Direct enantioselective approach to oxazolo[4,5-e]isoindoles from [(S)R]-1-aminosubstituted-4-(p-tolylsulfinyl)-1,3-butadienes

Article abstract of DOI:10.1016/S0957-4166(99)00356-0

The enantioselective construction of [3aS,5aR,8aR,8bR]-1-(p- methoxyphenyl)-3a,7-dimethyl-3a,5a,8b,8a-tetrahydro-1H-oxazolo[4,5- e]isoindole-2,6,8-trione is achieved from enantiopure [(S)R]-(1E,3E)-2- methyl-1-(p-methoxyphenyl)amino-4-(p-tolylsulfinyl)-1,3-butadiene and N- methylmaleimide through a short sequence involving a Diels-Alder reaction, a sulfoxide-sulfenate rearrangement and intramolecular cyclization.

Full text of DOI:10.1016/S0957-4166(99)00356-0

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3473–3477
Direct enantioselective approach to oxazolo[4,5-e]isoindoles from
[(S)R]-1-aminosubstituted-4-(p-tolylsulfinyl)-1,3-butadienes
S. Blasco, M. C. Carreño, M. B. Cid, J. L. García Ruano and M. R. Martín ∗
Departamento de Química Orgánica (C-1), Universidad Autónoma, Cantoblanco, 28049 Madrid, Spain
Received 2 August 1999; accepted 11 August 1999
Abstract
The enantioselective construction of [3aS,5aR,8aR,8bR]-1-(p-methoxyphenyl)-3a,7-dimethyl-3a,5a,8b,8a-
tetrahydro-1H-oxazolo[4,5-e]isoindole-2,6,8-trione is achieved from enantiopure [(S)R]-(1E,3E)-2-methyl-1-
(p-methoxyphenyl)amino-4-(p-tolylsulfinyl)-1,3-butadiene and N-methylmaleimide through a short sequence
involving a Diels–Alder reaction, a sulfoxide–sulfenate rearrangement and intramolecular cyclization. © 1999
Elsevier Science Ltd. All rights reserved.
With the development of several general routes to enantiopure dienyl sulfoxides1 has come an
increasing attention to their use as chiral partners in asymmetric Diels–Alder reactions.2 The synthesis
of systems bearing a sulfoxide at C-1 and aryl or alkyl groups as well as alkoxy substituents in different
positions of the butadiene framework has been successfully achieved. To date, no nitrogen substituents
have been introduced in such enantiomerically pure dienes. In 1983, Overman reported the synthesis
of racemic carbamate protected 1-amino-4-phenylsulfinyl-1,3-butadienes3 and studied their Diels–Alder
reactions with acrolein and phenyl vinyl ketone. While the regioselectivity was shown to be fully
controlled by the acylamino substituents, the low π-facial diastereoselectivity achieved prevented further
development of these reactions.
Our previous work devoted to the study of Diels–Alder reactions with enantiomerically pure (R)-1-(p-
tolylsulfinyl)-1,3-butadiene derivatives has shown a high degree of stereocontrol in their cycloadditions
with dienophiles such as N-methyl maleimide,4 maleic anhydride5or 1,2,4-triazoline-3,5-dione.6 In
order to test the behaviour of amino substituted dienyl sulfoxides in cycloadditions with such kinds
of dienophiles, we decided to focus on the enantiopure compound 4 bearing a nitrogen substituent
at C-1 and a sulfoxide at C-4. We describe herein the synthesis of [(S)R] N-Boc 2-methyl-1-(p-
methoxyphenyl)amino-4-(p-tolylsulfinyl)-1,3-butadiene 4 and the study of its Diels–Alder reactions with
N-methyl maleimide and show that an unprecedented and stereoselective construction of the tetrahydro-
1H-oxazolo[4,5-e]isoindole-2,6,8-trione skeleton can be achieved starting from 4 in a short sequence.
∗
Corresponding author. Fax: (34) 913973966; e-mail: rosario.martin@uam.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00356-0

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S. Blasco et al. / Tetrahedron: Asymmetry 10 (1999) 3473–3477
Enantiomerically pure derivative 4 was synthesized from [(S)R,2E]-2-methyl-4-(p-tolylsulfinyl)-2-
butenal 1 which resulted from the acidic treatment (10% HCl) of [(S)R]-4-ethoxy-3-methyl-1-(p-
tolylsulfinyl)-3-buten-2-ol, previously obtained by us from 3-ethoxy-methacrolein and (R)-methyl-p-
tolylsulfoxide.4 As shown in Scheme 1, aldehyde 1 was reacted with p-methoxyaniline 2, to give imine
3 which was immediately transformed into the N-Boc protected diene 4 by successive treatment with
LDA and (Boc)2O. Compound 4 was isolated pure in a 66% overall yield from 1 and was shown to be
enantiomerically pure {[α]D20 +109 (c=1, CHCl3); ee >98%}.7
Scheme 1.
With diene 4 in hand, we studied its Diels–Alder reactions with N-methyl maleimide. In CH2Cl2 at
room temperature, reaction was very slow at normal pressure, but cycloaddition occurred in 24 h when
the mixture was submitted to high pressure (13 Kbar). Under these conditions, diene 4 evolved into a
75:25 mixture of diastereoisomeric endo adducts 5 and 6 in quantitative yield (Scheme 2). Compounds
20
20
5 {[α]D +179.1 (c=1, CHCl3); ee >98% }7 and 6 {[α]D −1.7 (c=0.5, CHCl3); ee >98%}7 could be
isolated diastereomerically pure by flash column chromatography.
Scheme 2.
1
The configurational assignment of adducts 5 and 6 was established on the basis of their H NMR
parameters and by comparison with those of other similar adducts previously obtained from reactions of
a series of 1-dienyl sulfoxides,4–6 by assuming an extended boat conformation for the cyclohexene ring
in these adducts.4–6,8 The most significant data are indicated in Fig. 1 and correspond to the chemical
shifts of olefinic hydrogen H6 which is shielded in 5 (H6 and p-Tol 1,3-parallel) and deshielded in
6 (H6 and S–O 1,3-parallel) also due to the rigid disposition of the sulfinyl group shown. Similar
effects are observed in the chemical shifts of H7a which is deshielded in 5 and shielded in 6 due to
the influence of the sulfur substituents. Considering that the R configuration of the sulfoxide must not
change in the Diels–Alder reaction, the absolute [3aR,4R,7R,7aR,(S)R] for the major diastereomer 5 and
[3aS,4S,7S,7aS,(S)R] for the minor adduct 6 can be assigned.
Figure 1.
Taking into account the behaviour reported by Overman for N-benzyloxycarbonyl-4-phenylsulfinyl-
1,3-butadiene,3 which reacted with α,β-unsaturated carbonyl compounds at 25°C, the low reactivity
observed for N,N-disubstituted derivative 4, also bearing a carbamate substituent at the nitrogen, suggests

S. Blasco et al. / Tetrahedron: Asymmetry 10 (1999) 3473–3477
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that the methyl group at C-2 of the butadiene framework, as well as the increased size of the amine
function due to the presence of the p-methoxyphenyl substituent, must be the origin of the different
reactivity. It is likely that the E stereochemistry of the C1–C2 double bond (determined by NOE
experiments) in 4 is forcing the lone electron pair at nitrogen to the syn-planar position indicated in Fig. 2
to avoid the strong 1,3-allylic interaction which would appear if the p-MeOC6H4 or Boc substituents were
situated in such planar disposition.9 Thus, in compound 4, the lone electron pair cannot be delocalized
into the 1,3-diene preventing the expected activation of this electron donor substituent and explaining the
decreased reactivity observed for 4, which is very similar to that observed for 1-dienyl sulfoxides lacking
the amino substituent.4–6
The π-facial diastereoselectivity of these cycloadditions can be explained on the basis of the model
previously proposed by us,4 based on a steric and stereoelectronic approach control of the dienophile
on the less hindered face of the diene adopting an s-trans conformation (Fig. 2). This endo transition
state shows minimized electrostatic repulsions between the carbonyl and sulfinyl oxygens. Moreover, the
orientation of the Ar (p-MeOC6H4) and Boc groups towards both faces of the diene system would explain
the lower stereoselectivity observed in this case with respect to other 1-sulfinyldienes which evolve with
a complete π-facial diastereoselectivity.
Figure 2.
When the crude mixture of 5 and 6 (75:25) resulting from the cycloaddition was kept at −20°C for
a long time (41 days) we observed its spontaneous evolution to 1-(p-methoxyphenyl)-3a,7-dimethyl-
3a,5a,8b,8a-tetrahydro-1H-oxazolo[4,5-e]isoindole-2,6,8-trione 7 (50% ee) which was cleanly formed.
Starting from diastereomerically pure 5, tricyclic derivative 7 was obtained in 46% isolated yield in
enantiomerically pure form.7 Formation of this tricyclic derivative could be explained on the basis of
the mechanism depicted in Scheme 3 for the evolution of 5. This allylic sulfoxide can evolve in a
sterocontrolled manner through a sulfoxide–sulfenate rearrangement10 to the sulfenate intermediate I
easily transformed into the carbinol II by the cleavage of the S–O bond. The formation of all cis-
substituted cyclohexenol II through this process had already been reported for adducts similar to 5.4,5 The
evolution of II through an entropically favoured intramolecular attack to the vicinal CO carbonyl group
of the Boc substituent would explain the formation of the oxazolidinone ring of 7 as a sole diastereomer.
Scheme 3.
Considering that the transformation of 5 and 6 in tricyclic derivative 7 through I and II must occur in a
highly stereocontrolled manner according to the mechanism proposed above, the absolute configuration
of the enantiomer 7 generated from the major adduct 5 must be [3aS,5aR,8aR,8bR].

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S. Blasco et al. / Tetrahedron: Asymmetry 10 (1999) 3473–3477
Studies directed to improve the facial selectivity of these reactions are now in progress in order to
further apply these good results to the synthesis of complex molecules.
Acknowledgements
We thank Dirección General de Investigación Científica y Técnica (PB95-0174 and PB95-0035) for
financial support.
References
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1
7. The enantiomeric excess of 4, 5, 6 and 7 was determined by H NMR after complexation with (R)-1-(9-anthryl)-2,2,2-
trifluoroethanol as chiral solvating agent. Such determination required the synthesis of all racemic derivatives that was
achieved from racemic 1. Diene 4: Yield 66% (from aldehyde 1). Mp 112–113°C. [α]D20 +109 (c=1, CHCl3). Anal. calcd
for C24H29NO4S: C 67.42, H 6.84, N 3.28, S 7.50. Found: C 67.21, H 6.90, N 3.32, S 7.78. IR (nujol): 1695, 1630, 1510,
1340, 1300, 1250, 1160, 1045. 1H NMR: 7.49 and 7.28 (4H, p-tol), 7.07 and 6.83 (4H, p-methoxyphenyl), 7.06 (1H, H1),
7.04 (d, 1H, H3, J3,4=15.0), 6.11 (d, 1H, H4, J3,4=15.0), 3.79 (s, 3H, CH3O), 2.38 (s, 3H, CH3Ar), 1.46 (s, 9H, t-butyl), 1.16
(d, 3H, CH3, J1,Me=1.2). 13C NMR: 12.1 (CH3), 21.3 (CH3), 28.1 (3CH3), 55.4 (CH3O), 82.3 (C), 113.9 (CH), 119.5 (C),
124.6 (CH), 128.3 (CH), 129.3 (CH), 129.9 (CH), 133.7 (C), 135.8 (CH), 141.1 (C), 141.6 (C), 141.8 (CH), 153.3 (C),
20
157.9 (C). Adduct 5: [α]D +179.1 (c=1, CHCl3). Mp 88–89°C. IR (CHCl3): 1710, 1690, 1530, 1440, 1410, 1370, 1295,
1240, 1165. 1H NMR: 7.67 and 7.31 (4H, p-tol), 7.32 and 6.82 (p-methoxyphenyl), 5.19 (bs, 1H, H6), 3.93–3.80 (m, 2H,
H4 and H7a), 3.78 (s, 3H, CH3O), 3.42 (dd, 1H, H3a, J=8.6, J=10.2), 3.31 (m, 1H, H7), 2.98 (s, 3H, CH3N), 2.39 (s, 3H,
CH3Ar), 1.81 (s, 3H, CH3), 1.28 (s, 9H, t-butyl). 13C NMR: 21.1 (CH3), 21.5 (CH3), 25.0 (CH3N), 28.1 (3CH3), 39.7 (CH),
42.8 (CH), 55.4 (CH3O), 61.2 (CH), 61.4 (CH), 80.5 (C), 113.9 (CH), 115.0 (CH), 125.6 (CH), 128.3 (CH), 130.1 (CH),
137.1 (C), 141.0 (2C), 142.6 (C), 154.6 (C), 158.1 (C), 175.7 (C), 176.2 (C). MS (EI): 342 (9), 298 (44), 175 (89), 167 (92),
123 (79), 108 (80), 91 (90), 57 (100). Adduct 6: Mp 114–115°C. [α]D20 −1.7 (c=1, CHCl3). Anal. calcd for C29H34N2O6S:
C 64.66, H 6.36, N 5.20, S 5.95. Found: C 64.33, H 6.34, N 5.06, S 5.80. IR (CHCl3): 1690. 1H NMR: 7.75 and 7.36 (4H,
p-tol), 7.30 and 6.86 (4H, p-methoxyphenyl), 6.23 (bs, 1H, H6), 3.94 (bd, 1H, H4, J4–3a=10.2), 3.81 (s, 3H, CH3O), 3.28
(dd, 1H, H3a, J4–3a=10.2, J3a–7a=8.6), 3.20 (m, 1H, H7), 2.98 (s, 3H, CH3N), 2.61 (dd, 1H, H7a, J3a–7a=8.6, J7a–7=5.5), 2.40
(s, 3H, CH3Ar), 2.12 (s, 3H, CH3), 1.32 (s, 9H, t-butyl). 13C NMR: 20.8 (CH3), 21.2 (CH3), 25.0 (CH3N), 27.9 (3CH3),
41.4 (CH), 42.9 (CH), 55.2 (CH3O), 60.5 (CH), 63.7 (CH), 80.3 (C), 113.7 (CH), 117.5 (CH), 125.3 (CH), 128.0 (CH),
129.7 (CH), 136.9 (C), 139.2 (C), 139.7 (C), 142.1 (C), 154.4 (C), 157.8 (C), 175.3 (C), 175.7 (C). MS (EI): 342 (2), 298
(35), 175 (84), 167 (82), 123 (77), 108 (77), 91 (98), 57 (100). Oxazolo[4,5-e]isoindole-2,6,8-trione 7: Yield 46%. Mp
184–186°C. [α]D20 −32.4 (c=0.5, CHCl3). IR (CHCl3): 1750, 1705. 1H NMR: 7.14 and 6.89 (4H, p-methoxyphenyl), 6.18
(dd, 1H, H5, J5,4=10.2, J5,5a=3.8), 5.90 (dd, 1H, H4, J4,5=10.2, J4,5a=2.7), 4.62 (d, 1H, H8b, J8b,8a=4.3), 3.79 (s, 3H, CH3O),
3.38 (m, 1H, H5a), 3.22 (dd, 1H, H8a, J8a,8b=4.8, J8a,5a=8.1), 2.38 (s, 3H, CH3N), 1.66 (s, 3H, CH3). 13C NMR: 23.4 (CH3),
24.4 (CH3N), 39.0 (CH), 39.8 (CH), 55.4 (CH3O), 59.7 (CH), 76.8 (C), 114.3 (CH), 121.7 (CH), 126.6 (CH), 128.9 (C),

S. Blasco et al. / Tetrahedron: Asymmetry 10 (1999) 3473–3477
3477
129.5 (CH), 156.2 (C), 158.6 (C), 173.4 (C), 174.2 (C). MS (EI): 342 (M+, 62), 298 (16), 205 (43), 187 (100), 175 (43),
134 (31), 108 (37), 91 (31), 77 (25). HRMS: calcd for C18H18N2O5: 342.1215. Found: 342.1210.
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