Total Synthesis of (±)-Thebainone A by Intramolecular Nitrone Cycloaddition

Article abstract of DOI:10.1021/acs.orglett.0c00905

Using an intramolecular nitrone cycloaddition and a Heck cyclization as the crucial transformations, a total synthesis of the racemic morphine alkaloid thebainone A was accomplished in 22 steps commencing with isovanillin.

Full text of DOI:10.1021/acs.orglett.0c00905

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Letter
Total Synthesis of ( )-Thebainone A by Intramolecular Nitrone
Cycloaddition
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̈
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Yuzhou Wang, Andre Hennig, Thomas Kuttler, Christian Hahn, Anne Jager, and Peter Metz*
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ABSTRACT: Using an intramolecular nitrone cycloaddition and a
Heck cyclization as the crucial transformations, a total synthesis of the
racemic morphine alkaloid thebainone A was accomplished in 22 steps
commencing with isovanillin.
he alkaloids morphine (3) and codeine (2) present in
Tthe opium poppy (Papaver somniferum) are among the
most important drugs when the treatment of severe pain is
necessary (Scheme 1). Gates succeeded in the first total
synthesis of morphine (3) in 1952.1 Since then, more than 30
total and formal syntheses have been published.2−4 Due to
our interest in the application of intramolecular nitrone
cycloadditions toward the synthesis of morphine alkaloids,5,6
we recently devised a novel access to thebainone A (1),
which in turn is a known precursor for 2 and 3. This was
already shown by Gates in his pioneering work.1 A second
total synthesis of 1 was described by Tius in 1992.7
quaternary benzylic center being planned by a Heck
reaction.8
Already after the first four steps of the synthesis, all carbon
atoms required for the basic framework of thebainone A (1)
were assembled (Scheme 2). Iodination of isovanillin (6) to
Scheme 2. Conversion of Isovanillin (6) into Lactone 5
Scheme 1. Retrosynthetic Analysis
Received: March 11, 2020
As depicted in Scheme 1, we envisioned to trace
thebainone A (1) back to isoxazolidine 4. The heterocyclic
moiety in 4 might be generated by a nitrone cycloaddition of
a substrate derived from bisacetal 5. Ultimately, readily
available isovanillin (6) serves as the starting material for the
bisacetal 5, with the demanding construction of the
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Scheme 3. Synthesis of Morphinan 20 from Lactone 5
give derivative 79 was followed by a Wittig reaction with the
ylide derived from phosphonium salt 8 to provide a
diastereomeric mixture of enol ethers 9 and subsequent
conversion of 9 into the known acetal 1010 in very good
yield.
Scheme 4. Transformation of Isoxazolidine 4 to
Morphinan 20 by Mitsunobu Reaction
By avoiding the use of protecting groups, the published
routes from 6 to 10 could be streamlined to three steps.
Esterification of phenol 10 with acid 118,11 through activation
with BOPCl12 led to ester 12 with high efficiency. After
intense screening of reaction conditions, the Heck cyclization
of 12 to give lactone 5 was best effected without any
phosphine ligands8a in the presence of silver carbonate.
For the key nitrone cycloaddition, the two protected
carbonyl functions of 5 first had to be deblocked. This was
cleanly achieved with the mild Lewis acid Pd(MeCN)2Cl2 in
acetone (Scheme 3).13 It was not necessary to purify the
labile keto aldehyde 13 on silica gel. Thus, nitrone formation
and subsequent intramolecular cycloaddition were carried out
with crude 13 and N-methylhydroxylamine. Running this
reaction at low temperature effected a high diastereoselectiv-
ity in the formation of the desired isoxazolidine 14 (14:8-epi-
14 ca. 10:1). Since this keto lactone was also rather unstable,
it was immediately reduced with a large excess of lithium
aluminum hydride to give dihydroxy phenol 4 in good overall
yield from 13. The relative configuration of 4 was confirmed
by X-ray diffraction analysis. An efficient transformation of
the primary alcohol of 4 into a tosylate without competing
phenol ether formation succeeded by chemoselective
silylation to give silylether 15 followed by double acetylation
and desilylation of the resultant diacetate 16 to provide
alcohol 17 and finally tosylation.14 Tosylate 18 was then
subjected to reductive cleavage of the heterocycle with
concomitant intramolecular nucleophilic substitution to
generate piperidine 19.5b Subsequent saponification of 19
provided dihydroxy phenol 20 that was also characterized by
X-ray diffraction analysis.
While we sometimes observed the formation of morphinan
20 in good yield, this reaction turned out to be rather
capricious, and we could not find suitable conditions for the
conversion of 21 to 20 in a reproducible fashion. Never-
theless, even though some more steps are required for the
sequence leading from 4 to 20 in Scheme 3, its overall yield
(75%) is far better than the best result obtained according to
Scheme 4.
Completion of the synthesis of thebainone A (1) is shown
in Scheme 5. In order to activate the C-6 position for
introduction of the ketone function, the cis diol moiety of 20
was reductively eliminated by formamide acetal pyrolysis16
with simultaneous esterification of the phenol to give olefin
22. Prior to allylic oxidation, the tertiary amine was converted
to ethyl carbamate 23.17 Subsequent reaction of 23 with
selenium dioxide18 and further oxidation of the resultant
allylic alcohol to the ketone with the Dess−Martin period-
inane (DMP)3b,8a,18c,d afforded enone 24 in moderate overall
yield. We first opted for a reduction/oxidation sequence in
order to convert 24 to 1. However, treatment of 24 with
lithium aluminum hydride to give α-thebainol19 led to partial
overreduction of the enone, and reoxidation of the highly
sterically hindered allylic alcohol in α-thebainol featuring a
free phenol could not be achieved by Swern oxidation. Thus,
ketone 24 was protected as the dioxolane 25 without
migration of the double bond20 under mild reaction
conditions.21 Finally, lithium aluminum hydride reduction
of the carbamate17 and acetate function in 25 gave rise to
acetal 26 that was deprotected uneventfully to provide
( )-thebainone A (1).
We also investigated a potentially shorter route from
isoxazolidine 4 to morphinan 20 using a Mitsunobu reaction
of trihydroxy phenol 21 that was readily obtained from 4 by
hydrogenolytic cleavage of the N−O bond (Scheme 4). In
order to avoid a competing intramolecular alkylation of the
phenol oxygen, triethylamine hydrochloride was added.15
The relatively low yield of the allylic oxidation of 23 at C-6
is probably due to an unfavorable conformation of the C ring
cyclohexene (Scheme 6). All of the tetracyclic morphine
precursors that have been successfully subjected to selenium
B
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Scheme 5. Completion of the Synthesis of Thebainone A (1)
Dresden, Germany; orcid.org/0000-0002-0592-9850;
Email: peter.metz@chemie.tu-dresden.de
Scheme 6. Allylic Oxidation of Cyclohexene 23
Authors
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Yuzhou Wang − Fakultat Chemie und Lebensmittelchemie,
̈
Organische Chemie I, Technische Universitat Dresden, 01062
Dresden, Germany
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Andre Hennig − Fakultat Chemie und Lebensmittelchemie,
̈
Organische Chemie I, Technische Universitat Dresden, 01062
dioxide oxidation adopt a boat conformation of the C ring
with axial orientation of 6β-H.18 In contrast, 23 lacking the
tetrahydrofuran E ring features a half-chair conformation of
the C ring. As a consequence, the sterically more accessible
6β-H is oriented equatorially, while 14-H is properly aligned
with the adjacent π-system for a hetero ene reaction with
selenium dioxide. Indeed, the C-14 hydroxylated morphinan
27 was isolated as another major product of this reaction.22
With this shortest total synthesis of thebainone A (1) so
far, a synthesis of codeine (2) and morphine (3) is formally
completed, too. However, the known route from 1 to 2 and 3
still leaves room for improvement.1,23 Work along this line as
well as further optimization of the allylic oxidation of 23 is
currently under investigation.
Dresden, Germany
Thomas Ku
Organische Chemie I, Technische Universitat
Dresden, Germany
Christian Hahn − Fakultat
̈
ttler − Fakultat Chemie und Lebensmittelchemie,
̈
̈
Dresden, 01062
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Chemie und Lebensmittelchemie,
̈
Organische Chemie I, Technische Universitat
Dresden, Germany
Anne Jager − Fakultat
Organische Chemie I, Technische Universitat
Dresden, 01062
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̈
Chemie und Lebensmittelchemie,
Dresden, 01062
̈
Dresden, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00905
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00905.
■
sı
ACKNOWLEDGMENTS
■
This work was supported by the Deutsche Forschungsge-
meinschaft (ME 776/22-1).
1
Experimental procedures, spectroscopic data, H and
13C NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
̈
Peter Metz − Fakultat Chemie und Lebensmittelchemie,
Organische Chemie I, Technische Universitat Dresden, 01062
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C
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D
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