Recent developments in asymmetric hetero-diels-alder reactions of dithioesters

Article abstract of DOI:10.1080/10426507.2012.729113

Recent studies dealing with asymmetric thia-Diels-Alder reactions of dithioesters as heterodienophiles are described. A diastereoselective version involving new chiral dithioesters and the first example of a catalytic enantioselective version are described. The absolute stereochemistry of the cycloadducts was assigned based on an X-ray structure and chemical correlation. In order to rationalize the sense of the chiral induction observed experimentally, stereochemical models for Cu(II)/BOX/dithioester complexes are proposed.

Full text of DOI:10.1080/10426507.2012.729113

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Phosphorus, Sulfur, and Silicon and the
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Recent Developments in Asymmetric
Hetero-Diels-Alder Reactions of
Dithioesters
Hélène Dentel a & Mihaela Gulea a
a Laboratoire de Chimie Moléculaire et Thio-Organique (LCMT) , UMR
CNRS 6507, INC3M, FR 3038, ENSICAEN, UCBN, 6 Bd. Maréchal Juin ,
14050 , Caen , France
Accepted author version posted online: 22 Oct 2012.Published
online: 29 May 2013.
To cite this article: Hélène Dentel & Mihaela Gulea (2013) Recent Developments in Asymmetric
Hetero-Diels-Alder Reactions of Dithioesters, Phosphorus, Sulfur, and Silicon and the Related
Elements, 188:4, 349-355, DOI: 10.1080/10426507.2012.729113
To link to this article: http://dx.doi.org/10.1080/10426507.2012.729113
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Phosphorus, Sulfur, and Silicon, 188:349–355, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.729113
RECENT DEVELOPMENTS IN ASYMMETRIC
HETERO-DIELS-ALDER REACTIONS OF DITHIOESTERS
He´le`ne Dentel and Mihaela Gulea
Laboratoire de Chimie Mole´culaire et Thio-Organique (LCMT), UMR CNRS 6507,
INC3M, FR 3038, ENSICAEN, UCBN, 6 Bd. Mare´chal Juin, 14050 Caen, France
GRAPHICAL ABSTRACT
Abstract Recent studies dealing with asymmetric thia-Diels-Alder reactions of dithioesters as
heterodienophiles are described. A diastereoselective version involving new chiral dithioesters
and the first example of a catalytic enantioselective version are described. The absolute stere-
ochemistry of the cycloadducts was assigned based on an X-ray structure and chemical cor-
relation. In order to rationalize the sense of the chiral induction observed experimentally,
stereochemical models for Cu(II)/BOX/dithioester complexes are proposed.
Keywords Asymmetric hetero-Diels-Alder reaction; thia-Diels-Alder reaction; chiral
dithioester; Cu(II)/bis(oxazoline) complex; stereochemical models
INTRODUCTION
The asymmetric carbo- and hetero-Diels−Alder (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 carbo-, oxa-, and aza-DA reactions, the
asymmetric thia-DA version has received much less attention, despite its potential utility
to afford chiral enantioenriched dihydrothiopyrans. Due to their easy access in a large
variety of structures, dithioesters represents convenient partners in cycloadditions.2 More-
over, when the thiocarbonyl group is activated via an electronwithdrawing substituent3 or
by addition of a catalyst (Lewis or Brønsted acid),4 dithioesters represents highly reactive
Received 2 July 2012; accepted 6 July 2012.
We acknowledge for the financial support the Ministe`re de la Recherche (grant to H.D.), the Centre de
Recherche Universitaire Normand de Chimie Organique (CRUNCH), the Re´gion Basse-Normandie, the CNRS,
and the EU (FEDER funding). We thank Pr. A.-C. Gaumont (the leader of our research group) and Dr. I. Chataigner
(Rouen), for helpful discussions.
Address correspondence to Mihaela Gulea, Laboratoire de Chimie Mole´culaire et Thio-Organique (LCMT),
UMR CNRS 6507, INC3M, FR 3038, ENSICAEN, UCBN, 6 Bd. Mare´chal Juin, 14050 Caen, France. E-mail:
mihaela.gulea@ensicaen.fr
349

350
H. DENTEL AND M. GULEA
Table 1 The HDA reactions of chiral dithioesters 1 and 2 with 2,3-dimethylbutadiene
Entry
Dithioester
Cycloadduct
dra
de (%)b
1
2
3
4
5
1a
1b
2a
2b
2c
3a
3b
4a
4b
4c
59/41
50/50
53/47
57/43
89/11
18
0
6
14
78
aDiastereomeric ratio determined by 1H NMR spectroscopy in the crude mixture. bDiastereomeric excess.
heterodienophiles for various applications.5 Before our study, only a few asymmetric HDA
reactions involving dithioesters as dienophiles6 had been described and the enantioselective
catalyzed version was unprecedented. Herein are summarized the most significant results
that we obtained in asymmetric Diels-Alder reactions with dithiooxalates and carbonylox-
azolidinone dithioesters, which were chosen as sulfur analogues of well studied acrylate
and glyoxalate derivatives.7
RESULTS AND DISCUSSION
Diastereoselective Version
Commercially available enantiopure menthol stereoisomers and oxazolidinones,
commonly used in asymmetric synthesis, were chosen as chiral auxiliaries to pre-
pare dithiooxalates 1 and carbonyloxazolidinone dithioesters 2, respectively. The chiral
dithioesters 1 and 2 were reacted with dimethyl-1,3-butadiene (Scheme 1, Tables 1). All
cycloadditions were carried out in dichloromethane, at room temperature, using 10 equiv-
alents of diene. Full conversions that translated into quantitative yields have been obtained
for the expected cycloadducts 3 and 4. (−)-Menthol induced a low diastereoselectivity
affording cycloadduct 3a with 18% de (entry 1), while no selectivity was obtained with its
epimer (+)-neomenthol having opposite configuration at C-1 (entry 2). Dithioesters 2a and
2b, derived from chiral 4-isopropyl and 4-benzyl oxazolidinones, led to the corresponding
cycloadducts with diastereoselectivities of 6% and 14%, respectively (entries 3 and 4). A
much higher diastereomeric excess of 78% was obtained with dithioester 2c derived from
a more hindered oxazolidinone (entry 5). An X-ray structure has been obtained for 2a
and showed that the stereodifferentiation of the Re and Si faces is small since the chiral
Z*
CH2Cl2, rt
MeS
Z*
SMe
O
*
> 98 % yield
see Table I
S
S
1, 2
3, 4
10 equiv
O
O
O
O
O
O
O
SMe
SMe
SMe
SMe
SMe
O
N
N
O
N
O
O
O
S
S
S
S
S
2a
1b
2c
1a
2b
Bn
Bn
iPr
Ph
Ph
Scheme 1

ASYMMETRIC HDA REACTIONS OF DITHIOESTERS
351
Table 2 Enantioselective HDA reactions of dithioesters 1x and 2x with 2,3-dimethylbutadiene, catalyzed by a
Cu(OTf)2/bis(oxazoline) complex
Entry
Dithioester
Cycloadduct
Ligand
mol% catalyst
ee (%)a
1
2
3
4
5
6
7
8
1x
1x
1x
1x
1x
1xa
1xb
1xc
2x
1x
2x
3x
3x
3x
3x
3x
3xa
3xb
3xc
4x
3x
4x
L1
L2
L3
L4
L5
L4
L4
L4
L4
L4
L4
5
5
5
5
5
5
5
5
5
2
54
0
82
0
10
78
10
4
9
10
11
100
100
82
42
aEnantiomeric excess determined by chiral HPLC.
center is placed too far from the reacting site. This is in line with the experimental poor
stereoselectivity observed in this case.
Enantioselective Version
Le dithiooxalate 1x and 2,3-dimethyl-1,3-butadiene was chosen as the cycloaddition
partners for the first series of experiments (Scheme 2, Table 2, entries 1–5). We decided to
start our study by testing Cu(OTf)2-bis(oxazoline) complexes as chiral catalysts, as they are
well known for their efficiency in various catalytic asymmetric carbo, oxa, and aza-Diels-
Alder reactions.8 Five commercially available bis(oxazolines) L1–L5 were tested as chiral
ligands. All reactions gave full conversion into the HDA cycloadducts, after less than 1 h.
No enantioselectivity was obtained with ligands L1, L3, and L5, but very promising results
were obtained with L2 (54% ee) and in particular with L4 (82% ee). Kipping the best
ligand L4, a screening of different parameters, temperature (−20 ◦C, 20 ◦C, 40 ◦C), solvent
(dietylether, acetonitrile, tetrahydrofurane, toluene, dichloroethane), Lewis acid [Zn(OTf)2,
Sn(OTf)2, CuCl2, Cu(ClO4)2] was done in order to improve the enantioselectivity of this
cycloaddition. Whatever the modifications performed, the enantiomeric excess did not
Cu(OTf)2/L
CH2Cl2, rt
S
Z
MeS
S
*
+
Z
SMe
see Table II
3x, 4x
1x, 2x
10 equiv.
O
1x: Z = CO2Et; 1xa: Z = CO2tBu; 1xb: Z = C(O)O
; 1xc: Z =
C(O)O
; 2x: Z =
C(O)N
O
O
O
O
O
N
O
O
O
N
O
O
O
Ph
Ph
N
N
N
N
N
N
N
N
Ph
tBu
Ph
Ph
But
Ph
Ph
Ph
L4
L1
L2
L3
L5
Scheme 2

352
H. DENTEL AND M. GULEA
Cu(OTf)2/L4 (5 mol%)
Z*
MeS
CH2Cl2, 20 °C
Z*
SMe
*
conv. 100 %
10 equiv
S
S
3, 4
1, 2
Scheme 3
exceed the previous result of 82% ee. Also in order to increase the enantioselectivity,
three more hindered dithiooxalates have been prepared and reacted in the same conditions
(Scheme 3, Table 2, entries 6–8). Tert-butyl and 3,3,4,4-tetramethyl-cyclohexyl derivatives
1xa and 1xc led to low ees of 10%. A better ee of 78% was obtained with 2,4-dimethylpentyl
dithiooxalate 1xb, however, still lower than with the ethyl derivative 1x. Placed in the same
reaction conditions, carbonyloxazolidinone 2x led to a very poor enantioselectivity of 4%
ee (Scheme 2, Table 2, entry 9). The use of a stoichiometric amount of catalyst was then
attempted (Table 2, entries 10–11). Similar enantioselectivity was obtained with 1x (Table 2,
entry 4 vs. entry 10), while with 2x the ee was considerably increased, from 4% to 42%
(Table 2, entry 9 vs. entry 11).
Double-Stereodifferentiating Experiments
Experiments combining the chiral induction of both auxiliary and catalyst were then
considered. This could bring additional information about the stereochemical outcome of
the cycloadditions and the metal center geometry of the reactive catalyst-dithioester com-
plexes. Chiral dithioesters 1 and 2 were reacted with 2,3-dimethylbutadiene in the presence
of 5 mol% of Cu(OTf)2/L4 (Scheme 3, Table 3). In these conditions, (−)-menthyl dithioox-
alate 1a led to a higher diastereomeric excess of 28% (vs. 18% in the uncatalyzed version),
but with an opposite chiral induction (Table 3, entry 1), representing the mismatched case.
The (+)-menthol derivative 1a’ gave matched reaction with a diastereoselectivity of 66%
(Table 3, entry 2). While no selectivity was observed with 1b in the uncatalyzed reaction,
the catalyzed version led to a high diastereomeric excess of 90% (Table 3, entry 3). The
results indicate that in this case the asymmetric induction comes mainly from the chi-
ral catalyst. The presence of the chiral catalyst in the cycloaddition of (S)-oxazolidinone
derivative 2c did not really change the diastereoselectivity compared to the uncatalyzed
reaction (80% vs. 78% de, Table 3, entry 4). The combination of the opposite enantiomer
2c’ with the chiral catalyst represents the mismatched pair, leading to 56% de (Table 3,
entry 5).
Table 3 HDA reactions of chiral dithioesters 1 and 2 catalyzed by Cu(OTf)2/L4
Entry
Dithioester
Cycloadduct
dr(a)
de (%)(b)
1
2
3
4
5
1a
1aꢁ
1b
2c
3a
3aꢁ
3b
4c
31/69
83/17
95/5
90/10
78/22
38
66
90
80
56
2cꢁ
4cꢁ
aDiastereomeric ratio determined by 1H NMR spectroscopy in the crude mixture. bDiastereomeric excess.

ASYMMETRIC HDA REACTIONS OF DITHIOESTERS
353
O
H
SMe
S
O
SMe
S
(+)-3x
HPLC
separation
O
N
EtO
1) KOH, H2O/EtOH, rt
2) (-)-brucine, MeOH, reflux
H
H
(-)-3x
O
rac-3x
H
HO
HO
SMe
S
*
N
SMe
S
SMe
S
O
O
Z
3 equiv. LiBH4
THF, rt, 72h
O
+
(-)-3x salt (1 dias.)
see Table IV
(S)-5
(R)-5
Z: CO2R (3x, 3a-b)
Z: C(O)oxazolidinone (4x, 4a-c)
Scheme 4
Assignment of Absolute Stereochemistry of Cycloadducts 3 and 4
We next tried to assign the absolute configuration of the quaternary stereogenic center
(C-2) formed during the cycloaddition in order to rationalize the stereochemical outcome
of this asymmetric HDA reaction. Starting from the racemic 3x, enantiomers (+)-3x, and
(−)-3x were separated by preparative chiral HPLC, then each one was hydrolyzed into the
carboxylic acid, and reacted with (−)-brucine (Scheme 4). The carboxylic acid derived
from the levorotatory ester formed a diastereomerically pure crystalline ammonium salt, of
which X-ray analysis allowed us to assign the (S) absolute stereochemistry to (-)-3x.
Then, cycloadducts 1 and 2 resulted from the different asymmetric cycloadditions
were reduced into the corresponding enantioenriched alcohol 5 (Scheme 4). The most
significant results are given in Table 4. After analysis by chiral HPLC we could correlate
the major alcohol (S)-5 to the major cycloadduct (S)-3x or (S)-4x (Table 4, entries 1, 2).
Cycloadducts 3a, 3a’, 3b, and 4c led to the major alcohol of (S)-configuration (Table 4,
entries 3–6). As expected, major alcohol (R)-5 was obtained from cycloadduct 3c’ (Table 4,
entry 7).
Table 4 Absolute stereochemical assignments of cycloadducts 3 and 4
Uncatalyzed HDA ee%b
(config. at C-2)
Catalyzed HDA ee%b
(config. at C-2)
Entry
Cycloadducta
1
2
3
4
5
6
7
3x
4x
3a
3ꢁ
3b
4c
4cꢁ
—
—
82 (S)
42 (S)(c)
28 (S)
66 (S)
90 (S)
80 (S)
56 (R)
18 (R)
18 (S)
0 (rac)
78 (S)
78 (R)
aCycloadducts obtained from the different asymmetric HDA reactions (see
Schemes 1–3, Tables 1–3). bEnantiomeric excess of 5, determined by chiral HPLC.
cWith 100 mol% chiral catalyst.

354
H. DENTEL AND M. GULEA
L
L
L
L
Cu
N
L
L
Cu
O
C
Cu
O
O
R
O
O
S
SMe
Ph
S
RO
N
O
SMe
SMe
S
III
O
R
I
II
Si
Ph
Ph
Ph
O
O
N
diene
diene
O
(S)-4x
(S)-3x
O
N
O
N
OEt
N
Cu O
O
Cu
steric
hindrance
Si
Ph
O
N
steric
hindrance
Ph
Ph
SMe
Ph
S
MeS
S
square-planar complex III-A(O,O)
tetrahedral complex I-B(S,O)
Stereochemical Models
A bidentate chelation catalyst-dithioester was considered (Scheme 5). Both of
dithiooxalate and carbonyloxazolidinone dithioester were supposed to coordinate the cop-
per via an oxygen and a sulfur atom (Scheme 5, complexes I and II). In the case of
dithioesters 2, the copper atom can also coordinate the two oxygen atoms of the carbony-
loxazolidinone moiety (Scheme 5, complex III) similarly to the known cases of acryloyl
and glyoxyl l,3-oxazolidin-2-ones. In order to rationalize the sense of the chiral induction
observed experimentally, we used by analogy models already proposed in the literature
for carbo- and oxa-dienophiles,9 Thus, for each of these complexes, two geometries of the
catalyst-dienophile10 complex were considered: a square-planar (A) and a tetrahedral (B).
Dithiooxalate case. In the asymmetric cycloaddition of dithiooxalate 1x catalyzed
by 5 mol% of Cu(OTf)2/L4 the major cycloadduct was of S-configuration (82% ee). Two
catalyst-dienophile complexes were considered: a square-planar I-A and a tetrahedral I-B,
both of them having Cu(S,O) coordination (Scheme 5). In the case of I-A, the Re-face
would be more accessible to the diene attack, leading preferentially to the cycloadduct with
R-configuration at C-2, while in the case of I-B, the Si-face should be the most accessible,
leading to the opposite isomer (S)-3x, which is in accordance with the experimental result.
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.
Carbonyloxazolidinone dithioester case. In the asymmetric catalyzed reaction of
dienophile 2x, the major (S)-cycloadduct was obtained with 42% ee, however, in the pres-
ence of a stoichiometric amount of Cu(OTf)2/L4. Two stereochemical models predict the
major (S)-cyloadduct (via a Si-face attack) in accordance with the experimental results: the
square-planar complex III-A with O,O-chelation mode10 and a tetrahedral complex of type
II-B with S,O-chelation mode (Scheme 5). When these two stereochemical models were
applied to the enantiomeric substrates 2c and 2c’, only the asymmetric induction predicted
by the square-planar complex of type III-A (O,O) fitted with the experimental results of the
double-differentiation study. These results suggesting a metal bidentate chelation between
the two oxygen atoms (similar to the acryloyl-oxazolidinones series) can explain the low
selectivities obtained in the asymmetric catalyzed HDA reaction involving carbonyloxa-
zolidinone dithioesters, as the chiral auxiliary is placed too far from the C S reacting
site.

ASYMMETRIC HDA REACTIONS OF DITHIOESTERS
355
CONCLUSION
New aspects of asymmetric thia-HDA reactions with dithioesters as heterodienophiles
were studied. In the diastereoselective version, the best result (78% de) was obtained with
a hindered oxazolidinone as the chiral auxiliary. In the enantioselective version, which
represent the first example in this topic, the best result remains 82% ee, which was ob-
tained in the cycloaddition of dithiooxalate with 2,3-dimethylbutadiene, catalyzed by a
Cu(II)/bis(oxazoline) chiral complex. The enantioselectivity of this type of cycloaddition
seems to be difficult to control because highly dependent of the substrate. The double-
differentiating experiments showed that in dithiooxalates series, the sense of the chiral
induction is mainly controlled by the chiral catalyst, whereas for the carbonyloxazolidi-
none dithioesters the chiral auxiliary dominates the stereochemical control. Stereochemical
models for catalyst/dithioester complexes were proposed in order to rationalize the sense
of the chiral induction obtained experimentally: a tetrahedral complex with a (S,O) metal
chelation for dithiooxalates and a square-planar complex with a (O,O) metal chelation for
the carbonyloxazolidinone dithioesters. Further studies are needed to expand the scope of
this asymmetric thia-HDA reaction.
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