Asymmetric Diels-Alder reactions of optically active oxazolidinone-derived vinylsulfonamides

Article abstract of DOI:10.1016/S0957-4166(01)00320-2

Chiral vinylsulfonamides bearing an oxazolidin-2-one moiety derived from (R)-2-phenylglycinol and (1R,2S)-norephedrine have been employed as dienophiles in asymmetric Diels-Alder reactions at normal pressure affording d.e.s of up to 99% when EtAlCl₂ or Et₂AlCl ewre employed as Lewis acids. Theoretical calculations justify the observed enantio- and diastereoselectivity.

Full text of DOI:10.1016/S0957-4166(01)00320-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1811–1815
Asymmetric Diels–Alder reactions of optically active
oxazolidinone-derived vinylsulfonamides
M. Carmen Bernabeu,a Rafael Chinchilla,a Larry R. Falvellob and Carmen Na´jeraa,*
aDepartamento de Qu´ımica Orga´nica, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
bDepartamento de Qu´ımica Inorga´nica, Instituto de Ciencias de los Materiales de Arago´n, Facultad de Ciencias,
Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
Received 29 June 2001; accepted 13 July 2001
Abstract—Chiral vinylsulfonamides bearing an oxazolidin-2-one moiety derived from (R)-2-phenylglycinol and (1R,2S)-
norephedrine have been employed as dienophiles in asymmetric Diels–Alder reactions at normal pressure affording d.e.s of up to
99% when EtAlCl2 or Et2AlCl were employed as Lewis acids. Theoretical calculations justify the observed enantio- and
diastereoselectivity. © 2001 Published by Elsevier Science Ltd.
1. Introduction
systems such as isothiazolin-3-one 1,1-dioxide have also
been employed as dienophiles in the search for potential
anxiolytic agents.12 In addition, vinylsulfonamides bear-
ing 1,3-diene moieties13 or a furan ring14 have been
employed for the synthesis of sultams by intramolecular
Diels–Alder reactions.
The Diels–Alder reaction can be considered as one of
the most powerful transformations in synthetic organic
chemistry. The stereospecific creation of up to four
stereogenic centers in a single step makes this cycload-
dition suitable for application to complex molecules.1
The development of asymmetric variants of the Diels–
Alder reaction has attracted a great deal of interest and
both the use of chiral auxiliaries, mainly chiral
dienophiles, and optically active Lewis acids have been
widely investigated.2
However, reports on the use of chiral a,b-unsaturated
sulfonamides as dienophiles in asymmetric Diels–Alder
reactions are scarce. Thus, only trifluoromethylated
vinyl sulfonamides such as 1,15 bearing a C2-symmetric
pyrrolidine chiral auxiliary and 2,16 bearing a 1,3-oxa-
zolidine auxiliary, have recently been employed. How-
ever, high-pressure conditions are required and the use
of Lewis acid catalysis afforded decomposition prod-
ucts due to the presence of labile moieties.
On the other hand, vinyl sulfonamides are well estab-
lished peptidomimetics3 and inhibitors of cysteine
proteases.4 Different methods for their preparation
have been reported,5 the most recent being the cleavage
of 1,2-thiazetidine 1,1-dioxides6 and the condensation
of N-Boc-methanesulfonamides with aldehydes.7 Vinyl-
sulfonamides have being utilized in various reactions
such as aziridine formation8 and 1,3-dipolar cycloaddi-
tions,9 and are also excellent Michael acceptors.10 Some
examples have also been reported on the use of vinyl
sulfonyl amides as dienophiles in Diels–Alder cycload-
dition reactions. Thus, vinylsulfonamides have been
used in cycloaddition reactions to hexachlorocyclopen-
tadiene and diphenylisobenzofuran,11 and related cyclic
O
O
O
O
O
O
Ph
S
S
Ph
F3C
N
F3C
N
O
O
O
Ph
1
2
In this context, we envisaged that the presence of a
carbonyl group close to the sulfonylamide moiety
would add an additional coordination point for a Lewis
acid, thus preventing rotation through the SꢀN bond
and therefore allowing for asymmetric induction. We
report the preparation of enantiomerically pure oxazo-
lidinone-derived vinylsulfonamides and their use as chi-
* Corresponding author. Tel.: +34-96-5903728; fax: +34-96-5903549;
e-mail: cnajera@ua.es
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00320-2

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M. C. Bernabeu et al. / Tetrahedron: Asymmetry 12 (2001) 1811–1815
ral dienophiles in asymmetric Diels–Alder cycloaddi-
tion reactions.
O
O
S
HO
NH2
Ph
HO
O
1) NaH
HN
2) Cl(CH2)2SO2Cl
(75%)
Ph
3
4
2. Results and discussion
O
O
S
(Cl3CO)2CO
O
N
Starting from 3-(vinylsulfonyl)oxazolidin-2-one, 5 was
prepared by deprotonation of (R)-2-phenylglycinol 3
with 1.5 equiv of NaH followed by reaction with 2-
chloroethanesulfonyl chloride, which gave vinylsulfon-
amide 4 in 75% yield after in situ elimination of
hydrogen chloride (Scheme 1). Subsequent reaction
with triphosgene afforded 5 in quantitative yield. Chiral
vinylsulfonamide 8 was obtained in 57% overall yield
from (1R,2S)-norephedrine following a similar proce-
dure (Scheme 1).
Et3N
(99%)
Ph
5
O
O
S
HO
Ph
NH2
Me
HO
1) NaH
HN
2) Cl(CH2)2SO2Cl
(81%)
Ph
O
Me
7
6
O
O
S
(Cl3CO)2CO
O
N
Et3N
(70%)
The chiral a,b-unsaturated sulfonamides 5 and 8 were
employed as dienophiles in asymmetric Diels–Alder
cycloaddition reactions. Thus, reaction of phenylgly-
cinol-derived chiral vinylsulfonamide 5 with cyclopenta-
diene at rt afforded the cycloadduct 9 in 1.8/1 endo/exo
ratio, each of these diastereoisomers in low d.e. (Table
1, entry 1). When the reaction was performed at −40°C
in the presence of a Lewis acid such as EtAlCl2 the
Ph
Me
8
Scheme 1. Preparation of starting chiral vinylsulfonamides.
observed d.e.s improved significantly (Table 1, entry 2),
but remained unchanged on performing the reaction at
a lower temperature (Table 1, entry 3).
Table 1. Diels–Alder reactions of chiral vinylsulfonamides 5 and 8

M. C. Bernabeu et al. / Tetrahedron: Asymmetry 12 (2001) 1811–1815
1813
The use of norephedrine-derived vinylsulfonamide 8 in
the cycloaddition reaction with cyclopentadiene at rt
afforded a slightly higher endo/exo ratio than previ-
ously, but no asymmetric induction was observed for
any of these diastereomers 10 (Table 1, entry 4). How-
ever, the addition of EtAlCl2 or Et2AlCl2 at −40°C had
a dramatic effect in this case, both on the endo/exo
stereoselectivity and asymmetric induction (Table 1,
entries 5 and 6).17 Thus, only one diastereomer 10a18
was detected in the crude product, its endo stereochem-
of the cyclopentadiene to the Re p-face would lead to
10a (Fig. 2).
In order to get further insight into the preferred endo
selectivity of this cycloaddition, we performed ab initio
transition state searches22 for endo and exo transition
structures in the reaction between cyclopentadiene and
1
istry being determined by H NMR experiments. The
X-ray diffraction analysis19 of 10a confirmed this
assignment and allowed us to determine unequivocally
the absolute configuration in all of the new stereocen-
ters (Fig. 1), resulting from attack of the diene to the
Re p-face of the dienophile. When vinylsulfonamide 8
reacted with 2,3-dimethylbuta-1,3-diene in the presence
of EtAlCl2, the reaction was very slow at −40°C and
was performed instead at 0°C, affording 80% d.e.
(Table 1, entry 7).
The observed enhancement of the asymmetric induction
and endo/exo ratio by addition of EtAlCl2 or Et2AlCl
to 8 could be justified as a result of the formation of a
cationic Lewis-acid–dienophile complex such as 12
(Scheme 2). Similar species have been proposed to
account for the high stereoselectivity in the asymmetric
Diels–Alder reactions with chiral a,b-unsaturated N-
acyloxazolidinones.20
Scheme 2. Activation of vinylsulfonamide 8 by Et2AlCl and
cycloaddition reaction with cyclopentadiene.
Et
Et
Al
O
O
S
O
+N
Semi-empirical (PM3) calculations21 performed on a
cationic Lewis acid–dienophile complex formed
between EtAlCl2 and 8 showed a preferred conforma-
tion with the Si-face of the vinyl system shielded mainly
for the methyl group of the oxazolidinone ring. Attack
O
Ph
Me
Figure 2. Approximation of the cyclopentadiene to Et2AlCl-
activated 8.
Figure 1. X-Ray diffraction structure of cycloadduct 10a.

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M. C. Bernabeu et al. / Tetrahedron: Asymmetry 12 (2001) 1811–1815
Figure 3. Endo and exo transition structures [B3LYP/6-31G(d,p)//HF/3-21G]. Distances are expressed in angstroms.
a cationic species formed by a Lewis-acid activated
vinylsulfonamide analogous to 8 but deprived of the
phenyl and methyl groups due to computational limita-
tions. The HF/3-21G level of theory was applied and
the located endo and exo transition structures were
characterized by frequency calculations. The structures
showed a high degree of asynchronicity with significant
zwitterionic character (Fig. 3), as is known in Lewis
acid-catalyzed Diels–Alder reactions.23 Subsequent sin-
gle point DFT calculations performed at the B3LYP/6-
31G(d,p) level showed a difference in energies of 1.5
kcal/mol favoring the endo transition state.24
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3. Conclusion
We conclude that a Lewis acid-activated vinylsulfon-
amide bearing a chiral norephedrine-derived oxazo-
lidin-2-one moiety can act, similarly to a,b-unsaturated
N-acyloxazolidinones, as an effective asymmetry-induc-
ing dienophile in Diels–Alder cycloaddition reactions.
7. Tozer, M. J.; Woolford, A. J. A.; Linney, I. D. Synlett
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Acknowledgements
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We thank the Ministerio de Educacio´n y Ciencia
(MEC) of Spain (DGICYT, research projects PB97-
0123 and PB95-0792) for financial support.
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19. Crystallographic data (excluding structure factors) for the
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the Cambridge Crystallographic Data Centre as supple-
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17. The following synthesis of cycloadduct 10a is representa-
tive: To a solution of 8 (100 mg, 0.3 mmol) in CH2Cl2 (5
mL) under nitrogen was added EtAlCl2 (1 M solution in
hexanes, 0.3 mL, 0.3 mmol) and freshly distilled
cyclopentadiene (247 mL, 3 mmol). The mixture was
stirred at −40°C for 5 h and to the resulting solution was
added aqueous HCl (1 M, 15 mL). The mixture was
extracted with CH2Cl2 (3×20 mL) and the organics were
dried (Na2SO4) and evaporated (15 Torr), affording a
residue which was purified by flash chromatography (sil-
ica gel, hexane/AcOEt gradients) affording adduct 10a.
18. Compound 10a: White solid, mp 154–155°C. [h]2D5=−13.4
(c 1.2, CHCl3). IR (KBr) w 3063, 3032, 1771, 1337, 1145,
1
1021, 972, 830, 764, 704. H NMR (CDCl3, 300 MHz): l
1.04 (d, J=6.7 Hz, 3H), 1.40 (d, J=9 Hz, 1H), 1.59 (d,
J=9 Hz, 1H), 1.64 (ddd, J=12.2, 4.9, 2.7 Hz, 1H), 2.25
(ddd, J=12.2, 9.5, 3.7 Hz, 1H), 3.07 (m, 1H), 3.42 (m,
1H), 4.44 (ddd, J=9.5, 4.9, 3.2 Hz, 1H), 4.60 (quint.,
J=6.7 Hz, 1H), 5.72 (d, J=7.3 Hz, 1H), 6.13 (dd, J=5.5,
2.9 Hz, 1H), 6.34 (dd, J=5.5, 3 Hz, 1H), 7.27–7.46 (m,
5H). 13C NMR (CDCl3, 75 MHz): l 16.7, 29.8, 42.8,
45.3, 49.8, 57.7, 63.3, 80.1, 125.7, 128.8, 129.1, 131.4,
132.8, 138.0, 152.5. Anal calcd for C17H19NO4S: C, 61.24;
H, 5.75; N, 4.20; S, 9.60. Found: C, 60.98; H, 5.71; N,
4.12; S, 9.40%.
24. The zero-point energies were obtained at HF/3-21G and
were scaled by a factor of 0.94 (Scott, A. P.; Radom, L.
J. Phys. Chem. 1996, 100, 16502–16513).