Thermodynamic equilibration of dihydropyridone enolates: application to the total synthesis of (+/-)-epiuleine

Article abstract of DOI:10.1016/j.tetlet.2003.10.030

Following 1,4-reduction of 2-substituted dihydropyridones (1), the requisite 'kinetic' enolate can be isomerized upon warming to allow the isolation of the thermodynamic enolate as its vinyl triflate (3). This enolate interconversion is dependent on the dihydropyridone C-2 substituent and can be interpreted in terms of conformational analysis. This novel scaffold (3) opens another avenue for the strategic deployment of dihydropyridones into both natural product synthesis and drug discovery. To this end, this method is highlighted by its use as a key step in a total synthesis of (+/-)-epiuleine (14).

Full text of DOI:10.1016/j.tetlet.2003.10.030

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9185–9188
Thermodynamic equilibration of dihydropyridone enolates:
application to the total synthesis of (+/−)-epiuleine
Edward S. Tasber and Robert M. Garbaccio*
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
Received 4 August 2003; revised 21 August 2003; accepted 6 October 2003
Dedicated to Professor Dale Boger on the occasion of his 50th birthday.
Abstract—Following 1,4-reduction of 2-substituted dihydropyridones (1), the requisite ‘kinetic’ enolate can be isomerized upon
warming to allow the isolation of the thermodynamic enolate as its vinyl triflate (3). This enolate interconversion is dependent on
the dihydropyridone C-2 substituent and can be interpreted in terms of conformational analysis. This novel scaffold (3) opens
another avenue for the strategic deployment of dihydropyridones into both natural product synthesis and drug discovery. To this
end, this method is highlighted by its use as a key step in a total synthesis of (+/−) epiuleine (14).
© 2003 Elsevier Ltd. All rights reserved.
Dihydropyridones such as 1 are versatile synthetic
building blocks that have found considerable use in
both natural product synthesis and medicinal chem-
istry.1–5 These dihydropyridones are easily prepared via
the addition of Grignard reagents or metallo-enolates
to 1-acylpyridinium salts6 or by the hetero Diels Alder
cyclocondensation of imines with siloxydienes,7 and
have been extensively employed in the synthesis of
substituted piperidines and tetrahydropiperidines.2 We
were interested in the 2,4-disubstituted-1,2,3,6-tetra-
hydropyridines which have been synthesized directly
from 2-substituted dihydropyridones such as 1 (Scheme
1) by 1,4 reduction and in situ trap of the resulting
enolate as its vinyl triflate (2).8 Vinyl triflate 2 is an
excellent substrate for coupling reactions to generate
diversity at C-4. The alternative olefin isomer, 4,6-di-
substituted-1,2,3,6-tetrahydropyridine 3, is also a desir-
able scaffold, but direct access to 3 from 1 had not been
described. This report concerns a route to these iso-
meric 4,6-disubstituted tetrahydropyridines (3) via the
thermodynamic equilibration of the enolate produced
by 1,4-reduction of dihydropyridone 1, and an applica-
tion of this method to the total synthesis of (+/−)-
epiuleine.
0°C allowed for enolate interconversion. The thermody-
namic enolate thus produced could be efficiently
trapped in situ with N-(5-chloro-2-pyridyl)triflimide (4)
yielding isomeric vinyl triflate 3 in good yield with
selectivity varying with the R group. Mechanistically,
this interconversion requires small amounts of satu-
rated ketone 5 to be produced as a proton shuttle
between enolates (Scheme 2). We suggest that unre-
acted dihydropyridone 1 serves as the proton source
(from C-3) to quench the enolate leading to 2, thus
producing a limited amount of ketone 5. Supporting
Scheme 1.
It was found that L-Selectride® (0.98 equiv.) mediated
1,4-reduction9 of 1 at −78°C followed by warming to
Keywords: dihydropyridone; tetrahydropyridine; enolate; epiuleine.
* Corresponding author. Tel.: +1-215-652-5391; fax: +1-215-652-6345;
e-mail: robert garbaccio@merck.com
Scheme 2.
–
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.030

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E. S. Tasber, R. M. Garbaccio / Tetrahedron Letters 44 (2003) 9185–9188
this hypothesis, when the reaction is conducted with
excess L-Selectride® (1.5 equiv.), ensuring complete
consumption of the starting dihydropyridone 1, this
equilibration does not occur under the same conditions.
Furthermore, direct enolization of the saturated ketone
5 (R=Ph, LHMDS, 0.98 equiv., −78°C), followed by
equilibration (0°C) revealed the identical ratio for vinyl
triflates 3b:2b as was obtained for 1b (Table 1).
that the energy cost of pseudoaxial placement of large
R groups in conformation A is significantly less than
axial placement in conformation B. With diminishing
size of R, the difference in relative energies can be
expected to diminish as was observed. Molecular mod-
eling was employed (Spartan)12 and Monte Carlo con-
formational analysis (AM1) corroborated the enolic
structures below as being global minimums. Relative
energies for the competing half-chairs were estimated
(MMFF) and these calculations revealed that the DG
values increased with the size of R, and reflected the
experimental order of selectivity for 1a–e.
To investigate the scope of this transformation, a brief
study was undertaken to correlate the vinyl-triflate
ratios with the R group at C-2, and to reveal the
underlying source of selectivity (Table 1). Dihydropyri-
dones (1) were synthesized in one step from 4-
methoxypyridine, benzyl chloroformate and the
appropriate
Grignard
according
to
literature
procedures.6
Table 1.
Figure 1.
To highlight the added advantage that results from this
method, a concise total synthesis of (+/−)-epiuleine (14)
was accomplished (Scheme 3). Epiuliene (14) is a mem-
ber of the Strychnos indole alkaloids, and was isolated
from Aspidosperma subincanum in 1967.13 The total
synthesis of epiuleine has been achieved in a number of
laboratories with diverse synthetic routes and starting
materials.14–21 We opted to initiate our efforts using the
N-acylpyridinium salt route to dihydropyridones.
Entry
R
3:2
Yield* (%)
1a
1b
1c
1d
1e
t-Butyl
Phenyl
N-Boc-indolyl
Isopropyl
n-Propyl
20:1
10:1
9:1
4:1
5:4
60
83
73
73
72
The addition of indole magnesium bromide (7)22 to
4-methoxypyridine (6) in the presence of benzylchloro-
formate gave 2-indolyl-dihydropyridone 8 in moderate
yield.23 Protection of the indole nitrogen to yield 9 was
required prior to the key vinyl triflate formation. 1,4-
Reduction was effected by L-Selectride® at −78°C
accompanied by thermodynamic equilibration at 0°C
and in situ trap as the vinyl triflate (1c). The ratio of
vinyl triflates reproduced on scale at 9:1 favoring the
thermodynamic product. Vinyl triflate 1c was subjected
to a Heck vinylation with n-butyl vinyl ether and was
hydrolyzed in situ to produce the C-4 methyl ketone
(10) that crystallized from the reaction mixture and
thereby separated from the isomer arising from the
minor vinyl triflate. This Heck coupling initially
required some improvement, and the combination of
THF, Pd(OAc)2 and mild temperature proved to be
optimal. The CBz group was removed by transfer
hydrogenation, and the crude free amine was directly
subjected to reductive amination with formaldehyde to
provide 11. Efforts to reduce this exchange to a single
step by conducting the transfer hydrogenation in the
presence of aq. formaldehyde were unsuccessful.
Deprotection of the indole 11 yielded N-methylamine
1224 (>95%) that intersects with the total synthesis
achieved by Husson and co-workers19 as well as the
formal asymmetric route to epiuliene as described by
Tanaka and Katsumura.21 To complete this concise
total synthesis, the established protocol was fol-
lowed,18,19 and gave, in similar yields to those reported,
(+/−)-epiuleine (14)25 in 9 linear steps.
* Isolated yields.
It was observed that the selectivity increased with the
size of the R group, with large R groups (1a–c) result-
ing in >9:1 selectivity, whereas small R groups (1d, 1e)
demonstrated reduced ratios.10 The observed trend is
consistent with the A-values for these groups.
The origin of this thermodynamic enolate equilibration
is likely found in relief of strain accompanying the
ability of the R group to adopt a pseudo-axial orienta-
tion in a half-chair conformation to avoid interaction
with the carbamate (see Fig. 1). A(1,3) strain in N-acyl
piperidines has been demonstrated to make 2-equatori-
ally substituted amines less stable than the 2-axial iso-
mers.11a This same argument has also been invoked for
the conformation of dihydropyridones,11b and, for these
two cases, may be even more pronounced as the axially
disposed R group suffers only a single 1,3-diaxial inter-
action in the half-chair. Inspection of the competing
half-chair conformations (Fig. 1) indicates that the
thermodynamic enolate A enables the R group to
occupy a pseudo-axial orientation to alleviate the inter-
action with the planar N-acyl group, although it must
acquire a modest A(1,2) strain from the adjacent olefin.
In the kinetic half-chair B, a large R group will require
a true axial orientation to avoid A(1,3) strain. It appears

E. S. Tasber, R. M. Garbaccio / Tetrahedron Letters 44 (2003) 9185–9188
9187
Scheme 3.
In conclusion, conditions were found that produce 4,6-
disubstituted 1,2,3,6-tetrahydropyridines (3) from 2-
substituted dihydropyridones (1). It was observed that
the enolate resulting from 1,4-reduction of the 2-substi-
tuted dihydropyridones (1) could be thermodynamically
equilibrated and that depending on the size of the R
group at C-2, useful levels of selectivity in vinyl triflate
production could be obtained. Such vinyl triflates can
undergo a variety of transformations to effect diversity
at C-4 producing molecules with properties that are not
only of interest to medicinal chemists,1 but also useful
synthetic intermediates in natural product synthesis as
was demonstrated for (+/−)-epiuleine.
Acknowledgements
We thank Dr. Maricel Torrent of Merck Molecular
Systems for helpful discussions and guidance in molecu-
lar modeling and calculations. We also thank Dr. San-
dor Varga for his NMR analysis as well as Chuck Ross
and Joan Murphy for their assistance in mass
spectrometry.
References
1. Joseph, S.; Comins, D. L. Curr. Opin. Drug Discov.
Devel. 2002, 6, 870–880.
2. Comins, D. L.; O’Connor, S. Progress in Heterocyclic
Representative experimental procedure: To a flame dried
flask equipped with stir bar was added benzyl 2-tert-
butyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (1a,
0.25 g, 0.88 mmol) and anhydrous THF (5.0 mL). The
resulting solution was cooled to −78°C under N2, and
treated with L-Selectride® (1.0 M soln. in THF, 0.86
mL, 0.86 mmol) and then placed in a 0°C bath for 3 h.
The yellow-tinted reaction was then cooled to −78°C,
treated with N-(5-chloro-2-pyridyl)triflimide (4, 0.37 g,
0.95 mmol) and warmed to 25°C over 2 h. The reaction
mixture was concentrated and subjected to flash chro-
matography (SiO2, 40 g RediSep® Column, 0–20%
EtOAc/hexanes gradient) provided benzyl 6-tert-butyl-
4-{[(trifluoromethyl)sulfonyl]-oxy}-3,6-dihydropyridine-
Chemistry 1997, 9, 222–248.
3. Comins, D. L.; Joseph, S. P. In Advances in Nitrogen
Heterocycles; Moody, C. J., Ed. Alkaloid synthesis using
1-acylpyridinium salts as intermediates; JAI Press, Inc:
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5. Waldmann, H. Synthesis 1994, 535–551.
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1
1(2H)-carboxylate (3a, 0.23 g, 60%) For 3a: H NMR
(300 MHz, CDCl3) l rotamers 7.35 (m, 5H), 5.90 and
5.86 (s, 1H), 5.16 (m, 2H), 4.62 and 4.47 (s, 1H), 4.49
and 4.34 (dd, J=13.7, 5.9 Hz, 1H), 3.20 (m, 1H), 2.52
(br m, 1H), 2.22 and 2.16 (app s, 1H), 1.00 and 0.96
(s, 9H). FABHRMS m/z 422.1234 (M+H+,
C18H22F3N1O5S requires 422.1244).
7. Kerwin, J. F., Jr.; Danishefsky, S. Tetrahedron Lett.
1982, 23, 3739–3742.
8. Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33,
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9. Fortunato, J. M.; Ganem, B. J. Org. Chem. 1976, 41,
2194–2200.

9188
E. S. Tasber, R. M. Garbaccio / Tetrahedron Letters 44 (2003) 9185–9188
10. Ratios were determined from both the crude and purified
1H NMR spectra. Isomeric vinyl triflates were insepara-
ble using this purification, however they resolved easily
following subsequent coupling reactions. The vinyl trifl-
ates can be stored neat under N2 at 0°C for several days,
but were found to partially decompose in CHCl3 within
hours at 25°C. Also, purification is not necessary for the
subsequent coupling reaction.
11. For a discussion and leading references, see: (a) Johnson,
F. Chem. Rev. 1968, 68, 375; (b) Brown, J. D.; Foley, M.
A.; Comins, D. L. J. Am. Chem. Soc. 1988, 110, 7445–
7447.
J=7.9 Hz, 1H), 7.66 (d, J=7.0 Hz, 1H), 7.32 (m, 6H),
7.19 (dd, J=8.1, 7.1 Hz, 1H), 7.07 (dd, J=7.9, 7.3 Hz,
1H), 7.04 (d, J=2.7 Hz, 1H), 6.14 (d, J=6.7 Hz, 1H),
5.42 (d, J=8.2 Hz, 1H), 5.25 (s, 2H), 3.15 (dd, J=16.5,
6.7 Hz, 1H), 2.86 (d, J=16.5 Hz, 1H); FABHRMS m/z
347.1387 (M+H+, C21H18N2O3 requires 437.3190).
1
For 9: H NMR (300 MHz, CDCl3) l rotamers 8.10 and
8.08 (s, 1H), 7.94 (s, 1H), 7.55 (s, 1H), 7.40−7.20 (m, 8H),
6.06 and 6.04 (s, 1H), 5.44 (d, J=8.3 Hz, 1H), 5.24 (s,
2H), 3.15 (dd, J=16.4, 7.1 Hz, 1H), 2.84 (d, J=16.4 Hz,
1H), 1.65 (s, 9H); FABHRMS m/z 447.1888 (M+H+,
C26H26N2O5 requires 447.1915).
See representative experimental above for 1c: 1H NMR
(300 MHz, CDCl3) l rotamers 8.13 (d, J=8.2 Hz, 1H),
7.87 (br s, 1H), 7.36 (m, 7H), 7.05 (m, 1H), 6.27 (br s,
1H), 6.08 (br s, 1H), 5.22 (br m, 2H), 4.15 (br m, 1H),
3.11 (ddd, J=14.0, 11.9, 4.3 Hz, 1H), 2.76 (br m, 1H),
2.29 (dd, J=17.1, 3.4 Hz, 1H), 1.66 (s, 9H); FABHRMS
m/z 603.1408 (M+Na+, C27H27F3N2O7S requires
603.1386).
12. For simplicity, the calculations were conducted on the
respective enols. Spartan ’02, Wavefunction, Inc. Irvine,
CA.
13. Gaskell, A. J.; Joule, J. A. Chem. Ind. (London); 1967; p.
1089.
14. (a) Wilson, N. D. V.; Jackson, A.; Gaskell, A. J.; Joule,
J. A. Chem. Commun. 1968, 584; (b) Jackson, A.; Wilson,
N. D. V.; Gaskell, A. J.; Joule, J. A. J. Chem. Soc. C.
1969, 2738–2747.
15. (a) Dolby, L. J.; Biere, H. J. Am. Chem. Soc. 1968, 90,
2699; (b) Dolby, L. J.; Biere, H. J. Org. Chem. 1970, 11,
3843–3845.
16. Kametani, T.; Suzuki, T. J. Org. Chem. 1971, 36, 1291–
1293.
17. Buechi, G.; Gould, S. J.; Naef, F. J. Am. Chem. Soc.
1971, 93, 2492–2501.
18. Natsume, M.; Kitagawa, Y. Tetrahedron Lett. 1980, 21,
839–840.
19. (a) Harris, M.; Besselievre, R.; Grierson, D. S.; Husson,
H. P. Tetrahedron Lett. 1981, 22, 331–334; (b) Grierson,
D. S.; Harris, M.; Husson, H. P. Tetrahedron 1983, 39,
3683–3694.
In a flame dried flask equipped with a stir bar and
,
activated molecular sieves (4 A), vinyl triflate 1c (2.94 g,
5.07 mmol) was dissolved in anhydrous THF (50 mL)
under an N2 atmosphere. N-Butylvinyl ether (6.56 mL,
50.6 mmol), dppf (0.28 g, 0.51 mmol) and Pd(OAc)2 (0.06
g, 0.25 mmol) were added successively and the reaction
was de-oxygenated alternating between vacuum and
nitrogen. Following the addition of Et3N (1.06 mL, 7.6
mmol), the reaction was warmed to 40°C for 6 h under
N2. Upon completion as judged by disappearance of 1c,
the reaction was concentrated under reduced pressure.
The crude residue was dissolved in a 1:1 CH3CN/H2O
solution containing 5% TFA and stirred for 2 h to effect
complete conversion of the enol ether to the methyl
ketone, and to cause precipitation. This mixture was
filtered to provide 10 (1.78 g 74%) as a white solid. For
10: 1H NMR (300 MHz, CDCl3) l 8.08 (d, J=8.5 Hz,
1H), 7.93 (br s, 1H), 7.35 (m, 7H), 7.21 (br m, 1H), 7.00
(br s, 1H), 6.21 (br s, 1H), 5.23 (d, J=12.3 Hz, 1H), 5.16
(d, J=12.3 Hz, 1H), 4.15 (br m, 1H), 3.11 (ddd, J=12.2,
12.2, 4.0 Hz, 1H), 2.56 (d, J=18.9 Hz, 1H), 2.38 (s, 3H),
2.32 (m, 1H), 1.68 (s, 9H); FABHRMS m/z 475.2233
(M+H+, C28H30N2O5 requires 475.2228).
20. Forns, P.; Diez, A.; Rubiralta, M.; Solans, X.; Font-Bar-
dia, M. Tetrahedron 1996, 52, 3563–3574.
21. Tanaka, K.; Katsumura, S. J. Am. Chem. Soc. 2002, 124,
9660–9661.
22. (a) Joyce, R. P.; Gainor, J. A.; Weinreb, S. M. J. Org.
Chem. 1987, 52, 1177–1185; (b) Xie, G.; Lown, J. W.
Tetrahedron Lett. 1994, 35, 5555–5558.
23. Freshly prepared indole Grignard 7 (3 M in THF, 178
mmol) was cooled to −78°C and treated dropwise with a
solution of 4-methoxypyridine (6, 18.7 mL, 184 mmol)
and warmed to −30°C over 30 min. Benzylchloroformate
(62.1 mL, 50% in toluene, 184 mmol) was added dropwise
and the reaction was kept at −20°C for 3 h. Aqueous HCl
(1 M, 450 mL) was poured into the reaction and stirred
for 30 min. The reaction was extracted with Et2O (3×200
mL), washed with brine (500 mL) and dried over MgSO4.
The reaction was filtered and concentrated under reduced
pressure. The crude solid was recrystallized from EtOAc/
hexanes to provide 8 as a white solid (34.8 g, 55%). For
For 11: 1H NMR (300 MHz, CDCl3) l 8.14 (d, J=7.6
Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.55 (s, 1H), 7.33 (dd,
J=8.0, 7.1 Hz, 1H), 7.23 (obs. by CDCl3 dd, J=7.5, 7.1
Hz, 1H), 6.65 (s, 1H), 4.11 (br s, 1H), 3.09 (app dt,
J=10.9, 3.4 Hz, 1H), 2.55 (m, 3H), 2.29 (s, 3H), 2.23 (s,
3H), 1.68 (s, 9H); FABHRMS m/z 355.1995 (M+H+,
C21H26N2O3 requires 355.2016).
24. 1H NMR and FABHRMS spectra for 12 match those
reported in Ref. 21.
25. 1H NMR and FABHRMS spectra for 14 match those
reported in Ref. 17.
1
8: H NMR (300 MHz, CDCl3) l 8.34 (s, 1H), 7.82 (d,