Total Synthesis of (?)-Morphine

Article abstract of DOI:10.1002/chem.201701438

Asymmetric total synthesis of (?)-morphine has been accomplished in 18 steps from commercially available 7-methoxy-2-tetralone. Our synthesis features a simple transformation from a readily prepared chiral intermediate, construction of the E-ring by acid-mediated cyclization, and singlet oxygen-mediated manipulation of the C-ring. Transformation of the final stage involves construction of the morphinan skeleton by means of 1,6-addition of in situ generated secondary amine.

Full text of DOI:10.1002/chem.201701438

A Journal of
Accepted Article
Title: Total Synthesis of (-)-Morphine
Authors: Hirotatsu Umihara, Satoshi Yokoshima, Masayuki Inoue, and
Tohru Fukuyama
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To be cited as: Chem. Eur. J. 10.1002/chem.201701438
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10.1002/chem.201701438
Chemistry - A European Journal
COMMUNICATION
Total Synthesis of (−)-Morphine
Hirotatsu Umihara,[b] Satoshi Yokoshima,[a] Masayuki Inoue,[b] and Tohru Fukuyama*[a]
Abstract: Asymmetric total synthesis of (–)-morphine has been
accomplished in 18 steps from commercially available 7-methoxy-2-
MeO
Friedel-
Crafts
reaction
MeO
O
MeO
HO
Baeyer-
Villiger
oxidation
tetralone. Our synthesis features a simple transformation from a
readily preparable chiral intermediate, construction of the E-ring by
acid-mediated cyclization, and singlet oxygen-mediated manipulation
of the C-ring. Transformation of the final stage involves construction
of the morphinan skeleton by means of 1,6-addition of in-situ
generated secondary amine.
O
OH
CO2Me
E ring
formation
tBuO
O
retro-aldol/
aldol reaction
2
3
4
O
X
MeO
HO
O
Morphine (1), the first “alkaloid” isolated from opium poppy,[1] is
well-known and an indispensable drug for controlling the pain of
cancer. In addition to the distinctive pharmacological features,
morphine has a unique pentacyclic skeleton, including a benzylic
quaternary carbon. Over the years extensive synthetic studies of
1 and related natural products have been conducted and more
than 30 total as well as formal syntheses have been reported to
date.[2,3] There are, however, several shortcomings in the
reported asymmetric synthesis of morphine, including the use of
chiral column chromatography, insufficient ee’s, and use of
expensive catalysts. We thus focused on the establishment of
an efficient asymmetric synthesis of morphine.
Our synthetic strategy is shown in Scheme 1. We planned to
take advantage of the chiral substrate 2, an intermediate in the
d’Angelo’s work,[4] because it could easily be prepared from 6
and has all the necessary carbons in the main skeleton of 1.
Friedel-Crafts reaction of 2 and subsequent retro-aldol/aldol
reaction would give 3, possessing a C-C bond for regioselective
introduction of oxygen functionality at the aromatic ring by
means of Baeyer-Villiger oxidation. 3 could be transformed to 4
for the construction of the E-ring. Manipulation of the C-ring
would give 5, a known intermediate of our previous work.[5,6]
Me
N
[1,6]-
addition
DNs
H
O
E
manipulation
of C ring
D
NMe
C
O
HO
5
morphine (1)
Scheme 1. Synthetic Strategy.
Our synthesis commenced with preparation of 2 from
commercially available 7-methoxy-2-tetralone 6 according to the
d’Angelo’s procedure (Scheme 2).[4] Treatment of 2 with TfOH
caused deprotection of the tert-butyl ester, Friedel-Crafts
reaction, and dehydration of the tert-alcohol moiety to give 7.
Hydroxyselenenylation[7] of the resulting olefin led to selenide 8.
Oxidation of the selenide with mCPBA and subsequent
selenoxide elimination by mild heating gave allyl alcohol 9.[8]
Upon treatment with cesium carbonate in ethanol at 60 °C, 9
underwent retro-aldol/aldol reaction to furnish enone 10 in
moderate yield.[9]
MeO
MeO
MeO
O
ref [4]
a
b
O
O
3 steps
52%
>99% ee
OH
O
O
OtBu
6
2
7
MeO
O
MeO
O
MeO
c
d
O
O
O
OH
OH
OH
SePh
O
8
9
10
[a]
[b]
Dr. S. Yokoshima, Prof. Dr. T. Fukuyama
Graduate School of Pharmaceutical Sciences
Nagoya University
Furo-cho, Chikusa, Nagoya, Aichi 464-8601, Japan
E-mail: fukuyama@ps.nagoya-u.ac.jp
Dr. H. Umihara, Prof. Dr. M. Inoue
Scheme 2. Friedel-Crafts and retro-aldol/aldol reactions. Reagents and
conditions: (a) TfOH-CH2Cl2 (1:9), 0 °C to rt, 60%; (b) PhSeCl, CH3CN-H2O
(5:1), rt, 75% (90% purity); (c) mCPBA, NaHCO3, CH2Cl2, 0 °C to reflux, 71%;
(d) Cs2CO3, EtOH (5 mM), 60 °C, 57% (80% purity). mCPBA
chloroperbenzoic acid; TfOH = trifluoromethanesulfonic acid.
= m-
Graduate School of Pharmaceutical Sciences
University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Supporting information for this article is given via a link at the end of
the document.
We next focused on construction of the dihydrofuran ring (E-
ring, Scheme 3). Baeyer-Villiger oxidation of 10 with mCPBA
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MeO
MeO
a
MeO
afforded lactone 11. Methanolysis of lactone 11 induced
elimination of the tert-alcohol moiety via formation of a lactone
with the resulting methyl ester moiety to give carboxylic acid 12,
which was methylated with TMSCHN2 to afford cross-conjugated
dienone 13. Luche reduction of the dienone moiety in 13 gave
dienyl alcohol 14, which, upon treatment with p-toluenesulfonic
acid, caused formation of a dienyl cation and immediate
Me
b
OH
N
O
CO2Me
O
O
DNs
15
MeO
16
17
MeO
interception
with
a
phenol
moiety
furnished
Me
N
Me
N
benzotetrahydrofuran 15. This 2-step transformation could be
carried out in one pot without any loss of the product yield by
treatment with hydrochloric acid.
d
c
O
DNs
O
DNs
O
OH
O
O
18
19
MeO
MeO
+
MeO
O
MeO
MeO
MeO
HO
Me
N
e
O
O
a
b
O
O
H
O
O
DNs
NMe
NMe
OH
OH
CO2H
O
codeinone (21)
O
neopinone (20)
5
O
O
O
10
11
12
f
MeO
HO
MeO
HO
MeO
HO
MeO
g
h
H
H
O
O
c
d
CO2Me
CO2Me
NMe
NMe
O
CO2Me
HO
codeine (22)
HO
morphine (1)
O
OH
15
13
14
Scheme 4. Manipulation of the C-ring and completion of the synthesis.
Reagents and conditions: (a)LiAlH4, THF, 0 °C; (b) DNsNHMe, DEAD, Ph3P,
toluene, 0 °C to rt, 80% (2 steps); (c) O2 (bubbling), hν (405 nm), TPP, CH2Cl2,
rt; Et3N, 86%.; (d) Martin’s sulufurane, CH2Cl2, 0 °C, 65% or Tf2O, 2,6-lutidine,
CH2Cl2, 0 °C, 80%; (e) PhSH, iPr2NEt, CH2Cl2, 0 °C, 51% (20:21 = 1:1.4); (f)
HCl in 1,4-dioxane, CHCl3, rt; (g) NaBH4, MeOH, rt, 62% (2 steps); (h) BBr3,
e
Scheme 3. Construction of the E-ring. Reagents and conditions: (a) mCPBA,
NaHCO3, CH2Cl2, rt, 71% (90% purity); (b) K2CO3, MeOH, rt; CH2Cl2, HCl aq.;
TMSCHN2, 76%; (c) NaBH4, CeCl3·7H2O, MeOH-CH2Cl2, 0 °C to rt; (d)
TsOH·H2O (10 mol%), toluene-CH2Cl2, 0 °C, 76% (2 steps); (e) NaBH4,
CeCl3·7H2O, EtOH-THF, 0 °C to rt; HCl aq., 0 °C, 76%. mCPBA = m-
chloroperbenzoic acid; TsOH = p-toluenesulfonic acid; TMS = trimethylsilyl.
CH2Cl2, rt, 51%. DEAD
dinitrobenzenesulfonyl; Tf2O
tetraphenylporphiline.
=
=
diethyl azodicarboxylate; DNS
trifluoromethanesulfonic anhydride; TPP
=
2,4-
=
In summary, we have accomplished an efficient total
synthesis of (–)-morphine (1) from a readily preparable chiral
intermediate.[4] The present asymmetric synthesis does not need
any special or expensive reagents. The unique functionalization
of the C-ring using singlet oxygen would add a new aspect to
morphine synthesis.
Having constructed the tetracyclic skeleton, the remaining
task is to construct the piperidine ring (D-ring) via the 1,6-
addition to the dienone. Prior to manipulation of the C-ring, a
nitrogen atom was introduced to the side chain via reduction of
the ester moiety in 15 and subsequent Mitsunobu reaction with
DNsNHMe (DNs = 2,4-dinitorobenzenesulfonyl).[10] The diene
moiety in the C-ring could be efficiently converted into the
dienone 5 by a 2-step sequence. Thus, treatment of 17 with
singlet oxygen[11,12] gave endoperoxide 18, which, upon addition
of triethylamine, underwent a facile cleavage of the O-O bond to
afford hydroxyenone 19. Initial attempts at dehydrating the tert-
alcohol in 19 under conventional conditions met with complete
failure.[13] After extensive investigation, we found that treatment
with Martin’s sulfurane[14] as well as Tf2O and 2,6-lutidine gave
the desired dienone 5 in good yields. As reported earlier,[5]
removal of the DNs group with PhSH[15] generated the
secondary amine, which underwent the 1,6-addition to the
dienone, giving a mixture of neopinone 20[16] and codeinone 21.
Acknowledgements
This work was financially supported by JSPS KAKENHI (Grant
Numbers 25221301, 26713001, 16H01141, 13J04813) and by
the Platform Project for Supporting Drug Discovery and Life
Science Research (Platform for Drug Discovery, Informatics,
and Structural Life Science) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan (MEXT) and
the Japan Agency for Medical Research and Development
(AMED).
[6]
The mixture converged to codeinone 21 by treatment with
Keywords: morphine • total synthesis • singlet oxygen • aldol
[18]
acid.[17] Reduction of the enone moiety in 21 with NaBH4
reaction • conjugate addition
followed by demethylation with BBr3[19] afforded (–)-morphine (1).
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NH2
MeO
Ph
benzene
reflux;
MeO
MeO
1) pyrrolidine
benzene, reflux
O
O
O
2) BrCH2CO2tBu
tBuOH
OH
tBuO
O
O
O
OtBu
6
2
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Entry for the Table of Contents
COMMUNICATION
Hirotatsu Umihara, Satoshi Yokoshima,
Masayuki Inoue, and Tohru Fukuyama*
Page No. – Page No.
Total Synthesis of (−)-Morphine
Asymmetric total synthesis of (–)-morphine has been accomplished in 18 steps. Our
synthesis features a simple transformation from a readily preparable chiral
intermediate, construction of the E-ring by acid-mediated cyclization, and singlet
oxygen-mediated manipulation of the C-ring. Transformation of the final stage
involves construction of the morphinan skeleton by means of 1,6-addition of in-situ
generated secondary amine. DNs = 2,4-dinitrobenzenesulfonyl.
This article is protected by copyright. All rights reserved.