Synthesis of (-)-Oxycodone

Article abstract of DOI:10.1021/ol503175n

Our novel synthetic route to (-)-oxycodone, a semisynthetic opioid analgesic, features a palladium-catalyzed direct intramolecular arylation of an aryl bromide, oxidative dearomatization of a dihydrophenanthrenol, formation of a benzylic quaternary carbon by an intramolecular Michael addition of a malonate moiety, and construction of the morphinan skeleton via a Hofmann rearrangement/lactamization cascade.

Full text of DOI:10.1021/ol503175n

Letter
pubs.acs.org/OrgLett
Synthesis of (−)-Oxycodone
Atsushi Kimishima,† Hirotatsu Umihara, Akihiro Mizoguchi, Satoshi Yokoshima,
,§
†,‡
†
‡
,
‡
and Tohru Fukuyama*
†Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
*
S Supporting Information
ABSTRACT: Our novel synthetic route to (−)-oxycodone, a semisynthetic opioid analgesic, features a palladium-catalyzed
direct intramolecular arylation of an aryl bromide, oxidative dearomatization of a dihydrophenanthrenol, formation of a benzylic
quaternary carbon by an intramolecular Michael addition of a malonate moiety, and construction of the morphinan skeleton via a
Hofmann rearrangement/lactamization cascade.
1
xycodone (1) is a semisynthetic analgesic that is
Scheme 1. Retrosynthesis
O
clinically prescribed as a primary opioid for cancer
pain management (Figure 1). Although the structure of
oxycodone is similar to morphine (2), oxycodone has a much
better oral bioavailability, making it superior for pain
2
management in some clinical studies. Because of these
advantages, it is hoped that more efficient analogues of
oxycodone will be developed. While a variety of its analogues
have been prepared to date, extensive modifications of
oxycodone are hampered by the fact that it is derived from
3
thebaine (3), a minor constituent of opium. In order to
synthesize a range of analogues that are not accessible from
thebaine, we initiated our studies on the first synthesis of
(
−)-oxycodone starting from readily available, simple sub-
strates.
nanthrenol 6, which in turn would be prepared by a direct
intramolecular arylation of aryl halide 7.
Our synthesis commenced with the preparation of aryl
bromide 13, a substrate for the direct intramolecular arylation
4
(
Scheme 2). Protection of 2-bromoisovanillin (8) with a
Figure 1. Structures of oxycodone, morphine, and thebaine.
5
MOM group, followed by reduction of the aldehyde moiety,
afforded alcohol 9, which was converted into benzyl bromide
Scheme 1 outlines our retrosynthesis of (−)-oxycodone.
Cleavage of the two heterocycles in 1 would lead to lactone 4.
The amine moiety in 4 could be derived from the carboxylic
acid of 5 via either a Curtius or a Hofmann rearrangement.
Stereoselective construction of the benzylic quaternary carbon
in 4 could be performed via an intramolecular Michael
addition of the malonate moiety of 5 by taking advantage of
the stereochemistry at C-14. Requisite 5 could be synthesized
via stereoselective oxidative dearomatization of dihydrophe-
6
1
0. Alkylation of the enolate derived from imide 11 with 10
7
proceeded diastereoselectively to furnish 12. Cleavage of the
oxazolidinone auxiliary with hydrogen peroxide and lithium
hydroxide, and subsequent methylation of the resulting
carboxylic acid with (trimethylsilyl)diazomethane provided
Received: October 31, 2014
©
XXXX American Chemical Society
A
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Letter
Scheme 2. Preparation of the Aryl Bromide
dearomatization (Scheme 4). An attempted reaction of 16
with singlet oxygen produced a 2:5 diastereomeric mixture of
10
Scheme 4. Oxidative Dearomatization
1
7, the desired isomer, and its epimer at C-14. Oxidation of 16
with (diacetoxyiodo)benzene in aqueous 1,1,1,3,3,3-hexafluoro-
11
2
-propanol (HFIP), on the other hand, afforded the desired
isomer 17 in 69% yield as the sole isomer. The drastic change
in the selectivity might be attributed to the participation of the
neighboring acetoxy group to form 18 as an intermediate.
Having successfully installed the C-14 hydroxy group, we
turned our attention to the formation of the benzylic
quaternary carbon (Scheme 5). Dienone 17 was subjected to
12
the desired aryl bromide 13 in good yield and in high
enantiomeric purity.
The crucial direct arylation was conducted according to
8
9
Fagnou’s conditions with some modifications (Scheme 3).
Scheme 3. Direct Intramolecular Arylation
Scheme 5. Construction of the Benzylic Quaternary Carbon
Thus, 13 was treated with palladium acetate (15 mol %) and
triphenylphosphine (45 mol %) in the presence of potassium
carbonate (3.0 equiv) and pivalic acid (30 mol %) in 1,4-
dioxane at 100 °C to provide 14 in good yield. A small amount
of the undesired debrominated product 15 was formed as an
inseparable mixture. However, a three-step conversion
involving reduction of the ester moiety, acetylation of the
resulting primary alcohol, and reductive cleavage of the benzyl
ether afforded pure dihydrophenanthrenol 16 in good yield
with preservation of the optical purity.
1
3
rhodium-catalyzed site-selective hydrogenation to give enone
19. Acylation of the tertiary alcohol of 19 with methyl malonyl
chloride afforded enone 20. Upon treatment of 20 with cesium
carbonate in acetonitrile, an intramolecular Michael addition
proceeded smoothly to yield the desired lactone 21 with a
benzylic quaternary carbon. Dealkoxycarbonylation of 21 and
subsequent cleavage of the methoxymethyl ether gave ketone
22 in high yield.
With the requisite substrate in hand, we next attempted to
introduce the C-14 hydroxy group via an oxidative
B
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With 22 in hand, the remaining tasks involved construction
of the dihydrobenzofuran and the piperidine (Scheme 6). Site-
tion cascade. Further improvement in the synthesis of
morphinan alkaloids is currently underway in our laboratories.
Scheme 6. Completion of the Synthesis
ASSOCIATED CONTENT
■
*
S
Supporting Information
Experimental details and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*
E-mail: fukuyama@ps.nagoya-u.ac.jp.
Present Address
§Department of Chemistry and Biochemistry, University of
California, San Diego, 9500 Gilman Drive, La Jolla, CA.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(
This work was financially supported by JSPS KAKENHI
Grant Nos. 20002004, 25221301, and 26713001), Platform
for Drug Discovery, Informatics, and Structural Life Science
MEXT), the Sumitomo Foundation, and the Tokyo
(
Biochemical Research Foundation. H.U. is a Research Fellow
of JSPS.
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