Synthesis of chiral nonracemic 4-trans-substituted pipecolic acid derivatives

Article abstract of DOI:10.1016/S0957-4166(99)00473-5

The syntheses and resolutions of enantiomerically enriched 4-phenyl, 4- tert-butyl, and 4-isopropyl pipecolic acids are described. Optically active diastereomers were prepared by diastereomeric salt formation with the chiral base, L-tyrosine hydrazide, to

Full text of DOI:10.1016/S0957-4166(99)00473-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4331–4341
Synthesis of chiral nonracemic 4-trans-substituted pipecolic acid
derivatives†
Terence P. Keenan,∗ David Yaeger and Dennis A. Holt
ARIAD Gene Therapeutics, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139-4234, USA
Received 22 September 1999; accepted 18 October 1999
Abstract
The syntheses and resolutions of enantiomerically enriched 4-phenyl, 4-tert-butyl, and 4-isopropyl pipecolic
acids are described. Optically active diastereomers were prepared by diastereomeric salt formation with the
chiral base, L-tyrosine hydrazide, to provide Cbz or Boc protected 4-cis-D-pipecolic acid derivatives in >98% ee.
Subsequent esterification followed by sodium methoxide catalyzed epimerization provided the isomeric 4-trans-
L-pipecolic esters. In addition, an efficient synthesis of 4-phenyl-cis-pipecolic acid is described. © 1999 Elsevier
Science Ltd. All rights reserved.
1. Introduction
As part of our program1 to synthesize high-affinity ligands for specifically designed mutants of the
intracellular protein FKBP12, we required efficient access to various 4-aryl/alkyl-trans-L-pipecolic acid
derivatives in high enantiopurity. The synthesis of substituted pipecolic acids has received heightened
attention2 over the last decade as the use of these building blocks in the synthesis of peptidomimetics
continues unabated. Research in the area of 4-substituted pipecolic acids alone has resulted in novel
therapeutically relevant agents (Fig. 1) in areas such as HIV-1 protease inhibition (Palinavir), N-methyl-
D-aspartic acid (NMDA) receptor antagonism (Selfotel), and thrombin inhibition (Argatroban). With
the exception of Argatroban, however, which incorporates the (2R,4R) 4-methyl-2-piperidinecarboxylate
(4-MPE), few examples exist in the literature specifically relating to the targeted synthesis of 4-trans-
substituted pipecolic acids.3,4
We describe a synthetic protocol (outlined in Scheme 1) to obtain the 4-isopropyl, 4-tert-butyl, and
4-phenyl trans-substituted pipecolic acids, starting from 4-cis-substituted pipecolic acids, which are
readily accessible via a variety of well documented methods (A).2 These adducts may then be derivatized
∗
†
Corresponding author. Fax: (617) 494 8144; e-mail: terry.keenan@ariad.com
Dedicated to Professor Ralph F. Hirschmann on the occasion of his receipt of the 1999 Arthur C. Cope Award.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00473-5
tetasy 3109

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Fig. 1.
as their respective benzyl or tert-butyl carbamates and resolved to afford diastereomerically enriched
products of the unnatural 2R configuration (B). Subsequent esterification and epimerization to the more
thermodynamically stable 4-trans-substituted pipecolic acids then provides the natural 2S configuration
(C). Final synthetic manipulation of the N-protected amino ester to the desired functionality for further
chemical elaboration is then easily attended (D).
Scheme 1.
2. Results and discussion
2.1. Synthesis of cis-substituted pipecolic acids
Both the 4-isopropyl, and the known 4-tert-butyl,5 cis-pipecolic acids were prepared by the method
of Schuman and co-workers5 from commercially available 4-alkylpyridines (Scheme 2). The result-
ing amino acids were then derivatized as their benzyl carbamates under standard Schotten–Baumann
conditions6 in order to provide a chromophore for aid in chiral HPLC analysis.
Scheme 2. Reagents and conditions: (a) H2O2, HOAc; (b) TMSCN, CH2Cl2, (CH3)2NCOCl; (c) HCl, H2O, reflux; (d) H2, PtO2,
EtOH/H2O; (e) CbzCl, H2O, NaOH; (f) sec-BuLi, Et2O, TMEDA, CO2(g)
Due to the problematic nature of the reduction of 4-phenylpyridine, we investigated alternate methods
of synthesis of 4-phenylpipecolic acid. While a five-step, 50% overall yield, synthesis of (±)-cis-4-
phenylpipecolic acid has been reported by Nazih and co-workers,7 it also utilizes 4-phenylpyridine as its
starting material which must be reduced via an N-acyl-dihydropyridine followed by a two-stage oxidative

T. P. Keenan et al. / Tetrahedron: Asymmetry 10 (1999) 4331–4341
4333
transformation of a 2-(phenyldimethylsilyl)methyl group to generate the 2-carboxyl group of pipecolic
acid. We opted, therefore, to utilize an alternative protocol involving the direct carboxylation of the
fully saturated piperidine derivative (Scheme 2). It is well known from the work of Beak, Seebach, and
Meyers that the dipole-stabilized carbanion resulting from removal of the α0-proton of appropriately N-
protected 4-substituted piperidines may be trapped by various electrophiles resulting in a highly selective
2,4-syn-equatorial relationship.8 We have found that the anion resulting from deprotonation of N-Boc-
4-phenylpiperidine with sec-BuLi and TMEDA in ether solution readily reacted at −78°C with gaseous
carbon dioxide to provide the cis-4-phenylpipecolic acid derivative, 3, which could be crystallized from
the crude reaction mixture in 61% yield. The pipecolyl C-2 proton of 3 exhibited the expected coupling
constants with the adjacent methylene of 10.5 and 5.6 Hz, indicating an equatorial disposition of the
carboxyl group. Likewise, adducts 1 and 2 exhibited similar coupling constants of 8.1, 6.5, and 10.7,
5.9 Hz, respectively. In point of interest, Fraser, in some of the earliest work in the field of α-amino
carbanions,9 reported the carboxylation of N-nitroso-4-phenylpiperidine with carbon dioxide to afford
exclusively the 2-trans-carboxy derivative in good yield. This method would afford ready access to (±)-
trans-4-phenylpipecolic acid.
2.2. Resolution of cis-substituted pipecolic acids
With the desired 4-substituted pipecolic acids in hand, we took advantage of the known ability of
L-tyrosine hydrazide to resolve the unnatural D form of either the benzyl or tert-butyl carbamate of
pipecolic acid10 as well as benzyl carbamate derivative of D-proline.11 Treatment of 1–3 with 0.9 equiv.
of L-tyrosine hydrazide in refluxing methanol resulted in an optically enhanced salt complex (∼1:1
complex by proton NMR) with an enrichment of 85, 79, and 40% ee, respectively. Recrystallization of the
diastereomeric salts provided material of 98, 99.0, and 82% ee, respectively. A second recrystallization
for the salts derived from 1 and 3 then afforded material of 99.0 and 98.5% ee, respectively. The overall
non-optimized yields for the free acids 4a–c were 37, 50 and 50% of theoretical. It should be noted that
resolution of the benzyl carbamate analogue of compound 3 does provide the identical diastereomer.
2.3. Epimerization of cis-substituted pipecolic acids
The resolved cis-D-amino acids 4a–c were converted to their corresponding trans-L-isomers by
catalytic epimerization with sodium methoxide via their respective methyl esters 5a–c (Scheme 3).
Although all acids could be converted to their corresponding methyl esters via a DCC/DMAP coupling in
excellent yields without detectable epimerization, we found it expedient to effect conversion of the acid
stable benzyl carbamates 4a and 4b by use of thionyl chloride in methanol. Equilibration of 5a–c to the
thermodynamically more stable axially substituted adducts 6a–c, thus relieving A1,3 strain,12 occurs in
∼98% yield (as evidenced by proton NMR analysis) with isolated yields of 95, 83, and 93%, respectively.
The pipecolyl C-2 protons of 6a–c exhibited the expected range of coupling constants with the adjacent
methylene of 4.5–5 Hz indicating an axial disposition of the carboxymethyl group. Removal of the
carbamate protecting groups by either catalytic hydrogenation or acid deprotection afforded the free
amines 7a,b and hydrochloride 7c which served as key starting materials for our research program.
2.4. CD analysis
In order to provide additional support13 in assigning the absolute stereochemistry of 7a–c, we
investigated the use of chiroptical methods of assignment. It is well known that circular dichroism

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Scheme 3. Reagents and conditions: (a) MeOH, SOCl2; (b) MeOH, DCC, DMAP, CH2Cl2, 0°C; (c) NaOMe, MeOH; (d) 10%
Pd/C, H2, MeOH; (e) HCl(g), CH2Cl2, 0°C
(CD) can be used to rapidly assign the absolute configuration of α-amino acids. All naturally occurring
and most synthetic α-amino acids, specifically reported are 2- or 6-alkyl substituted pipecolic acids,14
exhibit a diagnostic positive Cotton effect, generally attributed to the n–π* transition of the carboxyl
group, centered near 203 nm for the zwitterionic form in water and 210–208 nm for acidic solutions.
To this end, all three amino esters, as well as carbamates 5b and 5c, were hydrolyzed with 6 N HCl to
provide the amino acid hydrochlorides 8a–e (Scheme 4). CD spectra of 8a,b in water exhibited the
expected positive Cotton effect at 209 nm and were essentially identical with both L-pipecolic acid
hydrochloride and (2S,4S) trans-4-methyl-L-pipecolic acid hydrochloride which was prepared via an
asymmetric Aza-Diels–Alder protocol as described by Bailey and co-workers.4,15 In contrast, controls
8d and D-pipecolic acid hydrochloride exhibited negative Cotton effects at 208 and 210 nm, respectively.
Due to the presence of a chiroptically interfering chiral aromatic group in adduct 8c and its previously
reported enantiomer 8e,7 they were further derivatized as their N-2,4-dinitrophenyl (DNP) derivatives
by the use of Sanger’s reagent.16 A diagnostic negative Cotton effect in the range of 400–325 nm is
observed for DNP-derivatized cyclic L-amino acids with a specific study of pipecolic acid and closely
related analogues having been performed by Nagai and Kani.17 The DNP derivative of L-pipecolic acid
and 8c exhibited essentially identical CD spectra in methanol with a negative Cotton effect occurring
in the 400–325 nm region. Conversely, both the DNP derivative of D-pipecolic acid and 8e exhibited a
positive Cotton effect over this region.
Scheme 4.
In summary, we have described a useful preparative procedure for the synthesis of (±) cis-4-
phenylpipecolic acid as well as a general strategy for the resolution of various 4-substituted cis-D-
pipecolic acids and an efficient conversion to their corresponding trans-L-pipecolic acid isomers.

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4335
3. Experimental
All reagents and solvents were obtained from commercial sources and used without further puri-
fication. All melting points were measured on a Laboratory Devices MEL-TEMP II apparatus and are
1
uncorrected. All IR spectra were recorded on a Perkin–Elmer 1600 Series FT-IR and H, 19F, and 13C
spectra on a Bruker ARX-300 instrument. Chemical shifts are reported downfield from tetramethyl-
silane. Low resolution mass spectra (LRMS) were obtained on a Micromass Platform II quadrupole
mass spectrometer operating in electrospray mode while high resolution mass spectra (HRMS) were
obtained on a Micromass LCT time-of-flight (TOF) mass spectrometer operating in electrospray mode.
Data for HRMS were recorded at a nominal mass resolution of 5000 and internally calibrated using
reference ions from poly(ethylene glycol) or poly(propylene glycol) as appropriate. Optical rotations,
using a Perkin–Elmer 341 polarimeter, as well as elemental analyses, were obtained from Robertson
Microlit Labs (Madison, NJ, USA). CD spectra were obtained on a Jasco J-710 spectropolarimeter using
substrate concentrations of ∼1–3 mg/mL and a 0.1 cm pathlength. Flash chromatography was performed
on silica gel (Merck, 230–400 mesh). Analytical TLC was performed on silica gel 60 F254 plates (Merck).
Chiral HPLC was performed on Chiral Technologies Inc., (Exton, PA, USA) analytical columns.
3.1. (2R,4S)-cis-4-(2-Propyl)-1,2-piperidinedicarboxylic acid, 1-(phenylmethyl) ester (4a)
A solution of racemic Cbz-protected amino acid 1 (23.6 g, 77.3 mmol) in MeOH (200 mL) was treated
with L-tyrosine hydrazide (13.6 g, 69.6 mmol) and the mixture heated at reflux until a homogeneous
solution was achieved. The solution was allowed to cool and the precipitated salt collected (∼13 g) to
afford material of 85% ee. Recrystallization from MeOH (75 mL) afforded material (∼8 g) of 98% ee.
A final recrystallization from MeOH (75 mL) afforded material (∼7 g) of 99% ee. The free acid was
obtained by partitioning between EtOAc (100 mL) and 1 N HCl (100 mL). The organic phase was
washed with additional 1 N HCl (50 mL) followed by a brine solution (3×50 mL) then dried over
Na2SO4, filtered, and concentrated for material (4.4 g, 37% of theoretical) of similar diastereomeric
purity (99.0% ee by Chiralpak AD HPLC, 20% iso-PrOH/hexane, 0.2% TFA, retention time 5.3 min
for the (2S)-L-enantiomer and 6.2 min for the (2R)-D-enantiomer. Chiralcel OD HPLC may also be
used, 20% EtOH/hexane, 0.2% TFA, retention time 4.3 min for the (2S)-L-enantiomer and 10.9 min for
the (2R)-D-enantiomer): [α]D25=+42.8 (c=1.06, CHCl3); TLC (MeOH:CHCl3, 5:95) Rf=0.25; IR (neat)
2960, 1710, 1425, 1250 cm−1; 1H NMR (CDCl3, 300 MHz) 9.58 (br s, 1H), 7.31 (s, 5H), 5.13 (s, 2H),
4.35 (t, J=8.1 Hz, 1H), 3.64 (br s, 1H), 3.43 (br s, 1H), 2.08–2.00 (m, 1H), 1.78–1.71 (m, 2H), 1.54–1.31
(m, 3H), 0.90–0.85 (m, 6H); 13C NMR (CDCl3, 75 MHz) 178.4, 157.0, 136.8, 128.9, 128.4, 127.9, 67.9,
55.8, 40.7, 38.5, 31.2, 29.2, 26.8, 20.4, 20.3; LRMS (ES−): (M−H)− 304; HRMS (ES+): (M+H)+ calcd:
306.1705; meas.: 306.1692.
3.2. (2R,4S)-cis-4-(tert-Butyl)-1,2-piperidinedicarboxylic acid, 1-(phenylmethyl) ester (4b)
A solution of racemic Cbz-protected amino acid 2 (7.18 g, 22.5 mmol) in MeOH (50 mL) was treated
with L-tyrosine hydrazide (3.95 g, 20.2 mmol) and the mixture heated at reflux until a homogeneous so-
lution was achieved. The solution was allowed to cool and the precipitated salt collected (∼4 g) to afford
material of 79% ee. Recrystallization from MeOH (50 mL) afforded material (∼3 g) of 99% ee. The free
acid was isolated (1.78 g, 50% of theoretical) as described for compound 4a (99.0% ee by Chiralcel OD
HPLC, 10% 2-propanol/hexane, 0.2% TFA, retention time 6.0 min for the (2S)-L-enantiomer and 15.1
min for the (2R)-D-enantiomer): [α]D25=+55.2 (c=1.00, CHCl3); TLC (MeOH:CHCl3, 5:95) Rf=0.25;

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IR (neat) 2960, 1710, 1430, 1245 cm−1; 1H NMR (CDCl3, 300 MHz) 10.88 (br s, 1H), 7.33 (s, 5H), 5.14
(s, 2H), 4.26 (dd, J=10.8, 6.3 Hz, 1H), 3.64 (br s, 1H), 3.46 (br s, 1H), 2.13–2.08 (m, 1H), 1.83–1.80
(m, 1H), 1.60–1.48 (m, 1H), 1.41–1.25 (m, 2H), 0.86 (s, 9H); 13C NMR (CDCl3, 75 MHz) 178.4, 156.5,
136.4, 128.5, 128.0, 127.8, 67.5, 56.7, 42.0, 40.9, 32.6, 26.9, 24.2; LRMS (ES+): (M+Na)+ 342; (ES−):
(M−H)− 318; HRMS (ES+): (M+H)+ calcd: 320.1862; meas.: 320.1862.
3.3. (2R,4S)-cis-4-Phenyl-piperidine-1,2-dicarboxylic acid, 1-tert-butyl ester (4c)
A solution of 4-phenyl-piperidine-1,2-dicarboxylic acid, 1-tert-butyl ester (26.1 g, 100 mmol) in
diethyl ether (200 mL) was cooled to −78°C and treated with TMEDA (15.1 mL, 100 mmol) followed
by slow addition of a 1.3 M cyclohexane solution of sec-butyllithium (92.3 mL, 120 mmol) solution over
a 30 min period. The reaction mixture was allowed to slowly warm to −20°C and kept at this temperature
for 30 min, after which time the solution was re-cooled to −78°C and the solution purged with gaseous
carbon dioxide for 15 min. The mixture was removed from the cooling bath and allowed to warm to 0°C
when it was poured onto a biphasic mixture of EtOAc (200 mL) and 1 N HCl (500 mL). The organic
component was further washed with 1 N HCl (2×200 mL) followed by a brine solution (3×100 mL),
dried over Na2SO4, filtered, and evaporated to afford a crude oil. The crude product was diluted with
EtOAc (25 mL) and allowed to crystallize to afford 16.2 g (53%) of product as a colorless solid 3. A
second crop (2.5 g, 8%) of product was obtained on sitting for two days. The resolution of acid 3 was
achieved as follows. A solution of the Boc-protected amino acid (18.0 g, 59.0 mmol) in MeOH (125
mL) was treated with L-tyrosine hydrazide (10.4 g, 53.1 mmol) and the mixture heated at reflux until a
homogeneous solution was achieved. The solution was allowed to cool and the precipitated salt collected
(15.1 g) to afford material of ∼40% ee. Recrystallization from MeOH (100 mL) afforded material (9.6
g) of ∼80% ee. A final recrystallization from MeOH (75 mL) afforded material (7.2 g). The free acid
was isolated (4.5 g, 50% of theoretical) as an oil as described for compound 4 (98.5% ee by Chiralpak
AD HPLC, 10% 2-propanol/hexane, 0.1% TFA, retention time 7.2 min for the (2R)-D-enantiomer and
9.9 min for the (2S)-L-enantiomer): mp (2R/S racemate) 112.5–113°C; [α]D25=+19.4 (c=1.03, CHCl3);
1
TLC (EtOAc) Rf=0.45; IR (neat) 2975, 1700, 1395, 1250, 1160 cm−1; H NMR (CDCl3, 300 MHz)
11.69 (br s, 1H), 7.32–7.17 (s, 5H), 4.19 (dd, J=10.5, 5.6 Hz, 1H), 3.83–3.75 (m, 1H), 3.49–3.26 (m,
1H), 2.82–2.72 (m, 1H), 2.26 (dt, J=13.4, 4.1 Hz, 1H), 2.08–1.95 (m, 2H), 1.85–1.74 (m, 1H), 1.46 (s,
9H); 13C NMR (CDCl3, 75 MHz) 178.3, 156.0, 144.6, 128.6, 126.8, 126.6, 81.2, 56.7, 42.0, 38.5, 33.6,
30.8, 28.2; LRMS (ES−): (M−H)− 304. Anal. calcd for C17H23NO4 (2R/S racemate): C, 66.86; H, 7.59;
N, 4.59. Found: C, 66.8; H, 7.48; N, 4.40.
3.4. (2R,4S)-cis-4-(2-Propyl)-1,2-piperidinedicarboxylic acid, 2-methyl, 1-(phenylmethyl) ester (5a)
A solution of the resolved acid 4a (6.50 g, 21.3 mmol) in MeOH (30 mL) was added via a syringe to
a −20°C solution of MeOH (25 mL) containing thionyl chloride (5.07 g, 42.6 mmol). The solution was
allowed to warm to room temperature and stirred for 16 h, after which time the reaction was evaporated
and the crude material flash chromatographed on silica gel (15% then 25% EtOAc/hexane) to afford
product (6.34 g, 93%) as an oil: TLC (EtOAc:hexane, 15:85) Rf=0.29; IR (neat) 2955, 2870, 1745, 1710,
1415, 1330, 1245 cm−1; 1H NMR (CDCl3, 300 MHz) 7.33 (s, 5H), 5.18–5.07 (m, 2H), 4.30 (dd, J=8.1,
6.5 Hz, 1H), 3.66 (br s, 4H), 3.50 (br s, 1H), 2.02–1.95 (m, 1H), 1.79–1.69 (m, 2H), 1.55–1.38 (m, 2H),
1.36–1.30 (m, 1H), 0.89–0.86 (m, 6H); 13C NMR (CDCl3, 75 MHz) 173.6, 156.7, 136.9, 128.8, 128.4,
128.3, 67.7, 56.1, 52.4, 40.8, 38.7, 30.9, 29.5, 27.0, 20.4; LRMS (ES+): (M+H)+ 320, (M+NH4)+ 337,
(M+Na)+ 342; HRMS (ES+): (M+H)+ calcd: 320.1862; meas.: 320.1847.

T. P. Keenan et al. / Tetrahedron: Asymmetry 10 (1999) 4331–4341
4337
3.5. (2R,4S)-cis-4-(tert-Butyl)-1,2-piperidinedicarboxylic acid, 2-methyl, 1-(phenylmethyl) ester (5b)
Prepared from 4b by the method described for compound 5a. Product (2.0 g, 85%) was isolated as an
oil: TLC (EtOAc:hexane, 15:85) Rf=0.29; IR (neat) 2960, 2870, 1750, 1700, 1420, 1335, 1245 cm−1
;
1H NMR (CDCl3, 300 MHz) 7.33 (s, 5H), 5.18–5.06 (m, 2H), 4.18 (dd, J=10.7, 5.9 Hz, 1H), 3.66 (br s,
3H), 3.53 (br s, 2H), 2.06–2.02 (m, 1H), 1.81–1.71 (m, 1H), 1.54–1.42 (m, 1H), 1.38–1.31 (m, 2H), 0.85
(m, 9H); 13C NMR (CDCl3, 75 MHz) 173.6, 156.7, 136.9, 128.8, 128.4, 128.3, 67.7, 57.5, 52.4, 42.6,
41.7, 32.9, 27.6, 27.3, 24.8; LRMS (ES+): (M+H)+ 334, (M+NH4)+ 351, (M+Na)+ 356; HRMS (ES+):
(M+H)+ calcd: 334.2018; meas.: 334.2032.
3.6. (2R,4S)-cis-4-Phenyl-piperidine-1,2-dicarboxylic acid, 1-tert-butyl ester, 2-methyl ester (5c)
A solution of acid 4c (2.5 g, 8.19 mmol), MeOH (398 µL, 9.82 mmol), and DMAP (20 mg, 0.16
mmol) in CH2Cl2 (8.0 mL) at 0°C was treated with DCC (1.77 g, 8.60 mmol). The mixture was allowed
to stir for 2 h, after which time it was allowed to warm to room temperature, diluted with EtOAc (25
mL), and filtered through a plug of Celite. The filtrate was concentrated and the crude material flash
chromatographed on silica gel (10% then 20% EtOAc/hexane) to afford product (2.40 g, 92%) as an oil:
TLC (EtOAc:hexane, 1:9) Rf=0.19; IR (neat) 2975, 1750, 1700, 1455, 1400, 1365, 1250, 1170 cm−1
;
1H NMR (CDCl3, 300 MHz) 7.33–7.17 (s, 5H), 4.20 (dd, J=9.9, 5.5 Hz, 1H), 3.81–3.74 (m, 1H), 3.64
(s, 3H), 3.53–3.46 (m, 1H), 2.85–2.75 (m, 1H), 2.27–2.18 (m, 1H), 2.09–2.01 (m, 2H), 1.89–1.77 (m,
1H), 1.46 (s, 9H); 13C NMR (CDCl3, 75 MHz) 172.7, 156.0, 144.6, 128.6, 126.9, 126.5, 80.6, 56.6, 51.9,
41.9, 38.2, 33.6, 30.5, 28.3; LRMS (ES+): (M+Na)+ 342; HRMS (ES+): (M+H)+ calcd: 320.1862; meas.:
320.1876.
3.7. (2S,4S)-trans-4-(2-Propyl)-1,2-piperidinedicarboxylic acid, 2-methyl, 1-(phenylmethyl) ester (6a)
A solution of aminoester 5a (6.00 g, 18.8 mmol) in MeOH (6.0 mL) was treated with a 25 wt%
methanolic solution of sodium methoxide (430 µL) and allowed to stir at room temperature for four
days. The reaction mixture was then partitioned between EtOAc (50 mL) and 1 N HCl (50 mL). The
organic phase was washed with additional 1 N HCl (50 mL) followed by a brine solution (2×50 mL) then
dried over Na2SO4, filtered, and concentrated for crude material containing an ∼2:98 ratio of cis:trans
isomers. The crude material was flash chromatographed on silica gel (15% then 20% EtOAc/hexane) to
afford product (5.68 g, 95%) as an oil: TLC (EtOAc:hexane, 15:85) Rf=0.33; IR (neat) 2955, 1745, 1705,
1
1420, 1335, 1225, 1170, 1100 cm−1; H NMR (1:1 mixture of rotamers, CDCl3, 300 MHz) 7.35 and
7.31 (s, 5H), 5.49 (s, 2H), 5.01 and 4.90 (d, J=4.6 and 4.6 Hz, 1H), 4.13 (t, J=19.2 Hz, 1H), 3.73 and 3.67
(s, 3H), 3.10–2.91 (m, 1H), 2.22 (t, J=13.3 Hz, 1H), 1.71–1.60 (m, 1H), 1.49–1.35 (m, 2H), 1.19–1.09
(m, 2H), 0.88–0.85 (m, 6H); 13C NMR (CDCl3, 75 MHz) 172.6, 156.8 and 156.2, 137.1, 128.9, 128.4,
128.2, 67.7 and 67.6, 55.3 and 55.1, 52.5, 42.4, 39.1, 32.5, 30.8 and 30.6, 28.6 and 28.3, 19.9 and 19.9;
LRMS (ES+): (M+H)+ 320, (M+NH4)+ 337; HRMS (ES+): (M+H)+ calcd: 320.1862; meas.: 320.1848.
3.8. (2S,4S)-trans-4-(tert-Butyl)-1,2-piperidinedicarboxylic acid, 2-methyl, 1-(phenylmethyl) ester (6b)
Prepared from 5b by the method described for compound 6a. Product (5.2 g, 83%) was isolated as
an oil: TLC (EtOAc:hexane, 15:85) Rf=0.33; IR (neat) 2955, 1745, 1710, 1420, 1330, 1265, 1170, 1090
cm−1; 1H NMR (1:1 mixture of rotamers, CDCl3, 300 MHz) 7.35 and 7.31 (s, 5H), 5.16 (s, 2H), 5.03 and
4.91 (d, J=4.8 and 4.8 Hz, 1H), 4.21–4.10 (m, 1H), 3.73 and 3.67 (s, 3H), 3.10–2.90 (m, 1H), 2.31–2.22

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(m, 1H), 1.73–1.62 (m, 1H), 1.46–1.35 (m, 1H), 1.22–1.01 (m, 2H), 0.85 (m, 9H); 13C NMR (CDCl3, 75
MHz) 172.2, 156.8 and 155.8, 136.7, 128.5, 128.0, 127.8, 67.3 and 67.2, 55.1 and 54.9, 52.1, 42.7, 42.3
and 42.2, 32.0, 28.1 and 28.0, 27.1, 26.1 and 25.8; LRMS (ES+): (M+Na)+ 356; HRMS (ES+): (M+H)+
calcd: 334.2018; meas.: 334.2007.
3.9. (2S,4S)-trans-4-Phenyl-piperidine-1,2-dicarboxylic acid, 1-tert-butyl ester, 2-methyl ester (6c)
Prepared from 5c by the method described for compound 6a. Product (1.85 g, 93%) was isolated as an
oil: TLC (EtOAc:hexane, 1:9) Rf=0.29; IR (neat) 2975, 1745, 1695, 1455, 1395, 1365, 1235, 1160 cm−1
;
1H NMR (1:1 mixture of rotamers, CDCl3, 300 MHz) 7.33–7.17 (s, 5H), 5.07 and 4.88 (d, J=5.0 and 5.1
Hz, 1H), 4.19 and 4.08 (d, J=12.9 and 13.2 Hz, 1H), 3.78 and 3.76 (s, 3H), 3.16 and 3. 08 (td, J=13.1, 2.8
and 13.2, 2.9 Hz, 1H), 2.55 (tt, J=12.6, 3.2 Hz, 1H), 2.44–2.38 (m, 1H), 2.04–1.80 (m, 2H), 1.68–1.57
(m, 1H), 1.50 and 1.46 (s, 9H); 13C NMR (CDCl3, 75 MHz) 172.8 and 172.2, 155.8 and 155.4, 145.0,
128.6, 126.7, 126.6, 80.2, 55.2 and 54.0, 52.2, 42.2 and 41.4, 38.7 and 38.6, 34.0 and 33.8, 32.5 and 32.2,
28.4; LRMS (ES+): (M+Na)+ 342; HRMS (ES+): (M+H)+ calcd: 320.1862; meas.: 320.1851.
3.10. (2S,4S)-trans-4-(2-Propyl)-2-piperidinecarboxylic acid, methyl ester (7a)
A solution of the Cbz-protected aminoester 6a (6.00 g, 18.8 mmol) in MeOH (30 mL) was treated
with 10 wt% Pd/C (600 mg) and purged with hydrogen for 10 min followed by vigorous stirring in an
atmosphere of hydrogen (via balloon) for 4 h. The reaction mixture was filtered through a pad of Celite,
the filtrate evaporated, and material flash chromatographed on silica gel (5% then 10% MeOH/CH2Cl2)
to afford product (3.0 g, 86%) as a liquid: TLC (MeOH:CHCl3, 5:95) Rf=0.25; IR (neat) 2955, 1735,
1465, 1370, 1210, 1175 cm−1; 1H NMR (CDCl3, 300 MHz) 3.73 (s, 3H), 2.91 (dt, J=7.3, 3.5 Hz, 1H),
2.78 (td, J=11.3, 2.4 Hz, 1H), 2.24 (s, 1H), 2.13 (dd, J=13.1, 2.3 Hz, 1H), 1.60 (dd, J=10.4, 2.4 Hz, 1H),
1.57–1.40 (m, 2H), 1.24 (qd, J=11.4, 4.3 Hz, 1H), 1.15–1.06 (m, 1H), 0.90–0.86 (m, 6H); 13C NMR
(CDCl3, 75 MHz) 175.0, 56.1, 51.8, 42.9, 39.3, 32.2, 30.3, 28.9, 19.7, 19.5; LRMS (ES+): (M+H)+ 186;
HRMS (ES+): (M+H)+ calcd: 186.1494; meas.: 186.1503.
3.11. (2S,4S)-trans-4-(tert-Butyl)-2-piperidinecarboxylic acid, methyl ester (7b)
Prepared from 6b by the method described for compound 7a. Product (378 mg, 85%) was isolated as
a liquid: TLC (MeOH:CHCl3, 5:95) Rf=0.25; IR (neat) 3352, 2955, 1735, 1470, 1365, 1215, 1170 cm−1
;
1H NMR (CDCl3, 300 MHz) 3.74 (s, 3H), 2.95 (dt, J=6.8, 3.4 Hz, 1H), 2.77 (td, J=12.0, 2.6 Hz, 1H),
2.32 (s, 1H), 2.22 (dd, J=13.1, 2.6 Hz, 1H), 1.63 (dt, J=12.5, 2.7 Hz, 1H), 1.49 (td, J=12.7, 5.3 Hz, 1H),
1.24 (qd, J=12.2, 4.3 Hz, 1H), 1.02 (tt, J=12.3, 3.1 Hz, 1H), 0.86 (m, 9H); 13C NMR (CDCl3, 75 MHz)
174.3, 56.7, 52.0, 43.7, 32.5, 28.1, 27.4, 27.0; LRMS (ES+): (M+H)+ 200; HRMS (ES+): (M+H)+ calcd:
200.1650, meas.: 200.1660.
3.12. (2S,4S)-trans-4-Phenyl-piperidine-2-carboxylic acid, methyl ester hydrochloride (7c)
A solution of the Boc-protected aminoester 6c (435 mg, 1.36 mmol) in CH2Cl2 (15 mL) at 0°C was
treated with a steam of gaseous HCl for 5 min. The mixture was allowed to warm to room temperature
and stirred for 1 h, after which time it was diluted with CH2Cl2 (10 mL) and concentrated to afford
product: (free base, MeOH:CHCl3, 7.5:92.5) Rf=0.36; IR (free base, neat) 3185, 2950, 1740, 1600, 1450,
1245, 1170 cm−1; 1H NMR (CDCl3, 300 MHz) 10.56 (br s, 1H), 9.57 (br s, 1H), 7.35–7.22 (s, 5H), 4.71

T. P. Keenan et al. / Tetrahedron: Asymmetry 10 (1999) 4331–4341
4339
(br s, 1H), 3.89 (s, 3H), 3.67 (d, J=12.1 Hz, 1H), 3.47–3.43 (s, 1H), 2.74–2.67 (m, 1H), 2.62–2.46 (m,
2H), 2.35–2.24 (m, 1H), 2.03 (d, J=13.5 Hz, 1H); 1H NMR (free base, CDCl3, 300 MHz) 7.34–7.19 (s,
5H), 6.70 (br s, 1H), 4.19 (br s, 1H), 3.83 (s, 3H), 3.35–3.10 (m, 2H), 2.66–2.62 (m, 1H), 2.41 (d, J=12.6
Hz, 1H), 2.24–2.21 (m, 1H), 2.05–1.85 (m, 2H); 13C NMR (CDCl3, 75 MHz) 168.7, 142.7, 128.8, 127.2,
126.7, 54.3, 53.3, 41.6, 37.2, 31.3, 29.2; 13C NMR (free base, CDCl3, 75 MHz) 172.2, 144.6, 128.6,
126.8, 126.6, 55.3, 52.5, 42.4, 38.4, 32.8, 31.5; LRMS (ES+): (M+H)+ 220; HRMS (ES+): (M+H)+
calcd: 220.1337; meas.: 220.1332.
3.13. (2S,4S)-trans-4-(2-Propyl)-piperidine-2-carboxylic acid, hydrochloride (8a)
A solution of aminoester 7a (200 mg, 1.08 mmol) in 6 N HCl (2 mL) was heated at 95°C for 6 h then
1
evaporated to a free flowing powder: [α]D25=+16.3 (c=1.01, MeOH); H NMR (DMSO-d6, 300 MHz)
13.81 (br s, 1H), 9.88 (br s, 1H), 8.83 (br s, 1H), 4.20 (t, J=4.2 Hz, 1H), 3.11–2.96 (m, 2H), 1.99 (d,
J=13.8 Hz, 1H), 1.74–1.64 (m, 2H), 1.51–1.36 (m, 2H), 1.14–1.05 (m, 1H), 0.79 (d, J=2.4 Hz, 3H), 0.77
1
(d, J=2.4 Hz, 3H); 13C NMR (DMSO-d6, 75 MHz) 169.5, 52.8, 40.2, 36.4, 30.1, 27.1, 24.2, 19.0; H
NMR (D2O, 300 MHz) 4.37 (t, J=4.7 Hz, 1H), 3.45–3.28 (m, 2H), 2.34 (br d, J=14.6 Hz, 1H), 1.95 (br
dd, J=14.5, 2.3 Hz, 1H), 1.89–1.79 (m, 2H), 1.68–1.51 (m, 2H), 1.46–1.34 (m, 1H), 0.97 (d, J=4.5 Hz,
3H), 0.95 (d, J=4.5 Hz, 3H); 13C NMR (D2O, 75 MHz) 172.0, 54.9, 41.9, 37.1, 30.5, 28.2, 25.3, 19.2;
HRMS (ES+): (M+H)+ calcd: 172.1337; meas.: 172.1346.
3.14. (2S,4S)-trans-4-(tert-Butyl)-piperidine-2-carboxylic acid, hydrochloride (8b)
1
Prepared from 7b by the method described for compound 8a: [α]D25=+14.5 (c=0.96, MeOH); H
NMR (DMSO-d6, 300 MHz) 13.89 (br s, 1H), 10.14 (br s, 1H), 8.86 (br s, 1H), 4.34 (d, J=3.1 Hz, 1H),
3.20 (d, J=12.2 Hz, 1H), 3.05 (t, J=11.8 Hz, 1H), 2.15 (d, J=13.6 Hz, 1H), 1.79–17.0 (m, 2H), 1.52 (qd,
J=12.9, 4.1 Hz, 1H), 1.07 (t, J=12.3 Hz, 1H), 0.82 (s, 9H); 13C NMR (DMSO-d6, 75 MHz) 169.4, 53.1,
40.5, 40.4, 31.4, 26.3, 25.0, 22.3; 1H NMR (D2O, 300 MHz) 4.48 (d, J=3.9 Hz, 1H), 3.47 (br d, J=12.4
Hz, 1H), 3.31 (td, J=13.1, 3.1 Hz, 1H), 2.47 (br dd, J=14.6, 2.4 Hz, 1H), 2.00 (br dt, J=14.0, 2.4 Hz, 1H),
1.74 (td, J=12.8, 5.5 Hz, 1H), 1.50 (qd, J=13.0, 4.6 Hz, 1H), 1.29 (tt, J=12.4, 2.6 Hz, 1H), 0.93 (s, 9H);
13C NMR (D2O, 75 MHz) 171.7, 55.3, 42.6, 41.0, 31.6, 26.4, 26.1, 23.6; HRMS (ES+): (M+H)+ calcd:
186.1494; meas.: 186.1503.
3.15. (2S,4S)-trans-4-Phenyl-piperidine-2-carboxylic acid, hydrochloride (8c)
Prepared from 7c by the method described for compound 8a: [α]D25=+50.4 (c=1.02, MeOH); 1H NMR
(DMSO-d6, 300 MHz) 13.98 (br s, 1H), 10.17 (br s, 1H), 8.95 (br s, 1H), 7.29–7.24 (m, 2H), 7.18–7.13
(m, 3H), 4.32 (t, J=3.5 Hz, 1H), 3.17 (d, J=4.4 Hz, 2H), 2.69–2.62 (m, 1H), 2.18–2.15 (m, 2H), 1.99–1.79
(m, 2H); 13C NMR (DMSO-d6, 75 MHz) 170.0, 144.1, 129.0, 127.1, 126.9, 53.7, 41.1, 36.4, 31.1, 28.9;
1H NMR (D2O, 300 MHz) 7.52–7.37 (m, 5H), 4.49 (dd, J=5.0, 3.5 Hz, 1H), 3.53–3.49 (m, 2H), 2.97 (tt,
J=11.5, 3.5 Hz, 1H), 2.48 (dd, J=14.7, 1.8 Hz, 1H), 2.27 (qd, J=11.9, 5.3 Hz, 1H), 2.18–1.96 (m, 2H);
13C NMR (D2O, 75 MHz) 171.5, 143.7, 129.4, 127.6, 127.2, 55.0, 42.0, 36.2, 31.4, 28.9; HRMS (ES+):
(M+H)+ calcd: 206.1181; meas.: 206.1170.
8c-DNP: TLC (MeOH:CHCl3, 1:9) Rf=0.30; IR (neat) 2935, 1715, 1605, 1520, 1340 cm−1; 1H NMR
(CDCl3, 300 MHz) 8.74 (d, J=2.2 Hz, 1H), 8.31 (dd, J=9.1, 2.2 Hz, 1H), 7.35–7.24 (m, 6H), 4.32 (s,
1H), 3.74–3.65 (m, 1H), 3.48 (d, J=12.4 Hz, 1H), 2.77 (br s, 1H), 2.51 (d, J=13.1 Hz, 1H), 2.29–2.18
(m, 1H), 2.00 (br s, 1H); 13C NMR (CDCl3, 75 MHz) 176.2, 150.0, 143.8, 139.8, 139.2, 128.8, 128.3,

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T. P. Keenan et al. / Tetrahedron: Asymmetry 10 (1999) 4331–4341
127.0, 126.7, 123.3, 121.7, 61.3, 48.4, 38.2, 34.0, 32.1; HRMS (ES+): (M+H)+ calcd: 372.1195; meas.:
372.1208.
3.16. (2R,4S)-cis-4-(tert-Butyl)-piperidine-2-carboxylic acid, hydrochloride (8d)
1
Prepared from 5b by the method described for compound 8a: [α]D25=−13.7 (c=0.98, MeOH); H
NMR (D2O, 300 MHz) 3.94 (dd, J=11.7, 2.6 Hz, 1H), 3.61 (dt, J=13.0, 3.9 Hz, 1H), 3.05 (td, J =12.8,
3.0 Hz, 1H), 2.44 (br d, 1H), 2.04 (br d, 1H), 1.58–1.46 (m, 3H), 0.96 (s, 9H); 13C NMR (D2O, 75 MHz)
172.6, 58.2, 44.5, 44.2, 31.9, 27.8, 26.6, 23.1; HRMS (ES+): (M+H)+ calcd: 186.1494; meas.: 186.1503.
3.17. (2R,4S)-cis-4-Phenyl-piperidine-2-carboxylic acid, hydrochloride (8e)
Prepared from either 5c or 4c by the method described for compound 8a: [α]D25=−33.4 (c=0.99,
MeOH); 1H NMR (DMSO-d6, 300 MHz) 13.93 (br s, 1H), 9.67 (br s, 1H), 9.42 (br s, 1H), 7.41–7.36 (m,
2H), 7.31–7.27 (m, 3H), 4.14 (br s, 1H), 3.42 (d, J=12.4 Hz, 1H), 3.08–2.99 (m, 2H), 2.31 (d, J=13.4 Hz,
1H), 2.07–1.86 (m, 3H); 13C NMR (DMSO-d6, 75 MHz) 170.3, 144.4, 129.0, 127.0, 126.9, 56.4, 43.7,
39.2, 33.0, 28.7; 1H NMR (D2O, 300 MHz) 7.49–7.37 (m, 5H), 4.12 (dd, J=12.8, 3.2 Hz, 1H), 3.67 (qd,
J=12.9, 2.1 Hz, 1H), 3.25 (td, J=13.1, 3.1 Hz, 1H), 3.08 (tt, J=12.3, 3.6 Hz, 1H), 2.25 (dq, J=14.0, 3.2 Hz,
1H), 1.85 (d, J=14.5 Hz, 1H), 2.01–1.88 (m, 2H); 13C NMR (D2O, 75 MHz) 172.1, 144.0, 129.4, 127.7,
127.1, 57.9, 44.2, 39.8, 33.1, 29.0; HRMS (ES+): (M+H)+ calcd: 206.1181; meas.: 206.1189.
8e-DNP: [α]D25=−326.7 (c=1.046, MeOH); TLC (MeOH:CHCl3, 1:9) Rf=0.30; IR (neat) 2940, 1715,
1600, 1520, 1335 cm−1; 1H NMR (CDCl3, 300 MHz) 8.66 (d, J=2.3 Hz, 1H), 8.31 (dd, J=8.9, 2.0 Hz,
1H), 7.34–7.22 (m, 6H), 4.08 (dd, J=10.2, 3.4 Hz, 1H), 3.69–3.58 (m, 1H), 2.99–2.80 (m, 2H), 2.39
(d, J=12.8 Hz, 1H), 2.10–1.98 (m, 3H); 13C NMR (CDCl3, 75 MHz) 175.7, 150.7, 143.5, 142.5, 128.7,
127.8, 127.0, 126.8, 122.8, 122.0, 62.1, 54.0, 40.3, 36.6, 31.5; HRMS (ES+): (M+H)+ calcd: 372.1195;
meas.: 372.1211.
Acknowledgements
We thank Manfred Weigele for helpful discussions pertaining to the use of chiroptical methods of
analysis.
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