Chiral relay effect: 4-substituted 1,3-benzoxazol-2-(3H)-ones as achiral templates for enantioselective Diels-Alder reactions

Article abstract of DOI:10.1021/ol016966c

(matrix presented) A new strategy to control the enantioselectivity of Lewis acid catalyzed reactions has been investigated. The use of N-acryloyl-1,3-benzoxazol-2-(3H)-ones substituted at position 4 leads to the formation of diastereomeric complexes as a

Full text of DOI:10.1021/ol016966c

ORGANIC
LETTERS
2002
Vol. 4, No. 1
39-42
Chiral Relay Effect: 4-Substituted
1,3-Benzoxazol-2-(3H)-ones as Achiral
Templates for Enantioselective
Diels−Alder Reactions
Laura Quaranta, Olivier Corminboeuf, and Philippe Renaud*
Department of Chemistry and Biochemistry, UniVersity of Bern,
CH-3000 Bern 9, Switzerland
philippe.renaud@ioc.unibe.ch
Received October 28, 2001
ABSTRACT
A new strategy to control the enantioselectivity of Lewis acid catalyzed reactions has been investigated. The use of N-acryloyl-1,3-benzoxazol-
2-(3H)-ones substituted at position 4 leads to the formation of diastereomeric complexes as a result of the presence of a chiral axis. The
stereochemical outcome of the reaction is controlled by the chiral catalyst and by the chiral axis, leading to high enantioselectivity improvements
and, in one case, to an inversion of enantioselectivity.
The design of enantioselective Lewis acid catalyzed reactions
is currently receiving much attention.1 Diels-Alder reactions
are often used as test systems for the evaluation of the
efficiency of novel strategies for enantiocontrol.2 The vast
majority of the research has focused on the development of
novel chiral ligands to complex the metal centers used as
Lewis acids. For instance, the reaction of N-alkenoyl-1,3-
oxazolidin-2-ones with dienes has been thoroughly examined,
and very high levels of enantioselectivity have been achieved
with different types of Lewis acids.3 The choice of the 1,3-
oxazolidinone as template is mainly dictated by the pos-
sibility of chelation of the metal catalyst by the two carbonyl
groups to ensure a well defined conformation of the
intermediate complex.4 However, the design of an efficient
ligand for such reactions is difficult, and excellent results
have been obtained with relatively sophisticated chiral ligands
able to mask efficiently one face of the alkenoyl group. We
are interested in developing alternative achiral templates that
actively control the stereochemistry of the reactions and give
a high level of enantioselectivity with simple chiral Lewis
acids. We report here preliminary results obtained with
acrylamides derived from 4-substituted-1,3-benzoxazol-2-
(3H)-ones.5 The crucial role of the substituent at C(4) will
be rationalized as a chiral relay effect.6
(1) For an excellent and recent overview, see: Lewis Acids in Organic
Synthesis; Yamamoto, H. Ed.; Wiley-VCH: Weinheim, 2001; Vols. 1 and
2.
(2) For a review, see: Dias, L. C. J. Braz. Chem. Soc. 1997, 8, 289-
332.
(3) Selected examples of historical importance. Ti(IV): (a) Narasaka,
K.; Iwasawa, N.; Inoue, M. Yanmada, T.; Nakashima, M.; Sugimori, J. J.
Am. Chem. Soc. 1989, 111, 5340-5345. Iron(III): (b) Corey, E. J.; Imai,
N.; Zhang, H. J. Am. Chem. Soc. 1991, 113, 728-729. Mg(II): (c) Corey,
E. J.; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807-6810. Cu(II): (d)
Evans, D. A.; Miller, S. J.; Leckta, T. J. Am. Chem. Soc. 1993, 115, 6460-
6461. Zn(II): (e) Evans, D. A.; Kozlowski, M. C.; Tedrow, J. S. Tetrahedron
Lett. 1996, 37, 7481-7484. Al(III): Corey, E. J.; Sarshar, S.; Bordner, J.
The term “chiral relay” was introduced by Davies in chiral
auxiliary controlled reactions.7 Our approach differs because
J. Am. Chem. Soc. 1992, 114, 7938-7939. Yb(III): (f) Kobayashi, S.;
Hachiya, I.; Ishitani, H.; Araki, M. Tetrahedron Lett. 1993, 34, 4535-
4538. More example are cited in an excellent full paper: Evans, D. A.;
Miller, S. J.; Leckta, T.; von Matt, P. J. Am. Chem. Soc. 1999, 121, 7559.
(4) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325-335.
10.1021/ol016966c CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/14/2001

it is based on the development of achiral auxiliaries that can
adopt chiral conformations and thus relay the chiral informa-
tion of the catalyst to the reaction center.8,9 In this paper we
will focus on 4-substituted-1,3-benzoxazol-2-(3H)-ones. Upon
complexation with a chiral Lewis acid, the acrylamide 1
should lie in the two diastereomeric conformations A and B
as a result of the presence of a chiral axis in the substrate.
These two conformers should exist in unequal amounts and
react at different rates and with different stereoselectivity.
It is expected that by suitable choice of R, the chiral axis
will have an important role in controlling the stereoselectivity
of the reaction. Indeed, the chiral axis of A should favor a
si face attack of the acrylamide moiety, and the chiral axis
of B should favor the Re attack (Scheme 1).10 The stereo-
would induce a preferred conformation of the complex (either
A or B) and not influence the stereochemical outcome of
the reaction directly. In such a case, the stereochemical
outcome would only result from the substrate chiral axis,
which is relaying the chiral information present on the metal
ligand. The main interest of this approach is the possibility
of using simple and easily available chiral Lewis acids.
A series of 4-substituted-1,3-benzoxazol-2-(3H)-ones were
synthesized and the corresponding N-acryloyl derivatives
1a-h were prepared by reaction with acryloyl chloride in
the presence of triethylamine (see Supporting Information).
Their Diels-Alder reactions with cyclopentadiene were
examined in the absence of Lewis acids and in the presence
of 30 mol % of Lewis acids using the bisoxazoline (R)-2 as
a chiral ligand (eq 1). The simple diphenyl bisoxazoline (R)-2
Scheme 1. Conformations A and B of the Complexed
Acrylamide 1a
a Direction of attack favored by the atropisomerism is indicated
by the arrows.
was chosen as a ligand because it is easily available and
known to induce moderate to good enantioselectivity in many
reactions.11 To observe a chiral relay effect, it is important
to have a ligand that does not induce a complete face
shielding. In the absence of Lewis acids, the reactions were
performed at room temperature with 5 equiv of cyclopen-
tadiene. All of the reactions took place within 1-2 h and
were moderately endo stereoselective (endo/exo 5:1-15:1)
and high yielding (g95%) (see Supporting Information). No
reaction occurred at -40 °C; thus no competitive uncatalyzed
reaction would occur when the chiral Lewis acids were used
below -40 °C.
Reactions with zinc triflate at -40 °C are reported in Table
1 (entries 1 and 2). The ee’s were measured after reduction
of the crude product with LiBH4 or NaBH4 and GC analysis
on a chiral capillary column. The absolute configuration was
established by comparison of the observed [R]D with
literature data (see Supporting Information). As expected,
Lewis acid catalysis increased the endo selectivity relative
to the noncatalyzed reactions. With the nonsubstituted 1,3-
benzoxazol-2-(3H)-one derivative 1a, a very low level of
enantioselectivity was observed (entry 1, 11% ee). A marked
increase of stereoselectivity was observed with the Me-
substituted derivative 1b (42% ee). This first result was very
encouraging and supported our chiral relay hypothesis.
However, the reaction with zinc Lewis acids were too slow
(60 h) and were therefore abandoned. We turned next to
copper(II) triflate catalysis. With this system (Table 1, entries
3-5), reactions were over in 90 min and an excellent endo
selectivity was observed (endo/exo 100:1). A slight increase
chemical outcome of the reaction will result from a delicate
balance between the chiral Lewis acid and the axis of
chirality. In an ideal case of chiral relay, the Lewis acid
(5) For the use of 1,3-benzoxazol-2-(3H)-one in diastereoselective
reactions, see: Corey, E. J.; Houpis, I. N Tetrahedron Lett. 1993, 34, 2421-
2424. Li, G.; Wei, H.-X.; Gao, J. J.; Caputo, T. D. Tetrahedron Lett. 2000,
41, 1-5.
(6) Quaranta, L. Ph.D. Thesis, University of Fribourg, Switzerland, 2000.
The concept of chiral relay for enantioselective reaction has been presented
at the Fall Meeting of the New Swiss Chemical Society, October 12, 1999
(Quaranta, L.; Renaud, P. Chimia 1999, 53, 364, abstract 154) and at the
Second Swiss COST Chemistry Symposium, October 15, 1999 (Cormin-
boeuf, O.; Renaud, P. Chimia 1999, 53, 398, abstract 25).
(7) (a) Bull, S. D.; Davies, S. G.; Garner, A. C.; Seller, T. G. R. Pure
Appl. Chem. 1998, 70, 1501-1506. (b) Bull, S. D.; Davies, S. G.; Epstein,
S. W.; Ouzman, J. V. A. Chem. Commun. 1998, 659-660. (c) Bull, S. D.;
Davies, S. G.; Epstein, S. W.; Leech, M. A.; Ouzman, J. V. A. J. Chem.
Soc., Perkin Trans. 1 1998, 2321-2330.
(8) Recently, Sibi has presented a nice example of chiral relay using
alkylated pyralozidinones alkylated at N(1) and taking advantage of a labile
chiral nitrogen center: Sibi, M. P.; Venkatraman, L.; Liu, M.; Jasperse, C.
P. J. Am. Chem. Soc. 2001, 123, 8444-8445.
(9) Several examples of chiral relay in enantioselective reactions have
been identified in the literature. However, the concept of “chiral relay” has
only been explicitely used by us (ref 6) and Sibi (ref 8). (a) Watanabe, Y.;
Mase, N.; Furue, R.; Toru, T. Tetrahedron Lett. 2001, 42, 2981-2984. (b)
Yao, S.; Saaby, S.; Hazell, R. G.; Jørgensen, K. A. Chem. Eur. J. 2000, 6,
2435-2448. (c) Hiroi, K.; Ishii, M. Tetrahedron Lett. 2000, 41, 7071-
7074. (d) Ramo´n, D. J.; Guillena, G.; Seebach, D. HelV. Chim. Acta 1996,
79, 875-894. (e) Aggarwal, V. K.; Jones, D. E.; Martin-Castro, A. M. Eur.
J. Org. Chem. 2000, 2939-2945. (f) Evans, D. A.; Kozlowski, M. C.;
Murry, J. A.; Burgey, C.; Campos, K. R.; Connel, B. T.; Staples, R. J. J.
Am. Chem. Soc. 1999, 121, 669-685. (g) Corey, E. J.; Sarshar, S.; Lee,
D.-H. J. Am. Chem. Soc. 1994, 116, 12089-12090.
(10) Recently, an example of chiral relay in a chiral auxiliary controlled
reaction involving atropisomerism has been reported: Clayden, J.; Wah,
L.; Helliwell, M. Tetrahedron: Asymmetry 2001, 12, 695-698. Clayden,
J.; Pink, J. H.; Yasin, S. H. Tetrahedron Lett. 1998, 39, 105-108. See also
9g for a related enantioselective reaction.
(11) Review: Gosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron:
Asymmetry 1998, 9, 1-45.
40
Org. Lett., Vol. 4, No. 1, 2002

sensitive to water content (compare entries 1, 3 and 2, 4).
When magnesium perchlorate was used without extra drying,
substrate 1a gave a moderate 46% ee (entry 1), and the
Table 1. Diels-Alder Reaction According to Equation 1 in the
Presence of 30 mol % Zn(OTf)2 and Cu(OTf)2 and (R)-2
Lewis
acid
time
(h)
yield
ee
entry substrate
R
(endo/exo)
(endo)
Table 3. Diels-Alder Reactions of 1a-h in the Presence of
30 mol % Mg(ClO4)2 and (R)-2 According to Equation 1
1
2
3
4
5
1a
1b
1a
1b
1d
H
Zn(OTf)2 60
Me Zn(OTf)2 60
Cu(OTf)2
96% (34:1)
97% (18:1)
1.5 96% (100:1) (S) 44%
1.5 95% (100:1) (S) 55%
1.5 93% (100:1) (S) 64%
(S) 11%
(S) 42%
H
time
(h)
yield
ee
Me Cu(OTf)2
Bn Cu(OTf)2
entry
substrate
R
(endo/ exo)
(endo)
1
1a
1a
1b
1b
1d
H
H
Me
Me
Bn
1.5
15
1.5
17
97% (10:1)
96% (12:1)
96% (40:1)
98% (34:1)
92% (32:1)
(R) 46%
(R) 70%
(S) 82%
(S) 86%
(S) 88%
2a
3
4a
5
of enantioselectivity was observed on going from 1a (R )
H) to 1b (R ) Me) and 1d (R ) Bn), supporting a chiral
relay effect. These results were obtained by running the
reactions in parallel with the same solution of copper triflate.
However, this reaction was extremely sensitive to moisture,
and results varied for each new set of reactions. So, even if
this system was very promising from a synthetic point of
view, it was not pursued because a high reproducibility was
necessary to identify clearly the chiral relay effect.
2
a Freshly dried Mg(ClO4)2 was used.
reaction was finished within 90 min. With dried magnesium
perchlorate, the enantioselectivity went up to 70% ee, but
the reaction was slower and took 15 h (entry 2). In contrast
to all the previous examples, the major isomer had (R)-
configuration. By running the reaction with 1b, the absolute
configuration of the product was reversed to the “normal”
(S)-isomer; an enantiomeric excess of 82% was obtained with
magnesium perchlorate out of the bottle (entry 3) and 86%
ee with dried Lewis acid (entry 4). Again, the benzyl
derivative 1d was more selective, and an enantiomeric excess
of 88% was obtained without drying the magnesium per-
chlorate within 2 h.12,13
We investigated next magnesium-based Lewis acids (Table
2). In the presence of the MgBr2‚Et2O/bisoxazoline 2 (30
Table 2. Diels-Alder Reaction of 1a-h in the Presence of 30
mol % MgBr2 and (R)-2 According to Equation 1
time
(h)
yield
ee
entry
substrate
R
(endo/ exo)
(endo)
The structure of the magnesium complexes is highly
dependent on the counterion, reaction conditions (water
content), and steric bulk of the ligand. This renders the
discussion of the mechanism quite difficult, but it seems
reasonable to assume that the reactions with MgBr2 are going
through an octahedral complex and that reactions with dried
magnesium perchlorate are going through a tetrahedral
transition state.14 From Tables 2 and 3, it is clear that the
presence of a simple methyl group at C(4) has a dramatic
influence on the stereochemical outcome of the magnesium-
catalyzed processes. This correlates well with an increase
of the twisting angle (see Figure 1) around the C(O)-N bond
and to an increase of the steric bulk near the reactive olefinic
moiety.
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
H
3
7
7
5
5
10
9
9
98% (22:1)
97% (32:1)
97% (33:1)
97% (11:1)
98% (16:1)
98% (20:1)
97% (17:1)
95% (40:1)
(S) 14%
(S) 74%
(S) 76%
(S) 86%
(S) 88%
(S) 10%
(S) 72%
(S) 40%
Me
Et
Bn
PMB
CH2t-Bu
CH(Ph)2
SiMe3
1g
1h
mol %), the reactions were performed at -78 °C in 2-10
h. The nonsubstituted substrate 1a (R ) H) gave the endo
product with a good diastereoselectivity (endo/exo 22:1) but
low enantioselectivity (14% ee). The methyl-substituted
derivative 1b showed a dramatic increase of enantioselec-
tivity (entry 2, 74% ee). The ethyl-substituted derivative 1c
gave a slightly higher selectivity (entry 3, 78% ee). The best
results were obtained with the benzyl and p-methoxybenzyl
derivatives 1d and 1e (entries 4 and 5) with 86% and 88%
ee, respectively. Replacing the aryl group by the bulkier tert-
butyl group (compound 1f) led to a drop of ee (entry 6, 10%
ee). The diphenylmethyl-substituted substrate 1g afforded a
selectivity lower than that of the benzyl derivatives 1d and
1e (entry 7, 72% ee). Finally, the trimethylsilylsubstituted
compound 1h showed only a small increase of stereoselec-
tivity relative to the nonsubstituted system 1a (entry 8, 40%
ee).
In the case of the tetrahedral magnesium perchlorate
complexes, the nonsubstituted benzoxazolone reacts from the
(12) The reaction of 3-acryloyl-1,3-oxazolidin-2-one with cyclopentadiene
catalyzed by Mg(ClO4)2/2 affords the Diels-Alder adduct in 72-73% ee:
Carbone, P.; Desimoni, G.; Faita, G.; Filippone, S.; Righetti, P. Tetrahedron
1998, 54, 6099-6110. Takacs, J. M.; Lawson, E. C.; Reno, M. J.;
Youngman, M. A.; Quincy, D. A. Tetrahedron: Asymmetry 1997, 8, 3073-
3078.
(13) For magnesium(II)-catalyzed enantioselective Diels-Alder reactions,
see refs 3c and 12 and (a) Desimoni, G.; Faita, G.; Invernizzi, A. G.;
Righetti, P. Tetrahedron 1997, 53, 7671-7688. (b) Desimoni, G.; Faita,
G.; Righetti, P. Tetrahedron Lett. 1996, 37, 3027-3030. (c) Takacs, J. M.;
Quincy, D.; Shay, W.; Jones, B. E.; Ross, C. R. Tetrahedron: Asymmetry
1997, 8, 3079-3087. (d) Ghosh, A. K.; Mathivanan, P.; Cappiello, J.
Tetrahedron Lett. 1996, 37, 3815-3818. (e) Ordonez, M.; Guerrero-de la
Rosa, V.; Labastitda, V.; Llera, J. M. Tetrahedron: Asymmetry 1996, 7,
2675-2686.
A final series of experiments were run with magnesium
perchlorate (Table 3). In this case also, the system was
(14) For a discussion of the structure of magnesium(II)-bisoxazolines
complexes with 3-acryloyl-1,3-oxazolidin-2-one, see ref 13a.
Org. Lett., Vol. 4, No. 1, 2002
41

This complex has been examined by semiempirical PM3
calculations and a tentative model for the reactive conforma-
tion is presented in Figure 2. The model shows well the
important shielding role of the methyl group at C(4) of the
1,3-benzoxazol-2-(3H)-one moiety. The size and nature of
the R groups have a secondary influence on the stereohemical
outcome of the reaction since it can participate more or less
efficiently to the face shielding. For instance, we think that
the good result obtained with the benzyl group can be
attributed to a preferred conformation controlled by allylic
1,3-strain (Figure 2, E). The lower enantioselectivites
observed for larger substituents such as CH2t-Bu (1f), CH-
(Ph)2 (1g), and SiMe3 (1h) may possibly be attributed to a
large twisting (φ ) 59-64°) that does not allow for an
efficient chelation of the metal ion.
Figure 1. Dihedral angle φ as function of R calculated at the AM1
semiempirical level for the Z-s-cis conformer. (A more stable E-s-
cis conformer also exists but is not relevant for chelation-controlled
reactions).
si face to give the (R)-Diels-Alder adduct. This face is more
shielded by the ligand, but because of twisting of the system
it becomes less hindered than the Re face (Figure 2, C).
Introducing a methyl group at C(4) of the benzoxazolone
enhances the twisting and efficiently shields the Si face and
the reaction occurs again from the Re face (Figure 2, D).
Conclusions
By using a nonoptimized diphenyl bisoxazoline ligand 2, we
have demonstrated that proper choice of an achiral template
on the acrylamide facilitates a good level of stereocontrol
in Diels-Alder reactions with cyclopentadiene. These results
fit well with a chiral relay effect in which the achiral template
transmits the chiral information from the Lewis acid to the
reacting center via a preferred conformation where a novel
element of chirality (a chiral axis) is created. This strategy
combines the advantage of the double induction (chiral
catalyst plus chiral auxiliary) without the necessity of using
an enantiopure chiral auxiliary, since the element of chirality
is temporarily introduced during the chelation step.
Acknowledgment. This work was supported by the Swiss
National Science Foundation (Grant 21-55′386.98). O.C. is
very grateful to the Roche Research Foundation for a
fellowship.
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 1a-h and
3a-h, as well as analytical procedure for the determination
of ee’s. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 2. Proposed models for the magnesium-catalyzed reaction
(based on PM3 calculations).
OL016966C
42
Org. Lett., Vol. 4, No. 1, 2002