Diastereoselective synthesis of 3,4-dimethoxy-7-morphinanone: A potential route to morphine

Article abstract of DOI:10.1021/ol006172i

Diastereoselective synthesis of racemic 3,4-dimethoxy-7-morphinanone from racemic 2-(2,3-dimethoxyphenyl)cyclohexen-1-ol has been achieved. The relative structure has been determined by transformation of the product into the known 3,4-dimethoxy-6-morphina

Full text of DOI:10.1021/ol006172i

ORGANIC
LETTERS
2000
Vol. 2, No. 18
2785-2788
Diastereoselective Synthesis of
3,4-Dimethoxy-7-morphinanone:
A Potential Route to Morphine
Osamu Yamada and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
konol@mail.cc.tohoku.ac.jp
Received June 7, 2000
ABSTRACT
Diastereoselective synthesis of racemic 3,4-dimethoxy-7-morphinanone from racemic 2-(2,3-dimethoxyphenyl)cyclohexen-1-ol has been achieved.
The relative structure has been determined by transformation of the product into the known 3,4-dimethoxy-6-morphinanone. Resolution of the
starting cyclohexenol has also been accomplished for use in a future enantiocontrolled synthesis of morphine.
The synthesis of morphine 1 has engaged the interest of
organic chemists both from its characteristic physiological
activity and from its unique structure.1,2 We are interested
in the enantiocontrolled synthesis of (-)-morphine 1 from
2-(2,3-dimethoxyphenyl)cyclohexen-1-ol3,4 3 since we have
recently developed an efficient resolution method for the
closely related 2-arylcyclohexenols.4 In this paper, we report
the successful resolution of racemic 2-(2,3-dimethoxyphen-
yl)cyclohexen-1-ol 3, diastereoselective conversion of race-
mate (()-3 into 3,4-dimethoxyphenyl)cyclohexen-1-ol 3, and
diastereoselective conversion of racemate (()-3 into 3,4-
dimethoxy-6-morphinanone 2, the 4-O-methyl derivative of
the Gates ketone. The latter is the key intermediate in the
first synthesis of morphine 1.5 These studies position us to
pursue for future work on an enantiocontrolled synthesis of
morphine 1. The present study provides an efficient method
for the highly diastereoselective introduction of the C14
stereogenic center and the facile construction of the C9-
C10 bridge of the morphinan system (Scheme 1).
Scheme 1
Thus, by following the established procedure,4 (()-3 was
stirred with vinyl acetate (1 equiv) in tert-butyl methyl ether
for 3 days to give the enantiopure acetate6 (+)-4, [R]25
D
(1) For pertinent reviews for the synthesis of morphine, see: (a) Hudlicky,
T.; Butora, G.; Fearnley, S. P.; Gum, A. G.; Stabile, M. R. Studies in Natural
Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier, Amsterdam, 1966; pp
43-154. (b) Novak, B. H.; Hudlicky, T.; Reed, J. W.; Mulzer, J.; Trauner,
D. Curr. Org. Chem. 2000, 4, 343.
(2) For the synthesis of morphine after ref 1, see: (a) White, J. D.;
Hrncier, P. J. Org. Chem. 1999, 64, 7271. (b) White, J. D.; Hrncier, P.;
Stappenbeck, F. J. Org. Chem. 1999, 64, 7871.
+145.5 (c 1.0, CHCl3), in 47% yield, leaving the enantio-
enriched alcohol (-)-3, [R]31 -60.2 (c 0.9, CHCl3), (97%
D
ee),6 in 48% recovery yield. On alkaline methanolysis, (+)-4
afforded (+)-3, [R]26 +60.6 (c 1.0, CHCl3). The absolute
D
(3) Bergmann, E. D.; Pappo, R.; Ginsburg, D. J. Chem. Soc. 1950, 1369.
(4) Yamada, O.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 7747.
(5) Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1952, 74, 1109.
(6) Enantiomeric excess was determined by HPLC using a column with
a chiral stationary phase (CHIRALCEL OD, elution with PrOH-hexane
3:97 v/v).
i
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configuration of the resolution products was determined by
comparison with an authentic material, prepared from the
chiral 2-iodo-2-cyclohexen-1-ol7 and 3,4-dimethoxyphenyl-
boric acid by Suzuki coupling conditions.8 This comparison
revealed (+)-3 to be R and (-)-3 to be S (Scheme 2).
Scheme 2
Figure 1.
with chromium trioxide and 3,5-dimethylpyrazole complex12
in dichlomethane to give rise to cyclohexenone 15 by allylic
oxidation (Scheme 3).
Scheme 3
On the other hand, transformation of the same racemic
alcohol (()-3 into morphinanone 2 was examined to prepare
for future utilization of (-)-(S)-3 for construction of natural
(-)-morphine 1. To construct the quaternary 13-stereogenic
center first, (()-3 was treated4,9 with ethyl vinyl ether in the
presence of N-bromosuccinimide (NBS) to give bromoacetal
5 as a mixture of two epimers. In contrast to the 3,4-
dimethoxyphenyl analogue which gave the cyclization
product in excellent yield,4 5 furnished the cyclization
product 6 in moderate yield under the same radical initiated
conditions,10 probably because of steric hindrance by the
2-substituent on the aromatic ring. Since we could not
optimize the conditions to improve the cyclization, we carried
out the present examination using product 6 obtained in 48%
yield. Thus, 6 was first transformed into lactone 7 on peracid
treatment in the presence of a Lewis acid.11 Product 7 was
then transformed into xanthate 10 by a sequential three-step
reaction via diol 8 and monopivalate 9. Upon thermolysis
under various conditions, 10 afforded no cyclohexene 14 but
instead gave a complex mixture. As this was presumed to
be due to steric repulsion between the xanthate moiety and
the axially disposed alkyl functionality in a transition state
(Figure 1, 10a), its epimer 13, with no such steric hindrance,
seems to be more appropriate for syn-elimination. Although
the Mitsunobu reaction of 9 failed to give the inverted alcohol
12, oxidation of 9 followed by reduction of the generated
ketone 11 with sodium borohydride furnished the epimeric
alcohol 12, diastereoselectively. The observed diastereo-
selective reduction may be due to prior coordination of the
pivalate moiety with the borohydride reagent which delivered
a hydride exclusively from the â-face of the molecule (Figure
1, 11a). As expected, on thermolysis in o-dichlorobenzene,
the epimeric xanthate 13, obtained from 12, afforded
cyclohexene 14 in satisfactory yield presumably through
conformer 13a (Figure 1). Intermediate 14 was then treated
To construct the C9-C10 bridge, an allyl functionality
was introduced at the C14 center of 15 under Sakurai
conditions13 which proceeded in a highly diastereoselective
manner. Thus, treatment of 15 with allyltrimethylsilane in
the presence of titanium(IV) chloride gave a readily separable
mixture of two products in yields of 71 and 5% (Scheme 4).
Although the stereochemistry of the products could not be
determined at this stage, the major product was determined
at a later stage as the stereoisomer 16 containing the 14-âH
configuration. The diastereoselective reaction observed at this
pivotal point which determined the direction of the natural
14-âH and the unnatural 14-RH stereochemistry was note-
worthy. This may be elucidated by assuming the structure
(7) Johnson, C. R.; Sakaguchi, H. Synlett 1992, 813.
(8) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(9) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M. J.
Am. Chem. Soc. 1982, 104, 5564.
(10) Stork, G.; Mook, R., Jr. J. Am. Chem. Soc. 1983, 105, 3720.
(11) Grieco, P. A.; Oguri, T.; Yokoyama, Y. Tetrahedron Lett. 1978,
419.
(12) Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem. 1978,
43, 2057.
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Org. Lett., Vol. 2, No. 18, 2000

interesting. We believe that 18 generates first the acetal 20
which is in equilibrium with the reactive oxonium intermedi-
ate 21 to initiate cyclization, giving rise to 19 via 22 and 23
(Scheme 5).
Scheme 4
Scheme 5
in transition state 15a in which the allyl functionality was
introduced from the stereoelectronically more favorable face
which is the side of the aryl group residing in a quasi-
equatorial conformation (Figure 2). Following introduction
Construction of the ring D piperidine was best carried out
under Parker conditions.15 Thus, the primary alcohol, gener-
ated from 19 by reductive removal of the pivaloyl function-
ality, was coupled with N-methyl-p-toulenesulfonylamide
under modified Mitsunobu conditions16 to give the tertiary
sulfonamide 24. Upon treatment with sodium naphthalenide
Scheme 6
Figure 2.
of the C14-functionality, ketone 16 was transformed into
ketal 17, whose olefin functionality was oxidatively cleaved
to give aldehyde 18. On reflux in benzene containing
ethylene glycol in the presence of a catalytic amount of
p-toluenesulfonic acid, this furnished hydrophenanthrene 19
in excellent yield. The stereochemistry of the product was
confirmed at this stage by a NOESY experiment (Figure 2,
19a). Since it was reported14 that a similar aldehyde did not
cyclize under acid-catalyzed conditions, the present cycliza-
tion in the presence of ethylene glycol may be particularly
(13) Hosomi, A.; Sakurai, H. J. Am. Chem. Soc. 1977, 99, 1673.
(14) Trauner, D.; Bats, J. W.; Werner, A.; Mulzer, J. J. Org. Chem. 1998,
63, 5908.
(15) Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114, 9688.
(16) Tsunoda, T.; Yamamiya, Y.; Itoˆ, S. Tetrahedron Lett. 1993, 34,
1639.
(17) Evans, D. A.; Mitch, C. H. Tetrahedron Lett. 1982, 23, 285.
(18) Fujii, I.; Abe, M.; Hayakawa, K.; Kanematsu, K. Chem. Pharm.
Bull. 1984, 32, 4670. Spectroscopic data of 2 reported were identical with
those of the synthetic material.
(19) Takano, S.; Hiroya, K.; Ogasawara, K. Chem. Lett. 1983, 255.
(20) Woodward, R. B.; Pachter, I. J.; Scheinbaum, M. L. Organic
Syntheses; Wiley: New York, 1973; Collect. Vol. VI, p 1014.
Org. Lett., Vol. 2, No. 18, 2000
2787

generated in situ in THF, 24 furnished morphinan 25 cleanly
in 89% yield by concurrent de-N-sulfonylation and regiose-
lective cyclization.15 Acid-catalyzed hydrolysis of 25 afforded
the as yet unknown 3,4-dimethoxyphenyl-7-morphinanone
26 which was correlated to 3,4-dimethoxy-6-morphinanone
2, which is the O-methylated Gates ketone17 as well as the
degradation product of thebaine.18 Thus, ketone 26 was first
converted into R-diketone monothioketal 27 through pyrro-
lidine enamine 26 upon reaction with trimethylene dithio-
tosylate19 in the presence of triethylamine.20 Reduction of
27 with sodium borohydride occurred diastereoselectively
to give the single alcohol 28 which was transformed into
the acetate 29. The dithiane functionality of 29 was then
hydrolyzed under oxidative conditions21 to give the R-
acetoxyketone 30. Reductive elimination of the R-acetoxy
functionality was found to be unexpectedly difficult,22 and
it was accomplished to give 2 in 37% yield when 30 was
treated with samarium(II) iodide23 in THF containing metha-
nol (Scheme 6).
In summary, although the present approach does not
constitute a formal synthesis of morphine 1 and, moreover,
necessitates improvement in the construction of the quater-
nary C13-stereogenic center, it may be potentially useful for
an enantio- and diastereocontrolled synthesis of morphine 1
as no other serious obstacles seem to exist. We are presently
pursuing a new enantiocontrolled construction of morphine
1 via 3,4-dimethoxyphenyl-7-morphinanone 26 using the
enantiopure starting material 3.
(21) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(22) Takano, S.; Samizu, K.; Ogasawara, K. Chem. Lett. 1990, 1239.
(23) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135.
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