Lewis acid tuned facial stereodivergent HDA reactions using β-substituted N-vinyloxazolidinones

Article abstract of DOI:10.1021/ol062626l

(Chemical Equation Presented) The [4 + 2] acido-catalyzed heterocycloaddition between new β-substituted N-vinyl-1,3-oxazolidin-2-ones (with R′ = Me, Ar, CH₂ Ar) and β,γ-unsaturated α-ketoesters (R = Ar) afforded heteroadducts with high levels o

Full text of DOI:10.1021/ol062626l

ORGANIC
LETTERS
2007
Vol. 9, No. 2
211-214
Lewis Acid Tuned Facial
Stereodivergent HDA Reactions Using
â
-Substituted N-Vinyloxazolidinones
Fre´de´ric Gohier,† Keltoum Bouhadjera,§ Djibril Faye,† Catherine Gaulon,†
Vincent Maisonneuve,‡ Gilles Dujardin,*,† and Robert Dhal*,†
UMR 6011 CNRS-UniVersite´ du Maine, Laboratoire de Synthe`se Organique (UCO2M),
and UMR 6010, Laboratoire des Oxydes et Fluorures, Faculte´ des sciences,
AVenue OliVier Messiaen, 72085 Le Mans Cedex 9, France
rdhal@uniV-lemans.fr; dujardin@uniV-lemans.fr
Received October 25, 2006
ABSTRACT
The [4
-unsaturated
differentiation was achieved by varying the Lewis acid, leading to the stereoselective formation of either endo-
+
2] acido-catalyzed heterocycloaddition between new
-ketoesters (R Ar) afforded heteroadducts with high levels of endo and facial selectivities. A complete reversal of facial
or endo- adducts.
â-substituted N-vinyl-1,3-oxazolidin-2-ones (with R′ ) Me, Ar, CH2 Ar) and
â
,
γ
r
)
r
â
The hetero-Diels-Alder reaction is a common and powerful
method to create dihydropyrans1 combining C-C and O-C
bond formations with regio- and diastereoselectivity at
several centers. 3,4-Dihydro-2H-pyrans, which are important
intermediates for the synthesis of natural products, can be
obtained by electron inverse-demand cycloaddition between
π-electron-deficient heterodienes and electron-rich dieno-
philes. In this field, aza-substituted dienophiles have been
rarely used. Electron-rich enamines2,3 have aroused more
interest than weaker dienophiles like enamides or enecar-
bamates which are seldom reported. Hsung’s group4 has
developed the thermal inverse-electron-demand [4 + 2]
heterocycloaddition of chiral allenamides derived from lac-
tams, oxazolidinones, and imidazolidinones. They obtained
highly functionnalized pyranyl heterocycles with good ste-
reoselectivities. More recently, we have described the first
example of an inverse-electron-demand heterocycloaddition
using N-vinyl-1,3-oxazolidin-2-one,5 which proved a valuable
dienophile toward â,γ-unsaturated R-ketoesters6 under ap-
propriate Lewis acid conditions.
The work was extended to chiral N-vinyloxazolidinones7
leading to original heteroadducts with high endo and facial
selectivities under Eu(fod)3-catalyzed conditions (Scheme 1).
N-Vinyl-1,3-oxazolidine-2-thiones8 were also used under
these conditions but afforded only moderate facial selectivi-
ties. Our interest in this field for developing new stereocon-
† UMR 6011, UCO2M-Laboratoire de Synthe`se Organique.
‡ UMR 6010, Laboratoire des Oxydes et Fluorures.
§ Present address: Laboratoire de Chimie organique, Universite´ Aboubekre
Belkaid, Tlemcen, Algeria.
(1) (a) Jorgensen, K. A. Eur. J. Org. Chem. 2004, 2093. (b) Tietze, L.
F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1 and references therein.
(c) Boger, D. L.; Weinreb, S. M. Hetero-Diels-Alder Methodology in
Organic Synthesis; Wasserman, H., H., Ed.; Academic Press: San Diego,
CA, 1987.
(2) (a) Eiden, F.; Winkler, W.; Wanner, K. T.; Markhauser, A. Arch.
Pharm. 1985, 648.
(3) Reviews: (a) Lenz, G. R. Synthesis 1978, 489. (b) Hickmott, P. W.
Tetrahedron 1982, 38, 1975. (c) Hickmott, P. W. Tetrahedron 1982, 38,
3363. (d) Whitesell, J. K.; Whitesell, M. A. Synthesis 1983, 517. (e)
Rappoport, Z. The Chemistry of Enamines in the Chemistry of Functional
Groups; John Wiley and Sons: New York 1994.
(4) (a) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung, R. P. Tetrahedron
Lett. 1999, 40, 6903. (b) Wei, L.-L.; Hsung, R. P.; Xiong, H.; Mulder, J.
A.; Nkanseh, N. T. Org. Lett. 1999, 1, 2145. (c) Rameshkumar, C.; Hsung,
R. P. Synlett 2003, 1241.
(5) Gaulon, C.; Gizecki, P.; Dhal, R.; Dujardin, G. Synlett 2002, 952.
(6) For more recent examples with other activated heterodienes, see:
Palasz, A. Org. Biomol. Chem. 2005, 3, 3207.
(7) Gaulon, C.; Dhal, R.; Chapin, T.; Maisonneuve, V.; Dujardin, G. J.
Org. Chem. 2004, 69, 4192.
(8) Tardy, S.; Tatiboue¨t, A.; Rollin, P.; Dujardin, G. Synlett 2006, 1425.
10.1021/ol062626l CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/19/2006

Scheme 1. Heterocycloaddition of N-Vinyloxazolidin-2-ones
toward â,γ-Unsaturated R-Ketoesters
Table 2. Reactions between Achiral Styryl Oxazolidinone 9a
and Oxabutadiene 10 Promoted by Different Lewis Acids
promoter
entry (equiv)
conv (%)b selectivity
(yield, %) endo/exoc
conditionsa
1
5 days reflux
5 days reflux
2
3
4
Eu(fod)3
(0.05)
Et2AlCl
(0.5)
65 (54)
89/11
trolled cycloreactants led us to explore the reactivity of chiral
â-substituted N-vinyl-1,3-oxazolidin-2-ones in [4 + 2] cy-
cloaddition. This could permit access to adducts possessing
three contiguous stereogenic centers, the configuration of
which being completely controlled during the cycloaddition
process.
Dienophiles were conveniently prepared by a two-step
procedure9 based on the dehydroalkoxylation of N,O-acetals
8 using TMSOTf/Et3N (Table 1). Achiral and chiral N-
-78 °C to rt overnight
TiCl4
0 °C to rt overnight
<5
(0.5)
5
6
7
ZnCl2 (2)
ZnBr2 (1)
BF3‚Et2O
(0.5)
4 days reflux
11 days reflux
-78 °C to -20 °C
overnight
66 (34)
100 (48)
100 (72)
91/9
90/10
88/12
8
9
TMSOTf -78 to -20 °C overnight 98 (75)
96/4
(0.5)
SnCl4
(0.5)
-78 °C, 3 h
100 (81)
>98/2
a Reactions were performed in dichloromethane except entries 1 and 2
(cyclohexane). b The conversion is based on the remaining diene in the crude
reaction mixture analyzed by 400 MHz 1H NMR. c Selectivity endo/exo is
determined from the 400 MHz 1H NMR spectrum of the crude reaction
mixture.
Table 1. Preparation of â-Substituted
N-Vinyloxazolidin-2-ones
occurred even after 5 days at 80 °C in cyclohexane (entry 1,
Table 2). Eu(fod)3 used as catalyst gave rise to a slow but
very clean conversion (no degradation) into major endo
adduct. Et2AlCl and TiCl4 proved not efficient to promote
the cycloaddition: whereas TiCl4 gave no significant reactiv-
ity, we observed with Et2AlCl the nucleophilic addition of
an ethyl substituent on the ketone of the pyruvic benzylidene
methyl ester 10. In contrast, SnCl4 promoted efficiently the
cycloaddition between 10 and 9a (entry 9, Table 2). The
endo-11 racemic adduct was obtained without any trace of
the exo-11 and with a good yield after purification. Interest-
ingly, ZnCl2, BF3‚Et2O, TMSOTf and Eu(fod)3 proved to
give less selectively the endo product than SnCl4.10
a Isolated yield from the second step. b Overall yield, 8 has not been
isolated. c 9 (10%) is also formed at this step.
The endo-selectivity observed with (E)-dienophile 9a and
SnCl4 at low temperature (i) contrasts with previous results
reported by Tietze’s group11 with the same Lewis acid under
similar conditions when starting from a (Z)-â-substituted
vinyl ether and (ii) is in accordance with those obtained by
our group with SnCl4 when using cyclanone enol ethers12
(of the same E geometry). The stereochemical outcome of
vinyloxazolidinones 9a-e (Table 1) were generated with a
pure (E)-geometry in modest to good yields. Styryloxazo-
lidinones 9a and 9b were prepared in one pot from 6 and 7,
respectively. In these cases, the elimination of ethanol took
place in the first step presumably due to the higher stability
of the conjugated styryl structures 9a,b.
We have then embarked on a detailed investigation of the
cycloaddition between achiral styryloxazolidinone 9a and
benzylidene pyruvic methyl ester 10 varying the reaction
conditions (Table 2). Without any Lewis acid, no reaction
(10) In this paper, adducts were designed as “exo” and “endo” whatever
the presumed mechanism, concerted or not.
(11) Tietze, L. F.; Schneider, C. Synlett 1992, 755. A high exo-selectivity
(15/1) was reported by these authors when using SnCl4 as Lewis acid
promotor at -78 °C.
(12) (a) Dujardin, G.; Martel, A.; Brown, E. Tetrahedron Lett. 1998,
39, 8647. (b) Martel, A.; Leconte, S.; Dujardin, G.; Brown, Maisonneuve,
V.; Retoux, R. Eur. J. Org. Chem. 2002, 3, 514.
(9) Gaulon, C.; Gizecki, P.; Dhal, R.; Dujardin, G. Synthesis 2003, 2269.
212
Org. Lett., Vol. 9, No. 2, 2007

SnCl4-promoted cycloadditions involving these â-substituted
dienophiles appears thus as directly dependent on the (E/Z)
geometry of the dienophile: the formation of the adduct
featuring a trans relationship of substituents on the newly
created C-C bond is favored in both cases. This feature also
supports the hypothesis of a ionic stepwise10,13 cycloaddition
process (Michael-type addition-cyclization) with SnCl4,14
in contrast with the asynchronous concerted mechanism
generally considered in the reactions involving lanthanide
salts as the catalyst.
coupling constants on the 400 MHz 1H NMR spectrum and
X-rays of endo-R-13e and endo-â-13c allowed to attribute
by analogy the absolute configuration of all other heteroad-
ducts. All of the reactions involving â-substituted dienophiles
9b-e proceeded with modest to good yields and with a high
level of endo selectivity whatever the Lewis acid used.
As a surprising and interesting result, SnCl4 and Eu(fod)3
proved to induce a high but opposite facial diastereoselec-
tivity. Endo-R-13b cycloadduct was obtained with a high
stereoselectivity under Eu(fod)3-catalyzed conditions, whereas
endo-â-13b was selectively obtained using SnCl4 as the
promotor.
We have then extended the study, investigating the
cycloaddition of chiral styryl oxazolidinones 9b-e toward
arylidene pyruvic methyl esters 10 and 12 in the presence
of the most efficient Lewis acids (Table 3). The stereochem-
Tietze has already pointed out a facial stereodivergency
occurring during the HDA reaction of 1-oxa-1,3-butadienes
with an enol ether in the presence of TMSOTf or Me2AlCl.15
The reversed facial differenciation was reported to be due
to an asymmetric induction under chelation control (with
Me2AlCl) or nonchelation control (with TMSOTf). More-
over, in the course of the cycloaddition of an alkoxydihy-
dropyranone and a diene, Varela et al.16 have described that
a significant change in the facial selectivity could take place
using either a chelating Lewis acid (SnCl4, TiCl4) or a
monocomplexing one such as BF3‚Et2O.
Table 3. Diels-Alder Reactions between Oxazolidinones
9b-e and Oxabutadienes 10 and 12
In our case, a high degree of facial selectivity is obtained
only with chelating Lewis acids: Eu(fod)3 and SnCl4. Indeed,
the use of BF3‚Et2O and TMSOTf (entries 3 and 4, Table 3)
resulted in a poorer diastereofacial differenciation, possibly
due to the inability of both Lewis acids to form a chelate.17
A fact that might explain the facial stereodivergency would
be that only SnCl4 could chelate both carbonyls of the
pyruvic system. In contrast, Eu(fod)3 could act in the
concerted transition state by intermolecular chelation involv-
ing the oxazolidinone moiety of the dienophile.18 The facial
stereodivergency could thus result from the different con-
formations adopted by both reactants in the two different
modes of chelation (5-membered-ring Sn(IV) chelate vs
sandwiched Eu(III) chelate).
Some variations on the dienophile were next studied.
Without any â-substituent on the double bond,19 the cy-
cloaddition took place with high endo and facial selectivities
under Eu(fod)3 conditions, whereas an assay employing 0.5
equiv of SnCl4 furnished a mixture of all possible four
diastereoisomers (entries 1 and 2, Table 3). In contrast, the
cycloadduct 13c possessing a methyl group in C-2 (entries
7 and 8, Table 3) was obtained with very high endo and
facial selectivities under SnCl4 conditions. The presence of
a â-substituent on the dienophile is thus beneficial to the
SnCl4-promoted reaction in terms of diastereoselectivities and
yields. The cycloaddition was even more successful as
compared to the reaction with the dienophile bearing the
a Reactions with Eu(fod)3 (0.05 equiv) were refluxed in cyclohexane until
the disappearance of the dienophile and reactions with SnCl4 (0.5 equiv)
were realized in CH2 Cl2 at -78 °C during 3 h. b Purified yield. c Selectivity
was determined from the 1H NMR spectrum of the crude reaction mix-
ture. d Yield representing the mixture of four isomers. e Not determined.
f Exo-â/exo-R > 98/2.
1
phenyl group since no exo adduct could be detected by H
(15) (a) Tietze, L. F.; Schulz, G. Liebigs Ann. 1995, 1921. (b) Tietze, L.
F.; Schneider, C.; Grote, A. Chem. Eur. J. 1996, 2, 139.
(16) Iriarte Capaccio, C. A.; Varela, O. Tetrahedron Lett. 2003, 44, 4023.
(17) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556.
(18) Such an interaction would not exist in the case of heterocycload-
ditions involving N-vinyloxazolidine-2-thiones, for which weak facial
selectivities are observed (see ref 8).
istry of the obtained cycloadducts was fully elucidated as
follows: endo/exo selectivity was deduced from the observed
(13) Telan, L. A.; Poon, C. D.; Evans, S. A., Jr. J. Org. Chem 1996, 61,
7455.
(14) Sera, A.; Ueda, N.; Itoh, K.; Yamada, H. Heterocycles 1996, 43,
2205.
(19) Gaulon, C. Ph.D. Thesis, University of Maine, Le Mans, 2003.
Org. Lett., Vol. 9, No. 2, 2007
213

NMR (entry 6 vs entry 8). The effectiveness of these
cycloadditions prompted us to test the reaction with another
diene, the trimethoxybenzylidene pyruvate methyl ester 1220
(entries 9-14, Table 3). Under the optimized conditions
established, 12 was opposed to various dienophiles and
afforded the expected dihydropyranes 13d-f with high endo
and facial selectivities. From the heteroadduct 13f, more
elaborated molecules like norlignans21 (some of them have
shown some antitubuline activities and are inhibitors of
topoisomerase II)22 could be prepared as represented in
Scheme 2.
In this paper, we have described the first examples of
hetero-Diels-Alder reactions between chiral â-substituted
N-vinyloxazolidinones and 1-oxabutadienes, affording origi-
nal cycloadducts with high endo and facial selectivities. The
choice of the Lewis acid proved critical, affording selectively
either the endo R adduct using Eu(fod)3 as the catalyst or
endo â if the promotor was SnCl4. The ability to modulate
the substituents on the heterodiene and the dienophile without
affecting the stereoselectivity and the yield is very promising
to envision the access to a large diversity of interesting
structures, especially of the lignan-type.
Acknowledgment. This research was supported by CNRS
and the Universite´ du Maine.
Scheme 2. Synthesis of Norlignans from Dihydropyrans
Supporting Information Available: Materials and meth-
ods, experimental procedures, X-ray crystal structures, and
1H and 13C NMR data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL062626L
(20) Brown, E.; Dujardin, G.; Maudet, M. Tetrahedron 1997, 53, 9679.
(21) For a recent review see: Chang, J.; Reiner, J.; Xie, J. Chem. ReV.
2005, 105, 4581.
For this purpose, the oxidative cleavage of the double bond
to yield the aldehyde 14, a reaction already performed on
similar substracts in our team, is now in progress.
(22) Gupta, R. S. J. Natl. Cancer Inst. 1985, 74, 159.
214
Org. Lett., Vol. 9, No. 2, 2007