Total Synthesis of Codeine

Article abstract of DOI:10.1002/chem.201503594

In this paper, a new strategy towards the synthesis of codeine and morphine is reported. This new approach features a cascade cyclization to construct the dihydrofuran ring, and an intramolecular palladium catalyzed C-H olefination of unactivated aliphatic alkene to install the morphinan ring system.

Full text of DOI:10.1002/chem.201503594

DOI: 10.1002/chem.201503594
Communication
&
Alkaloids
Total Synthesis of Codeine
Qilin Li and Hongbin Zhang*[a]
synthesis.[4] Carbon–carbon and carbon–heteroatom bond for-
mation through CÀH activation enables novel disconnections
for retrosynthetic analysis, and improve the overall efficiency in
the total synthesis of natural products.[5] Although significant
advances have been made in method development, the appli-
cation of CÀH bond activation to the synthesis of structurally
complex natural products is still a challenge.[5a,c] Herein we
report a new approach towards the synthesis of (Æ)-codeine
and morphine. Our new strategy features a cascade cyclization
to construct the dihydrofuran ring and a palladium-catalyzed
CÀH olefination to furnish the morphinan ring system. The ret-
rosynthetic analysis is outlined in Scheme 1. The opium alka-
Abstract: In this paper, a new strategy towards the syn-
thesis of codeine and morphine is reported. This new ap-
proach features a cascade cyclization to construct the di-
hydrofuran ring, and an intramolecular palladium cata-
lyzed CÀH olefination of unactivated aliphatic alkene to in-
stall the morphinan ring system.
The opium alkaloids constitute a class of structurally related
natural products isolated from opium poppy, Papaver somnife-
rum.[1] Among them, morphine, one of the most effective anal-
gesic and anesthetic drugs with a serious addictive side effect,
and its derivatives (Figure 1) are especially attractive due to
Figure 1. Natural opium alkaloids.
their highly challenging molecular architecture and biological
activities.[1d] The structure of morphine contains a strained pen-
tacyclic core with five contiguous chiral centers including
a benzylic quaternary carbon (morphinan[1b,d] skeleton). Mor-
phine is considered to be one of the most interesting mole-
cules for testing contemporary synthetic methodologies.[2]
Since Gates published the first total synthesis of morphine,[3a,b]
the synthesis of morphinans has attracted the attention of
many generations of synthetic chemists. To date, there are
more than 30 reported routes for the total synthesis or formal
synthesis of codeine, morphine and its analogues.[3]
Scheme 1. Retrosynthetic analysis of codeine.
loids (1 and 2) shown in Figure 1 could be synthesized from in-
termediate 13 (Parker–Guillou procedure[3s,ak]) by a reductive
hydroamination to form the C9ÀN bond. A transition-metal-
mediated CÀH olefination of compound 12 to connect the
C10ÀC11 bond followed by functional-group transformation
might lead to intermediate 13. Lactone ring opening and dihy-
drofuran ring closing sequential reaction of epoxide 11 would
afford 12. The key all-carbon quaternary centers required for
the synthesis of opium alkaloids could be constructed by an
intramolecular alkylation of ketone 8. The enone (7) could be
obtained by a Suzuki coupling of commercially available start-
ing materials (6 and 5).
Over the past decade, direct CÀH functionalization has
emerged as a powerful and straightforward method in organic
[a] Q. Li, Prof. Dr. H. Zhang
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan Uni-
versity), Ministry of Education, School of Chemical Science and Technology
Yunnan University
No 2, North Cuihu Road, Kunming, Yunnan 650091 (P. R. China)
E-mail: zhanghb@ynu.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503594.
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Our synthesis commenced with arylboronic acid 6 and 2-io-
docyclohexenone (5), and the Suzuki coupling provided
phenol 7 in 89% yield. Treatment of 7 with ethyl vinyl ether
and bromine in dichloromethane (DCM)[3an] afforded 7a (99%).
Michael addition with vinyl magnesium bromide towards 7a in
the presence of copper(I) bromide resulted in a pair of diaste-
reoisomers (only anti-form relative stereochemistry for C13 and
C14 was observed, diastereoisomers were formed at the ketal
center, 8a and 8b, d.r.=1.8:1, Scheme 2) in 92% overall yield.
Scheme 3. Synthesis of intermediate 12.
tative yield by treatment of epoxide 11 with methanol in the
presence of sodium hydroxide (see Scheme 3).
Next, we came to the key stage of our research, the palladi-
um mediated CÀH activation to connect the C10ÀC11 bond.
Although the Fujiwara–Moritani reaction (or oxidative Heck re-
action) has been intensively studied for many years, trends are
directed towards introduction of new directing groups and
other transition metals to improve regioselectivity and reactivi-
ty.[7] The electrophiles are mainly olefins containing an elec-
tron-withdrawing group or styrene derivatives. To the best of
our knowledge, unactivated aliphatic terminal vinyl olefin has
rarely been used in Fujiwara–Moritani reaction and a preinstal-
led coordinating group is necessary to achieve CÀH olefina-
tion.[8] Utilization of intramolecular Fujiwara–Moritani-type cou-
pling as the key step in the total synthesis of natural products
was first reported in 1978 by Trost’s group.[9] After this pioneer-
ing work, a number of elegant works have been accomplished
using intramolecular arene–alkene coupling as the key step, in-
cluding Williams’s synthesis of paraherquamide B and notoami-
de B,[10] Corey’s synthesis of okaramine N,[11] Stoltz’s synthesis
of dragmacidin F,[12] Gaunt’s synthesis of rhazinicine,[13] and
Trauner’s synthesis of rhazinal.[14] To date, intramolecular Fuji-
wara–Moritani-type couplings of arene moiety with an alkene
unit are limited to indole or pyrrole derivatives[9–14] and, except
in protocols developed by Gaunt and Trauner, a stoichiometric
amount of palladium was required for the desired transforma-
tion.[9–12] The initial model reaction was then conducted with
spiro-ketal 9a. After some experiments, we finally found that
the desired product could be formed in the presence of PdCl2
and CuCl2 in THF under a dry oxygen atmosphere (Scheme 4),
a multifunctional-group-tolerated reaction condition. With the
optimized reaction condition in hand, we next carried out the
intramolecular Fujiwara–Moritani-type coupling with substrate
12 and the desired intermediate 12a was obtained in a 69%
yield. This is an intramolecular palladium-catalyzed oxidative
coupling of terminal unactivated vinylic CÀH bond without
using pre-installed coordinating groups, and with high regiose-
Scheme 2. Synthesis of intermediate 9a containing a benzylic all-carbon
quaternary center.
Compound 8b could be converted to 8a in a 48% yield (see
Supporting Information). Treatment of 8a with sodium hydride
in DMF afforded spiro-compound 9a in excellent yield (95%)
as a single diastereomer, and the relative stereochemistry was
confirmed by X-ray crystallography analysis (Scheme 2).
With 9a in hand, refunctionalization of the cyclohexane ring
was initiated. Reduction of ketone 9a with sodium borohy-
dride in methanol followed by dehydration with Burgess re-
agent[6] afforded olefin 9b. Treatment of 9b with p-toluenesul-
fonic acid (TsOH) in acetone followed by Jones reagent provid-
ed lactone 10 in a 63% yield. Chemoselective and diastereose-
lective epoxidation of olefin 10 with 3-chloroperbenzoic acid
(m-CPBA) in dichloromethane afforded epoxide 11 (the relative
stereochemistry was confirmed by X-ray crystallography) in an
81% yield. The key cascade cyclization was achieved in quanti-
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with p-toluene sulfonyl chloride in pyridine-furnished amide
13. Finally, amide 13 was converted to codeine in 60% yield
by following Guillou’s procedure.[3ak] The NMR spectra of our
synthetic sample were in complete agreement with the report-
ed data.[3]
In conclusion, we have developed a new strategy towards
the total synthesis of codeine and morphine (formal synthesis)
with a palladium-catalyzed CÀH olefination as the key step.
Based on this new disconnection, a general and flexible syn-
thetic strategy has been successfully established. This palladi-
um-catalyzed intramolecular Fujiwara–Moritani olefination,
with additional-directing-group-free CÀH olefination and multi-
functional group tolerance, should find further application in
the synthesis of morphine alkaloids as well as its medicinally
interesting analogues.
Scheme 4. Pd-catalyzed intramolecular Fujiwara–Moritani-type olefinations.
Acknowledgements
lectivity. Although this process might be a CÀH activation pro-
cess, we can’t rule out the possibility of olefin activation and
then an anti-Markovnikov carbo-palladation of the alkene, fol-
lowed by beta-hydride elimination.
This work was supported by grants from Natural Science Foun-
dation of China (20925205 and 21332007), the Program for
Changjiang Scholars and Innovative Research Team in Universi-
ty (IRT13095).
Having established the palladium-mediated procedure to
connect the C10ÀC11 bond, we next came to the final stage of
synthesis of codeine and morphine (see Scheme 5). Treatment
Keywords: alkaloids · CÀH olefination · codeine · palladium ·
total synthesis
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Received: September 8, 2015
Published online on October 2, 2015
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