturated aqueous NaHCO3 (10 mL), dried
(Na2SO4) and concentrated. The residue was purified by flash
chromatography on silica gel (EtOAc–hexanes, 7 : 3) to provide
55 mg (44%) of the amide 11 as a yellow gum.
IR: 3350, 2928, 1648, 1510, 1245, 1172, 1029 cm21; H NMR
1
(500 MHz, CDCl3): d 7.28–7.27 (d, 2H), 6.87–6.80 (br, 1H), 6.84–
6.81 (d, 2H, J = 8.8), 6.45–6.42 (d, 1H, J = 15.8), 6.04–5.98 (ddd, J
= 6.8, 8.4, 15.4, 1H), 3.79 (s, 3H), 2.84–2.80 (ddd, 1H, J = 1.3,
6.9, 8.5), 2.81 (d, 3H, J = 4.9), 2.46–2.42 (ddd, 1H, J = 1.0, 8.5,
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9.5), 1.45 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 176.2,
159.2, 134.4, 129.7, 127.4, 121.6, 114.0, 75.5, 55.3, 43.7, 26.1,
26.0; MS (APCI pos): m/z 250.1 (M + H); HRMS (CI, TOF): m/z
250.1445 (250.1443 calculated for C14H20NO3 (M + H)).
(APCI, pos.): m/z 282 (M + 1); HRMS: m/z 282.1342 (282.1341
calculated for C14H20NO5 (M + H).
(3R,5R)-5-(4-Methoxybenzyl)-3-hydroxy-1-methoxy-3-
methylpyrrolidin-2-one (15)
(R)-E-2-Hydroxy-N-methoxy-5-(4-methoxyphenyl)-2-methylpent-
4-enamide (13)
To a mixture of the pyrrolidinone 14 (180 mg, 0.64 mmol) and
triethylsilane (1.02 mL, 6.4 mmol) at 0 uC was added
trifluoroacetic acid (0.24 mL, 3.2 mmol) and the mixture was
stirred vigorously at ambient temperature for 7 h (the biphasic
reaction mixture turned homogeneous after 7 h). Aqueous
NaOH (1.0 M, 2.0 mL) was added and the mixture was
extracted with EtOAc (3 6 10 mL). The combined organic
layers were dried (Na2SO4) and concentrated to provide 280 mg
of a white solid which was purified by flash chromatography
on silica gel (8 : 2 EtOAc–hexanes) to obtain 130 mg (94%) of
15 as a white solid.
To solution of the acid 10 (400 mg, 2.54 mmol) in CH2Cl2 (15
mL) at 0 uC was added 4-methylmorpholine (0.29 mL, 2.66
mmol),
1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide
hydrochloride (536 mg, 2.80 mmol), methoxyamine hydro-
chloride (634 mg, 7.6 mmol) and solid Na2CO3 (694 mg, 7.6
mmol). The resulting clear, brown solution was warmed to
ambient temperature and stirred for 24 h. Aqueous HCl (0.5M,
5 mL) was added and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (2 6 10 mL). The combined
organic layers were washed with saturated aqueous NaHCO3
solution, dried (Na2SO4) and concentrated to provide 480 mg
Mp: 95–97 uC; IR (neat): 3391, 1707, 1510, 1249, 1181, 1023
1
cm21; H NMR (500 MHz, CDCl3): d 7.13–7.08 (d, 2H, J = 8.4),
1
6.85 (d, 2H, J = 8.4), 4.11–4.09 (m, 1H), 3.87 (s, 3H), 3.79 (s,
3H), 3.07–3.03 (dd, 1H, J = 3.7, 13.7), 2.75–2.70 (dd, 1H, J = 8.0,
13.7), 2.5 (bs, 1H), 2.16–2.12 (dd, 1H, J = 7.7, 13.7), 1.75–1.71
(dd, 1H, J = 5.9, 13.7), 1.18 (s, 3H); 13C NMR (75 MHz, CDCl3): d
170.9, 158.6, 130.6, 127.7, 114.1, 71.4, 62.0, 55.3, 54.9, 37.5,
36.7, 25.2; MS (APCI, pos.): m/z 266.1 (M + 1); HRMS m/z
265.1312 (265.1314 calculated for C14H19NO4 (M+); [a]D25 24.9 (c
1, CHCl3).
(72%) of the amide 13 as a brown gum. This was pure by H
NMR and was used without further purification. An analytical
sample was obtained by flash chromatography on silica gel
(EtOAc–hexanes, 7 : 3).
IR (neat): 3431, 2925, 1704, 1607, 1511, 1363, 1246, 1169
cm21; 1H NMR (300 MHz, CDCl3): d 9.14 (bs, 1H), 7.29 (d, 2H, J
= 8.7), 6.85 (d, 2H, J = 8.7), 6.48 (d, 1H, J = 15.8), 6.07–5.97 (m,
1H), 3.81 (s, 3H), 3.77 (s, 3H), 2.90–2.85 (dd, 1H, J = 7.2, 13.8),
2.44–2.40 (dd, 1H, J = 8.4, 13.8), 2.25 (bs, 1H), 1.49 (s, 3H); 13
C
(3R,5R)-5-(4-Methoxybenzyl)-3-hydroxy-3-methylpyrrolidin-2-
NMR (75 MHz, CDCl3): d 172.8, 159.2, 134.5, 129.0, 127.4,
121.1, 114.0, 75.5, 64.3, 55.3, 43.7, 26.0; MS (APCI pos.): m/z
266 (M + 1); HRMS (EI pos, TOF): m/z 265.1315 (265.1314 calc.
for C14H19NO4 (M+)); [a]D25 = +10.9 (c 1, CHCl3).
one (16)
To a solution of pyrrolidone 15 (60 mg, 0.22 mmol) in
CH3CN:H2O (15 : 1, 6.0 mL) was added Mo(CO)6 (119 mg, 0.45
mmol) and the mixture was heated to reflux under nitrogen for
24 h. The reaction mixture turned yellow after 2 h and
gradually turned green and then black. After 24 h the mixture
was cooled to room temperature and concentrated. The black
residue (180 mg) was purified by flash chromatography on
silica gel (hexanes–EtOAc, 3 : 7 followed by EtOAc–MeOH,
9.5 : 0.5) to provide 37 mg (71%) of the pyrrolidone 16 as a
white solid.
Mp: 87–89 uC; IR (neat): 3301, 2932, 1692, 1604, 1110, 612
cm21; 1H NMR (300 MHz, CD3OD): d 7.13–7.11 (d, 2H, J = 8.6),
6.87–6.85 (d, 2H, J = 8.7), 3.96–3.89 (m, 1H), 3.76 (s, 3H), 2.85–
2.79 (dd, 1H, J = 5.7, 13.5), 2.68–2.61 (dd, 1H, J = 7.4, 13.6),
2.18–2.08 (dd, 1H, J = 6.6, 13.3), 1.82–1.75 (dd, 1H, J = 6.5,
13.7), 1.24 (s, 3H); 13C NMR (75 MHz, MeOD4): d180.3, 160.1,
131.5, 130.5, 115., 75.3, 55.7, 53.5, 42.9, 42.0, 24.8; MS (APCI
pos.): m/z 235.3 (M+); HRMS (EI pos, TOF): m/z 235.1203
(235.1208 calc. for C13H17NO3 (M+)); [a]D25 25.5 (c 1.0, acetone).
(3R)-3-Hydroxy-5-(hydroxy(4-methoxyphenyl)methyl)-1-
methoxy-3-methylpyrrolidin-2-one (14)
To a stirred solution of the amide 13 (130 mg, 0.48 mmol) in
CH2Cl2 (5 mL) at 210 uC (ice-salt bath) was added bis(tri-
fluoroacetoxy)iodobenzene (252 mg, 0.58 mmol). The solution
was stirred at 210 uC for 90 min and aqueous NaOH (2.5M, 1.0
mL) was added. The mixture was stirred vigorously for 5 min at
ambient temperature and the resulting biphasic mixture was
separated. Aqueous layer was extracted with CH2Cl2 (2 6 10
mL) The combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure to provide a brown solid
which was purified by flash chromatography on silica gel
(EtOAc–hexanes, 4 : 1) to provide 88 mg (68%) of the
pyrrolidone 14 as a 5 : 1 mixture of diastereomers.
IR (neat): 3367, 1691, 1511, 1244, 1174, 1024 cm21; 1H NMR
(500 MHz, CDCl3): Major diastereomer: d 7.28–7.27 (d, 2H, J =
6.5 Hz), 6.92–6.89 (d, 2H, J = 8.7 Hz), 5.14 (br d, 1H, J = 2.3),
4.05–4.03 (m, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 2.21–2.20 (d, 1H, J
= 2.9), 2.12–2.08 (dd, 1H, J = 6.0, 13.7), 1.84–1.79 (dd, 1H, J =
8.1, 13.7), 1.44 (s, 3H). Visible peaks for the minor diaster-
eomer: d 7.96–7.94 (d, 2H, J = 9.0), 7.00–6.98 (d, 2H, J = 9.0),
4.20–4.16 (m, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 2.19–2.17 (d, 1H, J
= 12.3), 2.04–2.00 (dd, 1H, J = 5.4, 13.4), 1.94–1.90 (dd, 1H, J =
8.0, 14.0); 13C NMR (75 MHz, CDCl3): d 171.6, 159.3, 131.2,
127.0, 113.9, 71.6, 69.2, 62.1, 59.6, 55.3, 30.8, 24.9; visible
peaks for minor diastereomer: d 130.8, 128.1, 61.7, 34.3; MS
(3R,5R)-5-(4-Methoxybenzyl)-3-methylpyrrolidin-3-ol (17)
To a suspension of lithium aluminum hydride (129 mg, 3.4
mmol) in THF (1 mL) at 0 uC was added a solution of the
pyrrolidinone 16 (100 mg, 0.42 mmol) in THF (3 mL) dropwise.
The mixture was warmed to room temperature and then
heated to reflux for 12h. The mixture was cooled to 0 uC and
water (0.1 mL), aqueous NaOH (2.5 M, 1.3 mL) and water (0.3
mL) were added sequentially with a 15 min stirring period
between each addition and 20 min stirring after the last
addition. The resulting mixture was filtered with suction and
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the white precipitate was washed with THF (2 6 10 mL). The
combined filtrates were dried (Na2SO4) and concentrated. The
residue was dissolved in EtOAc (3 mL) and the solution was
extracted with aqueous HCl (1 M, pH 5, 2 6 3 mL). The
combined extracts were cooled (,5 uC) and basified to pH 9
with NaOH pellets. The basic solution was extracted with
EtOAc (3 6 10 mL) and the combined extracts were dried
(Na2SO4) and concentrated to provide 74 mg (79%) of the
pyrrolidine 17 as a yellow gum. This was pure by 1H NMR and
was directly used further. An analytical sample was obtained
by flash chromatography on silica gel (CH2Cl2–MeOH, 9 : 1
containing 1% aq. ammonia).
72/25, 254 nm, t1 = 7.4 min (minor), t2 = 8.9 min (major), Ee:
91%. (lit.3a t1 = 8.04 min (major), t2 = 9.80 min (minor) for (+)-
19). Other spectroscopic data (1H NMR, 13C NMR) is in
agreement with reported data.4f
(2)-(1R,4S)-8-Methoxy-1-methyl-4,5-dihydro-1H-1,4-
methanobenzo[d]azepine-3(2H)-carbaldehyde (20)
To a solution of 17 (30 mg, 0.13 mmol) in CH2Cl2 (2.5 mL) was
added acetic formic anhydride (14 mL, 0.15 mmol). The
mixture was stirred at room temperature for 4 h and then
concentrated under reduced pressure to provide 29 mg (97%)
the N-formyl derivative as a yellow gum. This was dissolved in
CH2Cl2 (0.5 mL) and the solution was added dropwise to a cold
(0 uC), stirred suspension of AlCl3 (162 mg, 1.21 mmol) in
CH2Cl2 (0.5 mL). The mixture was then stirred at ambient
temperature for 24 h, cooled to 0 uC and saturated aqueous
NaHCO3 (2 mL) was added. The biphasic solution was
transferred to a separatory funnel and extracted with CH2Cl2
(3 6 5 mL). The combined extracts were dried (Na2SO4) and
concentrated to provide a pale yellow gum. Purification by
flash chromatography on silica gel (9.5 : 0.5 CH2Cl2–MeOH)
provided 23 mg (88%) of 20 as a colourless gum.
1
IR (neat): 3301, 2924, 1511, 1243, 1034 cm21; H NMR (500
MHz, CDCl3): d 7.13 (d, 2H, J = 8.6, ArH), 6.85 (d, 2H, J = 8.6),
3.80 (s, 3H), 3.69–3.64 (m, 1H), 2.97–2.90 (AB system, 2H, J =
11.2), 2.75–2.67 (ABX system, 2H, J = 7.0, 13.6), 1.94–1.91 (dd,
1H, J = 6.3, 13.2), 1.51–1.46 (dd, 1H, J = 9.3, 13.2), 1.40 (s, 3H);
13C NMR (75 MHz, CDCl3): d 158.1, 131.5, 129.9, 113.9, 79.0,
59.7, 59.4, 55.3, 47.3, 41.5, 26.4; MS (APCI pos.): m/z 222.1 (M +
1); HRMS (CI+): m/z 222.1489 (222.1494 calc. for C13H20NO2(M
+ H)); [a]2D5 270.0 (c 0.5, CHCl3).
(2)-(3R,5R)-5-(4-Methoxybenzyl)-3-methyl-1-tosylpyrrolidin-3-
ol (18)
1
IR: 2955, 1657, 1612, 1417, 1233, 1036 cm21; H NMR (300
MHz, CDCl3): major rotamer : d 8.34 (s, 1H), 7.00–6.98 (d, 1H, J
= 8.3), 6.82 (d, 1H, J = 2.6), 6.75–6.71 (dd, 2H, J = 2.6, 8.3), 4.42–
4.41 (m, 1H), 3.78 (s, 3H), 3.54–3.52 (d, 1H, J = 11.2), 3.25–3.22
(d, 2H, J = 12.1), 2.94–2.91 (d, 2H, J = 16.6), 2.03–2.00 (dd, 1H, J
= 1.4, 5.5), 1.98–1.95 (dd, 1H, J = 1.3, 5.0), 1.55 (s, 3H), minor
rotamer: d 8.1(s, 1H), 7.03–7.01 (d, 1H, J = 8.4), 6.84 (d, 1H, J =
2.6), 4.65–4.64 (m, 1H), 3.79 (s, 3H), 3.49–3.47 (d, 1H, J = 9.2),
3.41–3.39 (d, 1H, J = 9.2), 3.14–3.11 (dd, 1H, J = 2.8, 16.5), 1.55
(s, 3H); 13C NMR (75 MHz, CDCl3): major rotamer: d 160.3,
157.9, 145.4, 130.2, 123.8, 111.6, 109.7, 58.8, 55.1, 52.5, 41.4,
38.9, 34.9, 20.7, minor rotamer: 160.4, 157.8, 144.6, 130.4,
125.2, 111.5, 109.8, 63.7, 60.6, 54.7, 40.4, 20.5; MS: (APCI pos.):
m/z 232.1 (M + 1); HRMS (EI+): m/z 231.1264 (231.1259 calc. for
To stirred solution of p-toluenesufonyl chloride (19.4 mg, 0.10
mmol) in THF (0.5 mL) was added freshly distilled triethyl
amine (19.0 mL, 0.14 mmol) at 0 uC, followed by a solution of
the amine 17 (15 mg, 0.07 mmol) in THF (1.0 mL). The mixture
was stirred for 8 h at ambient temperature and saturated,
aqueous NaHCO3 (2 mL) was added. The mixture was extracted
with CH2Cl2 (3 6 10 mL) and the combined extracts were
dried (Na2SO4) and concentrated. The residue was purified by
flash chromatography on silica gel (hexanes–EtOAc, 1 : 1) to
provide 19 mg (75%) of 18 as an off-white foam.
IR: 3508, 2929, 1511, 1331, 1245, 1151, 1088, 1033 cm21; 1H
NMR (300 MHz, CDCl3): d 7.81 (d, 2H, J = 8.1), 7.34 (d, 2H, J =
8.1), 7.15 (d, 2H, J = 8.6), 6.83 (d, 2H, J = 8.6), 4.02–3.94 (m, 1H),
3.78 (s, 3H), 3.40–3.37 (dd, 1H, J = 2.3, 12.4), 3.32–3.29 (dd, 1H,
J = 3.5, 13.5), 3.17 (d, 1H, J = 12.4), 2.89–2.81 (dd, 1H, J = 8.8,
13.5), 2.42 (s, 3H), 1.80–1.75 (ddd, 1H, J = 2.3, 6.9, 13.4), 1.63–
1.57 (dd, 1H, J = 9.7, 13.3), 1.19 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 158.3, 143.6, 135.0, 130.6, 129.72, 129.65, 127.8,
113.8, 76.0, 61.6, 61.1, 55.2, 45.6, 41.0, 24.2, 21.6; MS (APCI
pos.): m/z 376.1 (M + 1); HRMS (CI pos. TOF): m/z 376.1589
(376.1583 calc. for C20H26NO4S (M + H)); [a]2D5 276.8 (c 0.5,
CHCl3).
C
14H17NO2 (M+); [a]D25 223.2 (c 1, CHCl3).
(+)-8-O-Methylaphanorphine (2)
A solution of the formamide 20 (10 mg, 0.04 mmol) in ether
(0.5 mL) was added to a stirred suspension of lithium
aluminium hydride (5 mg, 0.12 mmol) in diethylether (0.5
mL) at 0 uC and the resulting mixture was stirred at ambient
temperature for 7 h. The mixture was then cooled to 0 uC and
treated sequentially with water (3 mL), aqueous NaOH (2.5 M,
50 mL), and water (9 mL) with 5 min of stirring after each
addition. The resulting mixture was filtered with suction and
the solid residue was washed several times with ether. The
combined filtrates were dried (Na2SO4) and concentrated to
provide 7 mg (74%) of (+)-8-O-methylaphanorphine (2) as a
yellow liquid.
(2)-(1R,4S)-8-Methoxy-1-methyl-3-tosyl-2,3,4,5-tetrahydro-
1H-1,4-methanobenzo[d]azaepin (19)
This was prepared from 18 (12 mg, 0.03 mmol) and AlCl3 (44
mg, 0.34 mmol) in CH2Cl2 (1 mL) at 0 uC according to the
literature procedure.4f Purification of the crude product by
flash chromatography on silica gel (hexanes–EtOAc 4.9 : 1)
provided 8 mg (72%) of 19 as a pale yellow solid.
IR: 2923, 1611, 1577, 1290, 1040, 804 cm21 1H NMR (500
;
MHz, CDCl3): d 7.02–7.01 (d, 1H, J = 8.3, ArH), 6.78–6.77 (d, 1H,
J = 2.6, ArH), 6.68–6.66 (dd, 1H, J = 2.6, 8.3, ArH), 3.77 (s, 3H,
OCH3), 3.40–3.39 (m, 1H, NCH), 3.04–3.00 (d, 1H, J = 16.7,
CH2), 2.86–2.84 (dd, 1H, J = 3.1, 7.9, ArCH2), 2.83 (d, 1H, J = 9.0,
ArCH2), 2.75–2.73 (d, 1H, J = 9.0, NCH2), 2.47 (s, 3H, OCH3),
2.03–2.00 (dd, 1H, J = 5.2, 10.8, CH2), 1.86–1.84 (d, 1H, J = 10.9,
CH2) 1.48 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d 157.4
Mp: 136–138 uC (lit.2b mp: 136–138 uC); IR: 2924, 1336, 1291,
1236, 1154, 1093, 1043, 809 cm21; MS: (APCI pos.): m/z 358.1
(M + 1); HRMS (EI+): m/z 357.1394 (357.1399 calc. for
C20H23NO3S (M+); [a]D25 218.9 (c 0.9, CHCl3; lit.2b [a]2D5 216.9
(c 0.89, CHCl3); HPLC: Chiralpak AD-H, hexanes/2-propanol
19132 | RSC Adv., 2013, 3, 19127–19134
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(ArC-OCH3), 147.9 (ArC-CCH3), 130.0 (ArC), 125.9 (ArCipso),
110.7 (ArC), 109.2 (ArC), 71.2 (CH-NCH3), 61.1 (CH2-NCH3),
55.0 (OCH3), 43.0 (CH2), 41.3 (NCH3), 35.5 (CCH3), 29.5 (CH2),
21.3 (CH3); MS (APCI pos): m/z 218.1 (M + 1); HRMS (CI pos.
TOF): m/z 217.1467 (217.1467 calc. for C14H19NO (M+); [a]D25
=
+11.3 (c 0.4, (CHCl3), lit.2g [a]D23: +9.39 (c 0.30, CHCl3). Other
spectroscopic data (1H NMR, 13C NMR) is in agreement with
reported data.4f
Acknowledgements
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We gratefully acknowledge financial support from the Natural
Sciences and Engineering Research Council of Canada and the
Canada Foundation for Innovation.
Notes and References
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anisole is tedious. In comparison, the carboxylic acid cross-
metathesis product 8 is easily isolated by bicarbonate
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was then subjected to cross-metathesis.
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17 The relative stereochemistry of 13 could not be ascertained
at this stage due to inconclusive NOE experiments. The
shown stereochemistry (cis orientation of the CH3 and
CH2Ar groups) was confirmed by comparison of the
spectral data for the pyrrolidine 16 with data reported for
a mixture of (3S,5S) and (3S,5R) 16 (ref. 3a) and that for
(3R,5S) 16 (ref. 4f). Notably, the chemical shift of the C5
methine proton is diagnostic (4.0 ppm for 16 with the CH3
and CH2Ar groups cis, and 3.8 ppm for 16 with the CH3 and
CH2Ar groups trans).
´
18 S. Serna, I. Tellitu, E. Domınguez, I. Moreno and
R. SanMartin, Tetrahedron, 2004, 60, 6533.
19 J. R. Fuchs and R. L. Funk, Org. Lett., 2001, 3, 3923. Also see
ref. 2i and 3a.
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