Asymmetric synthesis of a novel conformationally constrained D-lysine analogue with a piperidine skeleton

Article abstract of DOI:10.1002/ejoc.200800069

A practical asymmetric synthesis of enantiomerically pure (2R,4R)-1-(tert-butoxycarbonyl)-4-[2-(methoxycarbonylamino) ethyl]pipecolic acid starting from easily accessible (R)-2-[(S)-1,2-bis(benzyloxy)ethyl]-1-[(S)-1- phenylethyl]-4-piperidone in around 33% overall yield has been performed. The efficiency of the synthetic strategy developed for the synthesis of this novel conformationally constrained D-lysine analogue relies on the high-yielding Wadsworth-Emmons reaction of a 2-substituted 4-piperidone and the diastereoselective reduction of the exocyclic C=C double bond at the 4-position of the piperidine ring. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800069

FULL PAPER
DOI: 10.1002/ejoc.200800069
Asymmetric Synthesis of a Novel Conformationally Constrained
Analogue with a Piperidine Skeleton
D
-Lysine
Pablo Etayo,[a] Ramón Badorrey,[a] María D. Díaz-de-Villegas,*[a] and José A. Gálvez*[a]
Keywords: Amino acids / Asymmetric synthesis / Lysine / Piperidines / Stereoselectivity
A practical asymmetric synthesis of enantiomerically pure
(2R,4R)-1-(tert-butoxycarbonyl)-4-[2-(methoxycarbonyl-
amino)ethyl]pipecolic acid starting from easily accessible (R)-
2-[(S)-1,2-bis(benzyloxy)ethyl]-1-[(S)-1-phenylethyl]-4-
piperidone in around 33% overall yield has been performed.
The efficiency of the synthetic strategy developed for the
analogue relies on the high-yielding Wadsworth–Emmons
reaction of a 2-substituted 4-piperidone and the diastereo-
selective reduction of the exocyclic C=C double bond at the
4-position of the piperidine ring.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
synthesis of this novel conformationally constrained D-lysine
peptides that contain them,[7] and for this reason we consid-
ered that a pipecolic acid–lysine chimera (Figure 1) would
represent a novel and complementary conformationally
constrained lysine analogue.
Introduction
The introduction of non-natural amino acids into biolo-
gically active peptides has become one of the most powerful
tools to obtain detailed information about their structure–
activity relationships.[1] Specific structural, stereoelectronic,
steric and conformational properties can be examined by
the proper design of such peptides and in many cases the
substitution of natural amino acids by conformationally re-
stricted analogues in biologically active peptides has led to
derivatives much more selective and efficient than the native
peptides. These modified peptides usually show less side ef-
fects, an increased selectivity among different receptors, and
greater oral bioavailability due to a lower enzymatic degra-
dation that allows a longer biological activity.[2] Therefore,
the design and synthesis of conformationally constrained
amino acids and their incorporation into peptides have be-
come an essential task for modern drug discovery research.
Among the various approaches described to attain confor-
mational rigidity, the incorporation of the amino acid moi-
ety into a ring has been widely used.[3]
Lysine is an important proteinogenic amino acid that
strongly stabilises the α-helical conformation of peptides.[4]
In recent years the syntheses of several mimetics and ana-
logues of this amino acid have been reported,[5,6] and most
of the conformationally constrained lysine analogues de-
scribed are proline–lysine chimeras.[6] Cyclic amino acids
such as proline and pipecolic acid share the ability to exert
a significant influence on the local secondary structure of
Figure 1. Target pipecolic acid–lysine chimera.
In this paper we report the synthesis of an orthogonally
protected trans-(2R,4R)-4-(2-aminoethyl)pipecolic acid
derivative in an enantiomerically pure form as a novel con-
strained analogue of -lysine in which three torsion angles
(χ1, χ2 and φ) are simultaneously restricted to well-defined
values. Our strategy towards the synthesis of this compound
relies on diastereoselective functionalisation of 4-piperidone
1 via the corresponding 4-alkylidenepiperidine. The pro-
posed synthesis involves the following steps: (i) Wadsworth–
Emmons reaction (WE) of the 4-piperidone with the appro-
priate phosphonate, (ii) regioselective and stereocontrolled
reduction of the exocyclic α,β-unsaturated cyanide moiety
present in the compound obtained and (iii) transformation
of the piperidine ring substituents to obtain orthogonally
protected amine functionalities at the 1- and 4-positions,
and the carboxylic acid functionality at the 2-position.
[a] Departamento de Química Orgánica, Instituto de Ciencia de
Materiales de Aragón, Instituto Universitario de Catálisis
Homogénea, Universidad de Zaragoza – CSIC,
50009 Zaragoza, Spain
Results and Discussion
The synthesis started from valuable and versatile syn-
thetic intermediate 1,[8] obtained from (S)-N-[(S)-1-phen-
ylethyl]-2,3-di-O-benzylglyceraldimine as previously re-
Fax: +34-976761202
E-mail: loladiaz@unizar.es
jagl@unizar.es
3474
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3474–3478

Synthesis of a Lysine Analogue with a Piperidine Skeleton
ported.[9] It is worth mentioning that the starting imine is the free amine that results from the concomitant N-deben-
readily available on a multigram scale from inexpensive - zylation reaction and, thus, facilitates final product isola-
mannitol, which comes from renewable sources.
tion. Under these conditions a cis/trans mixture (ca. 65:35)
Wadsworth–Emmons olefination of compound 1 with an of compound 3b was obtained.
excess of diethyl cyanomethylphosphonate using DBU as
Conjugate reduction of α,β-unsaturated nitrile 2 using an
base in the presence of LiCl in CH3CN was not satisfactory. excess of L-Selectride® (4.0 equiv.) in anhydrous THF at
After total conversion the resulting E/Z[10] mixture of com- –78 °C gave 2,4-disubstituted piperidine 3a in an excellent
pound 2 was contaminated with variable amounts of other yield (94%) and with high trans diastereoselectivity (87:13).
unidentified olefinic derivatives, the extent of which de- Compound trans-3a was easily isolated by column
pended on the amount of DBU used. Fortunately, the use chromatography in a yield of 82% on the gram scale.
of LDA (3.5 equiv.) as base led to a 59:41 E/Z mixture of
The cis and trans relative configurations of the isolated
α,β-unsaturated nitrile 2 in 96% isolated yield when the re- diastereoisomers of compound 3a and 3b were determined
action was carried out with an excess of diethyl cyanometh- on the basis of their NMR spectroscopic data and 2D
ylphosphonate (3.0 equiv.) at room temperature for 60 min NOESY experiments (Figure 2) after the complete unequiv-
1
using anhydrous THF as solvent (Scheme 1).
ocal assignment of all the signals in the H NMR spectra
with the aid of 2D NMR experiments (COSY, HSQC,
HMBC).
Scheme 1. Synthesis of key intermediate 2.
Next, diastereoselective reduction of the exocyclic C=C
double bond of compound 2 to afford the corresponding
saturated 2,4-disubstituted piperidine was attempted under
different reaction conditions (Scheme 2) and the best results
are collected in Table 1.
Figure 2. Determination of the relative configurations of trans- and
cis-3 by means of NOE correlations.
The stereochemical course of the reaction could be ra-
tionalised by taking into account the fact that conjugate
addition of a hydride to exocyclic α,β-unsaturated nitrile
using a sterically demanding reducing agent, such as L-Se-
lectride®, occurs preferentially from the equatorial direction
to minimise steric repulsions, yielding trans-2,4-disubsti-
tuted piperidine as the major product.
Scheme 2. Reduction of key intermediate 2.
The transformation of compound trans-3a into the or-
thogonally protected pipecolic acid–lysine chimera was suc-
cessfully performed as depicted in Scheme 3. Reduction of
nitrile using LiAlH4 in THF and reaction of the resulting
crude primary amine with methyl chloroformate and potas-
sium carbonate in THF led to carbamate 4 in 83% yield.
From this compound the N-Boc derivative 5 was obtained
in 70% yield by selective hydrogenolytic N-debenzylation
in the presence di-tert-butyl dicarbonate using Pd/C as the
catalyst. Next, extensive O-debenzylation of 5 to give diol
6 was performed in a nearly quantitative yield by hydro-
genolytic debenzylation using molecular hydrogen and cata-
lytic amounts of Pd(OH)2/C. Finally oxidative cleavage of
Table 1. Diastereoselective reduction of the C=C double bond of
compound 2.
Reagents
Time [h] Product Yield[a] [%] cis/trans[b]
H2, Pt/C
H2, PtO2
72
15
72
20
3a
3a
3b
3a
43
60
87
94
58:42
60:40
65:35
13:87
[c]
H2, Pd/C, Boc2O
L-Selectride®
[a] Total yield of the isolated cis and trans diastereoisomers. [b]
Determined by 1H NMR analysis of the crude reaction mixture. [c]
0.1 equiv. of the catalyst was used to avoid concomitant reduction
of the cyano group.
Catalytic hydrogenation of compound 2 took place with the 1,2-diol moiety by treatment with excess sodium per-
low diastereoselectivity. By using Pt/C or PtO2 as the cata- iodate in the presence of a catalytic amount of anhydrous
lyst a cis/trans mixture (ca. 60:40) of compound 3a was ob- ruthenium trichloride gave the desired compound (2R,4R)-
tained. Hydrogenation of the C=C double bond with Pd/C 1-(tert-butoxycarbonyl)-4-[2-(methoxycarbonylamino)ethyl]-
was carried out in the presence of Boc2O in order to protect pipecolic acid (7) in 74% yield.
Eur. J. Org. Chem. 2008, 3474–3478
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3475

P. Etayo, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez
FULL PAPER
doublet of doublets. Selective ge-1D NOESY experiments were per-
formed with gradient pulses in the mixing time. Spectra were ac-
quired at 300 K with optimised mixing times and 128 transients
per spectrum using the Bruker standard selnogp pulse program.
Special precautions such as degassing of the sample were not taken.
NOESY spectra were acquired in the phase-sensitive mode with
gradient pulses in the mixing time as 2048ϫ256 hypercomplex files
with eight transients for 256 time increments. A mixing time of
750 ms was used and processing was carried out using a sine-bell-
squared function shifted by π/2 and a states-TPPI method. Special
precautions such as degassing of the sample were not taken. Op-
tical rotations were measured with a Jasco 1020 polarimeter at λ =
589 nm and 25 °C in a cell with a 10 cm path length; [α]D values
are given in 10–1 degcmg–1 and concentrations are given in g per
100 mL. High-resolution mass spectra were recorded using a
Bruker Daltonics MicroToF-Q electrospray instrument from meth-
anolic solutions using the positive electrospray ionisation mode
(ESI+). Microanalyses were performed using a Perkin–Elmer 2400
CHNS elemental analyser.
(E/Z)-(R)-4-Cyanomethylene-2-[(S)-1,2-bis(benzyloxy)ethyl]-1-[(S)-
1-phenylethyl]piperidine (2): A 2.0  solution of LDA in heptane/
THF/ethylbenzene (1.75 mL, 3.5 mmol) was added to a solution of
diethyl cyanomethylphosphonate (531 mg, 3.0 mmol) in anhydrous
THF (10 mL) at room temp. under argon and the mixture was
stirred for 10 min. A solution of compound 1 (444 mg, 1.0 mmol)
in anhydrous THF (20 mL) was added and the resulting mixture
was stirred at room temp. until conversion was complete (ca.
60 min, as monitored by TLC). The reaction was quenched with
water (30 mL) and extracted with CH2Cl2 (3ϫ50 mL). The com-
bined organic extracts were dried with anhydrous MgSO4, filtered,
evaporated under reduced pressure and subsequently purified by
chromatography on silica gel (Et2O/hexanes, 1:1) to yield com-
pound 2 (447 mg, 96%) as a 59:41 mixture of E/Z diastereoisomers.
Samples of the pure E and Z diastereoisomers were isolated for
analytical purposes by silica gel column chromatography (Et2O/
hexanes, 1:4 Ǟ Et2O/hexanes, 1:1).
Scheme 3. Synthesis of (2R,4R)-1-(tert-butoxycarbonyl)-4-[2-
(methoxycarbonylamino)ethyl]pipecolic acid 8 from trans-3a.
Conclusions
In summary, enantiomerically pure (2R,4R)-1-(tert-but-
oxycarbonyl)-4-[2-(methoxycarbonylamino)ethyl]pipecolic
acid is easily accessible from (R)-2-[(S)-1,2-bis(benzyloxy)-
ethyl]-1-[(S)-1-phenylethyl]-4-piperidone. The compound
obtained, a conformationally constrained -lysine, is an
interesting scaffold to test the role of the lysine side-chain
in the conformational preferences of biologically active pep-
tides.
(E)-2: Oil, [α]2D5 = +1.0 (c = 0.87, CHCl ). IR (neat): ν = 2214,
˜
3
1685 cm–1. H NMR (400 MHz, CDCl3): δ = 1.20 (d, J = 6.6 Hz,
1
3 H), 2.09 (dd, J = 13.7, 7.1 Hz, 1 H), 2.17–2.27 (m, 1 H), 2.39–
2.47 (m, 2 H), 2.58 (dd, J = 13.7, 4.0 Hz, 1 H), 2.64–2.72 (m, 1 H),
2.96–3.02 (m, 1 H), 3.57 (dd, J = 10.5, 6.2 Hz, 1 H), 3.81 (br. d, J
= 10.5 Hz, 1 H), 3.82–3.88 (m, 1 H), 4.02 (q, J = 6.6 Hz, 1 H), 4.47
(d, J = 12.1 Hz, 1 H), 4.51 (d, J = 12.1 Hz, 1 H), 4.56 (d, J =
11.8 Hz, 1 H), 4.74 (d, J = 11.8 Hz, 1 H), 4.93 (br. s, 1 H), 7.15–
7.35 (m, 15 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.3, 31.6,
35.2, 44.3, 56.9, 58.6, 70.8, 72.9, 73.5, 78.3, 92.8, 116.7, 126.8,
127.2, 127.6, 127.7, 127.7, 128.2, 128.3, 128.4, 138.0, 138.5, 144.4,
165.5 ppm. HRMS (ESI+): calcd. for C31H35N2O2 [M + H]+
467.2693; found 467.2697.
Experimental Section
General: All reagents were of analytical grade and were used as
obtained from commercial sources. Reactions were carried out
using anhydrous solvents. Whenever possible the reactions were
monitored by thin-layer chromatography (TLC). TLC was per-
formed on precoated silica gel polyester plates and products were
visualised by using UV light (254 nm) and ethanolic phosphomo-
lybdic acid solution followed by heating. Column chromatography
was performed using silica gel (Kiesegel 60, 230–400 mesh). Melt-
ing points were determined in open capillaries using a Gallenkamp
capillary melting point apparatus and are uncorrected. The FTIR
spectra of oils were recorded as thin films on NaCl plates and the
FTIR spectra of solids were recorded as KBr pellets using a
(Z)-2: Oil, [α]2D5 = –41.6 (c = 1.02, CHCl ). IR (neat): ν = 2215,
˜
3
1686, 1674 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.23 (d, J =
6.6 Hz, 3 H), 1.99–2.07 (m, 1 H), 2.13–2.22 (m, 1 H), 2.40 (dd, J
= 14.1, 5.9 Hz, 1 H), 2.46–2.54 (m, 1 H), 2.74 (ddd, J = 12.1, 7.7,
4.1 Hz, 1 H), 2.84 (dd, J = 14.1, 4.6 Hz, 1 H), 3.11–3.18 (m, 1 H),
3.63 (dd, J = 11.0, 6.5 Hz, 1 H), 3.78–3.84 (m, 2 H), 4.04 (q, J =
6.6 Hz, 1 H), 4.47 (d, J = 12.1 Hz, 1 H), 4.54 (d, J = 12.1 Hz, 1
H), 4.57 (d, J = 11.7 Hz, 1 H), 4.74 (d, J = 11.7 Hz, 1 H), 4.97 (br.
s, 1 H), 7.14–7.37 (m, 15 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 16.3, 33.0, 33.8, 44.6, 57.4, 57.8, 70.9, 72.9, 73.5, 79.1, 92.7,
116.8, 126.8, 127.2, 127.4, 127.5, 127.6, 127.7, 128.2, 128.3, 138.3,
138.7, 145.1, 165.5 ppm. HRMS (ESI+): calcd. for C31H35N2O2 [M
+ H]+ 467.2693; found 467.2688.
Thermo Nicolet Avatar 360 FT-IR spectrometer; ν
given for the main absorption bands. NMR spectra were acquired
with a Bruker AV-400 spectrometer operating at 400 MHz for H
values are
˜
max
1
NMR and 100 MHz for 13C NMR at room temperature in CDCl3
using a 5 mm probe. The chemical shifts (δ) are reported in parts
per million and are referenced to the residual solvent peak. Coup-
ling constants (J) are quoted in hertz. The following abbreviations
are used: s, singlet; d, doublet; q, quartet; dd, doublet of doublets;
m, multiplet; br. s, broad singlet; br. d, broad doublet; br. dd, broad
3476
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3474–3478

Synthesis of a Lysine Analogue with a Piperidine Skeleton
(2R,4R)-4-Cyanomethyl-2-[(S)-1,2-bis(benzyloxy)ethyl]-1-[(S)-1-
phenylethyl]piperidine (trans-3a): A 1.0  solution of L-Selectride®
in THF (4 mL, 4.0 mmol) was added dropwise to a 59:41 E/Z mix-
ture of compound 2 (466 mg, 1.0 mmol) dissolved in anhydrous
THF (20 mL) at –78 °C under argon and the mixture was stirred
for 20 h at –78 °C. The reaction mixture was warmed up to 0 °C
and then sat. aq. NH4Cl (30 mL) was added carefully with stirring
at 0 °C. After extraction with Et2O (3ϫ50 mL), the combined or-
ganic layers were dried with anhydrous MgSO4, filtered and the
solvents evaporated in vacuo to afford compound 3a as an 87:13
mixture of trans/cis diastereoisomers. Purification of the residue by
silica gel column chromatography (Et2O/hexanes, 1:2 Ǟ Et2O) gave
cis-3a (56 mg, 12%) and trans-3a (384 mg, 82%) as oils.
4.00 (m, 2 H), 4.40 (s, 2 H), 4.52 (d, J = 11.7 Hz, 1 H), 4.66 (d, J
= 11.7 Hz, 1 H), 4.71–4.79 (m, 1 H), 7.01–7.36 (m, 15 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 19.8, 28.8, 29.9, 31.1, 36.1, 38.3,
42.5, 51.7, 54.5, 59.3, 71.6, 72.5, 73.2, 78.0, 126.2, 127.0, 127.1,
127.4, 127.5, 127.5, 127.9, 128.0, 128.1, 138.1, 138.9, 147.0,
156.9 ppm. HRMS (ESI+): calcd. for C33H43N2O4 [M + H]+
531.3217; found 531.3223.
(2R,4R)-1-(tert-Butoxycarbonyl)-2-[(S)-1,2-bis(benzyloxy)ethyl]-4-
[2-(methoxycarbonylamino)ethyl]piperidine (5): Boc2O (492 mg,
2.25 mmol) and 10% Pd/C (139 mg) were added successively to a
solution of 4 (398 mg, 0.75 mmol) in absolute ethanol (12 mL) and
the mixture was stirred at room temp. under H2 for 48 h. After
completion of the reaction, the mixture was filtered through Celite®
545 and concentrated in vacuo. The residue was purified by silica
gel flash chromatography (Et2O/hexanes, 1:1 Ǟ Et2O/hexanes, 4:1)
trans-3a: [α]2D5 = –30.2 (c = 0.82, CHCl ). IR (neat): ν = 2245 cm–1.
˜
3
1H NMR (400 MHz, CDCl3): δ = 1.23 (d, J = 6.6 Hz, 3 H), 1.20–
1.27 (m, 1 H), 1.42 (ddd, J = 12.8, 12.8, 3.2 Hz, 1 H), 1.50–1.60 to afford compound 5 (276 mg, 70%) as an oil. [α]2D5 = –8.1 (c =
(m, 2 H), 1.97–2.09 (m, 1 H), 2.09 (dd, J = 7.4, 1.6 Hz, 2 H), 2.62–
2.67 (m, 2 H), 3.08–3.13 (m, 1 H), 3.54 (dd, J = 10.4, 4.9 Hz, 1 H),
3.58 (dd, J = 10.4, 3.4 Hz, 1 H), 3.83–3.89 (m, 1 H), 3.94 (q, J =
6.6 Hz, 1 H), 4.43 (d, J = 12.4 Hz, 1 H), 4.46 (d, J = 12.4 Hz, 1
H), 4.54 (d, J = 11.7 Hz, 1 H), 4.74 (d, J = 11.7 Hz, 1 H), 7.09–
0.63, CHCl ). IR (neat): ν = 3340, 1718, 1684, 1252 cm–1. 1H NMR
˜
3
(400 MHz, 328 K, CDCl3): δ = 0.96 (dddd, J = 12.6, 12.6, 12.6,
4.4 Hz, 1 H), 1.10–1.31 (m, 3 H), 1.33 (s, 9 H), 1.49 (br. d, J =
12.6 Hz, 1 H), 1.53–1.61 (m, 1 H), 1.65 (br. dd, J = 13.5, 1.6 Hz, 1
H), 2.63 (br. dd, J = 12.8, 12.8 Hz, 1 H), 2.96–3.11 (m, 2 H), 3.53
7.34 (m, 15 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.3, 24.0, (dd, J = 10.6, 4.9 Hz, 1 H), 3.56 (s, 3 H), 3.58 (dd, J = 10.6, 4.2 Hz,
28.8, 29.3, 30.6, 42.4, 54.6, 59.6, 71.9, 72.9, 73.4, 78.8, 118.6, 126.6, 1 H), 3.67–3.73 (m, 1 H), 3.85–4.00 (m, 1 H), 4.26–4.36 (m, 1 H),
127.2, 127.5, 127.6, 127.6, 127.8, 128.1, 128.3, 128.4, 138.2, 138.9,
4.40–4.47 (m, 1 H), 4.41 (d, J = 11.7 Hz, 1 H), 4.44 (d, J = 11.9 Hz,
146.7 ppm. HRMS (ESI+): calcd. for C31H37N2O2 [M + H]+ 1 H), 4.49 (d, J = 11.9 Hz, 1 H), 4.63 (d, J = 11.7 Hz, 1 H), 7.13–
469.2850; found 469.2845.
7.28 (m, 10 H) ppm. 13C NMR (100 MHz, 333 K, CDCl3): δ =
28.5, 29.1, 32.2, 33.1, 37.4, 38.6, 51.9, 55.3, 71.8, 72.6, 73.6, 77.7,
79.2, 127.4, 127.7, 127.8, 128.0, 128.2, 128.4, 138.4, 138.9, 155.3,
157.0 ppm. HRMS (ESI+): calcd. for C30H42N2O6Na [M + Na]+
549.2935; found 549.2940.
cis-3a: [α]2D5 = +9.8 (c = 0.66, CHCl ). IR (neat): ν = 2245 cm–1.
˜
3
1H NMR (400 MHz, CDCl3): δ = 0.99 (ddd, J = 12.0, 12.0,
12.0 Hz, 1 H), 1.06 (dddd, J = 12.6, 12.6, 12.6, 3.9 Hz, 1 H), 1.16
(d, J = 6.5 Hz, 3 H), 1.50–1.63 (m, 2 H), 2.03 (ddd, J = 11.8, 11.8,
1.9 Hz, 1 H), 2.14 (dd, J = 12.0, 2.5 Hz, 1 H), 2.19 (dd, J = 16.7,
6.7 Hz, 1 H), 2.28 (dd, J = 16.7, 5.6 Hz, 1 H), 2.42 (ddd, J = 11.8,
3.2, 3.2 Hz, 1 H), 2.68–2.74 (m, 1 H), 3.67 (dd, J = 10.5, 7.8 Hz, 1
(2R,4R)-1-(tert-Butoxycarbonyl)-2-[(S)-1,2-dihydroxyethyl]-4-[2-
(methoxycarbonylamino)ethyl]piperidine (6): 20 % Pd(OH)2/C
(133 mg) was added to a solution of 5 (265 mg, 0.50 mmol) in abso-
H), 4.04 (d, J = 10.5 Hz, 1 H), 4.08–4.15 (m, 2 H), 4.50 (d, J = lute ethanol (8 mL) and the mixture was stirred at room temp. un-
12.1 Hz, 1 H), 4.60 (d, J = 12.1 Hz, 1 H), 4.70 (d, J = 11.9 Hz, 1
H), 4.84 (d, J = 11.9 Hz, 1 H), 7.17–7.43 (m, 15 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 7.9, 24.3, 31.6, 32.3, 33.8, 44.6, 53.7, 59.1,
71.4, 72.9, 73.6, 77.5, 118.5, 126.5, 127.5, 127.6, 127.6, 127.8, 128.0,
128.3, 128.4, 128.4, 138.3, 138.8, 143.4 ppm. HRMS (ESI+): calcd.
for C31H37N2O2 [M + H]+ 469.2850; found 469.2865.
der H2 for 24 h. After completion of the reaction, the mixture was
filtered through Celite® 545 and concentrated in vacuo and used
in the next step without additional purification. A sample of pure 6
was isolated (as an oil) for analytical purposes by silica gel column
chromatography (Et2O/EtOH, 4:1). [α]2D5 = +23.0 (c = 0.76, CHCl3).
1
IR (neat): ν = 3345, 1722, 1691, 1256 cm–1. H NMR (400 MHz,
˜
328 K, CDCl3): δ = 1.11 (dddd, J = 12.8, 12.8, 12.8, 4.6 Hz, 1 H),
1.26–1.46 (m, 3 H), 1.47 (s, 9 H), 1.67 (br. d, J = 12.8 Hz, 1 H),
1.70–1.80 (m, 1 H), 1.81 (br. d, J = 13.9 Hz, 1 H), 2.56 (br. s, 2 H),
2.97 (br. dd, J = 12.2, 12.2 Hz, 1 H), 3.12–3.31 (m, 2 H), 3.54 (dd,
J = 11.5, 5.5 Hz, 1 H), 3.67 (s, 3 H), 3.69 (dd, J = 11.5, 4.5 Hz, 1
H), 3.88–3.94 (m, 1 H), 4.01–4.13 (m, 1 H), 4.25–4.33 (m, 1 H),
4.58–4.70 (m, 1 H) ppm. 13C NMR (100 MHz, 298 K, CDCl3): δ
= 28.4, 28.6, 31.9, 32.8, 37.4, 38.1, 41.1, 51.3, 52.1, 64.3, 72.9, 80.3,
157.2, 157.4 ppm. HRMS (ESI+): calcd. for C16H30N2O6Na [M +
Na]+ 369.1996; found 369.2012.
(2R,4R)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-4-[2-(methoxycarbonyl-
amino)ethyl]-1-[(S)-1-phenylethyl]piperidine (4): A 1.0  solution of
LiAlH4 in THF (2 mL, 2.0 mmol) was added dropwise to a solu-
tion of trans-3a (468 mg, 1.0 mmol) in anhydrous THF (20 mL) at
room temp. under argon and the mixture was stirred for 3.5 h. The
reaction mixture was cooled to 0 °C and then sat. aq. NH4Cl
(30 mL) was added carefully with stirring. After filtration through
a Celite® 545 pad and extraction with Et2O (3ϫ30 mL), the com-
bined organic layers were dried with anhydrous MgSO4, filtered
and the solvents evaporated in vacuo. Methyl chloroformate
(189 mg, 2.0 mmol) and anhydrous K2CO3 (828 mg, 6.0 mmol)
were added successively to a solution of the obtained crude in anhy-
drous THF (20 mL) at room temp. and the mixture was stirred
for 2 h. After filtration through a Celite® 545 pad the solvent was
evaporated in vacuo and the residue purified by silica gel column
chromatography (EtOAc/EtOH, 4:1) to afford compound 4
(2R,4R)-1-(tert-Butoxycarbonyl)-4-[2-(methoxycarbonylamino)-
ethyl]pipecolic Acid (7): NaIO4 (428 mg, 2.0 mmol) was added to a
stirred solution of crude 6 (173 mg, 0.50 mmol) obtained as above
in CH3CN/CCl4/H2O (2:2:3, 14 mL). After stirring vigorously for
5 min, RuCl3 (6 mg, 0.030 mmol) was added to the mixture and
stirring was continued for 2 h. The reaction mixture was diluted
with CH2Cl2 (10 mL) and water (10 mL) was added. The aqueous
(440 mg, 83%) as an oil. [α]2D5 = –17.8 (c = 1.23, CHCl3). IR (neat):
ν = 3347, 1717 cm–1. H NMR (400 MHz, CDCl ): δ = 0.97–1.08 phase was extracted with CH2Cl2 (3ϫ20 mL), the combined or-
1
˜
3
(m, 1 H), 1.17 (d, J = 6.5 Hz, 3 H), 1.18–1.29 (m, 2 H), 1.25–1.32 ganic layers were dried with anhydrous MgSO4 and the solvent
(m, 1 H), 1.36–1.43 (m, 2 H), 1.47–1.59 (m, 1 H), 2.41–2.57 (m, 2
evaporated in vacuo. The residue was purified by silica gel
H), 2.93–3.05 (m, 2 H), 3.03–3.14 (m, 1 H), 3.46 (dd, J = 10.7, chromatography (eluent: AcOEt) to afford compound 7 (123 mg,
5.2 Hz, 1 H), 3.51 (s, 3 H), 3.56 (dd, J = 10.7, 2.9 Hz, 1 H), 3.87– 74%) as an oil. [α]2D5 = +25.5 (c = 0.64, CHCl ). IR (neat): ν =
˜
3
Eur. J. Org. Chem. 2008, 3474–3478
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3477

P. Etayo, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez
FULL PAPER
3700–2250, 3338, 1721, 1671, 1259 cm–1. 1H NMR (400 MHz,
368 K, C6D5CD3): δ = 0.86 (dddd, J = 12.5, 12.5, 12.5, 4.8 Hz, 1
H), 0.99–1.08 (m, 1 H), 1.05–1.16 (m, 2 H), 1.28–1.38 (m, 1 H),
1.36–1.47 (m, 1 H), 1.45 (s, 9 H), 2.10–2.17 (m, 1 H), 2.88–3.03 (m,
2 H), 3.08 (ddd, J = 12.9, 12.9, 2.2 Hz, 1 H), 3.49 (s, 3 H), 4.00–
4.11 (m, 1 H), 4.60–5.00 (m, 1 H), 4.89–5.08 (m, 1 H), 8.58 (br. s,
1 H) ppm. 13C NMR (100 MHz, 368 K, C6D5CD3): δ = 28.7, 30.3,
31.9, 33.5, 37.0, 38.9, 42.2, 52.0, 54.9, 80.2, 154.7, 156.0,
174.5 ppm. HRMS (ESI+): calcd. for C15H26N2O6Na [M + Na]+
353.1683; found 353.1678.
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Acknowledgments
This work was supported by the Gobierno de Aragón. P. E. is
thankful for a predoctoral fellowship from the Spanish Ministerio
de Ciencia y Tecnología (MCYT).
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1
tios were determined by H NMR analyses of the crude reac-
tion mixtures.
Received: January 21, 2008
Published Online: May 27, 2008
3478
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3474–3478