Stereocontrolled synthesis of orthogonally protected 2-substituted 4-aminopiperidines

Article abstract of DOI:10.1039/b904948g

Expedient and highly stereoselective routes to orthogonally protected chiral 2-substituted 4-aminopiperidines have been developed. Diastereoselective nucleophilic substitution of the hydroxy group of (2R,4S)-2-[(S)-1,2- dibenzyloxyethyl]-4-hydroxy-1-[(S)-

Full text of DOI:10.1039/b904948g

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereocontrolled synthesis of orthogonally protected 2-substituted
4-aminopiperidines†
Ramo´n Badorrey, Elsa Portan˜a, Mar´ıa D. D´ıaz-de-Villegas* and Jose´ A. Ga´lvez*
Received 11th March 2009, Accepted 23rd April 2009
First published as an Advance Article on the web 27th May 2009
DOI: 10.1039/b904948g
Expedient and highly stereoselective routes to orthogonally protected chiral 2-substituted
4-aminopiperidines have been developed. Diastereoselective nucleophilic substitution of the hydroxy
group of (2R,4S)-2-[(S)-1,2-dibenzyloxyethyl]-4-hydroxy-1-[(S)-1-phenylethyl]piperidine using sodium
azide afforded the corresponding azido derivative, which could be reduced and selectively protected to
give (2R,4R)-1-tert-butoxycarbonyl-2-[(S)-1,2-dibenzyloxyethyl]-4-acetylaminopiperidine. This
compound was easily converted into optically active 2-substituted 4-aminopiperidines using different
synthetic methodologies such as epoxide nucleophilic ring opening reactions and Wittig olefination
reactions among others.
diversely 2-substituted trans 4-aminopiperidines in enantiomeri-
cally pure form using different synthetic strategies.
Introduction
Compounds containing 4-aminopiperidine as a structural motif
have shown a wide variety of biological activities. Fentanyl and its
analogues are extensively used for anesthesia and analgesia due
to their exceptional analgesic potency.1 4-Aminopiperidines with
different substitution patterns have been evaluated as serotonin
and norepinephrine re-uptake inhibitors2 to treat neurological
diseases, as CCR5 chemokine receptor ligands3 to be used as
anti-HIV agents, as melanin concentrating hormone agonists4 for
treatment of obesity, as potent antimalarial compounds effective
against Plasmodium falciparum,5 or as N-type calcium channel
blockers6 to treat neuropathic pain. This structural motif is
also present in selective inhibitors of protein kinases,7 platelet
activation factor receptor antagonists,8 selective agonist of the
human b3-adrenergic receptor9 or useful drugs for treatment of
diseases associated with dipeptidyl peptidase IV10 among others.
Although different approaches to the stereoselective synthesis
of substituted piperidines have been developed11 most of them
involve approaches specific to the synthesis of a target molecule
and the development of general synthetic methodologies in which
preformed chiral non-racemic building blocks are used for the
construction of a wide variety of simple or complex structures is
less common. So the development of new and general routes for
the synthesis of these classes of molecules from a single precursor
is of considerable importance.
Results and discussion
Synthetic strategy
As part of a programme aimed at the design and preparation
of polyfunctionalised chiral building blocks that are useful
for the asymmetric synthesis of biologically active nitrogen-
containing compounds, in recent years we have studied the be-
haviour of (R)-2-[(S)-1,2-dibenzyloxyethyl]-1-[(S)-1-phenylethyl]-
2,3-dihydro-4(1H)-pyridone (1) as a synthetic precursor. Under
optimised reaction conditions [low temperature, acetonitrile as
solvent, ZnI2 as Lewis acid] enaminone 1 is easily obtained
as a single diastereomer on a gram scale from inexpensive
D-mannitol,12 which comes from renewable sources.
This chiral compound has proven to be a versatile interme-
diate in the synthesis of enantiomerically pure pipecolic acid
derivatives,13 (R)- and (S)-2-substituted-4-alkylidenepiperidines,14
cis- and trans-2,4-disubstituted piperidines15 and cis- and trans-
2,3-disubstituted-2,3-dihydro-4(1H)-pyridones.16
Compound 1 can be stereoselectively reduced to (2R,4S)-2-[(S)-
1,2-dibenzyloxyethyl]-4-hydroxy-1-[(S)-1-phenylethyl]piperidine
(2) using sodium borohydride,13b so the introduction of an azido
group could be achieved by nucleophilic substitution of the 4-
hydroxy group in compound 2. The resulting 4-azido compound
could be used as a precursor in the synthesis of chiral 2-substituted
4-aminopiperidines (Fig. 1).
In this manuscript we wish to illustrate the potential of
the chiral intermediate (R)-2-[(S)-1,2-dibenzyloxyethyl]-1-[(S)-1-
phenylethyl]-2,3-dihydro-4(1H)-pyridone (1) for the synthesis of
Highly stereoselective introduction of the acetamido moiety at C4
Departamento de Qu´ımica Orga´nica, Instituto de Ciencia de Materiales
de Arago´n, Instituto Universitario de Cata´lisis Homoge´nea, Universi-
dad de Zaragoza-CSIC, E-50009, Zaragoza, Spain. E-mail: loladiaz@
unizar.es, jagl@unizar.es; Fax: +34 976 761202; Tel: +34 976 762274
† Electronic supplementary information (ESI) available: Characterisation
spectra for compounds 3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14 and 15; noesy
spectra for compounds 4 and 5; crystal structure data for compound 3.
CCDC reference number 723555. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/b904948g
The introduction of the acetamido moiety at C4 was performed
by nucleophilic substitution and subsequent reduction. The target
azido derivative 4 was obtained in enantiomerically pure form
from compound 2 in a two-step procedure similar to that described
by Machetti et al. for related racemic substrate.17 The hydroxy
group at the C4 position was first converted into a good leaving
group by treatment with methanesulfonyl chloride in a basic
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Fig. 1 Synthetic strategy for chiral 2-substituted 4-aminopiperidines.
medium. The configuration of the resulting mesylate 3 was
found by X-ray crystallography† to be that shown in Scheme 1.
Subsequent reaction of compound 3 with sodium azide in dry
DMF at 85 ◦C led to azido compound 4 with inversion of
configuration at C4 in ca 72% yield for the two steps.
Fig. 2 Diagnostic nOe cross-peaks for the unambiguous determination
of the configurations of compounds 4 and 5.
In the 1H NMR spectrum of compound 4 it is possible to
unambiguously assign the H6 and H6¢ resonances as those at
ca 2.60 and 2.50 ppm, respectively, as the resonance due to H6
clearly shows a cross-peak with the H2 resonance (ca 3.20 ppm)
in the noesy spectrum. In turn, H6¢ shows a clear cross-peak with
the H4 resonance (ca 3.90 ppm), indicating the cis relationship
between these two nuclei and the trans disposition of the C2 and C4
substituents on the piperidine ring. On the other hand, in the noesy
spectrum of compound 5 the cross-peak observed between H2 and
the NH resonance clearly shows the cis relationship between these
two nuclei. This situation results from a trans disposition between
the C2 and C4 substituents on the piperidine ring.
Transformation of the 1,2-dihydroxy moiety into achiral C2
substituents
Scheme 1 Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 5 h, rt (80%);
(b) NaN3, DMF, 12 h, 85 ◦C (89%); (c) Ac2O, Et3N, H2, Pd/C, AcOEt,
12 h, rt, 1 atm. (70%).
The synthetic potential of substrate 5 is derived from manipulation
of the 1,2-dibenzyloxy moiety at C2 as this can be easily
transformed into a wide variety of functional groups.
Finally, exposure of 4 to an atmosphere of hydrogen in the
presence of acetic anhydride, using palladium on charcoal as
catalyst, caused simultaneous azide reduction/N-acetylation to
give the desired compound 5 as a single diastereomer in 70% yield.
These reactions are shown in Scheme 1
Selective N-debenzylation/N-tert-butoxycarbonylation of
compound 5 was performed by hydrogenolysis in the presence of
di-tert-butyl dicarbonate using palladium hydroxide on charcoal
as the catalyst.
This protocol gave compound 6, which was subsequently
O-debenzylated by hydrogenolysis in the presence of a catalytic
amount of palladium hydroxide to afford diol 7 in 98% yield.
The oxidative cleavage of the diol moiety in compound 7 to
the carboxylic acid was performed under similar conditions to
those described previously for the synthesis of pipecolic acid
derivatives.13 In this way, treatment of 7 with NaIO4 in the
presence of a catalytic amount of RuCl3 provided the pipecolic
acid derivative 8 in 65% yield, as shown in Scheme 2.
1
Both the H NMR and 13C NMR spectra of compounds 4
and 5 showed only one set of signals and these corresponded to
two chair conformers in rapid equilibrium. The assignment of the
relative stereochemistry of compounds 4 and 5 was made on
the basis of their 1H NMR spectra and the trans disposition of the
two substituents in these compounds was deduced on the basis of
noesy experiments‡ (Fig. 2).
Oxidative cleavage of diol 7 with NaIO4 led to the forma-
tion of aldehyde 9 and this was used without purification.
Firstly, reduction of the carbonyl group with sodium boro-
hydride cleanly afforded 4-acetamido-N-tert-butoxycarbonyl-2-
hydroxymethylpiperidine 10 in excellent 98% yield (Scheme 3).
‡ NOESY spectra were acquired in the phase sensitive mode with gradient
pulses in the mixing time as 2048 ¥ 256 hypercomplex files with 8 transients
for 256 time increments. A mixing time of 600 ms was used and processing
was carried out using a sine-bell squared function shifted by p/2 and a
states-TPPI method. Special precautions such as degassing of the sample
were not taken.
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The reaction of aldehyde 9 with the stabilized ylide ethoxycar-
bonyltriphenylphosphorane under identical reaction conditions
led to an 85/15 mixture of E/Z diastereomers which, upon
hydrogenation at room temperature and atmospheric pressure
in the presence of a catalytic amount of palladium on char-
coal, afforded compound 12 in acceptable yield, 53%, from
diol 7 (Scheme 3). In all cases the spatial disposition of stere-
ogenic centers remained unchanged under the different reaction
conditions and 6–12 were obtained as enantiomerically pure
compounds.
Transformation of the 1,2-dihydroxy moiety into chiral C2
substituents
Scheme 2 Reagents and conditions: (a) Boc2O, EtOH, H2, Pd(OH)2/C,
3 h, rt, 1 atm. (83%); (b) H2, Pd(OH)2/C, EtOH, 17 h, rt, 1 atm. (98%);
(c) NaIO4, RuCl3, CH3CN/CCl4/H2O, 2 h, rt. (65%).
The 1,2-dibenzyloxy moiety at C2 can be considered as a masked
oxirane ring that can be opened with organometallic compounds
to provide a variety of chiral hydroxylated substituents. With this
aim in mind, diol 7 was treated with triphenylphosphine and
diethyl azodicarboxylate under Mitsunobu reaction conditions18
but, unfortunately, diol 7 was recovered unchanged. Finally, diol 7
was converted into epoxide 13 in a two-step procedure consisting
of activation of the primary hydroxy group by reaction with
p-toluenesulfonyl chloride and subsequent cyclization in a basic
medium.
In order to prove the versatility of the proposed synthetic strat-
egy, the reaction of epoxide 13 with some lithium dialkylcuprate
reagents was tested. Treatment of 13 with lithium dimethylcuprate
gave rise to the regioselective cleavage of the epoxide ring to
provide alcohol 14 in 89% yield. Alternatively, regioselective
cleavage of the epoxide ring in compound 13 with lithium
di-n-butylcuprate gave compound 15 as a single product in
60% yield. These reactions are represented in Scheme 4. This
synthetic protocol allows the preparation of enantiomerically pure
4-aminopiperidines bearing a chiral 1-hydroxyalkyl chain at C2.
This structural feature is present in many biologically active
alkaloids derived from piperidine.
Scheme 3 Reagents and conditions: (a) NaIO4, CH3OH, 45 min, rt;
(b) NaBH4, EtOH, 30 min, rt (98% from 7); (c) (i) Ph3PCH2PhCl,
NaOCH3, 1 h, rt (ii) H2, Pd/C, EtOH, 30 min, rt, 1 atm. (86% from 7);
(d) (i) Ph3PCH2CO2EtCl, NaOCH3, 2 h, rt (ii) H2, Pd/C, EtOH, 30 min,
rt, 1 atm. (53% from 7).
Wittig olefination is widely recognized as one of the most
useful synthetic methodologies for the creation of C–C bonds
from carbonyl compounds. The behavior of aldehyde 9 towards
several phosphoranes was studied in order to evaluate the ver-
satility of this methodology to gain access to new 2-substituted
4-aminopiperidines. The reaction of 9 with the semi-stabilized
ylide benzylidenetriphenylphosphorane involved treatment of
benzylidenetriphenylphosphonium chloride with sodium methox-
ide in benzene at room temperature and subsequent addition of
the carbonyl compound to the reaction mixture. This protocol
gave the corresponding unsaturated compound as a 67/33 mixture
of E/Z diastereomers, which was cleanly hydrogenated at room
temperature and atmospheric pressure in the presence of a catalytic
amount of palladium on charcoal to afford compound 11 in 86%
yield from diol 7.
Scheme 4 Reagents and conditions: (a) (i) nBu2SnO, Et3N, TsCl, CH2Cl2,
7 h, rt (ii) K2CO3, CH3OH, 0 ◦C, then 1 h, rt (85%); (b) (CH3)2CuLi, Et2O,
1 h, -35 ◦C (89%) (c) (n-Bu)2CuLi, Et2O, 1 h, -35 ◦C (60%).
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atoms. Hydrogen atoms were calculated at idealized positions, and
during refinement they were allowed to ride on their carrying atom
with an isotropic thermal factor fixed to 1,2 times the Ueq value of
the carrier atom (1.5 for the methyl protons).
Conclusions
In summary, the chemistry described above provides a con-
venient, efficient and versatile method for the stereoselective
synthesis of orthogonally protected chiral trans-2-substituted-4-
aminopiperidines and such compounds are potentially biologi-
cally active. Changes in the configuration of stereogenic centers
generally induce significant changes in the specificity or potency
of biologically active compounds and so the extension of the syn-
thetic methodologies described here to the stereoselective synthesis
of cis 2-substituted-4-aminopiperidines is now in progress and will
be published in due course.
Colourless single crystals of 3 were obtained by slow evapo-
ration from an ethanol solution. Crystallographic data: crystal
size 0.44 ¥ 0.40 ¥ 0.36 mm3. M = 523.67, crystal system
monoclinic, unit cell dimensions a = 10.0148(6), b = 10.6959(7),
◦
◦
◦
˚
c = 12.9949(8) A, a = 90 , b = 102.575(10) , g = 90 , V =
3
˚
1358.59(15) A , T = 293(2) K, space group P21, absorption
coefficient m (Mo-Ka) = 0.159 mm-1, 16360 reflections collected
6243 unique [R(int) = 0.0223] which were used in all calculations.
Final R indices [I > 2s(I)] R1 = 0.0401, wR2 = 0.1018R indices
(all data) R1 = 0.0418, wR2 = 0.1028.
Experimental
(2R,4S)-2-[(S)-1,2-Dibenzyloxyethyl]-4-mesyloxy-1-[(S)-1-
phenylethyl]piperidine (3). A solution of methanesulfonyl chlo-
ride (0.87 mL, 1.29 g, 11.24 mmol) in dry CH2Cl2 (7 mL) was
added dropwise to a solution of compound 2 (4.17 g, 9.37 mmol)
and Et3N (1.57 mL (1.14 g), 11.24 mmol) in dry CH2Cl2 (60 mL)
at 0 ◦C under argon. The solution was allowed to warm up to
room temperature and, after stirring for 5 h, the reaction mixture
was partitioned between saturated aqueous NaHCO3 (30 mL) and
CH2Cl2 (10 mL). The organic layer was separated and the aqueous
layer extracted with CH2Cl2 (3 ¥ 15 mL). The combined organic
layers were dried over anhydrous MgSO4, filtered and concentrated
in vacuo. Purification of the residue by flash chromatography
(Eluent: Et2O/hexane; 1:1) gave 3.93 g (80% yield) of compound
3 as a white solid; mp 99–101 ◦C; [a]D23= -2.9 (c 1.0 CHCl3); IR
All reagents for reactions 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 performed on pre-coated silica gel polyester plates and
products were visualised using UV light (254 nm) and ethanolic
phosphomolybdic acid solution followed by heating. Column
chromatography was performed using silica gel (Kiesegel 60,
230–400 mesh). (2R,4S)-2-[(S)-1,2-dibenzyloxyethyl]-4-hydroxy-
1-[(S)-1-phenylethyl]piperidine (2) was prepared according to the
previously described procedures.12,13b
Melting points were determined in open capillaries using
a Gallenkamp capillary melting point apparatus and are not
corrected. FTIR spectra of oils were recorded as thin films on
NaCl plates and FTIR spectra of solids were recorded as nujol
dispersions on NaCl plates using a Thermo Nicolet Avatar 360
FT-IR spectrometer; nmax values expressed in cm-1 are given for
the main absorption bands. Optical rotations were measured on
a Jasco 1020 polarimeter at l 589 nm and 25 ◦C in a cell with
10 cm path length, [a]D values are given in 10-1 deg cm g-1
and concentrations are given in g/100 mL. Microanalyses were
determined using a Perkin-Elmen 2400 CHNS elemental analyser.
1H NMR and 13C NMR spectra were acquired on a Bruker AV-
400 spectrometer or a Bruker AV-300 spectrometer operating at
400 or 300 MHz for 1H NMR and 100 or 75 MHz for 13C NMR
at room temperature or 333 K in CDCl3 using a 5 mm probe.
The chemical shifts (d) are reported in parts per million and were
referenced to the residual solvent peak The coupling constants
(J) are quoted in hertz. The following abbreviations are used: s,
singlet; d, doublet; t, triplet; m, multiplet; bs, broad signal; bd,
broad doublet; dd, doublet of doublets, ddd, doublet of doublet
of doublets. High resolution mass spectra were recorded using
a Bruker Daltonics MicroToF-Q instrument from methanolic
solutions using the positive electrospray ionization mode (ESI+).
1
absorption (nujol) 1353, 1175 cm-1; H NMR (400 MHz, room
temperature, CDCl3) d 1.14 (d, J = 6.8 Hz, 3H), 1.40–1.56 (m,
2H), 1.88–1.95 (m, 1H), 2.08 (ddd, J = 12,1 Hz, J = 12,1 Hz, J =
2.4 Hz, 1H), 2.45 (ddd, J = 12,1 Hz, J = 3.6 Hz, J = 3.6 Hz, 1H),
2.44–2.50 (m, 1H), 2.79 (ddd, J = 11.2 Hz, J = 4.5 Hz, J = 2.4 Hz,
1H), 2.97 (s, 3H), 3.67 (dd, J = 10.5 Hz, J = 7.5 Hz, 1H), 4.03 (dd,
J = 10.5 Hz, J = 1.2 Hz, 1H), 4.06–4.13 (m, 2H), 4.47–4.57 (m,
1H), 4.52 (d, J = 12.1 Hz, 1H), 4.62 (d, J = 12.1 Hz, 1H), 4.71 (d,
J = 12.0 Hz, 1H), 4.84 (d, J = 12.0 Hz, 1H), 7.26–7.42 (m, 15H);
13C NMR (75 MHz, room temperature, CDCl3) d 8.2, 32.7, 32.8,
39.0, 42.6, 53.8, 57.6, 70.8, 72.8, 73.6, 76.9, 80.3, 126.6, 127.4,
127.7, 127.8, 128.1, 128.4, 128.4, 138.1, 138.6, 143.1, Elemental
analysis calcd (%) for C30H37NO5S: C, 68.81; H, 7.12; N, 2.67; S,
6.12; found: C, 68.96; H, 7.21; N, 2.64; S, 6.23.
(2R,4R)-4-Azido-2-[(S)-1,2-dibenzyloxyethyl]-1-[(S)-1-phenyl-
ethyl]piperidine (4). NaN3 (831 mg, 12.79 mmol) was added to a
solution of 3 (3.345 g, 6.39 mmol) in dry DMF (50 mL) and the
◦
mixture was stirred at 85 C for 12 h. The reaction mixture was
allowed to cool, then EtOAc (100 mL) was added and the resulting
solution was washed with saturated aqueous NaCl solution (3 ¥
20 mL), dried over anhydrous MgSO4, filtered and evaporated in
vacuo. Purification of the residue by flash chromatography (Eluent:
Et2O/hexane; 1:4) gave 2.67 g (89% yield) of compound 4 as an
oil; [a]D24= +7.6 (c 1.0 CHCl3); IR absorption (nujol) 2094 cm-1;
1H NMR (400 MHz, room temperature, CDCl3) d 1.26 (d, J =
6.8 Hz, 3H), 1.45–1.58 (m, 3H), 2.04 (ddd, J = 13.2 Hz, J =
6.5 Hz, J = 3.8 Hz, 1H), 2.48 (ddd, J = 12.7 Hz, J = 6.1 Hz, J =
4.3 Hz, 1H), 2.60 (ddd, J = 12.7 Hz, J = 7.6 Hz, J = 4.3 Hz, 1H),
3.08–3.14 (m, 1H), 3.64 (dd, J = 10.5 Hz, J = 6.8 Hz, 1H), 3.83
(dd, J = 10.5 Hz, J = 2.3 Hz, 1H), 3.85–3.91 (m, 1H), 3.96–4.01
X-Ray diffraction
The X-ray diffraction data were collected at room temperature
on a four circle Siemens P-4 diffractometer, using graphite-
˚
monochromated Mo-Ka radiation (l = 0.71073 A). Reflections
were measured in the q/2q-scan mode in the q range 1.6 to 28.3◦.
The structure was solved by direct methods using SIR9219 and
refinement was performed using SHELXL 9720 by the full-matrix
least-squares technique with anisotropic thermal factors for heavy
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(m, 1H), 4.05 (c, J = 6.8 Hz, 1H), 4.50 (d, J = 12.1 Hz, 1H), 4.57
(d, J = 12.1 Hz, 1H), 4.68 (d, J = 11.7 Hz, 1H), 4.80 (d, J =
11.7 Hz, 1H), 7.18–7.42 (m, 15H); 13C NMR (100 MHz, room
temperature, CDCl3) d 13.5, 28.8, 29.8, 40.5, 54.4, 56.2, 56.2, 71.4,
72.9, 73.4, 78.4, 126.6, 127.4, 127.5, 127.5, 127.6, 127.9, 128.0,
128.3, 128.4, 138.2, 138.7, 144.7, HRMS (ESI+): m/z [M + H+]
calcd for C29H35N4O2: 471.2754; found 471.2728.
(98% yield) of compound 7 as a white solid; mp 103–105 ◦C;
[a]D26= +67.1 (c 1.0 CHCl3); IR absorption (nujol) 3440, 3323,
1674, 1651 cm-1; 1H NMR (400 MHz, 333 K, CDCl3) d 1.18–1.32
(m, 1H), 1.40–1.48 (m, 1H), 1.47 (s, 9H), 1.89–1.96 (m, 1H), 1.95 (s,
3H), 2.01–2.07 (m, 1H), 2.87 (bs, 2H), 3.06–3.20 (m, 1H), 3.56 (dd,
J = 11.6 Hz, J = 5.2 Hz, 1H), 3.69 (dd, J = 11.6 Hz, J = 5.2 Hz,
1H), 3.95 (ddd, J = 7.0, J = 5.2 Hz, J = 5.2 Hz,1H), 4.04–4.15 (m,
1H), 4.16–4.28 (m, 1H), 4.34–4.43 (m, 1H), 5.30 (bd, J = 6.5 Hz,
1H); 13C NMR (75 MHz, 333 K, CDCl3) d 23.3, 28.4, 32.1, 33.6,
40.1, 43.7, 51.8, 64.2, 73.1, 80.4, 156.3, 169.6, Elemental analysis
calcd (%) for C14H26N2O5: C, 55.61; H, 8.67; N, 9.26; found: C,
55.82; H, 8.79; N, 9.31.
(2R,4R)-4-Acetamido-2-[(S)-1,2-dibenzyloxyethyl]-1-[(S)-1-
phenylethyl]piperidine (5). Et3N (1.2 mL, 0.86 g, 8.53 mmol),
Ac2O (0.64 mL, 0.695 g, 6.80 mmol) and Pd/C (130 mg) was added
successively to a solution of 4 (2.67 g, 5.67 mmol) in EtOAc (65 mL)
and the resulting mixture was stirred at room temperature under
hydrogen at atmospheric pressure for 12 h. The reaction mixture
was filtered through a Celite pad and concentrated in vacuo.
Purification of the residue by flash chromatography (Eluents:
CH2Cl2; CH2Cl2/EtOH; 9:1) gave 1.94 g (70% yield) of compound
5 as an oil; [a]D22= -27.1 (c 1.0 CHCl3); IR absorption (nujol)
3293, 1645 cm-1; 1H NMR (400 MHz, room temperature, CDCl3)
d 1.29 (d, J = 6.6 Hz, 3H), 1.32–1.42 (m, 1H), 1.56–1.63 (m,
1H), 1.63–1.72 (m, 1H), 1.72–1.79 (m, 1H), 1.95 (s, 3H), 2.44–
2.53 (m, 1H), 2.57 (ddd, J = 12.1 Hz, J = 8.6 Hz, J = 3.3 Hz,
1H), 3.13–3.20 (m, 1H), 3.64 (dd, J = 10.8 Hz, J = 5.7 Hz, 1H),
3.84 (dd, J = 10.8 Hz, J = 2.2 Hz, 1H), 4.02–4.13 (m, 3H), 4.51
(d, J = 12.1 Hz, 1H), 4.56 (d, J = 12.1 Hz, 1H), 4.62 (d, J =
11.8 Hz, 1H), 4.82 (d, J = 11.8 Hz, 1H), 5.30 (bs, 1H), 7.14–7.45
(m, 15H); 13C NMR (75 MHz, room temperature, CDCl3) d 17.7,
23.4, 30.5, 32.0, 41.9, 44.0, 55.1, 58.8, 71.3, 72.9, 73.5, 78.6, 126.6,
127.3, 127.4, 127.4, 127.6, 127.9, 128.1, 128.2, 128.3, 138.6, 139.2,
146.1, 169.1, HRMS (ESI+): m/z [M + H+] calcd for C31H39N2O3:
487.2955; found 487.2952.
(2R,4R)-4-Acetamido-1-tert-butoxycarbonylpipecolic acid (8).
Small portions of NaIO4 (207 mg, 0.97 mmol) were added to a
stirred solution of 7 (75 mg, 0.248 mmol) in CH3CN/CCl4/H2O
(2:2:3, 7 mL). After being vigorously stirred for 5 min follow-
ing completion of the addition, the mixture was treated with
RuCl3·H2O (2 mg, 0.01 mmol) and stirring was continued for
2 h. CH2Cl2 (20 mL) was then added, the organic layer was
separated and the aqueous layer extracted with CH2Cl2 (3 ¥
10 mL). The combined organic layers were dried over anhydrous
MgSO4, filtered and concentrated in vacuo. Purification of the
residue by flash chromatography (Eluent: CH2Cl2/EtOH; 2:9)gave
46 mg (65% yield) of compound 8 as a white solid; mp 107–108 ◦C;
[a]D25= +18.1 (c 1.0 CHCl3); 1H NMR (400 MHz, 333 K, CDCl3)
d 1.24–1.31 (m, 1H), 1.42–1.50 (m, 1H), 1.47 (s, 9H), 1.94–2.00 (m,
1H), 1.97 (s, 3H), 2.49–2.56 (m, 1H), 3.09–3.22 (m, 1H), 3.83–3.95
(m, 1H), 3.97–4.15 (m, 1H), 4.80–5.05 (bs, 1H), 5.40–5.50 (m, 1H);
13C NMR (75 MHz, 333 K, CDCl3) d 23.2, 28.4, 31.6, 32.9, 40.7,
44.7, 53.7, 80.7, 155.7, 170.4, 172,6, Elemental analysis calcd (%)
for C13H22N2O5: C, 54.53; H, 7.74; N, 9.78; found: C, 54.76; H,
7.87; N, 9.83.
(2R,4R)-4-Acetamido-1-tert-butoxycarbonyl-2-[(S)-1,2-diben-
zyloxyethyl]piperidine (6). 20% Pd(OH)2/C (200 mg) was added
to a solution of 5 (1.90 g, 3.90 mmol) and di-tert-butyl dicarbonate
(2.55 g, 11.7 mmol) in absolute EtOH (35 mL) and the mixture
was stirred at room temperature under hydrogen at atmospheric
pressure for 3 h. The reaction mixture was filtered through a Celite
pad and concentrated in vacuo. Purification of the residue by flash
chromatography (Eluents: EtOAc/hexane; 1:4; EtOAc) gave 1.56 g
(83% yield) of compound 6 as an oil; [a]D23= -6.5 (c 1.0 CHCl3);
IR absorption (nujol) 3303, 1683 cm-1; 1H NMR (400 MHz, 333 K,
CDCl3) d 1.11–1.23 (m, 1H), 1.32–1.42 (m, 1H), 1.42 (s, 9H), 1.84–
1.91 (m, 1H), 1.93 (s, 3H), 1.94–2.01 (m, 1H), 2.78–2.89 (m, 1H),
3.64 (dd, J = 10.7 Hz, J = 5.0 Hz, 1H), 3.72 (dd, J = 10.7 Hz, J =
3.6 Hz, 1H), 3.80 (ddd, J = 8.5 Hz, J = 5.0 Hz, J = 3.6 Hz, 1H),
3.94–4.08 (m, 1H), 4.09–4.23 (m, 1H), 4.50–4.56 (m, 1H), 4.52 (d,
J = 12.0 Hz, 1H), 4.57 (d, J = 11.7 Hz, 1H), 4.58 (d, J = 12.0 Hz,
1H), 4.72 (d, J = 11.7 Hz, 1H), 5.11 (bd, J = 7.3 Hz, 1H), 7.21–
7.35 (m, 10H); 13C NMR (75 MHz, 333 K, CDCl3) d 23.3, 28.4,
32.3, 33.6, 39.3, 43.7, 52.1, 71.0, 72.7, 73.5, 77.9, 79.5, 127.4, 127.5,
127.6, 128.2, 128.3, 138.4, 138.5, 155.2, 169.1, HRMS (ESI+): m/z
[M + Na+] calcd for C28H38N2NaO5: 505.2673; found 505.2691.
(2R,4R)-4-Acetamido-1-tert-butoxycarbonyl-2-hydroxymethyl-
piperidine (10). NaIO4 (64 mg, 0.298 mmol) was added to a
solution of 7 (75 mg, 0.248 mmol) in CH3OH (2 mL). After
45 min at room temperature the reaction mixture was filtered,
extracted with CH2Cl2 and concentrated in vacuo. The crude
product was dissolved in CH2Cl2, filtered and evaporated under
reduced pressure to give aldehyde 9, which was used in the next
step without further purification. NaBH4 (8 mg, 0.215 mmol) was
added to a solution of compound 9 in EtOH (3 mL) and the
resulting mixture was stirred at room temperature for 30 min. H2O
(5 mL) was added and the solution was extracted with CH2Cl2 (3 ¥
15 mL). The combined organic layers were dried over anhydrous
MgSO4, filtered and concentrated in vacuo. Purification of the
residue by flash chromatography (Eluent: CH2Cl2/EtOH; 4:1)
gave 66 mg (98% yield) of compound 10 as a white solid; mp
◦
41–43 C; [a]D22= +37.8 (c 0.5 CHCl3); IR absorption (nujol)
1
3305, 1650 cm-1; H NMR (400 MHz, 333 K, CDCl3) d 1.15–
1.28 (m, 1H), 1.36 (ddd, J = 12.8 Hz, J = 12.8 Hz, J = 6.0 Hz,
1H), 1.43 (s, 9H), 1.87–1.92 (m, 1H), 1.92 (s, 3H), 1.99–2.06 (m,
1H), 2.65 (bs, 1H), 2.88–2.97 (m, 1H), 3.66 (dd, J = 11.0 Hz,
J = 7.0 Hz, 1H), 3.71 (dd, J = 11.0 Hz, J = 7.6 Hz, 1H), 3.96–
4.08 (m, 2H), 4.33–4.42 (m, 1H), 5.62 (bd, J = 7.1 Hz, 1H); 13C
NMR (100 MHz, 333 K, CDCl3) d 23.2, 28.4, 31.9, 32.1, 38.9,
43.2, 52.3, 61.5, 80.0, 155.5, 169.5, Elemental analysis calcd (%)
for C13H24N2O4: C, 57.33; H, 8.88; N, 10.29; found: C, 57.22; H,
8.62; N, 10.41.
(2R,4R)-4-Acetamido-1-tert-butoxycarbonyl-2-[(S)-1,2-dihy-
droxyethyl]piperidine (7). 20% Pd(OH)2/C (150 mg) was added
to a solution of 6 (1.32 g, 2.74 mmol) in absolute EtOH (30 mL)
and the mixture was stirred at room temperature under hydrogen
at atmospheric pressure for 17 h. The reaction mixture was filtered
through a Celite pad and concentrated in vacuo to give 0.81 g
2916 | Org. Biomol. Chem., 2009, 7, 2912–2918
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(2R,4R)-4-Acetamido-1-tert-butoxycarbonyl-2-(2-phenylethyl)-
piperidine (11). A 30% solution of NaOCH3 in CH3OH
(0.082 mL, 78 mg, 0.43 mmol) was added dropwise to a suspension
of benzyltriphenylphosphonium chloride (193 mg, 0.496 mmol)
in benzene (2 mL) at room temperature and the mixture was
stirred for 10 min at the same temperature. A solution of aldehyde
9 (obtained as above) in benzene/CH2Cl2 (1:0.5, 1.5 mL) was
added and stirring was continued for 1 h. H2O (5 mL) was added
and the solution was concentrated in vacuo until the organic
solvents were removed. The aqueous layer was extracted with
CH2Cl2 (3 ¥ 15 mL). The combined organic layers were dried over
anhydrous MgSO4, filtered and concentrated in vacuo to afford
a 67/33 mixture of alkenes. The residue was chromatographed
(Eluent: EtOAc/hexane; 3:1), dissolved in EtOH (5 mL) and
hydrogenated with Pd/C (10 mg) as catalyst at room temperature
and atmospheric pressure for 30 min. When the reaction was com-
plete the catalyst was removed by filtration through a Celite pad
and the mixture was concentrated in vacuo to afford compound
11. Purification of the residue by flash chromatography (Eluent:
CH2Cl2/EtOH; 9.5:0.5) gave 74 mg (86% yield) of pure compound
11 as a white solid; mp 31–32.5 ◦C; [a]D22= +28.6 (c 1.1 CHCl3); IR
absorption (nujol) 3290, 1650 cm-1; 1H NMR (400 MHz, 333 K,
CDCl3) d 1.14–1.26 (m, 1H), 1.35–1.43 (m, 1H), 1.46 (s, 9H), 1.77–
1.90 (m, 1H), 1.88–1.98 (m, 2H), 1.94 (s, 3H), 1.98–2.08 (m, 1H),
2.51–2.69 (m, 2H), 2.84–2.93 (m, 1H), 4.05–4.18 (m, 2H), 4.34–
4.46 (m, 1H), 5.20 (bd, J = 5.8 Hz, 1H), 7.13–7.20 (m, 3H), 7.23–
7.29 (m, 2H); 13C NMR (100 MHz, 333 K, CDCl3) d 23.3, 28.4,
32.4, 32.6, 32.7, 35.4, 37.9, 43.0, 50.6, 79.6, 125.9, 128.3, 128.4,
141.7, 154.9, 169.1, Elemental analysis calcd (%) for C20H30N2O3:
C, 69.33; H, 8.73; N, 8.09; found: C, 69.62; H, 8.59; N, 8.31.
172.8, Elemental analysis calcd (%) for C17H30N2O5: C, 59.63; H,
8.83; N, 8.18; found: C, 59.52; H, 8.62; N, 8.00.
(2R,4R)-4-Acetamido-1-tert-butoxycarbonyl-2-[(S)-oxiranyl]-
piperidine (13). nBu2SnO (6.6 mg, 0.026 mmol), Et3N (0.22 mL
(161 mg), 1.59 mmol) and p-toluenesulfonyl chloride (303 mg,
1.59 mmol) were added to a solution of 7 (400 mg, 1.32 mmol)
in dry CH2Cl2 (8 mL) and the mixture was stirred at room
temperature for 7 h. Brine was added (10 mL) and the solution
was extracted with CH2Cl2 (3 ¥ 15 mL). The combined organic
layers were dried over anhydrous MgSO4, filtered and evaporated
in vacuo. The residue was passed through a short pad of silica gel
(Eluents: Et2O; CH2Cl2/EtOH; 9:1) to give the corresponding
tosylate. K2CO3 (219 mg, 1.59 mmol) was added to a stirred
solution of tosylate in CH3OH (10 mL) at 0 ◦C and the solution
was allowed to warm up to room temperature. After stirring
for an additional 1 h, saturated aqueous NH4Cl (10 mL) was
added and the solution was extracted with CH2Cl2 (3 ¥ 10 mL).
The combined organic layers were dried over anhydrous MgSO4,
filtered and evaporated in vacuo. Purification of the residue by
flash chromatography (Eluent: CH2Cl2/EtOH; 9:1) gave 320 mg
(85% yield) of compound 13 as an oil; [a]D23= +41.4 (c 1 CHCl3);
IR absorption (nujol) 3310, 1743, 1662 cm-1; 1H NMR (400 MHz,
room temperature, CDCl3) d 1.16–1.28 (m, 1H), 1.42–1.53 (m, 1H),
1.45 (s, 9H), 1.92–1.98 (m, 1H), 1.96 (s, 3H), 2.03–2.10 (m, 1H),
2.57 (dd, J = 4.4 Hz, J = 2.8 Hz, 1H), 2.78 (dd, J = 4.4 Hz, J =
4.1 Hz, 1H), 3.14 (ddd, J = 4.1 Hz, J = 4.0 Hz, J = 2.8 Hz, 1H),
4.00–4.14 (m, 1H), 4.14–4.25 (m, 1H), 4.26–4.49 (m, 1H), 5.28 (bd,
J = 7.3 Hz, 1H); 13C NMR (75 MHz, room temperature, CDCl3)
d 23.4, 28.3, 31.8, 33.7, 40.1, 43.7, 44.8, 50.4, 53.2, 80.1, 154.9,
169.4, HRMS (ESI+): m/z [M + H+] calcd for C14H24N2NaO4:
307.1628; found 307.1634.
(2R,4R)-4-Acetamido-1-tert-butoxycarbonyl-2-(2-ethoxycarbo-
nylethyl)piperidine (12). A 30% solution of NaOCH3 in CH3OH
(0.082 mL, 78 mg, 0.43 mmol) was added dropwise to a suspension
of 80% (ethoxycarbonylmethyl)triphenylphosphonium chloride
(238 mg, 0.496 mmol) in benzene (2 mL) at room temperature
and the mixture was stirred for 10 min at the same temperature.
A solution of aldehyde 9 (obtained as above) in benzene/CH2Cl2
(1:0.5, 1.5 mL) was added and stirring was continued for 2 h. H2O
(5 mL) was added and the solution was concentrated in vacuo
until the organic solvents were removed. The aqueous layer was
extracted with CH2Cl2 (3 ¥ 15 mL), and the combined organic
layers were dried over anhydrous MgSO4, filtered and concentrated
in vacuo to afford an 85/15 mixture of alkenes. The residue
was chromatographed (Eluent: EtOAc/hexane; 3:1), dissolved in
EtOH (5 mL) and hydrogenated with Pd/C (10 mg) as catalyst
at room temperature and atmospheric pressure for 30 min. When
the reaction was complete the catalyst was removed by filtration
through a Celite pad and concentrated in vacuo. Purification of the
residue by flash chromatography (Eluent: EtOAc/EtOH; 9.5:0.5)
gave 45 mg (53% yield) of compound 12 as a white solid; mp 55–
57 ◦C; [a]D22= +19.5 (c 1.68 CHCl3); IR absorption (nujol) 3291,
1731, 1658 cm-1; 1H NMR (400 MHz, 333 K, CDCl3) d 1.10–1.21
(m, 1H), 1.22 (t, J = 7.1 Hz, 3H), 1.34–1.42 (m, 1H), 1.42 (s, 9H),
1.71–1.80 (m, 1H), 1.80–1.87 (m, 1H), 1.88–1.95 (m, 1H), 1.91 (s,
3H), 1.98–2.10 (m, 1H), 2.18–2.33 (m, 2H), 2.80–2.90 (m, 1H),
4.00–4.10 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 4.30–4.40 (m, 1H),
5.37 (bs, 1H); 13C NMR (100 MHz, 333 K, CDCl3) d 14.1, 23.2,
25.8, 28.4, 31.2, 32.5, 35.6, 37.7, 42.9, 50.3, 60.3, 79.7, 154.7, 169.1,
(2R,4R)-4-Acetamido-1-tert-butoxycarbonyl-2-[(R)-1-hydroxy-
propyl]piperidine (14). A 1.4M solution of CH3Li in Et2O
(2.51 mL, 3.52 mmol) was added dropwise to a suspension of
◦
CuI (335 mg, 1.76 mmol) in dry Et2O (10 mL) at -35 C under
argon. After stirring for 30 min at -35 ◦C, a solution of compound
13 (100 mg, 0.352 mmol) in dry Et2O (1.3 mL) was added and the
mixture was stirred for an additional 1 h at the same temperature.
The reaction mixture was diluted with EtOAc (20 mL) and
carefully quenched at -35 ◦C with saturated NH4Cl (10 mL). After
the addition of H2O (10 mL) the reaction mixture was allowed
to warm up to room temperature with vigorous stirring. The
organic layer was separated and extracted with EtOAc (3 ¥ 15 mL).
The combined organic layers were dried over anhydrous MgSO4,
filtered and concentrated in vacuo. Purification of the residue by
flash chromatography (Eluent: CH2Cl2/EtOH; 9:1) gave 94 mg
(89% yield) of compound 14 as a white solid; mp 158–160 ◦C;
[a]D23= +42.7 (c 0.88 CHCl3); IR absorption (nujol) 3282, 1691,
1
1640 cm-1; H NMR (400 MHz, 333 K, CDCl3) d 1.00 (t, J =
7.4 Hz, 3H), 1.16–1.30 (m, 1H), 1.32–1.46 (m, 2H), 1.45 (s, 9H),
1.64–1.75 (m, 1H), 1.88–1.95 (m, 1H), 1.92 (s, 3H), 1.95–2.10 (m,
1H), 2.06 (bs, 1H), 2.97–3.07 (m, 1H), 3.79 (ddd, J = 8.6 Hz, J =
8.5 Hz, J = 3.2 Hz, 1H), 4.00–4.12 (m, 2H), 4.12–4.20 (m, 1H),
5.35 (bd, J = 5.8 Hz, 1H); 13C NMR (100 MHz, 333 K, CDCl3) d
9.2, 23.2, 27.5, 28.5, 32.3, 33.1, 39.4, 43.6, 55.8, 71.6, 80.2, 156.3,
169.1, Elemental analysis calcd (%) for C15H28N2O4: C, 59.98; H,
9.40; N, 9.33; found: C, 60.20; H, 9.61; N, 9.55.
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(2R,4R)-4-Acetamido-1-tert-butoxycarbonyl-2-[(R)-1-hydroxy-
hexyl]piperidine (15). A 1.6M solution of BuLi in hexane
(2.70 mL, 4.32 mmol) was added dropwise to a suspension of
5 (a) K. M. Brinner, M. A. Powles, D. M. Schmatz and J. A. Ellman,
Bioorg. Med. Chem. Lett., 2005, 15, 345–348; (b) C. Boss, T. Weller, C.
Grisostomi and O. Corminboeuf, WO patent 2005058822, 2005; (c) C.
Boss, O. Corminboeuf, C. Grisostomi, T. Weller, D. Burd, L. Pradel,
T. Hiyoshi and T. Tamuta WO patent 2006056930, 2006.
◦
CuI (412 mg, 2.16 mmol) in dry Et2O (10 mL) at -35 C under
argon. After stirring for 30 min at -35 ◦C, a solution of compound
13 (115 mg, 0.40 mmol) in dry Et2O (1.5 mL) was added and the
mixture was stirred for an additional 1 h at the same temperature.
The reaction mixture was diluted with EtOAc (20 mL) and
carefully quenched at -35 ◦C with saturated NH4Cl (10 mL). After
the addition of H2O (10 mL) the reaction mixture was allowed
to warm up to room temperature with vigorous stirring. The
organic layer was separated and the aqueous layer extracted with
EtOAc (3 ¥ 15 mL). The combined organic layers were dried over
anhydrous MgSO4, filtered and concentrated in vacuo. Purification
of the residue by flash chromatography (Eluent: CH2Cl2/EtOH;
9:1) gave 83 mg◦(60% yield) of the compound 15 as a yellowish
solid; mp 46–47 C; [a]D23= +45.5 (c 0.83 CHCl3); IR absorption
(nujol) 3307, 1691, 1659 cm-1; 1H NMR (400 MHz, 333 K, CDCl3)
d 0.89 (t, J = 6.7 Hz, 3H), 1.18–1.48 (m, 8H), 1.45 (s, 9H), 1.48–
1.56 (m, 1H), 1.56–1.65 (m, 1H), 1.88–1.96 (m, 2H), 1.91 (s, 3H),
1.96–2.03 (m, 1H), 3.02 (ddd, J = 13.9 Hz, J = 13.8 Hz, J =
2.5 Hz, 1H), 3.80–3.87 (m, 1H), 4.03–4.12 (m, 2H), 4.13–4.18 (m,
1H), 5.27 (bs, 1H); 13C NMR (100 MHz, 333 K, CDCl3) d 13.8,
22.5, 23.2, 24.8, 28.4, 31.9, 32.2, 33.0, 34.8, 39.3, 43.4, 56.0, 70.4,
80.1, 156.2, 169.1, Elemental analysis calcd (%) for C18H34N2O4:
C, 63.13; H, 10.01; N, 8.18; found: C, 63.33; H, 9.87; N, 7.98.
6 (a) T. R. Ryder, L. Y. Hu, M. F. Rafferty, M. R. Feng, S. M. Lotarski,
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M. G. Rowlands, G. W. Aherne, L. K. Hunter, K. Taylor, R. Ruddle,
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Tillet, Bioorg. Med. Chem. Lett., 2001, 11, 3123–3127.
10 M. Boehringer, D. Hunziker, B. Kuhn, B. M. Loeffler, T. Luebbers, F.
Rickin and B. Loeffler, US patent 2006135561, 2006.
11 Most recent reviews: (a) S. Laschat and T. Dickner, Synthesis, 2000,
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Acknowledgements
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The financial support of the Spanish Ministry of Science and In-
novation and European Regional Development Fund (CTQ2008-
00187/BQU) and the Government of Arago´n (GA E-71) is
acknowledged.
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2918 | Org. Biomol. Chem., 2009, 7, 2912–2918
This journal is
The Royal Society of Chemistry 2009
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