Synthesis of (-)-morphine

Article abstract of DOI:10.1021/ja027882h

The preparation of the diastereomerically pure β-tetralone ketal 4 is reported. Intramolecular alkylidene C-H insertion followed by hydrolysis of 4 proceeded to give the enantiomerically pure cyclopentene 15. The key step in this synthesis was the bis-intramolecular cyclization of keto aldehyde 2 to give the tetracyclic intermediate 20. Enone 20 was converted over several steps to (-)-morphine 1. Copyright

Full text of DOI:10.1021/ja027882h

Published on Web 09/28/2002
Synthesis of (-)-Morphine
Douglass F. Taber,* Timothy D. Neubert, and Arnold L. Rheingold§
Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
Received July 26, 2002
Scheme 1
Morphine (1) is the principal alkaloid of opium, derived from
PapaVer somniferum L., or P. album Mill, PapaVeraceae.1 Mor-
phine is also found in normal brain, blood, and liver tissue.2 The
morphine alkaloids comprise a family of structurally related natural
products of unique clinical importance in medicine.3 The unusual
architecture of morphine has offered a continuing challenge to the
art and science of organic synthesis.4-6
Scheme 2 a
We envisioned that (-)-morphine 1 could ultimately be con-
structed from the easily prepared 5,6-dimethoxy-â-tetralone 5
(Scheme 1). A key step in this approach was the bis-intramolecular
cyclization of the keto aldehyde 2. The challenge was the
introduction of the formyl substituent at C-13 (morphine number-
ing). Conjugate addition to an enone such as 6 would not be
possible, as the enone 6 would tautomerize to the â-naphthol 7.
We hypothesized that initial alkylation of 5 at the C-14 position
followed by ketalization with (S,S)-(-)-hydrobenzoin would give
the bromoalkene 4. Intramolecular alkylidene C-H insertion7 would
then convert bromoalkene 4 to the cyclopentene 3, and thus give
access to 2.
a Conditions: (a) CH3I, K2CO3, DMF; (b) NaOCH3, collidine, CuI,
MeOH, reflux; (c) Na, EtOH, reflux; (d) HCl, H2O, reflux; (e) (CH3O)2CO,
NaOMe, MeOH, reflux; (f) LDA (2 equiv), THF, 0 °C; (g) LiCl, DMSO,
H2O, reflux.
Scheme 3 a
Our approach to the synthesis of (-)-morphine 1 began with
the preparation of â-tetralone 13 (Scheme 2). Using modifications
of the published procedures,8 we alkylated 1,6-dibromo-2-naphthol
8 with iodomethane to give the methoxynaphthalene 9. Ullman
coupling with sodium methoxide then gave the desired trimethoxy-
naphthalene 10. Dissolving metal reduction followed by hydrolysis
led to the desired â-tetralone 5. The â-tetralone 5 would tend to
alkylate at the benzylic position. The procedure of Aristoff,9
methoxycarbonylation, dianion alkylation using cis-1,3-dibromo-
2-methyl-1-propene,10 and decarboxylation, was therefore employed
to obtain the alkylated â-tetralone 13.
a Conditions: (a) p-TSA, HC(OEt)3, CH2Cl2; (b) KHMDS, Et2O; (c)
AcOH, H2O, reflux; (d) L-selectride, THF, 0 °C; (e) (PhO)2P(O)N3, DEAD,
Ph3P, THF; (f) LAH/EtOH - (1/1), Et2O; (g) PhSO2Cl, Et3N, CH2Cl2.
Protection of the â-tetralone 13 (Scheme 3) with (S,S)-(-)-
hydrobenzoin gave the diastereomeric ketals 14 and 4, which, as
anticipated, were separable by silica gel chromatography. The
undesired diastereomer 14 was readily recycled to the racemic
â-tetralone 13. Cyclization of ketal 4 via alkylidene carbene C-H
insertion7 followed by hydrolysis led to the enantiomerically pure
ketone 15. The beauty of this approach is that while â-tetralone 13
can readily racemize, â-tetralone 15 cannot.
16 was smoothly converted to the azide via Mitsunobu coupling.
Reduction and protection then gave sulfonamide 17.
The key to the assembly of morphine was the anticipated
selective bis-cyclization of keto aldehyde 2 (Scheme 4). Alkylation
of the sulfonamide 17 with 1,2-dibromoethane under phase-transfer
conditions provided 18, which upon ozonolysis gave the desired
keto aldehyde 2. The benzylic proton R to the aldehyde in 2 is the
most acidic, so we expected to obtain the aldehyde enolate
selectively. Although the keto aldehyde 19 could be isolated after
brief exposure to base, it was more practical to continue heating,
to cleanly obtain the tetracycle 20. The final conversion to complete
the core structure of morphine 1 was the construction of the ether
ring. Reduction of the enone 20 gave a single alcohol 21 (Scheme
The sterically congested ketone 15 was selectively reduced to
the cis alcohol 16. Direct displacement of the alcohol by a
functionalized amine could not be achieved. Fortunately, the alcohol
* To whom correspondence should be addressed. E-mail: taberdf@udel.edu.
§ For X-ray analysis.
9
12416
J. AM. CHEM. SOC. 2002, 124, 12416-12417
10.1021/ja027882h CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4 a
spectroscopy, and to Kenner C. Rice for many helpful discussions.
This work is dedicated to the memory of Henry Rapoport and
Arthur G. Schultz, masters of the science and art of alkaloid
synthesis.
Note Added after Print Publication: Due to a production error,
the graphics were incomplete in the version published on the Web
09/28/2002 (ASAP) and in the October 23, 2002 issue (Vol. 124,
No. 42, pp 12416-12417); the correct electronic version of the
paper was published on 11/27/02 and an Addition and Correction
appears in the December 25, 2002 issue (Vol. 124, No. 51).
a Conditions: (a) BrCH2CH2Br, 1 N NaOH, TBAB, toluene, reflux; (b)
O3, CH2Cl2, -78 °C, Ph3P; (c) K2CO3, TBAB, toluene, reflux; (d) NaBH4,
EtOH; (e) BBr3, CH2Cl2, -40 °C.
Supporting Information Available: Details for the preparation of
compounds 1-27 (PDF), and X-ray data for compound i (CIF).15 This
material is available free of charge via the Internet at http://pubs.acs.org.
Scheme 5 a
References
(1) Santavy, F. Alkaloids 1979, 17, 385.
(2) Benyhe, S. Life Sci. 1994, 55, 969.
(3) (a) Swerdlow, M. Br. J. Anaesth. 1967, 39, 699. (b) Bilfinger, T. V.;
Kushnerik, V. AdV. Neuroimmunol. 1994, 4, 133. (c) Przewlocki, R.;
Przewlocka, B. Eur. J. Pharmacol. 2001, 429, 79.
(4) For leading references to previous syntheses of enantiomerically pure
morphine, see: (a) Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem.
Soc. 1993, 115, 11028. (b) White, J. D.; Hrnciar, P.; Stappenbeck, F. J.
Org. Chem. 1997, 62, 5250. (c) Trauner, D.; Bats, J. W.; Werner, A.;
Mulzer, J. J. Org. Chem. 1998, 63, 5908. (d) Nagata, H.; Miyazawa, N.;
Ogasawara, K. Chem. Commun. 2001, 1094.
(5) For leading references to previous syntheses of racemic morphine, see:
(a) Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1952, 74, 1109. (b) Elad,
D.; Ginsburg, D. J. Am. Chem. Soc. 1954, 76, 312. (c) Grewe, R.;
Friedrichsen, W. Chem. Ber. 1967, 100, 1550. (d) Morrison, G. C.; Waite,
R. O.; Shavel, J., Jr. Tetrahedron Lett. 1967, 41, 4055. (e) Kametani, T.;
Ihara, M.; Fukumoto, K.; Yagi, H. J. Chem. Soc. C 1969, 2030. (f)
Schwartz, M. A.; Mami, I. S. J. Am. Chem. Soc. 1975, 97, 1239. (g) Lie,
T. S.; Maat, L.; Beyerman, H. C. Recl. TraV. Chim. Pays-Bas 1979, 98,
419. (h) Rice, K. C. J. Org. Chem. 1980, 45, 3135. (i) Evans, D. A.;
Mitch, C. H. Tetrahedron Lett. 1982, 23, 285. (j) Moos, W. H.; Gless, R.
D.; Rapoport, H. J. Org. Chem. 1983, 48, 227. (k) Toth, J. E.; Fuchs, P.
L. J. Org. Chem. 1987, 52, 473. (l) Tius, M. A.; Kerr, M. A. J. Am. Chem.
Soc. 1992, 114, 5959. (m) Parker, K. A.; Fokas, D. J. Org. Chem. 1994,
59, 3933.
(6) For leading references to previous approaches to the ring system of
morphine, see: (a) Monkivic, I.; Conway, T. T.; Wong, H.; Perron, Y.
G.; Patchter, I. J.; Belleau, B. J. Am. Chem. Soc. 1973, 95, 7910. (b)
Schultz, A. G.; Lucci, R. D. J. Chem. Soc., Chem. Commun. 1976, 925.
(c) Ciganek, E. J. Am. Chem. Soc. 1981, 103, 6261. (d) Boger, D. L.;
Patel, M.; Mullican, M. D. Tetrahedron Lett. 1982, 23, 4559. (e) Hudlicky,
T.; Boros, C. H.; Boros, E. E. Synthesis 1992, 174.
(7) Taber, D. F.; Sahli, A.; Yu, H.; Meagley, R. P. J. Org. Chem. 1995, 60,
6571.
(8) (a) Davis, W. A. J. Chem. Soc. 1900, 33. (b) Horn, A. S.; Grol, C. J.;
Dijkstra, D.; Mulder, A. H. J. Med. Chem. 1978, 21, 825. (c) McDermed,
J. D.; McKenzie, G. M.; Phillips, A. P. J. Med. Chem. 1975, 18, 362.
(9) Aristoff, P. A.; Johnson, P. D.; Harrison, A. W. J. Am. Chem. Soc. 1985,
107, 7967.
a Conditions: (a) Red-Al, toluene, reflux; (b) ClCOOEt, Et3N, CH2Cl2;
(c) [(C8H17)3NCH3]+3[PO4[W(O)(O2)2]43-, H2O2, DCE, reflux; (d) Ph-
SeSePh, NaBH4, EtOH, reflux; (e) NaIO4, THF, H2O; (f) Na2CO3, toluene,
H2O; (g) MnO2, CH2Cl2; (h) LiAlH4, THF, reflux; (i) BBr3.
4), which upon brief exposure to BBr3 gave clean cyclization to
22, having the pentacyclic morphine skeleton.
The next challenge (Scheme 5) was the removal of the robust
phenylsulfonyl protecting group. Although dissolving metal condi-
tions failed, we found that Red-Al was very effective11 for this
difficult deprotection. Reprotection immediately followed to give
the carbamate 23.
To effect the final oxidation to the allylic alcohol of morphine,
we first epoxidized the alkene 23 with H2O2.12 Regioselective ring
opening of the epoxide 24 then gave the selenide 25. The expected
selectivity exhibited in both the epoxidation and the epoxide opening
was controlled by the strong steric influence of the arene ring, which
effectively blocks both the lower face of the C ring and the backside
attack at the C-6 position. Oxidation of the selenide 25 followed
by elimination yielded the allylic alcohol 26 with the configuration
at C-6 opposite to that of morphine. Manganese dioxide oxidation
followed by LiAlH4 reduction proceeded with the reported13 high
diastereocontrol to deliver codeine 27. Finally, O-demethylation14
gave morphine 1, identical (TLC, 1H NMR, 13C NMR, [R]D) with
natural material.
(10) The Z-bromoalkene alkylating agent was used to limit the complexity of
1H NMR and 13C NMR and also to simplify the chiral ketal product
distribution and separation.
(11) (a) Gold, E. H.; Babad, E. J. Org. Chem. 1972, 37, 2208. (b) Sodium
bis(2-methoxyethoxy)aluminum hydride is sold as both Red-Al and
Vitride.
A â-tetralone-based approach to the synthesis of (-)-morphine
1 has been achieved, in 23 steps from 5, with an overall yield of
0.77%. This synthesis opens the way to the preparation of a variety
of C-10, C-15, and C-16 substituted morphine analogues that have
previously not been available. The strategy outlined here for the
enantioselective construction of three contiguous stereogenic centers
and the novel ring cyclizations that followed will have many
applications in target-directed organic synthesis.
(12) (a) Venturello, C.; D’Aloisio, R. J. Org. Chem. 1988, 53, 1553. (b)
Attempted epoxidation with peracids led to extensive decomposition.
(13) Iijima, I.; Rice, K. C.; Silverton, J. V. Heterocycles 1977, 6, 1157.
(14) Rice, K. C. J. Med. Chem. 1977, 20, 164.
(15) â-Tetralone 13 was initially ketalized with (R,R)-(+)-hydrobenzoin. The
first ketal diastereomer to elute via chromatography was converted to the
p-bromobenzenesulfonamide i. This was determined by X-ray analysis
to have the configuration at C-9, C-13, and C-14 shown.
Acknowledgment. We thank DuPont Agricultural Products and
the NIH (GM60287) for financial support of this work. We express
our appreciation to Michael Kline and John C. Groce for NMR
JA027882H
9
J. AM. CHEM. SOC. VOL. 124, NO. 42, 2002 12417