An efficient synthesis of enantiomerically pure (R)-pipecolic acid, (S)-proline, and their N-alkylated derivatives

Article abstract of DOI:10.1021/jo062382i

Enantiomerically pure (R)-(+)-pipecolic acid was synthesized in four steps and 42% overall yield starting from dihydropyran and (R)-α- methylbenzylamine. A general short strategy is also described for preparing (S)-proline (47.5% overall yield) and derivatives.

Full text of DOI:10.1021/jo062382i

An Efficient Synthesis of Enantiomerically Pure (R)-Pipecolic Acid,
(S)-Proline, and Their N-Alkylated Derivatives
Antoine Fadel* and Nabil Lahrache
Laboratoire de Synthe`se Organique et Me´thodologie, CNRS, UMR 8182, Institut de Chimie Mole´culaire et
des Mate´riaux d’Orsay, Baˆt. 420, UniV Paris-Sud, 91405 Orsay, France
antfadel@icmo.u-psud.fr
ReceiVed NoVember 20, 2006
Enantiomerically pure (R)-(+)-pipecolic acid was synthesized in four steps and 42% overall yield starting
from dihydropyran and (R)-R-methylbenzylamine. A general short strategy is also described for preparing
(S)-proline (47.5% overall yield) and derivatives.
Introduction
synthetic drugs.6 The importance of (S)-pipecolic acid, which
occurred in nature as a nonproteinogenic amino acid, has
fostered the development of many synthetic approaches involv-
ing enzymatic reactions,7 alkylation of chiral glycine enolates,8
derivatization of natural amino acids,9 enantioselective reac-
tions,10 resolution,11 and asymmetric Strecker reaction.12 Nev-
ertheless, many synthetic precursors had been very limited by
Cyclic R-amino acids are expected to play key roles, once
incorporated into proteins, in improving their biological activity
and functions.1 In peptides, these cyclic amino acids confer
rigidity on the protein, which influences cell recognition
events.2,3 In this context, the asymmetric synthesis of proline
and pipecolic acid (homoproline) is of importance because they
are key constituents of bioactive molecules and are useful
building blocks for asymmetric synthesis4,5 and used in many
(7) (a) Ng-Youn-Chen, M. C.; Serreqi, A. N.; Huang, Q.; Kazlanskas,
R. J. J. Org. Chem. 1994, 59, 2075-2081. (b) Nazabadioko, S.; Perez,
R. J.; Brieva, R.; Gotor, V. Tetrahedron: Asymmetry 1998, 9, 1597-1604.
(c) Sa`nchez-Sancho, F.; Herrado`n, B. Tetrahedron: Asymmetry 1998, 9,
1951-1965 and references cited therein. (d) Liljeblad, A.; Lindborg, J.;
Kanerva, A.; Katajisto, J.; Kanerva, L. T. Tetrahedron Lett. 2002, 43, 2471-
2474. (e) Eichhorn, E.; Roduit, J. P.; Shaw, N.; Heinzmann, K.; Kiener, A.
Tetrahedron: Asymmetry 1997, 8, 2533-2536. (f) Petersen, M.; Sauter,
M. Chimia 1999, 53, 608-612. (g) Wisdom, R. A.; Lee, C. S.; Ricaud, P.
M. Chiroscience, Ltd, UK, Patent, PCT int. Appl. WO 9510604 A1
19950420; Chem. Abstr. 1995, 123, 110268. (h) Watanabe, L.-A.; Haranaka,
S.; Jose, B.; Yoshida, M.; Kato, T.; Moriguchi, M.; Soda, K.; Nishino, N.
Tetrahedron: Asymmetry 2005, 16, 903-908. (i) Yasuda, M.; Ueda, M.;
Muramatsu, H.; Mihara, H.; Esaki, N. Tetrahedron: Asymmetry 2006, 17,
1775-1779.
(8) (a) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39,
5347-5350. (b) Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W.
J. Am. Chem. Soc. 1997, 119, 656-673. (c) Berrien, J. F.; Royer, J.; Husson,
H.-P. J. Org. Chem. 1994, 59, 3769-3774. (d) Agami, C.; Kadouri-Puchot,
C.; Kizirian, J.-C. Synth. Commun. 2000, 30, 2565-2572. (e) Seebach, D.;
Dziadulewicz, E.; Behrendt, L.; Cantoreggi, S.; Fitzi, R. Liebigs Ann. Chem.
1989, 1215-1232. (f) Scho¨llkopf, U.; Hinrichs, R.; Lonsky, R. Angew.
Chem., Int. Ed. Engl. 1987, 26, 143-145. (g) Hou, D.-R.; Hung, S.-Y.;
Hu, C.-C. Tetrahedron: Asymmetry 2005, 16, 3858-3864.
(1) (a) For a review, see: Hanessian, S.; Mc Naughton-Smith, G.;
Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789-12854. (b)
Barrett, G. C., Ed. Chemistry and Biochemistry of the Amino Acids;
Chapman and Hall: London, 1985.
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J. Am. Chem. Soc. 1995, 117, 3808-3819. (b) Hayashi, T.; Asai, T.; Ogoshi,
H. Tetrahedron Lett. 1997, 38, 3039-3042.
(3) For example, see: Smith, A. B., III; Benowitz, A. B.; Sprengeler,
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Soc. 1999, 121, 9286-9298.
(4) For reviews on the applications of amino acids to asymmetric
synthesis, see: (a) Jurczak, J.; Golebiowski, A. Chem. ReV. 1989, 89, 149-
164. (b) Sardina, F. J.; Rapoport, H. Chem. ReV. 1996, 96, 1825-1872. (c)
Remuzon, P. Tetrahedron 1996, 52, 13803-13835. (d) Bailey, P. D.;
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2112.
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M.; Taga, T. J. Am. Chem. Soc. 1987, 109, 5031-5033. (d) Vezina, C.;
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35-46 and references cited therein.
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Org. Chem. 1990, 55, 5551-5553. (c) Pauly, R.; Sasaki, N. A.; Potier, P.
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Katho`, A. Synthesis 1982, 163. (e) Aketa, K.; Terashima, S.; Yamada, S.
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10.1021/jo062382i CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/26/2007
1780
J. Org. Chem. 2007, 72, 1780-1784

Short Asymmetric Synthesis of Cyclic Amino Acids
TABLE 1. Synthesis of Amino Nitriles 5 and 6 from Cyclic Enol
Ethers 3 and 4
SCHEME 1
5-6 (yield%)a
entry
enol
amine 9
(S,S)
(R,R)
deb (%)
1
2
3
3
4
3
R
R
S
5 (86)
6 (86)
>98
>96
>98
5 (86)
a Isolated yields of major products. b Diastereoisomeric excesses were
1
determined by H NMR spectra from (2R,1′R)/(2S,1′R) crude mixture.
SCHEME 2
a lack of simple synthetic methods for their preparation in high
enantiomeric purity and on a multigram scale.
We decided in connection with our ongoing program on the
asymmetric Strecker reaction13 to study a new diastereoselective
synthesis of proline 1 and pipecolic acid 2 from inexpensive
and commercially available dihydrofuran 3 and dihydropyran
4, respectively.
SCHEME 3
This methodology is based on the combination of the known
Strecker reaction already developed to prepare racemic amino
acid14,15 and subsequent cyclization. We anticipated that this
method should occur: (i) with an efficient stereocontrol of
asymmetric Strecker reaction in the presence of chiral amine
and (ii) with good cyclization without racemization of the newly
formed chiral center (Scheme 1).
Results and Discussion
The amino nitriles (R,R)-5 and -6 and (S,S)-5 were readily
prepared by a one-pot ring-opening reaction at room temperature
of the corresponding 2,3-dihydrofuran 3 and 3,4-dihydro-2H-
pyran 4, using a modified literature procedure,14d in the presence
of optically active methylbenzylamine (R)- or (S)-9, respectively,
and sodium cyanide in HCl aqueous solution (Scheme 2 and
Table 1). Thus, these amino nitriles were generated, within 2-4
days,16 with high yields and excellent diastereoselectivity in 98
and 96% de for 5 and 6, respectively, and can be improved to
>99% de after a simple crystallization. These diastereoisomeric
liquid residue that remained after crystallizations of the crude
amino nitriles 5 and 6 (see the Supporting Information).
In all cases, the diastereoselectivity achieved by this method
can be explained on the basis of the aza analogue of the Anh-
Eisenstein hypothesis.17 According to this hypothesis, nucleo-
philic attack should take place antiperiplanar to the R-phenyl
group with an unlike approach, on the more stable iminium
intermediate A, giving exclusively the major amino nitriles
(2R,1′R)-5-6 when using amine (R)-9 and (2S,1′S)-5 when
starting from amine (S)-9. Likewise, the reaction is under
thermodynamic control (2-4 days reaction);16 consequently, the
resulting major amino nitriles should be the thermodynamic
compounds 5-6 (Scheme 3). The major isomers 5 and 6 were
assumed to have the (2R,1′R)- or (2S,1′S) configuration in
accordance with the stereochemistry of the resulting (R)- or (S)-
proline 1 and (R)- or (S)-pipecolic acid 2 described below.
1
excesses were determined by H and 13C NMR of the mother
(10) (a) Fernandez-Garcia, C.; Mc Kervey, M. A. Tetrahedron: Asym-
metry 1995, 6, 2905-2906. (b) Foti, C. J.; Comins, D. L. J. Org. Chem.
1995, 60, 2656-2657. (c) Ginesta, X.; Perica`s, M. A.; Riera, A. Tetrahedron
Lett. 2002, 43, 779-782. (d) Wilkinson, T. J.; Stehle, N. W.; Beak, P. Org.
Lett. 2000, 2, 155-158. (e) Bajgrowicz, J.; El Achquar, A.; Roumestant,
M.-L.; Pigie`re, C.; Viallefont, P. Heterocycles 1986, 24, 2165-2167.
(11) (a) Hockless, D. C. R.; Mayadunne, R. C.; Wild, S. B. Tetrahe-
dron: Asymmetry 1995, 6, 3031-3037. (b) Shiraiwa, T.; Shinjo, K.;
Kurokawa, H. Bull. Chem. Soc. Jpn. 1991, 64, 3251-3255. (c) Beck, W.;
Heinzmann, K.; Peterson, M.; Wo Patent, WO 0012745 (Lonza, AG, CH);
Chem. Abstr. 2000, 132, 207015.
(12) Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Yobayashi, S. J. Am.
Chem. Soc. 2000, 122, 762-766.
Under basic conditions, the cyclizations of (S,S)-5 and (R,R)-6
were achieved by using MsCl/NEt3 in the presence of catalytic
DMAP in CH2Cl2 to furnish cyclic nitriles in good yields as
inseparable diastereomeric mixtures of (S,S)-12/(2R,1′S)-13 and
(R,R)-14/(2S,1′R)-15, respectively. Neither changing reaction
solvent (Et2O, toluene, or hexane) nor using other conditions
(PPh3/DEAD) improved the diastereomeric ratio. Only a 70:30
(13) (a) Fadel, A. Synlett 1993, 503-505. (b) Fadel, A.; Khesrani, A.
Tetrahedron: Asymmetry 1998, 9, 305-320. (c) Truong, M.; Lecornue´,
F.; Fadel, A. Tetrahedron: Asymmetry 2003, 14, 1063-1072. (d) Hazelard,
D.; Fadel, A.; Girard, C. Tetrahedron: Asymmetry 2006, 17, 1457-1464.
(14) (a) Gaudry, R. Can. J. Chem. 1951, 29, 544-551. (b) Gaudry, R.
Can. J. Res. Sect. B 1948, 26, 387-392. (c) Maurer, P. J.; Miller, M. J. J.
Am. Chem. Soc. 1982, 104, 3096-3101. (d) Gaudry’s reaction14a of
dihydrofuran has been performed with sodium cyanide in 0.2 N HCl aqueous
solution in the presence of NH4Cl, followed by adding (NH4)2CO3 and then
heating at 50-60 °C for 3 h to afford 5-γ-hydroxypropylhydantoin.
(15) For a ring-opening reaction of semicyclic N,O-acetals, see: Sugiura,
M.; Kobayashi, S. Org. Lett. 2001, 3, 477-480.
(17) (a) Anh, N. T.; Eisenstein, O. NouV. J. Chem. 1977, 1, 61-70. (b)
Broeker, J. L.; Hoffmann, R. W.; Houk, K. N. J. Am. Chem. Soc. 1991,
113, 5006-5017 and references cited therein.
(16) Strecker reaction was known to perform slowly and gave in our
case the thermodynamic amino nitriles in only 50% yield after 1 day.
J. Org. Chem, Vol. 72, No. 5, 2007 1781

Fadel and Lahrache
SCHEME 4
SCHEME 6
SCHEME 7
SCHEME 5
racemization of the C-2 centers. Thus, amide (2S,1′S)-7 was
hydrogenolyzed under mild conditions (20% Pd(OH)2/C, and
1 atom H2, in EtOH), affording the (S)-prolinamide 19 ([R]D
-105 (c 2.00, EtOH)) in good yield, in agreement with the
literature ([R]D -106 (c 2.00, EtOH)).19 Consequently, its
enantiomeric excess was >98%. Subsequent treatment of the
(S)-prolinamide 19 with 6 M HCl at reflux, followed by the
addition of propylene oxide in ethanol in order to remove HCl,
furnished free (S)-proline 1 in 92% yield {[R]D -83.2 (c 4.00,
H2O); authentic sample [R]D -84 (c 4.00, H2O)} (Scheme 7).
The same reaction sequence, applied to amide (R,R)-8,
afforded the pipecolinamide (R)-20 ([R]D +33.1 (c 2.00, EtOH))
and the pipecolic acid (R)-(+)-2 ([R]D + 26.7 (c 1.00, H2O))
in good yields, respectively. The specific rotation of (R)-2 was
in agreement with the literature ([R]D +26.3 (c 1.00, H2O));7h
its enantiomeric excess was >98%.
ratio, by using ether, was obtained in moderate yield (53%)
(Scheme 4).
Subsequent acidic hydrolysis of cyclic nitriles 12/13 and 14/
15 (epimeric mixture) was carried out with concd H2SO4 (18
M) at 20 °C in CH2Cl2. Amides 7/16 and 8/17 were obtained
with good (n ) 1) to moderate (n ) 2) yields with the same
epimeric mixture, respectively, and were easily separated by
chromatography.
Conclusion
To avoid epimerization at the C-2 centers during the
cyclization reaction, we decided to transform amino nitrile under
acidic conditions into amide prior to cyclization. To our surprise,
treatment of the amino nitrile (S,S)-5 (n ) 1) with concd H2-
SO4 (18 M) at room temperature gave exclusively, via a one-
pot reaction, the cyclic amide (S,S)-7 in good overall yield
without any epimerization at the C-2 center. This product was
probably formed via an easy 5-membered-ring cyclization of
C followed independently by a hydrolysis of nitrile function of
D into amide, before or after such cyclization. On the other
hand, it may again by either an SN1 or SN2 route be attacked
by the nucleophile HSO4-, converting to E,18 which in turn
cyclized into D as depicted in Scheme 5.
We have developed an easy and efficient four-step synthesis
of enantiopure pipecolic acid (R)-2 and proline (S)-1, starting
from commercially available dihydropyran 4 and dihydrofuran
3. These acids were obtained from amino nitriles 5-6, which
were prepared by asymmetric Strecker reaction with excellent
selectivity (dr up to 99.5:0.5). The final products can be obtained
in any configuration in very high enantiomeric purity (>99%
ee). This approach can be used in the synthesis of other
heterocyclic rings, a possibility that is currently being explored
in our group.
Experimental
However, the same treatment applied to (R,R)-6 gave only
4% of 6-membered ring amide 8 and acyclic amide 18 in a
4:96 ratio, respectively (Scheme 6). Subsequent cyclization of
18 with I2/PPh3/imidazole furnished the desired amide 8 in 97%
yield without any epimerization, while, when MsCl/NEt3 was
used for cyclization, 50% yield of amide 8 was only obtained.
For the general experimental methods, see the Supporting
Information.
General Procedure A: Preparation of Hydroxyaminonitrile
5-6 by a Modified Gaudry’s Procedure.14 To an aqueous solution
of HCl (0.2 M, 80 mL) was added dihydrofuran 3 or dihydropyran
4 (0.300 mol), and the mixture was stirred at rt until complete
dissolution of adduct (10 min). Then the resulting solution was
slowly added to another solution of NaCN (0.360 mol, 1.2 equiv)
At this point, it was crucial to measure the enantiomeric
excesses of the final products in order to check the possible
(18) For formation of inorganic ester with sulfuric acid from alcohol,
see: Feuer, H.; Hooz, J. In The Chemistry of Ether Linkage; Patai, S., Ed.;
Interscience: New York, 1967; pp 457-460 and 468-470.
(19) (a) Johnson, R. L.; Rajukumar, G.; Mishra, R. K. J. Med. Chem.
1986, 29, 2100-2104. (b) Aldrich Library of 13C and 1H FT NMR Spectra;
Aldrich: Milwaukee, 1992; Vol. 1, pp 889 A-C, 1085B.
1782 J. Org. Chem., Vol. 72, No. 5, 2007

Short Asymmetric Synthesis of Cyclic Amino Acids
and chiral amine 9 (0.30 mol) in 1 M HCl solution (320 mL), and
the mixture was stirred at rt for 2-4 days. The basic mixture was
then extracted with EtOAc (3 × 200 mL), and the combined organic
layers were dried (MgSO4), filtered, and then concentrated under
vacuum to give the crude hydroxy aminonitriles 5-6. Purification
was performed by flash chromatography (FC) on silica gel or by
crystallization from ether/pentane mixture.
128.3, 144.0, 179.9; MS (EI) m/z 218 (M+) (1.5), 175 (15), 174
(94), 105 (100), 70 (92); ES+MS m/z 241.1 [M + Na]+; HRMS
(EI) calcd for C13H18N2O 218.1419, found 218.1421.
(2R,1′R)-6-Hydroxy-2-(1-phenylethylamino)hexanamide [(+)-
18]. Following procedure C: From amino nitrile (2R,1′R)-6 (464
mg, 2 mmol), concd H2SO4 (18 M, 3 mL), and CH2Cl2 (7 mL)
with stirring at rt for 3 days was obtained after FC (eluent, MeOH/
EtOAc 10/90) 290 mg (58%) of pure hydroxy amide (2R,1′R)-18,
and 14 mg (3%) of cyclic amide (2R,1′R)-8.
(2S,1′S)-5-Hydroxy-2-(1′-phenylethylamino)pentane nitrile
[(S,S)-(+)-5]. Following procedure A: From 2,3-dihydrofuran 3
(21 g, 300 mmol), (S)-R-phenylethylamine (S)-9 (36.30 g, 300
mmol), and NaCN (17.65 g, 360 mmol) in 1 M HCl (300 mL),
stirring at rt for 2-4 days, was obtained 65.20 g of crude desired
amino nitrile (S,S)-5. Crystallization from ether/pentane afforded
56.20 g (86%, in three crops) of pure amino nitrile: mp 97.0 °C;
[R]D -212.4 (c 1.00, CHCl3); tR ) 12.68 min (Cydex B, 130 °C,
1 bar); Rf ) 0.16 (EtOAc/petroleum ether 3/7); IR (neat) 3238,
Data for the major acyclic amide (2R,1′R)-18: mp 74.5 °C; [R]D
+37.8 (c 1.00, CHCl3); Rf ) 0.20 (MeOH/AcOEt 5/95); IR (neat)
1
3355, 3249, 3178, 1674, 1455 cm-1; H NMR δ 1.35 (d, J ) 6.6
Hz, 3H), 1.20-1.74 (m, 6H), 2.40 (br s, 2H, NH and OH), 2.86
(dd, J ) 7.1 Hz, J ) 5.8 Hz, 1H), 3.56 t, J ) 5.8 Hz, 1H), 3.68 (q,
J ) 6.6 Hz, 1H), 5.81 (br s, J ) 3.6 Hz, 1H),), 6.89 (br s, J ) 3.6
Hz, 1H), 7.18-7.40 (m, 5H); 13C NMR δ 21.8, 24.3, 32.1, 33.6,
57.0, 60.0, 61.8, 126.4, 127.1, 128.5, 144.7, 178.4; HRMS (EI)
m/z calcd for C14H22N2O2 250.1681, found 250.1664.
1
2225, 1453, 1265 cm-1; H NMR δ 1.41 (d, J ) 6.6 Hz, 3H),
1.60-1.94 (m, 4H), 2.02 (br s, 2H, NH and OH), 3.19 (t, J ) 6.8
Hz, 1H), 3.50-3.80 (m, 2H), 4.11 (q, J ) 6.6 Hz, 1H), 7.20-7.72
(m, 5H); 13C NMR δ 24.6, 28.9, 30.8, 47.9, 56.5, 61.6, 120.3, 126.6,
126.8, 127.6, 142.8; MS (EI) m/z no peak parent, 190 (1.3), 176
(41), 160 (11), 106 (51), 105 (100), 104 (55), 79 (19). Anal. Calcd
for C13H18N2O: C, 71.53; H, 8.31; N, 12.83. Found: C, 71.57; H,
8.16; N, 13.03.
Data for the minor cyclic amide (2R,1′R)-8 are identical with
those noted below.
(2R,1′R)-1-(1′-Phenylethyl)piperidine-2-carboxamide [(+)-
(8)]. Cyclization of Hydroxy Amide 18 with I2/PPh3/Imidazole.
To a solution of hydroxy amide 18 (2 mmol) in toluene (30 mL)
were successively added at rt PPh3 (630 mg, 2.4 mmol) and
imidazole (163 mg, 2.4 mmol) and then dropwise a solution of I2
(610 mg, 2.4 mmol) in toluene (4 mL). The mixture was then heated
at reflux for 3 h. After being cooled to rt, the solvent was removed
and the residue was washed with ether (2 × 10 mL). The solid
residue was basified to pH 9 with a 1 M solution of NaHCO3 and
then extracted with EtOAc (3 × 60 mL). The combined organic
layers were dried over MgSO4, filtered, and then concentrated under
vacuum to yield after flash chromatography on silica gel (eluent:
MeOH/CH2Cl2 3/97 f 10/90), as an amorphous solid, 450 mg
(97%) of pure amide (2R,1′R)-8, ee > 99% determined by GC using
a chiral column: tR ) 122.96 min for (R,R)/tR ) 125.55 min for
(S,S) (Cydex B, 25 m, 140 °C, 1 bar).
(2R,1′R)-6-Hydroxy-2-(1′-phenylethylamino)hexanonitrile[(R,R)-
(+)-6]. Following procedure A: From 3,4-dihydropyran 4 (8.40
g, 100 mmol), (R)-R-phenylethylamine (R)-9 (12.1 g, 100 mmol),
and NaCN (5.88 g, 120 mmol) in 1 M HCl (100 mL), stirring at rt
for 2 days, was obtained 23.5 g of crude desired amino nitrile (R,R)-
6. Crystallization from ether/pentane furnished 20.20 g (86.2%, in
three crops) of pure amino nitrile: mp 59.1 °C; [R]D +185 (c 1.00,
CHCl3); tR ) 13.18 min (Cydex B, 130 °C, 1 bar); Rf ) 0.24
(EtOAc/petroleum ether: 3/7); IR (neat) 3323, 2226, 1453 cm-1
;
1H NMR δ 1.39 (d, J ) 6.7 Hz, 3H), 1.45 (br s, 2H, NH and OH),
1.40-1.67 (m, 4H), 1.67-1.90 (m, 2H), 3.17 (t, J ) 6.8 Hz, 1H),
3.55-3.77 (m, 2H), 4.09 (q, J ) 6.7 Hz, 1H), 7.20-7.46 (m, 5H);
13C NMR δ 21.7, 24.6, 31.6, 33.1, 48.0, 56.3, 61.7, 120.2, 126.6,
127.4, 128.5, 143.0; MS (EI) m/z no peak parent, 204 (3), 190 (49),
172 (30), 147 (62), 106 (50), 105 (100), 79 (18). Anal. Calcd for
C14H20N2O: C, 72.38; H, 8.68; N, 12.06. Found: C, 72.32; H, 8.71;
N, 12.11.
Data for amide (2R,1′R)-(+)-8: mp 92.0 °C; [R]D +80.5 (c 1.00,
CHCl3); ee >99%; tR ) 122.96 min (Cydex B, 140 °C, 1 bar);
Rf ) 0.38 (MeOH/CH2Cl2 1/9); IR (neat) 3445, 3000, 1675, 1452
cm-1; 1H NMR (CDCl3) δ 1.05-1.25 (m, 1H), 1.25-1.45 (m, 1H),
1.46 (d, J ) 7.0 Hz, 3H), 1.53-1.78 (m, 3H), 1.78-2.00 (m, 2H),
2.92 (ddd, J ) 11.5 Hz, J ) 4.6 Hz, J ) 4.6 Hz, 1H), 3.06 (dd, J
) 4.1 Hz, J ) 8.8 Hz, 1H), 4.01 (q, J ) 7.0 Hz, 1H), 5.75 (br s,
1H), 6.81 (br s, 1H), 7.16-7.45 (m, 5H); 13C NMR δ 19.4, 22.9,
23.95, 28.8, 44.5, 59.7, 63.5, 127.2, 127.9, 128.7, 139.2, 177.9;
MS (EI) 232 (M+, 0.1), 188 (44), 105 (65), 103 (8), 84 (100), 77
(15); HRMS (EI) calcd for C14H20N2O 232.1576, found 232.1583.
General Procedure C: Formation of Amides 7 and 8 from
Nitriles 5 and 6. A solution of nitrile 5 or 6 (10 mmol) in CH2Cl2
(30 mL) was cooled to 0 °C, and concd sulfuric acid (18 M, 15
mL) was added very slowly with efficient stirring. The reaction
mixture was allowed to warm to rt and stirred for 8-48 h. The
aqueous layer was separated, washed with CH2Cl2 (4 mL), poured
onto crushed ice (30 g), and then slowly basified with concd
ammonia. The mixture was extracted with EtOAc (4 × 100 mL),
dried over MgSO4, and then concentrated to give, after FC (silica
gel, 75 g, eluent: MeOH/EtOAc: 4/96), the title amide 7 or 8.
Procedure D: Hydrogenolysis of Benzylic Amine. To a
solution of amino amide adduct 7 or 8 (2.00 mmol) in a mixture of
EtOH/AcOH (1:1) (4 mL) was added 20% Pd(OH)2/C (Pearlman’s
catalyst, 150 mg). The mixture was stirred at rt under H2 (1 atm)
for 10 h and then degassed under a stream of argon and filtered
through Celite, and the collected solid was washed with EtOH
(3 × 10 mL). The combined filtrate and washings were concen-
trated, and the residue was neutralized with concd NH4OH (2 mL)
then subjected to FC (eluent, MeOH/CH2Cl2/concd NH4OH 50/
50/1) to afford pure free amino amides 19 or 20.
(2S,1′S)-1-(1′-Phenylethyl)pyrrolidine-2-carboxamide [(2S,1′S)-
(-)-7]. One-pot formation from hydroxyamino nitrile, according
to procedure C: From hydroxyamino nitrile (2S,1′S)-5 (21.8 g, 10
mmol), concd H2SO4 (18 M, 15 mL), and CH2Cl2 (30 mL) with
stirring at rt for 2 days was obtained after FC (eluent, MeOH/EtOAc
4/96) 1.700 g (78%) of pure amide (2S,1′S)-7: mp 80.3 °C; [R]D
-73 (c 1.00, CHCl3); tR ) 55.97 min (Cydex B, 130 °C, 1 bar);
2-Piperidinecarboxamide [(R)-Pipecolinamide] [(R)-(+)-20].
Following procedure D: From amino amide (2R,1′R)-8 (232 mg,
1 mmol), AcOH (4 mL), and 20% Pd(OH)2/C (100 mg) with stirring
at rt for 10 h was obtained, after FC, 95 mg (85%) of pure (R)-
pipecolinamide 20: [R]D + 33.1 (c 2.00, EtOH) [lit.20a [R]D + 33
Rf ) 0.23 (EtOAc/CH2Cl2: 5/5); IR (neat) 3423, 1682, 1454 cm-1
;
1H NMR δ 1.40 (d, J ) 6.7 Hz, 3H), 1.57-1.83 (m, 2H), 1.87-
2.07 (m, 1H), 2.07-2.40 (m, 2H), 2.85 (ddd, J ) 8.4 Hz, J ) 4.2
Hz, J ) 3.7 Hz, 1H), 3.33 (dd, J ) 10.5 Hz, J ) 3.7 Hz, 1H), 3.60
(q, J ) 6.7 Hz, 1H), 6.35 (br s, 1H), 7.14-7.39 (m, 5H), 7.44 (br
s, 1H); 13C NMR δ 22.7, 24.3, 31.4, 53.4, 64.4, 64.7, 127.1, 127.2,
(20) (a) Hardtman, G. E.; Houlihan, W. J.; Giger, R. K. A. US Patent,
4.760.065, July 26, 1988. (b) Perumattam, J.; Shearer, B. G.; Confer,
W. L.; Mathew, R. M. Tetrahedron Lett. 1991, 32, 7183-7186.
J. Org. Chem, Vol. 72, No. 5, 2007 1783

Fadel and Lahrache
(c 2.00, EtOH)]; mp 161.0-162.5 °C (from EtOH/hexane) (lit.20b
mp 162-163 °C); Rf ) 0.45 (MeOH/CH2Cl2/concd NH4OH 50/
50/1); IR (neat) 3382, 3303, 3191, 1620, 1408, 1318 cm-1; 1H NMR
(CDCl3) δ 1.30-1.75 (m, 4H), 1.73-1.90 (m, 1H), 1.90-2.08 (m,
1H), 2.19 (br s, 1H), 2.57-2.80 (m, 1H), 3.05 (dt, J ) 12.2 Hz,
J ) 2.5 Hz, 1H), 3.22 (dd, J ) 9.8 Hz, J ) 3.3 Hz, 1H), 5.95 (br
s, 1H), 6.75 (br s, 1H); 13C NMR δ 24.1, 25.9, 23.0, 45.8, 60.2,
177.2; HRMS (EI) calcd for C6H12N2O 128.0950, found 128.0949.
Supporting Information Available: Experimental procedures,
1H and 13C NMR spectra, and characterization data for (2S,1′S)-5,
(2R,1′R)-5, (2R,1′R)-6, (2R,1′R)-6/(2S,1′R)-11, (2S*,1′S)-12 and 13,
(2R*,1′R)-14 and 15, (2S,1′S)-7, (2R,1′S)-16, (2R,1′R)-8, (2S,1′R)-
17, (2R,1′R)-18, (S)-19, (R)-20, (S)-1, and (R)-2‚HCl. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO062382I
1784 J. Org. Chem., Vol. 72, No. 5, 2007