First stereoselective synthesis of (1R,2R,4R)- and (1S,2R,4S)-2- substituted-1-azabicyclo [2.2.1] heptanes

Article abstract of DOI:10.1002/ejoc.200801216

The first stereoselective synthesis of two diastereomeric 1- azabicyclo[2.2.1] heptanes substituted at the 2-position from an easily accessible (R)-2-substituted-4-piperidone is reported. The synthetic route involves the asymmetric one-carbon homologation

Full text of DOI:10.1002/ejoc.200801216

FULL PAPER
DOI: 10.1002/ejoc.200801216
First Stereoselective Synthesis of (1R,2R,4R)- and (1S,2R,4S)-2-Substituted-1-
azabicyclo[2.2.1]heptanes
Pablo Etayo,[a] Ramón Badorrey,[a] María D. Díaz-de-Villegas,*[a] and José A. Gálvez*[a]
Keywords: Asymmetric synthesis / Ketones / Nitrogen heterocycles / Diastereoselectivity
The first stereoselective synthesis of two diastereomeric 1-
azabicyclo[2.2.1]heptanes substituted at the 2-position from
an easily accessible (R)-2-substituted-4-piperidone is re-
lecular SN2-type cyclisation and led to target compounds in
high overall yield by using a simple procedure in which puri-
fication of the intermediate compounds is not required.
ported. The synthetic route involves the asymmetric one-car- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
bon homologation of a chiral ketone followed by an intramo-
Germany, 2009)
Introduction
Results and Discussion
On the basis of our experience with the use of diastereo-
selective aza-Diels–Alder reactions to obtain enantiomer-
ically pure 2-alkyl-4-piperidone derivatives,[4] we envisaged
that these heterocyclic compounds could be useful starting
materials for the stereoselective synthesis of 2-alkyl-1-aza-
bicyclo[2.2.1]heptanes A. We reasoned that target com-
pound A could be obtained from alcohol B by an intra-
molecular SN2-type cyclisation. Straightforward reduction
of aldehyde C would give primary alcohol B, and aldehyde
C can be synthesised by asymmetric one-carbon homologa-
tion from 4-piperidone D (Scheme 1).
The synthesis and the biological activity of compounds
containing the 1-azabicyclo[2.2.1]heptane scaffold is docu-
mented by more than 350 publications.[1] Depending on the
substitution pattern of the 1-azabicyclo[2.2.1]heptane, dif-
ferent activities have been reported, and many of these com-
pounds have been used in the treatment of central nervous
system disorders. Among the 1-azabicyclo[2.2.1]heptane de-
rivatives, those with a substituent at C2 are of relevance,
because they have shown high affinity for histamine, opioid,
muscarinic and nicotinic cholinergic receptors.[2] This be-
haviour is important in the treatment of diseases such as
Alzheimer’s dementia, schizophrenia, anxiety, attention-
deficit hyperactivity disorder, depression, obesity, allergy,
drug addiction and chronic pain. Moreover, 2-substituted-
1-azabicyclo[2.2.1]heptanes have a close structural resem-
blance to cinchona alkaloids, so these compounds could be-
have as chiral ligands or organocatalysts for catalytic asym-
metric transformations. In this regard, these new com-
pounds feature a basic centre, which is a stereogenic nitro-
gen atom with a defined configuration.
Scheme 1. Retrosynthetic analysis.
Versatile stereocontrolled routes to 2-substituted-1-aza-
The addition of a one-carbon unit to a ketone to homo-
bicyclo[2.2.1]heptanes are of interest due to the important logate it to a new carbonyl derivative is an important trans-
properties of this class of compounds. In this context, sev- formation that chemists have approached in different ways.
eral methods for the preparation of racemic products have Strategies using epoxides, vinyl heteroatoms, nitriles, ketals,
been reported.[2,3] Our interest is focused on the develop- alcohols or alkenes as intermediates have all been devel-
ment of the first asymmetric synthesis of this azabicyclic oped.[5] In this context, it has been reported[6] that ketones
scaffold.
and aldehydes react through a Wadsworth–Emmons ole-
fination by using diethyl isocyanomethylphosphonate to
give α,β-unsaturated isocyanides and that hydrolysis of iso-
cyanides under acidic conditions affords the corresponding
homologated aldehydes.[7] This strategy has shown to be ap-
propriate to homologate sterically hindered ketones, cyclic
ketones, enolisable ketones and several aliphatic and aro-
matic aldehydes. Recently, we reported[8] the first asymmet-
[a] Departamento de Química Orgánica, Instituto de Ciencia de
Materiales de Aragón, Instituto Universitario de Catálisis
Homogénea, Universidad de Zaragoza – CSIC,
50009 Zaragoza, Spain
Fax: +34-976761202
E-mail: loladiaz@unizar.es
jagl@unizar.es
1372
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1372–1376

Synthesis of (1R,2R,4R)- and (1S,2R,4S)-2-Substituted-1-azabicyclo[2.2.1]heptanes
ric version of this synthetic methodology, which consists of stitution of the hydroxy group by bromine in compound
Wadsworth–Emmons olefination of (R)-2-[(S)-1,2-bis(ben- trans-6 with the use of a mixture of CBr4 and Ph3P/PS and
zyloxy)ethyl]-1-[(S)-1-phenylethyl]-4-piperidone (1) with an subsequent intramolecular SN2-type cyclisation gave 7 in
excess amount of diethyl isocyanomethylphosphonate quantitative yield (two steps, one pot). In this way, 7 was
(5 equiv.) under the reaction conditions described by Masa- obtained in 49% overall yield from piperidone 1 by using a
mune and Roush[9] and subsequent hydrolysis of intermedi- simple six-step procedure in which most of the intermediate
ate α,β-unsaturated isocyanide 2 with HCl at room tem- compounds did not require purification. The whole se-
perature in a two-phase system (diethyl ether/water). Under quence for the synthesis of 7 is shown in Scheme 3.
these conditions, aldehyde 3 was obtained as a thermody-
namically unstable 25:75 mixture of cis and trans diastereo-
isomers,[10] in which trans-3 was the major compound.
Next, the obtained 25:75 diastereomeric mixture of cis
and trans aldehyde 3 was dissolved in 4:1 MeOH/H2O and
immediately reduced by using NaBH4 to yield alcohol 4 as
a 25:75 mixture of cis and trans diastereoisomers[10]
(Scheme 2). After easy separation by column chromatog-
raphy (CC), cis-4 and trans-4 were obtained in 17 and 59%
yield, respectively, from starting piperidone 1.
Scheme 3. Synthesis of compound 7.
Upon standing, trans-3 slowly epimerised to the thermo-
dynamically more-stable cis-3. Thus, when crude aldehyde
3 (cis/trans = 25:75) was dissolved in chloroform and the
resulting solution was heated under reflux for 7 d, the initial
diastereomeric ratio progressively evolved to reach a con-
stant value of 76:24 in favour of the cis diastereoisomer. It
is of note that the epimerisation rate increased upon heat-
ing, but not under basic conditions. The resulting dia-
stereomeric mixture was subsequently reduced with the use
of NaBH4 to give alcohol 4 as a 76:24 mixture of cis and
trans diastereoisomers, from which alcohols cis-4 and trans-
Scheme 2. Asymmetric homologation of chiral piperidone 1.
4 were isolated by column chromatography in 48 and 26%
yield, respectively, from starting piperidone 1. Conversion
of cis-4 into 1-azabicyclo[2.2.1]heptane 8 was performed by
following the same route as before (Scheme 3). N-Deben-
zylation of cis-4 by using palladium on carbon as a catalyst
It is worth mentioning that the use of water as cosolvent
in the reduction step is essential to avoid the formation of
compound 5 as a byproduct (Figure 1). Compound 5 is
probably derived from intermolecular reductive amination
and water as a cosolvent gave cis-6 in 79% yield. Substitu-
of aldehyde 3 with diethyl aminomethylphosphonate gener-
tion of the hydroxy group by bromine followed by intramo-
ated through acidic hydrolysis of the diethyl isocyano-
lecular SN2-type cyclisation gave 8 in quantitative yield (two
methylphosphonate reagent used in high excess.
steps, one pot). Compound 8 was obtained in 38% overall
yield from piperidone 1 by using a simple seven-step pro-
cedure in which most of the intermediate compounds did
not require purification. The complete sequence for the syn-
thesis of 8 is shown in Scheme 4.
Following complete assignment of the 1H NMR reso-
nances with the aid of 2D NMR spectroscopic studies
(COSY, HSQC, HMBC) the cis and trans configurations of
compounds cis-4 and trans-4 were unequivocally deter-
mined by 2D NOESY experiments. NOE crosspeaks ob-
Figure 1. Structure of byproduct 5.
Conversion of trans-4 into desired 1-azabicyclo[2.2.1]- served between Ha (δ = 2.61–2.67 ppm, m) and Hc (δ =
heptane scaffold 7 was performed as follows. N-Deben- 1.25–1.33 ppm, m) in compound cis-4 are consistent with a
zylation of trans-4 by using palladium on carbon as a cata- cis relative configuration for this compound (Figure 2). The
lyst gave piperidine trans-6 in 83% yield. It is noteworthy assignment of the trans configuration to the diastereomeric
that the use of water as cosolvent proved to be essential for compound trans-4 is consistent with the observation of
the success of the hydrogenolysis process, as in the absence NOE crosspeaks between Ha (δ = 3.14–3.20 ppm, m) and
of water the starting material was recovered unaltered. Sub- the methylene groups at C4 (δ = 3.28 ppm, dd; δ =
Eur. J. Org. Chem. 2009, 1372–1376
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1373

P. Etayo, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez
FULL PAPER
Experimental Section
General Methods: All reagents were of analytical grade and were
used as obtained from commercial sources with the exception of
anhydrous lithium chloride, which was dried under vacuum at
140 °C overnight before use. Reactions were carried out by using
anhydrous solvents with the exception of chloroform, methanol
and ethanol. Whenever possible, the reactions were monitored by
thin-layer chromatography (TLC). TLC was performed on pre-
coated silica-gel polyester plates, and the products were visualised
by using UV light (254 nm) and ethanolic phosphomolybdic acid
solution followed by heating. Column chromatography was per-
formed with silica gel (60 Å, 35–70 µm). Microanalyses were deter-
mined by using a Perkin-Elmen 2400 CHNS elemental analyser.
Melting points were determined in open capillaries with a Gallen-
kamp apparatus and are uncorrected. FTIR spectra of oils were
recorded as thin films on NaCl plates and those of solids were
recorded as KBr pellets with a Thermo Nicolet Avatar 360 FTIR
spectrometer; ν values are given for the main absorption bands.
˜
Optical rotations were measured with a Jasco P-1020 polarimeter
at λ = 589 nm and 25 °C in a cell with 10 cm path length. NMR
spectra were acquired with a Bruker AV-400 spectrometer or a
Scheme 4. Synthesis of compound 8.
1
Bruker AV-500 spectrometer operating at 400 or 500 MHz for H
NMR and 100 or 125 MHz for 13C NMR by using a 5-mm probe.
The chemical shifts were referenced to the residual solvent peak.
The following abbreviations are used: s, singlet; d, doublet; q, quar-
tet; m, multiplet; dd, doublet of doublets; dq, doublet of quartets;
ddd, doublet of doublet of doublets; dddd, doublet of doublet of
doublet of doublets; dddq, doublet of doublet of doublet of quar-
tets; ddddd, doublet of doublet of doublet of doublet of doublets;
br. s, broad singlet; br. d, broad doublet; br. dd, broad doublet of
doublets. NOESY spectra were acquired in the phase-sensitive
mode with gradient pulses in the mixing time as 2048ϫ256 hiper-
complex files with 8 transients for 256 time increments. An op-
timised mixing time of 750 ms was used and processing was carried
out by 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. High-resolution mass spectra were recorded
with a Bruker Daltonics MicroToF-Q instrument from methanolic
solutions by using the positive electrospray ionisation mode
(ESI+).
3.31 ppm, dd) as well as between Hc (δ = 1.67–1.77 ppm,
m) and the methine proton of substituent at C2 (δ = 3.91–
3.97 ppm, m) (Figure 2).
(2R,4R)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-4-hydroxymethyl-1-[(S)-1-
phenylethyl]piperidine (trans-4): NaBH4 (76 mg, 2.0 mmol) was
added to a solution of the 25:75 mixture of cis-3/trans-3 (914 mg,
2.0 mmol) obtained as described previously[8] in CH3OH/H2O (4:1,
5 mL). After vigorously stirring for 2 h at room temperature, the
reaction mixture was evaporated under reduced pressure. The ob-
tained crude was solved in Et2O (50 mL), treated with saturated
aqueous NH4Cl (30 mL) and extracted with Et2O (3ϫ50 mL). The
combined organic extract was dried with anhydrous MgSO4, fil-
tered and evaporated under reduced pressure. Purification by col-
umn chromatography (EtOAc/hexanes, 1:1; then EtOAc/EtOH,
4:1) of the obtained crude obtained allowed the isolation of 542 mg
Figure 2. Determination of the relative configuration of com-
pounds cis-4 and trans-4 by 2D NOESY experiments.
(59%) of pure trans-4. Oil. [α]2D5 = –21.6 (c = 1.00, CHCl3). IR
1
(neat): ν = 3388 cm–1. H NMR (400 MHz, CDCl ): δ = 1.05–1.16
Conclusions
˜
3
(m, 1 H), 1.23 (d, J = 6.5 Hz, 3 H), 1.34 (br. dd, J = 13.1, 3.5 Hz,
1 H), 1.43–1.49 (m, 2 H), 1.67–1.77 (m, 1 H), 2.51–2.62 (m, 2 H),
2.71 (br. s, 1 H), 3.14–3.20 (m, 1 H), 3.28 (dd, J = 10.8, 6.4 Hz, 1
H), 3.31 (dd, J = 10.8, 6.5 Hz, 1 H), 3.51 (dd, J = 10.6, 5.3 Hz, 1
H), 3.62 (dd, J = 10.6, 2.9 Hz, 1 H), 3.91–3.97 (m, 1 H), 3.98 (q, J
= 6.5 Hz, 1 H), 4.43 (s, 2 H), 4.56 (d, J = 11.7 Hz, 1 H), 4.72 (d, J
= 11.7 Hz, 1 H), 7.06–7.36 (m, 15 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 20.0, 26.5, 28.0, 34.4, 42.6, 54.3, 59.7, 67.6, 71.6, 72.7,
In summary, we have developed the first diastereoselec-
tive synthesis of (1R,2R,4R)- and (1S,2R,4S)-2-substituted-
1-azabicyclo[2.2.1]heptanes 10 and 11 from piperidone 1.
The products were obtained in enantiomerically pure form
with very high overall yield, 49 and 38%, respectively. This
synthesis represents another example of the utility of piperi-
done 1 as a versatile chiral starting material.[8,11]
1374
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1372–1376

Synthesis of (1R,2R,4R)- and (1S,2R,4S)-2-Substituted-1-azabicyclo[2.2.1]heptanes
73.3, 78.2, 126.4, 127.2, 127.3, 127.5, 127.6, 127.7, 128.0, 128.2,
128.3, 138.3, 139.0, 146.9 ppm. HRMS (ESI+): calcd. for
C30H38NO3 [M + H]+ 460.2846; found 460.2846.
1.43–1.56 (m, 1 H), 1.54–1.65 (m, 2 H), 2.51 (br. dd, J = 11.5,
11.5 Hz, 1 H), 2.70 (br. s, 2 H), 2.63–2.72 (m, 1 H), 3.04 (br. d, J
= 11.5 Hz, 1 H), 3.29–3.40 (m, 3 H), 3.50 (dd, J = 10.6, 4.6 Hz, 1
H), 3.64 (dd, J = 10.6, 3.1 Hz, 1 H), 4.43 (d, J = 12.1 Hz, 1 H),
4.44 (d, J = 11.2 Hz, 1 H), 4.48 (d, J = 12.1 Hz, 1 H), 4.66 (d, J =
11.2 Hz, 1 H), 7.16–7.30 (m, 10 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 29.0, 31.4, 38.8, 45.7, 57.1, 67.8, 69.4, 72.9, 73.3, 82.5,
127.6, 127.7, 127.9, 128.3, 128.3, 128.4, 138.1, 138.4 ppm. HRMS
(ESI+): calcd. for C22H30NO3 [M + H]+ 356.2220; found 356.2223.
(2R,4S)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-4-hydroxymethyl-1-[(S)-1-
phenylethyl]piperidine (cis-4): NaBH4 (76 mg, 2.0 mmol) was added
to a solution of the 76:24 mixture of cis-3/trans-3 (914 mg,
2.0 mmol) obtained as described previously[8] in CH3OH/H2O (4:1,
5 mL). After vigorously stirring for 2 h at room temperature the
reaction mixture was evaporated under reduced pressure. The ob-
tained crude was dissolved in Et2O (50 mL), treated with saturated
aqueous NH4Cl (30 mL) and extracted with Et2O (3ϫ50 mL). The
combined organic extract was dried with anhydrous MgSO4, fil-
tered and evaporated under reduced pressure. Purification by col-
umn chromatography (EtOAc/hexanes, 1:1; then EtOAc/EtOH,
4:1) of the obtained crude obtained allowed the isolation of 440 mg
C
22H29NO3 (355.47): calcd. C 74.33, H 8.22, N 3.94; found C
74.52, H 8.11, N 3.90.
(1R,2R,4R)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-1-azabicyclo[2.2.1]-
heptane (7): CBr4 (498 mg, 1.5 mmol) was added to a stirred solu-
tion of trans-6 (178 mg, 0.5 mmol) in anhydrous CH2Cl2 (20 mL),
and the reaction mixture was cooled to 0 °C. Then, resin polysty-
rene-supported PPh3 (3 mmol/g, 498 mg, 1.5 mmol) was added
slowly, and the reaction mixture was stirred under reflux conditions
for 8 h, filtered through Celite 545 and concentrated in vacuo. To
a solution of the obtained crude in CH2Cl2 (15 mL) at 0 °C was
added 1% aqueous NaOH solution (15 mL). After stirring at room
temperature for 1 h the reaction mixture was extracted with CH2Cl2
(3ϫ15 mL), and the combined organic layer was dried with anhy-
drous MgSO4 and filtered and the solvents evaporated in vacuo to
afford compound 7 in quantitative yield. Oil. [α]2D5 = –18.8 (c =
(48%) of pure cis-4. Oil. [α]2D5 = +10.4 (c = 1.25, CHCl3). IR (neat):
1
ν = 3354 cm–1. H NMR (400 MHz, CDCl ): δ = 0.69–0.87 (m, 2
˜
3
H), 1.07 (d, J = 6.8 Hz, 3 H), 1.25–1.33 (m, 1 H), 1.38 (br. d, J =
13.0 Hz, 1 H), 1.56 (br. s, 1 H), 1.92 (ddd, J = 11.1, 11.1, 2.2 Hz,
1 H), 1.98 (br. d, J = 13.0 Hz, 1 H), 2.31 (ddd, J = 11.1, 3.1, 3.1 Hz,
1 H), 2.61–2.67 (m, 1 H), 3.25 (dd, J = 10.5, 6.4 Hz, 1 H), 3.31
(dd, J = 10.5, 6.0 Hz, 1 H), 3.59 (dd, J = 10.6, 7.8 Hz, 1 H), 3.96
(br. d, J = 10.6 Hz, 1 H), 4.00 (q, J = 6.8 Hz, 1 H), 4.01–4.08 (m,
1 H), 4.40 (d, J = 12.2 Hz, 1 H), 4.50 (d, J = 12.2 Hz, 1 H), 4.63
(d, J = 12.0 Hz, 1 H), 4.73 (d, J = 12.0 Hz, 1 H), 7.02–7.35 (m, 15
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 7.7, 28.9, 29.1, 39.2,
44.6, 53.6, 58.8, 67.7, 71.1, 72.6, 73.4, 77.7, 126.2, 127.4, 127.4,
127.4, 127.5, 127.7, 127.8, 128.2, 128.3, 138.3, 138.8, 143.7 ppm.
HRMS (ESI+): calcd. for C30H38NO3 [M + H]+ 460.2846; found
460.2854.
1.03, CHCl ). IR (neat): ν = 1604, 1097, 1028 cm–1 1H NMR
.
˜
3
(400 MHz, CDCl3): δ = 0.64 (ddd, J = 8.0, 6.3, 1.6 Hz, 1 H), 0.85–
0.94 (m, 1 H), 1.42 (ddddd, J = 15.2, 15.2, 11.2, 7.6, 4.1 Hz, 1 H),
1.55 (dddd, J = 14.8, 11.2, 7.8, 4.1 Hz, 1 H), 2.35 (dd, J = 9.4,
1.0 Hz, 1 H), 2.40 (dd, J = 4.1, 4.1 Hz, 1 H), 2.42 (br. d, J = 9.4 Hz,
1 H), 2.54 (ddd, J = 12.2, 11.9, 5.2 Hz, 1 H), 2.77 (ddddd, J = 12.2,
10.7, 7.5, 4.4, 2.2 Hz, 1 H), 3.02–3.11 (m, 1 H), 3.48 (ddd, J = 8.7,
5.4, 2.8 Hz, 1 H), 3.58 (dd, J = 10.5, 5.4 Hz, 1 H), 3.64 (dd, J =
10.5, 2.8 Hz, 1 H), 4.45 (d, J = 12.0 Hz, 1 H), 4.50 (d, J = 12.0 Hz,
1 H), 4.58 (d, J = 11.9 Hz, 1 H), 4.78 (d, J = 11.9 Hz, 1 H), 7.16–
7.36 (m, 10 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 31.0, 33.5,
37.7, 46.9, 61.4, 64.6, 72.2, 72.5, 73.4, 78.5, 127.3, 127.6, 127.6,
127.8, 128.2, 128.3, 138.2, 138.8 ppm. HRMS (ESI+): calcd. for
C22H28NO2 [M + H]+ 338.2115; found 338.2101.
(2R,4R)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-4-hydroxymethylpiperidine
(trans-6): 10% Pd/C (92 mg) was added to a solution of trans-4
(459 mg, 1.0 mmol) in absolute EtOH (15 mL) and water (2 mL),
and the mixture was stirred at room temperature under an atmo-
sphere of H2 at atmospheric pressure for 24 h. After completion of
the reaction, the mixture was filtered through Celite 545, and the
Celite 545 was gently washed with EtOAc. The combined organic
extract was concentrated in vacuo to afford 295 mg (83%) of pure
trans-6. M.p. 88–90 °C. [α]2D5 = –17.9 (c = 1.32, CHCl3). IR (KBr):
(1S,2R,4S)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-1-azabicyclo[2.2.1]-
heptane (8): CBr4 (498 mg, 1.5 mmol) was added to a stirred solu-
tion of cis-6 (178 mg, 0.5 mmol) in anhydrous CH2Cl2 (20 mL), and
the reaction mixture was cooled to 0 °C. Then, resin polystyrene-
supported PPh3 (3 mmol/g, 498 mg, 1.5 mmol) was added slowly,
and the reaction mixture was stirred under reflux conditions for
8 h, filtered through Celite 545 and concentrated in vacuo. To a
solution of the obtained crude in CH2Cl2 (15 mL) at 0 °C was
added 1% aqueous NaOH solution (15 mL). After stirring at room
temperature for 1 h the reaction mixture was extracted with CH2Cl2
(3ϫ15 mL), and the combined organic layer was dried with anhy-
drous MgSO4 and filtered and the solvents evaporated in vacuo to
afford compound 8 in quantitative yield. Oil. [α]2D5 = –25.0 (c =
1
ν = 3298, 1642 cm–1. H NMR (400 MHz, CDCl ): δ = 1.34–1.45
˜
3
(m, 1 H), 1.41–1.52 (m, 2 H), 1.52–1.64 (m, 1 H), 1.69–1.80 (m, 1
H), 2.57–2.63 (m, 2 H), 2.83–2.91 (m, 1 H), 2.90 (br. s, 2 H), 3.37–
3.47 (m, 2 H), 3.44–3.51 (m, 1 H), 3.47 (dd, J = 12.1, 4.3 Hz, 1 H),
3.60 (dd, J = 12.1, 4.9 Hz, 1 H), 4.42 (d, J = 12.1 Hz, 1 H), 4.42
(d, J = 11.3 Hz, 1 H), 4.48 (d, J = 12.1 Hz, 1 H), 4.68 (d, J =
11.3 Hz, 1 H), 7.14–7.30 (m, 10 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 27.1, 28.8, 33.9, 40.7, 52.5, 64.5, 69.5, 72.6, 73.3, 79.5,
127.6 (ϫ2), 127.7, 128.0, 128.3, 128.3, 137.9, 138.2 ppm. HRMS
(ESI+): calcd. for C22H30NO3 [M + H]+ 356.2220; found 356.2229.
C22H29NO3 (355.47): calcd. C 74.33, H 8.22, N 3.94; found C
74.60, H 8.08, N 3.88.
(2R,4S)-2-[(S)-1,2-Bis(benzyloxy)ethyl]-4-hydroxymethylpiperidine
(cis-6): 10% Pd/C (92 mg) was added to a solution of cis-4 (459 mg,
1.0 mmol) in absolute EtOH (15 mL) and water (2 mL), and the
mixture was stirred at room temperature under an atmosphere of
H2 at atmospheric pressure for 24 h. After completion of the reac-
tion, the mixture was filtered through Celite 545, and the Celite
545 was gently washed with EtOAc. The combined organic extract
was concentrated in vacuo to afford 280 mg (79%) of pure cis-6.
0.58, CHCl ). IR (neat): ν = 1605, 1094, 1028 cm–1. 1H NMR
˜
3
(400 MHz, CDCl3): δ = 0.96–1.07 (m, 1 H), 1.12–1.20 (m, 1 H),
1.27–1.35 (m, 1 H), 1.49 (ddddd, J = 18.3, 15.2, 11.3, 7.2, 4.2 Hz,
1 H), 2.15 (br. d, J = 9.5 Hz, 1 H), 2.42 (br. dd, J = 3.9, 3.8 Hz, 1
H), 2.42–2.49 (m, 1 H), 2.54 (br. d, J = 9.5 Hz, 1 H), 2.66 (ddd, J
= 7.0, 6.9, 6.8 Hz, 1 H), 2.78 (ddd, J = 11.4, 11.4, 5.7 Hz, 1 H),
3.23–3.30 (m, 1 H), 3.56 (dd, J = 10.2, 5.0 Hz, 1 H), 3.62 (dd, J =
10.2, 4.1 Hz, 1 H), 4.43 (d, J = 12.0 Hz, 1 H), 4.48 (d, J = 12.0 Hz,
1 H), 4.66 (d, J = 12.1 Hz, 1 H), 4.73 (d, J = 12.1 Hz, 1 H), 7.15–
7.37 (m, 10 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 29.2, 34.4,
36.8, 55.8, 57.5, 66.0, 71.0, 72.8, 73.4, 80.3, 127.2, 127.5, 127.6,
M.p. 73–76 °C. [α]2D5 = –4.2 (c = 0.79, CHCl ). IR (KBr): ν = 3320,
˜
3
1645 cm–1. H NMR (400 MHz, CDCl3): δ = 0.83 (ddd, J = 12.1,
1
12.1, 12.1 Hz, 1 H), 1.05 (dddd, J = 11.5, 11.5, 11.5, 1.9 Hz, 1 H),
Eur. J. Org. Chem. 2009, 1372–1376
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1375

P. Etayo, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez
FULL PAPER
[4] R. Badorrey, C. Cativiela, M. D. Díaz-de-Villegas, J. A.
Gálvez, Tetrahedron 1999, 55, 7601–7612.
[5] N. F. Badham, Tetrahedron 2004, 60, 11–42.
127.7, 128.1, 128.3, 138.3, 139.1 ppm. HRMS (ESI+): calcd. for
C22H28NO2 [M + H]+ 338.2115; found 338.2118.
[6] a) U. Schöllkopf, R. Schöder, D. Stafforst, Justus Liebigs Ann.
Chem. 1974, 44–53; b) U. Schöllkopf, D. Stafforst, R. Jentch,
Justus Liebigs Ann. Chem. 1977, 1167–1173.
[7] a) J. Moskal, A. M. van Leusen, Recl. Trav. Chim. Pays-Bas
1986, 105, 141–142; b) J. Moskal, A. M. van Leusen, Recl.
Trav. Chim. Pays-Bas 1987, 106, 137–141.
[8] P. Etayo, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez, J.
Org. Chem. 2008, 73, 8594–8597.
[9] M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfield, S. Ma-
samune, W. R. Roush, T. Sakai, Tetrahedron Lett. 1984, 25,
2183–2186.
Acknowledgments
The financial support of the Spanish Ministry of Science and Inno-
vation and European Regional Development Fund (CTQ2008-
00187/BQU) and the Government of Aragón (GA E-71) is ac-
knowledged. P. E. thanks the Instituto Universitario de Catálisis
Homogénea for a postdoctoral fellowship.
[10] The cis/trans diastereomeric ratio was determined by 1H NMR
spectroscopic analysis of the crude reaction mixture.
[11] a) P. Etayo, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez,
Chem. Commun. 2006, 3420–3422; b) P. Etayo, R. Badorrey,
M. D. Díaz-de-Villegas, J. A. Gálvez, Synlett 2006, 2799–2803;
c) P. Etayo, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez,
Tetrahedron: Asymmetry 2007, 18, 2812–2819; d) P. Etayo, R.
Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez, J. Org. Chem.
2007, 72, 1005–1008; e) P. Etayo, R. Badorrey, M. D. Díaz-de-
Villegas, J. A. Gálvez, Tetrahedron Lett. 2008, 49, 2251–2253;
f) P. Etayo, R. Badorrey, M. D. Díaz-de-Villegas, J. A. Gálvez,
Eur. J. Org. Chem. 2008, 3474–3478.
Scifinder® substructure search.
[1]
[2] a) P. Sauerberg, P. H. Olesen, WO Patent 20496, 1994; b) W. S.
Caldwell, M. Bencherif, G. M. Dull, P. A. Crooks, P. M. Lippi-
ello, B. S. Bhatti, N. M. Deo, A. Ravard, WO Patent 00385,
1999; c) M. H. Yen, C. T. Fan, WO Patent 097608, 2003; d)
B. S. Bhatti, C. H. Miller, J. D. Schmidt, WO Patent 005293,
2004; e) T. J. Clark, WO Patent 009599, 2004; f) M. Bencherif,
C. H. Miller, G. P. Hawkins, B. S. Bhatti, U. S. Patent 220214,
2004; g) E. S. C. Wu, M. H. Yen, C. T. Fan, C. T. U. S. Patent
107415, 2005; h) H. R. Howard Jr, WO Patent 099423, 2007.
[3] J. P. Strachan, R. C. Whitaker, C. H. Miller, B. S. Bhatti, J. Org.
Chem. 2006, 71, 9909–9911.
Received: December 4, 2008
Published Online: February 6, 2009
1376
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1372–1376