Enantiopure n-acyldihydropyridones as synthetic intermediates: Asymmetric synthesis of benzomorphans

Article abstract of DOI:10.1021/ol990738p

(Matrix presented) Concise asymmetric syntheses of several benzomorphan derivatives have been accomplished using enantiopure 2,3-dihydro-4-pyridones as chiral building blocks.

Full text of DOI:10.1021/ol990738p

ORGANIC
LETTERS
1999
Vol. 1, No. 4
657-659
Enantiopure N-Acyldihydropyridones as
Synthetic Intermediates: Asymmetric
Synthesis of Benzomorphans
Daniel L. Comins,* Yue-mei Zhang, and Sajan P. Joseph
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received June 15, 1999
ABSTRACT
Concise asymmetric syntheses of several benzomorphan derivatives have been accomplished using enantiopure 2,3-dihydro-4-pyridones as
chiral building blocks.
The natural opium alkaloids (-)-morphine (1a) and (-)-
codeine (1b), and the simpler analogues morphinan (2) and
benzomorphan (3), are important analgesics or antitussive
agents.1 Although morphine is an important narcotic anal-
gesic, it exhibits undesired addicting side effects. Structural
ring system, i.e., 4, have proven to be particularly interesting
and hold promise in the search for nonaddictive narcotic
analgesics.2 Several racemic syntheses of the benzomorphan
4a and metazocine 4b have been achieved.1,2 In contrast,
the only enantioselective syntheses of benzomorphans 4
without using optical resolution were accomplished by the
groups of Meyers3 and Marazano.4 Using chiral dihydro-
pyridones as building blocks, we have developed a versatile
asymmetric route to various benzomorphan derivatives.
Syntheses of 4a and 4b were carried out as shown in Scheme
1.
The appropriate benzylic Grignard reagent was added to
a mixture of 4-methoxy-3-(triisopropylsilyl)pyridine5 and the
(1) (a) Lednicer, D.; Mitscher, L. A. The Organic Chemistry of Drug
Synthesis; John Wiley & Sons: New York, 1977; pp 286-312. (b) Lednicer,
D. Central Analgesics; John Wiley & Sons: New York, 1982; pp 137-
213.
(2) (a) Eddy, N. B.; May, E. L. Synthetic Analgesics, Part B; Pergamon
Press: Oxford, London, 1966. (b) Palmer, D. C.; Strauss, M. J. Chem. ReV.
1977, 77, 1. (c) Lednicer, D. Strategies for Organic Drug Synthesis and
Design; John Wiley & Sons: New York, 1998; pp 161-184.
(3) Meyers, A. I.; Dickman, D. A.; Bailey, T. R. J. Am. Chem. Soc.
1985, 107, 7974.
(4) Ge´nisson, Y.; Marazano, C.; Das, B. C. J. Org. Chem. 1993, 58,
2052.
(5) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc.
1994, 116, 4719.
modification can reduce this problem to a considerable
extent. Synthetic analogues containing the benzomorphan
10.1021/ol990738p CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/09/1999

°C; MeI) to give 8a and 8b in 89% and 92% yields,
respectively. Subjection of 8 to basic conditions (K2CO3/
THF) gave the cis 2,3-disubstituted compounds due to
epimerization at C-3. By comparison of the 1H NMR spectra
of crude 8 with that of the epimerized cis product, it was
determined that only the trans 2,3-disubstitued product was
formed in the enolate alkylation reaction. Treatment of 8
with L-Selectride effected regioselective 1,4-reduction to give
piperidones 9 in high yields.9 Regioselective 1,2-addition was
realized by adding a methylcerium species, generated from
a mixture of methyllithium and anhydrous cerium chloride
in THF.10
Scheme 1
A mixture of diastereomeric 1-acyl-4-piperidinols 10 in a
ratio of 3.75:2 was then reduced by lithium aluminum
hydride to give 1-methyl-4-piperidinols 11 in 90-95% yield.
Diastereoisomers 11 were separated by radial PLC; however,
the stereochemistry at the C-4 position of the isomers was
not determined in this case since it is unimportant for the
subsequent reaction. Both isomers of 11a and 11b were
subjected to acid-catalyzed cyclization to afford R-benzo-
morphans 4a and 4b in 81% and 70% yields, respectively
[4a, [R22D] +62 (c 0.81, CHCl3); lit.4 [R]D +63 (c 0.6,
CHCl3); 4b, [R]25 + 82.6 (c 0.91, EtOH); lit.3 [R]25
+
D
D
81.8 (c 0.83, EtOH)]. In both cases, a small quantity (5-
8%) of â-isomers (C-11 â-methyl) was detected by 1H NMR
analysis of the crude products. The overall yield is 37% for
4a and 33% for 4b in eight steps starting from 4-methoxy-
3-(triisopropylsilyl)pyridine.
The benzomorphans 12 and 13 can also be synthesized
from intermediate 7b as described in Scheme 2. The 1,4-
reduction of enantiopure 7b with L-Selectride gave piperi-
done 14, which on treatment with lithium aluminum hydride
Scheme 2
chloroformate of (+)-TCC.6 After purification, dihydro-
pyridones 5a and 5b were obtained in 86% and 89% yields,
respectively. The de was determined by HPLC analysis of
the crude products to be 92% for 5a and 90% for 5b. One-
pot cleavage of the chiral auxiliary (>98%) and the C-5
triisopropylsilyl group7 afforded an 89% yield of 6a and 88%
yield of 6b, which were deprotonated by n-butyllithium and
acylated with phenyl chloroformate. The resulting dihydro-
pyridones 7 were methylated at C-38 (LiHMDS, THF, -78
(6) Comins, D. L.; Salvador, J. M. J. Org. Chem. 1993, 58, 4656. (b)
The (+)- and (-)-TCC alcohols are available from Aldrich Chemical Co.
(7) Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J. J. Org. Chem.
1999, 64, 2184.
658
Org. Lett., Vol. 1, No. 4, 1999

Benzomorphans 19 and 21 were prepared in three steps
from enantiopure dihydropyridone 6a as shown in Scheme
3. N-Methylation of 6a gave a near quantitative yield of 17,
which on catalytic hydrogenation provided piperidinols 18
(>7:1, cis:trans) in good yield. A Grewe-type cyclization
Scheme 3
gave the target benzomorphan11b,12 19, [R]23 +116 (c 0.1,
D
CHCl3).
Alternatively, dihydropyridone 17 could be reduced with
L-Selectride in 87% yield to give piperidone 20, which on
treatment with HBr provided the enantiopure benzomorphan
21,11c [R]26 +24.6 (c 0.39, CHCl3).
D
The concise asymmetric syntheses of 4, 12, 13, 19, and
21 have amply demonstrated the versatility of our new
approach to benzomorphan derivatives using enantiopure 2,3-
dihydro-4-pyridones as chiral building blocks.13 The route
is practical as it uses the readily available chiral auxiliary
TCC, which can be prepared economically on a large scale
as either antipode6 and easily recycled.
Acknowledgment. We express appreciation to the
National Institutes of Health (Grant GM 34442) for financial
support of this research. Y.Z. also thanks the Burroughs
Wellcome Fund for a graduate fellowship.
Supporting Information Available: Characterization
data for compounds 4-9, 11, 14-15, and 17-21 and
comparison tables of NMR data for synthetic 4a,b, 19, and
21. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL990738P
(8) (a) Al-awar, R. S.; Joseph, S. P.; Comins, D. L. J. Org. Chem. 1993,
58, 7732. (b) Comins, D. L.; Green, G. M. Tetrahedron Lett. 1999, 40,
217.
(9) (a) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1989, 30,
5053. (b) Comins, D. L.; Morgan, L. A. Tetrahedron Lett. 1991, 32, 5919.
(c) Waldmann, H.; Braun, M. J. Org. Chem. 1992, 57, 444. (d) Hattori, K.;
Yamamoto, H. J. Org. Chem. 1992, 57, 3264.
(10) (a) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392. (b) Paquette, L. A.;
Thompson, R. C. J. Org. Chem. 1993, 58, 4952.
(11) (a) Takeda, M.; Jacobson, A. E.; Kanematsu, K.; May, E. L. J. Org.
Chem. 1969, 34, 4154. (b) Takeda, M.; Jacobson, A. E.; Kanematsu, K.;
May, E. L. J. Org. Chem. 1969, 34, 4158. (c) Takeda, M.; May, E. L. J.
Med. Chem. 1970, 13, 1223.
(12) (a) Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V. Synlett
1998, 58. (b) Stella, L.; Raynier, B.; Surzur, J. M. Tetrahedron 1981, 37,
2843.
(13) The structure assigned to each new compound is in accordance with
its IR, 1H NMR, and 13C NMR spectra and elemental analysis or high-
resolution mass spectra.
(THF, reflux) provided a 91% yield of cis and trans
4-piperidinols 15 in a ratio of 2:1 with the trans 2,4-
disubstitued isomer as the major product. Determination of
stereochemistry at C-4 was assigned by an HOMO decoup-
ling experiment. The chemical shift of the axial proton at
C-4 is 3.48 ppm whereas the equatorial proton is found at
4.04 ppm. Conversion of 15 to benzomorphan 12 has been
reported by May using a Grewe-type carbocation cycliza-
tion.11 Subjection of 15 to pyridinium dichromate (PDC)
oxidation gave 1-methyl-4-piperidone 16 [R]23 +17.1 (c
D
0.21, CHCl3). Again, the last step leading to 2′,5-dihydroxy-
6,7-benzomorphan 13 is a literature procedure.11b Therefore,
analgesics 12 and 13 can be prepared from 2,3-dihydro-4-
pyridone 7 in a concise, asymmetric fashion.
Org. Lett., Vol. 1, No. 4, 1999
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