Efficient stereoselective synthesis of enantiopure cis- and trans-1,2,4-trisubstituted piperidines

Article abstract of DOI:10.1016/j.tetasy.2007.10.042

Enantiomerically pure (2R,4S)- and (2R,4R)-2-[(S)-1,2-dibenzyloxyethyl]-4-[2-(diphenylmethoxy)ethyl]-1-[(S)-1-phenylethyl]piperidines cis-1 and trans-1 have been synthesised from N-[(S)-1-phenylethyl]-(S)-2,3-di-O-benzylglyceraldimine in six steps in 31%

Full text of DOI:10.1016/j.tetasy.2007.10.042

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2812–2819
Efficient stereoselective synthesis of enantiopure cis- and
trans-1,2,4-trisubstituted piperidines
*
*
´
´
´
´
´
Pablo Etayo, Ramon Badorrey, Marıa D. Dıaz-de-Villegas and Jose A. Galvez
Departamento de Quı´mica Orga´nica, Instituto de Ciencia de Materiales de Arago´n, Instituto Universitario de Cata´lisis Homoge´nea,
Universidad de Zaragoza-CSIC, E-50009 Zaragoza, Spain
Received 16 October 2007; accepted 31 October 2007
Abstract—Enantiomerically pure (2R,4S)- and (2R,4R)-2-[(S)-1,2-dibenzyloxyethyl]-4-[2-(diphenylmethoxy)ethyl]-1-[(S)-1-phenylethyl]-
piperidines cis-1 and trans-1 have been synthesised from N-[(S)-1-phenylethyl]-(S)-2,3-di-O-benzylglyceraldimine in six steps in 31%
and 18% overall yields, respectively. The efficiency of the synthetic strategy developed for the synthesis of these compounds relies on:
(a) the totally diastereoselective tandem Mannich–Michael reaction between Danishefsky’s diene and the starting glyceraldimine, (b)
the high yielding Wadsworth–Emmons reaction of the 4-piperidone intermediate and (c) the diastereodivergent reduction of the exocyclic
C–C double bond at C4 of the piperidine ring. These transformations led to 1,2,4-trisubstituted piperidines with two new stereogenic
centres with excellent stereoselectivity.
ꢀ 2007 Elsevier Ltd. All rights reserved.
OCHAr2
( )n
1. Introduction
CH2OCHPh2
CH2OCHPh2
*
Chiral polysubstituted piperidines represent one of the
most common building blocks in natural products with
biological activity1–5 and have been identified as important
therapeutic agents for the treatment of a range of dis-
eases.1–8 In recent years, thousands of piperidine com-
pounds have been mentioned in clinical and preclinical
studies directed towards the development of new drugs.
As a consequence, the development of new and efficient
stereoselective syntheses of not only the active compounds
but also of chemically modified analogues is of major inter-
est within medicinal chemistry. In this context, methods for
the stereoselective synthesis of substituted piperidines have
recently been reviewed.9–13
*
N
N
R2
N
R1
R1
Ph
I
II
III
Figure 1. Structures of 1-benzyl-4-[2-(diphenylmethoxy)ethyl]piperidine I
and related compounds.
Although structural analogues of compound I with different
substituents at the 1- and 4-positions of the piperidine ring
have been synthesised, to the best of our knowledge struc-
tural analogues of compound I with one substituent at C2
(compounds III in Fig. 1) have not been previously synthes-
ised. This new substitution pattern on the piperidine ring
leads to compounds with two stereogenic centres on the
ring, C2 and C4. As a result, four stereoisomers are possible
for each newly synthesised compound and this significantly
complicates the synthesis. On the other hand, trisubstituted
piperidines incorporate a third site for structural diversity,
in addition to stereochemical diversity, a situation that pro-
vides a powerful scaffold to further investigate the develop-
ment of new drugs with activity on the central nervous
system (CNS). For this reason, it should be interesting to
develop new and efficient stereoselective processes to over-
come the aforementioned synthetic difficulties.
Biologically active piperidines which contain a 4-[2-(di-
arylmethoxy)ethyl] unit have shown a high affinity and
selectivity for dopamine (DAT), serotonin (SERT) and
norepinephrine (NET) transporters14–17 with 1-benzyl-4-
[2-(diphenylmethoxy)ethyl]piperidine (compound
I
in
Fig. 1) being one of the most potent and selective DAT
inhibitors described to date.18
*
Corresponding authors. Tel.: +34 976762274; fax: +34 976 761202
(M.D.D.); tel.: +34 976762273; fax: +34 976 761202 (J.A.G.); e-mail
addresses: loladiaz@unizar.es; jagl@unizar.es
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.042

P. Etayo et al. / Tetrahedron: Asymmetry 18 (2007) 2812–2819
2813
Herein we report in full detail on the asymmetric synthesis
of two diastereoisomers of a 2-substituted 1-benzyl-4-[2-
(diphenylmethoxy)ethyl]piperidine analogue from N-[(S)-
1-phenylethyl]-(S)-2,3-di-O-benzylglyceraldimine, which is
easily available on a multigram scale from inexpensive
D-mannitol. These two analogues are (2R,4S)- and (2R,4R)-
2-[(S)-1,2-dibenzyloxyethyl]-4-[2-(diphenylmethoxy)ethyl]-
1-[(S)-1-phenylethyl]piperidine, cis-1 and trans-1, res-
pectively (Fig. 2), and they have both been obtained in
enantiomerically pure form.
The synthesis of compound cis-1 required the reduction of
the C–C double bond to take place opposite to the 1,2-di-
benzyloxyethyl substituent. With this aim in mind, the
heterogeneous catalytic hydrogenation of compound
(E/Z)-5 at room temperature and atmospheric pressure
using absolute ethanol as solvent was investigated. In all
cases, 2,4-disubstituted piperidines of cis configuration
were obtained preferentially with good yields and cis/trans
1
diastereoselectivities, as determined by H NMR analyses
of crude reaction mixtures, ranging from 58:42 to 87:13
after the starting material had been consumed. The struc-
ture of the resulting hydrogenation products was found
to depend upon the catalyst (Scheme 2).
CH2OCHPh2
CH2OCHPh2
H
H
N
OBn
N
OBn
CO2Et
OBn
Ph
OBn
Ph
CH3
cis-1
CH3
H2, cat, EtOH
rt, 1 atm
H
trans-1
N
OBn
H
Figure 2. Structures of target compounds cis-1 and trans-1.
OBn
cis/trans)-6
CHCO2Et
(
H
N
Ni-Raney®, 65%, dr = 72:28
Pd/C (10% Pd), 60%, dr = 87:13
PdO·xH2O (75% Pd), 56%, dr = 79:21
2. Results and discussions
2.1. Synthesis
OBn
OBn
Ph
CH3
(
CO2Et
H
E/Z)-5
H2, cat, EtOH
rt, 1 atm
Target compounds cis-1 and trans-1 can be prepared from
an imine derived from D-glyceraldehyde through a 2-substi-
tuted 4-alkoxycarbonylmethylidenepiperidine intermediate
provided that the configuration at the 4-position of the
piperidine ring could be controlled in a stereoselective
reduction of the exocyclic double bond.
N
OBn
OBn
Ph
CH3
cis
(
/trans)-7
Rh/Al2O3 (5% Rh), 84%, dr = 58:42
Pt/C (10% Pt), 90%, dr = 75:25
PtO2, 75%, dr = 70:30
Compound 5, an intermediate of this type, was prepared
from imine 2 in a three-step procedure in 71% overall yield
as a 97:3 mixture of alkenes of E- and Z-configuration
according to our previously described procedures (Scheme
1).19–21 The synthetic route consisted of: (a) a tandem
Mannich–Michael reaction (M–M) between Danishefsky’s
diene and imine 2 in the presence of ZnI2 to afford didehyd-
ropiperidone 3 with total diastereoselectivity; (b) a regio-
selective reduction of the enaminone C–C double bond
with L-Selectrideꢁ to afford 4-piperidone 4, a valuable
and versatile building block for the synthesis of several
biologically active compounds;22–24 and (c) a Wadsworth–
Emmons reaction (WE) of compound 4 with triethyl phos-
phonoacetate using LDA as the base.
Scheme 2. Hydrogenation of the exocyclic double bond in compound 5.
The use of Ni-Raneyꢁ, Pd/C or PdOÆxH2O as catalysts led
to hydrogenation of the exocyclic C–C double bond with
concomitant N-debenzylation. This gave secondary amine
6 as a mixture of cis- and trans-diastereoisomers and these
proved very difficult to isolate and gave only a moderate
yield after prolonged reaction times. When Rh/Al2O3 (5%
Rhꢀ), Pt/C (10% Ptꢀ) or PtO2 was used, the N-debenzy-
lation process was not detected and piperidine 7 was
obtained after shorter reaction times and in high yield as
a cis/trans mixture of diastereoisomers, which were easily
separated by column chromatography. The diastereomeric
ratio depended on the catalyst and, of the different catalysts
tested, Pt/C led to the best results in terms of yield and dia-
stereoselectivity. These conditions gave 68% isolated yield
of pure cis-7 on a gram scale.
O
CH3
N
H
M-M
[H-]
H
Ph
OBn
ref. 19
ref. 19
N
OBn
OBn
OBn
CH3
Ph
In an attempt to increase the cis-diastereoselectivity of the
hydrogenation reaction, several homogeneous catalysts
were tested. Upon using [Ir(COD)(Py)(PCy3)]PF6 (Crab-
tree catalyst)25,26 or Ru(PPh3)3Cl2 the hydrogenation did
not proceed to any noticeable extent. However, the use of
Rh(PPh3)3Cl (Wilkinson catalyst)27 gave compound 7 in
2
3 (86%)
CHCO2Et
O
WE
refs. 20,21
H
H
N
N
OBn
OBn
OBn
OBn
Ph
CH3
CH3
Ph
(E/Z)-5 (97%)
4 (85%)
ꢀ On using Rh/C (5% Rh) or Pt/C (3% Pt) as catalysts, compound 4 was
Scheme 1. Synthesis of intermediate 5.
recovered unaltered.

2814
P. Etayo et al. / Tetrahedron: Asymmetry 18 (2007) 2812–2819
moderate yield (59%) and low cis/trans diastereoselectivity
(58:42) when the hydrogenation was carried out at a hydro-
gen pressure of 20 atm.
11 with a trans-configuration, although it was necessary
to work at À20 ꢂC to achieve total conversion. Under these
conditions compound trans-11 was obtained in 91% iso-
lated yield on a gram scale.
The synthesis of trans-1 required the reduction of the C–C
double bond to take place from the same side as the 1,2-
dibenzyloxyethyl substituent. For this purpose, several
reducing agents were tested. The reduction of the double
bond of a,b-unsaturated ethyl ester (E/Z)-5 using Sm/I2
or Mg in anhydrous ethanol or Al–NiCl2Æ6H2O–THF
did not take place and only unreacted starting material
was recovered. The use of NaBH4–NiCl2Æ6H2O led to a
successful conjugate reduction and compound 7 was
obtained in 86% yield, albeit with a low cis/trans diastereo-
selectivity (60:40) which favoured the compound with the
cis-configuration. In an effort to increase the trans-selectiv-
ity, bulkier hydrides were used in this reaction. Compound
5 was inert towards Red-Alꢁ-CuI and Superhydrideꢁ,
while reaction with L-Selectrideꢁ at À78 ꢂC led to a 1:1
mixture of E/Z-8, derived from 1,2-addition, and com-
pound trans-9, derived from totally diastereoselective 1,4-
addition and the subsequent reduction of the ester moiety
(Scheme 3).
Enantiomerically pure cis-1 and trans-1 were prepared
from compounds cis-7 and trans-11. Reduction of the ethyl
and tert-butyl esters was achieved with LiAlH4 to give pri-
mary alcohols cis-9 (90%) and trans-9 (60%). Whereas
yields of coupling of benzhydryl bromide with the corres-
ponding alkoxide, generated by treatment of the alcohol
with sodium hydride, in the presence of tetra-n-butyl-
ammonium iodide were poor, acid-catalysed reaction of
alcohols cis-9 and trans-9 with benzhydrol under azeotro-
pic distillation conditions afforded the desired (2R,4S)-
and (2R,4R)-2-[(S)-1,2-dibenzyloxyethyl]-4-[2-(diphenyl-
methoxy)ethyl]-1-[(S)-1-phenylethyl]piperidines in 71%
and 46%, respectively (Scheme 4).
2.2. Stereochemical assignments
The cis- and trans-relative configurations of key com-
pounds were determined on the basis of their NMR data
and selective 1D gradient enhanced nuclear Overhauser
enhancement spectroscopy (ge-1D NOESY) or homo-
nuclear 2D-NOESY experiments (Fig. 3) after the com-
Pre-complexation of compound 5 with BF3ÆOEt228 was car-
ried out prior to reduction with L-Selectrideꢁ in an attempt
to avoid hydride attack on the carbonyl group. However,
this approach led to the recovery of compound (E/Z)-5.
Regioselective double bond reduction was finally achieved
by using the related substrate tert-butyl ester (E/Z)-10,
which was obtained according to our previously described
procedure.21 Reduction of compound (E/Z)-10 with L-
Selectrideꢁ led to the exclusive formation of compound
1
plete unequivocal assignment of all signals in H NMR
spectra with the aid of 2D-NMR experiments (COSY,
HSQC, HMBC).
For compounds cis-6 and cis-7, a doublet of doublets of
doublets, reduced to a quartet due to three identical J
values of ca. 12 Hz was observed for proton H-3 at 0.92
t
CO2 Bu
CH2OH
CHCO2R
CHCH2OH
L-Selectride®
L-Selectride®
H
H
H
H
+
–78 ºC
R = Et
–20 ºC
R = tBu
N
OBn
N
OBn
N
OBn
N
OBn
OBn
OBn
OBn
OBn
CH3
CH3
CH3
CH3
Ph
Ph
Ph
Ph
R = Et, (E/Z)-5
R = tBu, (E/Z)-10
(E/Z)-8 35%
trans-9 35%
trans-11 91%
Scheme 3. Reduction of exocyclic double bond in compounds 5 and 10.
CH2OCHPh2
H
CO2Et
H
CH2OH
Ph2CHOH,
p
-TsOH·H2O
LiAlH4
H
THF, rt, 1 h
toluene, Δ, 17 h,
N
OBn
N
OBn
N
OBn
OBn
Ph
OBn
Ph
OBn
CH3
cis-1 71%
CH3
CH3
Ph
cis-7
cis-9 90%
t
CH2OH
CH2OCHPh2
CO2 Bu
Ph2CHOH,
p-TsOH·H2O
LiAlH4
H
H
H
THF, rt, 2 h
toluene, Δ, 17 h,
N
OBn
N
OBn
N
OBn
OBn
OBn
Ph
OBn
Ph
CH3
CH3
CH3
Ph
trans-11
trans-9 60%
trans-1 46%
Scheme 4. Synthesis of target compounds cis-1 and trans-1.

P. Etayo et al. / Tetrahedron: Asymmetry 18 (2007) 2812–2819
2815
nOe
nOe
control of the stereochemistry of the new stereogenic centre
generated at C4 in the synthetic strategy relies on highly dia-
stereoselective reduction of the exocyclic C–C double bond
of intermediates 5 and 10, which in turn are obtained by a
Wadsworth–Emmons reaction on the enantiopure 4-piperi-
done 4. This synthesis highlights the utility of chiral 4-pip-
eridone 4 as a versatile synthetic intermediate.
H
H
H
CH2CO2Et
H
H
H
R
R
CH2CO2Et
N
N
H
H
R*
R*
H
H
R = H, cis-6
R = H, trans-6
R = (S)-1-phenylethyl, cis-7
R = (S)-1-phenylethyl, trans-7
4. Experimental
R* =
OBn
OBn
4.1. General experimental procedures
nOe
Microanalyses were determined using a Perkin–Elmer 2400
CHNS elemental analyser. Melting points were determined
in open capillaries using a Gallenkamp apparatus and are
uncorrected. FT-IR spectra of oils were recorded as thin
films on NaCl plates and FT-IR spectra of solids were
recorded as KBr pellets, using a Thermo Nicolet Avatar
360 FT-IR spectrometer; mmax values expressed in cmÀ1
are given for the main absorption bands. Optical rotations
were measured on a Jasco P-1020 polarimeter at k 589 nm
and 25 ꢂC in a cell with 10 cm path length, [a]D values are
given in 10À1 deg cm gÀ1 and concentrations are given in
g/100 mL. NMR spectra were acquired on a Bruker AV-
400 spectrometer operating at 400 MHz for 1H NMR
and 100 MHz for 13C NMR at room temperature 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. Coupling 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 doublet
of doublets. Selective ge-1D NOESY experiments were per-
formed with gradient pulses in the mixing time. Spectra
were acquired at 300 K with optimised mixing times and
128 transients per spectrum using the Bruker standard
selnogp pulse program. Special precautions such as degas-
sing of the sample were not taken. NOESY spectra were
acquired in the phase sensitive mode with gradient pulses
in the mixing time as 2048 · 256 hipercomplex files with 8
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 p/2 and a states-TPPI
method. High resolution mass spectra were recorded using
a Bruker Daltronics MicroToF-Q electrospray instrument
from methanolic solutions using the positive electrospray
ionisation mode (ESI+). Single crystal X-ray diffraction
studies were done on a Siemens P4 diffractometer.
H
H
CH2CO2tBu
H
H
H
N
t
CH2CO2 Bu
R
R
N
H
H
R*
BnO
H
H
H
OBn
nOe
R = (S)-1-phenylethyl, trans-11
Figure 3. NOE analysis of key compounds.
and 0.86 ppm, respectively. This indicates a diaxial rela-
tionship between H-3 and both H-2 and H-4 only possible
for a cis relationship between H-2 and H-4. This assign-
ment was confirmed by NOE data as irradiation of H-2,
at 2.68–2.75 ppm for cis-6 and 2.69–2.75 ppm for cis-7,
gave a significant enhancement of the H-4 proton, at
1.77–1.88 and 1.62–1.74 ppm, respectively.
For compound cis-7, an independent stereochemical
assignment, which further confirmed these results, was pos-
sible by single crystal X-ray analysis.
The assignment of trans configuration for trans-6 and
trans-7 follows by elimination and its also consistent with
the nuclear Overhauser enhancements observed for these
compounds, which were performed using C6D6 as solvent
to overcome signal overlapping. Irradiation of H-2, at
3.07–3.13 ppm for trans-6 and 3.45–3.55 ppm for trans-7,
gave a significant enhancement of the protons of the meth-
ylene group bonded to C-4, at 2.25–2.32 and 2.15–
2.20 ppm, respectively.
NOE cross-peaks observed by 1H–1H-NOESY between the
methylene group of the tert-butoxycarbonylmethyl substi-
tuent at C-4 (2.05 ppm) and H-2 (3.35–3.42 ppm) and
between the CH (3.94–4.01 ppm) group of substituent at
C-2 and H-4 (2.13–2.26 ppm) indicated a trans configura-
tion for compound trans-11 obtained in the reduction of
compound (E/Z)-10 with L-Selectrideꢁ. In this case NOE
experiments were performed using C6D6 as solvent to over-
come signal overlapping.
All reagents for reactions were of analytical grade and used
as obtained from commercial sources. Reactions were car-
ried out using anhydrous solvents except when absolute
ethanol was used as the solvent. Whenever possible, the
reactions were monitored by thin layer chromatography
(TLC). TLC was performed on precoated silica gel polyes-
ter plates and products were visualised using UV light
(254 nm) and ethanolic phosphomolybdic acid solution fol-
lowed by heating. Column chromatography was performed
using silica gel (Kiesegel 60, 230–400 mesh). (E/Z)-(R)-2-
[(S)-1,2-Dibenzyloxyethyl]-4-ethoxycarbonylmethylene-1-
[(S)-1-phenylethyl]piperidine (E/Z)-5 and (E/Z)-(R)-4-tert-
3. Conclusions
In conclusion, an efficient diastereodivergent synthesis of
enantiomerically pure cis- and trans-1,2-dialkyl-4-[2-(diphe-
nylmethoxy)ethyl]piperidines (cis-1 and trans-1), novel ana-
logues of dopamine transporter inhibitors has been
optimised, starting from the same chiral imine. Efficient

2816
P. Etayo et al. / Tetrahedron: Asymmetry 18 (2007) 2812–2819
butoxycarbonylmethylene-2-[(S)-1,2-dibenzyloxyethyl]-1-
[(S)-1-phenylethyl]piperidine (E/Z)-10 were prepared as
previously described in the literature.20,21
4.1.3. (2R,4S)-2-[(S)-1,2-Dibenzyloxyethyl]-4-ethoxycarbon-
ylmethyl-1-[(S)-1-phenylethyl]piperidine cis-7. To a 97:3
E/Z mixture of compound 5 (513 mg, 1.0 mmol) dissolved
in absolute EtOH (16 mL) was added 10% Pt/C (126 mg)
and the mixture was hydrogenated with H2 at 1 atm with
shaking at room temperature for 5 h. After completion of
the reaction, the mixture was filtered through Celiteꢁ 545
and concentrated in vacuo to afford compound 7 as a
75:25 mixture of cis and trans diastereoisomers. Purifica-
tion of the residue by silica gel column chromatography
(first eluent: Et2O/hexanes 1:1; second eluent: Et2O/
hexanes 4:1) allowed isolation of pure cis-7 (350 mg,
68%) and pure trans-7 (113 mg, 22%). Data for cis-7: Mp
69–71 ꢂC; [a]D = +10.3 (c 0.52, CHCl3); IR(KBr) mmax
4.1.1. (2R,4S)-2-[(S)-1,2-Dibenzyloxyethyl]-4-ethoxycarbo-
nylmethylpiperidine cis-6. An analytically pure sample of
compound cis-6 was isolated by silica gel column chromato-
graphy (first eluent: EtOAc/EtOH 2:1; second eluent:
EtOH) from an 87:13 mixture of cis/trans diastereoisomers
obtained in the hydrogenation of (E/Z)-5 using Pd/C as
catalyst. Oil; [a]D = À7.2 (c 1.14, CHCl3); IR(neat) mmax
3377, 1730 cmÀ1 1H NMR (400 MHz, CDCl3) d 0.92
;
(1H, ddd, J 11.9, 11.9, 11.9 Hz, H-3), 1.10 (1H, dddd,
J = 12.2, 12.2, 12.2, 4.1 Hz, H-5), 1.18 (3H, t, J = 7.1 Hz,
CO2CH2CH3), 1.55–1.66 (2H, m, H-3, H-5), 1.77–1.88
(1H, m, H-4), 2.14 (2H, d, J = 7.0 Hz, CH2CO2Et), 2.52
(1H, br s, NH), 2.56 (1H, ddd, J = 12.2, 12.2, 2.4 Hz, H-
6), 2.68–2.75 (1H, m, H-2), 3.05 (1H, br d, J = 12.2 Hz,
H-6), 3.06–3.42 (1H, m, CHOBn), 3.52 (1H, dd, J = 10.5,
4.8 Hz, CH(Ha)OBn), 3.64 (1H, dd, J = 10.5, 3.5 Hz,
CH(Hb)OBn), 4.06 (2H, q, J = 7.1 Hz, CO2CH2CH3),
4.45 (1H, d, J = 12.2 Hz, CH(Ha)Ph), 4.47 (1H, d,
J = 11.2 Hz, CH(Ha)Ph), 4.50 (1H, d, J = 12.2 Hz,
CH(Hb)Ph), 4.67 (1H, d, J = 11.2 Hz, CH(Hb)Ph), 7.19–
7.31 (10H, m, Ph); 13C NMR (100 MHz, CDCl3) d 14.3
(CO2CH2CH3), 32.4 (C-5), 33.3 (C-4), 34.9 (C-3), 42.1
(CH2CO2Et), 46.0 (C-6), 57.5 (C-2), 60.5 (CO2CH2CH3),
69.8 (CH2OBn), 73.1 (CH2Ph), 73.7 (CH2Ph), 82.3
(CHOBn), 127.7 (Ph), 127.7 (Ph), 128.0 (Ph), 128.0 (Ph),
128.4 (Ph), 128.4 (Ph), 138.1 (Cipso Ph), 138.5 (Cipso Ph),
172.7 (C@O); HRMS (ESI+) calcd for C25H34NO4
(MH+): 412.2482. Found: 412.2480.
1
1725 cmÀ1; H NMR (400 MHz, CDCl3) 0.86 (1H, ddd,
J = 12.4, 12.4, 12.4 Hz, H-3), 0.87 (1H, dddd, J = 12.2,
12.2, 12.2, 3.9 Hz, H-5), 1.13 (3H, d, J = 6.8 Hz, CH3CH),
1.18 (3H, t, J = 7.0 Hz, CO2CH2CH3), 1.44 (1H, br d,
J = 12.2 Hz, H-5), 1.62–1.74 (1H, m, H-4), 2.00 (1H,
ddd, J = 11.4, 11.4, 2.3 Hz, H-6), 2.02–2.06 (1H, m, H-3),
2.08 (1H, dd, J = 14.9, 5.8 Hz, CH(Ha)CO2Et), 2.17 (1H,
dd, J = 14.9, 6.5 Hz, CH(Hb)CO2Et), 2.32 (1H, ddd,
J = 11.4, 3.9, 3.9 Hz, H-6), 2.69–2.75 (1H, m, H-2), 3.63
(1H, dd, J = 10.6, 7.9 Hz, CH(Ha)OBn), 4.01 (1H, br d,
J = 10.6 Hz, CH(Hb)OBn), 4.04–4.11 (4H, m, CHOBn,
CH3CH, CO2CH2CH3), 4.46 (1H, d, J = 12.1 Hz,
CH(Ha)Ph), 4.57 (1H, d, J = 12.1 Hz, CH(Hb)Ph), 4.68
(1H, d, J = 11.9 Hz, CH(Ha)Ph), 4.78 (1H, d,
J = 11.9 Hz, CH(Hb)Ph), 7.13–7.38 (15H, m, Ph); 13C
NMR (100 MHz, CDCl3)
d
7.8 (CH3CH), 14.3
(CO2CH2CH3), 32.5 (C-5), 32.7 (C-3), 33.8 (C-4), 41.8
(CH2CO2Et), 44.8 (C-6), 53.7 (CH3CH), 59.0 (C-2), 60.3
(CO2CH2CH3), 71.2 (CH2OBn), 73.0 (CH2Ph), 73.6
(CH2Ph), 77.8 (CHOBn), 126.3 (Ph), 127.5 (Ph), 127.5
(Ph), 127.6 (Ph), 127.6 (Ph), 127.8 (Ph), 127.9 (Ph), 128.3
(Ph), 128.4 (Ph), 138.6 (Cipso Ph), 139.1 (Cipso Ph), 143.9
(Cipso Ph), 172.8 (C@O); HRMS (ESI+) calcd for
C33H42NO4 (MH+): 516.3108. Found: 516.3127. Anal.
Calcd for C33H41NO4: C, 76.86; H, 8.01; N, 2.72. Found:
C, 76.59; H, 7.91; N, 3.01.
4.1.2. (2R,4R)-2-[(S)-1,2-Dibenzyloxyethyl]-4-ethoxycarbon-
ylmethylpiperidine trans-6. An analytically pure sample
of compound trans-6 was isolated by silica gel column
chromatography (first eluent: EtOAc/EtOH 2:1; second
eluent: EtOH) from an 87:13 mixture of cis/trans diastereo-
isomers obtained in the hydrogenation of (E/Z)-5 using
Pd/C as catalyst. Oil; [a]D = À17.2 (c 0.97, CHCl3); IR-
1
(neat) mmax 3346, 1731 cmÀ1; H NMR (400 MHz, CDCl3)
4.1.4. (2R,4R)-2-[(S)-1,2-Dibenzyloxyethyl]-4-ethoxycarbon-
ylmethyl-1-[(S)-1-phenylethyl]piperidine trans-7. Isolated
by silica gel column chromatography (first eluent: Et2O/
hexanes 1:1; second eluent: Et2O/hexanes 4:1) from a
75:25 mixture of cis/trans diastereoisomers obtained in
the hydrogenation of (E/Z)-5 using Pt/C (10% Pt) as a cat-
alyst. Oil; [a]D = À23.2 (c 0.81, CHCl3); IR(neat) mmax
d 1.16 (3H, t, J = 7.1 Hz, CO2CH2CH3), 1.32 (1H, ddd,
J = 13.0, 10.1, 5.1 Hz, H-5), 1.37–1.44 (1H, m, H-3), 1.52
(1H, ddd, J = 12.9, 8.5, 4.2 Hz, H-3), 1.63 (1H, ddd,
J = 13.0, 10.8, 6.3 Hz, H-5), 2.15–2.22 (1H, m, H-4), 2.23
(1H, dd, J = 14.8, 6.5 Hz, CH(Ha)CO2Et), 2.28 (1H, dd,
J = 14.8, 7.9 Hz, CH(Hb)CO2Et), 2.31 (1H, br s, NH),
2.66–2.69 (2H, m, H-6, H-6), 2.92 (1H, ddd, J = 8.1, 8.1,
3.5 Hz, H-2), 3.46–3.52 (2H, m, CHOBn, CH(Ha)OBn),
3.63 (1H, dd, J = 9.1, 2.3 Hz, CH(Hb)OBn), 4.03 (2H, q,
J = 7.1 Hz, CO2CH2CH3), 4.44 (1H, d, J = 11.3 Hz,
CH(Ha)Ph), 4.46 (1H, d, J = 12.5 Hz, CH(Ha)Ph), 4.49
(1H, d, J = 12.5 Hz, CH(Hb)Ph), 4.69 (1H, d, J =
11.3 Hz, CH(Hb)Ph), 7.18–7.29 (10H, m, Ph); 13C NMR
(100 MHz, CDCl3) d 14.0 (CO2CH2CH3), 28.6 (C-4), 30.6
(C-5), 32.3 (C-3), 38.5 (CH2CO2Et), 40.8 (C-6), 52.5 (C-
2), 60.3 (CO2CH2CH3), 69.8 (CH2OBn), 73.0 (CH2Ph),
73.5 (CH2Ph), 79.8 (CHOBn), 127.7 (Ph), 127.8 (Ph),
128.1 (Ph), 128.4 (Ph), 128.4 (Ph), 128.5 (Ph), 138.2 (Cipso
Ph), 138.4 (Cipso Ph), 172.9 (C@O); HRMS (ESI+) calcd
for C25H34NO4 (MH+): 412.2482. Found: 412.2494.
1732 cmÀ1 1H NMR (400 MHz, CDCl3) d 1.19 (3H, t,
;
J = 7.1 Hz, CO2CH2CH3), 1.26 (3H, d, J = 5.5 Hz,
CH3CH), 1.21–1.23 (1H, m, H-5), 1.40–1.44 (1H, m, H-
5), 1.49–1.55 (2H, m, H-3, H-3), 2.07–2.14 (1H, m, H-4),
2.12–2.16 (2H, m, CH2CO2Et), 2.54–2.62 (2H, m, H-6,
H-6), 3.18–3.25 (1H, m, H-2), 3.56 (1H, dd, J = 10.7,
5.4 Hz, CH(Ha)OBn), 3.71 (1H, dd, J = 10.7, 1.8 Hz,
CH(Hb)OBn), 3.98–4.03 (2H, m, CHOBn, CH3CH), 4.06
(2H, q, J = 7.1 Hz, CO2CH2CH3), 4.48 (2H, s, CH2Ph),
4.62 (1H, d, J = 11.6 Hz, CH(Ha)Ph), 4.75 (1H, d,
J = 11.6 Hz, CH(Hb)Ph), 7.11–7.39 (15H, m, Ph); 13C
NMR (100 MHz, CDCl3) d 17.9 (CO2CH2CH3), 19.6
(CH3CH), 29.0 (C-4), 29.8 (C-5), 30.2 (C-3), 41.0
(CH2CO2Et), 42.6 (C-6), 54.2 (C-2), 59.5 (CH3CH), 60.2

P. Etayo et al. / Tetrahedron: Asymmetry 18 (2007) 2812–2819
2817
(CO2CH2CH3), 71.4 (CH2OBn), 72.6 (CH2Ph), 73.5
(CH2Ph), 78.3 (CHOBn), 126.4 (Ph), 127.3 (Ph), 127.3
(Ph), 127.5 (Ph), 127.6 (Ph), 127.8 (Ph), 128.1 (Ph), 128.2
(Ph), 128.3 (Ph), 139.3 (Cipso Ph), 139.5 (Cipso Ph), 147.2
(Cipso Ph), 171.0 (C@O); HRMS (ESI+) calcd for
C33H42NO4 (MH+): 516.3108. Found: 516.3121.
80.1 (CO2C(CH3)3), 126.4 (Ph), 127.3 (Ph), 127.3 (Ph),
127.5 (Ph), 127.6 (Ph), 127.8 (Ph), 128.1 (Ph), 128.2 (Ph),
128.4 (Ph), 138.6 (Cipso Ph), 139.2 (Cipso Ph), 147.2 (Cipso
Ph), 172.3 (C@O); HRMS (ESI+) calcd for C35H46NO4
(MH+): 544.3421. Found: 544.3432.
4.1.7. (2R,4S)-2-[(S)-1,2-Dibenzyloxyethyl]-4-[2-(hydroxy)-
ethyl]-1-[(S)-1-phenylethyl]piperidine cis-9. To a solution
of compound cis-7 (515 mg, 1.0 mmol) in anhydrous
THF (20 mL) at room temperature under argon was added
dropwise a 1.0 M solution of LiAlH4 in THF (1.2 mL,
1.2 mmol) and the mixture was stirred for 1 h at room tem-
perature. Saturated aqueous NH4Cl (30 mL) was added
carefully with stirring at 0 ꢂC. The resulting mixture was fil-
tered through Celiteꢁ 545 and extracted with Et2O
(3 · 50 mL). The combined organic layers were dried over
anhydrous MgSO4 and the solvent was evaporated in
vacuo to afford a crude product, which was purified by sil-
ica gel column chromatography (first eluent: Et2O/hexanes
4:1; second eluent: EtOAc/EtOH 1:1) to give pure cis-9
(426 mg, 90%). Oil; [a]D = +1.4 (c 0.86, CHCl3); IR(neat)
4.1.5. (E)-(R)-2-[(S)-1,2-Dibenzyloxyethyl]-4-[2-(hydroxy)-
ethylidene]-1-[(S)-1-phenylethyl]piperidine
(E)-8. Data
drawn from spectra of the 97:3 E/Z mixture of diastereoi-
somers obtained in the reduction of compound (E/Z)-5
with L-Selectrideꢁ. IR(neat) mmax 3364, 2846 cmÀ1 1H
;
NMR (400 MHz, CDCl3) d 1.18 (3H, d, J = 6.7 Hz,
CH3CH), 1.83–1.92 (1H, m, H-5), 1.96 (1H, dd, J = 13.4,
8.2 Hz, H-3), 2.07–2.18 (1H, m, H-5), 2.18–2.26 (1H, m,
H-6), 2.48 (1H, dd, J = 13.4, 4.2 Hz, H-3), 2.51 (1H, dd,
J = 10.7, 4.8 Hz, H-6), 2.91–2.98 (1H, m, H-2), 3.61 (1H,
dd, J = 10.7, 6.8 Hz, CH(Ha)OBn), 3.90 (1H, dd, J =
10.7, 1.4 Hz, CH(Hb)OBn), 3.92–3.97 (1H, m, CHOBn),
4.02 (2H, dd, J = 7.0, 1.5 Hz, CH2OH), 4.05 (1H, q, J =
6.7 Hz, CH3CH), 4.47 (1H, d, J = 12.0 Hz, CH(Ha)Ph),
4.54 (1H, d, J = 12.0 Hz, CH(Hb)Ph), 4.61 (1H, d, J =
11.8 Hz, CH(Ha)Ph), 4.73 (1H, d, J = 11.8 Hz, CH(Hb)Ph),
5.31 (1H, br s, HC@C), 7.12–7.38 (15H, m, Ph); 13C NMR
(100 MHz, CDCl3) d 12.8 (CH3CH), 28.0 (C-5), 36.1 (C-3),
45.0 (C-6), 56.5 (CH3CH), 58.5 (CH2OH), 58.7 (C-2), 71.2
(CH2OBn), 72.7 (CH2Ph), 73.7 (CH2Ph), 78.3 (CHOBn),
121.8 (HC=C), 126.5 (Ph), 127.4 (Ph), 127.5 (Ph), 127.6
(Ph), 127.7 (Ph), 127.7 (Ph), 128.1 (Ph), 128.3 (Ph), 128.4
(Ph), 138.4 (Cipso Ph), 139.2 (Cipso Ph), 140.8 (Cipso Ph),
144.8 (C-4); HRMS (ESI+) calcd for C31H38NO3 (MH+):
472.2846. Found: 472.2838.
1
mmax 3387 cmÀ1; H NMR (400 MHz, CDCl3) d 0.85 (1H,
ddd, J = 11.7, 11.7, 11.7 Hz, H-3), 0.90 (1H, dddd,
J = 11.5, 11.5, 11.5, 3.6 Hz, H-5), 1.13 (3H, d, J = 6.8
Hz, CH3CH), 1.20–1.31 (1H, m, H-3), 1.32–1.48 (3H, m,
H-5, CH2CH2OH), 1.95–2.05 (2H, m, H-6, H-4), 2.34
(1H, br d, J = 11.3 Hz, H-6), 2.70 (1H, br d, J = 11.7 Hz,
H-2), 3.61 (2H, dd, J = 6.8, 6.8 Hz, CH2CH2OH), 3.66
(1H, dd, J = 10.7, 8.1 Hz, CH(Ha)OBn), 4.02 (1H, dd,
J = 10.7, 6.6 Hz, CH(Hb)OBn), 4.06–4.12 (2H, m,
CHOBn, CH3CH), 4.47 (1H, d, J = 12.2 Hz, CH(Ha)Ph),
4.57 (1H, d, J = 12.2 Hz, CH(Hb)Ph), 4.67 (1H, d,
J = 12.0 Hz, CH(Ha)Ph), 4.79 (1H, d, J = 12.0 Hz,
CH(Hb)Ph), 7.13–7.39 (15H, m, Ph); 13C NMR
(100 MHz, CDCl3) d 7.8 (CH3CH), 32.5 (C-5), 33.0 (C-
3), 33.1 (C-4), 39.7 (CH2CH2OH), 45.1 (C-6), 54.1
(CH3CH), 59.2 (C-2), 60.6 (CH2CH2OH), 71.3 (CH2OBn),
72.8 (CH2Ph), 73.5 (CH2Ph), 77.9 (CHOBn), 126.3 (Ph),
127.5 (Ph), 127.5 (Ph), 127.6 (Ph), 127.6 (Ph), 127.8 (Ph),
127.9 (Ph), 128.3 (Ph), 128.4 (Ph), 138.4 (Cipso Ph), 139.0
(Cipso Ph), 144.0 (Cipso Ph); HRMS (ESI+) calcd for
C31H40NO3 (MH+): 474.3003. Found: 474.3026.
4.1.6. (2R,4R)-4-tert-Butoxycarbonylmethyl-2-[(S)-1,2-di-
benzyloxyethyl]-1-[(S)-1-phenylethyl]piperidine
trans-11.
To a 98:2 E/Z mixture of compound 10 (541 mg, 1.0 mmol)
dissolved in anhydrous THF (22 mL) at À20 ꢂC under
argon was added dropwise a 1.0 M solution of L-Select-
rideꢁ in THF (4.0 mL, 4.0 mmol) and the mixture was stir-
red for 24 h at À20 ꢂC. Saturated aqueous NH4Cl (30 mL)
was added carefully with stirring at 0 ꢂC. The reaction mix-
ture was extracted with Et2O (3 · 50 mL). The combined
organic layers were dried over anhydrous MgSO4 and the
solvent was evaporated in vacuo to afford a crude product
in which cis-11 was not detected. The residue was purified
by silica gel column chromatography (first eluent: Et2O/
hexanes 1:2; second eluent: Et2O/hexanes 4:1) to give pure
trans-11 (494 mg, 91%). Oil; [a]D = À25.2 (c 0.86, CHCl3);
4.1.8. (2R,4R)-2-[(S)-1,2-Dibenzyloxyethyl]-4-[(2-hydroxy)-
ethyl]-1-[(S)-1-phenylethyl]piperidine trans-9. To a solu-
tion of compound trans-11 (543 mg, 1.0 mmol) in
anhydrous THF (20 mL) at room temperature under argon
was added dropwise a 1.0 M solution of LiAlH4 in THF
(4.0 mL, 4.0 mmol) and the mixture was stirred for 2 h at
room temperature. Saturated aqueous NH4Cl (30 mL)
was added carefully with stirring at 0 ꢂC. The resulting
mixture was filtered through Celiteꢁ 545 and extracted with
Et2O (3 · 50 mL). The combined organic layers were dried
over anhydrous MgSO4 and the solvent was evaporated in
vacuo to afford a crude product, which was purified by sil-
ica gel column chromatography (first eluent: Et2O/hexanes
4:1; second eluent: EtOAc/EtOH 1:1) to give pure trans-9
(286 mg, 60%). Oil; [a]D = À17.7 (c 0.81, CHCl3); IR(neat)
1
IR(neat) mmax 1726 cmÀ1; H NMR (400 MHz, CDCl3) d
1.06–1.21 (2H, m, H-5, H-5), 1.24 (3H, d, J = 6.6 Hz,
t
CH3CH), 1.37 (9H, s, Bu), 1.47–1.53 (2H, m, H-3, H-3),
t
2.00–2.08 (3H, m, CH2CO2 Bu, H-4), 2.50–2.55 (2H, m,
H-6, H-6), 3.17–3.23 (1H, m, H-2), 3.55 (1H, dd,
J = 10.7, 5.6 Hz, CH(Ha)OBn), 3.71 (1H, dd, J = 10.7,
2.4 Hz, CH(Hb)OBn), 3.97–4.02 (1H, m, CHOBn), 3.99
(1H, q, J = 6.6 Hz, CH3CH), 4.47 (2H, br s, CH2Ph),
4.60 (1H, d, J = 11.7 Hz, CH(Ha)Ph), 4.74 (1H, d,
J = 11.7 Hz, CH(Hb)Ph), 7.08–7.38 (15H, m, Ph); 13C
1
NMR (100 MHz, CDCl3)
d
19.7 (CH3CH), 28.4
mmax 3366 cmÀ1; H NMR (400 MHz, CDCl3) d 1.06–1.20
(CO2C(CH3)3), 29.3 (C-4), 30.0 (C-5), 31.6 (C-3), 42.2
(CH2CO2 Bu), 42.6 (C-6), 54.1 (C-2), 59.6 (CH3CH), 71.6
(CH2OBn), 72.7 (CH2Ph), 73.4 (CH2Ph), 78.3 (CHOBn),
(1H, m, H-5), 1.26 (3H, d, J = 6.4 Hz, CH3CH), 1.30–
1.43 (3H, m, H-5, CH2CH2OH), 1.41–1.51 (2H, m, H-3,
H-3), 1.65–1.74 (1H, m, H-4), 2.54–2.63 (2H, m, H-6,
t

2818
P. Etayo et al. / Tetrahedron: Asymmetry 18 (2007) 2812–2819
H-6), 3.14–3.22 (1H, m, H-2), 3.51 (1H, dd, J = 10.6, 4.2
Hz, CH(Ha)OBn), 3.53 (2H, dd, J = 6.6, 6.6 Hz,
CH2CH2OH), 3.63 (1H, dd, J = 10.6, 3.3 Hz,
CH(Hb)OBn), 3.97–4.03 (2H, m, CHOBn, CH3CH), 4.44
(1H, d, J = 12.1 Hz, CH(Ha)Ph), 4.48 (1H, d,
J = 12.1 Hz, CH(Hb)Ph), 4.59 (1H, d, J = 11.7 Hz,
CH(Ha)Ph), 4.71 (1H, d, J = 11.7 Hz, CH(Hb)Ph), 7.10–
7.36 (15H, m, Ph); 13C NMR (100 MHz, CDCl3) d 19.9
(CH3CH), 28.0 (C-4), 30.6 (C-5), 31.5 (C-3), 39.1
(CH2CH2OH), 43.0 (C-6), 54.9 (C-2), 59.7 (CH3CH), 60.7
(CH2CH2OH), 71.6 (CH2OBn), 73.0 (CH2Ph), 73.4
(CH2Ph), 78.0 (CHOBn), 126.5 (Ph), 127.3 (Ph), 127.4
(Ph), 127.6 (Ph), 127.8 (Ph), 127.8 (Ph), 128.1 (Ph), 128.3
(Ph), 128.4 (Ph), 138.4 (Cipso Ph), 139.3 (Cipso Ph), 139.8
(Cipso Ph); HRMS (ESI+) calcd for C31H40NO3 (MH+):
474.3003. Found: 474.3018.
(228 mg, 1.2 mmol) and the mixture was heated at reflux
under azeotropic distillation conditions for 17 h. The reac-
tion mixture was cooled to room temperature, neutralised
with saturated aqueous NaHCO3 and extracted with
Et2O (3 · 50 mL). The combined organic layers were dried
over anhydrous MgSO4 and the solvent was evaporated
in vacuo to afford a crude product, which was purified by
silica gel column chromatography (first eluent: Et2O/hex-
anes 1:4; second eluent: Et2O/hexanes 1:1) to give pure
trans-1 (294 mg, 46%). Oil; [a]D = À18.1 (c 0.35, CHCl3);
IR(neat) mmax 1095, 1028 cmÀ1 1H NMR (400 MHz,
;
CDCl3) d 1.02–1.16 (1H, m, H-5), 1.24 (3H, d, J = 7.3
Hz, CH3CH), 1.28–1.39 (1H, m, H-5), 1.42–1.60 (4H, m,
H-3, H-4, CH2CH2OCHPh2), 1.69–1.79 (1H, m, H-3),
2.47–2.59 (2H, m, H-6, H-6), 3.13–3.21 (1H, m, H-2),
3.38 (2H, t, J = 6.6 Hz, CH2CH2OCHPh2), 3.49 (1H, dd,
J = 10.7, 5.5 Hz, CH(Ha)OBn), 3.65 (1H, br d,
J = 10.7 Hz, CH(Hb)OBn), 3.94–4.05 (2H, m, CHOBn,
CH3CH), 4.41 (2H, br s, CH2Ph), 4.59 (1H, d,
J = 11.6 Hz, CH(Ha)Ph), 4.72 (1H, d, J = 11.6 Hz,
CH(Hb)Ph), 5.23 (1H, br s, CHPh2), 7.09–7.37 (25H,
m, Ph); dC (100 MHz, CDCl3) 19.2 (CH3CH), 28.5 (C-4),
30.3 (C-3), 31.8 (C-5), 35.9 (CH2CH2OCHPh2), 42.7 (C-
6), 54.3 (C-2), 59.3 (CH3CH), 67.0 (CH2CH2OCHPh2),
71.6 (CH2OBn), 72.7 (CH2Ph), 73.3 (CH2Ph), 78.3
(CHOBn), 83.7 (CHPh2), 126.3 (Ph), 126.9 (Ph), 126.9
(Ph), 127.3 (Ph), 127.3 (Ph), 127.4 (Ph), 127.5 (Ph), 127.7
(Ph), 128.0 (Ph), 128.2 (Ph), 128.3 (Ph), 128.3 (Ph),
128.4 (Ph), 138.4 (Cipso Ph), 139.2 (Cipso Ph), 139.2
(Cipso Ph), 142.5 (Cipso Ph), 147.1 (Cipso Ph); HRMS
(ESI+) calcd for C44H50NO3 (MH+): 640.3785. Found:
640.3782.
4.1.9. (2R,4S)-2-[(S)-1,2-Dibenzyloxyethyl]-4-[2-(diphenyl-
methoxy)ethyl]-1-[(S)-1-phenylethyl]piperidine cis-1. To a
solution of compound cis-9 (473 mg, 1.0 mmol) in anhy-
drous toluene (45 mL) under argon were added successively
benzhydrol (473 mg, 3.2 mmol) and p-TsOHÆH2O (228 mg,
1.2 mmol) and the mixture was heated at reflux under aze-
otropic distillation conditions for 17 h. The reaction mix-
ture was cooled to room temperature, neutralised with
saturated aqueous NaHCO3 and extracted with Et2O
(3 · 50 mL). The combined organic layers were dried over
anhydrous MgSO4 and the solvent was evaporated in va-
cuo to afford a crude product, which was purified by silica
gel column chromatography (first eluent: Et2O/hexanes
1:8; second eluent: Et2O/hexanes 1:4) to give pure cis-1
(545 mg, 71%). Oil; [a]D = +8.8 (c 1.05, CHCl3); IR(neat)
mmax 1098, 1028 cmÀ1 1H NMR (400 MHz, CDCl3) d
;
0.69–0.85 (2H, m, H-3, H-5), 1.08 (3H, d, J = 6.7 Hz,
CH3CH), 1.26–1.37 (2H, m, H-4, H-5), 1.34–1.45 (1H, m,
CH(Ha)CH2OCHPh2), 1.45–1.55 (1H, m, CH(Hb)CH2-
OCHPh2), 1.92 (1H, br dd, J = 11.0, 11.0 Hz, H-6), 1.99
(1H, br d, J = 10.5 Hz, H-3), 2.26 (1H, ddd, J = 11.0,
2.9, 2.9 Hz, H-6), 2.61–2.67 (1H, m, H-2), 3.34 (2H, t,
J = 6.6 Hz, CH2CH2OCHPh2), 3.59 (1H, dd, J = 10.6,
6.3 Hz, CH(Ha)OBn), 3.97 (1H, br d, J = 10.6 Hz,
CH(Hb)OBn), 4.01–4.07 (2H, m, CHOBn, CH3CH), 4.40
(1H, d, J = 12.2 Hz, CH(Ha)Ph), 4.52 (1H, d, J =
12.2 Hz, CH(Hb)Ph), 4.65 (1H, d, J = 12.0 Hz, CH(Ha)-
Ph), 4.73 (1H, d, J = 12.0 Hz, CH(Hb)Ph), 5.20 (1H, br s,
CHPh2), 7.06–7.34 (25H, m, Ph); 13C NMR (100 MHz,
CDCl3) d 7.9 (CH3CH), 32.6 (C-5), 33.1 (C-3), 33.7 (C-
4), 37.0 (CH2CH2OCHPh2), 45.1 (C-6), 53.8 (CH3CH),
59.2 (C-2), 66.9 (CH2CH2OCHPh2), 71.4 (CH2OBn), 72.8
(CH2Ph), 73.6 (CH2Ph), 78.0 (CHOBn), 83.8 (CHPh2),
126.4 (Ph), 126.6 (Ph), 127.0 (Ph), 127.1 (Ph), 127.4 (Ph),
127.4 (Ph), 127.6 (Ph), 127.6 (Ph), 127.7 (Ph), 127.9 (Ph),
127.9 (Ph), 128.0 (Ph), 128.4 (Ph), 128.4 (Ph), 128.5 (Ph),
138.6 (Cipso Ph), 139.2 (Cipso Ph), 142.7 (Cipso Ph), 142.7
(Cipso Ph), 144.1 (Cipso Ph); HRMS (ESI+) calcd for
C44H50NO3 (MH+): 640.3785. Found: 640.3774.
4.1.11. X-ray diffraction analysis of cis-7. Single crystals of
cis-7 were obtained by slow evaporation from an absolute
ethanol solution. The X-ray diffraction data were collected
at room temperature using graphite-monochromated Mo
˚
Ka radiation (k = 0.7103 A). Structure was solved by direct
methods using the SHELXS-9729 program and refinement
was performed using the SHELXL-9730 program by the
full-matrix least-squares technique with anisotropic ther-
mal factors for heavy atoms. Hydrogen atoms were calcu-
lated at idealised positions, and during refinement they
were allowed to ride on their carrying atom with an isotro-
pic thermal factor fixed to 1.2 times the Ueq value of the
carrier atom. Crystallographic data have been deposited
with the Cambridge Crystallographic Data Center as sup-
plementary publication no. CCDC 649978. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
+44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
Deposited data may be accessed by the journal and
checked as part of the refereeing process.
Acknowledgements
4.1.10. (2R,4R)-2-[(S)-1,2-Dibenzyloxyethyl]-4-[2-(diphenyl-
methoxy)ethyl]-1-[(S)-1-phenylethyl]-piperidine
To a solution of compound trans-9 (473 mg, 1.0 mmol) in
anhydrous toluene (45 mL) under argon were added suc-
cessively benzhydrol (590 mg, 3.2 mmol) and p-TsOHÆH2O
trans-1.
This work was supported by the Spanish MCYT and FED-
ER (Project CTQ2004-05358) and the Gobierno de Arag-
´
on. P.E. was supported by a Spanish MCYT Predoctoral
Fellowship.

P. Etayo et al. / Tetrahedron: Asymmetry 18 (2007) 2812–2819
2819
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