Direct Synthesis of Noroxymorphone from Thebaine: Unusual CeIV Oxidation of a Methoxydiene-Iron Complex to an Enone-γ-Nitrate

Article abstract of DOI:10.1002/ejoc.201600153

Noroxymorphone was prepared from thebaine in seven operations. The key steps involved the successive N- A nd O-demethylations of an iron tricarbonyl complex of thebaine followed by the unusual ceric ammonium nitrate oxidation of the methoxydiene moiety to the corresponding enone-γ-nitrate during the decomplexation of the iron tricarbonyl functionality. A protocol for the conversion of thebaine to noroxymorphone via C-14 oxidation is described.

Full text of DOI:10.1002/ejoc.201600153

DOI: 10.1002/ejoc.201600153
Communication
Opioid Synthesis
Direct Synthesis of Noroxymorphone from Thebaine: Unusual
CeIV Oxidation of a Methoxydiene-Iron Complex to an Enone-
γ-Nitrate
Ales Machara,*[a] Mary Ann A. Endoma-Arias,[b] Ivana Císařová,[c] D. Phillip Cox,[d] and
Tomas Hudlicky*[b]
Abstract: Noroxymorphone was prepared from thebaine in followed by the unusual ceric ammonium nitrate oxidation of
seven operations. The key steps involved the successive N- and the methoxydiene moiety to the corresponding enone-γ-nitrate
O-demethylations of an iron tricarbonyl complex of thebaine during the decomplexation of the iron tricarbonyl functionality.
Introduction
ether. Many solutions exist for all of these processes but further
refinements would be welcome.
The commercial production of opiate-derived analgesic phar-
maceutical agents and antagonists, such as naltrexone (3) and
naloxone (4) shown in Figure 1, depends on semi-synthesis
from naturally occurring morphine alkaloids. Convenient start-
ing materials for the large-scale synthesis are the morphine
congeners thebaine (1) and oripavine (2).
We have recently reported several diverse methods for the
N-demethylations of morphinans and their derivatives.[1] These
include the nucleophilic demethylation of quaternary salts,[2]
palladium-catalyzed oxidative demethylation with intramolec-
ular acyl transfer from C-14,[3] Burgess reagent demethylation
of N-oxides,[4] and fungal cytochrome oxidative demethylation
The conversions require efficient solutions to several issues: of several morphine alkaloids to the corresponding secondary
(a) oxidation of the diene unit to introduce C-14 hydroxyl; (b) amines.[5] A direct synthesis of naltrexone and (R)-methyl nal-
replacement of the N-methyl group with other alkyl groups; trexone became available by singlet oxygen addition to quater-
and (c), in case of thebaine, O-demethylation of the C-3 methyl nary salts of oripavine.[6]
Figure 1. Various morphinans and their conversion to C-14 hydroxylated antagonists.
[a] Department of Organic Chemistry, Faculty of Science, Charles University in
Prague,
Results and Discussion
Hlavova 8, 12843 Prague 2, Czech Republic
E-mail: macharaa@natur.cuni.cz
In 2014 we published the conversion of thebaine to oripavine
and to hydromorphone[7] via the O-demethylation of the iron
carbonyl complex 6 and hydrolysis. Realizing that the best com-
mon starting material for the synthesis of the various antago-
nists would be either noroxymorphone (5) or nororipavine (10)
we set out this time to explore the conversion of thebaine to
nororipavine as shown in Scheme 1. Thebaine was converted
quantitatively to the iron carbonyl complex 6[8] whose von
Braun demethylation provided the N-cyano derivative 7. O-De-
methylation with BBr3 furnished cleanly phenol 8, which was
acylated to complex 9 prior to the decomplexation and hydroly-
[b] Chemistry Department and Centre for Biotechnology, Brock University,
1812 Sir Isaac Brock Way, St. Catharines, ON L2S 3A1, Canada
E-mail: thudlicky@brocku.ca
http://www.brocku.ca/mathematics-science/departments-and-centres/chem-
istry/people/faculty/tomas-hudlicky
[c] Department of Inorganic Chemistry, Faculty of Science, Charles University
in Prague,
Hlavova 8, 12843 Prague 2, Czech Republic
[d] Noramco, Inc.,
503 Carr Road, Suite 200, Wilmington, DE 19809, USA
E-mail: PCox2@its.jnj.com
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600153.
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Scheme 1.
Scheme 2.
sis. Previously we have used photolytic decomplexation of com- promotes oxidative condensation of ketones with dienes, with
pounds similar to 9 in order to free the methoxy diene moiety the occasional formation of nitrate esters in some of the prod-
but this procedure suffered from low conversions of starting ucts.[11] The nitrate ester was slowly hydrogenated to hydroxy
material to product. When the iron carbonyl complex 9 was enone 13. In order to complete full hydrogenation to the satu-
exposed to ceric ammonium nitrate (CAN)[9] the decomplexa- rated ketone 14 additional hydrogenation step was required,
tion occurred in good yield to produce the free diene 11, along presumably because the equivalent of ammonia released dur-
with small amounts (≈ 10 %) of over-oxidized product identified ing the reduction of the nitrate may act as a catalyst poison.
as the nitrate ester 12, Scheme 2. The X-ray analysis confirmed Hydrogenation in the presence of two equivalents of acetic acid
the structure as shown in Figure 2.[10]
proceeded at a faster rate. However, the C-14 nitrate functional-
ity also severely hinders the C-7/C-8 double bond in 12 and we
have also encountered similar issues with the very slow rate of
hydrogenation of C-14 acetoxy derivative of 12. Finally, noroxy-
morphone (5) was obtained from 14 by hydrolysis according to
the protocol published by Rice.[12]
This surprising transformation led to a direct synthesis of
noroxymorphone (5) that serves as a much more convenient
intermediate for the production of compounds such as naltrex-
one and naloxone. In this paper we report the details of this
unusual C-14 oxidation of the methoxy diene functionality and
the preparation of noroxymorphone from thebaine.
In summary, the unusual ceric ammonium nitrate oxidation
The treatment of either diene 11 or the iron complex 9 with of the methoxy diene moiety in 11 or in the iron tricarbonyl
excess ceric ammonium nitrate produced the γ-nitrate ester 12 complex 9 provides for a new direct route from thebaine to
in excellent yields. This transformation is without precedent in noroxymorphone, a compound that serves as one of the most
the literature although it is known that ceric ammonium nitrate convenient starting materials for a variety of opiate-derived
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Conclusions
The protocol for large-scale conversion of the methoxydiene
unit to the corresponding γ-hydroxyenone is well established
through the use of common oxidation conditions, for example:
H2O2 and HCO2H,[15] m-CPBA,[16] and singlet oxygen.[6] The CAN
process offers an interesting alternative to the C-14 hydroxyla-
tion of thebaine or oripavine. We will report on the optimiza-
tion of this unusual process as well as on its general applica-
tions to the cerium-mediated oxidations of dienes in due
course.
Supporting Information (see footnote on the first page of this
article): Experimental procedures and 1H and 13C NMR spectra are
provided for key compounds.
Acknowledgments
The authors are grateful to the following agencies for financial
support of this work: Noramco, Inc., Natural Sciences and Engi-
neering Research Council of Canada (NSERC) (Idea to Innova-
tion and Discovery Grants), Canada Research Chair Program, Ca-
nada Foundation for Innovation (CFI), TDC Research, Inc., TDC
Research Foundation, the Ontario Partnership for Innovation
and Commercialization (OPIC), the Advanced Biomanufacturing
Centre (Brock University) and University Center of Excellence of
Charles University in Prague, Czech Republic (UNCE).
Figure 2. Structure of nitrate ester 12 obtained by X-ray crystallography as a
methanol solvate.
agents. We can speculate on the possible mechanism of this
transformation as shown in Figure 3. Ceric ammonium nitrate
is an efficient one-electron oxidant and has been shown to gen-
erate α-ketoalkyl radicals from trimethylsilyl enol ethers and to
oxidize silyl dienol ethers to α-carbonylallyl radicals.[13] The ce-
rium(IV)-mediated oxidation is believed to proceed by a radical
mechanism involving successive one-electron transfers. In the
proposed mechanism CAN reacts with the methoxydiene moi-
ety of 11 to generate radical cation 15. Subsequently, this spe-
cies undergoes transfer of a nitrate radical from the second
molecule of CAN to yield intermediate 17. The fact that ceric
ammonium nitrate has been shown to efficiently nitrate radicals
by ligand transfer mechanism would support this proposal.[14]
The observed regioselectivity may be rationalized by consider-
ing that the reaction of nitrate with the tertiary radical at C-14
position leads eventually to a conjugated enone, formed by
hydrolysis in 17.
Keywords: Medicinal chemistry · Opioids · Alkaloids · Iron
complexes · Oxidation
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Received: February 12, 2016
Published Online: February 26, 2016
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