Diastereoselective synthesis of 3,4-disubstituted 5-(p-tolylsulfinyl)-5,6- dehydropiperidin-2-ones: Chirality transfer in the enantioselective synthesis of ethyl (+)-(3S,4aS,7aS)-1-oxo-octahydro-1H-cyclopenta[c]pyridine-3-carboxylate

Article abstract of DOI:10.1016/j.tetasy.2005.11.009

The base-mediated reaction of enantiomerically pure α- sulfinylketimine (+)-1 with (E)-α,β-disubstituted propenoate esters afforded 3,4-disubstituted-5-(p-tolylsulfinyl)-5,6-dehydropiperidin-2-ones 9α-13α and 14 with high or complete diastereoselectivity. A sole diastereomer of the four possible ones, with regard to the nature of ester, was isolated, which revealed the stereocontrol of the chiral sulfinyl group in the Michael reaction and transenolization steps. In addition, the enantioselective synthesis of ethyl (+)-(3S,4aS,7aS)-1-oxo-octahydro-1H-cyclopenta[c]pyridine-3- carboxylates (+)-17α is described (five steps; 47% yield; ee ≥97%). The absolute configuration of stereocentres introduced in (+)-17α was assigned on the basis of ¹H NMR data.

Full text of DOI:10.1016/j.tetasy.2005.11.009

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 4034–4044
Diastereoselective synthesis of 3,4-disubstituted
5-(p-tolylsulfinyl)-5,6-dehydropiperidin-2-ones:
chirality transfer in the enantioselective synthesis
of ethyl (+)-(3S,4aS,7aS)-1-oxo-octahydro-
1H-cyclopenta[c]pyridine-3-carboxylate
*
´
Hassan Acherki, Carlos Alvarez-Ibarra, Juan F. Collados Lujan and
´
´
Marıa L. Quiroga-Feijoo
Departamento de Quı´mica Orga´nica, Facultad de Ciencias Quı´micas, Universidad Complutense, Ciudad Universitaria,
28040 Madrid, Spain
Received 5 October 2005; accepted 1 November 2005
´
´
Dedicated to Professor Antonio Garcıa-Martınez on the occasion of his 65th birthday
Abstract—The base-mediated reaction of enantiomerically pure a-sulfinylketimine (+)-1 with (E)-a,b-disubstituted propenoate
esters afforded 3,4-disubstituted-5-(p-tolylsulfinyl)-5,6-dehydropiperidin-2-ones 9a-13a and 14 with high or complete diastereoselec-
tivity. A sole diastereomer of the four possible ones, with regard to the nature of ester, was isolated, which revealed the stereocontrol
of the chiral sulfinyl group in the Michael reaction and transenolization steps. In addition, the enantioselective synthesis of ethyl (+)-
(3S,4aS,7aS)-1-oxo-octahydro-1H-cyclopenta[c]pyridine-3-carboxylates (+)-17a is described (five steps; 47% yield; ee P97%). The
1
absolute configuration of stereocentres introduced in (+)-17a was assigned on the basis of H NMR data.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
We have recently reported a highly efficient method for
the synthesis of substituted pipecolic acid derivatives 7
and 8, based on the Michael addition of the a-sulfinyl
ketimine (+)-1 to isopropyl and methyl (E)-crotonate
and (E)-cinnamate 2 (Scheme 1).7 Diastereomeric lac-
tams 5 and 6 were obtained from a one-pot procedure
upon cyclization of the aza-enolates 4, which are
achieved from the transient adducts 3 (Scheme 1). The
reaction times and diastereoselectivities were entirely
dependent on the nature of the O-alkyl group in the
ene ester. Thus, isopropyl ene esters required the highest
reaction times (P2 days) for completion of the cycliza-
tion to lactams, whereas methyl ene esters only needed
2–6 h. In addition, we observed that the diastereoselec-
tivity was completely in favour of isomers 5 with isopro-
pyl ene esters, whereas the lowest diastereoselectivities
were obtained with methyl ene esters (de = 32–76%).
Subsequent transformations of the lactam and oxazoli-
dine moieties of 5 (Scheme 1; R = Me) allowed us to
transfer the chirality of the sulfinyl group to the 2-, 4-
and 6-positions of the piperidine ring. This represents
Substituted and functionalized 6-oxopipecolic acids
are precursors of a-aminoadipic acid derivatives. The
a-aminoadipic acid (homoglutamic acid) is a constituent
of tripeptide d-(L-a-aminoadipoyl)-L-cysteinyl-D-valine,
which serves as a biosynthetic precursor of penicillins
and cephalosporins.1 Furthermore, substituted pipecolic
acid derivatives have been used as conformationally
constrained amino acids and, for this reason, could serve
as building blocks for the synthesis of peptidomimetics,2
immunosuppressor agents,3 enzyme inhibitors,4 and
NMDA antagonists.5 For all these goals, easy and chiral
routes for these substances with different substitution on
the piperidone and piperidine ring have yet to be
proposed.6
*
Corresponding author. Tel.: +34 913944223; fax: +34 913944103;
e-mail: caibarra@quim.ucm.es
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.11.009

H. Acherki et al. / Tetrahedron: Asymmetry 16 (2005) 4034–4044
4035
a new approach to the enantioselective synthesis of 4-
O
H
and 4,6-disubstituted L-pipecolates 7 and 8, respectively
R5
R4
6
3
N
2
(Scheme 1).7,8
5
O
4
7
H
S
O
p-Tol
O
O
N
+
OR'
R4
R5
Compound
R
2
S
O
p-Tol
(CH2)3
9α
1
n-BuLi/THF
(CH2)4
Ph
10α
11α
12α
13α
-78oC to -30oC
Ph
OR'
OR'
O
-
Ph
Me
Me
O
O
O
~H+
O
N
N
H
Me
CF3
R
R
S
S
O
14
H
p-Tol
p-Tol
-30 oC to rt
4
3
2 h to 6 days
Chart 1.
O
S
O
S
N
N
>>
O
O
R
R
O
S
H
O
O
O
p-Tol
Ra-Ni W-2
H
H
p-Tol
N
O
N
H
5
6
O
H
O
EtOH/∆
p-Tol
R = Me
100%; 100% de
(+)-15
(-)-9α
H2NOC
EtO2C
O
H
1. AcOH/H2O 10%, ∆
N
HN
EtO2C
HO
Me
Me
H
1. Jones' reagent
2. SO2Cl/pyr
8
O
7
O
H
H
HN
Scheme 1.
HN
EtO2C
3. EtOH/∆
HOH2C
H
H
H
H
Herein, we report the diastereoselective synthesis of
polycyclic lactams 9a and other structurally related
compounds 10–14 through the sulfoxide-mediated dia-
stereoselective one-pot procedure (Michael addition-
trans-enolization-cyclization) from a-sulfinylketimine
(+)-1 and (E)-a,b-disubstituted ene esters (Chart 1).
Furthermore, we describe an approach to the synthesis
of 4,5-disubstituted 6-oxopipecolic esters such as (+)-
17a through desulfuration and reduction of the piperid-
inone ring with Ra Ni W2, followed by deprotection of
the masked 1,2-amino alcohol functionality and subse-
quent transformation of the hydroxymethyl group to
an ester derivative (+)-17a (Scheme 2).
(+)-17α
(+)-16α
Scheme 2.
oretical calculations on the compounds 9a and 5
(R = Me) are in agreement with the observed vicinal
coupling constants for hydrogens H4 and H5. The newly
observed stereocontrol in the trans-enolization step to
create the second stereogenic centre of C5 afforded a high
value to this synthetic methodology. A study aimed at
extending this to a-heterosubstituted ene esters and other
functionalized Michael acceptors is currently in progress.
NMR analysis of the reaction mixtures leading to lactams
9–13 revealed the formation of a cyclic compound with a
cis-stereochemistry as a major component (series a), the
trans-isomer (series b) being present in minor amounts.
The analysis of the observed coupling pattern for vicinal
hydrogens H4 and H5 allowed us to establish the stereo-
chemistry of the new stereogenic centres C4 and C5. The-
2. Results and discussion
2.1. Synthesis and structural analysis of (+)-17a
The synthesis of (+)-17a was accomplished from (ꢀ)-9a
as outlined in Scheme 2. Compound (ꢀ)-9a was success-

4036
H. Acherki et al. / Tetrahedron: Asymmetry 16 (2005) 4034–4044
fully prepared as the sole diastereomer from a-sulfinyl-
ketimine (+)-1 and ethyl cyclopenten-1-carboxylate by
following the general procedure reported previously by
us.7 The best results were obtained by the addition of
n-BuLi (1.2 equiv) to (+)-1 at ꢀ78 ꢁC, and then allowing
the temperature to rise to ꢀ30 ꢁC before the unsaturated
ester was added. Next, the reaction mixture was allowed
to reach room temperature and stirred for seven days to
drive the cyclization to lactam (ꢀ)-9a to completion,
which was then isolated by flash chromatography in
83% yield. The open chain adducts were detected in
the reaction mixture (TLC; silica gel; hexane/EtAcO:
6:1, two spots) but their separation was unsuccessful.
have been previously reported by us.7 The stereochemi-
cal pathway proposed for the formation of lactam (ꢀ)-
9a is outlined in Figure 2. Thus, the Michael addition
step gives the sole diastereomer 21 (anti-adduct) through
a re–re attack (transition state 20), which is more fa-
voured than a si–re approach (transition state 24). In
any case, the facial selectivity of the Z-enolate is always
re (anti to the p-tolyl group) while the relative stereodis-
position of OEt group of the ene ester and the oxazoli-
dine moiety is anti for the re–re approach and syn for
the si–re attack. Hence, the former would be sterically
more favoured than the second attack. Since lactam
(ꢀ)-9a was isolated as the sole stereoisomer with a cis-
stereodisposition of the hydrogens at the carbon atoms
of the ring fusion, the subsequent trans-enolization to
aza-enolate 23 must occur with complete stereocontrol.
A reactive conformation of the anti-adduct such as 21
could be responsible for this reaction pathway, since
the metal ion complexation allows that the equilibrium
between imine–enamine to be diastereoselective. Thus,
the sole E-isomer 22 can be formed in the reaction med-
ium and, consequently, an s-trans conformation of the
sulfinyl group would allow the proton transfer to be anti
versus the bulkiest p-tolyl substituent.
The structure and relative configuration of compound
(ꢀ)-9a were easily established by analysis of its 1H
NMR (500 MHz) spectrum. The stereochemistry of the
stereogenic centres C4 and C5 of the fused rings was
established from the observed vicinal coupling constants
3JH4,H5 (8.3 Hz). This value is very close to the gauche
constant described by Hua et al.9 for the cis-isomer 18
(3J = 9.3 Hz) and is very different from the reported vic-
inal coupling constant for the trans-isomer 19
(3J = 14.0 Hz) (Fig. 1).
Next, lactam (ꢀ)-9a was reduced with freshly prepared
Ni-Raney W-210 (5 equiv) in refluxing ethanol over
30 min to give (+)-15 in quantitative yield (Scheme 2).
O
O
H
H
N
N
1
The H NMR (500 MHz) analysis of 15 revealed the
H
H
presence of a sole diastereomer. As expected, the config-
uration of the new stereocentre C2 became S taking into
account the stereodifferentiation effects developed by the
carbons C4 and C5, which induce an anti-orientation of
the hydrogen H2 with regard to cyclopentane ring. Fur-
S
S
O
p-Tol
O
p-Tol
18
19
3JH/H=9.3 Hz
3JH/H=14.0 Hz
Figure 1. Significant 1H NMR data for compounds 18 and 19.
thermore, this configuration is in accordance with the
1
observed H NMR vicinal coupling constants (3JH3 ;H4
0
3
0
The absolute configuration of (ꢀ)-9a was easily estab-
lished by taking into account other structurally analo-
gous lactams obtained by the same procedure which
and JH3 ;H2) for methine hydrogens H2 and H4
(Fig. 3). The high observed values of these vicinal coup-
ling constants (12.6 Hz and 11.3 Hz, respectively) fall in
H
re
OEt
M+
O
M+
OEt
4
O
O
re
NH
N
O
H
O
1,3[H]
EtO
re-re
OEt
H
H
4
p-Tol
S
N
S
H
S
M
O
O
p-Tol
O
p-Tol
21
20
22
anti adduct
O
O
S
EtO
H
O
si
N
O
N
M+
H
~H
H
O
re
4
H
H
O
p-Tol
S
S
p-Tol
N
O
p-Tol
M
9α
O
23
24
Figure 2. Stereochemical pathway proposed for the formation of lactam 9a between parenthesis ET leading to syn-adduct by a si–re approach.
¼

H. Acherki et al. / Tetrahedron: Asymmetry 16 (2005) 4034–4044
4037
from the acid chloride (SOCl2) and ethanol in 47%
O
23
yield from (+)-1 and its specific rotation f½aꢁD
¼
N
O
þ2:1 ðc 2:1; CHCl3Þg was determined on an analytical
sample obtained by flash chromatography (EtAcO).
1H NMR chiral shift experiments with (+)-Eu(hfc)3 con-
firmed that no racemization occurs during the synthesis
(ee P97%).
H5
H3’
12.6
H7’
11.3
9.3
H2
H4
5.6
H3
2.6
H7
2.2. Synthesis of substituted 5-(p-tolylsulfinyl)-5,6-
dehydropiperidine-2-ones
5.9
9.9
Our previous results on the reactivity of a-sulfinyl keti-
mine (+)-1 with either methyl, ethyl or isopropyl
b-substituted ene esters7 prompted us to apply this
methodology for obtaining chiral non-racemic 3,4-
disubstituted 5-(p-tolylsulfinyl)-5,6-dehydropiperidin-2-
ones (Table 1). Compounds 57 and 14 (4-substituted
examples) have been included for the sake of compari-
son. In all cases, the procedure was the same as that pre-
viously described for the compound (ꢀ)-9a. The
reaction mixtures were monitorized by TLC (silica gel)
and, under these conditions, we were able to observe
the evolution of the open chain adducts with an increase
in reaction time until their disappearance [these inter-
mediate derivatives displayed a higher Rf than the cyclic
products in hexane/EtAcO mixtures (6:1 to 3:1) as elu-
ent]. This reaction required between 2 h and 7 days
depending on the nature of the ene ester (Table 1). A
sole b-monosubstituted ene ester was used to prepare
lactam 14 (Table 1; cf. entry 7) and, thus, to compare
the observed diastereoselectivity with the result of the
reaction with the isopropyl crotonate (Table 1; cf. entry
8). An analogous result was observed to that which pro-
vided lactam 5 with the diastereoselectivity controlled by
the stereodifferentiation effect of the R-group in the ester
(+)-15
1
Figure 3. Observed H NMR vicinal coupling constants (Hz) for (+)-
15.
line with a pseudoaxial orientation of the implied hydro-
gens and, therefore, with a relative syn-configuration of
the hydrogens H2 and H4. On the other hand, the rela-
tive
magnitudes
of
the
coupling
constants
JH7 ;H2 ¼ 9:5 Hz, 3JH3,H4 = 5.6 Hz and 3JH4,H5 = 9.3 Hz
3
0
are in agreement with the proposed structure. The most
3
averaged values of the coupling constants JH7;H2 and
JH7 ;H2 are the result of pseudorotation of the oxazoli-
3
0
dine ring.
Next, we accomplished the hydrolysis of the N,O-ketal
moiety in (+)-15 with an AcOH/H2O mixture (10:90:
v/v) at reflux over 12 h to afford the alcohol 16a in high
yield (98%).7 The reaction mixture was treated directly
with JonesÕ reagent11 to give the carboxylic acid, which
was used without further purification for the subsequent
transformations. Ethyl ester (+)-17a was obtained
Table 1. Reaction of a-sulfinylketimine (+)-1 with (E) ene estersa
O
S
O
S
H
R5
R5
R4
H
N
N
R5
O
O
+
O
N
R4
OR
i) n-BuLi/THF
ii) -78oC to rt
R4
+
H
H
O
H
O
O
S
p-Tol
p-Tol
O
p-Tol
β−isomer
α−isomer
Entry
R
R4
R5
Product
Reaction time (h)
Yieldb (%)
Diastereoselectivityc a:b
1
2
3
4
5
6
7
8
9
Et
Et
–(CH2)3–
–(CH2)4–
9
10
11
11
12
13
14
5
168
192
120
194
24
24
48
24
24
83
76
70
20
100:–
100:–
90:10
100:–
Me
i-Pr
i-Pr
Et
i-Pr
i-Pr
Me
Ph
Ph
Ph
Ph
Ph
Me
Me
H
48
88:12
Me
CF3
CH3
CH3
77 (16)d
75
87:13 (85:15)d
100:–
H
H
70
61 (31)e
100:–
66 (34)e
5
a The E-configuration of all the esters was confirmed from the analysis of their 1H NMR data.
b Isolated cyclic isomers.
c Evaluated from integration of the key signals in the 1H NMR spectra (500 MHz) of the reaction crudes.
d Isolated as a mixture of four isomers (13a: 71.8%; 13b: 10.8%; 13c: 14.7%; 13d: 2.6%), two of them (13c/13d) display an opposite configuration at
the C4 carbon to that of their 13a/13b isomers.
e Isolated as a mixture of two isomers; between parenthesis is the epimer with an opposite configuration in C4 with regard to the isomers titled as a or
b.

4038
H. Acherki et al. / Tetrahedron: Asymmetry 16 (2005) 4034–4044
(Table 1; cf. entries 8 and 9). However, this effect was
not significant for b-phenyl a,b-disubstituted ene esters
(Table 1; cf. entries 3–5) because the sole cyclic com-
pounds isolated were epimers at the C5 carbon irrespec-
tive of the nature of R in the ene ester. An identical
result was observed for ethyl cycloalkenyl esters (Table
1; cf. entries 1 and 2). Thus, it can be established that
the presence of a second substituent in the a-position
of the ene ester amplifies the stereoselectivity of the
Michael reaction. Also, this effect could be observed in
the reaction of ethyl itaconate (Table 1; cf. entry 6) since
the major epimer in C4 was obtained in 82.7% yield versus
the minor epimer, whereas the methyl crotonate, a mono-
substituted ene ester, displayed a minor diastereoselec-
tivity (66:34) in favour of the same epimer (Table 1; cf.
entry 9).
a relative trans-configuration (vide infra) is formed in a
higher ratio than the d-epimer (cis-isomer) (13c/
13d = 85:15). This result seems to point out that the ste-
reocontrol in the trans-enolization step is originated by
the sulfinyl group with independence of the configura-
tion of the most next stereocentre (carbon C4) (Fig. 4).
2.3. Structural analysis of substituted 5-(p-tolylsulfinyl)-
5,6-dehydropiperidin-2-ones
The structure and stereochemistry of the major isomers
a, isolated by flash chromatography from the reaction
1
crudes were established by analysis of their H NMR
(500 MHz; CDCl3) spectra. Under these conditions, a
good signal separation was observed, which allowed a
full assignment (see Table 2). In our hands, compound
13a became inseparable from its epimer 13b, but a care-
ful spectroscopic analysis of the fraction containing both
isomers allowed the assignment of their signals. Simi-
larly, the fraction containing isomers 13c and 13d was
carefully analyzed to establish the stereochemistry from
the key signals of the spectrum. By an analogous analy-
sis of NMR data, the structure and stereochemistry of
the minor isomers 11b and 12b could be easily estab-
lished from samples, which were contaminated with
the major epimers 11a and 12a, respectively, after the
isolation of each of them was carried out.
An explanation for this effect can be based on the previ-
ously proposed transition states for the formation of lac-
tam (ꢀ)-9a (Fig. 2). In fact, a re–si approach, which
determines a relative syn-orientation of the R-group
and the oxazoline moiety, obviously provides a similar
relative arrangement of the groups R4 and R5 (Fig. 4;
R4 = R5 = Me) on the basis of an s-cis conformation
for the acceptor. These interactions strongly destabilize
transition state 25 but are not present in the transition
state, which would form the anti-adduct through a re–re
approach since the three substituents of the ester (OR,
R4 and R5) become in anti with regard to the oxazolidine
ring. Thus, the R5 group works in the same sense as the
groups R4 and OR to decide the stereoselectivity in favour
of the anti-adduct.
Table 2 summarizes the spectroscopic data of lactams 9–
14 together with the data of compound 5 (Scheme 1;
R = Me), which can be used as a reference to establish
the absolute configuration of all the a major stereoiso-
mers. In fact, the absolute configuration of 5 has been
established taking into account the different observed
chemical shifts for the methyl group attached at carbon
C4 (d = 0.418 ppm for the major isomer and
d = 1.210 ppm for the minor one) and by comparison
of these values with the data described by Hua et al.9
for similar compounds whose absolute configuration
was established by X-ray diffraction.
On the other hand, the formation of the isomer with a
a-configuration at the C5 carbon as the major epimer
has been generally observed (Table 1; cf. entries 1–6).
This result can be rationalized, just like the formation
of lactam (ꢀ)-9a (Table 1; cf. entry 1), through the
extensive stereocontrol induced by the sulfinyl group
(Fig. 4).
From a mechanistic point of view, it is interesting to
take into account the ratio of epimers 13c/13d that are
formed as minor products in the reaction of (+)-1 with
ethyl (E)-itaconate (Table 1; cf. entry 6). Both com-
pounds are epimers at the C5 carbon and are formed
from the (4S)-or syn-adduct (Fig. 4). The c-epimer with
Conversely, it is interesting to note that the observed dif-
ference for the chemical shifts of the hydrogens in the
CH2–O group in the epimers 13a and 13b was negligible,
whereas this difference in the epimers 13c and 13d was
0.23 and 0.24 ppm, respectively. When the whole series
of chemical shifts for the compounds with a configura-
Me
OEt
EtO
si
O
Me
OEt
M+
N
H
-
Me
Me
H
O
H
Me
Me
O
S
O
N
O
N
O
Me
Me
O
M+
S
~H
re
H
re-si
S
H
H
H
S
H
p-Tol
S
S
N
O
p-Tol
O
p-Tol
O
p-Tol
M
O
syn- adduct
13γ
27
26
25
Figure 4. Stereochemical pathway leading to 13c from the syn-adduct (minor isomer) formed through a re–si approach of the reactants. Imine–
enamine isomerization of the adduct followed by transenolization to the aza-enolate become anti versus the most bulkiest p-tolyl group of the actual
inductor centre.

H. Acherki et al. / Tetrahedron: Asymmetry 16 (2005) 4034–4044
4039
Table 2. 1H NMR (500 MHz) Observed chemical shifts (ppm) and coupling constants (Hz) of the compounds 9–14 and 5
Compd.
R4
R5
H4ax
H4ec
—
H5ax
—
H5ec
9a
–(CH2)3–
2.936 (dt, 3J = 8.3,
9.8, 9.8)
2.881 (dt, 3J = 2.7,
8.3, 8.3)
2.684 (dt, 3J = 2.7,
6.3, 6.3)
3.635 (d, 3J = 1.4)
10a
–(CH2)4–
2.703 (dt, 3J = 3.5,
6.3, 6.3)
—
—
11a
11b
12a
Ph
Ph
Ph
Ph
Ph
Me
3.998 (d, 3J = 1.4)
4.169 (d, 3J = 7.1)
3.405 (d, 3J = 1.7)
—
—
—
—
3.800 (d, 3J = 7.1)
—
—
2.479 (qd, 3J = 7.3,
1.7)
—
12b
13a
Ph
Me
Me
Me
3.643 (d, 3J = 7.3)
2.432 (qd, 3J = 1.7,
—
—
2.937 (quint., 3J = 7.3)
—
2.287 (qd, 3J = 1.7,
7.2)
7.0)
—
13b
13c
13d
Me
Me
Me
Me
Me
Me
2.705 (qd, 3J = 5.5,
—
2.681 (cd, 3J = 5.5, 7.0)
6.6)
—
2.310 (quint.,
3J = 6.8)
2.34–2.20 (m)
—
2.269 (quint.,
3J = 6.8)
—
—
2.139 (ABX3 system,
3J = 7.3, 1.8)
3
14
5
CF3
Me
H
H
2.940 (ddq, 3J = 7.3, 1.7, JH,F=8.4)
2.860 (qd, 3J = 6.9, 6.9, 2.3)
—
—
—
2.21–2.50 (m)
21.30 (dd, 2J = 15.9;
3J = 2.3)
2.380 (dd, 2J = 15.9; 3J = 6.9)
tion a or b are compared (Table 2), it becomes clear that
there is a minimum difference (Dd = 0.088 ppm) between
these values. Hence, this behaviour in the series of stud-
ied compounds can also be related with the configura-
tion of the C4 carbon.
lations have been carried out with Gaussian 0315 using
the B3LYP functional16 and the 6-31G(d) split
valence-shell basis set.17 Vibrational frequencies were
calculated for all the structures at the B3LYP/6-31G(d)
level to confirm the absence of imaginary frequencies.
In addition, the relative configurations of a/b and c/d
can be established by taking into account the coupling
pattern of the hydrogens bonded at carbons C4 and
C5. Thus, compounds 9a and 10a display typical values
for cis-coupling (axial–equatorial; 3J = 8.3 Hz and
6.3 Hz, respectively) that can be successfully contrasted
with the published data by Hua et al.9 for the com-
pounds 18 and 19 (Fig. 1) and, thus, the cis-fusion is
unequivocally established.
As a preliminary step, a conformational analysis around
the dihedral angle H5–C5–C4–H4 of compound 5 was
performed by means of a conformational search as
implemented in Hyperchem.13 Three conformations
were selected and optimized by PM3 semi-empirical cal-
culation and these structures were used as the starting
point for complete geometry optimizations at the DFT
level with the 6-31G(d) basis set. According to the
results, a unique conformer was unequivocally selected
and calculated; dihedral angles H4–C4–C5–H50 and
H4–C4–C5–H5 were ꢀ73.6ꢁ and 45.5ꢁ, respectively.
These values were introduced in the Altona equation18
Compounds 11a, 12a, 13a, 14 and 5 display a small cou-
pling (1.4–1.8 Hz) between hydrogens H4 and H5
whereas this coupling was significantly highest in the
epimeric compounds 11b, 12b and 13b (5.5–7.3 Hz). This
was also observed in the derivatives 14 and 5. In any
case, this finding represents a generalized behaviour,
which could be in agreement with a relative cis-configu-
ration for the series a and a trans-configuration for the
series b. Since it is related to the relative magnitude of
the dihedral angles between the vicinal hydrogens in
the carbon atoms C4 and C5, a computational study
was carried out (in vacuum) by means of semi-empirical
and DFT calculations. The semi-empirical calculations
were carried out using the PM3 model Hamiltonian12
as it is implemented in Hyperchem.13 The DFT14 calcu-
3
to calculate the vicinal coupling constants JH4,H5 and
3
0
JH4;H5 (Table 3). The excellent agreement between the
calculated and observed results supports the proposed
relative stereochemistry for hydrogens H4, H5 and H50
in 5 and by extension in the related compounds 11a,
12a, 13a and 11b, 12b, 13b.
In order to rationalize the observed vicinal coupling
constants in compound 9a, a complete geometry optimi-
zation of the initial structure was carried out using the
same procedure. The calculated dihedral angle H4–
C4–C5–H50 (ꢀ38.0ꢁ) was introduced in the Altona
equation18 to calculate a value of 6.7 Hz for the
3
3
0
Table 3. Theoretical and observed values of coupling constants JH4/H5 and JH4=H5 in lactams 5 and 9a and dihedral angles calculated with the
B3LYP/6-31G(d) chemistry model
Compound
Dihedral angle
H4–C4–C5–H5
Dihedral angle
H4–C4–C5–H50
3Jcalc
3Jobs
3Jcalc
H4/H50 (Hz)
3Jobs
H4/H50 (Hz)
H4/H5 (Hz)
H4/H5 (Hz)
5a
ꢀ73.6
ꢀ38.0
45.5
—
1.7
6.7
2.3
8.3
5.6
—
6.9
—
9a
a See Scheme 1 (R = Me).

4040
H. Acherki et al. / Tetrahedron: Asymmetry 16 (2005) 4034–4044
3JH4,H5 coupling constant, which is in excellent agree-
ment with the observed value (Table 3). This result
reproduces fairly the observed difference for the cou-
pling constant of this isomer and for its analogous com-
pound 10a.
the eluent was basic, and then passing dry acetone
through it. Chemicals for reactions were used as pur-
chased from the Aldrich Chemical Co. The synthesis
of starting compound (+)-1 has been previously
described.7 Isopropyl 3- and 2,3-substituted propenoate
esters 2 were obtained from commercially available acids
following standard procedures. 4-Methyl-2,2-penta-
methylene-2,5-dihydrooxazol7,19 and (ꢀ)-menthyl p-tolu-
enesulfinate20 were accomplished following the reported
procedures.
3. Conclusion
The base-mediated reaction of enantiomerically pure a-
sulfinylketimine (+)-1 with (E)-ene esters is a useful
method for the diastereoselective synthesis of enantio-
merically pure 3,4-disubstituted-5-(p-tolylsulfinyl)-5,6-
dehydropiperidin-2-ones. The presence of a second
substituent at the a-position of the unsaturated ester
strengthens the anti-selectivity observed with b-substi-
tuted ene esters. A double chirality transfer from the sul-
finyl group can be proposed to justify the high observed
distereoselectivity in these reactions. The application of
this methodology has allowed us to achieve an enantio-
selective synthesis of ethyl (ꢀ)-(3S,4aS,7aS)-1-oxo-octa-
hydro-1H-cyclopenta[c]pyridine-3-carboxylate (+)-17a
(five steps; 47% yield; ee P97%) through a simple trans-
formation of lactam (ꢀ)-9a.
4.2. Synthesis of 5-(p-tolylsulfinyl)-5,6-dehydro-piperidin-
2-ones 9–14. Typical procedures
Method A: To a cold (ꢀ78 ꢁC) solution of sulfinyl ket-
imine (+)-1 (524.5 mg, 1.8 mmol) in dry THF (40 mL)
under an argon atmosphere was added a solution of n-
BuLi (1.6 M in hexane, 1.25 mL, 2 mmol). The solution
was stirred at ꢀ78 ꢁC for 0.5 h, the temperature raised to
ꢀ30 ꢁC and the ene ester (3.6 mmol, 0.15 M solution in
THF) added. The reaction mixture was kept to rt and
stirred until disappearance of the open adducts was
complete (TLC analysis; 12 h to 7 days). Then, the
mixture was hydrolyzed with a saturated aqueous
NH4Cl solution (20 mL) and extracted with EtAcO
(3 · 20 mL). The combined organic layers were washed
with brine, dried over Na2SO4, concentrated under
reduced pressure and chromatographed.
4. Experimental
4.1. General
Method B: To a cold (ꢀ78 ꢁC) solution of sulfinyl keti-
mine (+)-1 (524.5 mg, 1.8 mmol) in dry THF (12 mL)
under an argon atmosphere, a cold (ꢀ25 ꢁC) solution
of LDA9 (2.25 mmol) in dry THF (4 mL) was added
through a cannular. Afterwards, the brown solution
was stirred at ꢀ78 ꢁC for 1 h and the ene ester
(2.2 mmol) was added through a syringe. The solution
was stirred at ꢀ78 ꢁC for 15 min, and at rt for 2 h.
The reaction mixture was poured into 40 mL of H2O,
and extracted with DCM (3 · 20 mL). The combined
organic layers were washed with H2O and brine, dried
over MgSO4 and concentrated under reduced pressure
and chromatographed.
1
The H and 13C NMR spectra were recorded at 200 or
500 MHz and 50 or 125 MHz, in a Bruker AC-200 or
Bruker AM-500 spectrometer, 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 indicated as s (singlet), d (doublet), t (triplet),
q (quartet), quint. (quintuplet) and m (multiplet). Ele-
mental analyses were performed with a Perkin–Elmer
2400 C, H, N analyzer. Optical rotations were measured
at room temperature (20–23 ꢁC) using a Perkin–Elmer
241 MC polarimeter (concentration in g/100 mL). Infra-
red spectra were recorded on a Perkin–Elmer 781 IR
spectrophotometer.
Diastereomeric ratios and conversions were determined
1
by analysis of H NMR spectra of the reaction crudes
All reactions in non-aqueous media were carried out
in flame-dried glassware under an argon atmosphere.
Reagents and solvents were handled by using standard
cannule or syringe techniques. Tetrahydrofuran (THF)
and diethyl ether were distilled from sodium and benzo-
phenone, dichloromethane from P2O5 and isopropanol
from CaH2. In all other cases, commercially available
reagent-grade solvents were employed without purifica-
tion. Analytical TLC was routinely used to monitor
reactions. Plates precoated with Merck silica gel 60
F254 of 0.25 mm thickness were used, and visualized with
UV light, with either anisaldehyde/sulfuric acid/ethanol
(2:1:100) or phosphomolibdic acid solution (PMA, 10%
in ethanol) as developing agents. Merck silica gel 60
(230-400 ASTM mesh) was employed for flash column
chromatography. Chromatography using deactivated
silica gel was performed by eluting with a 2% aqueous
solution of NaHCO3/MeOH (5:95, v/v) until pH of
prior to their isolation. Yields are quoted as isolated
products (Table 1).
4.2.1. (ꢀ)-(SS,5a0S,8a0R)-90-[(4-Methylphenyl)sulfinyl]-
10,5a0,60,70,80,8a0-hexahydro-50H-spiro[cyclohexane-1,30-
cyclopenta[d][1,3]oxazolo[3,4-a]pyridin]-50-one
(ꢀ)-9a.
Method A: Rf = 0.20 (hexane/EtAcO: 1:1; v/v). Yellow
25
solid. Mp 111–114ꢁC. ½aꢁD ¼ ꢀ45:7 ðc 1:7; CHCl3Þ.
1
IR (KBr) 2935, 1682, 1375 cmꢀ1. H NMR (500 MHz)
2
3
d 1.430 (dddt, 1H, J = 12.4, J = 12.4, 6.3, 3.3, cyclo-
pentyl), 1.55–1.75 (m, 11H, cyclohexyl, cyclopentyl),
1.830 (dddd, 1H, 2J = 13.7, 3J = 10.0, 8.3, 6.0, cyclopent-
2
3
yl), 2.250 (dddd, 1H, J = 13.7, J = 8.4, 5.0, 2., cyclo-
pentyl), 2.36–2.38 (m, 2H, cyclopentyl), 2.422 (s, 3H,
3
CH3-Ar), 2.881 (dt, 1H, J = 8.3, 8.3, 2.7, H5ec), 2.936
3
(dt, 1H, J = 9.8, 9.8, 8.3, H4ax), 4.875 (AB system, 1H,
2
2J = 13.7, H7), 4.963 (AB system, 1H, J = 13.7, H70),
7.311 (AA0XX0 system, 2H, 3J = 8.0, Hortho-CH3),

H. Acherki et al. / Tetrahedron: Asymmetry 16 (2005) 4034–4044
4041
3
7.473 (AA0XX0, 2H, J = 13.7, Hortho-SO). 13C NMR
(125 MHz) d 21.39, 22.84, 22.91, 23.24, 24.39, 27.19,
31.23, 31.94, 33.57, 34.38, 46.83, 65.02, 99.70, 113.31,
124.37, 129.86, 141.21, 141.96, 146.12, 164.24. Anal.
Calcd for C22H27NO3S: C, 68.54; H, 7.06; N, 3.63.
Found: C, 68.32; H, 7.01; N, 3.54.
3063, 3030, 2934, 1701, 1668, 1373 cmꢀ1
.
1H NMR
(200 MHz) d 1.40–1.90 (m, 8H, cyclohexyl), 2.046 (s,
3H, CH3-Ar), 2.20–2.40 (m, 2H, cyclohexyl), 3.800 (d,
1H, 3J = 7.1, H5ax), 4.169 (d, 1H, 3J = 7.1, H4ax),
5.165, (s, 2H, H7, H70), 6.15–6.20 (m, 2H, Ar), 6.46–
6.51 (m, 2H, Ar), 6.65–6.72 (m, 2H, Ar), 6.81–6.86 (m,
4H, Ar), 6.95–7.00 (m, 4H, Ar). 13C NMR (50 MHz) d
21.04, 22.94, 24.45, 29.68, 31.27, 33.99, 42.12, 55.96,
65.27, 100.14, 115.12, 124.36, 126.42, 127.07, 127.44,
127.60, 128.09, 128.96, 130.39, 134.07, 135.99, 137.11,
140.82, 144.84, 166.70. Anal. Calcd for C31H31NO3S: C,
74.82; H, 6.28; N, 2.81. Found: C, 74.69; H, 6.21, N, 2.90.
4.2.2. (ꢀ)-(SS,5a0S,9a0R)-100-[(4-Methylphenyl) sulfinyl]-
5a0,60,70,80,90,9a0-hexahydrospiro[cyclohexane-1,30-[1,3]-
oxazolo[3,4-b]isoquinolin]-50(10H)-one (ꢀ)-10a. Method
A: Rf = 0.32 (hexane/EtAcO: 1:2; v/v). Colourless oil.
25
½aꢁD ¼ ꢀ70:3 ðc 0:7; CHCl3Þ. IR (CCl4) 2940, 1675,
1390 cmꢀ1 1H NMR (500 MHz) d 0.850 (qd, 1H,
.
2J = 12.6, 3J = 12.6, 12.6, 3.2, cyclohexyl), 0.980 (qt,
4.2.4.
(+)-(SS,60S,70S)-60-Methyl-80-[(4-methylphenyl)
1H, 2J = 12.9, 3J = 12.9, 12.9, 3.4, 3.4, cyclohexyl),
sulfinyl]-70-phenyl-60,70-dihydrospiro[cyclohexane-1,30-[1,3]-
oxazolo]3,4-a]pyridin]-50(10H)-one, 12a, and (+)-(SS,60R,
70S)-60-methyl-80-[(4-methylphenyl)sulfinyl]-70-phenyl-60,
70-dihydrospiro[cyclohexane-1,30-[1,3]oxazolo[3,4-a]pyri-
din]-50(10H)-one, 12b. Method A: From methyl and iso-
propyl (E)-a-methylcinnamate. The last ene ester was
obtained from the a-methylcinnamic acid and isopropyl
alcohol following the standard Fischer procedure. The
crude ester was distilled at 150 ꢁC (0.1 Torr) (70% yield).
After addition of ene ester, the reaction mixtures were
stirred at rt for 16 h. The crude products were chro-
matographed on silica gel using gradient mixtures of
hexane and ethyl acetate (1:1 to 3:2) as eluent to give
79 mg of 12a and 11 mg of 12b. Yield: 48%.
2
3
1.200 (qt, 1H, J = 13.1, J = 13.1, 3.4, 3.4, cyclohexyl),
1.270 (qt, 1H, 2J = 12.2, 3J = 12.2, 12.2, 3.5, cyclo-
hexyl), 1.390 (qt, 1H, 2J = 13.4, 3J = 13.4, 13.4, 4.1,
4.1, cyclohexyl), 1.58–1.74 (m, 9H, cyclohexyl), 2.33–
2.46 (m, 4H, cyclohexyl), 2.422 (s, 3H, CH3-Ar), 2.684
(td, 1H, 3J = 6.3, 6.3, 2.7, H5ec), 2.703 (dt, 1H,
3J = 6.3, 6.3, 3.5, H4ax), 4.953 (AB system, 1H,
2J = 13.7, H7), 4.987 (AB system, 1H, J = 13.7, H70),
2
7.304 (AA0XX0 system, 2H, 3J = 8.0, Hortho-CH3),
7.507 (AA0XX0 system, 2H, 3J = 8.0, Hortho-SO). 13C
NMR (125MHz) d 21.41, 21.84, 22.81, 22.93, 24.42,
25.77, 27.78, 30.88, 31.25, 34.15, 43.52, 99.13, 114.75,
124.41, 129.84, 138.88, 141.41, 142.61, 168.98. Anal.
Calcd for C23H29NO3S: C, 69.14; H, 7.32; N, 3.51.
Found: C, 69.00; H, 7.21; N, 3.42.
Compound 12a: Rf = 0.21 (hexane/EtAcO: 1:1; v/v).
25
½aꢁD ¼ þ90:1 ðc 0:74; CHCl3Þ. Yellow oil. IR (film)
1
4.2.3. (+)-(SS,60R,70S)-60,70-80-[(4-methylphenyl) sulfinyl]-
60,70-diphenyl-60,70dihydrospiro[cyclohexane-1,30-[1,3]-oxa-
zolo[3,4-a]pyridin]-50(1H)-one, 11a, and (+)-(SS,60S,70S)-
80-[(4-methylphenyl) sulfinyl]-60,70-diphenyl-60,70-dihydro-
spiro[cyclohexane-1,30-[1,3]oxazolo[3,4-a]pyridin]-50(1H)-
one 11b. Method A: From methyl (E)-a-phenylcinna-
mate. The ene ester was obtained from a-phenylcin-
namic and methanol following the standard Fischer
procedure in 89% yield. After the ene ester was added,
the reaction mixture was stirred at rt for 20 h. The crude
product was chromatographed on silica gel using gradi-
ent mixtures of hexane and ethyl acetate as eluent to give
89 mg (63% yield) of (+)-11a and 10 mg (7% yield) of
(+)-11b.
2962, 2928, 1697, 1261 cmꢀ1. H NMR (200 MHz) d
1.188 (d, 3H, 3J = 7.3, CH3-C5), 1.52–1.68 (m, 8H,
cyclochexyl), 2.116 (s, 3H, CH3-Ar), 2.27–2.32 (m, 2H,
3
cyclohexyl), 2.479 (qd, 1H, J = 7.3, 1.7, H5ec), 3.405
(d, 1H, 3J = 1.7, H4ax), 5.077 (AB system, 1H,
2
2J = 13.9, H7), 5.116 (AB system, 1H, J = 13.9, H70),
6.545 (AA0XX0 system, 2H, 3J = 7.8, Hortho Ar-C4),
6.868 (AA0XX0 system, 2H, 3J = 8.3, Hortho Ar-C4),
6.77–6.92 (m, 3H, Ar), 7.098 (AA0XX0 system, 2H,
3J = 8.3, Ar). 13C NMR (50 MHz) d 12.11, 17.64,
21.08, 22.77, 22.882, 24.30, 31.22, 33.75, 46.48, 64.95,
99.27, 111.43, 124.42, 126.31, 129.07, 137.16, 140.91,
140.93, 143.20, 169.72. Anal. Calcd for C26H29NO3S:
C, 71.69; H, 6.71; N, 3.22. Found: C, 71.82; H, 6.57,
N, 3.40.
Compound 11a: Rf = 0.48 (hexane/EtAcO: 1:1; v/v).
25
½aꢁD ¼ þ314:05 ðc 0:42; CHCl3Þ. Yellow oil. IR (CCl4)
Compound 12b: Rf = 0.15 (hexane/EtAcO: 1:1; v/v).
3373, 3063, 2935, 1693, 1599, 1371 cmꢀ1
.
1H NMR
Yellow oil. IR film 2971, 2935, 1698, 1252 cmꢀ1
.
1H
3
200 MHz d 1.40–1.80 (m, 8H, cyclohexyl), 2.130 (s,
3H, CH3-Ar), 2.20–2.37 (m, 2H, cyclohexyl), 3.635 (d,
1H, 3J = 1.4, H5ec), 3.998 (d, 1H, 3J = 1.4, H4ax),
5.061 (AB system, 1H, 2J = 14.2, H7), 5.141 (AB system,
NMR (200 MHz) d 0.792 (d, 3H, J = 7.3, CH3-C5),
1.40–1.83 (m, 8H, cyclohexyl), 2.112 (s, 3H, CH3-Ar),
2.24–2.41 (m, 2H, cyclohexyl), 2.937 (quint., 1H,
3J = 7.3, H5ax), 3.643 (d, 1H, 3J = 7.3, H4ax), 5.062
(AB system, 1H, 2J = 13.9, H7), 5.088 (AB system,
2
1H, J = 14.2, H70), 6.66–7.33 (m, 14H, Ar). 13C NMR
2
(50 MHz) d 21.12, 22.75, 22.79, 24.30, 31.27, 33.54,
41.65, 56.27, 64.92, 99.40, 111.50, 124.47, 126.53,
126.60, 126.92, 127.64, 128.61, 128.85, 129.18, 137.33,
140.91, 141.05, 143.04, 166.46 Anal. Calcd for
C31H31NO3S: C, 74.82; H, 6.28; N, 2.81. Found: C,
74.90; H, 6.32, N, 2.65.
1H, J = 13.9, H70), 6.461 (AA0XX0 system, 2H,
3J = 8.2, Ar), 6.780 (AA0XX0 system, 2H, 3J = 8.3,
Ar), 6.67–6.99 (m, 3H, Ar), 7.033 (AA0XX0 system,
3
2H, J = 8.3, Ar). 13C NMR (50 MHz) d 11.56, 21.05,
22.89, 24.38, 24.95, 31.44, 39.81, 41.93, 42.98, 65.16,
99.62, 114.69, 124.37, 126.30, 127.96, 128.97, 136.29,
137.89, 139.97, 140.68, 144.94, 166.90. Anal. Calcd for
C26H29NO3S: C, 71.69; H, 6.71; N, 3.22. Found: C,
71.49; H, 6.63; N, 3.30.
Compound 11b: Rf = 0.17 (hexane/EtAcO: 1:1; v/v).
25
½aꢁD ¼ þ154:05 ðc 0:6; CHCl3Þ. Yellow oil. IR (CCl4)

4042
H. Acherki et al. / Tetrahedron: Asymmetry 16 (2005) 4034–4044
4.2.5. (SS,60S/R,70R/S)-60,70-Dimethyl-80-[(4-methylphen-
yl)sulfinyl]-60,70-dihydrospiro[cyclohexane-1,30-[1,3]oxa-
zolo[3,4-a]pyridin]-50(10H)-one, 13a/13b and 13c/13d.
Method A: From ethyl (E)-a-methylcrotonate. After
the ene ester was added, the reaction mixture was stirred
at rt for 16 h. The crude product was chromatographed
on silica gel (hexane/EtAcO: 3:2; v/v) to obtain two frac-
tions of Rf = 0.28 (86 mg; 77% yield) and Rf = 0.15
(18 mg, 16% yield), which were identified as a mixture
of two isomers.
propyl (E)-4,4,4-trifluoromethyl propenoate. After the
ene ester was added, the reaction mixture was stirred
for 12 h at rt. The crude was flash chromatographed
on silica gel (hexane/EtAcO: 2:1; v/v). Obtained
138 mg (75% yield) as a sole isomer.
Compound 14: Rf = 0.22 (hexane/EtAcO: 2:1; v/v).
25
½aꢁD ¼ þ50:4 ðc 0:46; CHCl3Þ. Colourless solid. Mp
1
151–153 ꢁC. IR (KBr) 3924, 1709, 1662, 1375 cmꢀ1. H
NMR (500 MHz) d 1.47–1.67 (m, 8H, cyclohexyl),
2.21–2.50 (m, 3H, cyclohexyl, H5ec), 2.352 (s, 3H,
CH3-Ar), 2.750 (dd, 1H, 2J = 17.1, 3J = 1.7, H5ec),
First fraction: 13a/13b. Rf = 0.16 (hexane/EtAcO: 3:2;
v/v). Colourless oil. 1H NMR (500 MHz) d 13a: 0.433 (d,
3H, 3J = 7.2, CH3-C4), 1.050 (d, 3H, 3J = 7.0, CH3-C5),
1.51–1.72 (m, 8H, cyclohexyl), 2.30–2.38 (m, 2H, cyclo-
3
3
2.940 (ddq, 1H, JH,F = 3J = 8.3, J = 1.7, H4ax), 5.014
(AB system, 1H, 2J = 14.6, H7), 5.033 (AB system,
2
1H, J = 14.6, H70), 7.259 (AA0XX0 system, 2H,
3
hexyl), 2.395 (s, 3H, CH3-Ar), 2.287 (qd, 1H, J = 7.2,
3J = 8.0, Hortho-CH3), 7.429 (AA0XX0 system, 2H,
3J = 8.0, Hortho-SO). 13C NMR (125 MHz) d 21.34,
22.59, 22.83, 24.18, 31.39, 33.30, 33.33, 35.42 (d,
3JC,F = 31.3), 65.43, 100.27, 105.07, 127.01 (q,
1JC,F = 133.1),124.14, 130.31, 138.96, 141.61, 19.38,
163.59. Anal. Calcd for C20H22F3NO3S: C, 58.10; H,
5.36; N, 3.39. Found: C, 58.23; H, 5.27; N, 3.53.
3
1.7, H5ec), 2.432 (qd, 1H, J = 7.2, 1.7, H4ax), 4.988 (s,
2H, H7, H70), 7.292 (AA0XX0 system, 2H, 3J = 8.3,
Hortho-CH3), 7.495 (AA0XX0 system, 2H, 3J = 8.3,
3
Hortho-SO). 13b: 0.266 (d, 3H, J = 7.0, CH3-C4), 1.090
(d, 3H, 3J = 6.6, CH3-C5), 1.51–1.72 (m, 8H, cyclohexyl),
2.30–2.38 (m, 2H, cyclohexyl), 2.408 (s, 3H, CH3-Ar),
2.681 (qd, 1H, 3J = 7.0, 5.5, H5ax), 2.705 (qd, 1H,
3J = 6.6, 5.5, H4ax), 4.966 (s, 2H, H7, H70), 7.302
(AA0XX0 system, 2H, 3J = 8.5, Hortho-Me), 7.505 (AA0X0
4.3. Synthesis of (+)-(5aS,8aS,9aS)-octahydro-50H-
spiro[cyclohexane-1,30-cyclopenta[d][1,3]oxazolo[3,4-a]-
pyridin]-50-one, (+)-15
3
system, 2H, J=8.5, Hortho-SO).13C NMR (125 MHz) d
13a: 15.89, 18.99, 21.34, 22.72, 22.80, 24.27, 30.69,
30.89, 33.88, 45.17, 64.70, 98.85, 113.50, 124.43, 129.77,
138.91, 141.00, 141.40, 170.59. 13b: 11.09, 12.32, 20.97,
22.80, 22.96, 24.35, 28.53, 31.04, 33.98, 42.54, 64.76,
98.97, 116.26, 128.47, 129.85, 138.48, 141.44, 142.69,
169.77. Anal. Calcd for C21H27NO3S: C, 67.53; H, 7.29;
N, 3.75. Found: C, 67.47; H, 7.38, N, 3.60.
To a stirred solution of (ꢀ)-9a (460 mg, 1.19 mmol) in
absolute EtOH (20 mL) was added Raney Nickel W-214
(2.3 g) and the reaction mixture refluxed for 20 min.
Then, it was cooled until rt, filtered on a thin pad of
Celite and the metallic salts washed with ether
(5 · 10 mL). The combined organic extracts were evapo-
rated at reduced pressure to give a colourless solid that
was purified by flash chromatography (silica gel; hex-
ane/EtAcO: 1:1; v/v). Obtained: 289 mg 97% yield.
Second fraction: 13c/13d. Rf = 0.31 (hexane/EtAcO:
1
3:2; v/v). Yellow oil. H NMR (500 MHz) d 13c: 0.974
(d, 3H, 3J = 6.8, CH3-C4), 1.014 (d, 3H, 3J = 6.8,
CH3-C5), 1.30–1.82 (m, 8H, cyclohexyl), 2.20–2.34 (m,
2H, cyclohexyl), 2.269 (quint., 1H, 3J = 6.8, H5ec),
Rf = 0.41 (hexane/EtAcO: 1:1; v/v). Colourless solid.
25
Mp 78–80 ꢁC. ½aꢁD ¼ þ42:0 ðc 0:7; CHCl3Þ. IR (KBr)
1
2935, 2852, 1630, 1448 cmꢀ1. H NMR (500 MHz) d
3
3
2.310 (quint, 1H, J = 6.8, H4ec), 2.353 (s, 3H, CH3-
1.040 (dt, 1H, 2J = 3J = 12.6, J = 11.3, H50), 1.24–
2
2
3
Ar), 4.778 (AB system, 1H, J = 13.6, H7), 5.019 (AB
1.32 (m, 1H, H150), 1.370 (dt, 1H, J = 12.7, J = 7.5,
2
system, 1H, J = 13.6, H70) 7.249 (AA0XX0 system,
7.5, 5.6, H140), 1.43–1.57 (m, 9H, cyclohexyl), 1.840
3
3
2H, J = 8.3, Hortho-CH3), 7.370 (AA0XX0 system, 2H,
(dddt, 1H, 2J = 3J = 13.1, J = 9.3, 9.3, 7.7, H160),
3
3J = 8.3, Hortho-SO). 13d: 0.511 (d, 3H, J = 7.3, CH3-
1.950 (ddt, 1H, 2J = 12.7, 3J = 7.6, 7.6, 5.1, H14),
1.980 (ddd, 1H, 2J = 12.6, 3J = 5.6, 2.6, H5), 2.090
(dddd, 1H, 2J = 12.7, 3J = 9.3, 7.9, 4.3, H16), 2.370
C5), 1.134 (d, 3H, 3J = 7.0, CH3-C4), 1.30–1.82 (m,
8H, cyclohexyl), 2.139 (ABX3 system, 1H, 3J = 7.3,
1.8, H5ax), 2.20–2.34 (m, 3H, cyclohexyl, H4ec), 2.247
(s, 3H, CH3-Ar), 4.809 (AB system, 1H, 2J = 13.6,
3
(dddt, 1H, J = 12.6, 9.2, 7.6, 5.6, 5.6, H4), 2.500 (dt,
1H, 2J = 3J = 13.3, 3J = 4.6, H9ax), 2.559 (dt, 1H,
2
3
3
H7), 5.033 (AB system, 1H, J = 13.6, H70), 7.308
2J = 3J = 14.0, J = 4.3, H13ax), 2.680 (q, 1H, J = 9.3,
H3), 3.450 (dd, 1H, 2J = 8.6, 3J = 9.9, H7), 3.690 (dddd,
1H, 3J = 11.3, 9.9, 5.9, 2.6, H6), 4.080 (dd, 1H, 2J = 8.6,
3J = 5.9, H70). 13C NMR (125 MHz) d 23.01, 23.07,
24.55, 29.80, 30.97, 32.67, 33.40, 33.87, 37.26, 46.02,
57.01, 68.86, 95.62, 170.15. Anal. Calcd for
C15H23NO2: C, 72.25; H, 9.30; N, 5.62. Found: C,
72.17; H, 9.3; N, 5.40.
(AA0XX0 system, 2H, 3J = 8.3, Hortho-Me), 7.355
(AA0X0 system, 2H, 3J = 8.3, Hortho-SO). 13C NMR
(125 MHz) d 13c: 11.10, 14.86, 21.35, 22.78, 22.90,
24.39, 31.41, 31.57, 33.82, 42.30, 64.74, 99.08, 115.40,
124.18, 129.97, 140.03, 140.91, 142.73, 169.16. 13d:
16.3, 21.03, 21.86, 22.82, 23.01, 27.00, 33.06, 31.22,
36.03, 44.98, 72.43, 95.51, 113.36 124.07, 129.97,
139.62, 140.79, 141.00, 170.01. Anal. Calcd for
C21H27NO3S: C, 67.53; H, 7.29; N, 3.75. Found: C,
67.68; H, 7.32, N, 3.67.
4.4. Synthesis of (+)-(3S,4aS,7aS)-3-(hydroxymethyl)
octahydro-1H-cyclopenta[c]pyridin-1-one, (+)-16a
4.2.6. (SS,70S)-80-[(4-Methylphenyl)sulfinyl]-70-(trifluoro-
methyl)-60,70-dihydrospiro[cyclohexane-1,30-[1,3] oxazolo-
[3,4-a]pyridin]-50(10H)-one, 14. Method B: From iso-
A stirred solution of (+)-15 (147 mg, 0.59 mmol) in
AcOH (10% v/v in H2O, 20 mL) was refluxed for 12 h.
Next, the reaction mixture was kept at rt for 12 hours

H. Acherki et al. / Tetrahedron: Asymmetry 16 (2005) 4034–4044
4043
then the temperature was reduced to 0 ꢁC and an aque-
Acknowledgements
We gratefully acknowledge the Spanish DGI (Ministerio
ous saturated solution of NaHCO3 carefully added until
pH 7. The reaction mixture was then extracted with
CHCl3/i-PrOH (8 · 15 mL; 80/20; v/v). The combined
organic layer was dried over Na2SO4, filtered and con-
centrated under reduced pressure at rt. The crude prod-
uct (98 mg; yield: 98%) was directly transformed in the
´
de Educacion y Ciencia) (Project: BQU2000-0792) for
support of this research. We would also like to thank
UCM for its facilities of Gaussian calculations and
NMR and Elemental Analysis Services.
carboxylic acid. Rf = 0.1 (EtAcO/EtOH: 3:1; v/v).
25
½aꢁD ¼ þ16:8 ðc 0:1; CHCl3Þ. Colourless solid. Mp
1
89–92 ꢁC. IR (KBr) 3265, 2926, 1622 cmꢀ1. H NMR
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(200 MHz) d 1.10 (dt, 1H, J = 12.9, J = 11.2, cyclo-
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25
less solid. Mp 42–45 ꢁC. ½aꢁD ¼ þ2:1 ðc 2:1; CHCl3Þ.
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3
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H100), 1.960 (tdd, 1H, J = 13.2, J=8.1, 8.1, 5.8, H8),
2.150 (dddd, 1H, 2J = 13.1, 3J = 9.1, 7.6, 4.4, H10),
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3
(ddddd, 1H, J = 12.5, 9.0, 8.0, 5.0, 4.4, H4ax), 2.690
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