An efficient synthesis of 3(S)-aminopiperidine-5(R)-carboxylic acid as a cyclic β,γ′-diamino acid

Article abstract of DOI:10.1016/S0040-4039(03)00002-9

An orthogonally protected β,γ′-diamino acid 6 possessing conformationally-constrained ring system was synthesized as a novel cyclic amino acid analogue. This synthesis involves as key steps chemoselective enzymatic hydrolysis of cis-piperidine-3,5-dicarboxylic ester derivative followed by efficient kinetic resolution of the partially resolved half-acid to afford the C₁-symmetric piperidine-3,5-dicarboxylic acid monoester in high enantiomeric excess (>98% ee). The optically active half-acid was transformed to the cyclic amino acid via Curtius-type rearrangement.

Full text of DOI:10.1016/S0040-4039(03)00002-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1611–1614
An efficient synthesis of 3(S)-aminopiperidine-5(R)-carboxylic
acid as a cyclic b,g%-diamino acid
Jin-Seong Park,a Chang-Eun Yeom,a Soo Hyuk Choi,a Yong Shik Ahn,a Sunggu Ro,b,†
Young Ho Jeon,b,† Dong-Kyu Shinb,† and B. Moon Kima,*
aSchool of Chemistry & Molecular Engineering and Center for Molecular Catalysis, Seoul National University, Seoul 151-747,
South Korea
bLG Life Science, PO Box 51, Yuseong, Science Town, Daejon 305-380, South Korea
Received 5 December 2002; revised 16 December 2002; accepted 24 December 2002
Abstract—An orthogonally protected b,g%-diamino acid 6 possessing conformationally-constrained ring system was synthesized as
a novel cyclic amino acid analogue. This synthesis involves as key steps chemoselective enzymatic hydrolysis of cis-piperidine-3,5-
dicarboxylic ester derivative followed by efficient kinetic resolution of the partially resolved half-acid to afford the C1-symmetric
piperidine-3,5-dicarboxylic acid monoester in high enantiomeric excess (>98% ee). The optically active half-acid was transformed
to the cyclic amino acid via Curtius-type rearrangement. © 2003 Elsevier Science Ltd. All rights reserved.
A great deal of research has been devoted to the design
and synthesis of new peptidomimetic building blocks.1
In particular, novel conformationally constrained and
optically active unnatural amino acids attract much
attention since these compounds can be utilized as
potential building blocks for biologically active
molecules.2 From our continuing effort in asymmetric
syntheses of unnatural amino acids and peptide sec-
ondary structure mimetics possessing interesting biolog-
ical activities, we have been interested in the
3,5-disubstituted piperidine ring system such as A and
B in Figure 1. These substituted piperidine structures
have been utilized as building blocks for ras farnesyl
protein transferase inhibitors3 and a scaffold for the
preparation of optically active indole alkaloids.4 The
conformational constraint in these structures could play
a significant role as a peptidomimetic template to nucle-
ase hydrogen-bonding pattern mimicking the peptide
secondary structure such as b-sheet5 or turn motifs.6
Especially compound A represents a conformationally
constrained b,g%-diamino acid derivative which may be
of a particular value when two amino groups can be
orthogonally protected. Due to these interesting per-
spectives, the optically active form of this cyclic unnat-
ural amino acid has been the target of considerable
synthetic efforts.4,7 Reported herein is a new, efficient
synthetic route for optically active cis-3,5-disubstituted
piperidine derivatives.
Key features of our synthetic approach for enantiomer-
ically enriched structures A and B involve chemoselec-
tive desymmetrization of s-symmetrical dimethyl
piperidine-3,5-dicarboxylate 3 through enzyme-medi-
ated hydrolysis with PLE,7b,7c,8 followed by kinetic
resolution with a chiral amine such as a-phenylethyl-
amine (a-PEA).9
As shown in Scheme 1, a ꢀ3:2 mixture of stereoiso-
meric dimethyl meso-N-t-butyloxycarbonyl-3,5-pipe-
ridine-dicarboxylate 3 was prepared from 3,5-pyridine
dicarboxylic acid 1 through esterification followed by
hydrogenation under acidic conditions. Separation of
the desired cis-isomer from the cis/trans mixture 3 was
accomplished either through column chromatography
on silica gel or simple recrystallization from n-hexane.
It was assumed that trans-3 would be less stable than
cis-3 due to its axial ester group. The crystalline com-
Figure 1.
* Corresponding author. Tel.: +82-2-880-6644; fax: +82-2-872-7505;
e-mail: kimbm@snu.ac.kr
† Present address: CrystalGenomics, Inc., Daeduk BioCommunity,
461-6, Jeonmin-dong, Yusung-gu, Daejeon 305-390, Korea.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00002-9

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J.-S. Park et al. / Tetrahedron Letters 44 (2003) 1611–1614
Scheme 1. a) HCl (g), MeOH; b) H2 (50 atm), Pd/C, AcOH;
c) Boc2O, Et3N, CH2Cl2; d) column chromatography or crys-
tallization.
Scheme 3. a) (S)-PEA, EtOH, 70°C to rt; b) DPPA, Et3N,
benzene; c) 2-(trimethylsilyl)ethanol; d) Ac2O, pyridine; e)
LiOH, dioxane–water; f) MeNH2, EDC, HOBT, CH2Cl2; g)
HCl (g), EtOAc.
half-acid ester intermediate 4 was confirmed through
HPLC analysis.
In order to desymmetrize the meso-diester cis-3,
enzyme-catalyzed kinetic resolution was attempted.7b
Following precedents in the literature for similar cases,
pig liver esterase (PLE) was chosen for the catalyst and
the desymmetrization results are listed in Table 1. Due
to poor water solubility of the solid substrate cis-3, a
small portion of surfactant (entry 1) or organic cosol-
vents such as MeCN or DMSO (entries 2 and 3,
respectively) were used.11 However, under any condi-
tions, efficient kinetic resolution has not been achieved,
giving only partially resolved half-acid 4 (Table 1). It
was of note, however, that the hydrolysis exhibited
complete chemoselectivity and the reaction stopped at
the half-acid stage.
Scheme 2. a) K2CO3, trace H2O, MeOH, reflux, 24 h; b)
CH3I, Cs2CO3, DMF.
pound was confirmed to be cis-3 from the comparison
1
of the H NMR spectrum of dimethyl cis-N-benzyl-3,5-
piperidinedicarboxylate derived from cis-3 (TFA,
CH2Cl2; PhCHO, NaBH(OAc)3H, dichloroethane) with
that reported in the literature.7
With this chemoselective enzyme-mediated hydrolysis
in hand, we have carried out the resolution of partially
resolved 4 with fractional crystallization using a-PEA
in good efficiency (Scheme 3).12 Fractional crystalliza-
tion was performed with both (R)-(+) and (S)-(−)-PEA.
(S)-(−)-PEA favored (+)-cis-4, which was the major
isomer of PLE-catalyzed hydrolysis products.13 Repeti-
tive crystallizations (five times) were carried out to yield
product of over 98% ee. Enantiomeric excess of opti-
cally-active half-acid (+)-cis-4 was determined through
normal phase HPLC analysis (HP hypersil column,
eluted with 1% i-PrOH in n-hexane, 1.0 mL/min) after
derivatization with (−)- or (+)-PEA.
Computational study (HyperChem™) supported our
hypothesis in that cis-3 has about 2.1 kcal/mol lower
energy for heat of formation than trans-3.
The transformation of trans-3 to cis-isomer was suc-
cessfully accomplished through isomerization during
the hydrolysis of trans-3 (Scheme 2). When trans-3 was
heated in MeOH in the presence of K2CO3 or Cs2CO3,
a 9:1 mixture of cis- and trans-diacid 5 was obtained.
This mixture was converted to the cis-enriched diester 3
quantitatively upon reaction with MeI in the presence
of cesium carbonate.10 The presence of a 7:3 mixture of
Table 1.
Entry
Medium
Reaction time
Yield (%)
% e.e.b
1
2
3
2 drops Triton-X/50 mg of cis-3
20% DMSO/phosphate buffer
20% MeCN/phosphate buffer
4 days
13 h
12 h
48
93
96
18
23
28
b % e.e. was determined by HPLC spectra analysis of diastereomeric amide.

J.-S. Park et al. / Tetrahedron Letters 44 (2003) 1611–1614
1613
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Scheme 4. a) Ac2O, pyr; b) LiOH, THF–water; c) MeNH2,
EDC, HOBt, DMF; d) TFA, CH2Cl2.
The absolute stereochemistry of the product (+)-cis-4
was determined by comparison of optical rotation of
(3S)-N-t-butyloxycarbonyl-3-hydroxymethyl-1-pipe-
ridine derived from (+)-cis-4 with literature data {[h]365
+60.7 (c 1, EtOH)}.7b,14 This result revealed that half-
acid (+)-cis-4 resolved with (−)-PEA is equipped with a
(3S,5R) absolute configuration as shown in Scheme 3.
Optically active half-acid (+)-cis-4 was converted into
b,g%-diamino acid derivative 6 through Curtius-type
rearrangement.15 Treatment of (+)-cis-4 with
diphenylphosphoryl azide (DPPA) and Et3N in anhy-
drous benzene provided isocyanate intermediate, which
was quenched with 2-(trimethylsilyl)ethanol to give
orthogonally protected diamino acid 6 (Scheme 3).
For preliminary conformational analysis of compounds
incorporating this unnatural cyclic amino acid unit, a
pseudopeptide derivative 9 was prepared from free
amine 7 through acetylation of the amine, hydrolysis of
the methyl ester, coupling of the corresponding free
carboxylic acid with methylamine followed by deprotec-
tion of the N-Boc group as shown in Scheme 4. Con-
formational search through molecular mechanics of the
resulting compound 9 followed by optimization using
ab initio calculation (HF/3-21G*, 41 conformations)
5. For some recent examples, see: (a) Schneider, J. P.; Kelly,
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1
and H NMR studies in water (DQF-COSY, ROESY,
and temperature variation experiment) indicate the
extended b-strand structure A as depicted in Scheme 4.
In conclusion, we have developed an efficient method
for the preparation of a conformationally constrained,
unnatural b,g%-diamino acid derivative 6. We are cur-
rently investigating the possibility of constructing a
combinatorial library toward various enzyme inhibitors
including serine and aspartyl proteases from this inter-
esting unnatural amino acid scaffold and the result will
be reported in due course.
Acknowledgements
We thank the Center for Molecular Catalysis at Seoul
National University through KOSEF and LGLS for
generous financial support for this work. J.S.P. and
C.E.Y. acknowledge the financial support in the form
of BK21 fellowships.

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J.-S. Park et al. / Tetrahedron Letters 44 (2003) 1611–1614
7. (a) Danieli, B.; Lesma, G.; Passarella, D.; Silvani, A.
MgSO4, filtered and concentrated to afford the partially
resolved cis-4 (96% yield, 28% ee) as a white solid.
12. General procedure for fractional crystallization: Partially
resolved cis-4 (28% ee) was dissolved in hot ethanol
Synth. Commun. 1997, 27, 69; (b) Danieli, B.; Lesma, G.;
Passadrella, D.; Silvani, A. Tetrahedron: Asymmetry
1996, 7, 345; (c) Danieli, B.; Lesma, G. J. Org. Chem.
1998, 63, 3492.
(70°C,
1 mL/mmol) and 1.01 equiv. of (S)-(−)-1-
8. For a review of enzymatic kinetic resolution, see: (a)
Drauz, K.; Waldmann, H. Enzyme Catalysis in Organic
Synthesis; VCH: Weinheim, 1995; (b) Wong, C. H.;
Whitesides, G. M. Enzymes in Synthetic Organic Chem-
istry; Pergamon: New York, 1992; (c) Farber, K. Bio-
transformations in Organic Chemistry; Springer-Verlag:
New York, 1992. (d) Schoffers, E.; Golebiowski, A.;
Johnson, C. R. Tetrahedron 1996, 52, 3769.
phenylethylamine was added dropwise with caution. The
solution was cooled to room temperature and allowed to
stand for 24 h, which resulted in the precipitation of a
salt. The salt was dissolved again in hot EtOH (70°C),
cooled to room temperature and allowed to stand for 24
h. After repeating the same process three times, the
resulting salt was dissolved in water, acidified with satd
aquiv KHSO4 solution and extracted three times with
EtOAc. The combined extracts were dried (anhydr.
MgSO4), filtered and concentrated to afford the (+)-cis-4
(55% yield, >98% ee) as a white crystalline solid: mp
9. For a review of a-PEA application to enantioselective
synthesis: Juaristi, E.; Escalante, J.; Leo´n-Romo, J. L.;
Reyes, A. Tetrahedron: Asymmetry 1998, 9, 715.
10. General procedure for epimerization of trans-3 to cis-3: To
a solution of trans-diester in methanol (5 mL/mmol) was
added 3 equiv. of K2CO3 and the mixture was refluxed
for 24 h. The reaction progress was monitored through
HPLC analysis. Filtration followed by concentration of
the mixture afforded a yellowish residue. To a solution of
the resulting residue in DMF (5 mL/mmol) were added
3.1 equiv. of CH3I and 3 equiv. of K2CO3 and the
mixture was stirred at room temperature for 12 h. The
crude mixture was filtered, concentrated in vacuo and
purified on a silica gel chromatographic column (10%
EtOAc in hexane) to provide cis-3 (85% yield) as a white
1
155–156°C, [h]2D6 +5.4 (c 1, CHCl3); H NMR (600 MHz,
CDCl3) l 4.37 (br, 2H), 3.71 (s, 3H), 2.73 (br, 2H),
2.65–2.35 (br, 3H), 1.72 (q, J=12.6 Hz, 1H), 1.47 (s, 9H);
13C NMR (150 MHz) l 177.8, 173.3, 154.9, 81.1, 61.3,
52.4, 45.6, 41.0, 30.4, 28.7, 14.5; HRMS calcd for
C13H22NO6 [M+1] 288.1447, obsd 288.1441.
13. Preparation of (−)-cis-4 was possible through employing
(R)-(+)-PEA following the same fractional crystallization
process.
14. The synthetic scheme for determination of optical rota-
tion is as follows (Barton, D. H. R.; Herve´, Y.; Potier, P.;
Thierry, J. Tetrahedron 1988, 44, 5479):
1
solid: TLC Rf=0.61 (1:2 EtOAc:hexane); H NMR (600
MHz, CDCl3) l 4.36 (br, 2H), 3.70 (s, 6H), 2.71 (br, 2H),
2.48 (br, 2H), 2.43 (m, 2H), 1.70 (q, J=12.8 Hz, 1H),
1.47 (s, 9H); 13C NMR (150 MHz) 173.2, 154.7, 80.7,
52.3, 45.7, 41.1, 30.5, 28.7; IR (neat) w 1736, 1697, 1426,
1170 cm−1; HRMS calcd for C14H23NO6 [M+1] 302.1604,
found 302.1605.
11. General procedure for PLE-catalyzed hydrolysis of cis-3:
cis-diester-3 was suspended in 0.1 M aq. KH2PO4 (30
mL/mmol) solution of pH 8.0 containing CH3CN (6
mL/mmol). To the stirred suspension was added PLE
(600 units/mmol) at 25°C in one portion and the pH was
maintained by addition of 2N aq. NaOH solution as
needed. Stirring was continued at 25°C for 12 h. After
complete consumption of cis-3, the resulting mixture was
filtered via a Celite pad, acidified with 2N HCl solution
and the aqueous layer was extracted five times with
EtOAc. The combined extracts were dried over anhydr.
a) 1) ClCO2Et, NMP, CH2Cl2, 2) 2-mercaptopyridine
N-oxide, Et3N, THF; b) t-BuSH, W-lamp, C6H6; c)
LiBH4, THF.
15. Haefliger, W.; Klo¨ppner, E. Helv. Chim. Acta 1982, 65,
1837.