Synthesis of (±)-4-substituted pipecolinic acids from 4-alkylpyridines

Article abstract of DOI:10.1055/s-1998-1954

Starting from various 4-alkylpyridines, the phenyldimethylsilyl group was introduced using their 1-acylpyridium salts and its oxidative unmasking afforded the corresponding pipecolinic acids.

Full text of DOI:10.1055/s-1998-1954

December 1998
SYNLETT
1337
Synthesis of (±)-4-Substituted Pipecolinic Acids from 4-Alkylpyridines
a
b
b
Abdesslame Nazih* , Marie-Reine Schneider and André Mann*
a Université Louis Pasteur-CNRS, Faculté de chimie, BP 296, F-67008 Strasbourg, France
b. Laboratoire de Pharmacochimie de la Communication Cellulaire - ERS 655 Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch Cedex,
France.
Fax (33) 3 88 67 68 86 ; E-mail André. mann@pharma. u-strasbg.fr
Received 6 Ocotober 1998
13
Abstract: Starting from various 4-alkylpyridines, the phenyldimethyl-
silyl group was introduced using their 1-acylpyridium salts and its
oxidative unmasking afforded the corresponding pipecolinic acids.
chromatography. Among the experimentated oxidative methods to
14
transform the phenyldimethylsilyl into the hydroxymethylene group,
we found that the mixture : (CF CO ) Hg (1.2 eq), AcOOH (20 eq),
3
2 2
AcOH was the best choice and represented an improvement of the
already existing methods. Indeed, the reaction was completed within 1 h
at room temperature and the N-protected piperidinols 3b-cis and 3c
Pipecolinic acid and derivatives have been widely used as cyclic
homologues of proline in numerous peptidomimetics. In this context
13
1
were obtained in 71% and 76% yield, respectively. The oxidation of 3b-
several syntheses of 4-substituted pipecolinic acids have been
15
cis and 3c under Sharpless conditions afforded the N-protected
2-11
performed.
In this letter, we report a new approach to pipecolinic
pipecolinic acids 4b (69%) and 4c (81%) which could be readily
deprotected with HCl 6 N to (±)-(cis)-4-methyl- and (±)-(cis)-4-
acids starting from commercially available 4-alkylpyridines.
5,13
13
phenylpipecolinic acid respectively 5b
and 5c in quantitive yields.
The presence of the phenyl rest in 4c gives us the opportunity to extend
the scope of our procedure in preparing the (±)-cis-2,4-piperidinedi-
16
carboxylic acid, a selective NMDA agonist, in the following way.
Compound 4c was traited with an ethereal solution of diazomethane at
15
0°C and submitted to the Sharpless conditions, adapted for oxidative
cleavage of an aromatic ring, to yield 6c in moderate yields. Finally the
rigid glutamic analogue 7c was obtained as hydrochloride under
hydrolytic conditions (Scheme 2).
In summary, we have developed a general method for the synthesis of
(±)-(cis)-4-substituted pipecolinic acids starting from 4-substituted
pyridines. This method takes advantage of the nucleophilic addition of
[(phenyldimethylsilyl)methyl]magnesium chloride to pyridinium salts
and of oxidative removal of the phenyldimethylsilyl moiety. We are
currently exploring the scope of this method for the synthesis of other
heterocyclic compounds.
As outlined in Scheme 1, our approach involved the nucleophilic
addition of [(phenyldimethylsilyl)methyl]magnesium chloride to the
1-acyl-4-substituted pyridinium salts and subsequent reduction of the
dihydropyridines (1a-c) which afforded the piperidines (2a-c). The
interconversion of the phenyldimethylsilyl group into the primary
alcohol yielded the piperidinols (3b-c) and subsequent oxidation, the
N-protected pipecolinic acids (4b-c). A final hydrolytic cleavage
afforded the pipecolinic acids (5b-c). This sequence needs some
comments.
Acknowledgment. We thank Dr. D. Heissler for making available
laboratory facilities at the Unité Mixte de Recherche 7509.
References and Notes
(1) Giannis, A.; Kolter, T. Angew. Chem. Int. Ed. Engl. 1993, 32,
The addition of Ph(Me) SiCH MgCl to 4-alkylpyridines, without
1244-1267.
2
2
precedent in the literature, was effective using the in situ generation of
the corresponding N-acyliminium ion. After acidic hydrolysis, and
(2) Bannett, F.; Patel, N. M.; Girijavallabhan, V. M.; Ganguly, A. K.
12
Synlett 1993, 703-704.
chromatographic purification, 1,2-dihydropyridines (1a-c) were
(3) Genin, M. J.; Gleason, W. B.; Johnson, R. L. J. Org. Chem. 1993,
58,860-866.
13
obtained in good yields.
The hydrogenation of the 1,2-
dihydropyridines afforded the piperidines (2a-c) : compounds 2a and 2c
were isolated as the cis diastereomers. Whereas compound 2b was
obtained as a diastereomeric mixture (cis / trans : 7 / 3), as evidenced by
(4) Smith III, A. B.; Condon, S. M.; McCauley, J. A. Acc. Chem. Res.
1998, 31, 35-38.
1
the integration of the corresponding methyl peaks in the H-NMR
(5) Shuman, R.T.; Ornstein, P. L.; Paschal, J. W.; Gesellchen, P. D. J.
Org. Chem. 1990, 55, 738-741.
spectra; the cis isomer (2b-cis) could be obtained in pure form after

1338
LETTERS
SYNLETT
(6) Bailey, C. P. D.; Brown, G. R.; Korber, F.; Reed, A.; Wilson, R. D.
room temperature, ether (50 ml) was added and the ether solution
Tetrahedron Asymmetry 1991, 2, 1263-1282.
washed with Na S O (20%), water, NaHCO , dried over Na SO
2 2 3 3 2 4
and concentrated in vacuo. The residue was purified by
chromatography on silica gel (25% AcOEt in Hexane) to afford
89 mg (71%) of piperidinol 3b-cis as a colorless oil. H NMR
(7) Agami, C.; Couty, F.; Poursoulis, M.; Vaissermann, J. Tetrahedron
1992, 48, 431-442.
1
(8) Ornstein, P. L.; Melikian, A.; Martinelli, M. J. Tetrahedron Lett.
1994, 35, 5759-5762.
(200 MHz, CDCl ) : δ 4.12 (q, J = 7.1 Hz, 2 H), 3.86 - 3.74 (m, 3
3
H), 3.45 (m, 3 H), 3.08 (m, 1 H), 1.76 - 1.55 (m, 3 H), 1.26 (t, 3 H,
J = 7.1 Hz), 1.35 - 1.0 (m, 2 H), 0.95 (d, 3 H, J = 6.2 Hz).
(9) Jackson, R. F. W.; Turner, D.; Block, M. H. Synlett 1997, 7 789-
790.
4b-cis : RuCl ,3H O (4 mg) was added to a solution of piperidinol
3
2
(10) Agami, C.; Bihan, D.; Morgentin, R.; Puchotkadouri, C. Synlett
1997, 7, 799-800.
3b-cis (80 mg, 0.40 mmol) and NaIO (350 mg, 1.64 mmol) in
4
H O (2.4 ml), CCl (1.6 ml) and CH CN (1.6 ml). After stirring at
2
4
3
room temperature for 4 h, ether (40 ml) and H O (10 ml) was
(11) Makra, G. M.; Marshall, G. R. Tetrahedron Lett. 1997, 38, 5069-
2
added, the organic layer were dried over Na SO and concentrated
5072.
2
4
in vacuo. The residue was purified by chromatography on silica
gel (10% MeOH in CH Cl ) to afford 59 mg (69%) of compound
(12) Comins, D. L.; Mantlo, N. B. J. Org. Chem. 1985, 50, 4410-4411.
2
2
(13) Experimental procedures and physical data:
4b-cis as a colorless oil.
1b [(Phenyldimethylsilyl)methyl-]magnesium chloride, prepared
from chloromethyl-dimethylphenylsilane (3 ml, 16.63 mmol) and
magnesium (424 mg, 17.46 mmol) in ether (17 ml), was added to
a solution of 4-picoline (1.47 ml, 15.12 mmol) in THF (15 ml) at
-20°C. Then a solution of ethyl choloroformate in THF (2 ml) was
added and the mixture was left to reach 0°C. After quenching with
5% HCl, the mixture was extracted with ether (2x30 ml), dried
1
H NMR (200 MHz, CDCl ) : δ 9.91 (brs, 1H), 4.48 (t, 1 H, 5.9
3
Hz), 4.1 (q, 2 H, J = 7.1 Hz), 3.8 - 3.55 (m, 1 H), 3.5 - 3.25 (m, 1
H), 2.15 - 1.6 (m, 4 H), 1.45 - 1.15 (m, 1 H), 1.24 (t, 3 H, J = 7.1
13
Hz), 1.02 (d, 3 H, J = 6.3 Hz). C NMR (50 MHz, CDCl ) : δ
3
178, 157, 62, 54, 39, 33, 31, 26, 19, 15.
5b-cis : A solution of 4b-cis (44 mg, 0.2 mmol) in 6 N HCl (2 ml)
was refluxed for 4h. The mixture was then cooled and
concentrated in vacuo. The resulting solid product was collected
and washed with ether to afford 36 mg (100%) of 5b-cis without
over Na SO and concentrated in vacuo. The residue was purified
2
4
by chromatography on silica gel (5% ether in hexane) to afford
4.31 g (90%) of dihydropyridine 1b as a colorless oil.
further purification.
1
H NMR [200 MHz, CDCl ] : δ 7.55 - 7.35 (m, 5 H), 6.68 and
1
3
F = 257 - 259°C. H NMR (200 MHz, D O) : δ 3.71 (dd, J = 12.7
2
6.52 (2d, J = 7.5 Hz and 7.7 Hz, 1H), 5.20 - 5.00 (m, 2 H), 4.90 -
4.70 (m, 1 H), 4.16 (m, 2 H), 1.63 (s, 3H), 1.50 - 0.85 (m, 2 H),
1.27 (t, J = 7.1 Hz, 3 H), 0.34 and 0.32 (2 s, 6 H).
Hz and 3.2 Hz, 1 H), 3.32 (dq, J = 12.8 Hz and 2.3 Hz, 1 H), 2.87
(td, J = 13.0 Hz and 2.8 Hz, 1 H), 2.15 (dq, J = 13.8 Hz and 2.4
Hz, 1H), 1.85 - 1.5 (m, 2 H), 1.3 - 1.0 (m, 2 H), 0.85 (d, J = 6.4 Hz,
2b-cis : A solution of dihydropyridine 1b (3 g, 9.51 mmol) in
3 H).
ethyl acetate (95 ml), was hydrogenated in the presence of PtO .
1
2
Compound 5c : F = 252-254°C. H NMR (200 MHz, D O) δ 7.28-
2
After stirring for 6 h, the mixture was filtred over celite and
concentrated in vacuo. The residue was purified by
7.10 (m, 5 H), 3.85 (dd, J = 12.7 Hz and 3.2 Hz, 1H), 3.43 (dq, J =
13.0 Hz and 2.3 Hz, 1H), 3.01 (td, 13.0 Hz and 3.2Hz, 1 H), 2.85
chromatography on silica gel (80% CH Cl in hexane) to afford
2
2
(tt, J = 12.3 Hz, 3.7 Hz, 1 H), 2.32 (dq, 14.1 Hz and 1.9 Hz) 1H),
2.83 g (93%) of 2b as a mixture of diastereomers (cis / trans :
7/3). A second purification by chromatography yielded 1.55 g
13
1.92 (m, 1 H), 1.81-1.58 (m, 2 H). C NMR (50 MHz, D O) δ
2
171, 142.7, 128.1, 126.3, 125.9, 56.9, 42.9, 38.6, 32.0, 27.7. MS
(53%) of pure 2b-cis.
+
(FAB) (C
H
NO ) : 206 (MH ).
12 15
2
1
H NMR (200 MHz, CDCl ) : δ 7.55 - 7.33 (m, 5 H), 5.50 (m, 0.3
1
3
7c-cis : H NMR (200 MHz, D O) : δ 3.75 (dd, J = 3.2 Hz and
2
H), 4.07 (q, J = 7.1 Hz, 2 H), 4.13 -3.93 (m, 1 H), 3.69 (ddd, J =
2.8 Hz, 7 Hz, and 13.6 Hz, 0.7 H), 3.04 (ddd, J = 6 Hz, 10.1 Hz
and 16.2 Hz, 0.7 H), 2.82 (dt, J = 6.3 Hz, 0.3 H), 1.9 - 1.48 (m, 2
H), 1.45 - 1.00 (m, 5 H), 1.22 and 1.21 (2 t, J = 7.1 Hz, 3 H), 0.91
and 0.79 (2 d, J = 6.7 Hz and 6.3 Hz, 3 H), 0.32, 0.31 and 0.29 (3
12.7 Hz, 1 H), 3.36 (dq, J = 2.3 Hz and 13.2 Hz, 1 H), 2.86 (dt, J =
3.2 Hz and 13.2 Hz, 1 H), 2.58 (td, J = 3.5 Hz and 12.3 Hz, 1H),
2.40 (m, 1 H), 2.02 (m, 1 H), 1.70 - 1.50 (m, 2 H).
(14) Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97, 2063-
2192.
s, 6 H). Anal. Calcd for C
H NO Si : C, 67.66 %; H, 9.15 %; N,
18 29 2
(15) Carlsen, P. H. J.; Katsuki ,T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981,46, 3936-3938.
4.38 %. Found : C, 67.55%; H, 9.33%; N, 4.35%.
3b-cis : Mercuric trifluoroacetate (294 mg, 0.69 mmol) was added
to a solution of 2b-cis (200 mg, 0.63 mmol) in peracetic acid (2.65
ml, 12.6 mmol) and acetic acid (2.6 ml). After 1 h of stirring at
(16) Davies; J.; Evans, R. H.; Francis, A. I.; Jonas, A. W.; Smith, D. A.
S.; Watkins, J. C. Neurosci Res. 1982, 7, 1119-1124.