Design of a New and Highly Effective Chiral Auxiliary for Diels-Alder Reaction of 1-Aminodiene

Article abstract of DOI:10.1021/jo0302049

A theoretical investigation of the selectivity of optically active oxazolidin-2-one-substituted dienes has been realized. This analysis enabled the development of (R)-4-phenyloxazolidin-2-thione as a very effective chiral auxiliary for cycloaddition of 1-

Full text of DOI:10.1021/jo0302049

ever, the literature dealing with cycloaddition of chiral
aminodienes is currently growing6-9 (even if a few
examples of asymmetric catalysis in the field of amino-
dienes were recently described10).
Design of a New a n d High ly Effective
Ch ir a l Au xilia r y for Diels-Ald er Rea ction
of 1-Am in od ien e
The first chiral aminodiene, developed by Smith, made
use of pyroglutamic ester auxiliary.6 Although the asym-
metric induction was good, there was no possibility of
removing the lactam group while retaining the nitrogen
functionality. Further investigations in the field of new
auxiliaries led recently to the development of chiral
oxazolidin-2-one substituted dienes.7 In the case of
N-(butadienyl)-4-phenyloxazolidin-2-one, the auxiliary
allowed further cleavage11 on the cycloadducts (to provide
the primary amine), but selectivities were moderate to
good (see below). Here, we describe our effort in the
optimization of the facial selectivity of this aminodiene
by proper structural modification which led us to design
a novel, very effective, chiral auxiliary for asymmetric
Diels-Alder reaction of 1-aminodiene.
It was previously reported that absolute configura-
tion of cyclohexenes obtained by Diels-Alder reaction
of chiral oxazolidinone (or lactam) substituted dienes
can be explained by the approach of the dienophile from
the less hindered face of the cisoid diene presenting an
anti12 conformation around the C(diene)-N(heterocycle)
bond.6a,d,7c To guide us in optimizing the facial selectivity
of the N-(butadienyl)-4-phenyloxazolidin-2-one, we have
first searched to identify the factors determining this
preferential cycloaddition of the diene in its anti confor-
mation.13 Considering N-(butadienyl)oxazolidin-2-one
Raphae¨l Robiette,† Karima Cheboub-Benchaba,†
Daniel Peeters,‡ and J aqueline Marchand-Brynaert*,†
Unite´ de Chimie organique et me´dicinale, Universite´
catholique de Louvain, Place L. Pasteur 1,
B-1348 Louvain-la-Neuve, Belgium, and Unite´ de Chimie
structurale et des me´canismes re´actionnels, Universite´
catholique de Louvain, Place L. Pasteur 1,
B-1348 Louvain-la-Neuve, Belgium
marchand@chim.ucl.ac.be
Received J une 23, 2003
Abstr a ct: A theoretical investigation of the facial selectivity
of optically active oxazolidin-2-one-substituted dienes has
been realized. This analysis enabled the development of (R)-
4-phenyloxazolidin-2-thione as a very effective chiral aux-
iliary for cycloaddition of 1-aminodiene.
The Diels-Alder reaction is one of the most widely
investigated and versatile pericyclic reactions in organic
synthesis.1 Its concerted mechanism enables the creation
of two σ bonds and up to four stereocenters in a single
step, in a regio- and stereoselective manner. So, it is not
surprising that the bulk of the investigations on asym-
metric synthesis over the past 30 years has been devoted
particularly to this reaction. To date, the vast majority
of the approaches to asymmetric [4 + 2] cycloaddition to
yield enantiomerically enriched six-membered ring com-
pounds is based on chiral catalysts (dienophile activation
by Lewis acids2 or, more recently, by nonmetallic orga-
nocatalysts3) or on the use of optically pure dienophiles.4
Fewer examples of asymmetric induction utilizing chiral
auxiliary modified dienes have been reported.4b,5 How-
(6) For N-dienyl pyroglutamates: (a) Menezes, R. F.; Zezza, C. A.;
Sheu, J .; Smith, M. B. Tetrahedron Lett. 1989, 30, 3295-3298. (b)
Defoin, A.; Pires, J .; Tissot, I.; Tschamber, T.; Bur, D.; Zehnder, M.;
Streith, J . Tetrahedron: Asymmetry 1991, 2, 1209-1221. (c) Behr, J .-
B.; Defoin, A.; Pires, J .; Streith, J .; Macko, L.; Zehnder, M. Tetrahedron
1996, 52, 3283-3302. (d) Robiette, R.; Marchand-Brynaert, J . J . Chem.
Soc., Perkin Trans. 2 2001, 11, 2155-2158.
(7) For N-dienyloxazolidin-2-ones: (a) Murphy, J . P.; Nieuwen-
huyzen, M.; Reynolds, K.; Sarma, P. K. S.; Stevenson, P. J . Tetrahedron
Lett. 1995, 36, 9533-9536. (b) McAlonan, H.; Murphy, J . P. Nieuwen-
huyzen, M.; Reynolds, K.; Sarma, P. K. S.; Stevenson, P. J .; Thompson,
N. J . Chem. Soc., Perkin Trans. 1 2002, 1, 69-79. (c) J aney, J . M.;
Iwama, T.; Kozmin, S. A.; Rawal, V. H. J . Org. Chem. 2000, 65, 9059-
9068. (d) Robiette, R.; Defacqz, N.; Stofferis, J .; Marchand-Brynaert,
J . Tetrahedron 2003, 59, 4167-4175.
† Unite´ de Chimie organique et me´dicinale.
‡ Unite´ de Chimie structurale et des me´canismes re´actionnels.
(1) For reviews on the Diels-Alder reaction, see: (a) Nicolaou, K.
C.; Snyder, S. A.; Montagnon, T.; Vassililogiannakis, G. Angew. Chem.,
Int. Ed. 2002, 41, 1668-1698. (b) Sauer, J . Angew. Chem., Int. Ed.
Engl. 1967, 6, 16-33. (c) Sauer, J .; Sustmann, R. Angew. Chem., Int.
Ed. Engl. 1980, 19, 779-807.
(8) For N-dienylpyrrolidines: (a) Kozmin, S. A.; Rawal, V. H. J . Am.
Chem. Soc. 1997, 119, 7165-7166. (b) Kozmin, S. A.; Rawal, V. H. J .
Am. Chem. Soc. 1999, 121, 9562-9573.
(2) For reviews, see: (a) Kagan, H. B.; Riant, O. Chem. Rev. 1992,
92, 1007-1019. (b) Morrison, J . D.; Mosher, H. S. In Asymmetric
Organic Reactions; Prentices Hall: Engelwood Cliffs, NJ , 1971; p 252.
(c) Paquette L. A. In Asymmetric Synthesis; Morrison, J . D., Ed.:
Academic Press: New York, 1984; Vol. 3B, p 455. (d) Oppolzer W.
Angew. Chem., Int. Ed. Engl. 1984, 23, 876-889. (e) Corey, E. J .
Angew. Chem., Int. Ed. 2002, 41, 1651-1667.
(3) (a) Riant, O.; Kagan, H. B. Tetrahedron Lett. 1989, 30, 7403-
7406. (b) Ahrendt, K. A.; Borths, C. J .; MacMillan, D. W. C. J . Am.
Chem. Soc. 2000, 122, 4243-4244. (c) Northrup, A. B.; MacMillan, D.
W. C. J . Am. Chem. Soc. 2002, 124, 2458-2460.
(9) For cycloaddition of chiral 2-aminodienes: (a) Enders, D.; Meyer,
O.; Raabe, G. Synthesis 1992, 1242-1243. (b) Barluenga, J .; Aznar,
F.; Valde´s, C.; Mart´ın, A.; Garc´ıa-Granda, S.; Martı´n, E. J . Am. Chem.
Soc. 1993, 115, 4403-4404. (c) Barluenga, J .; Aznar, F.; Ribas, C.;
Valde´s, C. J . Org. Chem. 1998, 63, 10052-10056.
(10) (a) Evans, D. A.; Barnes, D. M.; J ohnson, 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, 7582-7594. (b) Huang,
Y.; Iwama, T.; Rawal, V. H. J . Am. Chem. Soc. 2000, 122, 7843-7844.
(c) Huang, Y.; Iwama, T.; Rawal, V. H. J . Am. Chem. Soc. 2002, 124,
5950-5951.
(4) For reviews, see: (a) Taschner, M. J . Asymmetric Diels-Alder
Reactions; Taschner, M. J ., Ed.; J AI Press: Greenwich, 1989; Vol. 1,
pp 1-101. (b) Mulzer, J .; Altenbach, H.-J .; Braun, M.; Krohn, K. Ressig,
H.-U. Organic Synthesis Highlights; VCH Verlagsgesellschaft: Wein-
heim, 1991; pp 60-61.
(11) (a) Kocienski, P. J . In Protecting Groups; Thieme: Stuttgart,
New York, 2000; p 185. (b) Fisher, J . W.; Dunigan, J . M.; Hatfield, L.
D.; Hoying, R. C.; Ray, J . E.; Thomas, K. L. Tetrahedron Lett. 1993,
34, 4755-4758. (c) Meyers, A. I.; Burgess, L. E. J . Org. Chem. 1991,
56, 2294-2296.
(12) Throughout the paper, syn and anti notation refer to the
conformation around the C(diene)-N(heterocycle) bond.
(5) For a review on chiral dienes, see: Barluenga, J .; Sua´rez-Sobrino,
A.; Lo´pez, L. A. Aldrichim. Acta 1999, 32, 4.
10.1021/jo0302049 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/08/2003
J . Org. Chem. 2003, 68, 9809-9812
9809

F IGURE 2. Structure and relative energy (B3LYP 6-31G**)
of two relevant transition states for cycloaddition of ethylene
and N-dienyloxazolidin-2-one: (left) TSanti, 0 kcal‚mol-1
,
dihedral angle C(dO)-N-C(1)-C(2) ) 168.1°; (right) TSsyn,
2.79 kcal.mol-1, dihedral angle C(dO)-N-C(1)-C(2) ) 39.5°.
Key: gray, C; white, H; red, O; blue, N.
TABLE 1. In flu en ce of th e Exch a n ge of th e Ca r bon yl
Oxygen by a Su lfu r Atom on th e Rela tive En er gy (in
k ca l‚m ol-1; B3LYP /6-31G**) a n d th e Str u ctu r e of th e Tw o
Con for m er s of th e Dien e
F IGURE 1. Relative energies (B3LYP/6-31**) of anti and syn
conformers of the N-(butadienyl)oxazolidin-2-one (R ) H) and
the transition states of their reaction with ethylene (energy
of both transition states is relative to the sum of the reactants
energies considering the diene in its anti conformation).
(R ) H) as a model of the studied diene, we investigated
the equilibrium between the two conformers syn and anti
of the diene14 and the transition states of their reaction
with ethylene by theoretical methods15,16 (Figures 1 and
2). This led to the identification of four factors influencing
the discrimination between the two transition states.
The analysis of the two conformers of the diene
indicated that the higher energy obtained for the syn
structure could be explained by (i) a lower stabilization
by electronic delocalization than in the anti conformer,17
(ii) a destabilizing interaction between the dipoles of the
a
Dihedral angle.
dienyl and heterocyclic moieties in the syn structure, and
this despite (iii) the emergence of a stabilizing interaction
by hydrogen bond, between the oxygen of the carbonyl
function and the hydrogen of the carbon 2 of the dienyl
moiety, in the syn conformer.18 Moreover, the structure
of the transition states revealed that their difference in
energy can be attributed, in addition to these three
factors, to (iv) a steric interaction rising in TSsyn between
the dienophile and the hydrogen atom of the chiral center
that induces a rotation of the heterocyclic moiety and
then reduces over again the possibility of stabilization
by electronic delocalization.
(13) We presume that formation of other diastereoisomers is due to
cycloaddition of the diene in its syn conformation and not to the
approach of the dienophile from the most hindered face of the diene
in its anti conformation.
(14) The Diels-Alder reaction occurs from the conformer presenting
a cisoid conformation of the dienyl moiety; all the considered structures
of dienes in this publication will present a cisoid conformation.
(15) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Baboul, A. G.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R. L.; Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
J ohnson, B.; Chen, W.; Wong, M. W.; Andres, J . L.; Gonzalez, C.; Head-
Gordon, M.; Replogle, E. S. and Pople, J . A. Gaussian 98, Revision
A.7; Gaussian, Inc.: Pittsburgh, PA, 1998.
(16) (a) Becke, A. D. J . Chem. Phys. 1993, 98, 1372-1377. (b) Becke,
A. D. J . Chem. Phys. 1993, 98, 5648-5652. (c) Lee, C.; Yang, W.; Parr,
R. G. Phys. Rev. B 1988, 37, 785-789. (d) Frisch, J .; Chabalowski, C.
F.; Stephens, P. J .; Devlin, F. J . J . Phys. Chem. 1994, 98, 11623-11627.
(17) (a) Devaquet, A. J . P.; Townshend, R. E.; Hehre, W. J . J . Am.
Chem. Soc. 1976, 98, 4068-4076. (b) Garbay-J aureguiberry, C.;
Roques, B. P. Tetrahedron Lett. 1976, 16, 1285-1288.
This analysis drove us to imagine the substitution of
the exocyclic oxygen of the oxazolidinone auxiliary by a
(18) It was already demonstrated that the short (C-)H‚‚‚O contacts
are more attractive than repulsive ((a) Taylor, R.; Kennard, O. J . Am.
Chem. Soc. 1982, 104, 5063-5070. (b) Desiraju, G. R. Acc. Chem. Res.
1991, 24, 290-296). Moreover the C-H‚‚‚O angle (RC-H‚‚‚O ) 118.5°)
as well the distance between the hydrogen and oxygen atoms (dH‚‚‚O
)
2.30 Å) in the syn conformer are similar to those observed in structures
in which such C-H‚‚‚O hydrogen bonds were established; see, for
examples: (c) Pedireddi, V. R.; Sarma, J . A. R. P.; Desiraju, G. R. J .
Chem. Soc., Perkin Trans. 2 1992, 2, 311-320. (d) Sharma, C. V. K.;
Desiraju, G. R. J . Chem. Soc., Perkin Trans. 2 1994, 11, 2345-2352.
(e) Hartmann, M.; Wetmore, S. D.; Radom, L. J . Phys. Chem. A 2001,
105, 4470-4479. (f) Wang, Y.; Balbuena, P. B. J . Phys. Chem. A 2001,
105, 9972-9982. (g) Vishweshwar, P.; Thaimattam, R.; J asko´lski, M.;
Desiraju, G. R. J . Chem. Soc., Chem. Commun. 2002, 17, 1830-1831.
9810 J . Org. Chem., Vol. 68, No. 25, 2003

TABLE 2. Diels-Ald er Rea ction of
N-(Bu ta d ien yl)-4-p h en yloxa zolid in -2-on e a n d -th ion e
w ith Rep r esen ta tive Dien op h iles AdB
F IGURE 3. Structure and relative energy (B3LYP 6-31G**)
of two relevant transition states for cycloaddition of ethylene
and N-dienyloxazolidin-2-thione: (left) TSanti, 0 kcal‚mol-1
,
dihedral angle C(dS)-N-C(1)-C(2) ) 164.2°; (right) TSsyn,
4.60 kcal.mol-1, dihedral angle C(dS)-N-C(1)-C(2) ) 44.6°.
Key: gray, C; white, H; red, O; blue, N; yellow, S.
SCHEME 1. Syn th esis of
(R)-N-(Bu ta d ien yl)-4-p h en yloxa zilid in e-2-th ion e
sulfur atom to improve the facial selectivity. We antici-
pated indeed that this modification would decrease the
hydrogen bond interaction between the (thio)carbonyl
and the hydrogen fixed on the carbon 2 of the dienyl
moiety and hence increase the energetic discrimination
between the two transition states. To assess our hypoth-
esis, we carried on with computational studies.
a
Conversion measured by GC with phenanthrene as internal
b
reference. Diastereoisomeric ratios were determined by GC on
the crude mixtures. c Relative configurations were assigned by 1H
NMR. Diastereoisomeric excess of C(1). e Isolated yield. f Dias-
d
tereoisomeric ratio was determined in 1H NMR by integration of
Optimization of the two considered conformers of
N-(butadienyl)oxazolidin-2-thione revealed, as expected,
that oxygen substitution by a sulfur induces an increase
in the destabilization of the syn conformer of the diene
(Table 1). Analysis of the diene structures indicated that
this increase in the relative energy between the two
considered conformers with substitution (X ) O or S) can
be attributed to a weaker stabilizing effect by hydrogen
bond19 in the syn conformer and a higher dipole moment
of the heterocycle, in the case of the oxazolidin-2-thione
substituted diene (X ) S). Investigations of the transition
states of the Diels-Alder reaction of the respective
conformers with ethylene confirmed this higher relative
energy between the anti and syn structures in the case
of sulfur derivatives (Figure 3). The use of 4-phenylox-
OCH3 signal.
azolidin-2-thione as chiral auxiliary instead of the ox-
azolidin-2-one analogue would then improve significantly
the facial selectivity of the diene in Diels-Alder reaction.
Having this prediction in hand, we validated our concept
by experimental means.
To experimentally examine the incidence of the de-
signed structural modification of the diene on the facial
selectivity, we synthesized and cyclized both oxygen and
sulfur derivatives. Optically pure (R)-N-(butadienyl)-4-
phenyloxazolidin-2-one was obtained from (R)-phenyl-
glycinol by a previously described method.7b Application
of a similar strategy to the synthesis of the novel
oxazolidin-2-thione analogue provided the desired diene
in good overall yield (Scheme 1).20 Chiral oxazolidin-2-
one- and -thione-substituted dienes were then subjected
(19) For discussion on relative hydrogen bonding ability of amide
and thioamide, see: (a) Laurence, C.; Berthelot, M.; Le Questel, J .-Y.;
El Ghomari, M. J . J . Chem. Soc., Perkin Trans. 2 1995, 11, 2075-
2079. (b) Berny, F.; Wipff, G. J . Chem. Soc., Perkin Trans. 2 2001, 1,
73-82.
(20) See the Supporting Information for experimental details and
structural assignments.
J . Org. Chem, Vol. 68, No. 25, 2003 9811

SCHEME 2. Rep r esen ta tive Cycloa d d u cts
our theoretical predictions. Interestingly, a significant
increase in the endo/exo selectivity is also observed in
some cases. This can be explained, in our opinion, by
steric hindrance between the sulfur atom and the sub-
stituent in exo position in TSanti (see Figure 3). In the
case of symmetrically trans-disubstituted dienophiles
(DEAD and dimethyl fumarate), even if the selectivities
are significantly improved by the use of oxazolidin-2-
thione auxiliary, results remain however moderate.
In conclusion, we have documented a theoretical
analysis of the facial selectivity of optically active oxazo-
lidin-2-one-substituted dienes that has further enabled
the development of the most effective chiral auxiliary for
cycloaddition of 1-aminodiene thus far, namely 4-pheny-
loxazolidin-2-thione. The strategy of carbonyl oxygen
substitution by a sulfur atom in chiral oxazolidin-2-one
auxiliaries, to influence conformational equilibrium and
so improve the facial selectivity, could be extended to
other systems.
to a series of cycloadditions with representative electron-
deficient dienophiles (Table 2).20 All reactions were
conducted in refluxing acetonitrile, as previously de-
scribed in nonchiral series.7d,21 In the case of unsym-
metrical dienophiles, one regioisomer was formed in
agreement with the “ortho rule” of the Diels-Alder
cycloaddition (Scheme 2).6d,7d Four diastereoisomers (but
usually less than four) could be detected by GC analysis
of the crude mixtures (see the Supporting Information);
the selectivities of Table 2 were calculated from their
respective ratios. Structural assignments resulted from
NMR analysis of pure samples of the major endo dias-
tereoisomers, and mixtures of known composition of the
minor isomers, isolated by liquid chromatography.
A number of conclusions can be drawn from the
collected data. First, the reactivity of the diene is not
drastically affected by the structural modification. Sec-
ond, the chiral 4-phenyloxazolidin-2-thione auxiliary
provides systematically better experimental facial selec-
tivities as compared to those obtained with the oxazoli-
din-2-one analogue. This is in complete agreement with
Ack n ow led gm en t. This work was supported by
FRIA (fellowship to R.R.), FDS (fellowship to R.R.), and
FNRS by its support to access computational facilities
(FRFC Project No. 2.4556.99 “Simulations nume´riques
et traitement des donne´es”). J .M.-B. is a senior research
associate of FNRS.
Su p p or tin g In for m a tion Ava ila ble: Description of meth-
odological approach and of the dipole calculation. Cartesian
coordinates, total energies at the B3LYP 6-31G(d,p) level, and
number of imaginary frequencies of the considered dienes and
transition states. Experimental procedures and structural
analyses for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(21) (a) Defacqz, N.; Touillaux, R.; Marchand-Brynaert, J. J . Chem.
Res. (M) 1998, 2273-2286. (b) Marchand-Brynaert, J .; Defacqz, N.;
Robiette, R. In Recent. Res. Devel. Org. Chem.; Pandalai, S. G., Ed.;
Transworld Research Network: Trivandrum, India, 2001; Vol. 5, pp
207-223.
J O0302049
9812 J . Org. Chem., Vol. 68, No. 25, 2003