Total synthesis of (±)-morphine

Article abstract of DOI:10.1021/ol062112m

The morphinan skeleton was effectively synthesized by an intramolecular Mannich-type reaction. Further transformation led to total synthesis of morphine.

Full text of DOI:10.1021/ol062112m

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5311-5313
Total Synthesis of (±)-Morphine
Kenji Uchida, Satoshi Yokoshima, Toshiyuki Kan, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and School of Pharmaceutical Sciences,
UniVersity of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
fukuyama@mol.f.u-tokyo.ac.jp
Received August 28, 2006
ABSTRACT
The morphinan skeleton was effectively synthesized by an intramolecular Mannich-type reaction. Further transformation led to total synthesis
of morphine.
Morphine (1) is a fascinating compound that has been used
as an efficient analgesic and is indispensable in treating pains
associated with cancer. However, morphine is strictly
controlled by authorities due to its addictive nature. On the
other hand, the structure of morphine is quite attractive from
a synthetic point of view. Its complicated pentacyclic
skeleton, including a quaternary carbon center, has stimulated
extensive synthetic efforts. Hence, a number of synthetic
studies and the total syntheses of morphine have been
reported to date.1 Among them, the Pd-mediated total
synthesis reported recently by Trost and co-workers seems
quite versatile.1b,c,2 In an effort to develop a novel morphine-
type drug that is not addictive, we initiated our own studies
of an efficient total synthesis of morphine. Herein, we
disclose a total synthesis of (()-morphine which involves a
unique construction of the morphinan skeleton.
successive aldol-Michael protocol or by a Mannich-type
reaction (vide infra). Ketoaldehyde 3 would be obtained via
Scheme 1
Our retrosynthetic analysis is shown in Scheme 1. Mor-
phine could be derived from ketone intermediate 2, which
in turn would be prepared from ketoaldehyde 3 either by a
(1) (a) Parker, K. A.; Fokas, D. J. Org. Chem. 2006, 71, 449. (b) Trost,
B. M.; Tang, W.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 14785. (c)
Trost, B. M.; Tang, W. J. Am. Chem. Soc. 2002, 124, 14542. (d) Taber, D.
F.; Neubert, T. D.; Rheingold, A. L. J. Am. Chem. Soc. 2002, 124, 12416.
(e) Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115,
11028. For a review and other syntheses, see: Zezula, J.; Hudlicky, T.
Synlett 2005, 388.
an intramolecular Heck reaction1b,c,2 of 4, which could be
prepared from phenol 5 and epoxide 63 by means of Tsuji-
Trost coupling.4
Our synthesis commenced with conversion of isovanillin
(7) into iodide 8 according to a known procedure (Scheme
(2) Similar strategies using the Heck reaction were employed to
synthesize galanthamine: (a) Pilger, C.; Westermann, B.; Flo¨rke, U.; Fels,
G. Synlett 2000, 1163. (b) Parsons, P. J.; Charles, M. D.; Harvey, D. M.;
Sumoreeah, L. R.; Shell, A.; Spoors, G.; Gell, A. L.; Smith, S. Tetrahedron
Lett. 2001, 42, 2209.
(3) Kaburagi, Y.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2004,
126, 10246. Although optically pure epoxide can be obtained in large
quantities according to our procedure, a racemate was used for this
preliminary study.
10.1021/ol062112m CCC: $33.50
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Published on Web 10/10/2006

mediated coupling reaction of phenol 11 and epoxide 6
proceeded smoothly to give 12 in 91% yield with complete
regio- and stereoselectivity.4
Scheme 2
Scheme 4
We then focused our attention on the functionalities of
the C ring (Scheme 3). After inversion of the hydroxy group
of 12 under Mitsunobu conditions,6 the t-butyldimethylsilyl
(TBS) group was removed to give alcohol 13. The alcohol
was then converted to nitrile 14 by means of a Mitsunobu
Scheme 5
2).1e,5 Acidic hydrolysis of the acetal and subsequent Wittig
olefination gave the enol ether 10, which, upon treatment
with methanolic HCl, furnished phenol 11. A palladium-
Scheme 3
reaction.7 To prevent the formation of an R,â-unsaturated
nitrile, cleavage of the p-nitrobenzoate was effected by
treatment with lithium borohydride. The resulting alcohol
was protected as the TBS ether 15. To suppress the reductive
cleavage of the aromatic iodide, the nitrile was reduced first
with diisobutylaluminum hydride (DIBAL) at -78 °C
followed by addition of methanol and sodium hydride to give
the desired amine, which was isolated as the corresponding
methyl carbamate 16 in 94% yield. The crucial intramolecular
Heck reaction of 16 proceeded smoothly in refluxing
acetonitrile to give a silyl enol ether, which, upon treatment
(4) (a) Tsuji, J.; Kataoka, H.; Kobayashi, Y. Tetrahedron Lett. 1981,
22, 2575. (b) Trost, B. M.; Molander, G. A. J. Am. Chem. Soc. 1981, 103,
5969. (c) Trost, B. M.; Warner, R. W. J. Am. Chem. Soc. 1983, 105, 5940.
(d) Review: Tsuji, J. Palladium Reagents and Catalysts; Wiley: New York,
1995.
(5) Plaumann, H. P.; Kaey, B. A.; Rodrigo, R. Tetrahedron Lett. 1979,
4921.
(6) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
(b) Mitsunobu, O. Synthesis 1981, 1.
(7) Wilk, B. K. Synth. Commun. 1993, 23, 2481.
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Org. Lett., Vol. 8, No. 23, 2006

proceeded via an intramolecular Mannich-type reaction rather
than an aldol condensation-Michael reaction.
Scheme 6
What remained was to elaborate the C ring to complete
the endgame (Scheme 6). Accordintg to Ito-Saegusa’s
method,8 ketone 18 was converted into enone 21. Both
epoxidation and subsequent reduction of the ketone occurred
from the less-hindered exo face to furnish epoxyalcohol 23
as the sole isomer. Conversion of the alcohol into thiocar-
bamate and subsequent exposure to radical conditions
induced the epoxide opening to provide allylic alcohol 24.9
The resulting alcohol was inverted by a two-step oxidation-
reduction sequence where the methyl carbamate was reduced
with lithium aluminum hydride to afford codeine (25).1d
Finally, the methyl ether was cleaved according to a literature
procedure to furnish (()-morphine (1).10
In summary, we have successfully synthesized morphine
using an intramolecular Mannich-type reaction to construct
the B and D rings. The substrate for this critical reaction
was efficiently prepared by taking advantage of two types
of palladium-catalyzed reactions. Further studies on a more
efficient and enantioselective total synthesis of morphine are
currently underway, and our results will be reported in due
course.
Acknowledgment. This work was financially supported
in part by Grants-in-Aid (15109001 and 16073205) from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan.
with tetra-n-butylammonium fluoride (TBAF), furnished
ketone 17 in 87% yield.
Supporting Information Available: Detailed experi-
mental procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
With the requisite ketone 17 in hand, we then focused on
a one-step construction of the B and D rings. After extensive
investigation, the double cyclization was accomplished by
refluxing 17 in methanolic hydrogen chloride to afford 18
in 94% yield as a sole product (Scheme 4). When the reaction
was stopped prematurely, eight-membered hemiaminal 19
could also be isolated, but enone 20 was not observed
(Scheme 5). These findings strongly suggest that the reaction
OL062112M
(8) Itoh, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
(9) Barton, D. H. R.; Motherwell, R. S. H.; Motherwell, W. B. J. Chem.
Soc., Perkin Trans. I 1981, 2363.
(10) Rice, K. C. J. Med. Chem. 1977, 20, 164.
Org. Lett., Vol. 8, No. 23, 2006
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