Straightforward synthesis of [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl] methanol and [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl](diphenyl)methanol: Novel chiral ligands for the catalytic addition of diethylzinc to benzaldehyde to give rise to an extensive turn in the sense of asymmetric induction

Article abstract of DOI:10.1016/j.tetasy.2010.07.035

Enantiopure [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl]methanol 5a and [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl]-(diphenyl)methanol 5b, new β-amino alcohols based on l-pipecolinic acid (homoproline), have been prepared straightforwardly from rac-alaninol and rac-2-amino-1,1-diphenylpropan- 1-ol, respectively. The described route constitutes as a model procedure for the preparation of other related C(4) or/and C(3)-substituted 2- piperidinylmethanols. The new chiral ligands have shown a singular behaviour on the stereocontrol of the benchmark reaction of benzaldehyde and diethylzinc compared with other C(4)-unsubstituted analogues prepared by ourselves from l-pipecolinic acid (compounds 5c, 5d, 5e and 5f). The catalytic activity, the sense of asymmetric induction and the degree of the enantioselectivity depend on the appropriate combination of the substituents on the structural scaffold, but also on the metal-alkoxide involved in the catalysis (zinc or lithium alkoxides). The enantioselective addition of diethylzinc to benzaldehyde mediated by ligands 5a and 5c has been studied with DFT methods. The theoretical evaluation was performed in connection with a working hypothesis based on the different loadings of cis- and trans-catalysts in the reaction medium.

Full text of DOI:10.1016/j.tetasy.2010.07.035

Tetrahedron: Asymmetry 21 (2010) 2334–2345
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Straightforward synthesis of [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl]-
methanol and [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl](diphenyl)
methanol: novel chiral ligands for the catalytic addition of diethylzinc to ben-
zaldehyde to give rise to an extensive turn in the sense of asymmetric induction
Carlos Alvarez-Ibarra a, , Juan F. Collados Luján b, , María L. Quiroga-Feijóo a
⇑
⇑
a Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28043 Madrid, Spain
b Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Carretera de San Vicente del Raspeig s/n, 03690 San Vicente del Raspeig, Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiopure [(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-yl]methanol 5a and [(2S,4R)-1-cyclohexyl-4-
Received 4 June 2010
Accepted 23 July 2010
Available online 19 October 2010
methylpiperidin-2-yl]-(diphenyl)methanol 5b, new b-amino alcohols based on
L-pipecolinic acid
(homoproline), have been prepared straightforwardly from rac-alaninol and rac-2-amino-1,1-diphenyl-
propan-1-ol, respectively. The described route constitutes as a model procedure for the preparation of
other related C(4) or/and C(3)-substituted 2-piperidinylmethanols.
The new chiral ligands have shown a singular behaviour on the stereocontrol of the benchmark reac-
tion of benzaldehyde and diethylzinc compared with other C(4)-unsubstituted analogues prepared by
Dedicated to Professor Antonio García
Martínez on his 70th birthday
ourselves from L-pipecolinic acid (compounds 5c, 5d, 5e and 5f). The catalytic activity, the sense of asym-
metric induction and the degree of the enantioselectivity depend on the appropriate combination of the
substituents on the structural scaffold, but also on the metal-alkoxide involved in the catalysis (zinc or
lithium alkoxides). The enantioselective addition of diethylzinc to benzaldehyde mediated by ligands
5a and 5c has been studied with DFT methods. The theoretical evaluation was performed in connection
with a working hypothesis based on the different loadings of cis- and trans-catalysts in the reaction
medium.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
We have recently reported a one-pot procedure for the diaste-
reoselective synthesis of (3),4-substituted 5,6-dehydropiperidin-
The addition of organozinc compounds to prochiral aldehydes in
the presence of chiral b-amino alcohols constitutes a highly efficient
procedure for the enantioselective construction of C–C bonds.1 Chi-
ral ligands for asymmetric catalysis have been generally derived
from a small number of readily available natural products.2–7
In order to obtain the two enantiomeric products it is necessary
to have the two enantiomeric ligands but, in many cases, this is
not possible because only one of them is available. Moreover, mod-
ulation of the catalytic properties through structural modifications
in origin could be limited by the nature of precursors. Thus, the
enantioselective synthesis of ligands, with either a different config-
uration of the stereocentres responsible for the asymmetric induc-
tion, or with key substituents to fine tune the catalytic properties,
can represent an advantageous alternative to ligands of natural
origin and can allow the circumvention of the aforementioned
limitation.8
2-ones such as 3a (Scheme 1) from a-sulfinyl ketimine 1a, which
is raised from rac-alaninol and alkyl acrylate 2.9 In addition, the
reaction with Ra-Ni and reduction of the acetal-amide intermedi-
ate with alane would result with the isolation of a sole amino alco-
hol enantiomer 5a. This strategy has important advantages: (a)
Although the chiral auxiliary, (ꢀ)-menthyl p-toluenesulfinate, is
sacrificed on the synthesis, this is easily prepared from (ꢀ)-men-
thol and sodium p-toluenesulfinate on a scale of 50 g. (b) A library
of lactams 3 can be prepared by modifying the nature of the start-
ing rac-amino alcohol and the alkyl acrylate, and also by changing
the chirality of the menthyl sulfinate. (c) The amino alcohols 5 are
obtained with full control of all structural and stereochemical
parameters. (d) This synthetic methodology generates up to three
stereocentres through the chiral control of reagent 1 in the conver-
gent step of the synthesis.
These advantages encouraged us to consider that properly
substituted pipecolinic acid-based ligands would constitute an
interesting class of chiral catalysts by comparison with other ones
such as 2-aziridinyl10 and 2-azetidinylmethanols,11 and proli-
nols,12 which have been largely evaluated in the alkylation reaction
⇑
Corresponding authors. Tel.: +34 913944223; fax: +34 913944103.
E-mail address: caibarra@quim.ucm.es (C. Alvarez-Ibarra).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.07.035

C. Alvarez-Ibarra et al. / Tetrahedron: Asymmetry 21 (2010) 2334–2345
2335
R3
respectively, through 5,6-dehydropiperidin-2-ones intermediates
(Scheme 1). Compound 1b was obtained from rac-2-amino-1,1-
diphenylpropan-1-ol in 60% yield, following the procedure
described for 1a and other analogues.9 Compound 1b was then
transformed into lactam 3b via the addition of (E)-methyl croto-
nate, mediated by butyllithium. Monitoring the reaction by TLC
shows a single adduct, with its evolution to the cyclic product
being complete within 16 h. The crude was purified by flash LC
and the structure of the isolated product (75% yield) was estab-
lished as 3b by 1H and 13C NMR. The absolute configuration of
the new stereocentre (C-4) was assigned as (R) by comparison with
3a.9 In this case, the key signal became that of the methyl group in
the piperidone ring [d 0.42 ppm for the (R)-configured diastereo-
mer and d 1.31 ppm for the (S)-configured one]. Compound 3b
showed a signal for the methyl group at d 0.29 ppm. Furthermore
the stereochemical course of the reaction would be also invoked
in order to establish an identical configuration for 3a and 3b.
Next, 3b was derivatised as the lactam, via desulfinylation Ra-
ney-Ni in EtOH/benzene at 60 °C. Despite the harsh reaction condi-
tions being explored, the enamine proved reluctant to react and
the product of the hydrogenation 4b could not be detected in the
reaction crude. Thus, the enamine-lactam was isolated and treated
with NaCNBH3/TFA in acetic acid for 16 h to give a product in 67%
yield, which was identified by NMR as 4b, the major isomer in a
mixture (86:14) of two diastereomers. Attempts to separate both
stereoisomers were unsuccessful. Thus, the mixture was treated
with a THF solution of alane, generated in situ from LiAlH4 and
AlCl3 (3:1), for 16 h at room temperature. After a careful work-
up, compound 5b was obtained as the only isomer in 58% yield.
Its structure and configuration were determined from the NMR
spectroscopic data.
O
S
R4
OR2
R3
R4
N
N
O
O
O
2
R1
R1
R1
p-Tol
R1
p-Tol
S
O
O
1a : R1=H
1b : R1=Ph
3a : R1=R3=H; R4=Me
3b : R1=Ph; R3=H; R4=Me
reduction
R3
R4
O
LAH / AlCl3
THF
N
R3
HO
R1
N
O
H
R1
R4
R1
H
R1
5a : R1=R3=H; R4=Me
5b : R1=Ph; R3=H; R4=Me
4a : R1=R3=H; R4=Me (Ra-Ni)
4b : R1=Ph; R3=H; R4=Me
(i) Ra-Ni; (ii) NaBH3CN
Scheme 1.
of aldehydes with organozinc reagents. The synthesis and evalua-
tion of 2-piperidinylmethanols have not been investigated, due
to the dual (cis–trans) stereochemistry of the bicyclic zinc-chelated
complexes formed from these b-amino alcohols, which are the ac-
tual catalytic species.13
Although the competitive transition states generated from the
coexistence of the two diastereomeric catalysts could result in a
low enantioselectivity, it can be used as a tool to gain information
on the role of the substituents in the ring and also in the side chain
on the stereochemical outcome of the reaction. The work described
herein details our efforts in this area.
On the other hand, compound 5a was obtained by an analogous
route from 3a, following the strategy depicted in Scheme 1. In this
case, precursor 4a was easily derived from 3a by hydrogenation
with Ra-Ni in EtOH at 60 °C for 20 min in a one-pot procedure
(quantitative yield), and its reduction with alane provided the ami-
no alcohol 5a (70% yield).
As expected, the configuration of the new stereocentre in the C-
2 became (S), taking into account the stereocontrol induced by the
substituent on C-4 of the enamine-lactam precursor allowing at-
tack of the reagent to be anti. The (S)-configuration is consistent
with the axial character of the hydrogen atom on C-2, together
with the values observed for the vicinal coupling constants
2. Results and discussion
3
3
3
JH2,H3 and JH2,H3 in 5a (3JH2,H3 = 11.4 Hz and JH2,H3 = 3.2 Hz)
2.1. Synthesis of b-amino alcohols
0
0
and also in 5b (3JH2,H3 = 11.4 Hz and JH2,H3 = 3.8 Hz).
3
0
The syntheses of amino alcohols 5a and 5b (Chart 1) were
carried out from the chiral
In order to compare the catalytic activity and enantioselectivity
of ligands 5a and 5b with other N-substituted (2S)-piperidinyl-
methanols, we obtained the b-amino alcohols 5c–5f from the com-
a-sulfinyl ketimines 1a and 1b,
mercially available
L-pipecolinic acid (Chart 1), following the
reaction sequences outlined in Scheme 2.
Overall yields in the range 42–89% were reached by application of
standard procedures in order to allow access to the ligands 5c–5f.
N
N
N
HO
HO
HO
Ph Ph
5b
HO
2.2. Enantioselective addition of diethylzinc to benzaldehyde
catalysed by 2-piperidinylmethanols
5a
5c
Our first aim was to evaluate the catalytic activity and the
degree of enantioselection shown by the chiral ligands 5a–5f in
the standard reaction of benzaldehyde and diethylzinc. Both
parameters should be key probes in order to gain a better insight
as to the structure of competitive transition states. Furthermore,
as the structure is dependent on the nature of the organometallic
species which is the actual catalyst, we carried out two sets of
experiments. In the first, we generated a zinc chelate in the reac-
tion medium from the diethylzinc reagent and a catalytic amount
of the ligand. In the second experiment, an organolithium complex
Ph
Me
Me
N
N
N
HO
HO
Ph Ph
5d
5e
5f
Chart 1.

2336
C. Alvarez-Ibarra et al. / Tetrahedron: Asymmetry 21 (2010) 2334–2345
O
HN
BH3·THF
N
N
HO
HO
HO
H2/Pd
O
O
12
5c (60%)
13
Ph
Ph
N
1. KOH-iPrOH
LAH
N
HO
HO
2. BnBr
3. H3O+
O
14
5d (64%)
Me
O
Me
N
N
BH3·THF
HCHO
H2/Pd
HO
HO
5e (89%)
15
HN
HN
PhMgBr
1. Cl2SO
2. EtOH
EtO
HO
Ph Ph
O
16
17
HCHO
Me
N
N
LAH
O
HO
AlCl3
Ph Ph
Ph Ph
5f (42%)
18
Scheme 2.
was generated by adding a stoichiometric amount of n-butyllitium
to the ligand, before the reagent and benzaldehyde were added.
The results are shown in Table 1. All reactions were carried out
at room temperature using an Et2Zn/C6H5CHO/ligand molar ratio
of 1.8:1:0.05 in toluene as solvent. As can be seen from Table 1,
enantioselectivities ranging from 82% (R) for the ligand 5a (entry
2) to 83% (S) for the ligand 5b (entry 4) were observed. With the
other ligands, a broad range of (R)-stereoselection ranging from
60% (R) (entry 6) to 2% (R) (entry 12) was achieved by modifying
the substituent on the nitrogen atom of the piperidine ring, but
also introducing a gem-diphenyl group in the side chain (entries
11 and 12). This group has been named as the magic group in cat-
alyst design and has been frequently used in recent years in order
to improve stereoselection.14
As can be seen in Table 1, the magic character of the gem-diphe-
nyl group is more apparent for ligand 5b (entries 3 and 4) than for
5f (entries 11 and 12). Nevertheless, the same trend was observed
in both cases in terms of the comparison with their analogous 5a
(entries 1 and 2) and 5e (entries 9 and 10), respectively. Thus, it
seems that the gem-diphenyl group enhances the S-stereoselection
or like-induction.15,16 In fact, these results are in agreement with
those observed for other conformationally restricted heterocyclic
ligands bearing the gem-diphenyl group on the side chain (com-
pounds 6, 8, 10 and 11, Fig. 1).
It is important to note that other gem-dialkyl groups such as
dimethyl and diethyl in the N-benzylprolinol (compounds 7a and
7b, Fig. 1)12a do not cause the same effect on the asymmetric
induction. On the other hand, the extent of the change observed
in going from N-methylprolinol 95 to its derivative 8 is more
important than that observed for compound 5f from 5e, but less
than that observed for 5b from 5a, both bearing the methyl group
at the 4-position of the piperidine ring and the bulkier cyclohexyl
substituent on the nitrogen atom.
In spite of the catalytic activity, which was evaluated after 1 or
2 h of reaction, all reactions were generally completed within 18 h
(Table 1). The stereocontrol depends on the nature of the metal and
the substitution on the ring and the side chain, as we have already
mentioned. The reaction when controlled by ligands 5a, 5b and 5c,
displayed a slight increase in the stereoselectivity when lithium in-
stead of zinc complexes were involved (Table 1, entries 1–6), but
an opposite effect was observed (unlike-induction) in the reaction
controlled by ligands 5d, 5e and 5f (Table 1, entries 7–12). Further-
more, the lithium alkoxides that arose from these ligands became
more active than the zinc ones. This finding was also observed for

C. Alvarez-Ibarra et al. / Tetrahedron: Asymmetry 21 (2010) 2334–2345
2337
Table 1
The enantioselective addition of Et2Zn to benzaldehyde using L-pipecolinic acid-based ligandsa,b
Et
H
1. Et2Zn / L*
2. H3O+
H Et
PhCHO
+
(R)
(S)
Ph
OH
Ph
OH
*
*
Entry
Ligand (L )
Chiral cat. (L ꢀ M)
% yieldc
ee (config.)d
Conv. (%)e
1
2
5a-Zn
5a-Li
98
98
76 (R)
82 (R)
—/84
46/71
N
HO
5a
3
4
5b-Zn
5b-Li
98
98
79 (S)
83 (S)
60/—
84/—
N
HO
Ph Ph
5b
5
6
5c-Zn
5c-Li
98
98
57 (R)
60 (R)
79/93
45/70
N
HO
5c
7
8
5d-Zn
5d-Li
57
98
53 (R)
27 (R)
26/35
50/69
Ph
N
HO
5d
9
10
Me
5e-Zn
5e-Li
80
90
53 (R)
23 (R)
16/22
17/28
N
HO
5e
11
12
5f-Zn
5f-Li
77
98
11 (R)
2 (R)
23/31
50/68
Me
N
HO
Ph Ph
5f
a
b
c
Reactions were run in toluene at room temperature using Et2Zn/C6H5CHO/L* molar ratio of 1.8:1:0.05 (0.125 M solution of C6H5CHO).
All experiments were performed three times to ensure reproducibility.
Determined by GC (Cyclodex) at 18 h of reaction (yields: varied by 2).
Analysis of the samples at different reaction times showed that ee to be unchanged within the standard limits (enantiomeric excesses: varied by 2).
Determined by the standard procedure at 1 h/2 h of reaction in all cases (conversions: varied by 2).
d
e
ligand 5b (Table 1, entries 3 and 4) since its catalytic activity as
lithium alkoxide increased at the same time the stereocontrol
(like-induction) did.
ing the guidelines proposed by various research groups and using
the transition state structure analysis.17
In Figure 2, we have shown the steps that afford the (R)-config-
ured 1-phenyl-1-propanol, which arises from the cis-chelate com-
plex cis-cat via a sole transition state (B), which has been named
cis-transoid-anti-R (its geometry is based on Noyori’s 5/4/4 mod-
el13). This notation reports the relative configuration of the substit-
uents at the atoms belonging to the fusion between nuclei of the 6/
5/4/4 tetracyclic system [H/R1: cis; R1/Et(Zn1): transoid; Et(Zn1)/
Et(Zn2): anti and, in addition, the prochirality of the carbonyl
group: (R) or (S)]. Another competitive transition state arising from
the trans-chelate complex named trans-transoid-anti-S is also out-
lined in Figure 2. The mechanism proposed by Noyori is applied
here in a simplified scheme, which includes the product-forming
mixed complex or a catalyst-reagents complex A involved in the turn-
over-limiting step affording the catalyst-product complex (cis-R).
Up to 24 diastereomeric transition states with a 6/5/4/4 geom-
etry of type B could be considered, due to the presence of four
Ligands 5a and 5c show a different trend. Despite their degree
of (R)-stereocontrol, the change of metal in the chelate complex
from zinc to lithium led to a decrease in the chemical conversion
(Table 1, entries 1, 2 and 5, 6). Consequently, all these findings
show that the ligands submitted to the comparison bring about
very different geometries or relative configurations in the transi-
tion states responsible for the stereocontrol in going from the zinc
to the lithium alkoxide.
2.3. DFT mechanistic analysis
In order to examine the origin of the enantioselectivity in the
reaction of benzaldehyde and diethylzinc mediated by 2-piperidi-
nylmethanols, the reaction mechanism involving ligands 5a and
5c was investigated theoretically by means of DFT methods follow-

2338
C. Alvarez-Ibarra et al. / Tetrahedron: Asymmetry 21 (2010) 2334–2345
Figure 1. Analogies observed in the effect of the configuration and the substitution on the side chain of 1,2-dialkylsubstituted heterocyclic ligands on the stereocontrol of the
reaction of benzaldehyde and diethylzinc.
Et2Zn
H
H
H
R4
PhCHO
R4
slow
R4
R1
R1
Et
*
R1
N
N
N
O
O
O
Et
Et
1
fast
Zn
Zn
Zn
*
2
*
Zn
Et
Zn
O
Et
Et
cis-cat
O
*
H
Ph
H
Ph
cat-reagents complex
Et
H
N
cis-transoid-anti-R
R4
A
1
H
Zn
B
O
O
2
Ph
Zn
R1
Et
Et2Zn
H
trans-transoid-anti-S
R4
R1
N
O
Et
Zn
Zn
Et
O
EtZn
O
PhCHO
H
Et
R
Ph
H
Et
Ph
cat-prod. complex
cis-R
Figure 2. Hypothetical reaction pathways of diethylzinc and benzaldehyde involving cis- and trans-chelate complexes (cis- or trans-cat) for (2S)-piperidinylmethanols, based
on Noyori’s outcomes.13,17a
new stereocentres. However, only the four of them have an anti-
configuration between the non-transferred ethyl groups (and an
E-relationship between the phenyl group and the coordinative
O–Zn1 bond) were chosen (cis-transoid-anti-R, cis-cisoid-anti-S,
trans-transoid-anti-S and trans-cisoid-anti-R). This simplification
was checked with other cases.8,17b,17g
zinc and, as a consequence, two catalytic species are generated non-
reversibly, being different in both catalytic efficiency and
concentration or actual load (Fig. 3). Hence, a statistical factor
weighting the different loading of each catalyst in the reaction med-
ium should be introduced in Eq. (1) that reports the final stereoselec-
tivity [NR/NS is the molar fraction of the (R)- and (S)-1-phenyl-1-
At this point, it should be noted that the cis/trans-configuration is
pertinent to the acid-base reaction between the ligand and diethyl-
propanol] as exp ꢀ ð
D
G–cisꢀcat
ꢀ
D
G–transꢀcatÞ=RT, accounting for stereo-
control in the step, which leads to the cis- and trans-catalysts (Fig. 3).

C. Alvarez-Ibarra et al. / Tetrahedron: Asymmetry 21 (2010) 2334–2345
2339
H
R4
R1
CH3 CH3
H
H
N
R4
ZnEt2
O
R4
R1
Zn
Et
R1
N
Zn
N
O
OH
H
H
CH2
CH3
(C)
Et
N
cis-cat
H
CH3 CH3
Et
R4
R4
Zn Et
ZnEt2
N
Zn
O
O
R1
(D)
CH2 CH3
H
R1
trans-cat
Figure 3. Competitive acid-base reactions between ligands 5 and diethylzinc affording cis and trans catalytic species.
On the other hand, the second factor in Eq. (1), exp ꢀ ðDDG–cisðRÞꢀ
DDG–transðSÞÞ=RT, considers a single competitive reaction pathway at
each turnover limiting step giving rise to a single enantiomer [(R)
from the cis-cat and (S) from trans-cat, Figure 2]. Thus, an evalua-
tion of the relative efficiency of the catalysts requires the energetic
differences between each transition state and the appropriate
ground state of the same configuration (DDG–) to be calculated.
In doing so, the reaction pathway which matches the lowest en-
ergy transition state and the least stable product-forming mixed
complex will be the most efficient in the migration of the ethyl
group to the incoming carbonyl one.
the B3LYP21/6-31G(d)22 (for C, H, O and N) and LandL2DZ23 (for
Zn) levels. All the final structures of transition states showed a sin-
gle imaginary frequency corresponding to either the transfer of the
hydrogen atom at the hydroxyl group of the ligand to diethylzinc
(in the in situ formation of the catalyst) or the migration of the
suitably oriented ethyl group to the carbonyl carbon during the
rate limiting step (Fig. 2).
On the other hand, non imaginary frequencies were found in the
analysis of optimised structures of product-forming mixed com-
plexes A (Fig. 2). Both the geometries and energy levels are sum-
marszed in the Tables 2–4 for ligands 5a and 5c.
The characterisations of the transition states affording each cat-
alyst were performed and the results are reported in Table 2. The
ring inversion of the piperidine ligands has three reaction path-
ways that should be considered. Thus, ligand 5a becomes more
stereoselective than 5c. This seems to be due to the methyl group
at C4 of the piperidine ring, which prevents all axial conformers
being competitive (Table 2, entry 2). A different behaviour was ob-
served with ligand 5c, since the 1,2-diaxial conformer (Table 2, en-
try 5) became the most reactive in terms of the energy level of its
transition state. This is possible because the antiperiplanar rela-
tionship of the two substituents prevents their mutual interaction.
Thus, a statistical factor weighing the different loading of cis-
and trans-catalysts of 22.8 has been calculated for ligand 5a and
ꢀðDDG–cisðRÞꢀDDGt–ransðSÞÞ=RT
G–cisꢀcat
ꢀD
G–transꢀcatÞ=RT
NR
NS
D
¼ eꢀð
ꢁ e
ð1Þ
Despite the dual cisoid/transoid configuration of the two prod-
uct-forming mixed complexes (Fig. 2), a mechanism of dissociation
and recombination could be assumed,17a allowing an equilibrium
to be established to stabilise the diastereomeric complexes
through each catalytic species and the reagents. Hence, a dynamic
kinetic asymmetric transformation (DYKAT)18 would occur, pro-
viding the two enantiomeric alkoxide–products in one preferential
bias (unlike- or like-induction) from each catalyst [cis(R) and
trans(S), respectively].
In order to check these working hypotheses, the geometries and
relative energies of the structures A and B (Fig. 2), and C and D
(Fig. 3) were calculated in the first approach by using the ground
state and transition state searching algorithms implemented in
GAUSSIAN 03.19 The geometries were preoptimised by a PM3 semi-
empirical method20 and the final structures were optimised at
other one of 6.3 for 5c fexp ꢀ ð
D
G–cisꢀcat
ꢀ
D
G–transꢀcatÞg=RT in Eq. (1).
The relative energies calculated for the optimised geometries of
transition states corresponding to the migration of ethyl group
from the product-forming mixed complexes of type A (Fig. 2) are
summarised in Tables 3 and 4 for ligands 5a and 5c, respectively.
Table 2
Geometries and DFT B3LYP/6-31G(d):LanL2DZ relative energies (kcal/mol) calculated for transition states giving to the cis- and trans-catalyst for ligands 5a and 5c
TS (type)a
TS geometryb
ERHFc/a.u.
mi (cmꢀ1
)
ZPEd
Relative energiese (kcal/mol)
Ncis or Ntrans
f
Entry
Ligand
1
2
3
4
5
6
5a
5a
5a
5c
5c
5c
C (cis)
C (cis)
D (trans)
C (cis)
C (cis)
eq,eq,eq
ax,ax,ax
ax,eq,eq
eq,eq
ax,ax
ax,eq
ꢀ864.398445
ꢀ864.390980
ꢀ864.395496
ꢀ825.081098
ꢀ825.082371
ꢀ825.080838
994.7i
0.499374
0.500012
0.499175
0.471407
0.471661
0.471282
0
95.8
n.pg
4.2
17.8
68.5
13.7
1011.1i
1087.7i
1049.3i
1008.5i
1069.6i
4.68
1.85
0.80
0
D (trans)
0.96
a
b
c
d
e
f
H/Chex (cis or trans) as described for cis-cat and trans-cat in Figure 3.
Conformational isomerism related to the substituents on the nitrogen, C(2) and C(4) atoms at the piperidine ring, respectively.
Optimised geometries at the B3LYP/6-31G(d) (for C, H, O and N) and LanL2DZ (for Zn) level.
Unscaled zero-point correction.
All energies are relative to the most stable transition state.
Calculated stereoselectivity assuming a Boltzmann distribution at room temperature.
Non-participating way.
g

2340
C. Alvarez-Ibarra et al. / Tetrahedron: Asymmetry 21 (2010) 2334–2345
Table 3
Geometries and DFT B3LYP/6-31G(d):LanL2DZ relative energies (kcal/mol) of ground and transition states with respect to the most stable ground
state for ligand 5a
Structurea
ERHFb/a.u.
mi (cmꢀ1
)
ZPEc
Relative energies (kcal/mol)
cis-cisoid
cis-transoid
trans-cisoid
trans-transoid
cis-cisoid-anti-S
cis-transoid-anti-R
trans-cisoid-anti-R
trans-transoid-anti-S
ꢀ1354.240231
ꢀ1354.248616
ꢀ1354.236102
ꢀ1354.241854
ꢀ1354.218736
ꢀ1354.235035
ꢀ1354.218209
ꢀ1354.229121
0.668618
0.667776
0.668816
0.668044
0.670000
0.669229
0.669273
0.669764
5.26
0.00
7.85
4.24
18.75
8.52
195.1i
222.6i
237.6i
229.6i
19.08
12.23
a
H/Chex (cis or trans), Chex-Et(Zn1) (cisoid or transoid) and Et(Zn1)/Et(Zn2) anti as described for cis(trans)-cat and TS corresponding to Figure 2.
See Table 2 for optimised geometries, unscaled zero-point correction and relative energies.
b,c,d
Table 4
Geometries and DFT B3LYP/6-31G(d):LanL2DZ relative energies (kcal/mol) of ground and transition states with respect to the most stable ground
state for ligand 5c
Structurea
ERHFa/a.u.
mi (cmꢀ1
)
ZPEa
Relative energies (kcal/mol)
cis-cisoid
cis-transoid
trans-cisoid
trans-transoid
cis-cisoid-anti-S
cis-transoid-anti-R
trans-cisoid-anti-R
trans-transoid-anti-S
ꢀ1314.931699
ꢀ1314.933905
ꢀ1314.928942
ꢀ1314.927233
ꢀ1314.911050
ꢀ1314.920122
ꢀ1314.909090
ꢀ1314.914364
0.640993
0.639883
0.640643
0.640298
0.641540
0.640930
0.641472
0.640582
1.04
0.00
3.11
4.19
14.34
8.65
194.4i
218.4i
234.1i
228.9i
15.57
12.26
a
See Table 3.
Table 5
Catalytic efficiency of chelate—complexes involved in the turnover limiting steps affording cis and trans-catalyst-product complexes for the reaction of
diethylzinc and benzaldehyde promoted by ligands 5a and 5c
*
a
L
Structure
DDG– (kcal molꢀ1
)
Relative energyb
exp-DDG–/RT (Ni)c/%
5a
5a
5a
5a
5c
5c
5c
5c
cis-cisoid-anti-S
13.48
8.52
11.23
7.99
12.96
8.65
12.46
8.07
5.50
0.53
3.24
0.00
4.89
0.58
4.39
0.00
cis-transoid-anti-R
trans-cisoid-anti-R
trans-transoid-anti-S
cis-cisoid-anti-S
cis-transoid-anti-R
trans-cisoid-anti-R
trans-transoid-anti-S
0.41 (29.1)
1.00 (70.9)
0.38 (27.5)
1.00 (72.5)
a
Energy differences between each transition state and the ground state of the same configuration (calculated from the relative energies
summarised in the Tables 3 and 4).
b
Relative energies with respect to lowest value of DDG–
Calculated stereoselectivity on the turnover limiting steps.
.
c
The zero-point energy values (ZPE) and imaginary frequencies
have been included for their characterisation. The correlative
geometries of precursors such as A, cis-cisoid(transoid) and trans-
cisoid(transoid) have also been calculated in each case. Hence, only
two turnover limiting steps to each cis(R) and trans(S) catalyst-
product complexes became competitive.
The similar results observed for both reactions mediated by li-
gands 5a and 5c are more apparent from the calculation of DDG–
values in Eq. (1), as can be seen in Table 5. It can be seen from the
values obtained for the catalytic efficiency of cis- and trans-cata-
lysts performed from 5a and 5c (0.41 and 0.38, respectively), that
the trans-transoid product-forming mixed complex is more
efficient than the cis-transoid one for each ligand, although non-
remarkable differences between ligands were found. By introduc-
ing each factor and their exponential statistical ones in Eq. (1),
the stereoselectivity could be calculated as (NR/NS)5a = 9.36 and
(NR/NS)5c = 2.39 which implies enantiomeric excesses up to 80.8%
(R) for 5a and 41% (R) for 5c. These results are in good agreement
with the observed values (76% and 57%, respectively). In addition,
this indicates that the stereochemical outcome of the reaction is
mainly determined by the stereoselection provided in preforming
the cis- and trans-catalyst.
Inspection of the four structures drawn in the Figure 4 disclosed
that the most preorganised ground state affording the trans-tran-
soid-anti-S transition state is the most competitive pathway. It is
consistent with the data about the non-bonding distance between
the carbon atom of carbonyl group and the ethyl radical which is
considerably foreshortened in the trans-transoid ground state with
respect to the cis-transoid one (3.779 Å for 5a and 3.457 Å for 5c vs
3.821 Å for 5a and 3.779 Å for 5c, respectively).
All geometric parameters at the 4/4 core of the hypothetical
structures are in agreement with those calculated by Yamakawa
and Noyori.17k This analysis provides the correct sense and exten-
sion of the stereoselectivity, and in addition, it explains the modu-
lation caused by the substituent on C4 at the piperidine ring on the
stereocontrol. An extensive experimental and theoretical study is
currently in progress in order to clarify other structural effects on
the basis of the DYKAT checked herein.

C. Alvarez-Ibarra et al. / Tetrahedron: Asymmetry 21 (2010) 2334–2345
2341
Figure 4. Significant calculated structures for cat-reagent complexes and transition states of ligand 5a.
the final stereoselectivity. Further experiments and theoretical
calculations are now in progress in order to study other structural
effects on the stereochemical outcomes of the reaction.
3. Conclusions
In conclusion, enantiopure [(2S,4R)-1-cyclohexyl-4-methylpi-
peridin-2-yl]methanol 5a and [(2S,4R)-1-cyclohexyl-4-methylpi-
peridin-2-yl](diphenyl)methanol 5b have been straightforwardly
prepared from rac-alaninol and rac-2-amino-1,1-diphenylpropan-
1-ol, respectively.
4. Experimental section
4.1. Materials and methods
These chiral ligands show a singular behaviour on the stereo-
control of the benchmark reaction of benzaldehyde and diethylzinc
compared with other piperidinylmethanols 5c, 5d, 5e and 5f
prepared by ourselves from L-pipecolinic acid, but also with other
previously reported on the related proline.
The 1H and 13C NMR spectra were recorded at 300 or 500 MHz
and 75 or 125 MHz, in a Bruker AC-300 or Bruker AM-500 spectrom-
eter, respectively, using CDCl3. The chemical shifts (d) refer to TMS
(1H) or deuterated chloroform (13C) signals. Coupling constants (J)
are reported in Hertz. Multiplicities in the proton spectra are indi-
cated as s (singlet), d (doublet), t (triplet), q (quartet), quint. (quintu-
plet) and m (multiplet). Elemental analyses were performed with a
Perkin–Elmer 2400 C, H, N analyzer. Optical rotations were mea-
sured at room temperature (20–23 °C) using a Perkin–Elmer 241
MC polarimeter (concentration in g/100 mL). Infrared spectra were
recorded on a Shimadzu FTIR-8300 spectrophotometer or a Bruker
Tensor 27 spectrophotometer. The HRMS (EI) were performed on a
Bruker APEX Qe 4.7 T spectrometer by electrospray ionisation
(ESI). The enantiomeric excesses were determined by GC
(Hewlett–Packard 5890) using a capillary column Ciclodex-B and
nitrogen as carrier gas.
All reactions in non-aqueous media were carried out in a flame-
dried glassware under an argon atmosphere. Reagents and solvents
were handled by using standard cannulae or syringe techniques.
Tetrahydrofuran (THF) and diethyl ether were distilled from
sodium and benzophenone, dichloromethane from P2O5 and
isopropanol from CaH2. In all other cases, commercially available
reagent-grade solvents were employed without purification.
Analytical TLC was routinely used to monitor reactions. Plates pre-
coated with Merck Silica Gel 60 F254 of 0.25 mm thickness were
used, and visualised with UV light, with either anisaldehyde/sulfu-
ric acid/ethanol (2:1:100) or phosphomolybdic acid solution (PMA,
Thus, ligand 5a gave the highest stereoselection (unlike induc-
tion), up to 82% (R), while 5b switched the enantiomeric excess
up to 83% (S) (like induction). The 4-unsubstituted ligands 5c–5f
showed a weak stereoselection [60–2% ee of (R)-1-phenyl-1-propa-
nol] which could be modulated not only by modifying the size of
the substituent on the nitrogen atom (Chex > Bn > Me) but also
by introducing the gem-diphenyl group on the sidechain. Further-
more, the use of the most reactive lithium alkoxides prepared from
these latter ligands provided a lowest (R)-stereoselection due to
the fact that those transition states affording (S)-1-phenyl-1-pro-
panol are relatively stabilised when Li-catalysts are used.
Theoretical studies based on Noyori’s 5/4/4 model and DFT
methods have allowed us to justify the effect of the substituents
at C4 of the piperidine ring of ligands 5a and 5c on the stereocon-
trol of the benchmark reaction. It has been supported in a working
hypothesis proposing that the two catalysts (cis and trans) are
formed in the reaction medium, each one giving rise to two prod-
uct-forming mixed complexes to be in fast equilibrium with the
catalyst and the reagents. Among of all the turnover limiting steps
leading to (R)- and (S)-configured products, only one from each
catalyst, cis-R and trans-S, became efficient (trans-S more than
cis-R). Despite their relative catalytic activity, a statistical factor
related to the actual loading of each catalyst, is responsible for

2342
C. Alvarez-Ibarra et al. / Tetrahedron: Asymmetry 21 (2010) 2334–2345
10% in ethanol) as developing agents. Merck Silica Gel 60 (230–400
ASTM mesh) was employed for flash column chromatography.
Chemicals for reactions were used as purchased from the Aldrich
Chemical Co.
4.4. Synthesis of (70S, 8a0S)-70-methyltetrahydrospiro
[ciclohexane-1,30-[1,3]oxazolo[3,4a]pyridin]-50(10H)-one, 4a
To a stirred solution of (ꢀ)-3a (779 mg, 1.85 mmol) in absolute
EtOH (20 mL) was added Raney Nickel W-224 (2.4 g; 4 mL) and the
reaction mixture was heated at 60 °C for 20 min. Then, it was
cooled down to rt, filtered on a thin pad of Celite and the metallic
salts were washed with ether (5 ꢂ 5 mL). The combined organic
extracts were evaporated at reduced pressure to give a colourless
solid that was purified by flash chromatography (silica gel; hex-
ane/EtAcO: 4:1; v/v) obtaining 470 mg (91% yield) of 4a. White so-
4.2. Theoretical calculations
DFT calculations were performed using the GAUSSIAN 03 software
package with the option TS of Opt keyword to request optimisa-
tions to a transition state.19 All structures were optimised using
density functional theory and the non-local hybrid Becke’s three-
parameters exchange functional (denoted as B3LYP)21 with
LanL2DZ pseudopotential and the associated basis set for Zn,23
and the 6-31G(d)22 basis set for C, H, O and N atoms. All transition
states and local minima were validated through frequency
analysis.
lid; mp 102–103 °C;
[a]D = +24.0 (c 1.1, CHCl3); IR (ATR)
1645 cmꢀ1 1H NMR (300 MHz, CDCl3) d 1.02 (d, 3H, 3J = 6.2 Hz,
;
CH3), 0.99–1.08 (m, 1H, CH2CHCH3), 1.20–1.70 (m, 8H, cyclohexyl),
1.87–2.00 (m, 3H, COCH2, CHCH3, CH2CHCH3), 2.40–2.60 (m, 3H,
COCH2, cyclohexyl), 3.40 (dd, 1H, 2J = 8.3 Hz, 3J = 10.3 Hz, CH2O),
3.65 (dddd, 1H, 3J = 11.1, 10.3, 5.4, 3.0 Hz, CHN), 4.04 (dd, 1H,
3J = 8.3 Hz, 3J = 5.4 Hz, CH2O), 13C NMR (75 MHz, CDCl3) d 21.5
(CH3), 23.0, 23.1, 24.5 (cyclohexyl), 28.4 (CHCH3), 30.9 (cyclo-
hexyl), 33.9 (CH2CHN), 34.3 (cyclohexyl), 41.1 (COCH2), 57.4
(CHN), 69.1 (CH2O), 95.9 (C ipso), 166.8 (C@O). Anal. Calcd for
4.3. Synthesis of 5-(p-tolylsulfinyl)-5,6-dehydro-piperidin-2-
ones 3a and 3b. Typical procedure
To a cold (ꢀ78 °C) solution of sulfinyl ketimine (+)-1a or (+)-1b
(3.17 mmol) in dry THF (60 mL) under an argon atmosphere was
added a solution of n-BuLi (1.6 M in hexane, 2.3 mL, 3.68 mmol).
The solution was stirred at ꢀ78 °C for 0.5 h, after which the temper-
ature was raised to ꢀ30 °C and methyl (E)-2-butenoate (6.33 mmol,
0.15 M solution in THF) was added. The reaction mixture was then
kept at rt and stirred for 3 h. The mixture was hydrolysed with a sat-
urated aqueous NH4Cl solution (25 mL) and extracted with EtAcO
(3–30 mL). The combined organic layers were washed with brine,
dried over Na2SO4, concentrated under reduced pressure and chro-
matographed (silica gel; hexane/EtAcO: 1:1; v/v).
C13H21NO2: C, 69.92; H, 9.48; N, 6.27. Found: C, 69.94; H, 9.51;
N, 6.23.
4.5. Synthesis of (70S,8a0S)-70-methyl-1,10-diphenyltetrahydrospi-
ro[ciclohexane-1,30[1,3]oxazolo [3,4a]pyridin]-50(10H)-one, 4b
From (ꢀ)-3b (130 mg, 0.25 mmol) in EtOH (2 mL) and benzene
(1 mL), and Raney-Nickel (1.2 g; 2 mL) at 50 °C during 16 h, follow-
ing the procedure described for 4a. A colourless solid was isolated
in 91% yield (86 mg), which upon flash chromatography (silica gel;
hexane/EtAcO: 4:1; v/v) gave an intermediate desulfinylated 4b-
4.3.1. (ꢀ)-(Ss,70R)-70-Methyl-80-[(4-methylphenyl)sulfinyl]-60,70-
dihydrospiro[cyclohexane-1,30-[1,3]oxazolo[3,4-a]pyridin]-
50(10H)-one, (ꢀ)-3a
enamide: white solid; mp 166–168 °C; [
a]D = +82.8 (c 1.0, CHCl3);
IR (ATR) 1678, 1448, 1340 cmꢀ1 1H NMR (300 MHz, CDCl3) d 0.77
;
(d, 3H, 3J = 5.5 Hz, CH3), 1.22–2.06 (m, 8H, cyclohexyl), 2.11–2.34
(m, 2H, COCH2, CHCH3), 2.50 (m, 1H, COCH2), 2.82 (td, 1H,
2J = 3J = 13.4 Hz, 3J = 4.6 Hz, cyclohexyl), 2.93 (td, 1H, 2J = 3J =
13.4 Hz, 3J = 3.7 Hz, cyclohexyl), 4.58 (d, 1H, 3J = 2.4 Hz, CH@C),
7.11–7.69 (m, 10H, ArH); 13C NMR (75 MHz, CDCl3) d 20.2 (CH3),
23.2, 23.3, 24.9 (cyclohexyl), 27.4 (CH), 34.1, 35.0 (cyclohexyl),
41.2 (COCH2), 87.3, 97.4 (CO, OCN), 105.8 (CH@C), 125.5, 125.6,
125.9, 126.0, 126.3, 128.5 (ArCH), 140.9, 144.4, 144.6 (ArC, CH@C),
165.8 (C@O). Anal. Calcd for C25H27NO2: C, 80.40; H, 7.29; N, 3.75.
Found: C, 80.45; H, 7.22; N, 3.79.
From (+)-1a (927 mg, 3.17 mmol) and methyl (E)-2-butenoate
(6.33 mmol, 0.15 M solution in THF) following the procedure de-
scribed above. Two fractions of 695 mg and 353 mg of 3a and its
C(70)-epimer, respectively, were obtained in 92% yield. Both iso-
mers were identified through NMR spectroscopic data by compar-
ison with samples previously prepared.
4.3.2. (ꢀ)-(Ss,70R)-70-Methyl-80-[(4-methylphenyl) sulfinyl]-10,10-
diphenyl-60,70-dihydrospiro[cyclohexane-1,30-[1,3]oxazolo[3,4-
a]pyridin]-50(10H)-one (ꢀ)-3b
To
a
solution of 70 mg of the desulfinylated enamine
L of TFA (0.065 mmol) and
From (+)-1b (413 mg, 0.931 mmol) and methyl (E)-2-butenoate
(1.85 mmol, 0.15 M solution in THF) following the procedure de-
scribed above. The reaction mixture was stirred at rt for 16 h and
the crude was purified by LC to obtain 375 mg of (ꢀ)-3b (75%
(0.19 mmol) in AcOH (4 mL) at rt, 5
l
30 mg of NaCNBH3 (0.48 mmol) were added under argon. After
stirring for 16 h, a 3 M solution of NaOH was added dropwise until
neutral pH. The reaction mixture was then extracted with DCM
(3 ꢂ 10 mL) and the combined extracts were washed with brine,
dried over Na2SO4, filtered and concentrated at reduced pressure.
The residue was purified by flash chromatography (silica gel; tolu-
ene/MeOH: 40:1; v/v) to obtain 47 mg of a inseparable mixture
(86:14) of epimers of 4b (67% yield). IR (ATR) 1660, 1447, 1407,
yield). White solid; mp 210–211 (decomp.); [
a]
D = ꢀ367.0 (c 1.0,
CHCl3); IR (ATR) 1689, 1646, 1369, 1319, 1030 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 0.29 (d, 3H, J = 7.0 Hz, CHCH3), 0.87 (d, 1H,
2J = 12.8 Hz, cyclohexyl), 1.16–1.45 (m, 2H, cyclohexyl), 1.50 (dt,
1H, 2J = 3J = 13.0 Hz, 3J = 3.5 Hz, cyclohexyl), 1.57–1.93 (m, 4H,
cyclohexyl), 2.13 (td, 1H, 2J = 3J = 13.0 Hz, 3J = 4.9 Hz, cyclohexyl),
2.36 (dd, 1H, 2J = 16.1 Hz, 3J = 1.9 Hz, COCH2), 2.32 (s, 3H, ArCH3),
2.64 (m, 1H, cyclohexyl), 2.79 (dd, 1H, 2J = 16.1 Hz, 3J = 6.2 Hz,
COCH2), 3.05 (cdd, 1H, 3J = 7.0, 6.2 Hz, 1.9 Hz, CHCH3), 6.54 (AA0XX0
system, 2H, 3J = 8.2 Hz, ArHortho-CH3), 7.07 (AA0XX0 system, 2H,
3J = 8.2 Hz, ArHortho-SO), 7.75–7.79 (m, 2H, ArH), 7.31–7.54 (m,
8H, ArH); 13C NMR (75 MHz, CDCl3) d 18.0 (CHCH3), 21.2, 21.2
(ArCH3, CHCH3), 22.7, 22.7, 24.3, 31.7, 36.1, 41.7 (COCH2, cyclo-
hexyl), 89.2 (CO), 98.2 (OCN), 120.3 (SC@C), 124.4, 127.8, 127.9,
128.6, 128.7, 128.7, 129.4, 130.1 (ArCH), 137.0, 140.8, 141.2,
144.6, 145.7 (C@CN, ArC), 166.9 (C@O). Anal. Calcd for C32H33NO3S:
C, 75.11; H, 6.50; N, 2.74. Found: C, 75.20; H, 6.57; N, 2.68.
1046, 1022, 742, 701 cmꢀ1 1H NMR (300 MHz, CDCl3) d 0.96 (d,
;
3H, 3J = 6.2 Hz, CH3) 1.26–2.10 (m, 13H, cyclohexyl, COCH2,
CHCH2CH), 2.38 (ddd, 1H, 2J = 16.3 Hz, 3J = 4.7, 4J = 1.7 Hz,
CHCH2CH), 3.05 (td, 1H, 2J = 13.1 Hz, 3J = 5.0 Hz, COCH2), 4.41 (dd,
1H, 3J = 11.8, 3.2 Hz, NCH), 7.22–7.43 (m, 8H, ArCH), 7.49–7.54
(m, 2H, ArCH); 13C NMR (75 MHz, CDCl3) d 21.5 (CH3), 22.9, 23.4,
25.1 (cyclohexyl, CHCH2CH), 29.1 (CHCH3), 33.2, 34.4, 35.7 (cyclo-
hexyl), 41.2 (COCH2), 65.4 (NCH), 86.2 (OC), 96.5 (OCN), 126.0,
127.2, 127.4, 127.5, 127.7, 128.1 (ArCH), 143.0, 146.1 (ArC), 167.8
(C@O). Anal. Calcd for C25H29NO2: C, 79.96; H, 7.78; N, 3.73. Found:
C, 80.01; H, 7.77; N, 3.65.

C. Alvarez-Ibarra et al. / Tetrahedron: Asymmetry 21 (2010) 2334–2345
2343
4.6. Synthesis of (ꢀ)-[(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-
White solid; mp 187–188 °C (decomp.); [
a]
D = ꢀ53.4 (c 0.71,
yl]methanol, (ꢀ)-5a
MeOH); IR (ATR) 3425, 2929, 2859, 1613, 1399 cmꢀ1 1H NMR
;
(300 MHz, CDCl3) d 1.03–1.48 (m, 5H, CHCH2CH2, cyclohexyl),
1.50–1.74 (m, 2H, cyclohexyl), 1.75–1.98 (m, 5H, CHCH2CH2CH2,
cyclohexyl), 2.00–2.25 (m, 3H, NCH2CH2, cyclohexyl), 2.31–2.41
(m, 1H, CHCH2), 2.66 (td, 1H, 2J = 3J = 12.1 Hz, 3J = 2.8 Hz, NCH2),
3.52 (d, 1H, 2J = 12.1 Hz, NCH2), 3.59 (dd, 1H, 3J = 11.9, 3.4 Hz,
COCH), 3.69 (tt, 1H, 3J = 11.7, 3.1 Hz, NCH); 13C NMR (75 MHz,
CDCl3) d 22.8, 23.8, 26.3, 26.4, 26.5, 29.6, 29.9 (CHCH2CH2CH2,
Cyclohexyl), 47.0 (NCH2), 67.3, 65.4 (NCH, COCH), 173.8 (C@O).
Anal. Calcd for C12H21NO2: C, 68.21; H, 10.02; N, 6.63. Found: C,
68.29; H, 10.00; N, 6.57.
To a cold (0 °C) suspension of LiAlH4 (44 mg, 1.16 mmol) in dry
THF (1.2 mL) under an argon atmosphere was added dropwise a
solution of AlCl3 (52 mg, 0.387 mmol) in dry THF (3 mL). The solu-
tion was stirred for 25 min at rt, then it was cooled to ꢀ78 °C and a
solution of amido acetal 4a (95 mg, 0.425 mmol) in dry THF
(3.6 mL) was added. The solution was stirred at ꢀ78 °C for
45 min, the temperature raised to 0 °C and stirred for another
35 min. Then, the mixture was carefully hydrolysed with 1 M HCl
until hydrogen evolution stopped and extracted with CHCl3/i-
PrOH, 80:20. The organic phase was washed with 1 M NaOH and
then with brine, dried over anhydrous MgSO4, filtered and concen-
tred under reduced pressure to obtain 63 mg of pure product (ꢀ)-
4.8.2. Synthesis of (ꢀ)-[(2S)-1-cyclohexylpiperidin-2-
yl]methanol, (ꢀ)-5c
5a (70% yield). White solid; mp 151–153 °C; [
a]
D = ꢀ27.8 (c 0.6,
To a suspension of acid (ꢀ)-13 (88 mg, 0.416 mmol) in dioxane
(2 mL) under an argon atmosphere was added dropwise a 1.0 M
solution of BH3ꢁTHF (1.3 mL), and the mixture was stirred for
24 h and carefully hydrolysed with 6 M HCl (2 mL). Next, it was
stirred for another 30 min and neutralised with NaOH until neu-
tral–basic pH. This solution was extracted with a CHCl3/i-PrOH,
80:20 mixture, dried over MgSO4, filtered and concentred under re-
duced pressure. The crude was identified as (ꢀ)-5c (66 mg, 80%
CHCl3); IR (ATR) 3256, 2932, 1452, 1101 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 0.95 (d. 3H, 3J = 6.3 Hz, CH3), 1.03–1.14 (m,
1H, cyclohexyl), 1.16–1.55 (m, 6H, NCH2CH2, CHCH3, cyclohexyl),
1.56–1.70 (m, 4H, NCH2CH2, NCHCH2, cyclohexyl), 1.79–1.86 (m,
2H, cyclohexyl), 1.94 (d, 1H, 2J = 11.4 Hz, cyclohexyl), 2.39 (td,
1H, 2J = 11.8 Hz, 3J = 2.6 Hz, NCH2), 2.78 (dc, 1H, 3J = 11.4, 3.2 Hz,
NCHCH2O), 3.14 (dt, 1H, 2J = 11.8 Hz, 3J = 3.3 Hz, NCH2), 3.11–3.19
(m, 1H, NCH), 3.55 (d, 1H, 2J = 11.5 Hz, CH2OH), 3.92 (ddd, 1H,
2J = 11.5 Hz, 3J = 5.4, 3.2 Hz, CH2OH); 13C NMR (75 MHz, CDCl3) d
21.7 (CH3), 24.0, 25.6, 26.1, 26.2 (cyclohexyl), 30.6 (CHCH3), 31.0
(cyclohexyl), 33.2 (NCH2CH2), 37.4 (NCHCH2), 45.4 (NCH2), 58.0
(NCH), 59.1 (NCHCH2O), 62.4 (CH2OH). Anal. Calcd for C13H25NO:
C, 73.88; H, 11.92; N, 6.63. Found: C, 73.97; H, 12.00; N, 6.56. HRMS
(ESI): calcd for C13H25NO 211.1936; found 211.1942.
yield). White solid; mp 59–60 °C; [
a
]
D = ꢀ37.6 (c 0.25, MeOH); IR
(ATR) 3288, 1452, 1181 cmꢀ1 1H NMR (300 MHz, CDCl3) d 0.98–
;
1.85 (m, 16H, CHCH2CH2CH2, cyclohexyl), 2.39 (ddd, 1H,
2J = 12.2 Hz, 3J = 9.4, 2.8 Hz, NCH2), 2.71 (dc, 1H, 3J = 8.3, 4.3 Hz,
OCH2CH), 2.81 (tt, 1H, 3J = 11.0, 2.9 Hz, NCH), 2.92 (ddd, 1H,
2J = 12.2 Hz, 3J = 5.7, 3.5 Hz, NCH2), 3.20–3.54 (s, 1H, OH), 3.47
(dd, 1H, 2J = 10.7 Hz, 3J = 4.3 Hz, CH2OH), 3.70 (dd, 1H,
2J = 10.7 Hz, 3J = 4.3 Hz, CH2OH); 13C NMR (75 MHz, CDCl3) d 23.2,
25.0, 25.8, 26.2, 26.2, 26.3, 27.9, 31.9 (CHCH2CH2CH2, cyclohexyl),
44.5 (NCH2), 57.2, 58.2 (CHNCH), 61.6 (CH2OH). Anal. Calcd for
4.7. Synthesis of (ꢀ)-[(2S,4R)-1-cyclohexyl-4-methylpiperidin-2-
yl](diphenyl)methanol, (ꢀ)-5b
C12H23NO: C, 73.04; H, 11.75; N, 7.10. Found: C, 73.00; H, 11.68;
From 4b (38 mg, 0.105 mmol) in dry THF (1.2 mL) following the
procedure described for 5a. The reaction mixture was left at rt for
16 h, and then it was carefully hydrolysed with 1 M HCl until the
hydrogen evolution stopped and was extracted with CHCl3/i-PrOH,
80:20. The organic phase was washed with 1 M NaOH and then
with brine, dried over anhydrous MgSO4, filtered and concentred
under reduced pressure to obtain 22 mg of (ꢀ)-5b (58% yield) as
N, 7.14. HRMS (ESI): calcd for C12H23NO 197.1780; found 197.1776.
4.9. Synthesis of ligand 5d
4.9.1. (ꢀ)-(2S)-1-Benzylpiperidine-2-carboxylic acid, (ꢀ)-14
To a heated (40 °C) mixture of L-pipecolinic acid (100 mg,
0.774 mmol) and KOH (130 mg, 2.32 mmol) in i-PrOH (1.5 mL)
was added dropwise (over 2 h, using a syringe pump) a solution
of benzyl bromide (99 lL, 0.828 mmol) in i-PrOH (0.5 mL) and was
a single isomer. Waxy oil; [
3257, 1450, 1033, 702 cmꢀ1
a]
D = ꢀ25.1 (c 0.4, CH2Cl2); IR (ATR)
;
1H NMR (300 MHz, CDCl3) d 0.75 (d,
3H, 3J = 6.4 Hz, CH3), 0.78–1.65 (m, 14H, CH2CHCH2, cyclohexyl),
2.40 (dt ap., 1H, 2J = 11.1 Hz, 3J = 3.4 Hz, cyclohexyl), 2.48 (dt, 1H,
2J = 11.7 Hz, 3J = 3.2 Hz, NCH2), 2.93 (dt, 1H, 2J = 11.7 Hz, 3J =
4.2 Hz, NCH2), 3.65 (t, 1H, 3J = 6.6 Hz, NCH), 3.74 (dd, 1H,
3J = 11.4, 3.8 Hz, NCHC), 7.05–7.32 (m, 6H, ArCH), 7.49–7.55 (m,
2H, ArCH), 7.69–7.75 (m, 2H, ArCH); 13C NMR (75 MHz, CDCl3) d
22.4 (CH3), 25.2, 25.4, 26.0, 26.5 (cyclohexyl, CH2), 30.4 (CH3CH),
32.3, 33.8, 37.3 (cyclohexyl, CH2), 44.5 (NCH2), 57.5, 61.9 (CH),
77.3 (CO), 124.4, 125.6, 125.8, 126.5, 127.7, 128.1 (ArCH), 147.0,
150.4 (ArC). Anal. Calcd for C25H33NO: C, 82.60; H, 9.15; N, 3.85.
Found: C, 82.67; H, 9.18; N, 3.86. HRMS (ESI): calcd for C25H33NO
363.2562; found 363.2563.
stirred for another 6 h at the same temperature. The mixture was
hydrolysed with concd HCl (0.16 mL approx.) until pH 5–6,
extracted with CHCl3, dried over anhydrous MgSO4, filtered and con-
centred at reduced pressure. The crude was purified by flash chro-
matography (silica gel, methanol) to obtain 134 mg of (ꢀ)-14 (79%
yield). Colourless oil; [
a]
D = ꢀ16.2 (c 0.5, EtOH); IR (ATR) 3401,
1623, 1402, 701 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 1.47–1.96 (m,
5H, CHCH2CH2CH2), 2.37–2.20 (m, 1H, CHCH2), 3.02 (td, 1H,
2J = 12.0 Hz, 3J = 3.5 Hz, NCH2), 3.41 (d, 1H, 2J = 12.0 Hz, NCH2),
3.65 (dd, 1H, 3J = 11.4, 3.2 Hz, CH), 4.18 (d, 1H, 2J = 12.6 Hz, NCH2Ph),
4.61 (d, 1H, 2J = 12.6 Hz, NCH2Ph), 7.61–7.40 (m, 5H, ArCH); 13C NMR
(75 MHz, CDCl3) d 22.3, 22.6, 29.6 (CHCH2CH2CH2), 58.3 (NCH2), 70.0
(NCH2Ph), 70.9 (CH), 129.1, 129.9, 131.8, 133.2, (ArCH, ArC), 170.5
(C@O). Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found:
C, 71.15; H, 7.73; N, 6.43.
4.8. Synthesis of ligand 5c
4.8.1. (ꢀ)-(2S)-1-Cyclohexylpiperidine-2-carboxylic acid, (ꢀ)-13
A mixture of
L
-pipecolinic acid (200 mg, 1.548 mmol), cyclohex-
4.9.2. Synthesis of (ꢀ)-[(2S)-1-benzylpiperidin-2-yl]methanol,
(ꢀ)-5d
anone (120 lL, 1.548 mmol) and 10% Pd on activated charcoal (tip
of spatula) in dry methanol (6.5 mL) was stirred for 24 h under a
hydrogen atmosphere (1.1 atm). The crude was then filtered on a
thin pad of Celite, and the solvent was removed under reduced
pressure and the residue was purified by flash chromatography
(silica gel, methanol) to obtain 238 mg (73% yield) of acid (ꢀ)-13.
To a cold (0 °C) suspension of (ꢀ)-14 (94 mg, 0.429 mmol) in
dry diethyl ether (2 mL) under an argon atmosphere was cannuled
a solution of LiAlH4 (65 mg, 1.715 mmol) in dry diethyl ether
(1 mL), and the mixture was stirred for 1 h at the same tempera-
ture and then overnight at rt. Then, the mixture was cooled to

2344
C. Alvarez-Ibarra et al. / Tetrahedron: Asymmetry 21 (2010) 2334–2345
0 °C and was carefully hydrolysed with a saturated solution of
Na2SO4 (2 mL), extracted with a CHCl3/i-PrOH, 80:20 mixture,
dried over MgSO4, filtered and concentred under reduced pressure
SOCl2 was removed by evaporation under reduced pressure and
the residue was dissolved in absolute ethanol (3 mL) and stirred
for another 6 h. The solvent was removed under reduced pressure
to obtain 75 mg of (ꢀ)-5d (85% yield). Colourless oil; [
a
]
;
D = ꢀ31.4
yielding 144 mg (95% yield) of (ꢀ)-16. Colourless oil; [
a
]
D = ꢀ11.8
(c 0.5, CHCl3); IR (ATR) 3393, 1452, 1061, 734, 698 cmꢀ1
1H NMR
(c 0.28, CHCl3); 1H NMR (300 MHz, CDCl3) d 1.28 (t, 3H, 3J = 7.2 Hz,
CH3), 1.40–1.62 (m, 4H, CHCH2CH2CH2), 1.74–1.84 (m, 1H,
NHCH2CH2), 1.97 (dc, 1H, 2J = 12.7 Hz, 3J = 3.2 Hz, CHCH2), 2.06 (s,
1H, NH), 2.67 (ddd, 1H, 2J = 12.2 Hz, 3J = 10.3, 3.2 Hz, NCH2), 3.10
(dtd, 1H, 2J = 12.2 Hz, 3J = 3.7, 1.2 Hz, NCH2), 3.35 (dd, 1H, 3J = 9.7,
3.2 Hz, CH), 4.18 (c, 2H, 3J = 7.2 Hz, OCH2); 13C NMR (75 MHz,
CDCl3) d 14.3 (CH3), 24.0, 25.8, 29.1 (CHCH2CH2CH2), 45.7 (NCH2),
58.6 (CH), 60.6 (OCH2), 173.4 (C@O).
(300 MHz, CDCl3) d 1.14–1.73 (m, 6H, CHCH2CH2CH2), 2.11 (ddd,
1H, 2J = 12.3 Hz, 3J = 10.3, 3.1 Hz, NCH2), 2.42 (dc, 1H, 3J = 8.5,
4.1 Hz, CH), 2.76 (s, 1H, OH), 2.83 (dddd, 1H, 2J = 12.3 Hz, 3J = 5.1,
3.7 Hz, 4J = 1.3 Hz, NCH2), 3.29 (d, 1H, 2J = 13.4 Hz, NCH2Ph), 3.49
(ABX system, 1H, 2J = 10.9 Hz, 3J = 4.1 Hz, CH2OH), 3.83 (ABX sys-
tem, 1H, 2J = 10.9 Hz, 3J = 4.1 Hz, CH2OH), 4.03 (d, 1H, 2J = 13.4 Hz,
NCH2Ph), 7.17–7.34 (m, 5H, ArCH); 13C NMR (75 MHz, CDCl3) d
23.3, 24.0, 27.2 (CHCH2CH2CH2), 50.8 (NCH2), 57.6 (NCH2Ph), 60.9
(CH), 62.2 (CH2OH), 127.0, 128.3, 128.8 (ArCH), 138.9 (ArC). Anal.
Calcd for C13H19NO: C, 76.06; H, 9.33; N, 6.82. Found: C, 76.21;
H, 9.41; N, 6.78. HRMS (ESI): calcd for C13H19NO 205.1467; found
205.1471.
4.11.2. (ꢀ)-Diphenyl-[(2S)-piperidin-2-yl]methanol, (ꢀ)-17
To a cold (0 °C) solution of (ꢀ)-16 (143 mg, 0.783 mmol) in dry
THF (8 mL), under an argon atmosphere, was added a solution of
PhMgBr (2.3 mL, 6.64 mmol). The mixture was stirred for 16 h at
rt, and then was diluted with diethyl ether (100 mL) and carefully
hydrolysed with a saturated aqueous NH4Cl solution (25 mL). The
organic layer was washed with brine (25 mL), dried over anhydrous
MgSO4, filtered and concentred under reduced pressure. The crude
was purified by flash chromatography (silica gel; DCM and MeOH)
to obtain 144 mg (73% yield) of the alcohol (ꢀ)-17. White solid;
4.10. Synthesis of ligand 5e
4.10.1. Synthesis of (ꢀ)-(2S)-1-methylpiperidine-2-carboxylic
acid, (ꢀ)-15
A mixture of L-pipecolinic acid (100 mg, 0.774 mmol), parafor-
maldehyde (47 mg, 1.55 mmol) and 10% Pd on activated charcoal
(tip of spatula) in dry methanol (3.5 mL) was stirred for 24 h under
a hydrogen atmosphere (1.1 atm). The crude was then filtered on a
thin pad of Celite, and the solvent was removed under reduced
pressure. The residue was purified by flash chromatography (silica
gel, methanol) to obtain 111 mg (ca. quantitative yield) of acid (ꢀ)-
mp 74–75 °C; [
a]
D = ꢀ75.7 (c 0.75, CHCl3); IR (ATR) 3297, 3061,
2941, 1588, 1449, 745 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 1.28–
1.41 (m, 2H, CHCH2CH2), 1.42–1.69 (m, 3H, NCH2CH2, CHCH2), 1.80
(dt, 1H, 2J = 12.8 Hz, 3J = 3.8 Hz, CHCH2CH2), 2.78 (dt, 1H,
2J = 11.8 Hz, 3J = 3.0 Hz, NCH2), 3.14 (d, 1H, 2J = 11.8 Hz, NCH2),
3.65 (dd, 1H, 3J = 11.7, 2.5 Hz, CH), 5.34 (s, 2H, NH, OH), 7.11–7.67
(m, 10H, ArCH); 13C NMR (75 MHz, CDCl3) d 24.1, 24.6, 24.9
(CHCH2CH2CH2), 46.6 (NCH2), 62.7 (CH), 78.3 (COH), 125.4, 125.8,
126.5, 127.1, 128.0, 128.7 (ArCH), 144.0, 145.4 (ArC). Anal. Calcd
for C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.91; H, 7.99;
N, 5.20.
15. White solid; mp 213–214 °C (decomp.); [
a]
D = ꢀ62.2 (c 0.8,
MeOH); IR (ATR) 3425, 2942, 1620, 1320, 1179 cmꢀ1
;
1H NMR
(300 MHz, CDCl3) d 1.46–1.61 (m, 1H, CHCH2CH2), 1.65–1.91 (m,
4H, CHCH2CH2CH2), 2.15–2.24 (m, 1H, CHCH2), 2.81 (s, 3H, CH3),
2.91 (td, 1H, 2J = 12.3 Hz, 3J = 3.3 Hz, NCH2), 3.28 (dd, 1H,
3J = 11.4, 3.5 Hz, CH), 3.39 (dt, 1H, 2J = 12.3 Hz, 3J = 4.0 Hz, NCH2);
13C NMR (75 MHz, CDCl3) d 23.1 (CHCH2CH2), 24.5 (NCH2CH2),
29.8 (CHCH2), 43.4 (CH3), 55.5 (NCH2), 70.7 (CH), 174.4 (C@O).
Anal. Calcd for C7H13NO2: C, 58.72; H, 9.15; N, 9.78. Found: C,
58.81; H, 9.24; N, 9.73.
4.11.3. (8aS)-1,1-Diphenylhexahydro[1,3]oxazolo[3,4-
a]pyridine, 18
A mixture of (ꢀ)-17 (112 mg, 0.419 mmol) and paraformalde-
hyde (111 mg, 3.686 mmol) in MeOH (4.4 mL) was stirred for 3 h.
Next, the mixture was cooled to 0 °C and NaBH4 (72 mg,
1.885 mmol) was added. The mixture was stirred for another 16 h
at rt and then was concentrated under reduced pressure. The crude
was dissolved in water (15 mL) and extracted with ethyl acetate
(2ꢁ15 mL). The combinated organic extracts were dried over anhy-
drous MgSO4, filtered and concentred under reduced pressure. The
crude was identified as the intermediate oxazolidine 18 (67 mg,
57% yield) and was directly transformed into the alcohol. Colourless
oil. 1H NMR (300 MHz, CDCl3) d 0.83–0.91 (m, 1H, CHCH2), 1.41–1.51
(m, 2H, NCH2CH2), 1.60–1.69 (m, 1H, CHCH2CH2), 1.75–1.84 (m, 1H,
CHCH2CH2), 1.87–1.96 (m, 1H, CHCH2), 2.13 (ddd, 1H, 2J = 10.6 Hz,
3J = 11.7, 3.1 Hz, NCH2), 2.82 (dd, 1H, 3J = 11.0 Hz, 2.3 Hz, CH), 3.14
(dt, 1H, 2J = 10.6 Hz, 3J = 3.8 Hz, NCH2), 4.02 (d, 1H, 2J = 1.5 Hz,
OCH2N), 4.99 (d, 1H, 2J = 1.5 Hz, OCH2N), 7.19–7.51 (m, 10H, ArCH);
13C NMR (75 MHz, CDCl3) d 23.97, 24.02 (NCH2CH2CH2), 28.1
(CHCH2), 46.7 (NCH2), 70.4 (CH), 85.9 (OCH2N), 88.2 (OC), 126.6,
126.7, 127.1, 127.2, 127.4, 128.0 (ArCH), 143.9, 145.4 (ArC).
4.10.2. Synthesis of (+)-[(2S)-1-methylpiperidin-2-yl]methanol,
(+)-5e
To a suspension of acid (ꢀ)-15 (50 mg, 0.349 mmol) in dioxane
(1 mL) under an argon atmosphere was added dropwise a 1.0 M
solution of BH3ꢁTHF (1.1 mL), and the mixture was stirred for 24 h
and carefully hydrolysed with 6 M HCl (1 mL). The mixture was stir-
red for another 30 min and neutralised with NaOH until neutral–ba-
sic pH. This solution was extracted with a CHCl3/i-PrOH, 80:20
mixture, dried over MgSO4, filtered and concentred under reduced
pressure to obtain (+)-5e (40 mg, 89% yield). Waxy solid;
[a] ;
D = +3.9 (c 0.25, MeOH); IR (ATR) 3322, 1462, 1060 cmꢀ1 1H
NMR (300 MHz, CDCl3) d 1.22–1.43 (m, 1H, NCH2CH2), 1.61–1.85
(m, 4H, CHCH2CH2), 2.24–2.41 (m, 2H, NCH2CH2), 2.47 (s, 3H, CH3),
3.05 (dtd, 1H, 2J = 11.9 Hz, 3J = 3.5 Hz, 4J = 1.2 Hz, NCH2), 3.53 (dd,
1H, 2J = 11.5 Hz, 3J = 3.0 Hz, CH2OH), 3.60–3.77 (m, 1H, CH), 3.80
(dd, 1H, 2J = 11.5 Hz, 3J = 3.7 Hz, CH2OH), 4.18 (s, 1H, OH); 13C NMR
(75 MHz, CDCl3) d 23.4, 24.4, 27.5 (CHCH2CH2CH2), 42.0 (CH3), 56.4
(NCH2), 62.5 (CH), 64.7 (CH2OH). Anal. Calcd for C7H15NO: C,
65.07; H, 11.70; N, 10.84. Found: C, 65.00; H, 11.62; N, 10.81. HRMS
(ESI): calcd for C7H15NO 129.1154; found 129.1156.
4.11.4. Synthesis of (ꢀ)-(2S)-1-methylpiperidin-2-yl)
(diphenyl)methanol, (ꢀ)-5f
To a cold (0 °C) suspension of LiAlH4 (28 mg, 0.783 mmol) in dry
THF (2 mL) under an argon atmosphere was added dropwise a
solution of AlCl3 (32 mg, 0.24 mmol) in dry THF (2.5 mL). The solu-
tion was stirred for 30 min at rt, then cooled to ꢀ78 °C and a solu-
tion of 18 (67 mg, 0.24 mmol) in dry THF (2 mL) was added. The
solution was stirred at ꢀ78 °C for 45 min. The temperature was in-
creased to 0 °C and the mixture was carefully hydrolysed with 1 M
4.11. Synthesis of ligand 5f
4.11.1. Ethyl (ꢀ)-(2S)-piperidine-2-carboxylate, (ꢀ)-16
A solution of L-pipecolinic acid (100 mg, 0.774 mmol) in freshly
distilled SOCl2 (2 mL) was stirred for 16 h at rt. Then, the excess

C. Alvarez-Ibarra et al. / Tetrahedron: Asymmetry 21 (2010) 2334–2345
2345
8. (a) Jimeno, C.; Pastó, M.; Riera, A.; Pericás, M. A. J. Org. Chem. 2003, 68, 3130; (b)
Reddy, K. S.; Solá, L.; Moyano, A.; Pericás, M. A.; Riera, A. Synthesis 2000, 165;
(c) Reddy, K. S.; Solá, L.; Moyano, A.; Pericás, M. A.; Riera, A. J. Org. Chem. 1999,
64, 3969; (d) Puigjaner, C.; Vidal-Ferrán, A.; Moyano, A.; Pericás, M. A.; Riera, A.
J. Org. Chem. 1999, 64, 7902.
9. (a) Alvarez Ibarra, C.; Collados Luján, J. F.; Quiroga Feijóo, M. L.; Rodríguez, G.
Tetrahedron: Asymmetry 1411, 2008, 19; (b) Acherki, H.; Alvarez Ibarra, C.;
Collados Luján, J. F.; Quiroga Feijóo, M. L. Tetrahedron: Asymmetry 2005, 16,
4034; (c) Acherki, H.; Alvarez Ibarra, C.; Guzmán Fernández, S.; Quiroga Feijóo,
M. L. Tetrahedron: Asymmetry 2004, 15, 3419; (d) Acherki, H.; Alvarez Ibarra, C.;
de Dios, A.; Gutiérrez, M.; Quiroga Feijóo, M. L. Tetrahedron: Asymmetry 2001,
12, 3173.
10. Lawrence, C. F.; Nayak, S. K.; Thijs, L.; Zwanenburg, B. Synlett 1999, 1571.
11. (a) Wang, M.-C.; Zhang, Q.-J.; Zhao, W.-X.; Wang, X.-D.; Ding, X.; Jing, T.-T.;
Song, M.-P. J. Org. Chem. 2008, 73, 168; (b Shi, M.; Jiang, J.-K. Tetrahedron:
Asymmetry 1673, 1999, 10; (c) Behnen, W.; Mehler, T.; Martens, J. Tetrahedron:
Asymmetry 1413, 1993, 4.
12. (a) Zhao, G.; Li, X.-G.; Wang, X.-R. Tetrahedron: Asymmetry 2001, 12, 399; (b)
Yang, X.; Shera, J.; Da, C.; Wang, R.; Choi, M. C. K.; Yang, L.; Wong, K.
Tetrahedron: Asymmetry 1999, 10, 133; (c) Watanabe, M.; Soai, K. J. Chem. Soc.,
Perkin 1 1994, 3125.
HCl until hydrogen evolution ceased. The resulting suspension was
extracted with CHCl3/i-PrOH, 80:20 (3 ꢂ 10 mL) and the combinat-
ed organic extracts were washed with 1 M NaOH (10 mL) and then
with brine (10 mL), dried over anhydrous MgSO4, filtered and con-
centred under reduced pressure to obtain 65 mg of pure product
(ꢀ)-5f (97% yield). Colourless oil; [
a]
D = ꢀ75.8 (c 1.0, CHCl3); IR
(ATR) 3349, 1449, 1030, 706 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d
1.21–1.35 (m, 2H, piperidine), 1.50–1.71 (m, 4H, piperidine), 2.02
(s, 3H, CH3), 2.47 (td, 1H, 2J = 3J = 11.5 Hz, 3J = 4.0 Hz, NCH2), 2.96
(ddd, 1H, 2J = 11.5 Hz, 3J = 5.3, 3.5 Hz, NCH2), 3.36 (dd, 1H, 3J = 9.7,
4.3 Hz, CH), 7.06–7.76 (m, 10H, ArCH); 13C NMR (75 MHz, CDCl3)
d 23.9 (CHCH2CH2), 24.7 (NCH2CH2), 27.9 (CHCH2), 46.4 (CH3),
57.6 (NCH2), 67.7 (CH), 77.4 (CO), 124.9, 125.7, 125.8, 126.2,
127.9, 128.1 (ArCH), 146.6, 149.8 (ArC). Anal. Calcd for C19H23NO:
C, 81.10; H, 8.24; N, 4.98. Found: C, 81.21; H, 8.34; N, 4.79. HRMS
(ESI): calcd for C19H23NO 281.1780; found 281.1787.
13. (a) Paleo, M. R.; Cabeza, I.; Sardina, F. J. J. Org. Chem. 2000, 65, 2108; (b)
Kitamura, S.; Oka, H.; Noyori, R. Tetrahedron 1999, 55, 3605.
14. Braun, M. Angew. Chem., Int. Ed. 1996, 35, 486.
Acknowledgements
15. This term is used to indicate that the absolute configuration of the major
enantiomer correlates with the configuration of the hydroxyl-bearing
stereocenter of the ligand.
16. For a discussion on the like/unlike stereochemical descriptors, see: (a) Seebach,
D.; Prelog, V. Angew. Chem., Int. Ed. Engl. 1982, 21, 654; See also: (b) Juaristi, E.
Introduction to Stereochemistry and Conformational Analysis; John Wiley & Sons:
New York, 1991.
We gratefully acknowledge the Spanish DGES (MEC) (project
CTQ2007-67103-C02-01) and Proyecto Santander-UCM (Project
PR34/07-15782) for the support of this research. We also thank
UCM for its facilities for NMR spectra, Servicio de Espectrometría
de Masas del Centro de Espectroscopía, Elemental Analysis Service
and Centro de Cálculo for the theoretical calculations on GAUSSIAN 03.
17. (a) Burguete, M. I.; Escorihuela, J.; Luis, S. V.; Lledós, A.; Ujaque, G. Tetrahedron
2008, 64, 971; (b) Szakonyi, Z.; Bálazs, A.; Martinek, T. A.; Fülop, F. Tetrahedron:
Asymmetry 2006, 17, 199; (c) Rudolph, J.; Bolm, C.; Norrby, P.-O. J. Am. Chem.
Soc. 2005, 127, 1548; (d) Zozlowski, M. C.; Dixon, S. L.; Panda, M.; Lauri, G. J. Am.
Chem. Soc. 2003, 125, 6614; (e) Panda, M.; Phuan, P.-W.; Kozlowski, M. C. J. Org.
Chem. 2003, 68, 564; (f) Rasmussen, T.; Norrby, P.-O. J. Am. Chem. Soc. 2001,
123, 2464; (g) Vázquez, J.; Pericás, M. A.; Maseras, F.; Lledós, A. J. Org. Chem.
2000, 65, 7303; (h) Goldfuss, B.; Steigelmann, M. J. Mol. Model. 2000, 6, 166; (i)
Brandt, P.; Hedberg, C.; Laworn, K.; Pinho, P.; Andersson, P. G. Chem. Eur. J.
1999, 5, 1692; (k) Yamakawa, M.; Noyori, R. Organometallics 1999, 18, 128; (j)
Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 6327.
18. For a classification of stereochemical transformations, see: (a) Faber, K. Chem.
Eur. J. 2001, 7, 5005; (b) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry
of Organic Compounds; Wiley & Sons: New York, 1994. Chapter 7.
19. GAUSSIAN 03, Revision C.02: Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria,
G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.;
Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda,
Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian, Inc., Wallingford CT, 2004.
References
1. (a) Pu, L.; Yu, H. B. Chem. Rev. 2001, 101, 757; (b) Soai, K.; Shibata, T. In
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pflatz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; p 911; (c) Seyden-Penne, J. Chiral Auxiliaries and
Ligands in Asymmetric Synthesis; John Wiley & Sons: New York, 1995; (d)
Fitzpatrick, K.; Hultst, R.; Kellogg, R. Tetrahedron: Asymmetry 1861, 1995, 6; (e)
Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New
York, 1994. Chapter 5; (f) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833; (g) Noyori,
R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49.
2. From ephedrine: (a) Chaloner, P. A.; Langadianou, E. Tetrahedron Lett. 1990, 31,
5185; (b) Chaloner, P. A.; Perera, S. A. R. Tetrahedron Lett. 1987, 28, 3013; (c)
Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1987, 28, 5233; (d) Corey, E. J.;
Hannon, F. J. Tetrahedron Lett. 1987, 28, 5237; (e) Soai, K.; Nishi, M.; Ito, Y. Chem.
Lett. 1987, 2405; (f) Itsuno, S.; Fréchet, J. M. J. J. Org. Chem. 1987, 52, 4140.
3. From norephedrine: (a) Soai, K.; Yokoyama, S.; Hayasaka, T. J. Org. Chem. 1991,
56, 4264; (b) Soai, K.; Yokoyama, S.; Ebihara, K.; Hayalaka, T. J. Chem. Soc., Chem.
Commun. 1987, 1690.
4. From camphor and fenchone: (a) García Martínez, A.; Teso Vilar, E.; García
Fraile, A.; de la Moya Cerero, S.; Martínez Ruiz, P.; Chicharro; Villas, P.
Tetrahedron: Asymmetry 2002, 13, 1; (b) García Martínez, A.; Teso Vilar, E.;
García Fraile, A.; de la Moya Cerero, S.; Martínez Ruiz, P. Tetrahedron:
Asymmetry 2002, 13, 1457; (c) Goldfuss, B.; Teigelmann, M.; Rominger, F. Eur.
J. Org. Chem. 2000, 1785; (d) Goldfuss, B.; Steigelmann, M.; Khan, S. I.; Houk, K.
N. J. Org. Chem. 2000, 65, 77; (e) Suzuki, Y.; Ogata, Y.; Hiroi, K. Tetrahedron:
Asymmetry 1999, 10, 1219; (f) Goldfuss, B.; Houk, K. N. J. Org. Chem. 1998, 63,
8998; (g) Genov, M.; Kostova, K.; Dimitrov, V. Tetrahedron: Asymmetry 1997, 8,
1869; (h) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989,
111, 4028; (i) Kitamura, M.; Suga, S.; Kaway, K.; Noyori, R. J. Am. Chem. Soc.
1986, 108, 6071.
5. From proline: (a) Agami, M.; Inonoue, S. Chem. Lett. 1991, 685; (b) Soai, K.;
Ookawa, A.; Ogawa, K.; Kaba, T. J. Chem. Soc., Chem. Commun. 1987, 467; (c)
Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K. J. Am. Chem. Soc. 1987, 109, 7111.
6. From pinane: Cherng, Y.-J.; Fang, J. M.; Lu, T.-J. J. Org. Chem. 1999, 64, 3207.
7. From cinchona alkaloids: Smaardijk, A. A.; Wynberg, H. J. Org. Chem. 1987, 52,
135.
20. For PM3 parameters, see: (a) Stewart, J. J. P. J. Comput. Chem. 1991, 12, 320; (b)
Stewart, J. J. P. J. Comput. Chem. 1989, 10, 221; (c) Stewart, J. J. P. J. Comput.
Chem. 1989, 10, 209.
21. (a) Lee, C.; Yang, W.; Parr, G. Phys. Rev. B 1998, 37, 785; (b) Becke, A. D. J. Chem.
Phys. 1993, 98, 1372; (c) Becke, A. D. J. Chem. Phys. 1993, 98, 5648; (d) Parr, R.
G.; Yang, W. Density Functional Theory of Atoms and Molecules; Oxford
University Press: New York, 1994.
22. Höllwarth, A.; Bohme, M.; Dapprich, S.; Ehlers, A.; Gobbi, A.; Jonas, V.; Kohler,
K.; Stegmann, R.; Veldkamp, A.; Frenhing, G. Chem. Phys. Lett. 1993, 208, 237.
23. (a) Hay, P. I.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270; (b) Wadt, W. R.; Hay, P. J.
J. Chem. Phys. 1985, 82, 284.
24. Mozingo, R. Org. Synth. 1955, Coll. Vol. 3, 181.