Nucleophilic addition to 3-substituted pyridinium salts: Expedient syntheses of (-)-L-733,061 and (-)-CP-99,994

Article abstract of DOI:10.1021/ol048624n

(Chemical Equation Presented) The addition of nucleophiles to 3-substituted pyridinium salts prepared from N-methylbenzamide and various pyridines has been investigated. Good to excellent regioselectivities favoring the 2,3-disubstituted 1,2-dihydropyridines were observed. The resulting 1,2-dihydropyridines led to the corresponding 2,3-disubstituted pyridines upon treatment with Mn(OAc)₃/NaIO₄. This methodology was also successfully applied to the enantioselective syntheses of (-)-L-733,061 and (-)-CP-99,994, two members of a new class of highly potent, nonpeptide, Substance P antagonists.

Full text of DOI:10.1021/ol048624n

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3517-3520
Nucleophilic Addition to 3-Substituted
Pyridinium Salts: Expedient Syntheses
of (−)-L-733,061 and (−)-CP-99,994
Alexandre Lemire, Michel Grenon, Mehrnaz Pourashraf, and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
andre.charetta@umontreal.ca
Received July 16, 2004
ABSTRACT
The addition of nucleophiles to 3-substituted pyridinium salts prepared from N-methylbenzamide and various pyridines has been investigated.
Good to excellent regioselectivities favoring the 2,3-disubstituted 1,2-dihydropyridines were observed. The resulting 1,2-dihydropyridines led
to the corresponding 2,3-disubstituted pyridines upon treatment with Mn(OAc)3/NaIO4. This methodology was also successfully applied to the
enantioselective syntheses of (−)-L-733,061 and (−)-CP-99,994, two members of a new class of highly potent, nonpeptide, Substance P antagonists.
Efficient syntheses of 2,3-disubstituted piperidines are
becoming increasingly important since several studies have
highlighted their unique biological activities.1 For example,
several Substance P antagonists such as L-733,060 (1) and
CP-99,994 (2) contain this important pharmacophore unit
(Figure 1).2 Routes leading to enantiopure 13 rely either on
reported.7 Likewise, routes leading to enantioenriched 28
include resolution of racemic intermediates9 or linear syn-
theses starting from L-serine,10 (R)-1-phenyl-1,2-ethanediol,11
(1) For recent reviews on the synthesis of piperidines, see: (a) Buffat,
M. G. P. Tetrahedron 2004, 60, 1701-1729. (b) Felpin, F.-X.; Lebreton,
J. Eur. J. Org. Chem. 2003, 3693-3712. (c) Weintraub, P. M.; Sabol, J.
S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953-2989.
(2) For a review on Substance P, see: Datar, P.; Srivastava, S.; Coutinho,
E.; Govil, G. Curr. Top. Med. Chem. 2004, 4, 75-103.
(3) For a racemic route to 1, see: Tomooka, K.; Nakazaki, A.; Nakai,
T. J. Am. Chem. Soc. 2000, 122, 408-409.
(4) Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg. Med.
Chem. Lett. 1994, 4, 2545-2550.
(5) Huang, P.-Q.; Liu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org. Lett. 2003,
5, 1927-1929.
(6) Bhaskar, G.; Rao, B. V. Tetrahedron Lett. 2003, 44, 915-917.
(7) (a) Bodas, M. S.; Upadhyay, P. K.; Kumar, P. Tetrahedron Lett. 2004,
45, 987-988. (b) Lee, J.; Hoang, T.; Lewis, S.; Weissman, S. A.; Askin,
D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 2001, 42, 6223-6225.
(c) Stadler, H.; Bo¨s, M. Heterocycles 1999, 51, 1067-1071. (d) Calvez,
O.; Langlois, N. Tetrahedron Lett. 1999, 40, 7099-7100.
(8) For a racemic route to 2, see: Desai, M. C.; Thadeio, P. F.; Lefkowitz,
S. L. Tetrahedron Lett. 1993, 34, 5831-5834.
Figure 1. Structure of Substance P antagonists and precursors.
(9) Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K. P.; Snider,
R. M. J. Med. Chem. 1992, 35, 4911-4913.
resolution techniques4 or lengthy syntheses from a variety
of chiral building blocks such as L-glutamic acid5 and
L-phenylglycine.6 Efficient syntheses of piperidines 3 and
4, valuable precursors for the synthesis of 1, have also been
(10) Chandrasekhar, S.; Mohanty, P. K. Tetrahedron Lett. 1999, 40,
5071-5072.
(11) Yamazaki, N.; Atobe, M.; Kibayashi, C. Tetrahedron Lett. 2002,
43, 7979-7982.
10.1021/ol048624n CCC: $27.50
© 2004 American Chemical Society
Published on Web 08/28/2004

or L-glutamic acid.2 A catalytic asymmetric approach to 2,
based on a nitro-Mannich reaction, has also been recently
reported.12
zamide and substituted pyridines 10a-d (3 equiv) proceeded
well to give predominantly, and in some cases exclusively,
2,3-disubstituted 1,2-dihydropyridines 11 (Table 1). Although
Our research group has been involved in the development
of new methodologies for the preparation of useful enan-
tiopure piperidine-derived building blocks from cheap chemi-
cal commodities such as pyridine. A strategy that has been
frequently used to prepare piperidine alkaloids involves the
addition of a nucleophile to an N-alkyl- or an N-acylpyri-
dinium salt such as 5 or 6, as illustrated in Figure 2. We
Table 1. Nucleophilic Addition to 3-Substituted Pyridinium
Salts Derived from 9 and 10 and Oxidation to 2,3-Disubstituted
Pyridines
Figure 2. Pyridinium salts as precursors to dihydropyridines.
recently reported that the addition of nucleophiles to 7 (R1
) H), a new class of pyridinium salts readily accessible from
secondary amides,13 proceeds with very high diastereo- and
regiocontrol to produce dihydropyridines 8 (R1 ) H).14,15
To extend the scope of our methodology to access more
substituted piperidines from cheap precursors, we investi-
gated the addition of nucleophiles to 3-substituted pyridinium
salts (7, R1 * H). Obviously, the addition can occur either
at the C-2, C-4, or C-6 position to give potentially three
regioisomeric dihydropyridines.16 On the basis of both the
strong directing effect of the imidate nitrogen and stereo-
electronic effects,16 we anticipated that high regiocontrol
would be obtained and an expedient route to 2,3-disubstituted
piperidines could be developed.17
a Ratio was determined by 1H NMR. b Isolated yield of 11. c Combined
yield of both isomers is 89%. d Combined yield of both isomers is 83%.
the addition reactions of methylmagnesium bromide provided
ratios of products comparable to those observed with N-acyl-
pyridinium salts,17d the addition of phenylmagnesium bro-
mide proceeded in much higher regioselectivity.18 The minor
2,5-isomer (12) occurred from nucleophilic addition at C-6,
and we did not observe any product arising from attack at
C-4.
To clearly establish the regiochemical outcome of these
reactions, the major dihydropyridine adduct was oxidized
to yield the corresponding 2,3-disubstituted pyridine. Much
to our surprise, the oxidation turned out to be problematic.
After extensive experimentation using a variety of oxidants,
we found that the use of a substoichiometric amount of
manganese triacetate and periodic acid as the terminal oxidant
in acetic acid afforded pyridines 13 in good to excellent
yields (Table 1).
With these encouraging results in hand, the diastereose-
lective version of the reaction was investigated in the con-
text of the synthesis of the antipode of L-733,060 (1) and
CP-99,994 (2) (Scheme 1). Deprotonation of 3-hydroxypy-
ridine (14) with NaH in DMF, followed by addition of 3,5-
bis(trifluoromethyl)benzyl bromide (15), afforded pyridine
16 in 70% yield.
Activation of amide 1719 in the presence of pyridine 16
(3 equiv) followed by the addition of phenylmagnesium
bromide led to 1,2-dihydropyridine 18 in 84% yield and as
a single regio- and diastereomer. The amount of pyridine
The addition reactions of methyl- and phenylmagnesium
bromide to the pyridinium salts derived from N-methylben-
(12) Tsuritani, N.; Yamada, K.-I.; Yoshikawa, N.; Shibasaki, M. Chem.
Lett. 2002, 276-277.
(13) Charette, A. B.; Grenon, M. Can. J. Chem. 2001, 79, 1694-1703.
(14) Charette, A. B.; Grenon, M.; Lemire, A.; Pourashraf, M.; Martel,
J. J. Am. Chem. Soc. 2001, 123, 11829-11830.
(15) For another example of a pyridinium salt giving 1,2,5,6-tetrahy-
dropyridines in a highly regioselective process, see: Legault, C.; Charette,
A. B. J. Am. Chem. Soc. 2003, 125, 6360-6361.
(16) For a discussion of the factors responsible for the preferential
formation of the 1,2-adduct over the 1,6-adduct, see: Sundberg, R. J.;
Hamilton, G.; Trindle, C. J. Org. Chem. 1986, 51, 3672-3679.
(17) For examples of addition of organomagnesium reagents to N-acyl
3-substituted pyridinium salts, see: (a) Chia, W.-L.; Shen, S.-W.; Lin, H.-
C. Tetrahedron Lett. 2001, 42, 2177-2179. (b) Comins, D. L.; Myoung,
Y. C. J. Org. Chem. 1990, 55, 292-298. (c) Comins, D. L.; Mantlo, N. B.
Tetrahedron Lett. 1987, 28, 759-762. (d) Krow, G. R.; Cannon, K. C.;
Carey, J. T. J. Heterocycl. Chem. 1985, 22, 131-135. (e) Comins, D. L.;
Mantlo, N. B. J. Heterocycl. Chem. 1983, 20, 1239-1243. (f) Comins, D.
L.; Abdullah, A. H. J. Org. Chem. 1982, 47, 4315-4319. (g) Lyle, R. E.;
Marshall, J. L.; Comins, D. L. Tetrahedron Lett. 1977, 18, 1015-1018.
For examples of addition of organotin reagents leading to 1,2-dihydropy-
ridines, see: (h) Itoh, T.; Hasegawa, H.; Nagata, K.; Okada, M.; Ohsawa,
A. Tetrahedron 1994, 50, 13089-13100. (i) Yamaguchi, R.; Moriyasu, M.;
Yoshioka, M.; Kawanisi, M. J. Org. Chem. 1988, 53, 3507-3512. (j)
Yamaguchi, R.; Hata, E.-I.; Utimoto, K. Tetrahedron Lett. 1988, 29, 1785-
1788. (k) Yamaguchi, R.; Moriyasu, M.; Yoshioka, M.; Kawanisi, M. J.
Org. Chem. 1985, 50, 287-288.
(18) For example, the addition of PhMgCl to N-acyl-3-picolinium salt
(analogue to entry 2) gives a 16:66:15 mixture of C2:C6:C4 nucleophilic
addition regioisomers (ref 17f).
3518
Org. Lett., Vol. 6, No. 20, 2004

Scheme 1. Synthesis of (-)-L-733,061
Scheme 2. Preparation and Nucleophilic Addition to 21
This unfortunate situation prompted us to devise a chiral
amide with a latent hydroxy group on the aryl substituent to
facilitate the hydrolysis of the amidine (Scheme 3).
Scheme 3. Hydroxy-Assisted Cleavage of the Auxiliary
16 could be reduced to 1.5 equiv if 2,6-di-t-butyl-4-meth-
ylpyridine was added as the proton scavenger. The yield
dropped slightly to 70% using this procedure.20 The diaste-
reoselective hydrogenation of 18 from the opposite face of
the phenyl ring at C-2 afforded piperidine 19 as a single
diastereomer (>95:5) in 52% yield. Finally, alane reduction
of the amidine yielded (-)-L-733,061 in 75% yield.
To further illustrate the potential of this methodology, we
elected to prepare the antipode of CP-99,994 (2) by adding
the appropriate organometallic reagent to the pyridinium salt
derived from amide 17 and pyridine 21. The presence of a
much more sterically hindered group at C-3 may lower the
regioselectivity of addition. The synthesis of pyridine 21 was
straightforward, starting from 3-aminopyridine (20) (Scheme
2). Deprotonation of 20 with NaHMDS (2 equiv),21 followed
by addition of di-tert-butyl-dicarbonate, afforded a 78% yield
of the mono-Boc-protected pyridine. Alkylation with o-meth-
oxybenzyl bromide yielded pyridine 21 in 78% yield. As
anticipated, the addition of various organometallic reagents
to the pyridinium salt derived from amide 17 and pyridine
21 proved to be somewhat troublesome. Addition of PhLi
and PhMgBr produced mixtures of dihydropyridines. How-
ever, we were pleased to see that the addition of Ph2Zn pro-
ceeded extremely well to give 1,2-dihydropyridine 22 in 77%
yield. The hydrogenation of 22 proceeded uneventfully; how-
ever, the cleavage of the chiral auxiliary proved to be
problematic.22
TBDMS-protected amides 28 and 29 were easily prepared
according to the sequence outlined in Scheme 4. Opening
Scheme 4. Synthesis of Novel Amides
of phthalide (23) with 2-methoxyethylamine (24) using
Weinreb’s procedure afforded hydroxyamide 26.23 A slightly
lower yield was obtained when O-methyl valinol (25) was
used (68%), probably due to steric factors. Protection of the
benzylic alcohol with TBDMSCl proceeded efficiently with
both substrates to give amides 28 and 29 in excellent yields.
(19) For the preparation of amide 17 and its use in the stereoselective
synthesis of 1,2-dihydropyridines, see ref 14.
(20) See Supporting Information for details.
(22) Demethylation of the aromatic methyl ether occurred during the
amidine reduction step.
(23) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 18,
4171-4172.
(21) Use of 1.1 equiv of NaHMDS resulted in the exclusive formation
of the bis-Boc-protected pyridine in 42% yield (50% max yield); see
Supporting Information.
Org. Lett., Vol. 6, No. 20, 2004
3519

The addition of Ph2Zn to the pyridinium salts derived from
amides 28 or 29 and pyridine 21 produced the expected 1,2-
dihydropyridines in 54 and 53% yields, respectively (Scheme
5). Hydrogenation of dienes 30 and 31 with PtO2, followed
by cleavage of the auxiliary under mildacidic conditionsand
removal of the N-Boc protecting group with TFA, afforded
(()- and (-)-CP-99,994 (2), respectively.
In conclusion, we have shown that the addition of or-
ganometallic reagents to pyridinium salts substituted with
an electron-donating group at the C-3 position gives pre-
dominantly the 1,2-dihydropyridine adducts. These can be
readily oxidized to 2,3-disubstituted pyridines with manga-
nese triacetate and periodic acid. Moreover, the resulting 1,2-
dihydropyridines can be further used for the synthesis of 2,3-
disubstituted piperidines. This was demonstrated by the
concise syntheses of (-)-L-733,061 and (-)-CP-99,994.
Further applications of this methodology will be reported in
due course.
Scheme 5. Synthesis of CP-99,994
Acknowledgment. This work was supported by the
National Science and Engineering Research of Canada
(NSERC), Merck Frosst Canada & Co., Boehringer Ingel-
heim (Canada), Ltd., and the Universite´ de Montre´al. A.L.
thanks NSERC (Canada) and FQRNT (Que´bec) for a
postgraduate fellowship. We also thank Prof. William D.
Lubell for helpful discussions.
Supporting Information Available: General information,
experimental procedures, and characterization data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL048624N
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Org. Lett., Vol. 6, No. 20, 2004