A practical asymmetric synthesis of the ACNO fragment of morphine alkaloids

Article abstract of DOI:10.1055/s-2008-1078021

Asymmetric total synthesis of the ACNO skeleton of morphine alkaloids has been achieved in excellent overall yields and optical purities using the Ru-catalyzed asymmetric transfer hydrogenation, Pd-catalyzed cyclization, and Pt-catalyzed hydrogenation as key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078021

LETTER
2299
A Practical Asymmetric Synthesis of the ACNO Fragment of Morphine
Alkaloids
A
symmetric Syn
i
thesis
n
of
A
CNO Fr
g
agment of
M
-
orphineWei Hsin,* Li-Te Chang, Huei-Ling Liou
Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, Number 1, Section 1, Jen-Ai Road,
Room 1336, Taipei, Taiwan 10018, R. O. C.
Fax +886(2)23512086; E-mail: lwhsin@ntu.edu.tw
Received 16 April 2008
Retrosynthetic analysis of the ACNO ring system of mor-
phine alkaloids is briefly depicted in Scheme 1. Stereose-
lective reduction of enamine 4 yields 3 with the desired
trans CN ring junction. The O ring of 4 could be formed
by treatment of haloaryl ethers 5 or 6 via Pd-catalyzed cy-
clization reactions. Coupling of aminoalcohol 9 with aryl
halides 7 and 8 provides 5 and 6, respectively. Alcohol 9
is accessible via N-methylation of compound 10 followed
by partial reduction. Asymmetric reduction of ketone 11
provides optically active compound 10. In this strategy,
the chirality of C-7a in compound 10 could be used to con-
trol the chirality of other chiral centers in ACNO skeleton
formed in the following steps by its directing effect.
Abstract: Asymmetric total synthesis of the ACNO skeleton of
morphine alkaloids has been achieved in excellent overall yields
and optical purities using the Ru-catalyzed asymmetric transfer hy-
drogenation, Pd-catalyzed cyclization, and Pt-catalyzed hydrogena-
tion as key steps.
Key words: asymmetric catalysis, total synthesis, transition metals,
hydrogenation, Heck reaction
Morphine alkaloids have been widely used in clinics as
analgesics, antidiarrheals, and antitussives for decades.1
Although morphine is a potent and inexpensive pain kill-
er, its abuse liability and undesired adverse effects contin-
ue to stimulate the search for nonaddictive and safer
analgesics. trans-Octahydro-1H-benzo[4,5]-furo[3,2-e]-
isoquinolin-9-ol, which contains the ACNO partial struc-
ture of morphine (Figure 1), is an attractive class of mor-
phine fragment. The N-cyclopropylmethyl derivative 1
has potent oral analgesic and narcotic-antagonism activi-
ties and thus, might have a low potential for addiction
similar to nalbuphine and buprenorphine.2
Asymmetric transfer hydrogenation of ketone 11, which
was synthesized in two steps according to the literature
procedure,7 using Noyori and Hashiguchi’s chiral Ru(II)
catalysts8 provided alcohol 10 in high optical purity.
Treatment of ketone 11 with Et3N and formic acid at room
temperature in the presence of a catalytic amount (sub-
strate/catalyst = 200) of Ru(II) catalyst, RuCl[(R,R)-Tsd-
pen](p-cymene) [(R,R)-17; Tsdpen: N-(p-toluenesul-
fonyl)-1,2-diphenylethylenediamine], afforded alcohol
(–)-10 in quantitative yield with 96% ee (Scheme 2).9
To further study the structure-activity relationship (SAR)
and evaluate the therapeutic potential of ACNO com-
pounds as novel nonaddictive analgesics, preparation of
optically pure ACNO derivatives for pharmacological
studies is essential and therefore, an efficient route for the
preparation of various ACNO derivatives is highly de-
sired. Despite several synthetic strategies that have been
reported in the literature,3–6 the need for a practical and
stereoselective synthetic strategy has not been met. Herein
we report a concise asymmetric synthesis of the ACNO
fragment of morphine alkaloids starting from commer-
cially available 5,6,7,8-tetrahydroisoquinoline.
Initial attempts to transform alcohol (–)-10 to compound
(+)-9 using the same reaction conditions for the prepara-
tion of compound ( )-9 from ( )-104 yielded (+)-9 with a
poor ee (<70%). A possible mechanism is shown in
Scheme 3.
After N-methylation of (–)-10, the acidity of H-5 in the
pyridinium ion was substantially increased. An equilibri-
um between the pyridinium ion and the dihydropyridine
intermediate might have existed in the presence of basic
R1O
HO
A
A
1 R1 = H; R2 = cyclopropylmethyl
2 R1 = H; R2 = Me
O
O
B
N
O
O
HO
7a
3 R1 = Me; R2 = Me
N
C
C
4a
N
NMe
R2
H
H
ACNO
morphine
Figure 1 Morphine and its ACNO partial structure
SYNLETT 2008, No. 15, pp 2299–2302
1
5
.0
9
.2
0
0
8
Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078021; Art ID: W06008ST
© Georg Thieme Verlag Stuttgart · New York

2300
L.-W. Hsin et al.
LETTER
OH
OH
MeO
MeO
MeO
O
(–)-10
5
O
O
N+
N+
X
Me
Me
7a
4a
NMe
NMe
NMe
H
3
4
5 X = Br
6 X = I
OH
OH
+
N+
N
H
Me
OH
OH
MeO
Scheme 3 Possible mechanism of racemization
7a
7a
+
N
NMe
HO
proach, treatment of halides 5 or 6 under palladium-cata-
lyzed (Heck) reaction conditions yielded phenol 14 via a
Claisen rearrangement.5 We thought that the basic nitro-
gen atoms in halides 5 and 6 might be responsible for the
failure of the cyclization reactions. Therefore, carbamate
15 was synthesized and subjected to the Heck reaction
condition, and compound 16 with the ACNO ring system
was obtained in a moderate yield.5 Based on this key
transformation, the first asymmetric synthesis of the
ACNO fragment of morphine alkaloids was achieved in
12 steps with a total yield of 4.2%.6 However, this lengthy
synthetic route and the low overall yield were not satisfac-
tory for the preparation and pharmacological studies of
various ACNO derivatives.
X
10
9
7 X = Br
8 X = I
O
N
N
11
Scheme 1 Retrosynthetic analysis of compound 3
(–)-10 and resulted in significant racemization. Therefore,
alcohol (–)-10 was methylated in CH2Cl2 at –25 °C and
then reduced with NaBH4 in MeOH at 0 °C to yield (+)-9.
Coupling of compound (+)-9 with aryl iodide 8 under Mit-
sunobu reaction conditions provided aryl ether (–)-6 in
88% yield and 92% ee when the reaction was conducted
at –30 °C. Higher reaction temperature was detrimental to
the optical purity of compound (–)-6.
To avoid the production of phenol 14 and identify the crit-
ical reaction parameters for successful Heck reaction, io-
dide 6 was treated with various Pd catalysts, phosphine
ligands, bases, and solvents. It is interesting to note that
the tetracyclic enamine 4 was obtained when PPh3 was re-
placed with (o-tolyl)3P in this Pd-catalyzed cyclization,
and there was no rearranged product 14 formed in the re-
action mixture. Thus, treatment of iodide (–)-6 with
Previously, intramolecular radical cyclization of bromide
5 provided a mixture of trans isomer 3, cis isomer 12, and
a rearranged product 13 (Scheme 4).4 In another ap-
OH
OH
O
1. MeI, CH2Cl2, –25 °C
RuCl[(R,R)-Tsdpen](p-cymene)
N
HCO2H, Et3N, r.t.
100%, 96% ee
N
NMe
2. NaBH4, MeOH, 0 °C
93%
11
(–)-10
(+)-9
MeO
O
MeO
O
Pd(OAc)2, (o-Tol)3P
Et3N, MeCN, 120 °C
8, (n-Bu)3P, DEAD
I
conventional: 16 h, 66%
microwave: 30 min, 73%
93% ee
THF, –30 °C
88%, 92% ee
NMe
NMe
(+)-4
(–)-6
MeO
O
HO
1. H2, PtO2, EtOH, r.t. (76%, 93% ee)
BBr3⋅SMe2, reflux
O
DCE
85%
2. HCl
3. recrystallization (>99% ee)
NMe
(–)-3
NMe
(–)-2
H
H
Scheme 2 A concise total synthesis of (–)-2
Synlett 2008, No. 15, 2299–2302 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of ACNO Fragment of Morphine
2301
MeO
O
MeO
O
MeO
MeO
Bu3SnH, AIBN (cat.)
benzene, 130 °C
O
O
+
+
Br
NMe
NMe
NMe
NMe
H
H
5
3 25%
12 16%
13 17%
MeO
NMe
OH
Pd(OAc)2, Ph3P, Et3N
MeCN, 125 °C
O
X
OMe
NMe
5 X = Br
6 X = I
14 40% (from 5); 44% (from 6)
MeO
MeO
O
Pd(OAc)2, Ph3P, (n-Bu)4NBr
K2CO3, MeCN, 125 °C, 41%
O
I
N
N
CO2Et
CO2Et
16
15
Scheme 4 Intramolecular radical cyclization,4 palladium-catalyzed Claisen rearrangement,5 and palladium-catalyzed Heck cyclization5
Pd(OAc)2, (o-Tol)3P, and Et3N in acetonitrile at 120 °C in chiral reagent used in this asymmetric total synthesis. Ap-
a sealed bottle gave the Heck reaction product (+)-4 with plication of this synthetic strategy for the preparation of
the tetracyclic ACNO ring system. By using microwave- other morphine fragments and related alkaloids such as
assisted heating,10 the yield of enamine (+)-4 was in- galanthamine are currently under investigation.
creased from 66% to 73% and the reaction time was short-
en from 16 hours to 30 minutes. In contract to the
preceding steps, conducting this palladium-catalyzed re-
action at high reaction temperature by either conventional
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
or microwave-assisted heating did not affect the ee of (+)-
4 (93%).
Acknowledgment
Catalytic hydrogenation of enamine (+)-4 over PtO2 af-
We acknowledge the National Science Council of the People’s Re-
public of China (Grant No. NSC 96-2323-B-002-022) for financial
forded (–)-36 with the desired trans CN ring junction. This
optically active (–)-3 (ee = 93%) was transformed to its support of this research.
hydrochloride salt and then recrystallized to obtain opti-
cally pure (–)-3 (ee >99%).6 O-Demethylation of com-
References and Notes
pound (–)-3 using BBr3·SMe2 in 1,2-dichloroethane
(1) (a) Willette, R. E. Analgesic Agents, In Wilson and Gisvold’s
furnished trans-octahydro-1H-benzo[4,5]furo[3,2-e]iso-
quinolin-9-ol (–)-26 in 85% yield.11 In contrast to the pre-
vious carbamate pathway (12 steps; 4.2% yield),6 this new
synthetic route provided compound (–)-2 in eight steps
with a total yield of 27.4% starting from commercially
available 5,6,7,8-tetrahydroisoquinoline.
Textbook of Organic Medicinal and Pharmaceutical
Chemistry, 10th ed.; Delgado, J. N.; Remers, W. A., Eds.;
Lippincott-Raven: Philadelphia, 1998, 687–708. (b) Fries,
D. S. Opioid Analgesics, In Foye’s Principles of Medicinal
Chemistry, 5th ed.; Lemke, T. L.; Williams, D. A., Eds.;
Lippincott Williams & Wilkins: Baltimore, MD, 2002, 453–
479. (c) Michne, W. F. Chemistry of Opiate Analgesics and
Antagonists, In Analgesics: Neurochemical, Behavioral, and
Clinical Perspectives; Kuhar, M.; Pasternak, G., Eds.;
Raven Press: New York, 1984, 125–148.
In conclusion, a practical asymmetric synthesis of the
ACNO fragment of morphine alkaloids was demonstrat-
ed. The three chiral centers in trans-octahydro-1H-ben-
zo[4,5]furo[3,2-e]isoquinolin-9-ol were stereoselectively
established via metal-catalyzed asymmetric transfer hy-
drogenation, Heck reaction, and hydrogenation, respec-
tively as exemplified by the synthesis of (–)-2. In addition,
a catalytic amount of Ru(II) catalyst (R,R)-17 was the only
(2) Ciganek, E. U.S. Patent 4243668, 1981; Chem. Abstr. 1981,
95, 809241.
(3) (a) Ciganek, E. J. Am. Chem. Soc. 1981, 103, 6261.
(b) Moos, W. H.; Gless, R. D.; Rapoport, H. J. Org. Chem.
1981, 46, 5064. (c) Shenvi, A. B. U.S. Patent 4421916,
1983. (d) Shenvi, A. B.; Ciganek, E. J. Org. Chem. 1984, 49,
Synlett 2008, No. 15, 2299–2302 © Thieme Stuttgart · New York

2302
L.-W. Hsin et al.
LETTER
2942. (e) Weller, D. D.; Weller, D. L. Tetrahedron Lett.
1982, 23, 5239. (f) Weller, D. D.; Stirchak, E. P.; Weller,
D. L. J. Org. Chem. 1983, 48, 4597. (g) Cheng, C. Y.; Hsin,
L.-W.; Tsai, M. C.; Schmidt, W. K.; Smith, C.; Tam, S. W.
J. Med. Chem. 1994, 37, 3121. (h) Laronze, J.-Y.; Laronze,
J.; Patigny, D.; Lévy, J. Tetrahedron Lett. 1986, 27, 489.
(i) Sapi, J.; Dridi, S.; Laronze, J.; Sigaut, F.; Patigny, D.;
Laronze, J.-Y.; Lévy, J.; Toupet, L. Tetrahedron 1996, 52,
8209.
temperature was measured and feedback controlled with an
infrared device under the reaction vessel.
24
(11) Spectral Data: Compound (–)-10: pale yellow solid; [a]D
–31.1 (c = 1.00, MeOH); ee = 96.3%. 1H NMR (300 MHz,
CDCl3): d = 1.61–1.74 (m, 2 H), 1.85–2.03 (m, 2 H), 2.57–
2.61 (m, 2 H), 4.59 (t, J = 5.9 Hz, 1 H), 5.30 (s, 1 H), 7.32 (d,
J = 5.0 Hz, 1 H), 8.07 (s, 1 H), 8.11 (d, J = 5.0 Hz, 1 H). 13
C
NMR (75 MHz, CDCl3): d = 19.2, 25.8, 31.8, 66.6, 122.3,
132.4, 146.2, 148.8, 149.2. HRMS (EI): m/z [M]+ calcd for
C9H11NO: 149.0841; found: 149.0839.
(4) Cheng, C.-Y.; Hsin, L.-W.; Liou, J.-P. Tetrahedron 1996,
52, 10935.
(5) Hsin, L.-W.; Chang, L.-T.; Chen, C.-W.; Hsu, C.-H.; Chen,
H.-W. Tetrahedron 2005, 61, 513.
(6) Hsin, L.-W.; Chen, C.-W.; Chang, L.-T. J. Chin. Chem. Soc.
(Taipei) 2005, 52, 339.
(7) Lardenois, P.; Frost, J.; Dargazanli, G.; George, P. Synth.
Compound (+)-9: yellow oil; [a]D20 +60.0 (c = 0.10, MeOH).
1H NMR (400 MHz, CDCl3): d = 1.37–1.41 (m, 1 H), 1.43–
1.49 (m, 1 H), 1.54–1.66 (m, 4 H), 1.82–1.88 (m, 1 H), 2.12
(s, 3 H), 2.27–2.37 (m, 3 H), 2.56 (s, 2 H), 3.69 (s, 1 H), 4.12
(s, 1 H). 13C NMR (100 MHz, CDCl3): d = 18.3, 26.8, 27.5,
32.3, 45.2, 52.2, 57.9, 67.0, 128.9, 129.2. HRMS (EI): m/z
[M]+ calcd for C10H17NO: 167.1310; found: 167.1317.
Compound (–)-6: pale yellow oil; [a]D20 –51.1 (c = 1.90,
MeOH); ee = 92%. 1H NMR (200 MHz, CDCl3): d = 1.39–
1.62 (m, 2 H), 1.89–1.91 (m, 2 H), 1.96–2.20 (m, 2 H), 2.29
(m, 1 H), 2.31 (s, 3 H), 2.35–2.39 (m, 1 H), 2.60–2.73 (m, 3
H), 2.91 (d, J = 15.7 Hz, 1 H), 3.76 (s, 3 H), 4.66 (s, 1 H),
6.69 (t, J = 8.0 Hz, 1 H), 6.82 (dd, J = 1.5, 8.2 Hz, 1 H), 7.31
(dd, J = 1.6, 7.8 Hz, 1 H). 13C NMR (50 MHz, CDCl3): d =
18.4, 27.80, 27.84, 28.3, 45.6, 52.5, 55.3, 58.4, 77.5, 93.5,
112.4, 124.9, 126.4, 130.9, 132.6, 147.4, 152.5. HRMS
(FAB): m/z [M + H]+ calcd for C17H23INO2: 400.0774;
found: 400.0783.
Commun. 1996, 26, 2305.
(8) (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.;
Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285.
(b) Bennett, M. A.; Huang, T.-N.; Matheson, T. W.; Smith,
A. K. Inorg. Synth. 1982, 21, 74. (c) Okano, K.; Murata, K.;
Ikariya, T. Tetrahedron Lett. 2000, 41, 9277.
(9) Chiral HPLC Analysis: The free base of the sample was
dissolved in 1% isopropanol (IPA) in n-hexane. Then the
sample solution (10 mL) was eluted using 1.5% [for
compound (+)-4], 2.5% [for compounds (–)-3 and (–)-6], or
8% [for compound (–)-10] IPA in n-hexane in the presence
of 0.2% diethylamine as mobile phase on the CHIRALCEL
OD column (250 × 4 mm, DAICEL). The ee values were
calculated based on the UV absorption (l = 254 nm) areas of
the two enantiomers.
(10) Microwave Experiments: The reactions under microwave
irradiation were conducted in sealed heavy-walled Pyrex
tubes. Microwave heating was carried out with a single
mode cavity Discover Microwave Synthesizer (CEM
Corporation, P.O. Box 200, Matthews, NC 28106, USA),
producing continuous irradiation at 2.45 GHz. The reaction
Compound (+)-4: pale yellow oil; [a]D20 +105.0 (c = 0.92,
MeOH); ee = 92.5%. 1H NMR (200 MHz, CDCl3): d = 1.10–
1.26 (m, 1 H), 1.35–1.47 (m, 1 H), 1.50–1.68 (m, 1 H), 1.84–
1.93 (m, 4 H), 2.00–2.17 (m, 1 H), 2.62 (s, 3 H), 2.71–2.82
(m, 2 H), 3.88 (s, 3 H), 4.46 (dd, J = 6.1, 9.4 Hz, 1 H), 5.91
(s, 1 H), 6.74–6.90 (m, 3 H). 13C NMR (50 MHz, CDCl3):
d = 22.7, 29.3, 29.7, 37.1, 43.0, 45.9, 46.7, 55.9, 90.8, 106.8,
111.4, 116.8, 120.6, 134.2, 138.2, 145.2, 146.2. HRMS (EI):
m/z [M]+ calcd for C17H21NO2: 271.1572; found: 271.1569.
Synlett 2008, No. 15, 2299–2302 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.