DOI: 10.1002/chem.

201701438 Communication

& Asymmetric Synthesis

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 avail-
able 7-methoxy-2-tetralone. Our synthesis features
a simple transformation from a readily prepared chiral in-
termediate, construction of the E-ring by acid-mediated
cyclization, and singlet oxygen-mediated manipulation of
the C-ring. Transformation of the final stage involves con-
struction of the morphinan skeleton by means of 1,6-addi-
tion of in situ generated secondary amine.

Morphine (1), the first “alkaloid” isolated from opium poppy,[1] Scheme 1. Synthetic strategy.

is well-known and an indispensable pain-relief medication. In

addition to the distinctive pharmacological features, morphine Our synthesis commenced with preparation of 2 from com-
has a unique pentacyclic skeleton, including a benzylic quater- mercially available 7-methoxy-2-tetralone 6 according to the
nary carbon. Over the years, extensive synthetic studies of d’Angelo’s procedure (Scheme 2).[4] Treatment of 2 with TfOH
1 and related natural products have been conducted and
more than 30 total as well as formal syntheses have been re-
ported 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 values,
and use of expensive catalysts. Therefore, we focused on the
establishment of an efficient asymmetric synthesis of mor-
phine.
Our synthetic strategy is shown in Scheme 1. We planned to
take advantage of the chiral substrate 2, an intermediate in
d’Angelo’s work,[4] because it could easily be prepared from 6
and has all the necessary carbons for the main skeleton of 1. A
Friedel–Crafts reaction of 2 and subsequent retro-aldol/aldol
reaction would give 3, bearing a C@C bond for regioselective Scheme 2. Friedel–Crafts and retro-aldol/aldol reactions. Reagents and con-
introduction of an oxygen functionality at the aromatic ring by ditions: (a) TfOH-CH2Cl2 (1:9), 0 8C to RT, 60 %; (b) PhSeCl, CH3CN-H2O (5:1),
means of Baeyer–Villiger oxidation. The intermediary product 3 RT, 75 % (90 % purity); (c) mCPBA, NaHCO3, CH2Cl2, 0 8C to reflux, 71 %;
(d) Cs2CO3, EtOH (5 mm), 60 8C, 57 % (80 % purity). mCPBA = m-chloroperben-
could then be transformed to 4 for the construction of the E- zoic acid; TfOH = trifluoromethanesulfonic acid.
ring. Manipulation of the C-ring would give 5, a known inter-
mediate of our previous work.[5, 6]
caused the removal of the tert-butyl group, and subsequent
Friedel–Crafts reaction and dehydration of the tert-alcohol
[a] Dr. S. Yokoshima, Prof. Dr. T. Fukuyama moiety gave 7. Hydroxyselenenylation[7] of the resulting olefin
Graduate School of Pharmaceutical Sciences
gave selenide 8. Oxidation of the selenide with mCPBA and
Nagoya University
Furo-cho, Chikusa, Nagoya, Aichi 464-8601 (Japan) subsequent selenoxide elimination by mild heating gave allyl
E-mail: [email protected] alcohol 9.[8] Upon treatment with cesium carbonate in ethanol
[b] Dr. H. Umihara, Prof. Dr. M. Inoue at 60 8C, 9 underwent a retro-aldol/aldol reaction to furnish
Graduate School of Pharmaceutical Sciences enone 10 in moderate yield.[9]
University of Tokyo
We next focused on construction of the dihydrofuran ring
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
(E-ring, Scheme 3). Baeyer–Villiger oxidation of 10 with mCPBA
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under https://doi.org/10.1002/ afforded lactone 11. Methanolysis of lactone 11 induced elimi-
chem.201701438. nation of the tert-alcohol moiety by formation of a lactone

Chem. Eur. J. 2017, 23, 6993 – 6995 6993 T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Communication

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, CeCl3·7 H2O, MeOH-CH2Cl2, 0 8C to RT;
(d) TsOH·H2O (10 mol %), toluene–CH2Cl2, 0 8C, 76 % (2 steps); (e) NaBH4,
CeCl3·7 H2O, EtOH-THF, 0 8C to RT; HCl aq., 0 8C, 76 %. TsOH = p-toluenesulfon-
ic acid; TMS = trimethylsilyl.

with the resulting methyl ester moiety to give carboxylic acid

12, which was methylated with TMSCHN2 to afford cross-conju-
gated dienone 13. Luche reduction of the dienone moiety in Scheme 4. Manipulation of the C-ring and completion of the synthesis. Re-
13 gave dienyl alcohol 14, which, upon treatment with p-tol- agents and conditions: (a) LiAlH4, THF, 0 8C; (b) DNsNHMe, DEAD, Ph3P, tolu-
uenesulfonic acid, caused formation of a dienyl cation and im- ene, 0 8C to RT, 80 % (2 steps); (c) O2 (bubbling), hn (405 nm), TPP, CH2Cl2, RT;
Et3N, 86 %.; (d) Martin’s sulfurane, CH2Cl2, 0 8C, 65 % or Tf2O, 2,6-lutidine,
mediate interception with a phenol moiety furnished benzote- CH2Cl2, 0 8C, 80 %; (e) PhSH, iPr2NEt, CH2Cl2, 0 8C, 51 % (20:21 = 1:1.4); (f) HCl
trahydrofuran 15. This 2-step transformation could be carried in 1,4-dioxane, CHCl3, RT; (g) NaBH4, MeOH, RT, 62 % (2 steps); (h) BBr3,
out in one pot without any loss of the product yield by treat- CH2Cl2, RT, 51 %. DEAD = diethyl azodicarboxylate; DNs = 2,4-dinitrobenzene-
ment with hydrochloric acid. sulfonyl; Martin’s sulfurane = bis[a,a-bis(trifluoromethyl)benzenemethanola-
to]diphenylsulfur; Tf2O = trifluoromethanesulfonic anhydride; TPP = tetraphe-
Having constructed the tetracyclic skeleton, the remaining nylporphiline.
task is to construct the piperidine ring (D-ring) via the 1,6-addi-
tion to the dienone. Prior to manipulation of the C-ring, a nitro- Acknowledgements
gen atom was introduced to the side chain by reduction of
the ester moiety in 15 and subsequent Mitsunobu reaction This work was financially supported by JSPS KAKENHI (Grant
with DNsNHMe (Scheme 4).[10] The diene moiety in the C-ring Numbers 25221301, 16H01141, 13J04813) and by the Platform
could be efficiently converted into the dienone 5 by a 2-step Project for Supporting Drug Discovery and Life Science Re-
sequence. Thus, treatment of 17 with singlet oxygen[11, 12] gave search (Platform for Drug Discovery, Informatics, and Structural
endoperoxide 18, which, upon addition of triethylamine, un- Life Science) from the Ministry of Education, Culture, Sports,
derwent a facile cleavage of the O@O bond to afford hydroxye- Science and Technology of Japan (MEXT) and the Japan
none 19. Initial attempts at dehydrating the tert-alcohol in 19 Agency for Medical Research and Development (AMED).
under conventional conditions met with failure.[13] After exten-
sive investigation, we found that treatment with Martin’s sulfu-
rane[14] as well as Tf2O and 2,6-lutidine gave the desired dien- Conflict of interest
one 5 in good yields. As reported earlier,[5] removal of the DNs
group with PhSH[15] generated the secondary amine, which un- The authors declare no conflict of interest.
derwent the 1,6-addition to the dienone, giving a mixture of
neopinone 20[16] and codeinone 21.[6] The mixture converged
Keywords: aldol reaction · conjugate addition · morphine ·
to codeinone 21 by treatment with acid.[17] Reduction of the
singlet oxygen · total synthesis
enone moiety in 21 with NaBH4[18] followed by demethylation
with BBr3[19] afforded (@)-morphine (1).
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Chem. Eur. J. 2017, 23, 6993 – 6995 www.chemeurj.org 6994 T 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 Communication

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Chem. Int. Ed. 2016, 55, 14306 – 14309; Angew. Chem. 2016, 128, 14518 – Accepted Article published: April 4, 2017
14521. Final Article published: April 25, 2017

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