Enantioselective synthesis of (-)-codeine and (-)-morphine

Article abstract of DOI:10.1021/ja0283394

A new synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges employing a Pd-catalyzed asymmetric allylic alkylation to set the stereochemistry. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate, the latter available from glutaraldehyde and the Emmons-Wadsworth-Horner phosphate reagent. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine is formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine. Copyright

Full text of DOI:10.1021/ja0283394

Published on Web 11/15/2002
Enantioselective Synthesis of (-)-Codeine and (-)-Morphine
Barry M. Trost* and Weiping Tang
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received August 29, 2002
Scheme 1. Retrosynthetic Analysis
The nearly 2 000 years of therapeutic use of opiates has made
the active principles and related substances represented by (-)-
morphine 1, (-)-codeine 2, (-)-thebaine 3 (see Figure 1) as well
Figure 1. Opium and amaryllidaceae alkaloids.
as simpler morphinan and benzomorphan analogues quintessential
targets for synthesis. Even though 2002 is the 50th anniversary of
the first synthesis of morphine,1 interest in developing improved
asymmetric total synthetic routes continues2 because of the broad
ranging pharmacological properties and the growing importance
of related amaryllidaceae alkaloids such as galanthamine 4 and its
analogues such as (-)-SPH 1339 5. Despite the extensive synthetic
work, only one asymmetric synthesis of galanthamine3 and two of
morphine4 without using resolution appeared prior to our work.5
Morphine and galanthamine share the same tricyclic core and,
biosynthetically, derive from an oxidative bisphenolic coupling.
Previously, we reported an efficient asymmetric total synthesis of
galanthamine and its analogue 5.6 Herein, we report that both
alkaloid families can be accessed synthetically from a common
intermediate in which the final ring closure involves a novel
intramolecular hydroamination.
molecular Heck vinylation to the sterically congested neopentyl
carbon created the tetracycle 14 in good yield under the same
conditions used for the Heck reaction in the synthesis of precursor
8.6
Scheme 1 outlines two strategies based upon formation of the
piperidine ring as the final ring-forming event.7 In path a, a
straightforward displacement of amino alcohol 6 envisions forma-
tion of the latter via a carbonyl ene reaction of aldehyde 7 which,
in turn, may derive by homologation of cyanoaldehyde 8. Path b
outlines a more intriguing, but more speculative, strategy in which
the piperidine ring would arise by a hydroamination of amine 9
which, in turn, may derive from Heck vinylation of (Z)-vinyl
bromide 10. A simple olefination protocol should allow the latter
to derive from the same aldehyde 8. In our synthesis of galan-
thamine, we established a practical synthesis of this cyanoaldehyde6
in only six steps from bromovanillin 118 and the allylic ester 129
which is available in two steps from glutaraldehyde and the
Emmons-Wadsworth-Horner reagent (eq 1). Equation 2 outlines
the initial efforts based upon path a. Homologation of the aldehyde
proceeded uneventfully via rearrangement of an epoxide intermedi-
ate. All attempts to effect the intramolecular carbonyl ene reaction
to form alcohol 13 failed.
Thwarted in attempts to execute path a, we turned to path b.
Olefination10 followed by chemoselective reduction of the (E)-vinyl
bromide11 provided the cyclization substrate 10 (eq 3). Intra-
* To whom correspondence should be addressed. E-mail: bmtrost@stanford.edu.
9
14542
J. AM. CHEM. SOC. 2002, 124, 14542-14543
10.1021/ja0283394 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. End Gamea
and two Heck-type reactions, create the entire carbon framework
and form four of the five rings. The one pot reduction-transami-
nation-reduction of nitriles significantly shortens the route. Most
noteworthy is the effectiveness of the intramolecular hydroamination
promoted by visible light - a reaction that should prove more
generally useful in alkaloid synthesis. Strategically, the commonality
of the amaryllidaceae and opium alkaloids from a chemical
synthesis perspective has also now been established.
Acknowledgment. We thank the National Science Foundation
and the National Institute of Health, General Medical Sciences
(GM13598), for their generous support of our programs. Mass
spectra were provided by the Mass Spectrometry Facility of the
University of California-San Francisco, supported by the NIH
Division of Research Resources.
a (a) SeO2, dioxane, sand, 75 °C, then DMP, room temperature. (b)
DIBAL-H, THF/Et2O. (c) DIBAL-H, CH2Cl2/Et2O, then NH4Br, MeNH2,
and then NaBH4. (d) LDA/THF with tungsten bulb. (e) See ref 17.
With the skeleton of morphine in hand, attention focused on
allylic functionalization (Scheme 2). On the basis of the known
conformation of morphine,12 both Ha and Hb of alkene 14 are
stereoelectronically and sterically favored for allylic oxidation.
Despite Ha being doubly allylic, its removal with selenium dioxide
is clearly strained due to creation of the bridgehead double bond.
Indeed, subjecting 14 to this reagent only involves abstraction of
Hb to give the corresponding alcohol accompanied by the over-
oxidation product ketone 15. Directly adding the Dess-Martin
periodinane to the reaction mixture prior to workup allowed the
ketone 15 to be isolated in 58% yield. Its reduction proceeded
stereoselectively with DIBAL-H in THF-ether to give the required
alcohol 16 almost quantitatively. No reaction of the nitrile was
observed in this solvent system. Furthermore, none of alcohol 16
was detected in the initial allylic oxidation.
Supporting Information Available: Experimental details and
analytical data for all new compounds and data for synthetic codeine
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1952, 74, 1109.
(2) For reviews, see: Novak, B. H.; Hudlicky, T.; Reed, J. W.; Mulzer, J.;
Trauner, D. Curr. Org. Chem. 2000, 4, 343. Hudlicky, T.; Butora, G.;
Fearnley, S. P.; Gum, A. G.; Stabile, M. R. Stud. Nat. Prod. Chem. 1996,
18, 43. Blakemore, P. R.; White, J. D. Chem. Commun. 2002, 1159.
(3) Shimizu, K.; Tomioka, K.; Yamada, S.; Koga, K. Chem. Pharm. Bull.
1978, 26, 3765. Shimizu, K.; Tomioka, K.; Yamada, S.; Koga, K.
Heterocycles 1977, 8, 277.
(4) Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115,
11028. White, J. D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1997,
62, 5250.
Adapting a known protocol,13 the nitrile 16 was converted to
the secondary amine 9 in a one pot operation. Switching from THF
to methylene chloride allowed nitrile reduction with DIBAL-H to
the imine aluminum complex. Addition of ammonium bromide in
dry methanol destroyed excess DIBAL-H and freed the imine.
Subsequent addition of excess methylamine converted the primary
imine to the more stable secondary one. The final stage involved
addition of sodium borohydride, wherein amine 9 was obtained
quantitatively from alcohol 16. Performing this same protocol on
ketone 15 also converted it to amine 9, thereby saving one step.
The stage was set for the key speculative last step, an intra-
molecular hydroamination.14 Simply treating 9 with LDA or
n-butyllithium in refluxing THF led to recovered starting material
up to 2 h and extensive decomposition after 8 h. With the notion
that the addition might be facilitated by single electron transfer,15
promotion of the latter by irradiation of the basic solution with an
ordinary tungsten light bulb was envisioned. Indeed, subjecting the
solution of amine 9 and LDA in THF to such irradiation with a
150 W tungsten light bulb led to cycloisomerization to form (-)-
codeine whose spectral data are identical to those previously
reported.16 Demethylation as reported by Rice17 with boron tribro-
mide converts this route into a synthesis of (-)-morphine as well.
From the common intermediate 8, which required only two steps
to convert to (-)-galanthamine, (-)-codeine is now available in
six steps and 15.4% overall yield. This very short asymmetric total
synthesis arises because of the minimal use of protecting groups.
Palladium-catalyzed reactions, asymmetric allylic alkylation (AAA)
(5) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 11262.
(6) Trost, B. M.; Tang, W. Angew. Chem., Int. Ed. 2002, 41, 2795.
(7) Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114, 9688. Toth, J. E.;
Fuchs, P. L. J. Org. Chem. 1987, 52, 473.
(8) Toth, J. E.; Hamann, P. R.; Fuchs, P. L. J. Org. Chem. 1988, 53, 4694.
(9) Amri, H.; Rambaud, M.; Villieras, J. Tetrahedron 1990, 46, 3535.
(10) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(11) Uenishi, J. I.; Kawahama, R.; Shiga, Y.; Yonemitsu, O.; Tsuji, J.
Tetrahedron Lett. 1996, 37, 6759.
(12) Mackay, M.; Hodgkin, D. C. J. Chem. Soc. 1955, 3261.
(13) Zandbergen, P.; Van den Nieuwendijk, A. M. C. H.; Brussee, J.; Van der
Gen, A.; Kruse, C. G. Tetrahedron 1992, 48, 3977.
(14) For reviews, see: Muller, T. E.; Beller, M. Chem. ReV. 1986, 86, 675.
Molander, G. A.; Romero, J. A. C. Chem. ReV. 2002, 102, 2161. For
base-catalyzed intermolecular hydroamination of styrene derivatives,
see: Beller, M.; Breindl, C.; Riermeier, T. H.; Eichberger, M.; Trauthwein,
H. Angew. Chem., Int. Ed. 1998, 37, 3389. Beller, M.; Breindl, C.
Tetrahedron 1998, 54, 6359. Seijas, J. A.; Vazquez-Tato, M. P.; Entenza,
C.; Martinez, M. M.; Onega, M. G.; Veiga, S. Tetrahedron Lett. 1998,
39, 5073. For Pd-catalyzed intermolecular hydroamination of vinylarenes,
see: Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546.
For acid-catalyzed intramolecular hydroaminations, see: Schlummer, B.;
Hartwig, J. F. Org. Lett. 2002, 4, 1471. For lanthanocene-catalyzed
intramolecular hydroaminations, see: Molander, G. A.; Dowdy, E. D. J.
Org. Chem. 1999, 64, 6515. Molander, G. A.; Dowdy, E. D.; Pack, S. K.
J. Org. Chem. 2001, 66, 4344. Li, Y.; Marks, T. J. J. Am. Chem. Soc.
1998, 120, 1757. Ryu, J.-S.; Marks, T. J.; McDonald, F. E. Org. Lett.
2001, 3, 3091.
(15) Ashby, E. C.; Goel, A. B.; DePriest, R. N. J. Org. Chem. 1981, 46, 2429.
Ashby, E. C.; Goel, A. B.; DePriest, R. N. Tetrahedron Lett. 1981, 22,
4355. Newcomb, M.; Burchill, M. T.; Deeb, T. M. J. Am. Chem. Soc.
1988, 110, 6528.
(16) White, J. D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1999, 64, 7871.
Carroll, F. I.; Moreland, C. G.; Brine, G. A.; Kepler, J. A. J. Org. Chem.
1976, 41, 996.
(17) Rice, K. C. J. Med. Chem. 1977, 20, 164.
JA0283394
9
J. AM. CHEM. SOC. VOL. 124, NO. 49, 2002 14543