Dynamic kinetic resolution and desymmetrization processes: A straightforward methodology for the enantioselective synthesis of piperidines

Article abstract of DOI:10.1002/chem.200600420

A straightforward procedure for the synthesis of enantiopure polysubstituted piperidines is reported. It involves the direct generation of chiral non-racemic oxazolo[3,2-a]piperidone lactams that already incorporate carbon substituents on the heterocyclic ring and the subsequent removal of the chiral auxiliary. The key step is a cyclocondensation reaction of (R)-phenylglycinol or other amino alcohols with racemic or prochiral δ-oxo (di)acid derivatives in highly stereoselective processes involving dynamic kinetic resolution and/or desymmetrization of diastereotopic or enantiotopic ester groups.

Full text of DOI:10.1002/chem.200600420

DOI: 10.1002/chem.200600420
Dynamic Kinetic Resolution and Desymmetrization Processes: A
Straightforward Methodology for the Enantioselective Synthesis of
Piperidines
Mercedes Amat,*[a] Oriol Bassas,[a] Nfflria Llor,[a] Margalida Cantó,[a] Maria PØrez,[a]
Elies Molins,[b] and Joan Bosch*[a]
Abstract: A straightforward procedure for the synthesis of enantiopure polysubsti-
tuted piperidines is reported. It involves the direct generation of chiral non-race-
mic oxazolo
A
Keywords: asymmetric synthesis ·
chiral auxiliaries · cyclocondensa-
tion · dynamic kinetic resolution ·
enantioselectivity · piperidines
on the heterocyclic ring and the subsequent removal of the chiral auxiliary. The
key step is a cyclocondensation reaction of (R)-phenylglycinol or other amino al-
cohols with racemic or prochiral d-oxo (di)acid derivatives in highly stereoselective
processes involving dynamic kinetic resolution and/or desymmetrization of diaster-
eotopic or enantiotopic ester groups.
Introduction
matically changes when the racemic substrate or the two di-
astereomers resulting from the initial reaction with a chiral
reagent have a chirally labile stereogenic center capable of
undergoing in situ racemization[2] or epimerization during
the reaction to form a chirally stable enantiopure product in
up to 100% chemical yield (dynamic kinetic resolution).[3]
Although these processes represent a viable and useful tool
for preparing enantiopure chiral compounds, they have
rarely been used in synthetic sequences as a result of the
structural restrictions imposed by the substrate. When the
reaction involves the generation of additional stereogenic
centers, this methodology can convert a racemic compound
into one of several possible enantiopure stereoisomers.
On the other hand, although enzyme-mediated desymmet-
rizations of prochiral or meso substrates, generally diesters,
also constitute classical approaches to the synthesis of enan-
tiopure compounds and have become powerful synthetic
tools,[4] the chemical, nonenzymatic differentiation of two
enantiotopic functional groups is still little developed in
spite of the impressive advances in this field in recent years.
Since the piperidine ring is the central structure of many
biologically active alkaloid natural products[5] and therapeu-
tic agents, much effort has been devoted to the development
of general methods and strategies for the enantioselective
synthesis of piperidine derivatives.[6] In this context, cyclo-
condensation reactions of d-oxo acid derivatives with chiral
non-racemic amino alcohols have received considerable at-
tention[7] since the resulting oxazolopiperidone lactams have
The development of new and efficient methodologies for
the generation or two or more stereogenic centers with high
diastereo- and enantioselectivity in a single synthetic step is
one of the most challenging subjects in organic synthesis,
particularly in the field of bioactive natural or synthetic
products. The preparation of a single enantiomer from a
racemate may be achieved by conventional resolution or by
exploiting differences in reactivity (kinetic resolution). Al-
though enzyme-catalyzed kinetic resolution of racemates
has become a classical approach for the synthesis of enantio-
pure compounds,[1] it suffers, like conventional resolution
processes, from the drawback that the maximum yield of
one enantiomer is always limited to 50%. This situation dra-
[a] Prof. M. Amat, Dr. O. Bassas, Dr. N. Llor, Dr. M. Cantó,
Dr. M. PØrez, Prof. J. Bosch
Laboratory of Organic Chemistry, Faculty of Pharmacy
University of Barcelona, Av. Joan XXIII s/n, 08028 Barcelona (Spain)
Fax : (+34)934-024-539
E-mail: amat@ub.edu
joanbosch@ub.edu
[b] Dr. E. Molins
Institut de Ci›ncia de Materials de Barcelona (CSIC)
Campus Universitari de Bellaterra, 08193 Cerdanyola (Spain)
Supporting information for this article (experimental details and char-
acterization data for all compounds) is available on the WWW under
http://www.chemeurj.org/ or from the author.
7872
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7872 – 7881
Pagination corrected Oct. 17, 2006

FULL PAPER
proven to be versatile building blocks for the enantioselec-
tive synthesis of piperidine-containing derivatives.[8] In par-
ticular, in previous work we have demonstrated that the
simple phenylglycinol-derived bicyclic lactams trans-2, cis-2,
and their enantiomers allow the stereocontrolled formation
ductive removal of the chiral auxiliary (Scheme 2). The key
step is the cyclocondensation reaction of (R)-phenylglycinol
or other amino alcohols with racemic or prochiral d-oxo
(di)acid derivatives in processes involving dynamic kinetic
resolution (DKR) and/or the desymmetrization of enantio-
topic or diastereotopic ester groups.
À
of C C bonds at different positions of the nitrogen hetero-
cycle.[7d,f–h,j] Our approach involves three phases: 1) a cyclo-
condensation reaction of (R)- or (S)-phenylglycinol with
methyl 5-oxopentanoate (1a) to generate the required bicy-
clic lactam, 2) successive stereoselective introduction of ring
substituents taking advantage of the functionalization and
conformational rigidity of the bicyclic lactam system, and 3)
reductive removal of the chiral auxiliary (Scheme 1). Al-
Scheme 2. Synthetic strategy: Second generation oxazolopiperidone lac-
tams.
Results and Discussion
Phenylglycinol-derived lactams: The efficiency of the ap-
proach depicted in Scheme 2 for the generation of 2-substi-
tuted piperidines from lactams bearing a substituent at the
angular 8a-position relies on the stereocontrol in the reduc-
tive opening of the oxazolidine ring.[9] To study the stereose-
lectivity of this process using an 8a-aryl-substituted lactam
we prepared lactam 3b, which was readily obtained in 90%
yield as a single stereoisomer by cyclocondensation of (R)-
phenylglycinol with 5-phenyl-5-oxopentanoic acid (1b,
Scheme 3).
Scheme 1. Synthetic strategy: First generation oxazolopiperidone lactams.
though this approach gives excellent results from the stereo-
selective and diversity points of view, leading to enantiopure
piperidines with a variety of substitution patterns, it has the
inconvenience that the substituents have to be introduced
step by step.
Interestingly, treatment of lactam 3b with sodium bis(2-
methoxyethoxy)aluminium hydride (Red-Al) gave 2-phenyl-
piperidine 4b (54%) as the only stereoisomer detectable by
spectroscopic methods. In contrast, reduction of 3b with 9-
Herein we report a more straightforward procedure for
the synthesis of enantiopure polysubstituted piperidines. It
involves the direct generation of chiral non-racemic oxazo-
lopiperidone lactams A that already incorporate the carbon
substituents on the heterocyclic ring and the subsequent re-
borabicyclo[3.3.1]nonane (9-BBN) stereoselectively provid-
A
ed 2-phenylpiperidine 5b (75%) by inversion of the configu-
ration at C-8a (5b:4b ratio 97:3). However, reduction of 3b
with AlH3 or BH3 showed poor stereoselectivity, affording
Abstract in Spanish: Se describe un procedimiento directo
para la síntesis enantioselectiva de piperidinas polisustituidas.
Consiste en la generación directa de oxazolo[3,2-a]piperi-
G
donas quirales no racØmicas que ya incorporan sustituyentes
carbonados en las diferentes posiciones del heterociclo, y en
la posterior eliminación del auxiliar quiral. La etapa clave es
una reacción de ciclocondensación entre el (R)-fenilglicinol,
u otros amino alcoholes quirales, con derivados de d-oxo
µcidos racØmicos o proquirales, en procesos altamente este-
reoselectivos que implican una resolución cinØtica dinµmica
y/o la desimetrización de grupos diastereotópicos o enantio-
tópicos.
Scheme 3. Enantiodivergent synthesis of 2-arylpiperidines. Enantioselec-
tive synthesis of (À)-anabasine.
Chem. Eur. J. 2006, 12, 7872 – 7881
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7873

M. Amat, J. Bosch et al.
mixtures of 4b and 5b in which the former was the major
stereoisomer (~7:3 ratio). Removal of the chiral inductor of
4b and 5b by hydrogenolysis using Pd/C as the catalyst gave
(S)-2-phenylpiperidine (6b) and (R)-2-phenylpiperidine
(ent-6b), respectively. The above three-step sequence offers
a short enantiodivergent route to 2-arylpiperidines from
readily available achiral d-oxo acids.
The remarkable difference in the stereoselectivity of the
above reductions can be explained in terms of the reactive
intermediates B and C (R1 =C6H5, R2 =H), as depicted in
Scheme 4. Thus, the stereoselectivity in the Red-Al reduc-
from the partial reduction of the heteroaromatic ring, more
satisfactorily, reduction with 9-BBN in refluxing THF pro-
vided (73%) a 37:63 mixture of isomers 4c and 5c, respec-
tively. The lower stereoselectivity of this reduction as com-
pared with the 9-BBN reduction of the related phenyl-sub-
stituted lactam 3b probably reflects the lower ability of pyri-
dine, a p-deficient heterocycle, to stabilize the intermediate
iminium ion C in comparison with a phenyl group. In this
series, the best result regarding stereoselectivity was ob-
tained when 3c was treated with an excess of LiAlH4. The
desired piperidine 4c was obtained in 78% yield along with
only minor amounts (6%) of its epimer 5c. Hydrogenolysis
of the pure isomer 4c over Pearlmanꢁs catalyst afforded
(À)-anabasine (6c).
We then examined the stereochemical outcome of the cy-
clocondensation reactions of (R)-phenylglycinol with race-
mic g-alkyl-d-oxo acid derivatives, both aldehydes and ke-
tones, which incorporate a chirally labile stereogenic center
capable of undergoing in situ racemization or epimerization
during reaction.[12] Cyclocondensation reactions of aldehyde
esters 1d–f, bearing an alkyl substituent at the a-position of
the aldehyde carbonyl group, took place in good chemical
yield and stereoselectivity, leading to the enantiopure oxazo-
lopiperidone 3-H/8a-H cis lactams 7d–f, respectively, as the
major products[13] (Table 1), thus indicating that a dynamic
kinetic resolution had occurred.[14] Minor amounts of the
corresponding diastereoisomeric 3-H/8a-H trans lactams 8
were also formed (approximate 7/8 ratio, 4–5:1). Similar
stereoselective cyclodehydration reactions occurred with a-
alkyl-substituted ketones 1g–i, including both dialkyl (non-
cyclic and cyclic) and alkyl aryl ketones, although in all
these cases the corresponding 3-H/8a-R1 trans lactams 8g–i
were the major products (approximate 7/8 ratio, 1:4).[15]
These results can be accounted for by considering that the
two diastereoisomeric imines initially formed in the reaction
of (R)-phenylglycinol with racemic oxo esters 1d–i are in
equilibrium via an enamine and, consequently, that a mix-
ture of four equilibrating oxazolidines is formed.[16,17] Subse-
quent irreversible lactamization occurs faster for the diaster-
eoisomer that allows a less hindered approach of the ester
group to the nitrogen atom via a transition state in which
the alkyl substituent in the incipient chair-like six-membered
lactam is equatorial (Scheme 5; A=C6H5, B=R3 =H, R1 =
H, alkyl, or aryl, R2 =alkyl).
Scheme 4. Stereoselective reduction of 8a-substituted lactams.
tion of 3b, leading to 2-substituted piperidine 4b with reten-
tion of configuration, also observed in the reduction of relat-
ed 8a-alkyl-substituted lactams,[8g,10] can be rationalized by
considering that, after the reduction of the carbonyl lactam,
the reductive cleavage of the oxazolidine ring takes place
through complexation of the oxygen atom with the reduc-
tant, followed by delivery of the hydride from the same face
À
of the C O bond (B). The opposite stereochemical result
observed in the reduction with 9-BBN suggests that, in this
case, the reaction takes place via the ion-paired intermedi-
ate C. The intramolecular delivery of the hydride under ster-
eoelectronic control from the preferred conformation C’ ac-
counts for the stereoselective formation of isomer 5b.
Owing to steric interactions, the 9-BBN reduction of inter-
mediate B is slower than the formation of the iminium salt
C. Moreover, the presence of the 8a-phenyl group (R1 =
C6H5) contributes to the stabilization of this intermediate C,
In contrast, cyclocondensation of d-oxo acid derivatives
(1j–l) bearing a protected hydroxy group at the a-position
of the aldehyde or ketone carbonyl group took place with
low stereoselectivity, thus indicating that the presence of an
oxygenated substituent on the epimerizable stereocenter in-
hibits DKR.[18]
À
making the C O bond more prone to cleavage than in relat-
ed 8a-alkyl-substituted lactams.
To further illustrate the potential of the cyclodehydration/
stereocontrolled reduction sequence developed here, we
synthesized the tobacco alkaloid (À)-anabasine.[11] The re-
quired bicyclic lactam 3c was obtained as a single stereo-
isomer by cyclocondensation of keto acid 1c with (R)-phe-
nylglycinol in refluxing toluene. Although treatment of 3c
with Red-Al or BH3 afforded complex mixtures resulting
To study enantioselective desymmetrizations of prochiral
d-oxo diesters with (R)-phenylglycinol, we selected the glu-
taric and pimelic acid derivatives 1m,n and 1r, respectively.
Interestingly, cyclocondensation of aldehyde diester 1m and
keto diester 1n with (R)-phenylglycinol stereoselectively af-
forded the lactams 9m (3-H/8a-H cis) and 10n (3-H/8a-R1
trans), respectively, as the major products, together with
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Chem. Eur. J. 2006, 12, 7872 – 7881

Enantioselective Synthesis of Piperidines
FULL PAPER
Table 1. Cyclocondensation reactions of racemic g-substituted d-oxo acid derivatives.
the prochiral carbon atom in
1s (R2 =Et) suppresses the dis-
crimination between the two
propionate chains and lactams
9s and 10s (9:1 ratio) were
formed along with equimolecu-
lar amounts of the correspond-
ing C-8 epimers 9s’ and 10s’.[19]
In this case, either the ethyl
substituent or one of the propi-
onate chains is axially orient-
ed.
As could be expected from
the above results, treatment of
racemic d-oxo diesters 1o–q
with (R)-phenylglycinol under
the usual conditions predomi-
nantly afforded one of the
eight possible stereoisomeric
lactams, 9o (3-H/8a-H cis in
the aldehyde series), 10p, and
10q (3-H/8a-R1 trans in the
ketone series), respectively.
Three stereogenic centers with
R
R1
H
R2
Et
Yield [%]
79
7/8 ratio
d
e
Me
4:1
Me
H
71
6:1
f
Me
H
H
H
C6H5
Me
-(CH2)4-
H
H
CH2CH=CH2
Et
Et
70
OTBDMS
OAc
OMEM
71
50
60
7:1
1[a]:4
1:4
g
h
i
j
k
l
H
1:5[b]
50
[c]
[d]
[e]
Me
Me
H
45
74
CH2OBn
[a] The minor stereoisomer was the C-8a epimer of 7g. [b] The relative stereochemistry of 8i was confirmed
by X-ray crystallography. [c] Lactam 7j, its C-8 epimer (3:2 ratio), and minor amounts of 8j (undetermined
stereochemistry at C-8). [d] Lactams 7k, 8a-epi-7k, and 8a-epi-8k in a 5:2:2 ratio. [e] Lactam 8l, its C-8
epimer (3:2 ratio), and minor amounts of 7l. TBDMS=tert-butylmethylsilyl, MEM=methoxyethoxymethoxy.
a well-defined absolute configuration have been generated
in a single synthetic step. These reactions involve DKR with
epimerization of the configurationally labile stereocenter in
the substrate and differentiation of the two diastereotopic
acetate chains via a transition state in which the substituents
R2 and R3 of the incipient chair-like six-membered lactam
are equatorial (Scheme 5).
Table 2. Cyclocondensation reactions of (R)-phenylglycinol with pro-
A
Scheme 5. Lactamization step during the cyclocondensation of d-oxo acid
derivatives with 1,2-amino alcohols.
minor amounts (approximate 4:1 ratio) of a second diaster-
eoisomer, 10m and 9n, respectively (Table 2). Similarly, cy-
clocondensation of the prochiral aldehyde diester 1r gave
lactam 9r (3-H/8a-H cis) with very high stereoselectivity
(ratio 9r/10r, 9:1). Note again that cyclocondensation reac-
tions involving aldehydes lead to lactams with a cis 3-H/8a-
H relationship whereas in the case of ketones the preferen-
tial formation of 3-H/8a-R1 trans isomeric lactams is ob-
served.
The above results can be rationalized by taking into ac-
count that, after the formation of the corresponding oxazoli-
dines, lactamization occurs faster through a chair-like transi-
tion state in which the diastereotopic acetate (R3 in
Scheme 5) or propionate chain (R2 in Scheme 5) that does
not undergo cyclization is equatorial. In accordance with
this interpretation, the presence of an ethyl substituent at
R’
R1
R2
Yield [%]
9/10 ratio
m
n
o
p
q
r
Me
Et
Et
Et
Me
–
H
Me
H
Me
Me
–
H
H
Et
nPr
Et
H
95
77[a]
77
4:1
1:4[b]
4:1
1:9
1:5
55[c]
81[c]
67
9:1
s
–
–
Et
50
9:1[d]
[a] Using p-TsOH as catalyst. [b] The relative stereochemistry of 10n was
confirmed by X-ray crystallography. [c] Using glacial AcOH as catalyst.
[d] Isomers 9s and 10s were isolated along with their respective C-8 epi-
mers (9s’ and 10s’; 1:1 mixtures).
Chem. Eur. J. 2006, 12, 7872 – 7881
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M. Amat, J. Bosch et al.
The substituted chiral lactams 7–10 are immediate precur-
sors of a variety of diversely substituted enantiopure piperi-
dine derivatives, including piperidine-4-acetates. Starting
from the 8a-phenyl-substituted bicyclic lactam 8g, the best
stereoselectivities in the reductive opening of the oxazoli-
dine ring were obtained, as in the reduction of the deethyl
analog 3b, with Red-Al (retention of the configuration at C-
8a) and 9-BBN (inversion) to give piperidines cis-11a
(56%) and trans-11a (86%), respectively, as single stereo-
isomers detectable by spectroscopic methods (Scheme 6).
stereoisomer (60 and 84% yields, respectively), thus provid-
ing an efficient entry to enantiopure cis-2,3-dialkylpiperi-
dines. Hydrogenolysis of 12a over Pearlmanꢁs catalyst in the
presence of (Boc)2O afforded cis-2-methyl-3-ethylpiperidine
12c (82%). Similarly, tricyclic lactam 8i was stereoselective-
ly reduced (70%) with AlH3 and then debenzylated in good
yield to the enantiopure cis-perhydroquinoline 13b, either
directly or via the N-Boc derivative 13c.
The reductive opening of the oxazolidine ring in the lac-
tams bearing an ester function was chemoselectively accom-
plished with borane. Thus, lactams 9o and 9r were efficient-
ly converted into trans-3-ethylpiperidine-4-acetate 14b
(70%) and piperidine-3-propionate 16b (91%), respectively,
by treatment with BH3·THF, followed by debenzylation of
the resulting piperidines 14a and 16a. Alternatively, hydro-
À
genolysis of the C N bond of 9o with calcium in liquid
NH3, followed by treatment of the resulting oxylactams with
Et3SiH in TFA, afforded the 6-oxo derivative 15b (48%),
the enantiomer of a crucial intermediate in the synthesis of
benzo[a]- and indolo
[2,3-a]quinolizidine alkaloids.[20] Reduc-
G
tions using borane were also highly stereoselective (reten-
tion of configuration) for 8a-methyl-substituted lactams 10n
and 10q, leading to the respective piperidineacetate deriva-
tives 17a (55%; the C-2 epimer was isolated in 19% yield)
and 18a (66%), which were debenzylated to give 17b (or
17c) and 18b in excellent yields. A similar two-step se-
quence starting from the minor lactam 9n led to ent-17b
and ent-17c.
The above results make evident that substituted phenyl-
glycinol-derived lactams 7–10, readily accessible by cyclo-
condensation reaction of (R)-phenylglycinol with racemic or
prochiral d-oxo acid derivatives, are useful chiral synthons
that allow the straightforward preparation of a variety of di-
versely substituted enantiopure piperidines.
Scheme 6. Synthesis of a diverse range of substituted enantiopure piperi-
dines.
Other amino alcohol derived lactams: With the aim of im-
proving the diastereoselectivity of the above phenylglycinol-
induced cyclocondensation reactions, we undertook a study
of the behavior of other amino alcohols in similar cyclocon-
densation reactions involving DKR and/or differentiation of
enantiotopic or diastereotopic ester groups. For this purpose
we selected several 1,3- and 1,2-amino alcohols[21] (19–23)
and a variety of d-oxo acid derivatives, including un-
branched aldehydes (1a) and ketones (1t), simple racemic
aldehydes (1d) and ketones (1h and 1u), prochiral aldehy-
do- (1m and 1r) and keto diesters (1n) bearing enantiotopic
ester groups, and racemic aldehydo- (1v) and keto diesters
(1q) bearing diastereotopic ester groups. The results are
summarized in Table 3.[22]
We initially explored the use of 1,3-amino alcohols 19 and
20.[23] Although amino alcohol rac-19, the higher homolog of
phenylglycinol, underwent cyclodehydration with aldehyde
esters 1a and 1d to give the corresponding bicyclic lactams
rac-24a,b and rac-25a,b, no reaction was observed with ke-
tones 1t and 1u. Taking into account, furthermore, that the
stereoselectivity of the above reactions with aldehydes was
low, no additional studies were performed with 19.
Reduction of 8g with AlH3 and BH3 showed the same level
of stereoselectivity as we had observed in the reduction of
3b, thus revealing that the C-8 substituent has no influence
on the stereoselectivity of the reduction (see Scheme 4; R1 =
C6H5, R2 =Et). Removal of the benzylic N-substituent of the
epimeric piperidines 11a by hydrogenolysis over palladium
afforded piperidines cis-11b (70%) and trans-11b (60%). In
this way, starting from readily available racemic g-substitut-
ed d-oxo acids, the above three-step sequence provides a
stereodivergent entry to enantiopure cis- and trans-3-alkyl-
2-arylpiperidines.
The phenyl substituent at the angular 8a-position has a
dramatic influence on the stereoselectivity of the above re-
ductions with 9-BBN because 9-BBN reduction of lactam
8h, bearing an 8a-methyl substituent, led to a 9:1 mixture
(55%) of cis-piperidine 12a (retention of the configuration
at C-8a) and its C-2 epimer. As expected, reduction of 8h
with Red-Al or AlH3 afforded cis-piperidine 12a as a single
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Chem. Eur. J. 2006, 12, 7872 – 7881

Enantioselective Synthesis of Piperidines
FULL PAPER
Table 3. Cyclocondensation reactions of amino alcohols with racemic or prochiral d-oxo acid derivatives.
Starting materials
Products
R1
R2
R3
Yield [%]
a/b ratio
1a+rac-19
1d+rac-19
rac-24
rac-25
–
–
H
Et
–
–
68[a]
70[a]
7:3
4[b]:3
[d]
1a+rac-20
1d+rac-20
1t+rac-20
1h+rac-20
1u+rac-20[e]
1n+rac-20[e]
rac-26[c]
rac-27
rac-28[c]
rac-29
rac-30
rac-31
H
H
CH3
CH3
CH3
CH3
H
Et
H
Et
C6H5
H
H
H
H
H
90
80
80
45
42
38
–
1:1[d]
[d]
–
9:1[d]
9:1[d]
3:2[d]
H
CH2CO2Et
1a+21
1d+21
1m+21
1t+21
1h+21
1u+21
1n+21[h]
1q+21
32
33
34
35
36
37[c]
38
39
H
H
H
CH3
CH3
CH3
CH3
CH3
H
Et
H
H
H
70
87
78
99
74
86
64
68
4:1
7:5:3[f]
4:1
CH2CO2Me
H
H
H
CH2CO2Et
CH2CO2Me
H
1:10
Et
C6H5
H
1:8[g]
1:13[g]
5:9
Et
2:3
1d+22
1m+22
1r+22
1v+22
1h+22
1q+22[h]
40
41
42
43
44
45
H
H
H
H
CH3
CH3
Et
H
H
78
86
80
1:9
1:14
1:20
1:15[i]
3:2
CH2CO2Me
H
CH2CO2Me
H
A
Et
Et
Et
77
81
CH2CO2Me
58[j]
5:2[k]
1v+23
46
–
–
–
70
2:1[l]
[a] The initially formed cis-oxazine, which did not undergo lactamization, was isolated in ~10% yield. [b] A 1:1 mixture of C-9 epimers. [c] The relative
stereochemistry of rac-26, rac-28, and 37b was confirmed by X-ray crystallography. [d] Trace amounts of the epimer at the piperidine a-position were
also detected. [e] In the presence of a catalytic amount of p-TsOH. [f] The a/b/c ratio (c is the epimer of b at the piperidine a-position). [g] Trace
amounts of the epimer at the piperidine b-position were also detected. [h] In the presence of a catalytic amount of glacial AcOH. [i] Minor amounts of
the epimer at the piperidine g-position were also isolated. [j] Based on consumed 1q. [k] Minor amounts of a third diastereomer were formed. [l] Other
stereoisomers (about 15%) were also formed.
In contrast, aminophenol rac-20 reacted with both alde-
hydes (1a and 1d) and ketones (1h, 1n, 1t, 1u). Although
no stereoselectivity was observed with racemic aldehyde 1d
or prochiral ketone 1n, reaction with racemic ketones 1h
and 1u gave the respective tricyclic lactams rac-29 and rac-
30 with good stereoselectivity (a/b diastereomeric ratios 9:1)
but only moderate chemical yields.[24] The isolation of con-
siderable amounts of 2-vinylphenol accounts for the low
yield of the above reactions.
More successful results were obtained when using cis-1-
amino-2-indanol (21),[25] a conformationally rigid analog of
phenylglycinol.[24] Thus, although no DKR was observed
with racemic aldehyde 1d, enantioselective desymmetriza-
tion of two enantiotopic ester groups occurred in the cyclo-
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M. Amat, J. Bosch et al.
condensation of 21 with aldehyde 1m, which took place in
good chemical yield with a stereoselectivity similar to that
previously observed when using phenylglycinol. Lactam 34a
was isolated in about 60% yield as the major product (a/b
diastereomeric ratio 4:1). Similarly, cyclocondensation of 21
with racemic ketones (1h and 1u) took place with excellent
chemical yields and even better stereoselectivity than when
using phenylglycinol. Enantiopure tetracyclic lactams 36b
and 37b were isolated in 61 and 77% yields, respectively,
after column chromatography, thus making evident that dy-
namic kinetic resolution with epimerization of the stereo-
center a to the ketone carbonyl had occurred to a consider-
able extent. However, only moderate stereoselectivities
were observed in cyclocondensation reactions involving de-
symmetrization of the acetate chains of keto diesters 1n and
1q. The higher stereoselectivities observed with racemic ke-
tones 1h and 1u as compared with racemic aldehyde 1d in
the above cyclocondensation reactions with amino alcohols
rac-20 and 21 could be explained by considering that lactam-
ization of the intermediate oxazine or oxazolidine, both of
them bearing an additional fused ring, occurs more slowly in
the case of the ketones due to steric effects. Consequently,
the oxazolidine–enamine equilibrium induces DKR.
Finally, to fully illustrate the synthetic usefulness of amino
alcohols 21 and 22 as chiral auxiliaries in the above cyclo-
condensation reactions, lactams 37b and 43b were convert-
ed into the corresponding enantiopure piperidines 48 and 50
by a two-step sequence involving borane reduction, followed
by removal of the auxiliary by catalytic hydrogenation of
the resulting N-substituted piperidines 47 and 49, respective-
ly (Scheme 7).
Scheme 7. Removal of the chiral auxiliary.
Conclusion
The best results in terms of chemical yield and stereose-
lectivity in cyclocondensation reactions with aldehydes were
obtained when using amino alcohol 22.[26] Thus, 22 reacted
with racemic aldehyde 1d to give a 9:1 stereoisomeric mix-
ture of lactams 40 in 78% yield, which clearly indicates that
DKR had again occurred. Similarly, prochiral aldehyde die-
sters 1m and 1r underwent highly enantioselective desym-
metrizations during cyclocondensation with 22 to give 14:1
and 20:1 stereoisomeric mixtures of the respective lactam
esters 41 and 42 in excellent yields. The major isomers b
were isolated in 80 and 76% yields, respectively. Finally, rac-
emic oxo diester 1v, on reaction with amino alcohol 22, ster-
eoselectively provided enantiopure lactam 43b, which was
isolated in 66% yield, in a highly stereoselective process
that involves the tandem DKR/desymmetrization of two di-
astereotopic acetate chains with the generation of three ster-
eogenic centers in a single synthetic step. In contrast with
the above satisfactory results, similar cyclocondensation re-
actions with racemic ketones 1h and 1q occurred with low
stereoselectivity.
The higher stereoselectivities observed in the cyclocon-
densation reactions promoted by amino alcohols 21 (with
ketones) and 22 (with aldehydes) as compared with phenyl-
glycinol can be rationalized by considering that the substitu-
ents at the 4- and 5-positions of the ring in the intermediate
oxazolidine (A and B in Scheme 5) are on the same face of
the ring, thus making the opposite face more easily accessi-
ble. In agreement with this interpretation, and in sharp con-
trast with the above result with erythro amino alcohol 22, cy-
clocondensation of threo amino alcohol 23[27] with racemic
diester 1v took place with low stereoselectivity to give a 2:1
diastereomeric mixture of lactams 46a and 46b, along with
other stereoisomers.
Cyclocondensation reactions of phenylglycinol with racemic
or prochiral d-oxo (di)acid derivatives in processes involving
dynamic kinetic resolution and/or desymmetrization of dia-
stereotopic or enantiotopic ester groups take place with con-
sistently good-to-excellent stereoselectivity (diastereoiso-
meric ratios 4–9:1). As both enantiomers of phenylglycinol
are commercially available, this amino alcohol provides easy
access to enantiopure piperidines in both enantiomeric
series. On the other hand, although aminoindanol 21 and
protected aminopropanediol 22 also promote highly stereo-
selective cyclocondensation reactions, their usefulness as
chiral inductors is less general. Thus, whereas aminoindanol,
whose two enantiomers are also commercially available,
gives excellent stereoselectivities (diastereoisomeric ratios
8–13:1) in cyclocondensation reactions with racemic ketones
involving DKR, the less accessible alcohol 22 reacts with ex-
ceptionally high stereoselectivities (diastereoisomeric ratios
9–20:1) in cyclocondensation reactions with aldehydes in-
volving either DKR or the desymmetrization of ester chains.
The highly enantioselective processes reported herein,
leading to a variety of (poly)substituted lactams in a single
synthetic step, represent a conceptual extension of the po-
tential of oxazolopiperidone lactams as chiral synthons for
the enantioselective synthesis of a diverse range of substitut-
ed piperidine derivatives.
Experimental Section
General procedure for the cyclocondensation reactions: A solution of
amino alcohol (1.2 equiv) and the 1,5-dicarbonyl compound (1 equiv) in
anhydrous toluene containing molecular sieves (4 Š) was refluxed for
12–66 h with azeotropic removal of water using a Dean–Stark apparatus.
7878
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Chem. Eur. J. 2006, 12, 7872 – 7881

Enantioselective Synthesis of Piperidines
FULL PAPER
The resulting suspension was filtered through Celite, the filtrate was con-
centrated, and the residue was taken up with EtOAc, dried, and concen-
trated. The resulting residue was purified by chromatography to afford
the desired lactams. The epimeric ratios were determined by using HPLC
and/or 1H NMR spectroscopy.
0.2n NaOH, and extracted with EtOAc. The combined organic extracts
were dried and concentrated and the residue was purified by chromatog-
raphy.
(2S)-1-[(1R)-2-Hydroxy-1-phenylethyl]-2-phenylpiperidine (4b): Follow-
ing the procedure described in the above Method B, from lactam 3b
(100 mg, 0.34 mmol) and Red-Al (0.1m in THF, 17 mL, 1.7 mmol) in an-
hydrous THF (2 mL) for 8 h, piperidine 4b (51.5 mg, 54%) was obtained
after flash chromatography (hexane): m.p. 61–628C (hexane) [lit.:[29]
60.98C]; [a]2D2 =À165.1 (c=0.95 in CHCl3) [lit:[29] [a]2D0 =À165.9 (c=1.0 in
CHCl3)]; 1H NMR (CDCl3, 300 MHz, COSY, HETCOR): d=1.12–1.26
(m, 1H, H-4), 1.53–1.76 (m, 5H, 2”H-3, H-4, 2”H-5), 1.91 (td, J=12.0,
2.1 Hz, 1H, H-6), 3.12 (dm, J=12.0 Hz, 1H, H-6), 3.29 (dd, J=10.8,
3.0 Hz, 1H, H-2), 3.38 (dd, J=9.0, 3.9 Hz, 1H, H-1’), 3.54 (brs, 1H, OH),
4.00 (dd, J=11.3, 3.9 Hz, 1H, H-2’), 4.03 (dd, J=11.3, 9.0 Hz, 1H, H-2’),
6.99–7.06 (m, 2H, ArH), 7.25–7.44 ppm (m, 8H, ArH); 13C NMR
(CDCl3, 75.4 MHz): d=24.9 (CH2), 26.3 (CH2), 37.8 (CH2), 45.7 (CH2),
59.3 (CH2), 61.8 (CH), 65.4 (CH), 127.1 (CH), 127.6 (CH), 127.8 (CH),
127.9 (CH), 128.7 (CH), 129.3 (CH), 134.4 (CH), 144.0 ppm (C); IR
(film): n˜ =3441 cmÀ1; elemental analysis calcd (%) for C19H23NO: C
81.10, H 8.24, N 4.98; found: C 80.86, H 8.33, N 4.91.
A
N
a]pyridine (3b): Following the above general procedure, from (R)-phe-
nylglycinol (1.7 g, 12.4 mmol) and 5-phenyl-5-oxopentanoic acid (1b; 2 g,
10.4 mmol) in anhydrous toluene (21 mL) for 25 h, lactam 3b (2.7 g,
90%) was obtained as a white solid after flash chromatography (SiO2
previously washed with hexane/Et3N; gradient 7:3 hexane/EtOAc to
EtOAc): m.p. 119–1228C (THF/hexane); [a]2D2 =+9.2 (c=1.0 in MeOH),
[a]2D2 =+20.4 (c=0.63 in CHCl3); 1H NMR (CDCl3, 300 MHz, COSY,
HETCOR): d=1.60 (m, 1H, H-7), 1.74 (m, 1H, H-7), 1.95 (ddd, J=14.0,
12.6, 3.9 Hz, 1H, H-8), 2.23 (ddd, J=12.6, 3.9, 0.9 Hz, 1H, H-8), 2.45
(ddd, J=18.6, 10.5, 7.8 Hz, 1H, H-6), 2.63 (ddd, J=18.6, 7.8, 0.9 Hz, 1H,
H-6), 3.62 (t, J=9.0 Hz, 1H, H-2), 4.39 (dd, J=9.0, 7.8 Hz, 1H, H-2),
5.28 (t, J=9.0 Hz, 1H, H-3), 7.08–7.20 (m, 5H, ArH), 7.31–7.39 (m, 3H,
ArH), 7.46–7.49 ppm (m, 2H, ArH); 13C NMR (CDCl3, 75.4 MHz): d=
15.3 (CH2), 30.7 (CH2), 36.8 (CH2), 60.4 (CH), 69.2 (CH2), 97.1 (C), 126.6
(CH), 127.6 (CH), 127.2 (CH), 128.3 (CH), 127.9 (CH), 137.8 (C), 141.2
(C), 170.8 ppm (C); IR (film): n˜ =1650 cmÀ1; elemental analysis calcd
(%) for C19H19NO2: C 77.79, H 6.53, N 4.77; found: C 77.83, H 6.51, N
4.76.
(2R)-1-[(1R)-2-Hydroxy-1-phenylethyl]-2-phenylpiperidine (5b): Follow-
ing the procedure described in the above Method A, from lactam 3b
(1 g, 3.4 mmol) and 9-BBN (0.5m in THF, 68.2 mL, 34 mmol) in THF
(40 mL) for 8 h, piperidine 5b (720 mg, 75%) was obtained after flash
chromatography (gradient hexane to 7:3 hexane/EtOAc): m.p. 77–788C
(Et2O/hexane), [lit.:[27] 788C]; [a]D22 =À30.2 (c=1.1 in CHCl3) [lit:[29]
[a]2D0 =À30.3 (c=1.08 in CHCl3)]; 1H NMR (CDCl3, 300 MHz, COSY,
HETCOR): d=1.25–1.80 (m, 7H, 2”H-3, 2H-4, 2”H-5, OH), 2.51 (td,
J=11.3, 2.7 Hz, 1H, H-6), 2.95 (dm, J=11.3 Hz, 1H, H-6), 3.76 (dd, J=
9.9, 2.7 Hz, 1H, H-2), 3.83 (t, J=6.6 Hz, 1H, H-1’), 4.04 (m, 2H, 2”H-
2’), 7.20–7.42 ppm (m, 10H, ArH); 13C NMR (CDCl3, 75.4 MHz): d=25.1
(CH2), 26.4 (CH2), 37.0 (CH2), 47.6 (CH2), 59.7 (CH2), 62.7 (CH), 65.8
(CH), 126.6 (CH), 127.0 (CH), 128.0 (CH), 127.6 (CH), 128.5 (CH),
140.1 (C), 144.8 ppm (C); IR (film): n˜ =3405 cmÀ1; elemental analysis
calcd (%) for C19H23NO: C 81.10, H 8.24, N 4.98; found: C 80.90, H 8.37,
N 4.95.
ACHTREUNG
ACHTREUNG
from (R)-phenylglycinol (1.26 g, 9.12 mmol) and 5-oxo-5-(3-pyridyl)pen-
tanoic acid[28] (1c; 1.48 g, 7.6 mmol) in toluene (15 mL) for 24 h, lactam
3c (1.2 g, 58%) was obtained after flash chromatography (95:5 Et2O/
Et2NH): m.p. 103–1068C (Et2O); [a]2D2 =+ 4.3 (c=1.0 in EtOH); 1H
NMR (CDCl3, 300 MHz, HETCOR): d=1.58 (m, 1H, H-7), 1.83 (m, 1H,
H-7), 1.98 (td, J=12.9, 3.9 Hz, 1H, H-8), 2.23 (dt, J=12.9, 3.9 Hz, 1H,
H-8), 2.51 (ddd, J=18.6, 10.5, 6.4 Hz, 1H, H-6), 2.68 (dd, J=18.6, 8.1 Hz,
1H, H-6), 3.65 (t, J=9.3 Hz, 1H, H-2), 4.46 (dd, J=9.3, 8.1 Hz, 1H, H-
2), 5.35 (t, J=8.1 Hz, 1H, H-3), 7.06–7.21 (m, 5H, ArH), 7.30 (ddd, J=
8.1, 4.8, 1.8 Hz, 1H, H-5pyr), 7.77 (dt, J=8.1, 2.4 Hz, 1H, H-4pyr), 8.60
(dd, J=4.8, 1.8 Hz, 1H, H-6pyr), 8.76 ppm (dd, J=2.4, 0.9 Hz, 1H, H-
2pyr); 13C NMR (CDCl3, 75.4 MHz): d=15.2 (CH2), 30.7 (CH2), 36.7
(CH2), 60.2 (CH), 69.3 (CH2), 95.9 (C), 122.9 (CH), 127.2 (CH), 127.5
(CH), 128.3 (CH), 134.5 (CH), 136.9 (C), 137.6 (C), 148.4 (CH), 149.8
(CH), 170.8 ppm (C); IR (KBr): n˜ =1653 cmÀ1; elemental analysis calcd
(%) for C18H18N202: C 73.45, H 6.16, N 9.52; found: C 73.51, H 6.25, N
9.64.
(2S)- and (2R)-1-[(1R)-2-Hydroxy-1-phenylethyl]-2-(3-pyridyl)piperidine
(4c and 5c): Lactam 3c (100 mg, 0.34 mmol) was slowly added to a sus-
pension of LiAlH4 (129 mg, 3.4 mmol) in anhydrous THF (6 mL) at room
temperature. The resulting mixture was stirred for 15 h and cooled to
08C. The reaction was quenched with H2O. The aqueous layer was ex-
tracted with EtOAc and the combined organic extracts were dried and
concentrated. Flash chromatography (EtOAc) afforded piperidines 4c
(70 mg, 78%) and 5c (5 mg, 6%).
General procedure for the reduction reactions: Method A: A mixture of
9-BBN (0.5m in THF, 1–10 equiv) and the lactam (1 equiv) was refluxed
for 5–8 h. Then the crude mixture was cooled to 08C, a 1:1 solution of
aqueous 2n NaOH and 30% H2O2 was slowly added, and the stirring
was continued at 08C for 30 min. Brine was added at 08C, the aqueous
phase was extracted with EtOAc, the combined organic extracts were
dried and concentrated, and the residue was purified by chromatography.
4c: [a]2D2 =À120.0 (c=1.3 in CHCl3) [lit.:[30] [a]2D2 =À123.1 (c=1.3 in
CHCl3)]; 1H NMR (CDCl3, 300 MHz): d=1.18–1.25 (m, 1H), 1.55–1.77
(m, 5H), 1.96 (td, J=12.0, 2.4 Hz, 1H), 3.13 (dm, J=12.0 Hz, 1H), 3.34
(dd, J=10.8, 2.4 Hz, 1H), 3.41 (dd, J=11.0, 5.4 Hz, 1H), 3.87 (dd, J=
11.0, 5.4 Hz, 1H), 4.05 (t, J=11.0 Hz, 1H), 6.97–7.00 (m, 2H), 7.31–7.34
(m, 3H), 7.37 (dd, J=8.1, 4.8 Hz, 1H), 7.78 (dt, J=8.1, 2.1 Hz, 1H),
8.56–8.59 ppm (m, 2H); 13C NMR (CDCl3, 75.4 MHz): d=24.7 (CH2),
26.2 (CH2), 37.8 (CH2), 45.7 (CH2), 59.5 (CH2), 62.4 (CH), 62.6 (CH),
123.9 (CH), 127.9 (CH), 128.0 (CH), 129.2 (CH), 133.9 (C), 135.2 (CH),
Method B: Red-Al (0.1m in THF, 2.5–5 equiv) was added to a solution of
the lactam (1 equiv) in anhydrous THF and the mixture was refluxed for
8 h. The crude mixture was diluted with EtOAc and ice/H2O, and the
aqueous layer was extracted with EtOAc. The combined organic extracts
were washed with brine, dried and concentrated, and the residue was pu-
rified by chromatography.
139.4 (C), 148.8 (CH), 149.7 ppm (CH); IR (film): n˜ =3408 cmÀ1
.
5c: [a]2D2 =À22.7 (c=1.0 in CHCl3); 1H NMR (CDCl3, 300 MHz): d=
1.41–1.88 (m, 6H), 2.55 (td, J=11.4, 2.7 Hz, 1H), 2.92 (dm, J=11.4 Hz,
1H), 3.78 (t, J=6.6 Hz, 1H), 3.93 (dd, J=11.1, 2.7 Hz, 1H), 4.03 (dd, J=
11.1, 6.6 Hz, 1H), 4.12 (dd, J=11.1, 6.6 Hz, 1H), 7.16–7.38 (m, 6H), 7.79
(dt, J=7.8, 1.8 Hz, 1H), 8.28 (dd, J=4.5, 1.8 Hz, 1H), 8.52 ppm (d, J=
1.8 Hz, 1H); 13C NMR (CDCl3, 75.4 MHz): d=24.9 (CH2), 26.2 (CH2),
37.0 (CH2), 46.9 (CH2), 59.8 (CH2), 62.6 (CH), 63.0 (CH), 123.6 (CH),
126.6 (CH), 127.8 (CH), 128.0 (CH), 135.2 (CH), 140.1 (C), 140.4 (C),
Method C: LiAlH4 (3.2–6.6 equiv) was slowly added to a cooled (08C)
suspension of AlCl3 (1.4–4.4 equiv) in anhydrous THF and the mixture
was stirred at room temperature for 30 min. The temperature was low-
ered to À788C, the corresponding lactam (1 equiv) was added, and the
resulting suspension was stirred at À788C for 90 min and at room tem-
perature for 2 h. The mixture was cooled to 08C and the reaction
quenched with H2O. The aqueous layer was extracted with CH2Cl2, the
combined organic extracts were dried and concentrated, and the residue
was purified by chromatography.
147.9 (CH), 149.1 ppm (CH); IR (film): n˜ =3355 cmÀ1
.
AHCTREUNG
(12a): Following the procedure described in the above Method C, from
lactam 8h (200 mg, 0.77 mmol), AlCl3 (154 mg, 1.1 mmol), and LiAlH4
(191 mg, 5.1 mmol) in anhydrous THF (15 mL), piperidine 12a (160 mg,
84%) was obtained after flash chromatography (1:1 hexane/EtOAc):
Method D: BH3 (1m THF, 3 equiv) was added to a solution of the lactam
(1 equiv) in anhydrous THF at À788C. The mixture was stirred at 08C
for 2 h and at room temperature for 3 h, poured into saturated aqueous
Chem. Eur. J. 2006, 12, 7872 – 7881
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7879

M. Amat, J. Bosch et al.
[a]2D2 =À15.2 (c=1.36 in MeOH); 1H NMR (CDCl3, 300 MHz, COSY):
d=0.79 (t, J=7.5 Hz, 3H, CH3), 0.85 (d, J=7.0 Hz, 3H, CH3), 1.19 (q,
J=7.0 Hz, 2H, CH2), 1.29–1.54 (m, 4H, H-3, 2”H-4, H-5), 1.61 (m, 1H,
H-5), 2.45 (m, 1H, H-6), 2.66 (dd, J=9.0, 3.6 Hz, 1H, H-6), 2.78 (ddd,
J=13.5, 6.6, 3.6 Hz, 1H, H-2), 3.78 (m, 3H, H-1’, H-2’), 7.24–7.35 ppm
(m, 5H, ArH); 13C NMR (CDCl3, 75.4 MHz): d=9.9 (CH3), 11.8 (CH3),
23.5 (CH2), 24.5 (CH2), 25.4 (CH2), 42.4 (CH), 44.0 (CH2), 53.7 (CH),
62.0 (CH2), 64.7 (CH), 127.4 (CH), 128.2 (CH), 128.3 (CH), 139.2 ppm
(C); IR (film): n=3414 cmÀ1; elemental analysis calcd (%) for C16H25NO:
C 76.68, H 10.19, N 5.66; found: C 76.39, H 10.12, N 5.51.
edged. Thanks are also due to the Ministry of Education, Culture and
Sport (Spain) for fellowships to O.B. and M.C.
[1] For reviews, see: a) H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988,
18, 249–330; b) M. Ohno, M. Otsuka, Org. React. 1989, 37, 1–55.
[2] For a review on the controlled racemization of optically active com-
pounds, see: E. J. Ebbers, G. J. A. Ariaans, J. P. M. Houbiers, A.
Bruggink, B. Zwanenburg, Tetrahedron 1997, 53, 9417–9476.
[3] For reviews, see: a) R. Noyori, M. Tokunaga, M. Kitamura, Bull.
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metry 1995, 6, 1475–1490; c) S. Caddick, K. Jenkins, Chem. Soc.
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16; e) U. T. Strauss, U. Felfer, K. Faber, Tetrahedron: Asymmetry
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7, 5005–5010; h) H. Pellissier, Tetrahedron 2003, 59, 8291–8327, and
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[4] For reviews, see: a) R. S. Ward, Chem. Soc. Rev. 1990, 19, 1–19;
b) B. Danieli, G. Lesma, D. Passarella, S. Riva in Advances in the
Use of Synthons in Organic Chemistry, Vol. 1 (Ed.: A. Dondoni),
JAI Press, London, 1993, pp. 143–219; c) S. R. Magnuson Tetrahe-
dron 1995, 51, 2167–2213; d) E. Schoffers, A. Golebiowski, C. R.
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Garcꢃa-Urdiales, I. Alfonso, V. Gotor, Chem. Rev. 2005, 105, 313–
353; see also ref. [1b].
Ethyl (3S,4S)-3-ethyl-1-[(1R)-2-hydroxy-1-phenylethyl]piperidine-4-ace-
tate (14a): Following the procedure described in the above Method D,
from lactam 9o (175 mg, 0.52 mmol) and BH3 (1m in THF, 1.58 mL,
1.58 mmol) in THF (8 mL), piperidine 14a was obtained (103 mg, 61%)
after flash chromatography (gradient 8:2 EtOAc/hexane to EtOAc):
[a]2D2 =À53.0 (c=0.5 in MeOH); 1H NMR (CDCl3, 300 MHz, COSY,
HETCOR): d=0.88 (t, J=7.2 Hz, 3H, CH3), 1.13 (m, 1H, CH2), 1.22 (t,
J=7.2 Hz, 3H, CH3), 1.23–1.43 (m, 3H, H-3, H-4, H-5), 1.49 (m, 1H,
CH2), 1.74 (m, 2H, H-5, H-6ax), 2.01 (dd, J=14.7, 8.7 Hz, 1H, CH2), 2.02
(t, J=10.5 Hz, 1H, H-2ax), 2.49 (dd, J=14.7, 4.0 Hz, 1H, CH2), 2.85 (m,
2H, H-2eq, H-6eq), 3.62 (dd, J=10.0, 5.2 Hz, 1H, H-2’), 3.72 (dd, J=
10.0, 5.2 Hz, 1H, H-1’), 3.97 (t, J=10.0 Hz, 1H, H-2’), 4.08 (q, J=7.2 Hz,
2H, CH2), 7.15–7.35 ppm (m, 5H, ArH); 13C NMR (CDCl3, 75.4 MHz,
HETCOR): d=11.1 (CH3), 14.2 (CH3), 23.6 (CH2), 31.7 (CH2), 37.1
(CH), 38.4 (CH2), 42.6 (CH), 46.0 (CH2), 56.9 (CH2), 60.0 (CH2), 60.2
(CH2), 70.0 (CH), 127.8 (CH), 128.1 (CH), 1.28.8 (CH), 135.2 (C),
173.0 ppm (C); IR (film): n=3440, 1732 cmÀ1; elemental analysis calcd
(%) for C19H29NO3: C 71.44, H 9.16, N 4.38; found: C 71.38, H 9.32, N
4.36.
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General procedure for the hydrogenolysis reactions: A solution of the pi-
peridine (1 equiv) in MeOH or EtOAc containing Pd/C or Pd(OH)2/C
was hydrogenated at 258C until the disappearance of the starting materi-
al was observed by TLC. The catalyst was removed by filtration and
washed with hot MeOH, and the solution was concentrated to give the
substituted piperidines after flash chromatography.
(S)-2-Phenylpiperidine (6b): Following the above general procedure,
from piperidine 4b (150 mg, 0.53 mmol) and Pd/C (10%, 37.5 mg) in
MeOH (25 mL), piperidine 6b (50 mg, 58%) was obtained as a transpar-
ent oil after flash chromatography (CH2Cl2): [a]2D2 =À26.9 (c=1.0 in
MeOH), [a]2D2 =À63.8 (c=0.5 in CHCl3) [lit.:[29] [a]2D0 =À27.0 (c=0.43 in
MeOH)]; 1H NMR (CDCl3, 300 MHz): d=1.43–1.93 (m, 6H), 2.78 (td,
J=11.6, 3.1 Hz, 1H), 3.19 (dm, J=11.6 Hz, 1H), 3.58 (dd, J=10.4,
2.4 Hz, 1H), 7.19–7.38 ppm (m, 5H); 13C NMR (CDCl3, 75.4 MHz) d=
25.4 (CH2), 25.9 (CH2), 34.9 (CH2), 47.8 (CH2), 62.3 (CH), 126.5 (CH),
126.9 (CH), 128.2 (CH), 145.4 ppm (C); IR (film): n=3420 cmÀ1; HMRS:
calcd for C11H15N: 161.1199; found: 161.1204.
(S)-3-(2-Piperidyl)pyridine [(À)-S-anabasine] (6c): Following the above
general procedure, from piperidine 4c (150 mg, 0.53 mmol) and 10%
Pd(OH)2/C (40 mg) in MeOH (12 mL) pure anabasine (6c, 70 mg, 81%)
was obtained as a transparent oil after flash chromatography (95:5
EtOAc/EtOH): [a]D22 =À74.7 (c=0.1 in CHCl3) [lit.:[30] [a]2D2 =À75.5 (c=
0.1 in CHCl3)], [a]D22 =À77.04 (c=0.5 in MeOH) [lit.:[31] [a]2D4 =À79.2 (c=
0.5 in MeOH)]; 1H NMR (CDCl3, 300 MHz): d=1.50–2.0 (m, 6H), 2.80
(td, J=11.4, 3.0 Hz, 1H), 3.20 (dm, J=11.4 Hz, 1H), 3.64 (dd, J=10.2,
2.7 Hz, 1H), 7.24 (dd, J=7.8, 4.8 Hz, 1H), 7.72 (dt, J=7.8, 1.5 Hz, 1H),
8.48 (dd, J=4.8, 1.5 Hz, 1H), 8.58 ppm (d, J=1.5 Hz, 1H); 13C NMR
(CDCl3, 75.4 MHz): d=25.2 (CH2), 25.6 (CH2), 34.7 (CH2), 47.6 (CH2),
59.8 (CH), 123.4 (CH), 134.1 (CH), 140.4 (C), 148.5 (CH), 148.6 ppm
(CH).
Acknowledgements
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Financial support from the Spanish Ministry of Science and Technology-
FEDER (project BQU2003-00505) and the DURSI, Generalitat de Cata-
lunya (grants 2001SGR-0084 and 2005SGR-0603) is gratefully acknowl-
7880
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 7872 – 7881

Enantioselective Synthesis of Piperidines
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Received: March 27, 2006
Published online: July 19, 2006
Chem. Eur. J. 2006, 12, 7872 – 7881
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7881