Chemoenzymatic synthesis of (S)-2-cyanopiperidine, a key intermediate in the route to (S)-pipecolic acid and 2-substituted piperidine alkaloids

Article abstract of DOI:10.1016/S0957-4166(98)00140-2

The preparation of (S)-2-cyanopiperidine 4 provides a new access to 2- substituted piperidines. This synthesis is based on an enantioselective (R)- oxynitrilase-catalyzed reaction for the preparation of (R)-(+)-6-bromo-2- hydroxyhexanenitrile 1 and the subsequent cyclization of this compound to yield the piperidine ring. The utilization of 4 as the starting material for the synthesis of (S)-2-aminomethylpiperidine 6, (R)-(-)-coniine 10 and (S)- (-)pipecolic acid 13 is also described.

Full text of DOI:10.1016/S0957-4166(98)00140-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1597–1604
Chemoenzymatic synthesis of (S)-2-cyanopiperidine, a key
intermediate in the route to (S)-pipecolic acid and 2-substituted
piperidine alkaloids
Serge Nazabadioko, Ramón J. Pérez, Rosario Brieva and Vicente Gotor ∗
Laboratorio de Bioorgánica, Departamento de Química Orgánica e Inorgánica, Universidad de Oviedo, 33071- Oviedo,
Spain
Received 13 March 1998; accepted 30 March 1998
Abstract
The preparation of (S)-2-cyanopiperidine 4 provides a new access to 2-substituted piperidines. This synthesis
is based on an enantioselective (R)-oxynitrilase-catalyzed reaction for the preparation of (R)-(+)-6-bromo-2-
hydroxyhexanenitrile1 and the subsequent cyclization of this compound to yield the piperidine ring. The utilization
of 4 as the starting material for the synthesis of (S)-2-aminomethylpiperidine 6, (R)-(−)-coniine 10 and (S)-(−)-
pipecolic acid 13 is also described. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Piperidine derivatives are present in a large number of natural products of biological importance.1
The development of methods for the asymmetric synthesis of these compounds constitutes an area of
considerable interest. Some significant examples such as enantiomerically pure 2-aminomethylpiperidine
6, coniine 10 and pipecolic acid 13 are 2-substituted piperidines.
The structure of 2-aminomethylpiperidine 6 is a valuable synthon for the preparation of
several pharmaceuticals2 and is also a useful chiral ligand for asymmetric synthesis.3 Froelich
et al. recently described the asymmetric synthesis of this structure using the versatile 2-cyano-
6-phenyloxazolopiperidine.4 In this procedure, the obtention of the piperidine ring, using (−)-
phenylglycinol as the source of chirality, is one exception to the general procedure in which the, not
easily available, enantiopure pipecolic acid is used as starting material.5 The interest in coniine and
its analogues is demonstrated by the wealth of published material.6 Finally, (S)-pipecolic acid 13,7
a nonproteinogenic amino acid, is a precursor to numerous bioactive compounds such as synthetic
∗
Corresponding author. E-mail: VGS@sauron.quimica.uniovi.es
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00140-2

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peptides,8 local anesthetics9 or potential enzyme inhibitors10 and is a component of biologically-
important natural products such as the immunomodulators rapamycin and demethoxyrapamycin,11 the
immunosuppressant FK50612 or the antitumor antibiotic sandramycin.13
On the other hand, (R)-oxynitrilase from almonds [EC 4.1.2.10] catalyses the enantioselective prepara-
tion of cyanohydrins from aldehydes or ketones.14 These cyanohydrins have been applied in the synthesis
of some bioactive products of great pharmaceutical importance.15 In a previous report,16 we prepared (R)-
(+)-6-bromo-2-hydroxyhexanenitrile 1 through an enzymatic transcyanation process catalyzed by (R)-
oxynitrilase. We believe that the cyanohydrin 1, obtained in high yield and enantiomeric excess, could be
an adequate starting material for the preparation of the above mentioned piperidine heterocycles. In this
paper, we propose a general approach to the synthesis of these heterocycles.
2. Results and discussion
The (R)-(+)-6-bromo-2-hydroxyhexanenitrile 1 seems to be a good starting material for the synthesis
of the cyanopiperidine cycle since only two simple steps are required (Scheme 1): the transformation of
the hydroxyl into a good leaving group by the formation of the trifluoromethanesulfonyloxy derivative 2
and the treatment of this compound with an amine or ammonia. This second step is a double substitution
process: the substitution of the trifluoromethanesulfonate group that should occur with inversion of the
configuration and the following slower substitution of the bromine to yield the piperidine ring.
Scheme 1.
The reaction of 1 with trifluoromethanesulfonic anhydride/pyridine affords 2 quantitatively. Neverthe-
less, treatment of 2 with a solution of ammonia/H2CCl2 at room temperature to yield the corresponding
2-cyanopiperidine, occurs with partial racemization.
In order to obtain a complete inversion of configuration during the substitution of the triflate group, we
studied the effect of temperature on this process. For this study the use of benzylamine as the nucleophile
was more efficient, because the reaction with ammonia has several inconveniencies, especially the control

S. Nazabadioko et al. / Tetrahedron: Asymmetry 9 (1998) 1597–1604
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of the amount of the nucleophile and the low reaction rate when the process is carried out at temperatures
below 0°C. The use of benzylamine has the additional advantage of the higher stability of the reaction
product and the easy removal of the benzyl group.
The substitution of the trifluoromethanesulfonate group is carried out with two equivalents of ben-
zylamine at −65°C. When this process is complete, triethylamine is added and the reaction is allowed
to warm to room temperature for the substitution of the bromine. Under these conditions, we obtained
(S)-(−)-N-benzyl-2-cyanopiperidine 4 without evidence of racemization.
These results are in accordance with those described by Effenberger et al. in the substitution process of
2-trifluoromethanesulfonyloxycarboxylic esters with amines, in which racemization or elimination side
reactions can be avoided when the reactions take place at low temperatures.17
The preparation of the (S)-(−)-2-aminomethylpiperidine bishydrochloride 6 is carried out by the
reduction of the cyanopiperidine 4 to the diamine 5 in a 96% yield (Scheme 2). The hydrogenolysis
of the benzyl group yields the bishydrochloride salt (6) quantitatively.
Scheme 2.
In order to verify the enantiomeric excess of the diamine 6, we prepared the racemate by hydrogenation
of the commercially available 2-aminopyridine. Both diamines 6 are transformed into their benzyloxycar-
bonyl derivatives and compared by HPLC analysis. This analysis confirms that the enantiomeric excess
of the starting cyanohydrin 1 remains after the synthetic process.
Treatment of 4 with DIBAL-H at −78°C, followed by a tartaric-buffer work up, yields the crude
aldehyde 8 (Scheme 3), which is added, without further purification, to the already prepared ethyl Wittig
ylide to afford the olefin 9 with a 74% overall yield. The hydrogenation of 9 and simultaneous removal
of the benzyl group yields (S)-coniine hydrochloride 10 quantitatively. The spectral data and specific
rotation of the coniine are in accordance with the literature values.18
Scheme 3.
Cyanopiperidine 4 could be a good starting material for the synthesis of pipecolic acid through
simple hydrolysis of the nitrile function. Nevertheless, when this process is carried out by refluxing the
cyanopiperidine 4 in concentrated HCl, racemic pipecolic acid is obtained. This result is in accordance
with the report by Berrien et al.7a
In view of the easy racemization in these processes we carried out the transformation of the nitrile
function into an imidate using ethanol saturated with anhydrous hydrochloric acid. The subsequent
hydrolysis of the imidate with diluted HCl yields the ester 11 in a 70% yield (Scheme 4). A further
hydrolysis of the ethyl ester with 6 N HCl at reflux and deprotection of the amino group by hydrogenation,
gives (−)-pipecolic acid in 96% yield. Comparison of the specific rotation of this compound with
the corresponding hydrochloride of the enantiopure commercial (−)-pipecolic acid, shows that no
racemization had occurred during the process.

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Scheme 4.
In conclusion, we have achieved an enantiospecific chemoenzymatic synthesis of 2-substituted
piperidines. The method is based on the utilization of an (R)-cyanohydrin obtained through an
oxynitrilase-catalyzed reaction. The versatility of this method is demonstrated by the preparation of three
significant examples: (S)-2-aminomethylpiperidine, (R)-(−)-coniine and (S)-(−)-pipecolic acid. Further
applications to the synthesis of other piperidine derivatives are currently in progress.
3. Experimental
Melting points were taken using a Gallenkamp apparatus and were uncorrected. Optical rotations
were measured using a Perkin–Elmer 241 polarimeter and are quoted in units of 10−1 deg cm2 g−1. IR
spectra were recorded on a Perkin–Elmer 1720-X FT infrared spectrophotometer. 1H and 13C NMR were
obtained with TMS (tetramethylsilane) as the internal standard; using a Bruker AC-300 (1H 300 MHz
and 13C 75.5 MHz) spectrometer. Mass spectra were recorded on a Hewlett Packard 5987A and Finigan
MAT/95 spectrometers. Microanalyses were performed on a Perkin–Elmer 240B elemental analyzer. All
reagents were purchased from Aldrich Chemie. Solvents were distilled over an adequate desiccant and
stored under nitrogen. Flash chromatography was performed using Merck silica gel 60 (230–400 mesh).
The ees were determined by chiral HPLC analysis using a CHIRALCEL-OD column (4.5×250 mm).
3.1. (R)-(+)-6-Bromo-2-hydroxyhexanenitrile (R)-1
The defatted ground almond meal was incubated with 5 ml of 0.02 M citrate buffer (pH 5.5) in a 250 ml
reaction vessel. After 15 minutes 50 ml of diisopropyl ether, distilled substrate 5-bromopentanal (1.38 g,
8.4 mmol) and (ꢀ)-2-hydroxy-2-methylpentanenitrile (1.6 g, 12.6 mmol) were added to the suspension.
The mixture was shaken at 30°C and 250 rpm in a rotatory shaker. After 24 h, the reaction mixture was
filtered and washed with CH2Cl2. The combined filtrates were concentrated in vacuo, and the residue
was purified by flash chromatography on silica gel with hexane:H2CCl2:AcOEt (7.5:1.5:1), to give the
25
cyanohydrin (R)-1 in 81% yield. [α]D +10.7 (c=1.0, CHCl3), ee 91%; 1H NMR (CDCl3) δ 1.63–2.14
(m, 6H), 3.15 (br s, 1H), 3.45 (t, 2H), 4.55 (t, 1H); 13C NMR (CDCl3) δ 23.1, 31.7, 33.0, 40, 60.8, 119.7;
HMRS calcd for C6H10BrNO 190.9946, found 190.9949.
3.2. (R)-6-Bromo-2-trifluoromethanesulfonyloxyhexanenitrile (R)-2
To a vigorously stirred solution of cyanohydrin (R)-1 (887 mg, 4.5 mmol) in pyridine (0.8 ml, 9 mmol)
and 60 ml of dry CH2Cl2 under N2 atmosphere at 0°C, was added dropwise trifluoromethanesulfonic
anhydride (1.2 ml, 6.8 mmol). The resulting mixture was stirred for 15 minutes, then filtered and the
solvent evaporated. The crude residue was purified by flash chromatography on silica gel (hexane:AcOEt,
8:1) to afford the compound (R)-2 as a colorless oil in 98% yield; [α]D25 +28.9 (c=1.1, CHCl3), ee 91%;
1H NMR (CDCl3) δ 1.75 (m, 2H), 1.97 (m, 2H), 2.13 (m, 2H), 3.44 (t, J=6.41 Hz, 2H), 5.38 (t, J=6.41

S. Nazabadioko et al. / Tetrahedron: Asymmetry 9 (1998) 1597–1604
1601
Hz, 1H); 13C NMR (CDCl3) δ 22.6, 31.1, 32.0, 32.7, 71.5, 113.5, 121.3; MS (EI) exact mass calcd for
(C7H9BrF3NO3S–CF3SO2) 189.9868, found 189.9867.
3.3. (S)-1-Benzyl-2-cyanopiperidine (S)-4
To a stirred solution of (R)-2 (1 g, 3.09 mmol) in 10 ml of CH2Cl2 at −65°C, was added dropwise (for
30 minutes) a solution of benzylamine (674 µl, 6.17 mmol) in 1 ml of H2CCl2. The resulting mixture
was stirred for 24 h at the same temperature, then 5 ml of Et3N was added and the reaction mixture was
allowed to warm to rt and stirred for 24 h. The resulting mixture was filtered over Celite and the solvent
evaporated under reduced pressure. The crude residue was purified by flash chromatography on silica
gel (hexane:H2CCl2:AcOEt, 7.5:1.5:1) to yield the compound (S)-4 as a colorless oil (450 mg, 73%);
25
[α]D −86.5 (c=1.4, CHCl3), ee 91%; 1H NMR (CDCl3) δ 1.50–1.88 (m, 6H), 2.42 (dt, J=10.68, 3.06
Hz, 1H), 2.77 (br d, J=11.51 Hz, 1H), 3.52 (d, J=13.1 Hz, 1H), 3.69 (d, J=13.10 Hz, 1H), 3.73 (br s,
1H), 7.25–7.40 (m, 5H); 13C NMR (CDCl3) δ 20.7, 25.2, 28.9, 50, 52.3, 61.0, 117, 127.8, 128.7, 129.3,
137.2; HRMS calcd for C13H16N2 200.1313, found 200.1319.
3.4. (S)-2-Aminomethyl-1-benzylpiperidine (S)-5
To a suspension of LiAlH4 (198 mg, 5.22 mmol) in 12 ml of anhydrous Et2O was added a solution
of (S)-4 (232 mg, 1.16 mmol) in 6 ml of anhydrous Et2O at −10°C and the reaction mixture was stirred
for 2 h at rt. To the resulting mixture was added a solution of NaOH (15%, 2.5 ml). The resulting white
precipitate was filtered and washed several times with Et2O. After removal of the solvent under reduced
pressure, the crude residue was purified by flash chromatography on silica gel (CHCl3:MeOH, 2:3) to
25
yield the compound (S)-5 as colorless oil (228 mg, 96% yield); [α]D −57.2 (c=3.0, EtOH), ee 91%;
25
lit.,5 [α]D −61.2 (c=3.0, EtOH); 1H NMR (CDCl3) δ 1.26–1.74 (m, 8H), 2.04 (br t, J=9.89 Hz, 1H),
2.26 (m, 1H), 2.78 (m, 2H), 3.01 (dd, J=13.32, 5.16 Hz, 1H), 3.23 (d, J=13.33 Hz, 1H), 4.02 (d, J=13.33
Hz, 1H), 7.30–7.32 (m, 5H); 13C NMR (CDCl3) δ 23.7, 24.7, 28.2, 43.2, 51.9, 57.5, 62.3, 126.6, 128.1,
128.7, 139.4; MS (EI) m/z 204 (M+<1), 174 (100), 91(100); FABS m/z 205 (M+1, 25), 174 (100), 147
(40).
3.5. (S)-2-Aminomethylpiperidine bishydrochloride (S)-6
To a suspension of (S)-5 (162 mg, 0.79 mmol) and palladium hydroxide (20% on charcoal, 13 mg)
in MeOH (2 ml) was added a solution of MeOH/3 N HCl (3 ml). The mixture was hydrogenated at 40
psi for 15 h. The resulting mixture was filtered over Celite and concentrated under reduced pressure to
afford a bishydrochloride salt as a white solid quantitatively; [α]D −4.7 (c=2.8, MeOH), ee 91%, lit.,4
25
[α]D −5.7 (c=0.42, MeOH); 1H NMR (D2O) δ 1.52, 1.83, 2.0 (m, 6H), 2.98 (td, 1H), 3.23 (dd, J=13.6,
25
7.0 Hz, 2H), 3.20 (dd, J=13.3, 5.8 Hz, 2H), 3.4 (m, 2H); 13C NMR (D2O) δ 21.5, 22.0, 26.5, 41.7, 45.7,
54.4; MS (EI) m/z 115 (M+1) (100), 84 (10). Anal. calcd for C6H16N2Cl2: C, 38.51; H, 8.61; N, 14.97.
Found: C, 38.25; H, 8.77; N, 14.59.
3.6. (S)-1-Benzyloxycarbonyl-2-[N-(benzyloxycarbonyl)aminomethylpiperidine] (S)-7
To a mixture of H2O (5 ml) and CH2Cl2 (2 ml) was added Na2CO3 (627 mg, 4.53 mmol) and
bishydrochloride (S)-6 (106 mg, 0.567 mmol). The mixture was cooled at 0°C and benzyloxycarbonyl
chloride (0.64 ml, 4.53 mmol) was added dropwise. After stirring for 16 h at rt the mixture was extracted

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S. Nazabadioko et al. / Tetrahedron: Asymmetry 9 (1998) 1597–1604
with CH2Cl2 following a general work up procedure. The obtained crude product was purified by flash
chromatography on silica gel (hexane:CH2Cl2:AcOEt, 7.5:1.5:1) to give the compound (S)-7 as a white
solid (119 mg, 55%); [α]D −27.8 (c=2.1, CHCl3), ee 91%; 1H NMR (CDCl3) δ 1.35–1.82 (6H), 2.91
25
(br t, 1H), 3.25 (m, 1H), 3.61 (br s, 1H), 4.10 (br s, 1H), 4.42 (br s, 1H), 5.07 (s, 2H), 5.10 (s, 2H),
7.25–7.42 (m, 10H); 13C NMR (CDCl3) δ 19.0, 25.1, 26.2, 39.4, 40.6, 50.3, 66.5, 67.0, 126.9, 127.9,
128.4, 136.5; MS (EI) 382 M+ (<1), 218 (17), 174 (33), 91 (100). Anal. calcd for C22H26N2O4: C,
69.09; H, 6.85; N, 7.32. Found: C, 68.77; H, 6.85; N, 7.25.
3.7. (ꢀ)-1-Benzyloxycarbonyl-2-[N-(benzyloxycarbonyl)aminomethylpiperidine] (ꢀ)-7
To a solution of 2-aminomethylpyridine (2 g, 18.5 mmol) in methanol (10 ml), was added a solution
of 3 N HCl (9 ml) and palladium hydroxide (20% on charcoal, 160 mg). The mixture was hydrogenated
at 300 psi for 15 h at rt. After filtration on Celite, the solvent was concentrated under reduced pressure
to give a white solid residue. 1H NMR shows a mixture of bischloride salt (ꢀ)-7 and a pyridinium salt of
the starting material (1:1). The pyridinium salt (ꢀ)-7 was precipitated from the mixture of MeOH–Et2O.
After filtration and removal of the solvent under reduced pressure, a pure piperidinium salt (ꢀ)-6 was
obtained as a white solid. The synthesis of the protected compound (ꢀ)-7 was carried out using the
general procedure for the preparation of the carbamate (S)-7, in 53% yield.
3.8. Determination of enantiomeric excess of (S)-7
A sample (20 µl) of a solution of (S)-7 or (ꢀ)-7 (3 mg) in a mixture of hexane:isopropanol, 80:20 (6
ml), was analyzed by HPLC with a flow rate of 0.8 cm3 min−1. Two peaks (tR 10.113 and 13.060) for
(ꢀ)-7 and (tR 10.949 and 14.978) for (S)-7 were resolved.
3.9. (S)-1-Benzyl-2-formylpiperidine (S)-8
To a stirred solution of nitrile (S)-4 (626 mg, 3.13 mmol) in 4 ml of CH2Cl2 at −78°C under N2
atmosphere was added dropwise a 1 M solution of DIBAH in CH2Cl2 (4.17 ml). The resulting mixture
was stirred at −78°C for 2 h, then poured into a 0°C solution of tartaric buffer (30 ml, pH 4). After being
stirred for 2 h at 0°C, the solution was adjusted to pH 9 by addition of 1 N NaOH. The aqueous phase was
extracted with ether (3×10 ml) and the combined organic fractions were washed with brine, dried over
Na2SO4, filtered and evaporated under vacuum to yield the aldehyde (S)-8 (496 mg). The aldehyde is
relatively stable after its purification but this process implies a considerable lost of yield; then, the crude
aldehyde was immediately used without further purification in the next step of the synthesis. Colorless
oil; 1H NMR (CDCl3) δ 1.25–1.81 (m, 6H), 2.05 (m, 1H), 2.88 (m, 2H), 3.34 (d, J=13.4 Hz, 1H), 3.78
(d, J=13.4 Hz, 1H), 7.32 (m, 5H), 9.59 (d, J=3.96 Hz, 1H); 13C NMR (CDCl3) δ 22.6, 24.7, 26.0, 51.0,
61.3, 70.5, 127.2, 128.2, 129.0, 137.5, 204.3.
3.10. (S)-cis-1-Benzyl-2-[1-propenyl]piperidine] (S)-9
A suspension of Ph3P(Et)(Br) (664 mg, 1.19 mmol) in Et2O (16.37 ml) was vigorously stirred for 15
minutes under N2 at rt and cooled to −65°C, then a solution of 1 M NaHMDS in THF (1.79 ml) was
added. The resulting mixture was stirred for 20 min before the slow addition of a solution of the crude
aldehyde (242 mg) in 2 ml of Et2O. The reaction mixture was allowed to warm to room temperature and
stirred for 2 h, then filtered over silica gel and the solvent evaporated. The crude residue was purified

S. Nazabadioko et al. / Tetrahedron: Asymmetry 9 (1998) 1597–1604
1603
by flash chromatography on silica gel to afford the propenylpiperidine (S)-9 as a colorless oil (243 mg,
25
95%); [α]D (cis) −58.64 (c=1.03, CHCl3), ee 91%; IR (KBr) υ (cis) 3026, 3024, 2933, 2854, 2933,
1
2854, 2791, 1658, 1604, 1450, 736, 717, 698 cm−1; H NMR (CDCl3) δ 1.25–1.75 (m, 7H), 1.70 (d,
J=5.28 Hz, 3H), 1.92 (dt, J=11.4, 3.52 Hz, 1H), 2.80–3.0 (m, 1H), 3.08 (d, J=13.2 Hz, 1H), 4.07 (d,
J=13.2 Hz, 1H), 5.50–5.68 (m, 2H, olefin), 7.15–7.40 (m, 5H); 13C NMR (CDCl3) δ 13.4, 24.1, 25.8,
32.6, 52.4, 59.2, 59.6, 124.7, 126.5, 127.9, 129.2, 134.5, 139; MS (EI) m/z 215 M+ (40), 174 (49), 91
(100)
3.11. (R)-2-Propylpiperidine hydrochloride, (−)-coniine (R)-10
A suspension of (S)-9 (170 mg, 0.79 mmol) and palladium hydroxide (20% on charcoal, 29 mg) in
MeOH (3 ml) and 3 N HCl (1 ml) was hydrogenated at 40 psi and 40°C for 15 h. The resulting mixture
was filtered over Celite and concentrated under reduced pressure to afford the coniine hydrochloride as
25
25
a white solid (124 mg, 96%); [α]D −5.2 (c=0.7, EtOH), ee 91%, lit.18 [α]D −5.8 (c=1, EtOH); 1H
NMR (CDCl3) d 0.90 (t, J=7.1 Hz, 3H), 1.28–2.09 (m, 10H), 2.51–3.0 (m, 2H), 3.40 (br d, 1H), 9.25
(br s, 2H); 13C NMR (CDCl3) δ 13.61, 18.44, 22.05, 22.29, 28.00, 35.20, 44.64, 57.02. Anal. calcd for
C8H18NCl: C, 58.70; H, 11.08; N, 8.56. Found: C, 58.75; H, 11.24; N, 8.64.
3.12. (S)-1-Benzyl-2-piperidinecarboxylic acid ethyl ester (S)-11
To a solution of nitrile (S)-4 (163 mg, 0.815 mmol) in dry EtOH (2 ml) at 0°C, was poured a saturated
anhydrous solution of HCl gas in EtOH (3 ml). The resulting solution was stirred for 24 h at the same
temperature. After removal of a part of the solvent under reduced pressure, a 0.5 N aqueous HCl solution
(5 ml) was added and the solution stirred for 48 h at 0°C. Solid Na2CO3 was added slowly and the
pH adjusted to between 8 and 9. The aqueous phase was extracted with ethyl acetate (3×5 ml) and
the combined organic fractions were dried, filtered and evaporated under reduced pressure to afford a
crude oil. The crude residue was purified by flash chromatography on silica gel (hexane:CH2Cl2:AcOEt,
25
7.5:1.5:1) to afford (S)-11 as a colorless oil (140 mg, 70%); [α]D −39.4 (c=0.6, CHCl3), ee 91%; 1H
NMR (CDCl3) δ 1.31 (t, J=7.0 Hz, 3H), 1.57 (m, 2H), 1.84 (m, 2H), 2.13 (m, 2H), 2.94 (m, 2H), 3.12
(m, 1H), 3.40 (d, J=13.1 Hz, 1H), 3.81 (d, J=13.1 Hz, 1H), 4.23 (q, J=7.0 Hz, 2H) 7.32 (m, 5H); 13C
NMR (CDCl3) δ 14.2, 22.5, 25.1, 29.5, 50.1, 60.2, 60.5, 64.6, 126.9, 128.0, 129.2, 138.0, 173.9; MS (EI)
m/z 247 M+ (<1), 174 (100), 91 (46).
3.13. (S)-2-Piperidine-2-carboxylic acid hydrochloride (S)-13
A solution of the ester (S)-11 (136.1 mg, 0.55 mmol) in 6 N HCl (5 ml) was refluxed for 10 h.
The solution was concentrated under reduced pressure. Methanol (3×5 ml) was added and the solvent
1
concentrated to yield a crude product as a solid material of N-benzylpipecolic acid (S)-12. H NMR
(MeOD) δ 1.85–2.15 (m, 6H), 1.50–62 (m, 1H), 3.33 (m, 1H), 3.63 (m, 1H), 4.20–4.45 (m, 1H), 4.87
(m, 1H), 7.73 (m, 5H); 13C NMR (MeOD) δ 22.2, 23.2, 29.0, 52.5, 60.7, 65.6, 130.1, 131.1, 132.6, 171.5.
The N-benzylpipecolic acid (S)-12 (171 mg) was dissolved in a (2:1) mixture MeOH:3 N HCl (3 ml)
and palladium hydroxide (20% on charcoal, 29 mg) was added. The resulting mixture was hydrogenated
for 15 h at room temperature and filtered over Celite. The solvent was concentrated under reduced
1
pressure to afford (S)-13 as a white solid (pure by H and 13C NMR), (124 mg, 96%); mp 261–264°C
25
25
1
[α]D −10.3 (c=0.2, H2O), ee 91%, [lit.19 mp 254–257°C, [α]D −11.5 (c=1.07, H2O)]; H NMR

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S. Nazabadioko et al. / Tetrahedron: Asymmetry 9 (1998) 1597–1604
(D2O) δ 1.45–1.70 (m, 3 H), 1.75–1.90 (m, 2H), 2.15–2.28 (m, 1H), 2.90–3.05 (m, 1H), 3.30–3.45 (m,
1H), 3.75–3.85 (m, 1H); 13C NMR (D2O) δ 24.2, 24.3, 28.7, 46.6, 60.1, 175.2.
Acknowledgements
The authors gratefully acknowledge the financial support of this work by the CICYT (project BIO-95-
0687). S. N. thanks the Ministerio de Educación y Ciencia and R. J. P. thanks the II PRI (Principado de
Asturias), for their corresponding fellowships.
References
1. (a) Strunz, G. M.; Findlay, J. A. Pyridine and Piperidine Alkaloids. In The Alkaloids; Brossi, A., Ed.; Academic Press:
New York, 1985; Vol. 26, pp. 89. (b) Fodor, G. B.; Colasati, B. Alkaloids: Chemical and Biological Perspectives; Pelletier,
S. W., Ed.; Wiley: New York, 1986; Vol. 3, p. 1. (c) Numata, A.; Ibuka, I. Alkaloids from Ants and Other Insects. In The
Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1987; Vol. 31, pp. 193. (d) Pinder, A. R. Nat. Prod. Rep. 1992, 9,
17. (e) Ibid. 491–504. (f) Wuonola, M. A. Org. Prep. Proced. Int. 1992, 583. (g) Plunkett, A. O. Nat. Prod. Rep. 1994, 11,
581. (h) Harrison, T. Cont. Org. Synth. 1995, 2, 209. Ibid. 1996, 3, 259.
2. (a) Norton, T. R.; Benson, A. A.; Seibert, R. A.; Bergstrom, F. W. J. Am. Chem. Soc. 1946, 68, 1330. (b) Banitt, E. H.;
Conard G. J. J. Labelled Compd. and Radiopharm. 1981, 28, 713. (c) Becchietti, V.; Signorini, M.; Giordani, A. Eur. Pat.
appl. EP 260, 041, 1988, (Chem. Abstr. 1988, 109, 92801g). (d) Terada, A.; Iizuka, Y.; Wachi. K.; Fujibayashi, K. Eur.
Pat. Appl. EP 356, 247, 1990. (Chem. Abstr. 1990, 113, 78419g).
3. (a) Froelich, O.; Bonin, M.; Quirion, J.-C.; Husson, H.-P. Tetrahedron: Asymmetry 1993, 4, 2335. (b) Asami, M.; Usui, K.;
Higuchi, S.; Inoue, S. Chem. Lett. 1994, 60, 297. (c) Kobayashi, S.; Hayashi, T. J. Org. Chem. 1995, 60, 1098. (c) Asami,
M.; Usui, K.; Higuchi, S.; Inoue, S. Chem. Lett. 1994, 60, 297.
4. Froelich, O.; Desos P.; Bonin, M.; Quirion, J.-C.; Husson, H.-P. J. Org. Chem. 1996, 61, 6700.
5. Perumattam, J.; Shearer, B. G.; Confer, W. L.; Mathew, R. M. Tetrahedron Lett. 1991, 32, 7183.
6. For recent synthesis of coniine, see: (a) Takahata, H.; Kubota, M.; Takahashi, S.; Momose, T. Tetrahedron: Asymmetry
1996, 7, 3047. (b) Moody, C. J.; Lighfot, A. P.; Gallagher, P. T. J. Org. Chem. 1997, 62, 746 and references cited therein.
(c) Weymann, H.; Pfrengle, W.; Schollmeyer, D.; Kunz, H. Synthesis 1997, 1151.
7. For asymmetric synthesis of pipecolic acid, see: (a) Berrien, J.-F.; Royer, J.; Husson, H.-P. J. Org. Chem. 1994, 59, 3769.
(b) Fernández-García, C.; McKervey, A. Tetrahedron: Asymmetry, 1995, 6, 2905. For resolution of pipecolic acid, see: (c)
Hardtman, G. E.; Houlihan, W. J.; Giger, A. US Patent, 4,760,065, Jul. 26, 1988. (Chem. Abstr. 1987, 107, 236730s). (d)
Ng-Youn Chem. M. C.; Serreqi, A. N.; Huang, Q.; Kazlauskas, R. J. J. Org. Chem. 1994, 59, 2075.
8. Copeland, T. D.; Wondrak, E. M.; Tozser, J.; Roberts M. M.; Oroszlan, S. Biochem. Biophys. Res. Commun. 1990, 169,
310.
9. Af Ekenstam, B. T.; Bovin C. US Patent 4695576, 1987. (Chem. Abstr. 1988, 108, 57228n).
10. (a) Kikumoto, R.; Tamao, Y.; Tezuka, T.; Tonomura, S.; Hara, H.; Ninomiya, K.; Hijikata, A.; Okamoto, S.; Biochemistry,
1984, 23, 85. (b) Flynn, G. A.; Giruox, E. L.; Dage, R. C. J. Am. Chem. Soc. 1987, 109, 7914.
11. Smith III, A. B.; Condon, S. M.; McCauley, J. A.; Leazer Jr., J. L.; Leahy, J. W.; Maleczka Jr., R. E. J. Am. Chem. Soc.
1997, 119, 962.
12. Ireland, R. E. Gleason; J. L.; Gegnas, L. D.; Highsmith, T. K. J. Org. Chem. 1996, 61, 5856.
13. Boger, D. L.; Chen, J.-H.; Saionz, K. W. J. Am. Chem. Soc. 1996, 118, 1629.
14. (a) Effenberger, F. Angew. Chem. Int. Ed. Eng. 1994, 33, 1555. (b) North, M. Synlett. 1993, 807. (c) Kanerva, L. T. Acta
Chem. Scand. 1996, 50, 234.
15. (a) Effenberger, F.; Jäger J. 1997, 62, 3867 and references cited therein. (b) Effenberger, F.; Jäger, J.; Chem. Eur. J. 1997,
3, 1370.
16. Menéndez, E.; Brieva, R.; Rebolledo, F.; Gotor, V. J. Chem. Soc., Chem. Commun. 1995, 989.
17. Effenberger, F.; Burkard, U.; Willfahrt, J. Liebigs Ann. Chem. 1986, 314.
18. Gerrier, L.; Royer, J.; Husson, H.-P. J. Am. Chem. Soc. 1983, 105, 7754.
19. Hockless, D. C. R.; Mayadunne, R. C.; Wild, S. B.; Tetrahedron: Asymmetry 1995, 6, 3031.