A new approach to vinyl glycine derivatives from (+)-(RS)-3-[(p- toluenesulfinyl)methyl]-1-oxa-4-azaspiro[4,5]decen-3-ene

Article abstract of DOI:10.1016/j.tetasy.2004.09.010

The diastereoselective reduction of α-benzyl-α-sulfinylketimine 1a with DIBAL-H/ZnCl₂, LiEt₃BH, and NaCNBH ₃/AcOH-TFA has been studied. Under the first conditions, the reaction was completely stereoselective and the sulfinyl group involving the formation of a chelated complex with the metallic ion became the sole chiral controller, regardless of the presence of the α-stereocentre. The title compound 6-I was derivatized as cyclic carbamate 2 and the base induced desulfinylation of this compound allowed the synthesis of the enantiomerically pure N,O-protected N-cyclohexyl-1,2-amino alcohol 3 with total regio- and stereocontrol.

Full text of DOI:10.1016/j.tetasy.2004.09.010

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3419–3426
A new approach to vinyl glycine derivatives from
(+)-(RS)-3-[(p-toluenesulfinyl)methyl]-1-oxa-4-
azaspiro[4,5]decen-3-ene
b
Hassan Acherki,a Carlos Alvarez-Ibarra,a, Gonzalo Garcıa-Navazo,
*
´
Elena Gomez-Sanchez and Marıa L. Quiroga-Feijoo
c
a
´
´
´
´
a
´ ´ ´
Departamento de Quımica Organica, Facultad de Ciencias Quımicas, Universidad Complutense,
Ciudad Universitaria, 28040 Madrid, Spain
b
´ ´ ´
Departamento de Quımica Organica, Facultad de Farmacia (Campus Universitario), Universidad de Alcala de Henares,
´
Ctra., Madrid-Barcelona, Km. 33,600, 28871 Alcala de Henares, Madrid, Spain
c
´ ´
Instituto de Quımica Organica General, CSIC, c/ Juan de la Cierva, 3, 28006 Madrid, Spain
Received 19 July 2004; accepted 9 September 2004
Dedicated to the memory of Juan Carlos del Amo-Aguado
Abstract—The diastereoselective reduction of a-benzyl-a-sulfinylketimine 1a with DIBAL–H/ZnCl2, LiEt3BH, and NaCNBH3/
AcOH–TFA has been studied. Under the first conditions, the reaction was completely stereoselective and the sulfinyl group involv-
ing the formation of a chelated complex with the metallic ion became the sole chiral controller, regardless of the presence of the a-
stereocentre. The title compound 6-I was derivatized as cyclic carbamate 2 and the base induced desulfinylation of this compound
allowed the synthesis of the enantiomerically pure N,O-protected N-cyclohexyl-1,2-amino alcohol 3 with total regio- and
stereocontrol.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
tives,6 Heck coupling approaches,7 and the Mannich
reaction involving its three components, the organobo-
ronic acid or boronate, the amine and a a-keto acid.8
b,c-Unsaturated a-amino acid derivatives have received
special attention since they are important enzyme inhibi-
tors. For example, it is known that a-vinyl amino acids
are inhibitors of pyridoxal phosphate-dependent en-
zymes and, in particular, of amino acid decarboxylases.1
They are also potential precursors to new a-branched
a-amino acids as building blocks for the novo peptide
design.2 Their unique conformational properties have
also been a matter of particular interest.3 The majority
of the synthetic efforts towards b,c-unsaturated amino
acids have been specifically directed towards vinyl gly-
cine,4 with few reports describing routes towards other
b,c-unsaturated amino acids.4b However, some general
strategies have been reported including olefination of
serine derivatives,5 reduction of alkynyl glycine deriva-
Herein we report our progress in the evaluation of the
ability of the sulfinyl group to control stereoselecti-
vity9,10 in the reduction of sulfinylketimine 1a (Chart
1). Previous studies have shown that analogue 1b (Chart
1) is reduced with DIBAL–H/ZnCl2 with total stereo-
control.11 Bearing this in mind, the first question to
address was whether the a-benzyl derivative 1a displays
a similar behaviour in spite of the new stereocentre at
the a-position.
Moreover, the elimination of the sulfinyl group under
basic conditions has been proved possible in the synthe-
sis of c,d-unsaturated b-amino alcohols in a regio- and
stereoselective manner. This methodology could be ap-
plied to the synthesis of b,c-unsaturated a-amino acids.
*
Herein we prove the capability of the sulfinyl group to
solely determine the stereoselective outcome of the
Corresponding author. Tel.: +34 91 3944223; fax: +34 91 3944103;
e-mail: caibarra@quim.ucm.es
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.09.010

3420
H. Acherki et al. / Tetrahedron: Asymmetry 15 (2004) 3419–3426
EtOAc: 2/1, 1/1, 1/2) in 72% yield. The analysis of the
spectrum between 4.5ppm (CH2O), 3.2–3.8ppm (H5,
O
0
H6, H6 ) and 2.2–2.5ppm (CH3–Ar) showed the presence
of three isomers (A:B:C = 56:34:10) (Table 1). Isomer A
was identified as a single enamine form, as shown by the
0
multiplicity of the methylene protons H6 and H6 (AB
system). Isomers B and C must be two imine epimers
0
in C5 since protons H3 and H3 appear as an apparent
O
N
O
O
N
N
H
H
Ph
Ph
H
S
S
S
O
O
p-Tol
O
p-Tol
p-Tol
(+)-1b
2
1a
0
singlet while protons H6 and H6 are split as a doublet
of doublets being appreciable its vicinal coupling with
proton H5, as shown in Table 1.
O
Ph
O
O
OH
NH
O
O
N
N
H
OEt
Compound 1a was reduced with different agents in the
conditions shown in Table 2. 1H NMR (200 or
500MHz) spectra allowed the analysis of the reaction
crudes. The assignment of the signals to protons of each
isomer was made possible by comparison with the spec-
tra of the pure isomers or concentrated fractions of
them. As shown by entries 1–3 and 4, respectively, the
reactions with DIBAL–H/ZnCl2 and LiEt3BH in THF
are fully diastereoselective in (2R)-amino alcohol 6-I
showing no dependence of the configuration of the adja-
cent stereocentre C3. This was determined by chemical
correlation between this compound and the ethyl ester
derivative of L-serine (+)-5, following the sequence de-
scribed in Scheme 1. Thus, 6-I was converted into 2-oxa-
zolidinone 2, which underwent elimination of p-
toluenesulfenic acid in the presence of DBU to afford
(+)-3. A small amount of 3 was oxidized with RuCl3/
NaIO4, and the resulting acid derivatized to ethyl (ꢀ)-
(4R)-3-cyclohexyl-2-oxo-1,3-oxazolidine-4-carboxylate
Ph
H
H
O
(+)-5
H
(+)-3
4
Chart 1.
reduction regardless of the presence of a second stereo-
centre next to the reaction site.
In addition, the sulfinyl grouping derivative 2 was re-
moved under basic conditions with entire regio- and
stereoselectivity to yield compound 3, an immediate pre-
cursor of (E)-N-cyclohexylstyryl glycine 4.12 The abso-
lute configuration was determined by chemical
correlation between the ethyl ester derivative of L-serine
(+)-5 and its enantiomeric counterpair obtained from
(+)-3 through RuCl3/NaIO4 oxidation (Chart 1).
2. Results
(ꢀ)-5 using conventional methods. The specific rotation,
25
D
½aꢁ ¼ ꢀ108:5 (c 8.6, CHCl3), was compared to that of
Compound 1a was prepared by benzylation of the a-sulf-
inylketimine 1b, which was obtained from 3-methyl-1-
oxa-4-azaspiro[4,5]dec-3-ene and methyl (SS)-(ꢀ)-p-tol-
uenesulfinate as previously reported by Khiar et al.
and ourselves.10,11 The a-sulfinylketimine 1a was iso-
lated by column chromatography using silica gel (Hex/
the derivative obtained from L-serine (OEt) as can be
seen in Scheme 1. According to the opposite sign of
the specific rotation in both compounds, (ꢀ)-5 has an
(R)-configuration and so does 6-I as a result. The reac-
tion of 1a with NaCNBH3 in AcOH/TFA was less stereo-
selective (Table 2, entry 5). Before purification, the
Table 1. 1H NMR (200MHz) spectroscopic dataa of compound 1a in CDCl3
b
1
O
3
NH
4
O
N
6
H
Ph
5
Ph
S
S
O
p-Tol
O
p-Tol
A
B/C
Isomer A
Isomer B
Isomer C
4.417
(AB system, 1H, 2J = 15.0, H3)
4.378
4.505
(s, 2H, H3, H3 )
3.907
4.865
(s, 2H, H3, H3 )
0
0
3.739
(dd, 1H, 3J = 4.0, 11.95, H5)
3.537
(dd, 1H, 2J = 13.1, 3J = 11.95, H6)
3.305
(dd, 1H, 2J = 13.1, J = 11.95, H6 )
2.408
(s, 3H, Me–Ar)
2
(AB system, 1H, J = 15.0, H30)
3.796
(dd, 1H, 3J = 6.6, 9.8, H5)
3.412
(AB system, 1H, 2J = 14.6, H6)
3.697
(dd, 1H, 2J = 14.0, J = 9.8, H6 )
3.217
(dd, 1H, 2J = 14.0, J = 9.8, H6 )
2.408
(s, 3H, Me–Ar)
3
0
2
(AB system, 1H, J = 14.6, H6 )
3
3
0
0
0
2.392
(s, 3H, Me–Ar)
a Chemical shifts are given in ppm, and coupling constants inHz.
b Spectroscopic data showing no difference are not included: 7.60–7.15 (m, 9H, Ar) and 1.71–1.30 (m, 10H, cyclohexyl).

H. Acherki et al. / Tetrahedron: Asymmetry 15 (2004) 3419–3426
Table 2. Reduction of 1a with different reducing agents (M–H)
3421
NH
NH
M-H
(LA)
S
1a
R
+
HO
HO
Ph
Ph
S(O)p-Tol
H
S(O)p-Tol
H
6-II
6-I
Entry
M–H (equiv)
LA (equiv)
Solvent
T (ꢁC)
Time (h)
Yield (%)
6-I/6-IIa (3R/3S)
1
2
3
4
5
DIBAL (2)
DIBAL (5)
DIBAL (5)
LiEt3BH
ZnCl2 (1.5)
ZnCl2 (2.0)
ZnCl2 (2.0)
THF
THF
DCM
THF
ꢀ78 to 23
ꢀ78 to 23
ꢀ78 to 23
0 to 23
16
16
16
12
12
35
98
98
19
92
56/43:<2
44/56:<2
44/56:<2
—
—
1
0/92:<8
47/18.5:23.5/11b
NaCNBH3
AcOH/TFA
0 to 23
a Diastereoselectivity was determined by H NMR (500 or 200MHz) analysis of the reaction crudes, using the chemical shifts of the AB part of the
ABX system corresponding to the HO–CH2–CH rest of each isomer. The assignment 3R/3S can be changed.
b A: 47%; B: 18.5%; C: 23.5%; D: 11%.
O
NH
H
O
O
Im2CO
DMAP
O
N
i) RuCl3/NaIO4
HO
DBU
O
N
H
Ph
O
N
ii) Cl2SO
iii) EtOH
Ph
S
∆
H
O
CO2Et
H
S
p-Tol
Ph
H
(+)-3
O
p-Tol
(-)-5
6-I
[α]D25= -108.5 (c
8.6, CHCl3)
2
O
i)
O
,
∆
Im2CO
NH2.HCl
CO2Et
NH
O
N
S
HO
HO
H
DMAP
H
CO2Et
ii) NaBH4, MeOH
CO2Et
(+)-5
[α]D25= +110 (c 3.7, CHCl3)
H
L-ser (OEt)
6
Scheme 1.
1
analysis of the spectral zones between 3.2–4.0ppm
(ABX system, HO–CH2) and 2.4–2.5ppm (Me–Ar) of
The H NMR (500MHz) spectra of the fractions al-
lowed the characterization of the different isomers, and
also their distribution in each fraction [fraction 1: A
(59%), D (41%); fraction 2: A (63%), B (37%); fraction
3: C (100%)]. The spectroscopic data are summarized
in Table 3.
1
the H NMR spectra (200MHz) of the crude showed
the presence of four isomers: A (47%), B (18.5%), C
(23.5%) and D (11%). The crude was then purified by
column chromatography in silica gel (DCM/acetone: 1/1).
Table 3. 1H NMR (500MHz) spectroscopic data for the configurational isomers 6-I (2R,3R/3S) and 6-II (2S,3R/3S)a
H
1
NH
3
HO
2
4
Ph
H
S(O)-p-Tol
Signal
H1
6-I (2R,3R/3S)
6-II (2S,3R/3S)
A
B
C
D
3.914 (ABX); 2J = 12.1, 3J = 3.7
3.700 (ABX); 2J = 12.1, 3J = 5.4
3.07–3.03 (m)
3.710 (ABX) 2J = 11.6, 3J = 6.6 3.720 (ABX); 2J = 10.6, 3J = 5.2
3.450 (ABX) 2J = 11.6, 3J = 3.7 3.659 (ABX); 2J = 10.6, 3J = 6.2
3.800 (m)
3.680 (m)
0
H1
H2
H3
H4
3.07–3.03 (m)
2.963 (td); 3J = 3J = 4.2, 3J = 14.6 3.00–2.93 (m)
3.150 (ddd); 3J = 6.2, 3J = 5.2, 3J = 2.5 3.40–3.25 (m)
3.168 (ddd); 3J = 7.7, 3J = 6.5 3J = 2.5 3.40–3.25 (m)
2.870 (dd); 2J = 14.3, 3J = 7.7
2.774 (dd); 2J = 14.3, 3J = 6.5
2.419 (s)
2.840 (dd); 2J = 14.7, 3J = 4.6
3.00–2.93 (m)
2.898 (dd); 2J = 13.6,
3J = 6.8
2.898 (dd); 2J = 13.6,
3J = 6.8
2.410 (s)
H4
2.762 (dd); 2J = 14.7, 3J = 3.9
2.817 (dd); 2J = 13.0, 3J = 5.7
0
Me–Ar 2.432 (s)
2.422 (s)
a Chemical shifts are in ppm, and coupling constants in Hz. All spectra were recorded in CDCl3 as solvent, using TMS as internal reference.

3422
H. Acherki et al. / Tetrahedron: Asymmetry 15 (2004) 3419–3426
as suggested by the restricted conformation A(I), and
an (R)-configuration for C3. This seems to be supported
by the significant difference in the chemical shifts of H1
H1
H
H3
H1
H
Bn
O
O
N
O
N
O
H
H
0
and H1 , indicative of a different steric shield. Since iso-
p-Tol
p-Tol
H1'
S
H1'
S
Bn
H3
mer B shows similar behaviour, an analogous trans-like
configuration can be tentatively proposed, again com-
patible with an (S)-configuration for C3 [B(I) in Fig. 1].
H2
H2
A (I)
B (I)
On the other hand, a cis-like configuration of the pseu-
do-bicyclic structure can be considered to explain the
opposite behaviour of isomer C. In this case, an equili-
brium between conformations C(II) and C(III) would
account for the low value of 3JH2,H3; it is worthy of note
that the relative stereoposition between the H2 and H3
nuclei is synclinal in both conformations. Also, the pro-
posed equilibrium would explain the similarly averaged
H3
Bn
N
O
N
O
H
H
H
H
H2
H2
p-Tol
p-Tol
S
S
Bn
H3
O
O
H1'
H1'
H1
H1
C (II)
D (II)
0
value for the chemical shifts of H1 and H1 . Thus, an
(R)-configuration for C3 is coherent with these data,
and since C and D are epimers in C3, an opposite (S)-
configuration can be assumed for D according to the
same model [D(II) and D(III); Fig. 1].
H2
H2
Bn
p-Tol
H
p-Tol
H
H1
H1
H1'
N
H
N
H3
S
S
H1'
O
O
H
O
O
Finally, transformation of compound 6-I (fraction 2) to
the cyclic carbamate 2 (Chart 1) allowed the regioselec-
tive elimination of p-toluenesulfenic acid induced by
DBU. The E configuration of compound 3 was deter-
mined from the experimental value of the vicinal cou-
pling constant (3Jtrans = 15.6Hz).
Bn
H3
C (III)
D (III)
Figure 1. Tentative structures for A, B, C and D isomers proposed on
the basis of spectroscopic data (1H NMR).
The spectrum of fraction 2 is identical to that of the
crude obtained in the reaction with DIBAL–H/ZnCl2.
This allows the identification of A and B as epimers at
C3, with an (R)-configuration for C2. In the same way,
isomers C and D must be epimers (2S,3R/3S) in this car-
bon. Both pairs of stereoisomers show very different
spectroscopic behaviour for the chemical shifts of pro-
3. Stereochemical outcomes of the 1a reduction
At this stage, it becomes necessary to comment on the
key step of the synthesis of 3, that is, the diastereoselec-
tive reduction of compound 1a. Regarding data in Table
2, it is obvious that the different systems used as reduc-
tion reagents yielded different stereochemical outcomes.
On the one hand, treatment of 1a with the DIBAL–H/
ZnCl2 (entries 1–3) system yields 6-I as a mixture of
the two epimers in C3 [(2R,3R/3S) and (2R,3S/3R)].
Two parallel reaction pathways Aꢀ and Bꢀ (Fig. 2)
would account for the observed stereochemical results.
The attack directed to the si face of the imine is pre-
ferred, the reason being the sulfinyl group (anti attack
vs p-Tol group) in the Zn-quelate complex, regardless
of the configuration of the C3 carbon.
0
tons H1 and H1 (DdA = 107Hz, DdB = 133Hz;
DdC = 30.5Hz; DdD = 24Hz). On the other hand, the
value of JH2/H3 could only be measured in the spectra
2
of fractions 2 and 3, for isomers A and C, respectively,
{[3JH2/H3]A = 14.6Hz; [3JH2/H3]C = 2.5Hz}.
3
From a first evaluation, the extreme values of JH2/H3
for A and C allows us to presume that in the conforma-
tion adopted by these isomers, H2 and H3 are in an anti-
periplanar and synclinal stereoposition, respectively. A
possible explanation for this behaviour lies in the pres-
ence of hydrogen bonding involving the basic centres
in the molecule, giving rise to the corresponding pseu-
do-bicyclic structures for A and C, as shown in Figure 1.
On the other hand, the observed stereoselectivity with
LiEt3BH is quite different. The major product in this
case is stereoisomer 6-I (2R,3S,RS). It seems that a rea-
gent both nucleophilic and basic, as the superhydride,
could make the kinetic substrate similar to an aza-enolate.
As depicted, a trans-like configuration between the two
cycles in A could account for the high value of JH2,H3
3
Cl
N
Cl
N
Cl
Cl
Zn
Zn
+
-HBEt3
Al
Al
H
H
Li
O
O
O
S
O
O
N
O
S
S
p-Tol
p-Tol
H
Bn
p-Tol
Bn
H
Bn
A
B
C
Figure 2. Proposed transition states in the diastereoselective reduction of 1a with DIBAl–H/ZnCl2 (Aꢀ and Bꢀ) and LiEt3BH (Cc).

H. Acherki et al. / Tetrahedron: Asymmetry 15 (2004) 3419–3426
3423
Thus, the si attack would be preferred owing to a chelat-
ing effect of Li+ similar to that of zinc (vide infra), so
that the (2R)-configuration in the product would be
favoured (Cꢀ; Fig. 2). Protonation of this product would
then be doubly induced by the two stereocentres Cꢂ2 and
S* (Fig. 3), the attack of the electrophile (H+) to the re
face of the enolate yielding the diastereomer (2R,3S,RS)
as major product (e.d. 84%).
ated chloroform (13C) signals. Coupling constants (J)
are reported in hertz. Multiplicities in proton spectra
are indicated as s (singlet), d (doublet), t (triplet), q
(quartet) and m (multiplet). Elemental analyses were
performed with a Perkin–Elmer 2400 C, H, N analyzer.
All reactions in non-aqueous media were carried out in
flame-dried glassware under an argon atmosphere. Rea-
gents and solvents were handled by using standard syr-
inge techniques. Tetrahydrofuran (THF) was distilled
from sodium and benzophenone, and dichloromethane
from P2O5. 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 0.25mm thickness were used, and visualized with
UV light or vainillin (acid solution in ethanol) or phospho-
molibdic acid solution (PMA, 10% in ethanol). Flash
column chromatography was carried out using Merck
silica gel (grade 60, 230–240 mesh). Deactivated silica
gel was performed by eluting with 2% aqueous solution
of NaHCO3/MeOH (5/95, v/v) until pH of the eluent
was basic, and then passing through it dry acetone.
Chemicals for the reactions were used as purchased from
the Aldrich Chemical Co. The synthesis for starting
compound (+)-1b has previously been described.
+
Li
N
H
O
S
H+
NH
H
O
S
Li+ -
O
OH
p-Tol
H+
p-Tol
Bn
Bn
Figure 3. Diastereoselective control in the protonation of the product
formed in the reduction of 1a with LiEt3BH.
Finally, the reduction of 1a with NaCNBH3 in AcOH/
TFA shows little diastereoselectivity. This is probably
due to protonation of the acetalic oxygen, which would
prevent the formation of a cyclic transition state. A
wider number of acyclic transition states would then
be formed because the non-restricted rotation of the
C2–C3 and C3–S bonds, resulting in an averaged distri-
bution of stereoisomers (Fig. 4).
5.2. Benzylation of (+)-(RS)-3-{[4-methyl(phenyl)sulfinyl]-
methyl}-1-oxa-4-azaspiro[4.5]dec-3-ene, 1b
[H-]
To a solution of 2g of (+)-1b (6.86mmol) in THF (9mL)
was added 5.57mL of a 1.6M solution of n-BuLi in hex-
ane (8.92mmol) at ꢀ50ꢁC. After stirring for 40min, a
solution of 2.35g of benzyl bromide (13.72mmol) in
THF (4mL) was added. The temperature was slowly
raised to 22ꢁC and the reaction mixture left stirring
for 12h. Next, a saturated solution of NaCl (10mL)
and EtOAc (10mL) were added and the aqueous phase
extracted with EtOAc (3 · 10mL). The combined organ-
ic extracts were washed with brine, dried over Na2SO4
and concentrated under reduced pressure. The residue
(3.5g) was purified by flash chromatography on silica
gel using hexane/EtOAc (2/1, 1/1, 1/2) as eluent. The un-
ique fraction of 1a (yield: 72%) was a mixture of enam-
ine A and two diastereomeric imines B and C
(A:B:C = 56:34:10).
+
O
H
N
O
S
H
p-Tol
Bn
[H-]
Figure 4. Open chain TSc in the stereochemical pathway of the
reduction 1a with NaCNBH3 in AcOH/TFA.
4. Conclusion
The synthesis of 3 has been achieved with complete re-
gio- and stereoselectivity in four steps with a 46% yield.
This sequence could be of general use for the synthesis
of other c,d-unsaturated amino alcohols. Taking into
account that the synthesis of the starting product 1b
can be scaled-up to multigram amounts, this can lead
to a useful strategy for the rapid generation of structur-
ally related b,c-unsaturated amino acid libraries in a
controlled manner.
5.2.1. (RS)-3-{[4-methyl(phenyl)sulfinyl]-2-phenylethyl}-
A
1-oxa-4-azaspiro[4.5]dec-3-ene, 1a.
Isomer: 1H
NMR (200MHz, CDCl3) d 1.30–1.71 (m, 10H, cyclo-
hexyl), 2.392 (s, 3H, Me–Ar), 3.637, 3.796 (AB system,
2H, 2J = 14.6Hz, CH2-S*), 4.378, 4.417 (AB system,
2
2H, J = 15.0Hz, CH2O), 7.15–7.60 (m, 9H, Ar).
1
B Isomer: H NMR (200MHz, CDCl3) d 1.30–1.71 (m,
5. Experimental
5.1. General
10H, cyclohexyl), 2.408 (s, 3H, Me–Ar), 3.217 (dd, 1H,
2J = 14.0Hz, 3J = 9.8Hz, CH2Ph), 3.412 (dd, 1H,
2J = 14.0Hz, 3J = 6.6Hz, CH2Ph), 3.907 (dd, 1H,
3J = 9.8, 6.6Hz, H–C(SO)), 4.505 (s, 2H, CH2O), 7.15–
7.60 (m, 9H, Ar).
1
The H and 13C NMR spectra were recorded at 200 or
500MHz and 50 or 125MHz, in a Bruker AC-200 or
Bruker AM-500 spectrometer, respectively, using CDCl3
for the chemical shifts, (d) refers to TMS (1H) or deuter-
1
C Isomer: H NMR (200MHz, CDCl3) d 1.30–1.71 (m,
10H, cyclohexyl), 2.408 (s, 3H, Me–Ar), 3.305 (dd, 1H,

3424
H. Acherki et al. / Tetrahedron: Asymmetry 15 (2004) 3419–3426
2J = 13.1Hz, 3J = 11.95Hz, CH2Ph), 3.537 (dd, 1H,
2J = 13.1Hz, 3J = 4.0Hz, CH2Ph), 3.739 (dd, 1H,
3J = 11.95, 4.0Hz, H–C(SO)), 4.865 (s, 2H, CH2O),
7.15–7.60 (m, 9H, Ar).
identified as a mixture of four stereoisomers A:B:C:D =
47:18.5:23.5:11. The crude product was purified by
flash chromatography on silica gel using DCM/acetone:
1/1 as eluent (92% yield). Three fractions were obtained:
fraction 1 (D: 41% and A: 59%), fraction 2 (A: 63%
and B: 37%), and fraction 3 (C: 100%). The key
spectroscopic data (1H NMR, 500MHz) are included
in Table 3.
13C NMR (50.32MHz, CDCl3) d 21.35, 21.50, 23.15,
23.20, 24.99, 25.02, 32.96, 34.15, 36.04, 36.11, 36.41,
36.50, 66.61 (B), 68.13 (A), 74.33 (A), 75.50 (B),
109.80 (B), 111.43 (A), 124.25, 125.32, 127.00, 127.10,
128.66, 128.71, 129.08, 129.10, 129.79, 129.93, 136.40,
136.81, 137.35, 138.49, 141.70 (A), 142.71 (B), 164.37
(A), 165.35 (B).
5.5.1. (RS)-2-(Cyclohexylamine)-3-[(4-methylphenyl)sulfin-
yl]-4-phenylbutan-1-ol, 6. 1H NMR (500MHz, CDCl3)
d 1.10–1.30 (m, 5H, cyclohexyl), 1.50–1.65 (m, 5H,
cyclohexyl), 2.10–2.44 (m, 1H, CH-cyclohexyl), 2.30–
2.40 (br s, 1H, NH), 2.41–2.43 (s, 3H, Me–Ar), 2.76–
2.90 (part AB of a six spins system, 1H, CH2Ph),
2.84–3.00 (part AB of a six spins system, 1H, CH2Ph),
3.25–3.40 (ddd, 1H, H2), 3.25–3.40 (ddd, 1H, H3),
3.45–3.70 (part AB of a six spins system, 1H, H1),
5.3. General procedure for DIBAL–H/ZnCl2 reduction
reactions
To a solution of 1a (1mmol) in THF (4mL), a solution
of ZnCl2 (1.5 or 2mmol) in THF (8mL) at 0ꢁC was
added under argon. After stirring for 1h at 0ꢁC, the
temperature was lowered to ꢀ78ꢁC and a 1.5M solution
of DIBAL–H in toluene (2 or 5mmol) added dropwise.
The reaction mixture was stirred for 0.5h at ꢀ78ꢁC and
then 15h at rt. Then, 2mL of MeOH were added and the
mixture concentrated under reduced pressure. The resi-
due was treated with NH4Cl (saturated solution) and
EtOAc (25mL). The aqueous phase was extracted with
EtOAc (2 · 15mL) and the combined extracts washed
with brine, dried over Na2SO4 and concentrated under
reduced pressure. The residue was analyzed by 1H
NMR (500MHz) and characterized as (RS,2R,3R/3S)-
2-(cyclohexylamine)-3-[(4-methylphenyl)sulfinyl]-4-phen-
ylbutan-1-ol (mixture of epimers A and B in C3; Tables 2
and 3).
0
3.71–3.91 (part AB of a six spins system, 1H, H1 ),
6.86–7.05 (AAꢁXXꢂ system, 2H, Hortho–Me, Tol), 7.05–
7.37 (m, 5H, Ph), 7.50–7.55 (AAꢁXXꢂ system, 2H,
Hortho–SO, Tol). 13C NMR (125MHz, CDCl3) 21.31–
21.43 (Me), 24.68–33.71 (CH2Ph, CH2 cyclohexyl),
53.63–54.72 (C3, CH cyclohexyl), 59.76–62.35 (CH2O),
67.40–72.11 (C2), 124.43–125.47 (Cortho–SO, Tol),
126.37–126.79 (Cpara, Ph), 128.55–129.94 (Cortho and
Cmeta–Ph and Cmeta–Tol), 137.82–142.07 (Cipso).
5.6. N,O-protection of 6-I
To a solution of 202mg of 6-I [epimeric mixture at C3,
(A + B)] (0.525mmol) in DCM (4mL) at rt, 298mg
(0.772mmol) of N,N-carbonyldiimidazol were added.
The reaction mixture was stirred for 16h and then con-
centrated under reduced pressure. The residue (214mg)
was purified by flash chromatography on silica gel using
DCM/EtOAc = 8/1 as eluent, yielding 200mg
(0.486mmol) of 2 (mixture of two epimeric compounds
at C3) (92% yield) as a colourless oil. 1H NMR
(200MHz, CDCl3) d 0.98–1.82 (m, 10H, cyclohexyl),
2.42 (A isomer), 2.45 (B isomer) (s, 3H, Me–Ar), 2.83–
5.4. LiEt3BH reduction
To a solution of 1g of 1a (2.622mmol) in THF (4mL) at
0ꢁC, a 1M solution of LiEt3BH in THF (3.1mL) was
added under argon. The temperature was kept at 22ꢁC
and after stirring for 2h, a saturated aqueous solution
of NaHCO3 (6mL) and 0.5mL of H2O2 (30%vol)
added. The reaction mixture was stirred for 15min and
then 10mL of H2O and 10mL of EtOAc added. The
aqueous phase was extracted with EtOAc (5 · 10mL)
and the combined extracts dried over Na2SO4, filtered
and concentrated at reduced pressure. The crude prod-
uct was analyzed by 1H NMR (200MHz) and character-
ized as (RS,2R,3R/3S)-2-(cyclohexylamine)-3-[(4-methyl-
phenyl)sulfinyl]-4-phenylbutan-1-ol (mixture of epimers)
(conversion: 19%). The results are summarized in Tables
2 and 3.
0
3.43 (m, 3H, H4, H4 3, CH-cyclohexyl), 3.43 (A isomer,
dd, 1H, J = 9.8Hz, J = 2.9Hz, H1), 3.793 (B isomer,
2
2
3
dd, 1H, J = 9.8Hz, J = 8.8Hz, H1), 4.014 (ddd, 1H,
3J = 9.0, 3.4, 2.1Hz, H3), 4.272 (A isomer, dd, 1H,
2J = 10.0Hz, 3J = 9.0Hz, H10), 4.559 (ddd, 1H,
3J = 8.9, 3.0, 2.1Hz, H2), 4.636 (B isomer, dd, 1H,
2
3
0
J = 10.0Hz, J = 3.4Hz, H1 ), 7.06–7.51 (m, 9H, Ar).
13C NMR/DEPT (50MHz, CDCl3) d A isomer: 21.28,
25.14, 25.53, 25.71, 29.31, 29.31, 29.93, 32.21, 51.34,
54.31, 64.24, 67.40, 123.85, 127.16, 128.98, 129.25,
130.04, 137.26, 138.52, 141.73, 157.91. B isomer: 21.40,
25.04, 25.74, 25.80, 27.68, 29.31, 31.31, 52.16, 54.99,
63.29, 66.44, 124.44, 126.88, 128.60, 128.81, 130.31,
136.14, 137.07, 142.53, 157.36. Anal. Calcd for
C24H29NO3S: C, 70.04; H, 7.10; N, 3.40. Found: C,
70.12; H, 7.22; N, 3.01.
5.5. NaCNBH3–AcOH–TFA reduction
To a solution of 1g of 1a (2.622mmol) in AcOH (4mL)
at 0ꢁC, 4lL of TFA and 576.3mg of NaCNBH3
(9.26mmol) were added under argon. After stirring for
12h at 0ꢁC, a 3M solution of NaOH was added
dropwise until neutral pH. The reaction mixture
was then extracted with DCM (3 · 10mL) and the
combined extracts washed with brine, dried over
Na2SO4, filtered and concentrated at reduced pressure.
5.7. Base induced desulfinylation of 2
To a solution of 200mg (0.486mmol) of 2 in toluene
(7mL) were added 615mg (4.04mmol) of DBU. The
reaction mixture was stirred at 70ꢁC during 4days.
1
The residue (929mg) was analyzed by H NMR and

H. Acherki et al. / Tetrahedron: Asymmetry 15 (2004) 3419–3426
3425
Next, a 20% solution of NH4Cl (10mL) and DCM
(10mL) were added and the aqueous phase was ex-
tracted with DCM (3 · 10mL). The combined extracts
were dried over Na2SO4, filtered and concentrated under
reduced pressure. The residue (107mg) was purified by
flash chromatography on silica gel (hexane/EtOAc = 1/1).
The product (93mg, 70.5% yield) was isolated as a col-
ourless oil and identified as 3.
5.8.2. Synthesis of ethyl (+)-(4S)-3-cyclohexyl-2-oxo-1,3-
oxazolidine-4-carboxylate from ethyl L-serinate, (+)-5.
To a solution of 300mg (1.77mmol) of L-serine. HCl in
anhydrous MeOH (4mL) at 0ꢁC were added 179.1mg
(1.77mmol) of Et3N and the mixture stirred at 0ꢁC for
10min. The temperature was then raised to 22ꢁC and
0.183mL (1.77mmol) of cyclohexanone added. After
stirring the reaction mixture for 2h, the temperature
was kept at 0ꢁC and 134mg (3.54mmol) of NaBH4
added over 30min. The temperature was raised to
22ꢁC and the reaction mixture stirred for 12h. Next,
15mL of a 20% solution of HCl and 15mL of Et2O were
added and the aqueous phase extracted with Et2O
(3 · 15mL). The combined organic extracts were
washed with brine, dried over Na2SO4 and concentrated
under reduced pressure. The residue (273mg) was iden-
tified as ethyl L-N-cyclohexylserinate, which was trans-
formed without previous purification in the compound
(+)-5.
5.7.1.
(+)-(4S)-3-Cyclohexyl-4-[(E)-2-phenylvinyl]-1,3-
25
oxazolidin-2-one, 3. ½aꢁ ¼ þ110:6 (c 2.5, CHCl3);
D
1H NMR (200MHz, CDCl3) d 1.20–1.51 (m, 10H, cyclo-
hexyl), 3.570 (tt, 1H, Jax,ax = 3Jax,ax = 11.7Hz, Jax,ec
=
3
3
3
3.9Hz, CH-cyclohexyl), 3.976 (ddd, 1H, J = 13.2, 8.5,
6.3Hz, CH–N), 4.434 (dd, 1H, 2J = 8.3Hz, 3J =
13.2Hz, CH2O), 4.523 (dd, 1H, 2J = 8.3Hz, 3J =
3
6.3Hz, CH2O), 6.100 (dd, 1H, Jtrans = 15.6Hz,
3J = 8.5Hz, CH@CHPh), 6.601 (d, 1H. 3Jtrans = 15.6Hz,
CH@CHPh), 7.30–7.42 (m, 5H, Ph). 13C NMR/DEPT
(50MHz, CDCl3) d 25.27, 25.76, 25.84, 30.06, 31.80,
54.13, 57.85, 67.36, 126.64, 127.99, 128.52, 128.80,
133.70, 135.51, 157,56. Anal. Calcd for C17H21NO2: C,
75.25; H, 7.80; N, 5.16. Found: C, 75.01; H, 7.95; N,
5.27.
5.8.2.1. Ethyl (4S)-3-cyclohexyl-2-oxo-1,3-oxazolidin-
25
D
4-carboxylate, (+)-5. ½aꢁ ¼ þ110 (c 3.7, CHCl3).
157mg were obtained (70% yield) from 198mg of crude
amino alcohol and carbonyldiimidazol under the
conditions described in Section 5.6. Spectroscopic data
were identical to those of compound (ꢀ)-5 arising from 3.
5.8. Chemical sequence to establish the configuration of 3
5.8.1. NaIO4/RuCl3 oxidation of 3. To 90mg
(0.332mmol) of 3, CH3CN (1.2mL), CCl4 (1.2mL)
and H2O (1.9mL) were added at rt. Next, 332mg
(1.36mmol) of NaIO4 and 1.5mg (0.0007mmol) of Ru-
Cl3ÆH2O were added and the reaction mixture stirred at
rt during 12h. The mixture was then extracted with
DCM (3 · 5mL) and the combined extracts dried over
Na2SO4, filtered and concentrated under reduced pres-
sure. The residue was dissolved in Et2O (10mL), and
passed through a short pad of Celite. The solvent was
concentrated and the crude product transformed with-
out further purification in the ethyl ester.
The enantiomeric excesses of the samples were con-
firmed from LIS experiment with (+)-Eu(hfc)3.
Acknowledgements
We gratefully acknowledge the Spanish DGI (Ministerio
´
de Ciencia y Tecnologıa) (Project: BQU2000-0792) for
support of this research. We would also like to thank
UCM for its facilities of NMR and Elemental Analysis
Services.
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1
CHCl3). H NMR (200MHz, CDCl3) d 1.321 (t, 3H,
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0
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59.80; H, 7.87; N, 5.71.

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