Asymmetric Diels-Alder, Michael, and aldol reactions using a planar chiral 1,3-oxazol-2(3H)-one derived from (R)-(+)-4-hydroxy-[2.2]paracyclophane

Article abstract of DOI:10.1021/jo016383g

(+)-(R)-[2.2]Paracyclophane[4,5-d]-1,3-oxazol-2(3H)-one exhibiting planar chirality has been used as a chiral auxiliary in asymmetric Diels-Alder, Michael, and aldol reactions of α,β-unsaturated carboxy and enolate imides, respectively. The endo-exo- and face-diastereoselectivity is good and is controlled by the spatial relationship between the prochiral center and the C9-C10 ethylene bridge of the [2.2]paracyclophane moiety. The chiral auxiliary is easily removed and quantitatively recovered.

Full text of DOI:10.1021/jo016383g

J . Org. Chem. 2002, 67, 2665-2670
2665
Asym m etr ic Diels-Ald er , Mich a el, a n d Ald ol Rea ction s Usin g a
P la n a r Ch ir a l 1,3-Oxa zol-2(3H)-on e Der ived fr om
(
R)-(+)-4-Hyd r oxy-[2.2]p a r a cyclop h a n e
Antonio Cipiciani, Francesco Fringuelli,* Oriana Piermatti,* Ferdinando Pizzo, and
Renzo Ruzziconi
Dipartimento di Chimica, Universit a` di Perugia, via Elce di Sotto, 8-06123 Perugia, Italy
frifra@unipg.it
Received December 18, 2001
(+)-(R)-[2.2]Paracyclophane[4,5-d]-1,3-oxazol-2(3H)-one exhibiting planar chirality has been used
as a chiral auxiliary in asymmetric Diels-Alder, Michael, and aldol reactions of R,â-unsaturated
carboxy and enolate imides, respectively. The endo-exo- and face-diastereoselectivity is good and
is controlled by the spatial relationship between the prochiral center and the C9-C10 ethylene
bridge of the [2.2]paracyclophane moiety. The chiral auxiliary is easily removed and quantitatively
recovered.
In tr od u ction
As a part of our research concerning the use of [2.2]-
paracyclophane in organic synthesis, we decided to use
this compound to prepare 1,3-oxazolones that exhibit
planar chirality.
7
While the importance of Evans chiral auxiliaries (1,3-
oxazolidin-2-ones) for asymmetric carbon-carbon forma-
tion (Diels-Alder, Michael, and aldol reactions) is well
documented, no investigation has been carried out, with
the exception of our preliminary communication, on the
use of chiral 1,3-oxazolones for asymmetric syntheses.
Most chiral 1,3-oxazolidinones have been derived from
naturally occurring compounds such as R-amino acids,
The [2.2]paracyclophane chemistry has attracted the
interest of researchers since the middle of the last
1
2
8
century. After a standstill period, investigations in this
7,9
area have received a new impulse and recently there
has been notable progress especially regarding the
3
10
synthesis of new derivatives and their application as
terpenes,4 carbohydrates,5 and tartaric acid,6 and the
chirality is secured by the presence of one or more chiral
centers. Moreover, to achieve high diastereo- and enan-
tioselectivities, the presence of an alkyl or aryl substitu-
ent at C4 of the 1,3-oxazolidinone ring is essential. This
strategy does not seem to be suitable for preparing
effectual chiral auxiliaries with a 1,3-oxazolonic moiety.
11
ligands of organometallic catalysts and as chiral aux-
10k,n,11c,d,g
iliaries in asymmetric reactions.
Here we report
the synthesis of the first planar chiral 1,3-oxazol-2-one
(7) (a) Cipiciani, A.; Fringuelli, F.; Mancini, V.; Piermatti, O.; Pizzo,
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(
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0 (1), 3-11. (b) Evans, D. A.; Miller, S. J .; Lectka, T.; von Matt, P. J .
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2
6, 1184-1187. (d) Evans, D. A.; Chapman, K. T.; Bisaha, J . J . Am.
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Org. Chem. 1998, 63, 6398-6400. (h) Palomo, C.; Airpurna, J . M.;
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(
2
(
6
(
4
(
Gaur, S.; Knight, K. S.; Smith, G. W.; Hodgson, P. K. G.; Cadogan, J .
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1
1, 423-433. (b) R u¨ ck-Braun, K.; Stamm, A.; Engel, S.; Kunz, H. J .
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1
994, 5, 2447-2458.
(
6) Lee, S.; Lim, C. W.; Kim, D. C.; Lee, J . K. Tetrahedron:
Asymmetry 2000, 11, 1455-1458.
1
0.1021/jo016383g CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/22/2002

2
666 J . Org. Chem., Vol. 67, No. 8, 2002
Cipiciani et al.
Sch em e 1
in situ by reaction with ethyl chloroformate to give 5 that
was directly converted to 7. Following this procedure
allowed preparation of the oxazolone 7 from 1 in 50%
overall yield. H and C NMR, IR, and elemental
analyses (see Experimental Section and Supporting
Information) support the structure of 7 and its precur-
sors.
1
13
Diels-Ald er Rea ction s. The preparation of dieno-
philes and the Diels-Alder reaction were performed in
1
d
an organic solvent according to the Evans procedure.
Reaction of 7 with MeMgBr or BuLi in anhydrous THF
followed by acylation with acryloyl chloride or crotonyl
chloride gave the unsaturated carboximides 8 and 9,
respectively. Diels-Alder cycloaddition of 8 with cyclo-
pentadiene in CH
2
Cl
2
at -100 °C12 in the presence of Et
-
2
AlCl (1.4 equiv)13 rapidly afforded (ca. 10 min) a mixture
of adducts A (R ) H) and C (R ) H) (Scheme 2) with
complete endo stereoselectivity and 86:14 endo face-
selectivity (Table 1, entry 1).
The Et
derivative 9 with the same diene carried out at -78 °C
entry 2) afforded, in 5 min, a mixture of adducts A (R )
2
AlCl cycloaddition reaction of (E)-crotonyl
(
Me), B (R ) Me), and C (R ) Me) in 90% yield with an
excellent endo/exo ratio (97.8:2.2) and a high level of A/C
endo face-selectivity (97.7:2.3). Uncatalyzed Diels-Alder
reaction of 9 (entry 3) was slow (40% conversion, after
derived from (+)-(R)-4-hydroxy-[2.2]paracyclophane (1)
and examples of its applications as a chiral auxiliary for
asymmetric carbon-carbon bond formation.
3
0 h); it again occurred with good endo-selectivity (endo/
exo ) 98:2), but with reversed face-diastereoselection,
with the C (R ) Me) adduct being the main reaction
product (85.6%). Using our experience of organic reac-
tions carried out in aqueous media,14 we also carried out
the cycloaddition of 9 with cyclopentadiene in water. This
reaction occurred under heterogeneous conditions (entry
4), was slow (42% conversion, after 30 h), and gave the
same endo-selectivity (endo/exo ) 97.6:2.4) in favor of the
Resu lts a n d Discu ssion
Syn th esis of (+)-(R)-[2.2]P a r a cyclop h a n e-[4,5-d ]-
1
,3-oxa zol-2-(3H )-on e. Ortho-directed metalation of
7
a
MOM-protected hydroxy derivative 2 (Scheme 1) with
butyllithium, followed by nucleophilic attack of the
corresponding lithium derivative with TsN
-azido-derivative 3. Reduction of 3 with LiAlH
-)-(R)-4-OMOM-5-amino-[2.2]paracyclophane (4) to be
isolated. Deprotection of 4 and successive reaction of the
resulting hydroxyamino compound 6 with ethyl chloro-
formate gave (+)-(R)-[2.2]paracyclophane-[4,5-d]-1,3-ox-
azol-2-(3H)-one (7) as a stable and optically pure com-
pound in ca. 20% overall yield from 1. Transformations
of 3 to 4 and 4 to 6 occurred with 95% conversions, but
and 6 were isolated in only 56 and 53% yields,
respectively. This is mainly due to their low solubility in
Et O and their reactivity toward solvents such as chlo-
roform, acetone, and ethyl acetate. Therefore, we planned
to prepare 7 from 2 without purifying or isolating the
intermediates. The crude azido 3 was converted into the
amino derivative 4, which was not isolated but protected
3
, gave the
5
(
4
allowed
C (R ) Me) adduct, as the reaction performed in sole CH
Cl at room temperature; only a slightly higher amount
of C/A-endo face-selectivity (91.5:8.5) was observed. By
using InCl (1.4 equiv) in an aqueous medium, we
2
-
2
3
observed no catalytic effect (entry 5).
The removal of the chiral auxiliary with lithium benzyl
oxide in THF (0 °C, 3 h)1d was performed with a good
yield and occurred with complete recovery of the chiral
auxiliary.
4
2
The structures of the Diels-Alder adducts are sup-
1
13
ported by H and C NMR spectra (see Experimental
(12) When the reaction was performed at -78 °C, the reaction yield
was only 30% because of the large propensity of acryloyl imide to
dimerize.
(
2
13) Et AlCl was added before the diene. With reversal of the order,
(
11) (a) Ludger, E.; Lars, W. Eur. J . Org. Chem. 1999, 1653-1663.
the cycloaddition occurs again with good yield (80%) and endo-
selectively (100%) but not face selectivity (A/C ) 54:46).
(
b) Buchholz, H. A.; H o¨ fer, J .; Noltemeyer, M.; de Meijere, A. Eur. J .
Org. Chem. 1998, 1763-1770. (c) Belokon, Y.; Moskalenko, M.;
Ikonnikov, N.; Yashkina, L.; Antonov, D.; Vorontsov, E.; Rozenberg,
V. Tetrahedron: Asymmetry 1997, 8, 3245. (d) Rossen, K.; Pye, P. J .;
Maliakal, A.; Volante, R. P. J . Org. Chem. 1997, 62, 6462-6463. (e)
Pye, P. J .; Rossen, K.; Reamer, R. A.; Volante, R. P.; Reider, P. J .
Tetrahedron Lett. 1998, 39, 4441-4444. (f) Rispens, M. T.; Manfredi,
A.; Pozzi, G.; Banfi, S.; Quinci, S. J . Mol. Catal. A: Chem. 1998, 136,
(14) (a) Fringuelli, F.; Germani, R.; Pizzo, F., Santinelli, F.; Savelli,
G. J . Org. Chem. 1992, 57, 1198. (b) Fringuelli, F.; Pani, G.; Piermatti,
O.; Pizzo, F. Tetrahedron 1994, 50, 11499-11508. (c) Brufola, G.;
Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles 1996, 43, 1257-
1266; 1997, 45, 1715-1721. (d) Ye, D.; Fringuelli, F.; Piermatti, O.;
Pizzo, F. J . Org. Chem. 1997, 62, 3748-3750. (e) Fringuelli, F.;
Piermatti, O.; Pizzo, F. In Organic Synthesis in Water; Grieco, P. A.,
Ed.; Blackie Academic and Professional Pb.: London, 1998; pp 223-
249, 250-261. (f) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L.
J . Org. Chem. 1999, 64, 6094-6096. (g) Fringuelli, F.; Pizzo, F.;
Vaccaro, L. Synlett 2000, 311-314. (h) Fringuelli, F.; Piermatti, O.;
Pizzo, F.; Vaccaro, L. Eur. J . Org. Chem. 2001, 439-455. (i) Fringuelli,
F.; Matteucci, M.; Piermatti, O.; Pizzo, Burla, M. C. J . Org. Chem. 2001,
66, 4661-4666. (j) Attanasi, O. A.; De Crescentini, L.; Filippone, P.;
Fringuelli, F.; Mantellini, F.; Matteucci, M.; Piermatti, O.; Pizzo, F.
Helv. Chim. Acta 2001, 84, 513-525. (k) Fringuelli, F.; Pizzo, F.;
Vaccaro, L. J . Org. Chem. 2001, 66, 4719-4722. Amantini, D.;
Fringuelli, F.; Pizzo, F.; Vaccaro, L. J . Org. Chem. 2001, 66, 4463-
4467.
1
3-22. (g) Pye, P. J .; Rossen, K.; Reamer, R. A.; Tson, N. N.; Volante,
R. P.; Reider, P. J . J . Am. Chem. Soc. 1997, 119, 6207-6208. (h)
Antonov, D. Yu.; Sergeva, E. V.; Vorontsov, E. V.; Rozenberg, V. I.
Russian Chem. Bull. 1997, 46, 1897-1900. (i) Bolm, C.; K u¨ hn, T.
Synlett 2000, 899-901. (j) Rozemberg, V. I.; Antonov, D. Y.; Zhuravsky,
R. P.; Vorontsov, E. V.; Khrustalev, V. N.; Ikonnikov, N. S.; Belokon,
Y. N. Tetrahedron: Asymmetry 2000, 11, 2683-2693. (k) Vetter, A.
H.; Berkessel, A. Tetrahedron Lett. 1988, 39, 1741-1744. (l) Wu, X.-
W.; Hou, X.-L.; Dai, L.-X.; Tao, J .; Cao, B.-X.; Sun, J . Tetrahedron:
Asymmetry 2001, 12, 529-523. (m) Hou, X.-L.; Wu, X.-W.; Dai, L.-X.;
Cao, B.-X.; Sun, J . Chem. Commun. 2000, 1195-1196. (n) Masterson,
D. S.; Glatzhofer, D. T. J . Mol. Catal. A: Chem. 2000, 161, 65-68.

Reactions Using a Planar Chiral 1,3-Oxazol-2(3H)-one
J . Org. Chem., Vol. 67, No. 8, 2002 2667
Sch em e 2
Ta ble 1. Diels-Ald er Rea ction s of Dien op h iles 8 a n d 9 w ith Cyclop en ta d ien e
entry
dienophile
catalyst
solvent
T (°C)
A (%)a
B (%)a
C (%)a
D (%)a
yield (%)a
b
1
2
3
4
5
8
9
9
9
9
Et2AlCl
Et2AlCl
CH2Cl2
CH2Cl2
CH2Cl2
H2O
-100
-78
rt
86
14
2.2
85.6
89.3
87.2
70
90
40
42
b
95.6
12.4
8.3
2.2
c
2.0
2.4
2.1
c,d
rt
rt
c
InCl3
H2O
10.7
30
a
Determined by 1H NMR. b Yield of isolated main reaction adduct. c Conversion determined by 1H NMR. d Yield of isolated C (R )
Me) adduct 35%.
Sch em e 3
Section and Supporting Information) and by conversion
of the cycloadduct A (R ) Me) to the known benzyl ester
1
d
1
3.
The stereochemical outcome of the EtAlCl
2
-promoted
Diels-Alder reactions is consistent with an endo addition
1
5
of cyclopentadiene on the more accessible re-face of the
s-cis bidentate Lewis acid-dienophile complexes 12a ,b
(
Scheme 2), in agreement with literature data.1b The
reversed endo face-selection observed in the cycloaddition
of 9 carried out in the absence of the catalyst is due to
the fact that the dienophile adopts the more stable s-cis
conformation 9a (Scheme 2) to minimize steric inter-
actions of the olefin moiety with the C9-C10 ethylene
bridge of [2.2]paracyclophane. As a consequence, the face
of the dienophile exposed to the diene attack is reversed
with respect to that of bidentate aluminum-dienophile
complex 12b (Scheme 2). The endo addition of cyclopen-
tadiene again occurs on the less sterically hindered face
of the dienophile, which in this case is the si-face, and
consequently, the endo adduct C (R ) Me) is the main
reaction product (Table 1, entries 3 and 4). This hypoth-
crotonyloxazolone 9, afforded the Michael adduct 16 in
15
8
5% yield. The reaction is g 99% re-face-selective. The
structure of 16 is supported by spectroscopic data (see
Experimental Section and Supporting Information) and
esis is supported by the Et
of crotonate 14, derived from 1, with cyclopentadiene
Scheme 3). The reaction, which occurred at -20 °C (3
2
AlCl-catalyzed cycloaddition
by its hydrolysis, which afforded the known acid 17 in
(
16,17
9
0% yield.
The chiral auxiliary 7 was recovered
h, 90% yield), is highly endo-selective (endo/exo ) 94:6),
but face-unselective (E/F ) 56:44) because the lack of a
bidentate dienophile complex allows the cycloaddition to
occur on the si-face and the re-face of 15a and 15b,
respectively, which are conformations of comparable
stability and that presumably give energetically compa-
rable transition states.
quantitatively and reused. The stereochemical
Mich a el Rea ction . Michael addition was accom-
plished using the Grignard reagent/cuprous bromide
outcome of the reaction is again consistent with the
conjugate addition of organometallic reagent to the less
system in THF/Me
the organometallic derived from bromobenzene, added to
2
S at -20 °C.16 Under these conditions,
(
16) Nicol a´ s, E.; Russell, K. C.; Hruby, V. J . Org. Chem. 1993, 58,
766-770.
(17) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141-6144.
(15) To facilitate the discussion of results, the si- and re-faces of
carboxy and enolate imides are defined with respect to the unsaturated
R-carbon of the CON group.

2
668 J . Org. Chem., Vol. 67, No. 8, 2002
Cipiciani et al.
Sch em e 4
and Michael additions. The Bu
2 3
BOTf/Et N-supported
aldol reaction is recognized to occur through the Zim-
2
0
merman-Traxler pericyclic chairlike transition state
involving the metal (G and H, Scheme 4), while this does
not occur in the Diels-Alder and Michael reactions for
which a metal-opened transition state has been sug-
gested.21 This fact makes the transition states H,
coming from the attack of the si-face of complexes 18 and
22
1
9 on the re-face of benzaldehyde, less sterically crowded
with respect to G, because the steric interactions of axial
butyl group with the C9-C10 ethylene bridge of the
paracyclophane moiety are reduced. The si-face diaste-
reoselectivity is therefore preferred.
Con clu sion
In conclusion, the (+)-(R)-[2.2]paracyclophane-[4.5-d]-
,3-oxazol-2(3H)-one 7, the first known member of the
1
oxazolone family with planar chirality, is an effective
chiral auxiliary in asymmetric Diels-Alder and Michael
reactions via R,â-unsaturated carboxy imides and in
asymmetric aldol addition via enolate imide. The spatial
relationship between the prochiral center and the C9-
C10 ethylene bridge of the [2.2]paracyclophane moiety
controls the diastereofacial selectivity so that the cata-
lyzed Diels-Alder and Michael reactions occur preva-
lently on the re-face of the acceptor, whereas the aldol
addition involves the si-face. Both enantiomers of the
auxiliary are available and can be removed easily and
quantitatively at the end of the asymmetric process.
sterically hindered re-face of 9, which has the two
carbonylic functionalities complexed by the metal cation
and the crotonyl side-chain in the s-cis conformation
likewise to aluminum complex 12b depicted in Scheme
Exp er im en ta l Section
NMR spectra were recorded at 400 or 200 MHz for proton
and at 100.6 or 50.3 MHz for carbon nuclei in CDCl
if not otherwise specified. Optical rotations were measured at
the sodium D line in CHCl solution, if not otherwise specified,
3
solution,
2
.
3
Ald ol R ea ct ion s. Oxazolones 10 and 11 and benz-
aldehyde were chosen to test the effectiveness of the
at room temperature. GC-MS analyses were carried out with
70 eV electron energy. GC analyses were performed with an
SPB-5 fused silica capillary column (30 m, 0.25 mm diameter)
on an “on column” injector system and an FID detector with
hydrogen as the carrier gas. Column chromatography was
carried out on silica gel 230-400 mesh. Reagents were
purchased and used without further purification. Tetrahydro-
furan and diethyl ether were dried using sodium metal and
then distilled from sodium benzophenone ketyl. Dichlo-
romethane was distilled from calcium hydride. Petroleum
ether was the 35-60 °C boiling fraction. The organic solution
obtained from workup of the reaction mixture was dried with
sodium sulfate and concentrated under reduced pressure on
a rotary evaporator with the water bath generally not exceed-
ing 40 °C.
chiral auxiliary in the aldol reaction.
Following standard procedures,18 we first treated
compounds 10 and 11, obtained in nearly quantitative
yields by N-acylation of lithium derivatives of 7 with
acetyl and propionyl chloride, respectively, with Bu
BOTf/Et N to give the boroenolates 18 and 19 (Scheme
), which were allowed to react in situ with benzaldehyde
2
-
3
4
at 0 °C. Oxidative workup allowed (+)-(R)-3-phenyl-3-
hydroxypropionic acid (20) (ee 71%) and (+)-(2R,3R)-syn-
-methyl-3-phenyl-3-hydroxypropionic acid (21) (ee 90%;
2
syn/anti ) 80:20) in 70 and 75% yields, respectively, to
be isolated. The cleavage of the auxiliary is quantitative,
very easy, occurs in a completely exocyclic way, and does
not require specific treatment. Once again, the removed
oxazolone 7 can be reused. The configurations of the
hydroxyacids 20 and 21 were proven by comparison with
(
+)-(R)-[2.2]P a r a cyclop h a n o[4,5-d ]-1,3-oxa zol-2(3H )-
on e (7). Butyllithium (21.4 mL, 1.6 M in hexane, 34.2 mmol)
(20) Zimmerman, H. E.; Traxler, M. D. J . Am. Chem. Soc. 1957,
79, 1920-1922.
1
9
(21) Iseki, K.; Oisshi, S.; Kobayashi, Y. Tetrahedron 1996, 52, 71-
4.
authentic specimens. The boron enolates 18 and 19
react preferentially with their si-face15 on the re-face of
benzaldehyde, showing that the addition occurs with a
reversed face-selectivity compared with the Diels-Alder
8
(22) As suggested by a reviewer, the oxazolone ring should be
oriented in the transition states as schematically depicted in G and H
of Scheme 4. This reflects either the stereoelectronic requirement of
amides and amines (the lone pair of nitrogen overlays the attached
CdO or CdC bonds) or that the dipole interaction between the enolic
oxygen and oxazolone carbonyl group is minimized. This allylic-like
(
18) (a) Gage, J . R.; Evans, D. A. Org. Synth. 1990, 68, 83-91. (b)
1
8d
Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E. Tetrahedron
Lett. 1987, 28, 39-42. (c) Iseki, K.; Oishi, S.; Kobayashi, Y. Tetrahedron
strain was observed by Evans for N-acyl oxazolidinone enolates. This
interaction is present in the transition structures in which the enolic
oxygen and the oxazolone carbonyl group preserve their starting cis
1
996, 52, 71-84. (d) Evans, D. A.; Takacs, J . M.; McGee, L. R.; Ennis,
2
M. D.; Mathre, D. J .; Bartroli, J . Pure Appl. Chem. 1981, 53, 1109-
relationship, but this prevents the rotation of 180° about the exocyclic
1
127.
C-N bond (during the addition of benzaldehyde), because it is
obstructed by the ethylene bridge of paracyclophane moiety. In any
case, the relative stability of the transition state of G and H does not
change.
(19) (a) Fringuelli, F.; Piermatti, O.; Pizzo, F. J . Org. Chem. 1995,
6
1
0, 7006-7009. (b) Fringuelli, F.; Piermatti, O.; Pizzo, F. Synthesis
996, 1207-1211.

Reactions Using a Planar Chiral 1,3-Oxazol-2(3H)-one
J . Org. Chem., Vol. 67, No. 8, 2002 2669
3
Calcd for C19H17NO : C, 74.25; H, 5.58; N, 4.56. Found: C,
was added dropwise to a solution of 27a (4.5 g, 16.8 mmol) in
anhydrous diethyl ether (70 mL) containing TMEDA (5.1 mL,
74.20; H, 5.60; N, 4.59.
3
4.0 mmol) and cooled at 0 °C under nitrogen and under
(-)-(R)-3-P r op ion yl-[2.2]p a r a cyclop h a n o[4,5-d ]-1,3-ox-
a zol-2(3H)-on e (11): prepared as described for 9 with pro-
pionyl chloride and purified by column chromatography eluting
stirring. The mixture was stirred at 0 °C for 1.5 h, and then
p-tosyl azide (6.74 g, 34.2 mmol) in anhydrous diethyl ether
(
20 mL) was added dropwise. Stirring was continued for 4 h
with n-hexane/ethyl acetate 8:2; yield 95%; mp 195-196 °C
1
at 0 °C; the reaction was quenched with water and the mixture
extracted with ethyl acetate. After the usual workup, the
residue, roughly purified by flash chromatography, afforded
crude 3 (ca. 5.5 g), which was reduced (0 °C for 15 min and 1
(n-hexane/ethyl acetate); [R]
D
-181.1 (c 0.50, CHCl
3
); H NMR
δ 1.39 (t, 3H, J ) 7.3 Hz), 2.31 (dt, 1H, J ) 13.4, 9.0 Hz), 2.65-
3.42 (m, 8H), 3.45 (ddd, 1H, J ) 13.8, 9.1, 1.0 Hz), 6.35-6.75
(m, 6H). Anal. Calcd for C20
3
H19NO : C, 74.75; H, 5.96; N, 4.36.
h at room temperature) by LiAlH
anhydrous diethyl ether (70 mL) under stirring and under
nitrogen. A 9:1 solution of THF/H O (10 mL) was then
cautiously added under stirring to the mixture followed by
ethyl chloroformate (4.5 mL, 47 mmol). After 1 h at room
temperature, the mixture was filtered through Celite and the
solid residue washed with ethyl acetate. The organic phase
was washed with brine and worked up as usual to give crude
4
(0.25 g, 11.8 mmol) in
Found: C, 74.86; H, 5.98; N, 4.32.
(-)-(R)-4-((E)-2-Bu ten oyl)-oxy[2.2]par acycloph an e (14):
Prepared as described for 9 with (+)-(R)-4-hydroxy[2.2]-
paracyclophane and (E)-crotonyl chloride and purified by
column chromatography eluting with n-hexane/ethyl acetate
2
95:5; yield 95%; mp 133-135 °C (n-hexane/ethyl acetate); [R]
D
1
-28.9 (c 0.6, CHCl ); H NMR δ 2.02 (dd, 3H, J ) 6.9, 1.7 Hz),
3
2.69 (m, 1H), 2.90-3.20 (m, 7H), 6.04 (d, 1H, J ) 1.6 Hz), 6.11
(dq, 1H, J ) 15.5, 1.7 Hz), 6.40-6.57 (m, 5H), 6.91 (dd, 1H, J
) 7.8, 1.9 Hz), 7.24 (dq, 1H, J ) 15.5, 6.9 Hz). Anal. Calcd for
5
(ca. 5.5 g), which was solubilized in dioxane (60 mL). The
mixture was acidified with concentrated HCl (2 mL) and
stirred for 1 h at room temperature. Potassium carbonate (8
g) was cautiously added and the mixture refluxed for 1 h. After
cooling, the mixture was filtered and the solid residue was
washed with ethyl acetate. The organic phase, washed with
brine and worked up as usual, gave crude 7, which was
purified by column chromatography eluting with petroleum
ether/acetone 4:1 to give pure 7 (2.35 g, 50% total yield from
C
20
H
20
O
2
: C, 82.16; H, 6.89. Found: C, 82.26; H, 6.91.
(-)-(R)-3-[(1′S,2′S,4′S)-Bicyclo[2.2.1]h ep t-5′-en -2′-ylca r -
b on yl]-[2.2]p a r a cyclop h a n o[4,5-d ]-1,3-oxa zol-2(3H)-on e
(A, R ) H). Diethylaluminum chloride (1.8 M in toluene, 0.12
mL, 0.21 mmol, 1.4 equiv) was first added to a stirred solution
of acrylate imide 8 (48 mg, 0.15 mmol) in anhydrous dichlo-
romethane (3 mL) cooled to -100 °C, and then precooled
cyclopentadiene (0.6 mL, 7.4 mmol, 50 equiv) was added. After
10 min, the mixture was poured in 1 M HCl (10 mL), extracted
1
): mp 315 °C dec. (ethyl acetate); [R] +12.8 (c 1.0, DMSO);
D
1
H NMR (acetone-d) δ 2.65-2.88 (m, 2H), 2.90-3.05 (m, 4H),
3
2
1
1
.10-3.27 (m, 2H), 6.42-6.66 (m, 6H); 13C NMR (DMSO) δ
8.5, 29.6, 32.9, 33.3, 121.6, 123.5, 125.2, 125.4, 126.6, 128.8,
31.9, 132.4, 133.3, 137.8, 138.0, 143.2, 155.9; IR (KBr) ν 3450,
760, 1425; MS m/z 265 (55), 161 (77), 133 (11) 104 (100), 78
1
with dichloromethane, and worked up as usual. H NMR
analyses revealed the presence of A (R ) H) and C (R ) H) in
an 86:14 ratio. Column chromatography, eluting with petro-
leum ether/diethyl ether 95:5, and recrystallization afforded
the major compound A as a crystalline solid (70% yield): mp
(12). Anal. Calcd for C17
2
H15NO : C, 76.96; H, 5.70; N, 5.28.
Found: C, 77.08; H, 5.69; N, 5.23.
203-205 °C (n-hexane/ethyl acetate); [R]
D
- 233.7 (c 0.46,
1
(
-)-(R)-3-(2-P r op en oyl)-[2.2]p a r a cyclop h a n o[4,5-d ]-1,3-
CHCl ); H NMR (400 MHz) δ 1.59 (d broad, 1H, J ) 8.3 Hz),
3
oxa zol-2(3H)-on e (8). A 3 M diethyl ether solution of MeMg-
Br (1.27 mL, 3.8 mmol) was added to a stirred solution of 7
1.63 (dq, 1H, J ) 8.3, 1.8 Hz), 1.71 (ddd, 1H, J ) 11.8, 4.4, 2.4
Hz), 1.98 (ddd, 1H, J ) 11.8, 8.8, 3.7 Hz), 2.54 (ddd, 1H, J )
13.3, 9.6, 7.6 Hz), 2.70-3.40 (m, 8H), 3.66 (s broad, 1H), 4.36
(ddd, 1H, J ) 8.3, 4.2, 4.0 Hz), 6.12 (dd, 1H, J ) 5.7, 2.7 Hz),
6.45 (dd, 1H, J ) 5.7, 3.1 Hz), 6.46-6.60 (m, 5H), 6.70 (dd,
1H, J ) 7.9, 1.7 Hz); 13C NMR (400 MHz) δ 28.60, 28.63, 33.57,
33.64, 34.62, 43.09, 44.20, 47.60, 51.05, 122.16, 125.82, 126.31,
127.10, 130.27, 131.14, 131.33, 131.47, 132.23, 132.95, 138.23,
(0.5 g, 1.9 mmol) in anhydrous THF cooled to 0 °C. The mixture
was stirred for 30 min at 0 °C, and then a solution of acryloyl
chloride (0.31 mL, 3.8 mmol) in anhydrous THF (2 mL) at -78
°
C was added. The mixture was stirred at -78 °C for 10 min
and at 0 °C for 20 min; the reaction was quenched with
saturated aqueous ammonium chloride, and then the mixture
was extracted with ethyl acetate. Usual workup and column
chromatography purification (eluent n-hexane/ethyl acetate
138.79, 139.54, 142.72, 151.82, 171.67. Anal. Calcd for C25
NO : C, 77.90; H, 6.01; N, 3.63. Found: C, 78.12; H, 6.07; N,
3.58.
23
H -
3
9
:1) afforded pure 8 (0.56 g, yield 93%): mp 159-161 °C
1
(hexane/ethyl acetate); [R]
D
-269.2 (c 0.60, CHCl
3
); H NMR
(-)-(R)-3-[((1′S,2′S,3′R,4′R)-3′-Meth ylbicyclo[2.2.1]h ep t-
5′en -2′-yl)car bon yl]-[2.2]par acycloph an o[4,5-d]-1,3-oxazol-
2(3H)-on e (A, R ) Me). Diethylaluminum chloride (1.8 M in
toluene, 0.12 mL, 0.21 mmol, 1.4 equiv) was added to a stirred
solution of crotonate imide 9 (50 mg, 0.15 mmol) and cyclo-
pentadiene (0.3 mL, 3.7 mmol, 25 equiv) in anhydrous dichlo-
romethane (0.3 mL) cooled to -78 °C. After stirring for 5 min
at -78 °C, the mixture was poured in 1 M HCl (10 mL),
δ 2.31 (dt, 1H, J ) 13.4, 8.9 Hz), 2.65-3.35 (m, 6H,), 3.38 (ddd,
1
6
1
H, J ) 13.9, 9.0, 1.0 Hz), 6.14 (dd, 1H, J ) 10.4, 1.5 Hz),
.40-6.72 (m, 6H), 6.78 (dd, 1H, J ) 16.9, 1.5 Hz), 7.56 (dd,
H, J ) 16.9, 10.4 Hz). Anal. Calcd for C20H17NO : C, 75.22;
3
H, 5.37; N, 4.39. Found: C, 75.30; H, 5.35; N, 4.40.
(
-)-(R)-3-((E)-2-Bu ten oyl)-[2.2]p a r a cyclop h a n o[4,5-d ]-
1
2
1
,3-oxa zol-2(3H)-on e (9). Butyllithium (1.6 M in n-hexane,
.4 mL, 3.8 mmol) was added to a stirred solution of 7 (0.5 g,
.9 mmol) in anhydrous THF cooled to 0 °C. The mixture was
1
extracted with dichloromethane, and worked up as usual. H
NMR analyses revealed the presence of three isomers in a 95.6:
2.2:2.2 ratio. Column chromatography eluting with petroleum
ether/diethyl ether 95:5 and recrystallization afforded the title
stirred for 20 min at 0 °C, and then a solution of (E)-crotonyl
chloride (0.36 mL, 3.8 mmol) in anhydrous THF (2 mL) was
added. The stirring was continued for 1 h at 0 °C. The mixture,
quenched with saturated aqueous ammonium chloride and
worked up as described above for 8, gave pure 9 (0.59 g, yield
compound as a crystalline solid (90% yield): mp 176-178 °C
1
(n-hexane/ethyl acetate); [R]
D
- 244.0 (c 0.55, CHCl
3
); H NMR
(400 MHz) δ 1.20 (d, 3H, J ) 7.0 Hz), 1.65 (dq, 1H, J ) 8.6,
1.7 Hz), 1.89 (d broad, 1H, J ) 8.6), 2.26 (m, 1H), 2.51 (ddd,
1H, J ) 13.3, 9.6, 7.7 Hz), 2.64 (s broad, 1H), 2.70-3.35 (m,
7H), 3.63 (s broad, 1H), 3.86 (dd, 1H, J ) 4.5, 3.4 Hz), 6.11
(dd, 1H, J ) 5.7, 2.7 Hz), 6.45-6.60 (m, 6H), 6.70 (dd, 1H, J
9
0
4%): mp 186-188 °C (hexane/ethyl acetate); [R]
D
-267.4 (c
1
.54, CHCl
3
); H NMR δ 2.11 (dd, 3H, J ) 6.4, 1.0 Hz), 2.32
(dt, 1H, J ) 13.4, 9.0 Hz), 2.60-3.45 (m, 7H), 6.40-6.75 (m,
6
6
H), 7.27 (dq, 1H, J ) 15.2, 1.0 Hz), 7.43 (dq, 1H, J ) 15.2,
1
3
.4 Hz). Anal. Calcd for C21 : C, 75.66; H, 5.74; N, 4.20.
H
19NO
3
) 7.9, 1.8 Hz): C NMR (400 MHz) δ 20.40, 28.59, 30.51,
33.66, 34.64, 36.19, 47.82, 48.24, 49.47, 53.01, 122.17, 125.79,
126.30, 127.08, 130.46, 131.12, 131.31, 131.48, 132.22, 132.96,
138.21, 138.78, 140.90, 142.73, 151.82, 171.43. Anal. Calcd for
Found: C, 75.72; H, 5.71; N, 4.22.
-)-(R)-3-Acyl-[2.2]p a r a cyclop h a n o[4,5-d ]-1,3-oxa zol-
(3H)-on e (10): prepared as described for 9 with acyl chloride
(
2
and purified by column chromatography eluting with n-
26 3
C H25NO : C, 78.17; H, 6.31; N, 3.51. Found: C, 78.29; H,
hexane/ethyl acetate 8:2; yield 95%; mp 206-208 °C (n-hexane/
6.33; N, 3.49.
1
ethyl acetate); [R]
D
-175.0 (c 0.54, CHCl
3
); H NMR δ 2.34
Rem oval of Ch ir al Au xiliar y. (-)-Ben zyl-(1S,2S,3R,4R)-
3-Meth ylbicyclo[2.2.1]h ep t-5-en e-2-ca r boxila te (13). Bu-
tyllithium (1.6 M in n-hexane, 0.125 mL, 0.2 mmol) was added
(
3
dt, 1H, J ) 13.4, 8.9 Hz), 2.65-3.35 (m, 6H), 2.84 (s, 3H),
.45 (ddd, 1H, J ) 13.8, 8.9, 0.8 Hz), 6.37-6.72 (m, 6H). Anal.

2
670 J . Org. Chem., Vol. 67, No. 8, 2002
Cipiciani et al.
to a stirred solution of benzyl alcohol (0.31 mL, 0.3 mmol) in
anhydrous THF (1 mL) cooled at -78 °C. A solution of the
adduct A (R ) Me) (39.9 mg, 0.1 mmol) in anhydrous THF (1
mL) was added and the mixture warmed to 0 °C. The solution
was stirred at this temperature for 3 h and the reaction
quenched with saturated aqueous ammonium chloride. The
mixture was concentrated in vacuo, diluted with water, and
extracted with dichloromethane. After the usual workup, the
residue was purified by column chromatography eluting with
6.35-6.62 (m, 5H), 7.20-7.50 (m, 5H); 13C NMR (400 MHz) δ
22.60, 28.37, 32.21, 33.58, 34.76, 36.03, 45.41, 122.26, 125.51,
125.90, 126.53, 128.82, 127.26, 128.69, 130.75, 130.94, 131.71,
131.81, 132.74, 138.22, 138.29, 142.55, 145.67, 151.76, 168.95.
Anal. Calcd for C27
C, 78.97; H, 6.09; N, 3.42.
Rem ova l of Ch ir a l Au xilia r y. (+)-(S)-3-P h en ylbu ta n oic
Acid s (17). H (30%, 0.045 mL) was added to a solution of
6 (41 mg, 0.1 mmol) in an 8:2 solution THF/H O (1.25 mL)
cooled to -5 °C. A 0.8 M aqueous solution of LiOH (0.2 mL,
.16 mmol) was then added dropwise keeping the temperature
below 0 °C. The mixture was stirred at 0 °C for 1 h, and then
a 1.3 M solution of Na SO (0.3 mL) was added. The organic
3
H25NO : C, 78.81; H, 6.12; N, 3.40. Found:
2
O
2
1
2
1
d
petroleum ether/diethyl ether 9:1 to give 13 (20 mg, 82%
yield), [R] -130 (c 0.5, CHCl ), and the chiral auxiliary 7 (24
mg, 91%).
+)-(R)-3-[((1′R,2′R,3′S,4′S)-3′-Meth ylbicyclo[2.2.1]h ep t-
D
3
0
(
2
3
5
2
2
9
′-en -2′-yl)car bon yl]-[2.2]par acycloph an o[4,5-d]-1,3-oxazol-
(3H)-on e (C, R ) Me). Cyclopentadiene (0.3 mL, 3.7 mmol,
5 equiv) was added to a stirred suspension of crotonate imide
solvent was evaporated, and the aqueous mixture was ex-
tracted with ethyl acetate. The organic phase was worked up
as usual to give the chiral auxiliary 7 (24 mg, 90%). The
mother liquor was acidified with concentrated HCl to pH 1-2
2
(50 mg, 0.15 mmol) in H O (1 mL). After stirring at room
temperature for 30 h, the mixture was extracted with dichlo-
16
and extracted with ethyl acetate. The usual workup gave 17
1
romethane and worked up as usual. H NMR analyses revealed
(
15 mg, 90% yield), [R] +54.0 (c 0.5, benzene).
D
the presence of three isomers in an 89.3:8.3:2.4 ratio. Column
chromatography eluting with petroleum ether/diethyl ether
Ald ol Rea ction . Hyd r oxya cid s 20 a n d 21. Triethylamine
(0.42 mL, 3 mmol) followed by dibutylboron triflate (1 M in
9
5:5 and recrystallization afforded the title compound as a
CH
2 2
Cl , 2.5 mmol) was added to a solution of acyloxazolone
crystalline solid (35% yield): mp 197-198 °C (hexane/ethyl
(10 or 11, 2 mmol) in anhydrous dichloromethane (10 mL)
1
acetate); [R]
D
+13.4 (c 0.50, CHCl ); H NMR (400 MHz) δ 1.30
3
cooled to -78 °C. The reaction mixture was allowed to warm
to 0 °C, and after 1 h, the solution was cooled again to -78 °C
and benzaldehyde (3 mmol) in dichloromethane (2 mL) was
added. After 30 min at -78 °C and 3 h at 0 °C, the reaction
was quenched with pH 7.0 phosphate buffer (0.1 M, 10 mL),
(
d, 3H, J ) 7.0 Hz), 1.57 (dq, 1H, J ) 8.7, 1.6 Hz), 1.80 (d
broad, 1H, J ) 8.7), 2.15 (m, 1H), 2.25 (ddd, 1H, J ) 13.6, 9.0
Hz), 2.65 (s broad, 1H), 2.65-3.35 (m, 7H), 3.46 (s broad, 1H),
3
6
(
.77 (dd, 1H, J ) 4.7, 3.1 Hz), 5.95 (dd, 1H, J ) 5.6, 2.8 Hz),
.40-6.60 (m, 6H), 6.68 (dd, 1H, J ) 8.0, 1.6 Hz); 13C NMR
methanol (10 mL), and a 1:1 solution of 30% H
mL). After 1 h at 0 °C, the mixture was concentrated in vacuo,
and the residue, diluted with saturated aqueous NaHCO (10
mL), was extracted with ethyl acetate. The organic phase was
dried (Na SO ) and concentrated in vacuo and afforded the
2 2
O /MeOH (10
400 MHz) δ 21.16, 28.28, 33.18, 33.61, 34.91, 41.47, 47.01,
4
1
1
7.09, 49.99, 53.03, 122.26, 125.51, 126.02, 127.04, 130.45,
30.52, 131.77, 131.80, 132.25, 132.89, 138.02, 138.37, 138.94,
42.52, 151.88, 172.48. Anal. Calcd for C26H25NO : C, 78.17;
3
3
2
4
H, 6.31; N, 3.51. Found: C, 78.29; H, 6.33; N, 3.49.
chiral auxiliary 7 (90% yield). The aqueous phase, acidified
(
-)-(R)-3-(3-P h en ylbu ta n oyl)-[2.2]p a r a cyclop h a n o[4,5-
with concentrated HCl and worked up as usual, allowed (+)-
d ]-1,3-oxa zol-2(3H)-on e (16). A 1 M solution of phenylmag-
19
(
(
(
R)-3-phenyl-3-hydroxypropionic acid 20 (ee 71%) and (+)-
nesium bromide in THF (3 mL, 3 mmol) was added to a stirred
19
2R,3R)-syn-2-methyl-3-phenyl-3-hydroxypropionic acid 21
ee 90%; syn/anti 80:20) in 70 and 75% yields, respectively, to
solution of CuBr‚SMe
2
(0.304 g, 1.5 mmol) in anhydrous THF
3.5 mL) and SMe (1.75 mL) cooled at -40 °C. After 15 min,
(
2
be isolated.
a solution of 9 (0.333 g, 1 mmol) in anhydrous THF (3 mL)
was added dropwise, over a period of 20 min, to the organo-
copper solution cooled at -20 °C and the resulting mixture
was stirred at this temperature for 30 min. The reaction was
quenched with saturated aqueous ammonium chloride and
extracted with ethyl acetate. Workup as usual and column
chromatography eluting with petroleum ether/diethyl ether
Ack n ow led gm en t. Ministereo dell’Universit a` per la
Ricerca Scientifica e Tecnologica (MURST) and Con-
siglio Nazionale delle Ricerche (CNR) are gratefully
acknowledged for financial support.
9
1
5:5 afforded 16 as a crystalline solid (0.35 g, 85% yield): mp
65-167 °C (hexane/ethyl acetate); [R] -88.3 (c 0.58, CHCl );
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
D
3
peak assignment, [R] , and MS m/z of compounds 2-11, 14,
D
1
H NMR (400 MHz) δ 1.32 (ddd, 1H, J ) 13.4, 10.0, 8.3 Hz),
A (R ) H), C (R ) H), A (R ) Me), C (R ) Me), and 16. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
.46 (d, 3H, J ) 7.0), 2.46-2.65 (m, 2H), 2.71 (ddd, 1H, J )
3.4, 10.5, 4.2 Hz), 2.85-3.10 (m, 3H), 3.23 (ddd, 1H, J ) 13.4,
0.3, 4.0 Hz), 3.34 (dd, 1H, J ) 17.2, 4.8 Hz), 3.61 (m, 1H),
.74 (dd, 1H, J ) 17.2, 9.6 Hz), 6.07 (dd, 1H, J ) 8.0, 1.5 Hz),
1
1
3
J O016383G