Stereospecific synthesis of pseudocodeine: [2,3]-sigmatropic rearrangement using selenium intermediates

Full text of DOI:10.1021/jo970447z

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J . Org. Chem. 1998, 63, 1704-1705
Notes
Sch em e 1
Ster eosp ecific Syn th esis of P seu d ocod ein e:
[2,3]-Sigm a tr op ic Rea r r a n gem en t Usin g
Selen iu m In ter m ed ia tes
Tushar A. Kshirsagar, Scott T. Moe, and
Philip S. Portoghese*
Department of Medicinal Chemistry, College of Pharmacy,
University of Minnesota, Minneapolis, Minnesota 55455
Received March 11, 1997
Pseudocodeine1 (1), an important intermediate for the
synthesis of opiate ligands, has been previously synthe-
sized by converting codeine 2 to its 6â-chloro derivative
3, which then was subjected to SN2′ displacement in
aqueous acetic acid. Since this reaction gives rise to a
mixture of isomers from which separation of 1 is tedious,
we sought a stereospecific route to 1 using selenium
group transfer chemistry.
Selenium and sulfur have been extensively used for
indirect functionalization by the transfer of a group from
the above to a carbon electrophile.2,3 Among the most
common reactions used for this purpose are the [2,3]-
sigmatropic rearrangements of the selenium or sulfur
oxides to an allylic carbon.4,5 Such rearrangements using
selenium involve the formation of a Se-C bond at an
allylic position to a double bond to yield a seleno ether
(Scheme 1). Subsequent oxidation of the ether can be
accomplished by convenient methods without the pos-
sibility of over oxidation. The allylic selenoxide then
often undergoes a spontaneous [2,3]-sigmatropic rear-
rangement to yield the selenic ester, which can be cleaved
under mild acidic conditions to afford the desired alcohol.
Here we describe an application of this chemistry for the
stereospecific synthesis of pseudocodeine 1.
The stereospecific route to 1 from codeine 2 is il-
lustrated in Scheme 2. Codeine 2 was reacted with
N-(phenylseleno)phthalimide6 and tri-n-butylphosphine
in dry THF to yield the 6â-(phenylseleno) intermediate
4. This conversion involved the inversion of the C-6
chiral center via an SN2′ displacement involving a cyclic
transition state that is characteristic of this type of
reaction. Intermediate 4 was isolated as the HCl salt
and was then oxidized to the phenylselenoxide 5 using
hydrogen peroxide. This allylic selenoxide underwent a
spontaneous [2,3]-sigmatropic rearrangement to yield the
selenic ester 6, which was hydrolyzed by the addition of
aqueous potassium hydroxide to provide pseudocodeine
(1). The coupling constants (J 5,6 ) 3.6 Hz, J 6,7 ) 10.2
Hz, J 7,8 ) 1.5 Hz) are in agreement with the 8â-hydroxy
stereochemistry of the product and were identical to those
obtained by the reported route.7 The overall yield of 1
from codeine by the above stereoselective procedure was
38%.
with the desired product 1, which was purified by
chromatography, conversion to the hydrochloride salt,
and crystallization. The overall yield of the free base was
24%.
Thus, the stereospecific synthesis of 1 involving sele-
nium intermediates has the advantage of higher yield
and greatly improved efficiency because it alleviated the
time-consuming purification that is necessary in the
reported procedure.
Exp er im en ta l Section
Melting points were determined on a Thomas-Hoover capillary
melting point apparatus and are uncorrected. Analytical thin-
layer chromatography (TLC) was performed on Analtech silica
gel GHLF glass plates. Column chromatography was performed
with silica gel (200-400 mesh, Aldrich Chemicals). Chromato-
graphic solvent system is reported as volume/volume. Nuclear
magnetic resonance spectra were recorded on a 300 MHz NMR
spectrometer at room temperature (18-20 °C). The δ (ppm)
scale was in reference to the deuterated solvent. The coupling
constants are reported in Hz. The mass spectra were obtained
from the Mass Spectrometry Laboratory of the Department of
Chemistry, University of Minnesota. Microanalysis were per-
formed by MHW laboratories, Phoenix, AZ.
6â-(P h en ylselen o)d esoxycod ein e (4). To a solution of 2
(300 mg, 1.0 mmol) and N-(phenylseleno)phthalimide (600 mg,
(1) (a)Portoghese, P. S.; Moe, S. T.; Takemori, A. E. J . Med. Chem.
1994, 37, 1886. (b) Lutz, R. E.; Small, L. J . Am. Chem. Soc. 1932, 54,
4715. (c) Small, L.; Lutz, R. E. J . Am. Chem. Soc. 1934, 56, 1741. (d)
Small, L.; Lutz, R. E. J . Am. Chem. Soc. 1934, 56, 1928. (e) Hosztafi,
S.; Makleit, S.; Miskolczi, Z. Acta Chim. Hung. 1983, 114, 63-68. (f)
Chatterjie, N.; Umans, J . G.; Inturrisi, C. E.; Chen, W.-T. C.; Clarke,
D. D.; Bhatnagar, S. P.; Weiss, U. J . Org. Chem. 1978, 43, 1003-1005.
(g) Fleischhacker, W.; Richter, B. Chem. Ber. 1980, 113, 3866-3880.
(2) Reich, H. J . [2,3]-Sigmatropic Rearrangements of Organosele-
nium Compounds. In Organoselenium Chemistry; Liotta, D., Ed.; J ohn
Wiley and Sons: New York, 1987; pp 365-394.
(3) Grieco, P. A.; Gilman, S.; Nishizawa, M. J . Org. Chem. 1976,
41, 1485.
(4) Clive, D. L.; Chittattu, G.; Neville, J . C.; Menchen, S. M. J . Chem.
Soc., Chem. Commun. 1978, 770.
(5) Reich, H. J . J . Org. Chem. 1975, 40, 2570.
(6) Grieco, P. A.; J aw, J . Y. J . Org. Chem. 1981, 46, 1215.
(7) (a) Small, L.; Lutz, R. E. In Chemistry Of Opium Alkaloids;
Government Printing Office: Washington, DC, U.S. Health Services
Suppl. 103, Public Health Reports, pp 215-229. (b) Yeh, H. J . C.;
Wilson, R. S.; Klee, W. A.; J acobson, A. E. J . Pharm. Sci. 1976, 65,
902. (c) Bentley, K. W. The Chemistry of Morphine Alkaloids; Claren-
don Press: 1954; pp 126-148. (d) Batterham, T. J .; Bell, K. H.; Weiss,
U. Aust. J . Chem. 1965, 18, 1799. (e) Knorr, L. Ber. 1908, 41, 972. (f)
Speyer, E. Ann. 1923, 432, 246.
To compare the yield of 1 in our stereospecific synthesis
with that of the reported procedure, we have repeated
the literature synthesis involving the 6â-chloro interme-
diate 3.1b,7e,f A mixture of isomers was obtained along
S0022-3263(97)00447-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/14/1998

Notes
J . Org. Chem., Vol. 63, No. 5, 1998 1705
Sch em e 2
1.98 mmol) in THF (50 mL) at 0 °C was added dropwise over a
period of 5 min n-Bu3P (500 µL, 1.98 mmol) in an inert
atmosphere. After 2 h at 0 °C, the solvent was evaporated under
vacuum. The residue was chromatographed on a 1 × 5 in.
vacuum-flash column (gradient elution with hexane/EtOAc 8:1
to hexane/EtOAc 1:8) to provide an oil 4 (approximately 400 mg,
88%). This material was further purified by precipitating the
HCl salt from an ether solution with ethereal HCl. The
precipitate was filtered and washed with ether (3 × 20 mL) to
provide 4‚HCl (300 mg, 63%): mp 219-220 °C dec; 1H NMR
(300 MHz, CDCl3) δ 7.59 (m, 2H), 7.30 (m, 3H), 6.56 (doublets,
2H, J ) 8.2 Hz), 5.95 (m, 1H), 5.48 (dd, 1H, J ) 2.0 Hz, 2.6 Hz),
4.99 (d, 1H), 3.79 (s, 3H), 3.29 (m, 1H), 3.06 (d, 1H), 2.54 (dd,
1H), 2.43 (s, 3H), 1.73 (dd, 1H); CIMS m/z 439 (M + 1). Anal.
Calcd for C24H25NO2Se‚HCl: C, 60.70; H, 5.52; N, 2.95. Found
C, 60.70; H, 5.67; N, 2.93.
P seu d ocod ein e (1). Meth od A. F r om 6â-Ch lor ocod ein e
(3). To a mixture of 3 (5 g, 15.7 mmol) suspended in H2O (50
mL) at 100 °C was added glacial AcOH dropwise (2.1 mL) until
the opiate had completely dissolved. The reaction was stirred
at 100 °C for 3 h under nitrogen and was then cooled to room
temperature and made basic with solid NaHCO3. The mixture
was extracted with CHCl3 (4 × 30 mL), and the combined
extracts were dried (anhydrous Na2SO4) and evaporated to give
an oil (5.4 g) that was chromatographed on a 2 × 5 in. vacuum-
flash column (CHCl3/MeOH/NH3 81:12:1). Fractions containing
the product were pooled, and the solvent was removed under
vacuum to give an oil (3.6 g) that was dissolved in absolute EtOH
(20 mL). Concentrated HCl (∼30 drops) was added until the
solution was acidic, and the ethanolic solution was evaporated
to dryness under vacuum. This solid was dissolved in hot 95%
EtOH (32 mL), filtered, and refrigerated at -5 °C for 12-18 h.
The crystalline material was collected on a filter and washed
with ice-cold 95% EtOH (2 mL) to give 1‚HCl, (1.29 g, 24.5%),
mp 217-218 °C (lit. 217-218 °C).7f A part of the product was
converted to the free base by treatment of the aqueous solution
with solid NaHCO3 and subsequent extraction with CHCl3: 1H
NMR (300 MHz, CDCl3, free base) δ 6.67 (doublets, 2H, J ) 7.1
Hz), 5.87 (dd, 1H, J ) 10.2 Hz, 1.5 Hz), 5.74 (dd, 1H, J ) 10.2
Hz, 3.6 Hz), 4.98 (d, 1H, J ) 3.6 Hz), 3.85 (s, 3H), 3.10 (d, 1H),
2.46 (s, 3H), 2.31 (dt, 1H), 2.25 (dd, 1H), 1.94 (dt, 1H); CIMS
m/z 300 (M + 1). Anal. Calcd for C18H21NO3‚HCl: C, 64.37; H,
6.60, N, 4.17. Found C, 64.21; H, 6.61, N, 3.96.
Meth od B. F r om 6â-(P h en ylselen o)d esoxycod ein e (4).
The HCl salt of 4 (1.6 g, 3.37 mmol) was suspended in H2O (20
mL), and hydrogen peroxide (687 µL, 30 wt % in H2O) was added
dropwise at 25 °C. After 10 min, concd aqueous KOH was added
to precipitate 1. The solid was collected and dried to give 1 (607
mg, 60%). Physical and spectral properties of this material were
identical in all respects with that of 1 prepared by method A.
J O970447Z