Asymmetric diastereoselective thia-hetero-Diels-Alder reactions of dithioesters

Article abstract of DOI:10.1016/j.tet.2012.01.039

Asymmetric thia-Diels-Alder reactions involving new dithioesters bearing a chiral auxiliary are described, with diastereoselectivities up to 78%. Double-stereodifferentiating experiments employing chiral substrates in the presence of a chiral Lewis acid c

Full text of DOI:10.1016/j.tet.2012.01.039

Tetrahedron 68 (2012) 2326e2335
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Asymmetric diastereoselective thia-hetero-DielseAlder reactions of dithioesters
a
b
a
a,
*
ꢀ ꢁ
Helene Dentel , Isabelle Chataigner , Jean-Franc¸ ois Lohier , Mihaela Gulea
a
ꢀ
ꢀ
ꢀ
Laboratoire de Chimie Moleculaire et Thioorganique, UMR CNRS 6507, INC3M, FR 3038, ENSICAEN, Universite de Caen Basse Normandie, 6, Bd. Marechal Juin, 14050 Caen, France
Universite de Rouen, UMR CNRS 6014, FR CNRS 3038, 76821 Mont Saint-Aignan Cedex, France
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric thia-DielseAlder reactions involving new dithioesters bearing a chiral auxiliary are de-
scribed, with diastereoselectivities up to 78%. Double-stereodifferentiating experiments employing chiral
substrates in the presence of a chiral Lewis acid catalyst have been also carried out and, in this case,
a diastereomeric excess of 90% was reached. The absolute stereochemistry of cycloadducts resulting from
dithiooxalates and carbonyloxazolidinone dithioesters was assigned based on an X-ray structure and
chemical correlation. In order to rationalize the sense of the chiral induction, stereochemical models for
Cu(II)/bis(oxazoline)/dithioester complexes are proposed.
Received 18 December 2011
Received in revised form 12 January 2012
Accepted 13 January 2012
Available online 21 January 2012
Keywords:
Asymmetric thia-hetero-DielseAlder
reaction
Ó 2012 Elsevier Ltd. All rights reserved.
Chiral dithioester
Bis(oxazoline)
Cu(II) catalyst
Double-stereodifferentiating experiments
Theoretical study
1. Introduction
computational means for the oxazolidinone dithioester, which rep-
resents a particular case.
The asymmetric carbo- and hetero-DielseAlder (DA and HDA)
reactions represent a powerful and atom-economical synthetic
method to obtain optically active six-membered carbocycles and
heterocycles.1 Compared to the asymmetric carbo-, oxa-, and aza-
DielseAlder reactions, the thia-DielseAlder version has received
much less attention, despite its potential utility to afford optically
active dihydrothiopyrans, in particular for thiaglycosidic struc-
tures.2,3 Only a few examples of asymmetric diastereoselective
versions involving a chiral thiocarbonyl partner (chiral thiadienes4,5
or thia-dienophiles6) have been reported. Concerning the enantio-
selective catalyzed versions, only two examples have been reported,
both based on the activation of the dienophile by a chiral Lewis acid:
the first, described by Saito, involves thiadienes and acryloyl 2-
oxazolidinones,7 and the second, recently reported by us, involves
unfunctionalized dienes and dithioesters as the heterodienophiles.8
In the present work, we describe asymmetric diastereoselective
thia-DA reactions involving new dithioesters bearing a chiral
auxiliary. Double-stereodifferentiating experiments employing
chiral substrates in the presence of a chiral Lewis acid catalyst are
also presented. Stereochemical models for Cu(II)/bis(oxazoline)/
dithioester complexes are proposed according to the experimental
results. Some theoretical aspects of the reaction are investigated by
2. Results and discussion
2.1. Chiral substrates
In this study three types of chiral substrates, phosphonodithio-
formate I, dithiooxalate II, and carbonyloxazolidinone dithioester III
were selected to perform the asymmetric thia-DielseAlder cyclo-
addition (Scheme 1). The chiral dithioesters shown in Fig. 1 were
synthesized according to the described procedure used in the achiral
series.8 Commercially available enantiopure alcohols and oxazolidi-
nones commonly used in asymmetric synthesis,9,10 were chosen as
chiral auxiliaries for this purpose. In the case of dithioesters 1a,11 2a,
and 3c, the corresponding enantiomers 1a0, 2a0, and 3c0 have been
also prepared.
Z*
MeS
HDA
Z*
SMe
*
R
R
S
S
1-3
O
O
O
P
O
R*O
R*O
SMe
SMe
SMe
chiral dithioesters:
R*O
N
*
O
S
II
S
III
S
I
R
Scheme 1. Asymmetric diastereoselective thia-DA with chiral dithioesters.
* Corresponding author. E-mail address: mihaela.gulea@ensicaen.fr (M. Gulea).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.039

H. Dentel et al. / Tetrahedron 68 (2012) 2326e2335
2327
Table 1
HDA reactions of chiral dithioesters 1e3 with 2,3-dimethyl-1,3-butadiene or 1,3-
butadiene
O
P
O
P
SMe
SMe
O
O
Entry
Dithioester
R
Product
Time
dra
Yield (%)
S
S
2
2
1a
1a'
1
2
3
4
5
6
7
8
1a
1a0
2a
2a0
2b
2c
2d
2e
3a
3b
3c
3c0
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4a
4a0
5a
5a0
5b
5c
5d
5e
6a
6b
6c
6c0
24 h
24 h
2 h
2 h
5 h
3 h
3 h
1 h
72 h
72 h
48 h
48 h
69/31
69/31
59/41
59/41
50/50
61/39
55/45
51/49
53/47
57/43
89/11
89/11
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
O
O
O
O
O
SMe
SMe
SMe
SMe
O
O
O
S
2a
S
2b
S
2a'
O
O
9
S
SMe
O
O
O
O
10
11
12
O
O
S
2c
SMe
O
O
Ph
S
2e
2d
S
O
O
O
O
O
O
O
O
13
14
15
16
1a
2a
3a
3b
H
H
H
H
7a
8a
9a
9b
72 h
48 h
120 h
120 h
62/38
56/44
56/44
60/40
79
74
58
51
SMe
SMe
SMe
SMe
N
N
N
N
O
O
O
S
S
S
Bn
Bn
Bn
iPr
Ph
Ph
Ph
Ph
a
3c
3c'
3a
3b
Diastereomeric ratio determined by NMR spectroscopy in the crude mixture
(
31P NMR for 4a, 7a and 1H NMR for 5e6, 8e9).
Fig. 1. Chiral dithioesters 1e3.
than menthol) led to cycloadduct 5c with a diastereoselectivity of
22% (entry 6). Cycloadducts 5d and 5e obtained from chiral
2.2. Diastereoselective cycloadditions
dithioesters derived from (ꢀ)-borneol and
b-D-fructopyranose,
have been obtained with low diastereoselectivities of 10 and 2%,
respectively (entries 7 and 8).
Dithioesters 1e3 were reacted with simple unfunctionalized
dienes, dimethyl-1,3-butadiene, and 1,3-butadiene, in order to
evaluate the chirality transfer on one newly formed stereocenter at
first (Scheme 2, Table 1). All reactions were carried out in
dichloromethane, at room temperature, using 10 equiv of diene.
With dimethyl-1,3-butadiene (Table 1, entries 1e12) we observed
full conversions that translated into quantitative yields for the ex-
pected cycloadducts 4e6. Purifications on chromatographic col-
umn were unnecessary, the reaction mixtures were clean enough to
isolate the adducts in pure form. The cycloadditions with 1,3-
butadiene (Table 1, entries 13e16) were performed in a pressure
tube and were not completed even after several days (56e82%
conv). After separation by column chromatography from the
starting unconsumed dithioesters, the resulting cycloadducts were
obtained in moderate to good yields (51e79%). As observed in the
case of achiral dithioesters, dithiooxalates reacted faster than
phosphonodithioformates and the oxazolidinone dithioesters were
the least reactive (Table 1, compare entries 3, 1, and 9).
Dithioesters 3a and 3b, derived from chiral 4-isopropyl and 4-
benzyl oxazolidinones, led to cycloadducts 6a and 6b with dia-
stereoselectivities of 6 and 14%, respectively (entries 9 and 10).
However, with a more hindered oxazolidinone (having the benzyl
group in 4-position and two phenyl groups in 5-position), a much
higher diastereomeric excess of 78% was observed for cycloadduct
6c (entry 11).
As expected, reactions with 2,3-dimethyl-butadiene dithioest-
ers 1a0, 2a0, and 3c0 induced an opposite chiral induction compared
to the one of their enantiomers 1a, 2a, and 3c, leading to cyclo-
adducts 4a0, 5a0, and 6c0 with 38%, 18%, and 78% de, respectively
(Table 1, entries 2, 4, and 12).
The reactions with 1,3-butadiene were effected with dithioest-
ers 1ae3a, and 3b. The diastereoselectivities were similar (24%, 12,
12, and 20%, respectively) to those obtained with dimethyl-buta-
diene (entries 13e16).
The presence of a Lewis acid chelating the heterodienophile can
modify the stereoselectivity of the reaction by modifying the con-
formation of the active species. We thus examined the cycloaddition
of chiral dithioesters with 2,3-dimethyl-butadiene in the presence
of an achiral Lewis acid (Table 2). The reactions were performed at
room temperature for 24 h and full conversions were observed in all
cases. For the four selected dithioesters (1a, 2a, 3b, and 3c), the
diastereoselectivity of the reaction performed in the presence of
a stoichiometric amount of Cu(OTf)2 were not significantly modified
compared to the uncatalyzed version (Table 2, entries 1e4). With
dithioester 1a, the reaction was checked also in the presence of
10 mol % de Cu(OTf)2 chelated by an achiral diamine (2,20-dipyridine
Z*
R
CH2Cl2, rt
MeS
R
R
Z*
SMe
*
see Table 1
S
R
S
1-3
4-9
10 equiv
O
O
NC(O)
1, 4, 7: Z = (R*O)2P(O); 2, 5, 8: Z = C(O)OR*; 3, 6, 9: Z =
*
R'
Scheme 2. HDA reactions of chiral dithioesters 1e3 with 2,3-dimethyl-1,3-butadiene
or 1,3-butadiene.
In the case of (ꢀ)-dimenthyl phosphonodithioformate 1a the
cycloaddition with 2,3-dimethyl-butadiene led to a quantitative
formation of the expected cycloadduct with moderate diaster-
eoselectivity (Scheme 2, Table 1, entry 1).
Table 2
Catalyzed HDA reactions of chiral dithioesters with 2,3-dimethyl-butadiene
Entry
Dithioester
Product
Catalyst (mol %)
dra
The reactions between chiral dithiooxalates 2aee and 2,3-
dimethyl-butadiene were then examined (Scheme 2, Table 1, en-
tries 3e8). The (ꢀ)-menthol induced a low diastereoselectivity
affording cycloadduct 5a with 18% de (entry 3), while no selectivity
was obtained with its epimer (þ)-neomenthol, which has opposite
configuration at C-1 (entry 5). Dithioester 2c derived from (1S,2R)-
2-(1-methyl-1-phenylethyl)cyclohexanol (more hindered at C-2
1
2
3
4
5
6
1a
2a
3b
3c
1a
1a
4a
5a
6b
6c
4a
4a
Cu(OTf)2 (100)
Cu(OTf)2 (100)
Cu(OTf)2 (100)
Cu(OTf)2 (100)
Cu(OTf)2/di-Py (10)
Cu(OTf)2/TMEDA (10)
69/31
59/41
52/48
81/19
68/32
59/41
a
Diastereomeric ratio determined by NMR spectroscopy in the crude mixture.

2328
H. Dentel et al. / Tetrahedron 68 (2012) 2326e2335
or tetramethylethyldiamine) and the diastereoselectivity was found
to be slightly lower (Table 2, entries 5 and 6).
Monocrystals suitable for X-ray diffraction analysis were obtained
in the case of two chiral dithioesters: the carbonyloxazolidinone
dithioester 3a and the phosphonodithioformate 1a. Examination of
the X-ray structure of 3a showed that the C]S bond is almost per-
pendicular (92ꢁ) to the plane of the oxazolidinone (Fig. 2). The ster-
eodifferentiation of the Re and Si faces12 is thus small since the chiral
center is placed too far from the reacting site. This is in line with the
experimental poor stereoselectivity (de¼6%) observed in this case.
Starting from dithioester (S)-3a, cycloadduct (Soxa,S)-6a should be
obtained if the diene approaches on the Si-face of the C]S plane,
while (Soxa,R)-6a would be obtained via the Re-face attack (Fig. 2).13
Fig. 4. The more stable optimized conformation for chiral oxazolidinone 3c, obtained
by DFT calculations.
2.3. Double-stereodifferentiating experiments
Experiments combining the chiral induction of both auxiliary
and catalyst were then considered. This could bring additional in-
formation about the stereochemical outcome of the cycloadditions
and the metal center geometry of the reactive catalystedithioester
complexes.17 Chiral dithioesters 1e3 were reacted with 2,3-
dimethyl-butadiene in the presence of the chiral catalyst
Cu(OTf)2/(4R,5S)-di-Ph-box, found to be the best in our previous
study (Scheme 3, Table 3).18
Fig. 2. X-ray crystallographic structure of dithioester 3a and stereochemical outcome
of the asymmetric HDA reaction.
Z*
Cu(OTf)2/L*
MeS
CH2Cl2, 20 °C
Z*
SMe
*
The X-ray structure of dimenthyl phosphonodithioformate 1a
(Fig. 3) revealed that the dihedral angle S]CeP]O is of about 63ꢁ.
Again, it is difficult to establish, which one of the diastereotopic
faces is more hindered, which is in line with the experimental
moderate diastereoselectivity (38% de).14
conv. 100 %
see Table 3
S
S
1-3
4-6
10 equiv
Ph
O
O
Ph
N
N
Ph
Ph
L*
Scheme 3. HDA reactions of chiral dithioesters 1e3 with 2,3-dimethyl-butadiene,
catalyzed by Cu(OTf)2/(4R,5S)-di-Ph-box.
Table 3
HDA reactions of chiral dithioesters 1e3 with 2,3-dimethyl-butadiene, catalyzed by
Cu(OTf)2/(4R,5S)-di-Ph-box
Entry
Dithioester
Cycloadduct
Cu(OTf)2/L* (mol %)
dra
1
2
3
4
5
6
7
8
1a
1a0
2a
2a0
2b
2c
2c
2d
2e
3a
3b
3c
3c
3c0
4a
4a0
5a
5a0
5b
5c
5c
5d
5e
6a
6b
6c
6c
6c0
(5)
(5)
(5)
(5)
(5)
(5)
(100)
(5)
(5)
(5)
(5)
(5)
(100)
(5)
67/33
65/35
31/69
83/17
95/5
71/29
79/21
57/43
50/50
54/46
60/40
90/10
91/9
Fig. 3. X-ray crystallographic structure of dithioester 1a and stereochemical outcome
of the asymmetric HDA reaction.
9
10
11
12
13
14
In order to rationalize the high diastereoselectivity (78%) ob-
tained with substrate 3c,15 its structure was examined by compu-
tational means. DFT calculations (B3LYP, 6-31þG(d,p)) show that
the more stable optimized conformation for chiral oxazolidinone 3c
is the one given in Fig. 4. The dithioester moiety lies in a plane quasi
perpendicular to the oxazolidinone, a result in line with the X-ray
structure of dithioester 3a. The Re-face of the C]S thus appears to
be hindered by this carbonyl and the benzyl groups and induces
a preferential attack of the diene on the Si-face of the dithioester
dienophile (Fig. 4).16
78/22
a
Diastereomeric ratio determined by NMR spectroscopy in the crude mixture.
With phosphonodithioformate 1a (or its enantiomer 1a0), the di-
astereomeric excesses obtained without (38% de) and in the presence
of Cu(OTf)2/(4R,5S)-di-Ph-box catalyst (34 and 30% de, respectively:
Table 3, entries1and2)weresimilar. Nomatchedemismatchedeffect

H. Dentel et al. / Tetrahedron 68 (2012) 2326e2335
2329
was observed in this case, indicating that the stereodifferenciation
was governed by the chiral auxiliary.
In the dithiooxalates series, the cycloaddition of 2a (derived
from (ꢀ)-menthol) in the presence of 5 mol % of chiral catalyst led
to a higher diastereomeric excess of 28% (vs 18% in the uncatalyzed
version), but with an opposite chiral induction (Table 3, entry 3),
representing the mismatched case. The opposite enantiomer 2a0
gave matched reaction with a much better diastereoselectivity of
66% (Table 3, entry 4).
While no selectivity was observed with (þ)-neomenthol de-
rivative 2b in the uncatalyzed reaction, the asymmetric catalyzed
version led to a high diastereomeric excess of 90% (Table 3, entry 5).
The results indicate that, in this case, the asymmetric induction
comes from the chiral catalyst. Thus, the chiral dithioester 2b be-
haves similarly to the achiral O-ethyl dithiooxalate 2x.
The presence of 5 mol % of chiral catalyst in the reaction of 2c
increased the diastereomeric excess from 22% (obtained in the
uncatalyzed version) to 42%, in favor of the same diastereomer
(Table 3, entry 6). This indicates a similar behavior of 2a0 and 2c
derived from (þ)-menthol and (1S,2R)-2-(1-methyl-1-phenylethyl)
cyclohexanol, respectively, giving matched reaction in the presence
of Cu(OTf)2/(4R,5S)-di-Ph-box. The use of a stoichiometric amount
of catalyst slightly increased the diastereomeric excess to 58%
(Table 3, entry 7).
Scheme 4. Absolute stereochemical assignments of cycloadduct 5x.
In the case of (ꢀ)-borneol derivative 2d the diaster-
eoselectivities of uncatalyzed and asymmetric catalyzed reactions
were similar (10% and 14%, respectively), but with an opposite
chiral induction (Table 3, entry 8). Finally, as in the uncatalyzed
version, the catalyzed reaction of 2e was not diastereoselective
(Table 3, entry 9: de¼0%).
The presence of the chiral catalyst in the cycloadditions of
dithioesters 3aec derived from chiral (S)-oxazolidinones brought
only a very poor increase of the diastereoselectivity compared to
the uncatalyzed reaction (from 6 to 8% for 6a, 14e20% for 6b, and
78e80% for 6c: Table 3, entries 10e12). The use of a stoichiometric
amount of chiral catalyst was then envisaged for the cycloaddition
of 3c, but the diastereomeric excess remained similar (82% de,
Table 3, entry 13). The combination of 3c0 with the Cu(OTf)2/
(4R,5S)-di-Ph-box catalyst represents the mismatched pair, leading
to 56% de (Table 3, entry 14).
Fig. 5. X-ray structure of salt 11.
reached ee (82% and 42% ee, respectively)20 were reduced into the
corresponding enantioenriched alcohol 12 (Scheme 5). After anal-
ysis by chiral HPLC we could correlate the major alcohol (S)-12
(retention time in HPLC: 15.6 min) to the major cycloadduct 5x or
6x of S-configuration at C-2.
2.4. Absolute stereochemical assignments of
cycloadducts 5 and 6
We next tried to assign the absolute configuration of the qua-
ternary stereogenic center (C-2) formed during the cycloaddition in
order to rationalize the stereochemical outcome of this asymmetric
hetero-DielseAlder reaction. In all our cases, it was not possible to
separate the two diastereomeric cycloadducts (or their derivatives)
by column chromatography on silica gel, nor to obtain crystals
suitable for X-ray analysis in order to determinate their absolute
stereochemistry. However, starting from the racemic mixture of
dihydropyrans 5x obtained from the cycloaddition of the achiral
dithiooxalate 2x and 2,3-dimethyl-1,3-butadiene,8 enantiomers
(þ)-5x and (ꢀ)-5x have been separated by preparative chiral HPLC.
After their hydrolyzes into the corresponding carboxylic acids 10
(Scheme 4) and reaction with (ꢀ)-brucine, the carboxylic acid 10
derived from (ꢀ)-5x formed a diastereomerically pure, crystalline
ammonium salt 11. X-ray analysis on a monocrystal of this latter
allowed us to assign the (S) absolute stereochemistry to the
levorotatory dihydropyran carboxylate (ꢀ)-5x (Scheme 4, Fig. 5).
This important information allowed us to assign the absolute
configuration of the major enantiomer of cycloadducts 5x and 6x,
resulting from the enantioselective catalyzed cycloadditions of
dithiooxalate 2x and carbonyloxazolidinone dithioester 3x with
2,3-dimethyl-butadiene.19 Cycloadducts 5x and 6x having the best
Scheme 5. Absolute stereochemical assignments of cycloadducts 5x and 6x obtained
from HDA reactions of achiral dithioesters 2x and 3x with 2,3-dimethyl-butadiene,
catalyzed by Cu(OTf)2/(4R,5S)-di-Ph-box.
Cycloadducts 5aee and 6aec resulting from both diaster-
eoselective uncatalyzed HDA reactions (Scheme 2, Table 1) or the
double-stereodifferentiating experiments (Scheme 3, Table 3), have
then been reduced using LiBH4 into the same alcohol 12 (Scheme 6,
Table 4). The values of the enantiomeric excesses of 12 measured by
chiral HPLC (Table 4) were found to be in good agreement with the
values of the diastereomeric excesses of 5aee and 6aec de-
termined by NMR spectroscopy (see Tables 1 and 3).

2330
H. Dentel et al. / Tetrahedron 68 (2012) 2326e2335
L
L
SMe
S
SMe
S
L
L
Cu
SMe
S
Cu
N
3 equiv. LiBH4
THF, rt, 72h
L
L
Z*
HO
HO
Cu
O
O
C
O
R
O
O
+
S
S
SMe
Table 2
RO
N
O
SMe
II
(R)-12
SMe
I
S
III
(S)-12
5a-e
6a-c
O
R
Scheme 6. Absolute stereochemical assignments of cycloadducts 5aee, 6aec.
Fig. 6. Possible complexes of dithioesters 2 and 3 with the Cu(II)-catalyst.
Table 4
Absolute stereochemical assignments of cycloadducts 5 and 6
2.5.1. The dithiooxalate case. If we consider the asymmetric cyclo-
additions of achiral dithiooxalate 2x and of the chiral derivatives
2aed catalyzed by Cu(OTf)2/(4R,5S)-di-Ph-box complex, in all the
cases, the major cycloadduct has an S-configuration at the newly
formed chiral center (see Schemes 3 and 4, and Table 4, last column,
entries 1e6). For this type of substrate, the sense of the chiral in-
duction is mainly controlled by the chiral catalyst, even if the steric
hindrance of the ester moiety has some impact on the stereo-
selectivity. In the case of dithiooxalate 2, the possible thiocarbonyl
sulfur and carbonyl oxygen chelations should lead to the formation
of a bidentate complex and two types of catalystedienophile com-
plexes can be considered: a squareeplanar complex A and a tetra-
hedral complex B (Scheme 7). In the case of complex A, the Re-face
would be more accessible to the diene attack, leading preferentially
to the cycloadduct 5 with R-configuration at C-2, while in the case of
complex B, the Si-face should be the most accessible, leading to the
opposite isomer (S)-5. The experimental results are in accordance
with the model represented by the tetrahedral complex B, as the
enantioselective catalyzed HDA with 2x led to the formation of
cycloadduct (S)-5x with 82% ee. It is however difficult to explain
reasonably the influence of the steric hindrance of the ester moiety,
especially in the case of the matched/mismatched effect observed
with the menthol derivatives (see Supplementary data).
Entry
Cyclo
Uncatalyzed
eeb (%)
With 5 mol % cat*
adducta
Config.
eeb (%)
Config.
at C-2
at C-2
1
2
3
4
5
6
7
8
9
5a
5a0
5b
5c
5d
5e
6a
6b
6c
6c0
18
18
0
22
10
2
R
S
rac
S
R
S
S
S
S
R
28
66
90
42
14
0
S
S
S
S
S
rac
S
S
S
6
8
16
78
78
20
80
56
10
R
a
Cycloadducts 5 and 6 obtained from the diastereoselective uncatalyzed HDA
reactions (see Scheme 2, Table 1) or from the double-stereodifferentiating experi-
ments (see Scheme 3, Table 3).
b
Enantiomeric excess of 12 determined by chiral HPLC.
Cycloadducts 5a0, 5c, 5e, and 6aec derived, respectively, from
(þ)-menthol, (1S,2R)-2-phenylpropyl-cyclohexanol,
b-D-fructopyr-
anose, and (S)-oxazolidinones, led to the major alcohol 12 of (S)
configuration (Table 4, entries 2, 4, 6e9). Cycloadducts 5a and 5d
derived from (ꢀ)-menthol and (ꢀ)-borneol, respectively, led to the
major alcohol (R)-12 (Table 4, entries 1 and 5). It was also confirmed
in the case of the (þ)-neomenthol derivatives that a racemic mix-
ture of 12 is obtained by reduction of cycloadduct 5b resulting from
the uncatalyzed reaction, while (S)-12 with 90% ee is formed from
5b resulting from the asymmetric catalyzed reaction (Table 4, entry
3). As expected, major alcohol (R)-12 was obtained from cyclo-
adduct 6c0 derived from (R)-(ꢀ)-5,5-diphenyl-4-benzyl-2-
oxazolidinone (Table 4, entry 10).
steric
Ph
hindrance
O
N
Ph
Ph
Ph
O
O
N
N
O
O
Cu
S
Ph
N
OR
Ph
Cu
O
steric
Si
Ph
SMe
Re
Ph
hindrance
SMe
S
OR
square-planar complex A(S,O)
diene
tetrahedral complex B(S,O)
Si-face attack
2.5. Stereochemical models
Re-face attack
diene
The stereoselectivityof theheterocycloadditionprocessappearsto
be highly dependant on the substrate/catalyst combination. In this
context, the understanding of the catalytic intermediate structures is
fundamental. The determination of the absolute configurations of
(R)-adduct
(S)-adduct
Scheme 7. Stereochemical outcome in the HDA reactions of dithiooxalates 2; possible
Cu(OTf)2/(4R,5S)-di-Ph-box/2 complexes.
cycloadducts resulting from dithiooxalates
2
or carbon-
yloxazolidinone dithioesters 3 allowed us to examine the possible
approaches in order to rationalize the sense of the chiral induction
observed experimentally. No study of an asymmetric catalyzed HDA
reaction involving a thia-dienophile has been described yet.21 By
analogy with models already proposed in the literature for carbo- and
oxa-dienophiles,22 we considered thefollowing structuralvariables in
the dienophileecatalyst complex: geometry of the copper complex
(squareeplanar vs tetrahedral),23 dienophile conformation (s-cis vs s-
trans), metaledienophile chelation. A bidentate chelation with the
copper atom coordinating an oxygen and a sulfur atom was supposed
in both cases of dithiooxalate complex I and of carbonyloxazolidinone
dithioester complex II (see Fig. 6). For the latter, a second binding
mode is possible, with the copper atom coordinating the two oxygen
atoms of the carbonyloxazolidinone moiety (complex III) similarly to
theknowncases of acryloyl andglyoxyl l,3-oxazolidin-2-ones. Also, in
the case of a complex of type III, only the O]CeC]S s-trans more
stable conformer of the dienophile was considered.24
2.5.2. The carbonyloxazolidinone dithioester case. In contrast to the
previous case, the results obtained in the cycloaddition of chiral
carbonyloxazolidinone dithioesters 3aec catalyzed by Cu(OTf)2/
(4R,5S)-di-Ph-box complex (see Scheme 4 and Table 4, last column,
entries 7e10), indicate a poor chiral induction by the catalyst: 8%
de, 20% de, and 80% de for 3aec, respectively (compared to 6%, 16%,
78% de in the uncatalyzed version).
Concerning the asymmetric catalyzed reaction with the achiral
dienophile 3x, cycloadduct (S)-6x was obtained with 4% ee in the
presence of 5 mol % of Cu(OTf)2/(4R,5S)-di-Ph-box complex, and in
42% ee with a stoichiometric amount of the same catalyst. The low
enantioselectivity (compared to dithiooxalate case) could be
explainedbythemultiplepossibilitiesofthisdienophiletocoordinate
the copper catalyst, the corresponding catalytic chiral intermediates
providing probably opposite senses of asymmetric induction. Two
stereochemical models predict the major (S)-6x cycloadduct via the
diene attack on the more accessible Si-face, in accordance with the

H. Dentel et al. / Tetrahedron 68 (2012) 2326e2335
2331
experimental results (Scheme 8): the squareeplanar complex A0
(with O,O-chelation mode) and the tetrahedral complex B0 (with S,O-
chelation mode).
Si
Ph
Ph
Ph
Ph
O
O
N
N
O
O
O
Cu
S
O
Fig. 7. [Cu(II)/2x] and [Cu(II)/3x] complexes (DFT calculations).
N
Cu O
N
O
O
N
Si
O
N
Ph
steric
steric
Ph
Ph
MeS
Ph
hindrance
hindrance
SMe
S
stereochemical model presented above with the squareeplanar
complex A0(O,O) on Scheme 8.
diene
Si-face attack
tetrahedral complex
square-planar complex
B'(S,O)
A'(O,O)
expected (S)-6x
3. Conclusion
Scheme 8. Possible [Cu(OTf)2/(4R,5S)-di-Ph-box/3x] complexes.
Asymmetric diastereoselective thia-DielseAlder reactions in-
volving new chiral dithioesters were studied. The best result (78%
de) was obtained with a hindered oxazolidinone as the chiral
auxiliary. In the series of experiments combining the chiral in-
duction of both dithioester and catalyst, the best diastereomeric
excess (90% de) was reached with the (þ)-neomenthyl dithioox-
alate in the presence of a Cu(II)/bis(oxazoline) chiral complex. In
dithiooxalate series type of substrate, the sense of the chiral in-
duction is mainly controlled by the chiral catalyst, whereas for the
carbonyloxazolidinone dithioesters the chiral auxiliary dominates
the stereochemical control. This is an important information for
further developments of these asymmetric thia-DA reactions, as
a diastereoselective or an enantioselective version could be chosen,
depending on the heterodienophile structure. The absolute ste-
reochemistry of cycloadducts resulting from dithiooxalates and
oxazolidinone dithioesters was assigned. Stereochemical models
for Cu(II)/bis(oxazoline)/dithioester complexes were proposed in
order to rationalize the sense of the chiral induction obtained ex-
perimentally. A tetrahedral complex with a (S,O) metal chelation
was proposed for the dithiooxalate, whereas a squareeplanar
complex with a (O,O) metal chelation was proposed for the car-
bonyloxazolidinone dithiester. In both cases, the Si-attack of the
diene should be favored, leading to the major cycloadduct of (S)
configuration, in accordance with the experimental results.
The matchedemismatched effect observed with the enantio-
meric substrates 3c and 3c0 (Table 4, entries 9 and 10) indicates
a stereochemical control dominated by the chiral auxiliary, as op-
posite senses of the chiral induction were obtained (de¼80% for
(Soxa,S)-6c25 and de¼56% for (Roxa,R)-6c0). If the same types of ste-
reochemical models are applied for the cycloaddition of 3c and 3c0,
only two cases fit with the experimental results (Scheme 9): the
squareeplanar complexes C(O,O) and C0(O,O), giving, respectively,
a matched reaction with 3c (the spatial arrangements of the ligand
and of the oxazolidinone substituents encumber the same stereo-
topic face) leading to the major cycloadduct (Soxa,S)-6c, and a mis-
matched reaction with 3c0 (the spatial arrangements of the ligand
and of the oxazolidinone substituents encumber opposite stereo-
topic faces), leading to (Roxa,R)-6c0. It is to notice that model of type
C/C0(O,O) corresponds to the case of the achiral oxazolidinone
dithioester to complex A0(O,O) (Scheme 8), which predicts indeed
a low stereoselectivity in the favor of the (S)-cycloadduct, as ob-
tained experimentally. The low stereoselectivity in this series could
be also due to a preferred s-trans conformation of the dienophile in
the proposed type of complex.
Ph
Ph
Ph
Ph
O
N
O
N
O
O
4. Experimental
4.1. General
N
N
Cu
Cu
O
O
MeS
MeS
Ph
Ph
O
O
steric hindrance
on same face Re
(matched case)
Ph
Ph
steric hindrance
on opposite face
(mismatched case)
N
N
S
S
O
O
Bn
Bn
Ph
Ph
Ph
Ph
square-planar complex C'(O,O)
Re-face attack
The solvents used in the reactions were purified using a PURE-
SOLVÔ apparatus developed by Innovative Technology Inc. Re-
actions were monitored by TLC using 0.25 mm thick Merck plates,
silica gel 60 F254. Products were purified by flash column chroma-
square-planar complex C(O,O)
C6H10
Si-face attack
C6H10
expected major: (Roxa,R)-6'
expected major: (Soxa,S)-6
tography on silica gel Merck (40e63 mm, 60.08 g/mol).
Scheme 9. Possible squareeplanar complexes with the Cu(OTf)2/(4R,5S)-di-Ph-box
catalyst of dithioesters (S)-3c (C) and (R)-3c0 (C0).
NMR spectra were recorded with a Bruker DRX 400 MHz or
a Bruker DRX 500 MHz spectrometer in CDCl3 or C6D6. 13C and 31P
NMR spectra were obtained with complete proton decoupling. The
All these results suggesting a metal bidentate chelation between
the oxygen atoms of the two carbonyl groups, can explain the low
selectivities obtained in the enantioselective catalyzed HDA re-
action involving carbonyloxazolidinone dithioesters, compared to
the acryloyleoxazolidinones series.
chemical shifts (
d) are given in parts per millions (ppm) relative to
tetramethylsilane (TMS) for 1H and 13C nuclei, and to H3PO4 for 31
P
nucleus. Conventional abbreviations are used: s¼singlet, d¼doublet,
t¼triplet, q¼quartet, qn¼quintet, m¼multiplet, br¼broad. Coupling
constants (J) are given in hertz (Hz). Mass spectra were obtained
on a GC/MS Saturn 2000 spectrometer. High-resolution mass
spectra (HRMS) were performed on Q-TOF Micro WATERS by elec-
trospray ionization (ESI). Infrared (IR) spectra were recorded with
a PerkineElmer 16 PC FT-IR spectrometer. Optical rotations were
measured on a JASCO P-2000 Polarimeter. Enantiomeric excess of
chiral alcohol 12 was determined by HPLC (Daicel Chiralpak IC ana-
lytical column) for each case.
2.6. Theoretical study
DFT optimizations of the possible complexation modes at the
B3LYP, 6-31þG(d,p) level suggest that Cu-complex III chelating both
carbonyl oxygen atoms is much more favorable than complex II in
which the copper atom lies between the oxygen and the sulfur
atoms, by 12.4 kcal molꢀ1 (see Fig. 6 vs Fig. 7).26 This type of complex
has been considered and its involvement is in agreement with the
(1R,2S,5R)-(ꢀ)-Menthol, (1S,2R,5S)-(þ)-menthol, (1S,2S,5R)-
(þ)-neomenthol, (1S,2R)-2-(1-methyl-1-phenylethyl)cyclohexanol,

2332
H. Dentel et al. / Tetrahedron 68 (2012) 2326e2335
(1S)-(ꢀ)-borneol, (S)-(ꢀ)-4-isopropyl-2-oxazolidinone, (S)-(ꢀ)-4-
benzyl-2-oxazolidinone, (S)-(þ)- and (R)-(ꢀ)-5,5-diphenyl-
4-benzyl-2-oxazolidinones, and the ligand 2,20-methylene bis
[(4R,5S)-4,5-diphenyl-2-oxazoline] were purchased from Sigmae
Aldrich. Preparation and spectroscopic data are given in the
Supplementary data for: dithioesters 1a, 2aee, 3aec, cycloadducts
7a, 8a, 9a, 9b, and compounds 13b, 14c.
configuration at C-2 not assigned). 1H NMR (400.13 MHz, CDCl3)
d
H3), 2.79e2.69 (m, 1H, H6), 2.55e2.10 (m, 5H), 2.32 (s, S-CH3-(M)),
2.29 (s, S-CH3-(m)), 1.74 (s, 3H, CH3), 1.67 (s, 3H, CH3), 1.71e1.60 (m,
4H), 1.51e1.27 (m, 4H), 1.25e1.10 (m, 2H), 1.08e0.76 (m, 22H). 31P
4.45e4.15 (m, 2H, 2H7), 3.36e3.23 (m, 1H, H6), 2.97e2.84 (m, 1H,
NMR (162 MHz, CDCl3)
d
18.0 (m), 17.4 (M). 13C NMR (100.6 MHz,
CDCl3)
d
123.9 (d 3JCP¼10.1 Hz, C4-(M and m)), 122.6 (d 4JCP¼1.0 Hz,
C5-(M and m)), 80.5 (d 2JCP¼9.5 Hz, C7-(M)), 79.4 (d 2JCP¼9.0 Hz, C7-
(m)), 78.7 (d 2JCP¼9.0 Hz, C7-(m)), 78.2 (d 2JCP¼8.9 Hz, C7-(M)), 51.5 (d
4.2. Diastereoselective cycloadditions with 2,3-dimethyl-1,3-
butadiene: preparation of 4a, 5aee and 6aec
1JCP¼145.9 Hz, C2-(M)), 51.4 (d JCP¼145.9 Hz, C2-(m)), 49.2 (d
2
3JCP¼8.0 Hz, C12-(M)), 49.1 (d JCP¼7.0 Hz, C12-(m)), 48.9 (d
3
3JCP¼5.0 Hz, C12-(m)), 48.6 (d 3JCP¼6.0 Hz, C12-(M)), 43.9 (CH2-(M)),
43.6 (CH2-(m)), 37.8 (C3-(M)), 37.7 (C3-(m)), 34.1 (2ꢂ CH2-(m)), 34.0
(2ꢂ CH2-(M)), 31.5 (2ꢂ CH-(M and m)), 28.4 (d 3JCP¼5.0 Hz, C6-(m)),
28.3 (d 3JCP¼5.0 Hz, C6-(M)), 25.1 (d 4JCP¼25.2 Hz, 2ꢂ CH-(M)), 25.0
(d 4JCP¼2.2 Hz, 2ꢂ CH-(m)), 22.7 (d 4JCP¼2.1 Hz, 2ꢂ CH2-(M and m)),
22.0 (CH3-(M and m)), 21.2 (d 4JCP¼2.1 Hz, CH3-(M and m)), 20.0 (2ꢂ
CH3-(M)), 19.3 (2ꢂ CH3-(m)), 16.0 (CH3-(M and m)), 15.0 (S-CH3-(m)),
14.9 (S-CH3-(M)). IR (neat): 2953, 2925, 2869, 1718, 1456, 1370, 1252,
1180, 987, 963, 889, 830 cmꢀ1. HRMS (ESIþ) m/z: calcd for
C28H51S2O3P [MꢀNa]þ 553.2915; found: 553.2903.
4.2.1. General procedure I: uncatalyzed cycloaddition. In a Schlenk
tube, to a solution of dithioester (1 mmol, 1 equiv) in dry dichloro-
methane (2 mL) was introduced the 2,3-dimethyl-1,3-butadiene
(10 mmol, 10 equiv) and the mixture was stirred at room tempera-
ture until reaction completion (visualized by the disappearing of the
pink color of the dithioesters and monitored by TLC). The solvent was
removed under reduced pressure to afford the crude product as an
inseparable mixture of two diastereoisomers (M: major; m: minor).
The product was purified by chromatography on silica gel.
4.2.2. General procedure II: catalyzed cycloaddition (with 5 mol % of
a chiral catalyst). In a Schlenk tube, were introduced Cu(OTf)2
(0.009 mmol, 0.05 equiv), bis(oxazoline) (0.010 mmol, 0.055 equiv),
and dry dichloromethane (1 mL), then the obtained green solution
was stirred for 1 h at room temperature. Dithioester (0.18 mmol)
and 2,3-dimethyl-1,3-butadiene (1.8 mmol, 10 equiv) were added
successively and the mixture was stirred at room temperature until
reaction completion (followed by TLC). The solvent was removed
under reduced pressure and the residue was filtered on a short pad
of silica gel to afford the crude product as an inseparable mixture of
two diastereoisomers (M: major; m: minor).
4.2.2.2. (1R,2S,5R)-2-Isopropyl-5-methyl-cyclohexyl 2-[4,5-
dimethyl-2-(methylsulfanyl)-3,6-dihydro-2H-thiopyranyl]carboxyl-
ate (5a). Cycloadduct 5a was obtained from dithioester 2a
according to the general procedure I as an inseparable mixture of
two diastereoisomers 5a-M and 5a-m in a 59:41 ratio (yellow oil,
3
98% yield). 1H NMR (400.13 MHz, CDCl3)
d
4.72 (td JHH¼10.9 and
4.6 Hz,1H, H8), 3.28 and 3.18 (AB system 2JAB¼16.3 Hz, H6-(m)), 2.94
2
2
and 2.83 (AB system JAB¼16.8 Hz, H6-(M)), 2.83 (d JHH¼16.3 Hz,
1H, 1H3), 2.44 (d JHH¼16.8 Hz, H3-(m)), 2.48 (d JHH¼16.6 Hz, H3-
(M)), 2.16 (s, S-CH3-(m)), 2.17 (s, S-CH3-(M)), 2.09e1.92 (m, 1H,1H9),
1.92e1.78 (m, 1H, CH(CH3)2), 1.76e1.60 (m, 5H, 1H11, 1H12 and CH3),
1.56e1.37 (m, 2H, H10 and H13), 1.13e0.93 (m, 2H, 1H9 and 1H12),
0.94e0.83 (m, 7H, 1H11 and 2ꢂ CH3), 0.80e0.69 (m, 6H, 2ꢂ CH3).
2
2
13C NMR (100.6 MHz, CDCl3)
d 169.5 (C]O-(M)), 169.6 (C]O-(m)),
125.0 (C5-(M)), 124.8 (C5-(m)), 122.6 (C4-(M)), 122.3 (C4-(m)), 76.0
(C8-(M and m)), 57.5 (C2-(m)), 57.1 (C2-(M)), 47.1 (C13-(m)), 47.0 (C13
-
(M)), 40.8 (C3-(M and m)), 40.3 (C9-(M and m)), 34.2 (C11-(M and
m)), 31.4 (C10-(M and m)), 31.2 (C6-(M)), 30.6 (C6-(m)), 25.9
(CH(CH3)2-(M and m)), 23.1 (C12-(m)), 22.9 (C12-(M)), 22.0 (CH3-(M
and m)), 21.0 (CH3-(M)), 20.8 (CH3-(m)), 20.2 (CH3-(M and m)), 19.1
(CH3-(M and m)), 16.1 (CH3-(m)), 15.8 (CH3-(M)), 13.9 (S-CH3-(m)),
13.7 (S-CH3-(M)). IR (neat): 2954, 2921, 2869,1718,1455,1370,1242,
1195, 1180, 1109, 1038, 1010, 982, 954, 912, 845, 752 cmꢀ1. HRMS
(ESIþ) m/z: calcd for C19H32S2O2 [MꢀNa]þ 379.1741; found:
379.1744. MSMS (ESIþ, 5 eV) m/z (%): 735 [2MꢀNa]þ (100), 379
[MꢀNa]þ (31).
4.2.2.3. (1S,2S,5R)-2-Isopropyl-5-methyl-cyclohexyl 2-[4,5-
dimethyl-2-(methylsulfanyl)-3,6-dihydro-2H-thiopyranyl]carboxylate
(5b). Cycloadduct 5b was obtained from dithioester 2b according to
the general procedure I, as an inseparable mixture of two di-
astereoisomers (dr¼1:1, yellow oil, 99% yield). According to the
general procedure II, as an inseparable mixture of two di-
astereoisomers 5b-M and 5b-m (dr¼95:5) was obtained. 1H NMR
(400.13 MHz, CDCl3)
d
5.25e5.21 (m, 1H, H8), 3.25 and 2.84 (AB
system 2JAB¼17.5 Hz, H6-(m)) 3.21 and 2.84 (AB system, 2JAB¼18.2 Hz,
H6-(M)), 2.93 and 2.49 (AB system JAB¼18.3 Hz, 2H, H3), 2.18 (s, S-
2
CH3-(m)), 2.17 (s, S-CH3-(M)), 1.97e1.91 (m, 1H, 1H9), 1.81e1.73 (m,
2H, 1H11 and 1H12), 1.73e1.67 (m, 6H, 2ꢂ CH3), 1.62e1.48 (m, 1H,
CH(CH3)2),1.41e1.28 (m, 2H, H10 and H13),1.10e0.94 (m, 2H, 1H9 and
1H12), 0.91e0.82 (m, 10H, 1H11 and 3ꢂ CH3). 13C NMR (100.6 MHz,
4.2.2.1. Di-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl) 2-[4,5-
dimethyl-2-(methylsulfanyl)-3,6-dihydro-2H-thiapyranyl]phosphonate
(4a). Cycloadduct 4a was obtained from dithioester 1a according to
the general procedure I as an inseparable mixture of two di-
astereoisomers 4a-M and 4a-m in a 69:31 ratio (yellow oil, 99% yield,
CDCl3)
d
169.5 (C]O-(m)), 169.4 (C]O-(M)), 124.8 (C5-(M and m)),
122.5 (C4-(M)), 122.4 (C4-(m)), 73.0 (C8-(m)), 72.8 (C8-(M)), 57.5 (C2-
(M and m)), 47.0 (C13-(m)), 46.8 (C13-(M)), 40.9 (C3-(M and m)), 38.9

H. Dentel et al. / Tetrahedron 68 (2012) 2326e2335
2333
(C9-(M and m)), 34.7 (C11-(M and m)), 30.8 (C10-(M and m)), 29.1 (C6-
(M)), 29.0 (C6-(m)), 26.6 (CH(CH3)2-(M and m)), 25.4 (C12-(m)), 25.3
(C12-(M)), 22.2 (CH3-(m)), 22.1 (CH3-(M)), 21.1 (CH3-(m)), 21.0 (CH3-
(M)), 20.7 (CH3-(M)), 20.5 (CH3-(m)), 20.2 (CH3-(M and m)), 19.1
(CH3-(M and m)), 13.6 (S-CH3-(m)), 13.7 (S-CH3-(M)). IR (neat): 2948,
2918, 1718, 1445, 1370, 1245, 1193, 1147, 1109, 1009, 984, 916, 892,
837, 816, 732 cmꢀ1. HRMS (ESIþ) m/z: calcd for C19H32S2O2 [MꢀNa]þ
379.1741; found: 379.1747. MSMS (ESIþ, 5 eV) m/z (%): 735 [2MꢀNa]þ
(100), 556 (15), 379 [MꢀNa]þ (33).
system 2JAB¼9.2 Hz, H13-(M)), 3.95 and 3.79 (AB system 2JAB¼9.2 Hz,
H13-(m)), 3.31e3.19 (m, 1H, 1H6), 2.94e2.83 (m, 2H, 1H6 and 1H3),
2.58e2.45 (m, 1H, 1H3), 2.21 (s, S-CH3-(m)), 2.19 (s, S-CH3-(M)),
1.73e1.66 (m, 6H, 2ꢂ CH3), 1.54e1.33 (m, 12H, 4ꢂ CH3). 13C NMR
(100.6 MHz, CDCl3)
d
169.9 (C]O-(M and m)), 124.8 (C5-(M)), 124.4
(C5-(m)), 122.5 (C4-(M and m)), 112.3 (C14-(m)), 112.0 (C14-(M)), 109.6
(C9-(M and m)), 103.5 (C12-(M and m)), 74.7 (C10-(m)), 74.5 (C10-(M)),
73.8 (C8-(M and m)), 71.8 (C13-(M and m)), 71.7 (C11-(M and m)), 60.6
(C7-(M)), 60.2 (C7-(m)), 57.7 (C2-(m)), 56.9 (C2-(M)), 40.8 (C3-(M)),
40.7 (C3-(m)), 30.7 (C6-(M and m)), 27.8 (CH3-(M)), 27.7 (CH3-(m)),
26.6 (CH3-(M)), 26.3 (2ꢂ CH3-(m)), 26.1 (2ꢂ CH3-(M)), 26.0 (CH3-
(M)), 20.1 (CH3-(m)), 20.0 (CH3-(m)), 19.1 (CH3-(M)), 19.0 (CH3-(m)),
13.6 (S-CH3-(M and m)). IR (neat): 2986, 2922,1730,1456,1382,1372,
1216, 1083, 1065, 1027, 975, 885, 849, 812, 733 cmꢀ1. HRMS (ESIþ)
m/z: calcd for C21H32S2O7 [MꢀNa]þ 483.1487; found: 483.1472.
4.2.2.4. (1S,2R)-2-(1-Methyl-1-phenylethyl)cyclohexyl 2-[4,5-
dimethyl-2-(methylsulfanyl)-3,6-dihydro-2H-thiopyranyl]carboxylate
(5c). Cycloadduct 5c was obtained from dithioester 2c according to
the general procedure I or II as an inseparable mixture of two di-
astereoisomers 5c-M and 5c-m (yellow oil, 89% yield). 1H NMR
(400.13 MHz, CDCl3) d 7.30e7.19 (m, 4H, Har), 7.15e7.03 (m, 1H, Har),
4.90 (td 3JHH¼10.3 and 4.4 Hz, H7-(M)), 4.77 (td 3JHH¼10.1 and 4.4 Hz,
4.2.2.7. (4S)-3-[(4,5-Dimethyl-2-(methylsulfanyl)-3,6-dihydro-2H-
thiopyranyl)carbonyl]-4-isopropyl-2-oxazolidinone (6a). Cycloadduct
6a was obtained from dithioester 3a according to the general pro-
cedure I or II as an inseparable mixture of two diastereoisomers
2
2
H7-(m)), 3.22 (d JHH¼17.1 Hz, 1H, 1H6), 2.85 (d JHH¼17.3 Hz, 1H6-
(m)), 2.81 (d 2JHH¼16.8 Hz, 1H6-(M)), 2.71 (d 2JHH¼17.8 Hz, 1H3-(m)),
2.34e2.325 (m,1H,1H3), 2.22 (s, S-CH3-(m)), 2.16e2.09 (m,1H3-(M)),
2.13 (s, S-CH3-(M)), 2.09e1.86 (m, 3H, H8, 1H12 and 1H9), 1.76e1.50
(m, 9H, 1H10, 1H11, 1H12 and 2ꢂ CH3), 1.48e1.19 (m, 6H, 2ꢂ CH3),
1.19e0.74 (m, 3H, 1H9, 1H10 and 1H11). 13C NMR (100.6 MHz, CDCl3)
(S,Soxa)-6a-M and (R,Soxa)-6a-m (yellow oil, 97% yield). 1H NMR
3
(400.13 MHz, CDCl3)
d
4.54 (ddd JHH¼6.9, 3.8 and 3.0 Hz, H7-(M)),
4.49 (ddd 3JHH¼8.0, 3.8 and 2.8 Hz, H7-(m)), 4.34e4.27 (m, 1H, 1H8),
4.21 (dd 2JHH¼9.1 Hz and 3JHH¼3.1 Hz,1H,1H8), 3.22 (d 2JHH¼13.6 Hz,
1H, 1H6), 3.18 (d 2JHH¼15.7 Hz, 1H3-(M)), 3.01e2.88 (m,1H6 and 1H3-
(m)), 2.81 (d 2JHH¼15.7 Hz, 1H, 1H3), 2.37e2.26 (m, 1H, H9), 2.10 (s, S-
CH3-(M)), 2.09 (s, S-CH3-(m)), 1.77e1.73 (m, 2ꢂ CH3), 0.94e0.89 (m,
d
169.1 (C]O-(m)), 168.9 (C]O-(M)), 150.7 (Cqar-(M)), 150.2 (Cqar-
(m)), 128.1 (2ꢂ CHar-(M)), 128.0 (2ꢂ CHar-(m)), 125.5 (CHar-(M)),
125.4 (CHar-(m)), 125.3 (2ꢂ CHar-(M and m)), 124.9 (C5-(m)), 124.5
(C5-(M)), 122.1 (C4-(m)), 121.9 (C4-(M)), 77.8 (C7-(M and m)), 58.0 (C2-
(M)), 56.9 (C2-(m)), 50.9 (C8-(m)), 50.3 (C8-(M)), 40.4 (C3-(m)), 40.3
(C13-(m)), 40.2 (C13-(M)), 39.1 (C3-(M)), 32.9 (C12-(m)), 32.6 (C12-(M)),
30.6 (C6-(m)), 30.4 (C6-(M)), 27.8 (CH3-(m)), 27.6 (CH3-(M)), 27.3
(CH3-(M and m)), 25.9 (C9-(m)), 25.6 (C9-(M)), 24.5 (C10-(m)), 24.4
(C10-(M)), 24.2 (C11-(M and m)), 20.2 (CH3-(M and m)), 19.8 (CH3-(M
and m)), 13.99 (S-CH3-(M and m)). IR (neat): 2926, 1715, 1496, 1444,
1229, 1188, 1108, 1017, 910, 765, 731, 699 cmꢀ1. HRMS (ESIþ) m/z:
calcd for C24H34S2O2 [MꢀNa]þ 441.1898; found: 441.1891. MSMS
(ESIþ, 10 eV) m/z (%): 441 [MꢀNa]þ (100), 241 (11).
2ꢂ CH3). 13C NMR (100.6 MHz, CDCl3)
d 169.8 (NeC]O-(M)), 160.0
(NeC]O-(m)), 151.8 (NeCO2-(M)), 151.8 (NeCO2-(m)), 126.9 (C5-
(m)), 126.3 (C5-(M)), 125.0 (C4-(M and m)), 63.3 (C8-(M and m)), 62.6
(C2-(m)), 62.4 (C2-(M)), 60.4 (C7-(M and m)), 39.5 (C3-(M and m)),
31.6 (C6-(m)), 31.4 (C6-(M)), 28.5 (C9-(M and m)), 19.9 (CH3-(M)), 19.7
(CH3-(m)), 18.9 (CH3-(M)), 18.7 (CH3-(m)), 17.9 (CH3-(M and m)), 14.7
(CH3-(M and m)), 14.0 (S-CH3-(m)), 13.9 (S-CH3-(M)). IR (neat): 2964,
1780, 1669, 1385, 1362, 1300, 1268, 1195, 1144, 1099, 1061, 911, 730,
703 cmꢀ1. HRMS (ESIþ) m/z: calcd for C15H23NS2O3 [MꢀNa]þ
352.1017; found: 352.1030. MSMS (ESIþ, 7 eV) m/z (%): 681
[2MeNa]þ (100), 352 [MꢀNa]þ (25).
4.2.2.5. (1S,2R,4R)-Bicyclo[2.2.1]heptanyl 2-[4,5-dimethyl-2-(meth-
ylsulfanyl)-3,6-dihydro-2H-thiopyranyl]carboxylate (5d). Cycloadduct
5d was obtained from dithioester 2d according to the general pro-
cedure II as an inseparable mixture of two diastereoisomers 5d-M and
4.2.2.8. (4S)-3-[(4,5-Dimethyl-2-(methylsulfanyl)-3,6-dihydro-
2 H - t h i o p y ra nyl ) c a r b o nyl ] - 4 - b e n z yl - 2 - o x a z o l i d i n o n e
(6b). Cycloadduct 6b was obtained from dithioester 3b according
to the general procedure I or II as an inseparable mixture of two
diastereoisomers (S,Soxa)-6b-M and (R,Soxa)-6b-m (yellow oil, 91%
5d-m (14% de, yellow oil, 99%). 1H NMR (400.13 MHz, CDCl3)
d 4.92
3
4
(ddd JHH¼9.8, 3.3 Hz and JHH¼2.3 Hz, 1H, H7), 3.26 and 2.90 (AB
system 2JAB¼16.5 Hz, 2H, H6), 2.88 and 2.48 (AB system 2JAB¼17.3 Hz,
2H, H3), 2.43e2.33 (m, 1H, 1H12), 2.21 (s, SCH3-(m)), 2.18 (s, S-CH3-
(M)), 2.04e1.94 (m,1H,1H9),1.82e1.67 (m, 8H,1H10, H11 and 2ꢂ CH3),
yield). 1H NMR (400.13 MHz, CDCl3)
d 7.37e7.31 (m, 2H, Har),
7.30e7.21 (m, 3H, Har), 4.79e4.69 (m, 1H, H7), 4.25e4.13 (m, 2H,
H8), 3.36e3.22 (m, 2H, 1H6 and 1H9), 3.19 and 2.95 (AB system
2
3
1.39e1.18 (m, 2H, 1H9 and 1H10), 0.97 (ddd JHH¼13.9 Hz, JHH¼6.1
and 3.1 Hz, 1H, 1H12), 0.92e0.84 (m, 9H, 3ꢂ CH3). 13C NMR
2JAB¼16.5 Hz, H3-(m)), 3.07 and 2.91 (AB system JAB¼16.1 Hz, H3-
2
2
(100.6 MHz, CDCl3)
d
170.4 (C]O-(m)), 170.3 (C]O-(M)), 124.8 (C5-
(M)), 2.85 (d JHH¼16.1 Hz, H6-(M)), 2.83 (d 2JHH¼16.1 Hz, H6-(m)),
(M and m)), 122.3 (C4-(M and m)), 81.8 (C7-(M)), 81.7 (C7-(m)), 57.3
(C2-(M)), 57.1 (C2-(m)), 49.0 (C8-(m)), 48.8 (C8-(M)), 47.9 (C13-(M and
m)), 44.8 (C11-(M and m)), 40.8 (C3-(M and m)), 36.7 (C12-(m)), 36.6
(C12-(M)), 30.8 (C6-(M and m)), 28.0 (C10-(m)), 27.9 (C10-(M)), 27.2 (C9-
(M and m)), 20.2 (CH3-(M and m)), 19.6 (CH3-(M and m)), 19.1 (CH3-
(M and m)), 18.8 (CH3-(M and m)), 17.9 (CH3-(M and m)), 13.8 (S-CH3-
(M)), 13.6 (S-CH3-(m)). IR (neat): 2953, 1721, 1454, 1376, 1246, 1111,
1018, 886, 826, 754 cmꢀ1
2.80e2.73 (m, 1H, H9), 2.13 (s, S-CH3-(M)), 2.12 (s, S-CH3-(m)),
1.79e1.75 (m, 6H, 2ꢂ CH3). 13C NMR (100.6 MHz, CDCl3)
d 170.0
(NeC]O-(M)), 169.7 (NeC]O-(m)), 151.2 (NeCO2-(m)), 151.1
(NeCO2-(M)), 135.3 (Cqar-(M)), 135.2 (Cqar-(m)), 129.4 (2ꢂ CHar-(M
and m)), 129.0 (2ꢂ CHar-(M and m)), 127.4 (CHar-(M and m)), 126.3
(C5-(M)), 126.2 (C5-(m)), 125.3 (C4-(M)), 124.9 (C4-(m)), 66.1 (C8-
(m)), 66.0 (C8-(M)), 62.5 (C2-(M and m)), 57.9 (C7-(M)), 57.6 (C7-(m)),
39.2 (C3-(m)), 39.1 (C3-(M)), 37.8 (C9-(m)), 37.7 (C9-(M)), 31.3 (C6-(M
and m)), 19.9 (CH3-(M and m)), 18.9 (CH3-(M and m)), 14.1 (S-CH3-
(M and m)). IR (neat): 2915,1782,1667,1454,1384,1348,1268,1208,
1186, 1116, 1076, 1051, 912, 912, 802, 736, 699 cmꢀ1. HRMS (ESIþ)
m/z: calcd for C19H23NS2O3 [MꢀNa]þ 400.1017; found: 400.1022.
4.2.2.6.
b-D-Fructopyranosyl diacetonide 2-[4,5-dimethyl-2-(meth-
ylsulfanyl)-3,6-dihydro-2H-thiopyranyl]carboxylate (5e). Cycloadduct
5e was obtained from dithioester 2e according to the general pro-
cedure I as an inseparable mixture of two diastereoisomers 5e-M and
5e-m (dr¼51:49, yellow oil, 98% yield). 1H NMR (400.13 MHz, CDCl3)
4.2.2.9. (4S)-3-[(4,5-Dimethyl-2-(methylsulfanyl)-3,6-dihydro-
2H-thiopyranyl)carbonyl]-4-benzyl-5,5-diphenyl-2-oxazolidinone
(6c). Cycloadduct 6c was obtained from dithioester 3c according to
the general procedure I or II as an inseparable mixture of two
3
3
d
5.16 (d JHH¼8.0 Hz, H11-(M)), 5.13 (d JHH¼8.0 Hz, H11-(m)), 4.33
(dd 3JHH¼8.0 and 5.2 Hz, H10-(M)), 4.28 (dd 3JHH¼8.0 and 5.1 Hz, H10
-
(m)), 4.24e4.20 (m, 1H, H8), 4.17e4.09 (m, 2H, H7), 3.96 and 3.85 (AB

2334
H. Dentel et al. / Tetrahedron 68 (2012) 2326e2335
diastereoisomers (S,Soxa)-6c-M and (R,Soxa)-6c-m (yellow oil, 98%
yield). 1H NMR (400.13 MHz, CDCl3)
7.54e7.49 (m, 2H, Har),
25.6 (C15), 20.2 (C4-CH3),19.2 (C5-CH3),14.4 (S-CH3). IR (neat): 3390,
2915, 1660, 1500, 1446, 1399, 1281, 1217, 1197, 1109, 1083, 988, 846,
768, 751 cmꢀ1. HRMS (ESIL) m/z (anion): calcd for C9H13S2O2 [M]
217.0357; found: 217.0353. MSMS (ESIꢀ 35 eV) m/z (%) (anion): 217
[M] (96), 173 (42), 125 (100). HRMS (ESIþ) m/z (cation): calcd for
C23H27N2O4 [M] 395.1971; found: 395.1960. MSMS (ESIþ 35 eV) m/z
(%) (cation): 395 [M] (100), 324 (55), 244 (43).
d
7.38e7.19 (m, 8H, Har), 7.12e7.06 (m, 3H, Har), 6.88e6.80 (m, 2H,
3
3
H
ar), 5.71 (dd JHH¼7.2 and 5.9 Hz, 1H, H7-(m)), 5.61 (dd JHH¼7.1
and 5.8 Hz, 1H, H7-(M)), 3.41 (d 2JHH¼16.0 Hz, 1H, 1H6-(m)), 3.08 (d
2JHH¼15.3 Hz, 1H, 1H6-(M)), 2.90e2.76 (m, 3H, 1H6 and 2H9),
2.64e2.51 (m, 2H, H3), 1.73 (s, 3H, CH3), 1.58 (s, 3H, S-CH3), 1.54 (s,
3H, CH3). 13C NMR (100.6 MHz, CDCl3)
d 170.0 (NeC]O-(m)), 168.9
(NeC]O-(M)), 149.9 (NeCO2), 141.6 (Cqar), 137.1 (Cqar), 136.2 (Cqar-
(M)), 135.8 (Cqar-(m)), 129.1 (2ꢂ CHar), 128.8 (2ꢂ CHar-(m)), 128.7
(2ꢂ CHar-(M)), 128.6 (CHar), 128.3 (2ꢂ CHar-(m)), 128.2 (2ꢂ CHar-
(M)), 128.2 (C5), 128.1 (3ꢂ CHar), 127.3 (C4-(M)), 126.7 (C4-(m)),
126.5 (CHar-(m)), 126.2 (CHar-(M)), 126.1 (2ꢂ CHar-(M)), 126.0 (CHar-
(m)), 125.7 (2ꢂ CHar-(M)), 125.5 (2ꢂ CHar-(m)), 88.3 (C8-(M)), 88.1
(C8-(m)), 64.9 (C7), 63.2 (C2-(m)), 61.4 (C2-(M)), 39.3 (C3-(M)), 39.1
(C3-(m)), 36.7 (C9), 32.0 (C6-(m)), 29.6 (C6-(M)), 20.0 (CH3-(m)), 19.5
(CH3-(M)), 19.1 (CH3-(m)), 18.7 (CH3-(M)), 13.1 (S-CH3-(M)), 12.6
(S-CH3-(m)). IR (neat): 2919, 1783, 1683, 1494, 1450, 1348, 1282,
1214, 1155, 1091, 1047, 997, 908, 730, 699 cmꢀ1. HRMS (ESIþ) m/z:
calcd for C31H31NS2O3 [MꢀNa]þ 552.1643; found: 552.1631.
4.2.3.3. Reduction of cycloadducts 5 or 6 into 4,5-dimethyl-2-
(methylsulfanyl)-2-(hydroxymethyl)-3,6-dihydro-2H-thiopyran (12).
General procedure. Cycloadduct 5a (0.81 mmol, 1 equiv) in 3 mL of
dry THF was added slowly to a suspension of 54 mg of LiBH4
(2.44 mmol, 3 equiv) in 3 mL of dry THF at 0 ꢁC. The solution was
stirred for 48 h at room temperature then a solution of aq NH4Cl with
HCl was added at 0 ꢁC. The solution was stirred for 20 min at room
temperature and the organic phase was extracted with dichloro-
methane, then dried over MgSO4 and the solvent was removed. The
crude product 12 was analyzed by HPLC without further purification
(yellow oil, 95% yield). 1H NMR (400.13 MHz, CDCl3)
d 3.60 and 3.54
2
(AB system JAB¼11.5 Hz, 2H, CH2OH), 3.27 and 2.86 (AB system
2JAB¼16.4 Hz, 2H, H6), 2.56 and 2.23 (AB system JAB¼17.6 Hz, 2H,
2
4.2.3. Absolute stereochemical assignments of 5 and 6: synthesis of
compounds (10), (11), and (12). 4.2.3.1. 2-[4,5-Dimethyl-2-(methyl-
H3), 2.37e2.18 (lb, 1H, OH), 2.06 (s, 3H, S-CH3), 1.73 (s, 3H, CH3), 1.68
(s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3) 125.0 (C5),122.4 (C4), 66.4
d
sulfanyl)-3,6-dihydro-2H-thiopyranyl]carboxylic
acid
(10). KOH
(CH2OH), 58.2 (C2), 40.4 (C3), 29.6 (C6), 20.1 (CH3), 19.1 (CH3), 11.7 (S-
CH3). IR (neat): 3420, 2915, 2870, 1677, 1419, 1332, 1246, 1125, 1061,
933, 732 cmꢀ1. HRMS (ESIþ) m/z: calcd for C9H16S2O [MꢀNa]þ
227.0540; found: 227.0543.
(25 mg, 0.45 mmol, 1.1 equiv) was dissolved in a mixture of H2O/
EtOH (0.03 mL/0.12 mL). This solution was added on the ester
(ꢀ)-5x8 (100 mg, 0.41 mmol,1 equiv) at 0 ꢁC and then stirred at room
temperature for 2 h. EtOH was evaporated, 1 mL of H2O was added,
the aqueous phase was acidified until pH¼3 with HCl 1 N and sat-
urated with NaCl, before it was extracted using CH2Cl2.The solution
was dried over MgSO4, filtered, and concentrated to give the acid 10.
The crude product was used without further purification (white
The enantiomeric excess of alcohol 12 was determined by HPLC
using a Daicel Chiralpak IC analytical column (n-heptane/ethanol:
90/10, flow rate: 1.0 mL/min, 210.0 nm). Retention time of the
corresponding peaks: tR¼7.5 min (R) and tR¼15.6 min (S).
crystals, 43% yield). 1H NMR (400.13 MHz, CDCl3)
d 7.72 (lb, 1H, C(O)
4.3. X-ray crystallographic study
OH), 3.27 and 2.91 (AB system 2JAB¼16.2 Hz, 2H, H6), 2.91 and 2.46
2
(AB system JAB¼17.4 Hz, 2H, H3), 2.23 (s, 3H, S-CH3), 1.73 (s, 3H,
Crystallographic data for compounds 1a, 3a, and 11 have been
deposited at the Cambridge Crystallographic Data Centre: CCDC No
843900 (1a), CCDC No 846899 (3a), and CCDC No 843898 (11). Copies
of this information may be obtained free of charge from The Director,
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (þ44 1223 336408;
e-mail: deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk).
CH3), 1.70 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3)
d 175.6 (C]O),
124.7 (C5), 122.3 (C4), 56.7 (C2), 40.2 (C3), 30.5 (C6), 20.1 (CH3), 19.1
(CH3), 14.0 (S-CH3). IR (neat): 2986, 2916, 2633, 1695, 1419, 1265,
1216, 1110, 936, 732, 707 cmꢀ1. HRMS (ESIL) m/z calcd for C9H14S2O2
[M]ꢀ 217.0357; found: 217.0368. MSMS (ESIꢀ, 7 eV) m/z (%): 218 [M]
(8), 217 [M]ꢀ (94), 173 (42), 126 (7), 125 (100).
Acknowledgements
4.2.3.2. 2-[4,5-Dimethyl-2-(methylsulfanyl)-3,6-dihydro-2H-thio-
pyranyl]carboxylic acid brucinium salt (11). Carboxylic acid 10
(101 mg, 0.46 mmol, 1 equiv) and (ꢀ)-brucine were dissolved in
25 mL of methanol. The solution was heated at reflux for 15 h,
before being evaporated. The white solid was crystallized in MeOH
to give the salt 11 as white crystals (yield¼40%). 1H NMR
We gratefully acknowledge for the financial support the Minis-
tere de la Recherche et des Nouvelles Technologies (grant to H.D.),
ꢁ
the ‘ CRUNCHOrga’ (Centre de Recherche Universitaire Normand de
Chimie Organique), the Region Basse-Normandie, the Centre Na-
tional de la Recherche Scientifique (CNRS), and the European Union
(FEDER funding). Prof. A.-C. Gaumont, the leader of our research
group, is acknowledged for helpful discussions. F. Le Cavelier,
ꢀ
(400.13 MHz, CDCl3)
d
7.78 (s, 1H, H20), 6.83 (s, 1H, H25), 6.27e6.20
3
(m, 1H, H9), 4.44e4.39 (m, 1H, H16), 4.33 (dt JHH¼8.3 and 3.1 Hz,
2
3
1H, H11), 4.22 (dd JHH¼14.0 Hz and JHH¼7.0 Hz, 1H, 1H10),
ꢀ
K. Jarsale, and R. Legay (LCMT, Caen) are acknowledged for the HPLC,
4.13e4.03 (m, 2H, 1H7 and 1H10), 3.94 (d JHH¼10.4 Hz, 1H, H18),
3
mass, and NMR analyses, respectively. The authors acknowledge the
CRIHAN for generous allocation of computer time.
3.89 (s, 3H, H22), 3.88 (s, 3H, H24), 3.82 (dd JHH¼11.5 Hz and
2
3JHH¼7.9 Hz, 1H, 1H28), 3.40 and 2.77 (AB system 2JAB¼16.7 Hz, 2H,
H6), 3.31e3.26 (m, 1H, H14), 3.15 (d 2JHH¼14.2 Hz, 1H, 1H7), 3.14 and
Supplementary data
2
3
3
2.66 (ABX system JAB¼17.6 Hz, JAx¼8.6 Hz, and JBx¼3.1 Hz, 2H,
H12), 3.09e2.99 (m, 1H, 1H28), 2.94 (d JHH¼18.1 Hz, 1H, 1H3),
3
Supplementary data associated with this article can be found in
the online version at. doi:10.1016/j.tet.2012.01.039.
2.61e2.50 (m, 2H, 1H3 and 1H15), 2.22 (s, 3H, S-CH3), 2.14 and 1.99
(ABX system JAB¼13.4 Hz, JAx¼7.8 Hz, and JBx¼6.0 Hz, 2H, H27),
2
3
3
1.73 (s, 3H, C5-CH3), 1.70 (s, 3H, C4-CH3), 1.64 (d JHH¼15.2 Hz, 1H,
2
References and notes
1H15), 1.37 (dt JHH¼10.4 Hz and JHH¼3.1 Hz, 1H, H13). 13C NMR
3
3
(100.6 MHz, CDCl3) d
176.3 (NeC]O), 168.5 (C2eC]O), 149.9 (C21),
1. See for reviews on asymmetric DielseAlder reactions: (a) Oppolzer, W. Angew.
Chem., Int. Ed. Engl. 1984, 23, 876e889; (b) Weinreb, S. M.; Staib, R. R. Tetrahedron
1982, 38, 3087e3128; (c) Waldmann, H. Synthesis 1994, 535e551; (d) Oh, T.;
Reilly, M. Org. Prep. Proced. Int. 1994, 26, 129e158; (e) Carmona, D.; Lamata, M. P.;
Oro, L. A. Coord. Chem. Rev. 2000, 200-202, 717e772; (f) Cycloaddition Reactions in
Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH: Weinheim,
146.7 (C23), 135.6 (C19), 134.6 (C8), 133.8 (C9), 125.2 (C5), 122.1 (C4),
119.8 (C26), 105.0 (C25), 100.9 (C20), 77.5 (C11), 64.1 (C10), 61.1 (C2),
59.8 (C16), 59.5 (C18), 56.4 (C24), 56.2 (C22), 52.1 (C7), 51.8 (C17), 49.5
(C28), 47.4 (C13), 42.2 (C3), 42.1 (C12), 40.9 (C27), 31.1 (C6), 30.8 (C14),

H. Dentel et al. / Tetrahedron 68 (2012) 2326e2335
2335
2002; (g) Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007e1019; (h) Tietze, L. F.;
Kettschau, G. Top. Curr. Chem. 1997, 189, 1e120; (i) Corey, E. J. Angew. Chem., Int.
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Reymond, S.; Cossy, J. Chem. Rev. 2008, 108, 5359e5406; (l) Pellissier, H.
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Minuti, L.; Taticchi, A. Tetrahedron 2006, 62, 5626e5631.
14. The Re-face seems to be less hindered, however it was not possible to assign
the absolute configuration of the major diastereomer of cycloadduct 4a.
15. No suitable crystals for X-ray analysis have been obtained for 3c.
16. This is in agreement with the absolute configuration (S,S), which was assigned
to the major diastereomer of cycloadduct 6c.
17. Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem. Soc. 1999, 121,
7559e7573.
18. As already observed in the achiral series, the catalyzed cycloadditions went
faster than the uncatalyzed ones, but all reactions were left for 24 h for a total
conversion.
19. The absolute configurations of these cycloadducts have been not determined in
our previous study (see Ref. 8).
5. Qin, Y.; White, A. J. P.; Williams, D. J.; Leung, P.-H. Organometallics 2002, 21,171e174.
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Takahashi, T.; Kurose, N.; Koizumi, T. Heterocycles 1993, 36, 1601e1616; (c)
Herczegh, P.; Zsely, M.; Szilagyi, L.; Bognar, R. Heterocycles 1989, 28, 887e898;
(d) Timoshenko, V. M.; Siry, S. A.; Rozhenko, A. B.; Shermolovich, Y. G. J. Fluorine
Chem. 2010, 131, 172e183.
7. (a) Saito, T.; Takekawa, K.; Nishimura, J.; Kawamura, M. J. Chem. Soc., Perkin
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Commun. 1999, 1001e1002.
20. Catalyst (5 mol %) was used in the reaction of 2x and 100 mol % in the reaction
of 3x.
21. We were not able in our case to obtained crystals of the catalystedithioester
complexes for a X-ray structural characterization. For the first and for instant
unique catalystedienophile complex characterized by X-ray crystallography,
see: Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. Chem.dEur. J. 2009, 15,
9674e9677.
22. See, as examples: (a) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von
Matt, P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos, K.
R. J. Am. Chem. Soc. 1999, 121, 7582e7594; (b) Landa, A.; Richter, B.; Johansen,
8. Dentel, H.; Chataigner, I.; Le Cavelier, F.; Gulea, M. Tetrahedron Lett. 2010, 51,
6014e6017.
€
R. L.; Minkkila, A.; Jørgensen, K. A. J. Org. Chem. 2007, 72, 240e245; (c)
9. See for application of menthol in asymmetric synthesis: Oertling, H.; Reck-
ziegel, A.; Surburg, H.; Bertram, H.-J. Chem. Rev. 2007, 107, 2136e2164.
10. See for application of chiral oxazolidinones in asymmetric synthesis: (a) Evans,
D. A.; Bartroli, J.; Shih, T. J. Am. Chem. Soc. 1981, 103, 2127e2129; (b) Evans, D. A.;
Johannsen, M.; Jørgensen, K. A. J. Org. Chem. 1995, 60, 5757e5762; (d) Yao,
S.; Saaby, S.; Hazell, R. G.; Jørgensen, K. A. Chem.dEur. J. 2000, 6,
2435e2448; (e) Aggarwal, V. K.; Anderson, E. S.; Jones, D. E.; Obierey, K. B.;
Giles, R. Chem. Commun. 1998, 1985e1986.
ꢀ
ꢀ ꢀ
Shaw, J. T. L’Actualite Chimique; Societe Chimique de France: Paris, 2003;
avrilemai25e38; (c) Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997,
30, 3e12.
23. It is to notice that the X-ray structures of some Cu(II)-box complexes and of
a Cu(II)-box/dienophile complex revealed a distorted squareepyramidal ge-
ometry; see in: Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106,
3561e3651 and in the present paper, Ref. 21.
24. The s-cis conformer is of 5 kcal/mol more stable than the s-trans conformer
(see theoretical calculations in the Supplementary data).
25. (S) configuration on oxazolidinone (Sox) and (S) configuration on the
thiopyran.
26. See Supplementary data.
11. Marchand, P.; Gulea, M.; Masson, S.; Saquet, M.; Collignon, N. Org. Lett. 2000, 2,
3757e3759.
12. To assign the Re/Si stereotopic faces, the order of priority according the
CahneIngoldePrelog rules is: SCH3>SC>C(O).
13. See in this paper the absolute stereochemical assignments of cycloadducts 5
and 6: the major obtained enantiomer is (S)-6a.