New chiral hydroxyoxazolines based on ketopinic acid and their use in the asymmetric Diels-Alder reaction

Article abstract of DOI:10.1055/s-2007-991052

Several chiral hydroxyoxazolines have been prepared starting from (1S)-(+)-ketopinic acid and enantiopure β-amino alcohols by short synthetic routes. They have been employed in the catalytic asymmetric Diels-Alder reaction, resulting in ee values of up to

Full text of DOI:10.1055/s-2007-991052

LETTER
2659
New Chiral Hydroxyoxazolines Based on Ketopinic Acid and Their Use in the
Asymmetric Diels–Alder Reaction
C
hiral Hydrox
a
yoxazoline
n
s
Based on
K
t
etopin
iic Acidago Barroso, Gonzalo Blay, Luz Cardona, José R. Pedro*
Departament de Química Orgànica, Facultat de Química, Universitat de València, 46100 Burjassot (València), Spain
Fax +34(96)3544328; E-mail: jose.r.pedro@uv.es
Received 7 February 2007
The general route for the synthesis of the ligands is out-
Abstract: Several chiral hydroxyoxazolines have been prepared
starting from (1S)-(+)-ketopinic acid and enantiopure b-amino
alcohols by short synthetic routes. They have been employed in the
catalytic asymmetric Diels–Alder reaction, resulting in ee values of
up to 90%.
lined in Scheme 1. Commercially available9 (S)-(+)-keto-
pinic acid (1) was treated with thionyl chloride and the
resulting acyl chloride was subsequently reacted with the
corresponding amino alcohol 3a–d in dichloromethane at
0 °C in the presence of excess of triethylamine. The
corresponding hydroxyamides 4a–d were obtained in
good yields of 80–90% (Table 1).
Key words: asymmetric catalysis, Diels–Alder reactions, copper,
alkenes, ligands
Asymmetric metal catalysis is one of the most important
and rapidly growing research fields in organic chemistry.1
In this context, it is particularly important to search for
new compounds which can serve as chiral ligands, and to
explore their applicability in the synthesis of optically
active compounds. In the last few years, considerable
success has been achieved in this field mainly with the
introduction of C2-symmetric2 compounds and, more
recently, of C1-symmetric compounds.3 Oxazoline-based
ligands have played an important role in asymmetric
metal-catalyzed reactions, especially with copper and
other transition metals. By far, most successful examples
involve the use of C2-symmetric bisoxazolines (BOX).4
Nevertheless, a number of C1-symmetric ligands con-
taining the oxazoline moiety have been employed in
asymmetric catalysis providing products with high enan-
tiomeric excesses.5 Recently, Bolm et al. have described
the catalytic asymmetric phenyl transfer reaction to alde-
hydes using a series of hydroxyoxazolines derived from
b-amino alcohols and mandelic acid6 or a-keto acid
derivatives7 (Figure 1). These examples prompted us to
look for other keto acids that can be used as scaffolds for
the synthesis of hydroxyoxazoline ligands (Figure 1).
(1S)-(+)-Ketopinic acid was considered a good candidate
since it bears a carboxylic acid, precursor for an oxazoline
ring, and a ketone moiety on a rigid norbornyl skeleton. A
number of compounds based on the norbornyl framework
have been used as chiral auxiliaries and ligands.8 In this
letter we describe the preparation of several hydroxyox-
azolines starting from (S)-(+)-ketopinic acid (Figure 1)
and their use as ligands in the copper(II)-catalyzed Diels–
Alder reaction. To the best of our knowledge, this is the
first example of a copper(II)–hydroxyoxazoline-catalyzed
reaction.
R
R
O
N
O
N
*
*
*
HO2C
HO
O
HO
R'
R
1
Bolm et al.
Ref. 6
Bolm et al.
Ref. 7
R3
R3
O
O
N
R4
R4
N
R2
R1
2a R1 = i-Pr, R2 = H, R3 = OH, R4 = H
2b R1 = Ph, R2 = H, R3 = OH, R4 = H
2c R1 = H, R2 = Ph, R3 = OH, R4 = H
2d R3 = OH, R4 = H
epi-2d R3 = OH, R4 = H
epi-2c R1 = H, R2 = Ph, R3 = H, R4 = OH
Figure 1
The next step involved cyclization of the hydroxyamide to
the oxazoline ring. With hydroxyamides 4a–c derived
from primary alcohols this step was achieved by treatment
with mesyl chloride and triethylamine, providing the
expected oxazolines 5a–c in good yields (81–96%). How-
ever, this method could not be used for the synthesis of
oxazoline 5d because epimerization of the carbon bearing
the hydroxyl group of the aminoindanol unit was possible.
Therefore, cyclization was carried out according to the
procedure described by Ishihara et al,10 using
(NH4)6Mo7O24·4H2O as catalyst in toluene at reflux tem-
perature. In this way, compound 5d was obtained in 64%
yield. The last step involved reduction of the C(2) ketone.
This carbonyl group could not be reduced with NaBH4 or
LiBH4. Treatment of 5a with LiAlH4 gave complex mix-
tures. Fortunately, reduction could be achieved by using
the LiAlH4·2THF complex in toluene at –40 °C. In this
way compounds 5a and 5b were reduced with complete
stereoselectivity to give hydroxyoxazolines 2a and 2b in
SYNLETT 2007, No. 17, pp 2659–2662
1
6
.1
0
.
2
0
0
7
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-991052; Art ID: D03807ST
© Georg Thieme Verlag Stuttgart · New York

2660
S. Barroso et al.
LETTER
MsCl, Et3N,
CH2Cl2
LiAlH4·2THF,
toluene, –10 °C
1. SOCl2, reflux
NH2
OH
or Mo(VI),
toluene, reflux
O
HO
HO2C
or NaBH4, CeCl3,
MeOH, –10 °C
O
O
O
O
2.
O
N
NH
HO
3
1
N
4
5
2
Et3N, CH2Cl2, 0 °C
HO
HO
NH2
NH2
HO
HO
NH2
NH2
c
d
3
b
a
Scheme 1 Synthesis of ligands 2 from (S)-(+)-ketopinic acid
63% and 70% yields, respectively. Reduction of com- The reaction was carried out using 10 mol% of ligand and
pound 5c under similar conditions gave the two epimeric copper(II) triflate with respect to dienophile and seven
alcohols in 62% yield for the exo alcohol 2c and 15% yield equivalents of diene. Evaluation of the ligands and some
for the endo alcohol epi-2c. Reduction of compound 5d relevant results of the optimization process are shown in
took place with no stereoselectivity affording both alco- Table 2. We first evaluated the effect of the substituent on
hols 2d and epi-2d in 45% and 47% yields, respectively. the oxazoline ring with ligands 2a and 2b (entries 1 and
In this case, hydroxyoxazoline 2d could be obtained 2). The presence of a phenyl group seemed to be advanta-
stereoselectively (5:1) using NaBH4 in the presence of geous and therefore some modifications of the reaction
CeCl3·7H2O in MeOH at –10 °C.
conditions were tested with 2b. Toluene and dichloro-
methane as solvent gave similar results, while the reaction
was much slower and less selective in acetone (entry 3).
However, the ee with this ligand was never higher than
47%. Fortunately, a change in the stereochemistry of the
stereogenic center of the oxazoline ring (as in 2c) brought
about an increase in the stereoselectivity, giving the
Diels–Alder adduct 8 with 75% ee at –65 °C (entry 6).
Remarkably, the Diels–Alder product was obtained with
the opposite absolute stereochemistry with respect to the
Table 1 Yields of Compounds 4, 5, and 2a
Entry 3
4
Yield
90%
84%
90%
80%
5
Yield
90%b
81%b
96%b
64%c
2
Yield
1
2
3
4
5
3a
4a
4b
4c
4d
5a
5b
5c
5d
2a
2b
2c
2d
2d
63%d
3b
3c
3d
70%d
62%d (15%)e
45%d (47%)e
50%f (10%)e
Table 2 Evaluation of Ligands and Optimization
a Isolated yield.
Entry L
Solvent
CH2Cl2
CH2Cl2
acetone
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
T (°C) T (h)
endo:exoa ee (endo)a,b
b Reaction conditions: MsCl, Et3N, CH2Cl2, r.t.
c Reaction conditions: (NH4)6Mo7O24·4H2O, toluene, reflux.
d Reaction conditions: [LiAlH4·2THF], toluene, –40 °C.
e Yield of the C2-epimer in brackets.
1
2
2a
–30
–30
–20
–30
–30
–65
–65
–78
–20
–78
45
0.6
85:15
80:20
90:10
85:15
89:11
92:8
19 (R)
46 (R)
24 (R)
47 (R)
70 (S)
75 (S)
90 (S)
90 (S)
24 (S)
6 (S)
2b
2b
2b
2c
f Reaction conditions: NaBH4, CeCl3·7H2O, MeOH, –10 °C.
3
20
1
4
Hydroxyoxazolines 2 were used as ligands in the asym-
metric catalytic Diels–Alder reaction between cyclo-
pentadiene (6) and 3-acryloyl-1,3-oxazolidin-2-one (7)
(Scheme 2). Substrates based on the oxazolidinone tem-
plate have proven to be very efficient substrates with a
large number of metal-based catalysts and have become
standard in tests for new catalyst development.11
5
1
6
2c
1
7
2d
2d
2dc
1
97:3
8
1
98:2
9
24
1
90:10
94:6
O
O
O
O
10
epi-2d CH2Cl2
10 mol% L
N
O
N
O
+
a Determined by chiral HPLC.
10 mol%
Cu(OTf)2
b Configuration of the C(2) carbon of the [2.2.1]bicyclo system in 8.
c Zn(OTf)2 was used instead of Cu(OTf)2. The reaction did not
proceed at lower temperatures.
6
7
8
7 equiv
Scheme 2 Diels–Alder reaction
Synlett 2007, No. 17, 2659–2662 © Thieme Stuttgart · New York

LETTER
Chiral Hydroxyoxazolines Based on Ketopinic Acid
2661
product obtained with ligands 2a and 2b. Finally when
rotation of the phenyl group was restricted as in the 2-ami-
noindanol-derived ligand 2d, an additional increase in the
enantioselectivity was observed, and the Diels–Alder
product was obtained in 90% ee with high diastereoselec-
tivity (entries 7 and 8). The use of Zn complexes gave the
product with lower ee (entry 9).
Acknowledgment
The authors thank the Ministerio de Educación y Ciencia (Grant
CTQ 2006-14199), Generalitat Valenciana (Grant GV 05/10) and
the Universitat de València (Grant UV-AE-20060244) for financial
support. S.B. thanks the Universitat de València for a pre-doctoral
grant (V Segles program).
The effect of the stereochemistry of the hydroxyl-bearing
carbon C(2) of the isobornyl framework was also studied.
Inversion of the stereochemistry of this carbon in ligand
epi-2d gave the Diels–Alder adduct with good diastereo-
selectivity, but the product was almost racemic (entry 10).
References and Notes
(1) (a) Transition Metals for Organic Synthesis; Beller, M.;
Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998.
(b) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, M.; Yamamoto, H., Eds.; Springer: Berlin, 1999.
(c) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
Wiley-VCH: Weinheim, 2000.
The reaction of 3-acryloyl-1,3-oxazolidin-2-one (7) with
other less reactive dienes was carried out using the com-
bination 2d–Cu(OTf)2 as catalyst. The results are shown
in Table 3. In general, these less reactive dienes required
higher reaction temperatures and the products were
obtained with good yields and fair to good enantioselec-
tivities. Remarkably, the product of the reaction with
isoprene at 0 °C (entry 3) was obtained with better stereo-
selectivity than that reported for the Cu(II)–BOX system
(endo/exo, 97:3 and 60% ee), one of the considered
‘privileged catalysts’.12
(2) For discussions on C2-symmetric ligands, see:
(a) Whitesell, J. Chem. Rev. 1989, 89, 1581. (b) Halm, C.;
Kurth, M. J. Angew. Chem. Int. Ed. 1998, 37, 510.
(3) For a discussion on C1-symmetric ligands, see: Humphries,
A. C.; Pfaltz, A. In Stimulating Concepts in Chemistry;
Vögtle, F.; Stoddart, J. F.; Shibashaki, M., Eds.; Wiley-
VCH: Weinheim, 2000, 89.
(4) For a review on BOX-catalyzed reactions see: Desimoni, G.;
Faita, G.; Jørgensen, K. A. Chem. Rev. 2006, 106, 3561.
(5) (a) Angell, R. M.; Barrett, A. G. M.; Braddock, D. C.;
Swallow, S.; Vickery, B. D. Chem. Commun. 1997, 919.
(b) Sagasser, I.; Helmchen, G. Tetrahedron Lett. 1998, 39,
261. (c) Davenport, A. J.; Davies, D. L.; Fawcett, J.; Garratt,
S. A.; Russell, D. R. J. Chem. Soc., Dalton Trans. 2000,
4432. (d) Chelucci, G.; Sanna, M. G.; Gladiali, S.
Tetrahedron 2000, 56, 2889. (e) Wu, X.-Y.; Xu, H.-D.;
Tang, F.-Y.; Zhou, Q.-L. Tetrahedron: Asymmetry 2001, 12,
2565. (f) Brunner, H.; Kagan, H.; Kreutzer, G. Tetrahedron:
Asymmetry 2003, 14, 2177. (g) Västila, P.; Pastor, I. M.;
Adolfsson, H. J. Org. Chem. 2005, 70, 2921. (h) Lee, J.-Y.;
Miller, J. J.; Hamilton, S. S.; Sigman, M. S. Org. Lett. 2005,
7, 1837.
Table 3 Diels–Alder Reaction of 3-Acryloyl-1,3-oxazolidin-2-one
and Some Dienes Catalyzed by the Complex Cu(II)–2d
Entry Diene
T
T
Yield endo/ ee
ee
(°C)
(h)
(%)
exo
(endo) (exo)
1
2
–78
1
98
98:2 90
52
78
25
18
87
98:2 77
(6) Bolm, C.; Zani, L.; Rudolph, J.; Schiffers, I. Synthesis 2004,
2173.
(7) Bolm, C.; Schmidt, F.; Zani, L. Tetrahedron: Asymmetry
2005, 16, 1367.
3
4
0
0
24
90
72
60
98:2 79a
55
56b
(8) (a) Chang, J.-W.; Jang, D.-P.; Uang, B.-J.; Liao, F.-L.;
Wang, S.-L. Org. Lett. 1999, 1, 2061. (b) Li, X.; Yeung, C.-
H.; Chan, A. S. C.; Yang, T.-K. Tetrahedron: Asymmetry
1999, 10, 759. (c) Chen, C.-J.; Chu, Y.-Y.; Liao, Y.-Y.;
Tsai, Z.-H.; Wang, C.-C.; Chen, K. Tetrahedron Lett. 1999,
40, 1141. (d) Yang, K.-S.; Chen, K. Org. Lett. 2000, 2, 729.
(e) Jang, D.-P.; Chang, J.-W.; Uang, B.-J. Org. Lett. 2001, 3,
983. (f) Gilbertson, S. R.; Fu, C. Org. Lett. 2001, 3, 161.
(g) Palomo, C.; Aizpurua, J. M.; Oiarbide, M.; García, J. M.;
González, A.; Odriozola, I.; Linden, A. Tetrahedron Lett.
2001, 42, 4829. (h) Chang, C.-W.; Yang, C.-T.; Hwang, C.-
D.; Uang, B.-J. Chem. Commun. 2002, 54. (i) Yang, K.-S.;
Chen, K. Org. Lett. 2002, 4, 1107. (j) Yang, K.-S.; Lee, W.-
D.; Pan, J.-F.; Kwmin, C. J. Org. Chem. 2003, 68, 915.
(k) Bunlaksananusorn, T.; Knochel, P. J. Org. Chem. 2004,
69, 4595. (l) Hari, Y.; Aoyama, T. Synthesis 2005, 583.
(m) Chen, J.-H.; Venkatesham, U.; Lee, L.-C.; Chen, K.
Tetrahedron 2006, 62, 887.
a Refers to the 1,4-disubstituted regioisomer.
b Refers to the 1,3-disubstituted regioisomer.
In summary, we have prepared new ligands for metal-cat-
alyzed reactions. These ligands, based on ketopinic acid,
combine an oxazoline ring and a hydroxyl group as
chelating groups. They are readily synthesized in a three-
step sequence with good yields and structural variety is
possible by modifying the starting amino alcohol. These
ligands are effective in the asymmetric copper-catalyzed
Diels–Alder reaction using N-alkenoyl-1,3-oxazolidin-2-
ones as dienophiles.13 Studies on the scope of the Diels–
Alder reaction as well as toward extending the use of these
ligands to other asymmetric reactions are underway.
(9) (S)-(+)-Ketopinic acid is commercially available, although it
can be readily prepared by oxidation of (1S)-(+)-10-
camphorsulfonyl chloride with KMnO4: Bartlett, P. D.;
Knox, L. H. Org. Synth., Coll. Vol. V; Wiley: New York,
1973, 689.
(10) Sakakura, A.; Kondo, R.; Ishihara, K. Org. Lett. 2005, 7,
1971.
Synlett 2007, No. 17, 2659–2662 © Thieme Stuttgart · New York

2662
S. Barroso et al.
LETTER
(11) (a) Evans, D. A.; Johnson, J. S. In Comprehensive
Asymmetric Catalysis, Vol. 3; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Berlin, 1999, 1177.
(b) Cycloaddition Reactions in Organic Synthesis;
Kobayashi, S.; Jørgensen, K. A., Eds.; Wiley: New York,
2002. (c) Lewis Acids in Organic Synthesis, Vol. 1;
Yamamoto, H., Ed.; Wiley: New York, 2000. (d) Lewis
Acids in Organic Synthesis, Vol. 2; Yamamoto, H., Ed.;
Wiley: New York, 2000.
J = 4.8, 9.3, 14.0 Hz, 1 H), 1.36 (ddd, J = 4.1, 9.2, 12.8 Hz,
1 H), 1.02 (s, 3 H), 0.73 (s, 3 H). 13C NMR (75.5 MHz,
CDCl3): d = 211.8 (s), 164.4 (s), 142.2 (s), 139.1 (s), 128.1
(d), 127.2 (d), 125.3 (d), 125.0 (d), 83.2 (d), 75.8 (d), 62.5
(s), 49.6 (s), 44.3 (d), 43.7 (t), 39.8 (t), 27.1 (t), 26.5 (t), 21.5
(q), 19.3 (q). MS (EI): m/z (%) = 295 (50) [M+], 280 (10),
267 (29), 252 (39), 226 (15), 165 (16), 130 (62), 115 (100),
104 (52), 77 (39), 67 (31). HRMS: m/z [M] calcd for
C19H21NO2: 295.1572; found: 295.1551.
(12) Evans, D. A.; Barnes, D. M.; Johnson, 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.
NaBH4 (22.6 mg, 0.6 mmol) was added to a solution of 5d
(178 mg, 0.6 mmol) and CeCl3·7H2O (223 mg, 0.6 mmol) in
MeOH (4 mL) at –10 °C. After 10 min, sat. aq NH4Cl (5 mL)
was added, the mixture was diluted with EtOAc (100 mL)
and washed with brine (2 × 10 mL), dried and concentrated
under reduced pressure. Column chromatography (hexane–
EtOAc, 8:2) gave 2d (88 mg, 50%) and epi-2d (18 mg).
Compound 2d: mp 98–101 °C; [a]D25 +214.2 (c = 0.80,
CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.47 (m, 1 H), 7.27
(m, 3 H), 5.79 (br s, 1 H), 5.58 (d, J = 8.1 Hz, 1 H), 5.29 (ddd,
J = 1.8, 7.2, 8.1 Hz, 1 H), 3.90 (dd, J = 3.5, 7.8 Hz, 1 H), 3.47
(dd, J = 7.0, 18.0 Hz, 1 H), 3.23 (dd, J = 1.6, 18.0 Hz, 1 H),
2.07 (m, 1 H), 1.91 (m, 1 H), 1.81 (m, 2 H), 1.71 (dd, J = 7.8,
(13) Experimental Procedure for the Synthesis of Compound
2d: A solution of (S)-(+)-ketopinic acid (1, 1.0 g, 5.5 mmol)
in SOCl2 (4.5 mL) was refluxed for 2 h and the excess SOCl2
was removed under reduced pressure. The residue dissolved
in CH2Cl2 (3.8 mL) was added dropwise to a solution of
(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (3d, 0.82 g, 5.5
mmol) and Et3N (0.75 mL, 5.5 mmol) in CH2Cl2 (3 mL) at
0 °C under nitrogen. After 1 h, the mixture was diluted with
EtOAc (150 mL), washed with 2 M HCl (2 × 30 mL), sat. aq
NaHCO3 (2 × 30 mL) and brine (30 mL), dried over MgSO4
and concentrated. The crude product was crystallized from
hexane–CH2Cl2 to give 4d; yield: 2.0 g (80%); mp 163–
165 °C; [a]D25 +28.5 (c = 0.69, CHCl3). 1H NMR (300 MHz,
CDCl3): d = 7.85 (d, J = 7.6 Hz, 1 H), 7.25 (m, 4 H), 5.47 (dd,
J = 5.0, 8.1 Hz, 1 H), 4.70 (ddd, J = 2.1, 5.1, 5.1 Hz, 1 H),
3.19 (dd, J = 5.2, 16.6 Hz, 1 H), 3.00 (dd, J = 2.0, 16.6 Hz, 1
H), 2.63 (m, 1 H), 2.53 (m, 1 H), 2.13–2.23 (m, 3 H), 2.00 (d,
J = 18.7 Hz, 1 H), 1.67 (m, 1 H), 1.46 (m, 1 H), 1.30 (s, 3 H),
1.10 (s, 3 H). 13C NMR (75.5 MHz, CDCl3): d = 216.6 (s),
169.7 (s), 140.6 (s), 140.1 (s), 128.0(d), 127.0(d), 125.3 (d),
124.2 (d), 73.5 (d), 65.4 (s), 57.5 (d), 50.1 (s), 43.7 (t), 43.4
(d), 39.6 (t), 27.9 (t), 27.5 (t), 20.8 (q), 20.7 (q). MS (FAB):
m/z (%) = 314 (100) [M+ + 1], 282 (45), 154 (40). HRMS:
m/z [M + H] calcd for C19H23NO3: 313.1751; found:
314.1749.
12.9 Hz, 1 H), 1.24 (s, 3 H), 1.10 (m, 2 H), 1.07 (s, 3 H). 13
C
NMR (75.5 MHz, CDCl3): d = 169.2 (s), 141.7 (s), 139.4 (s),
128.3 (d), 127.3 (d), 125.5 (d), 125.1 (d), 81.5 (d), 77.3 (d),
75.4 (d), 52.7 (s), 50.0 (s), 45.6 (d), 39.6 (t), 39.4 (t), 29.9 (t),
27.5 (t), 21.9 (q), 20.6 (q). MS (EI): m/z (%) = 297 (13) [M+],
282 (50), 269 (69), 254 (61), 228 (17), 214 (42), 186 (13),
151 (14), 132 (20), 115 (100), 104 (23), 77 (24). HRMS:
m/z [M] calcd for C19H23NO2: 295.1729; found: 297.1723.
Experimental Procedure for the Enantioselective Diels–
Alder Reaction: Copper triflate (9.0 mg, 0.025 mmol) in a
Schlenk tube was dried at 90 °C under vacuum for 1 h. The
tube was filled in with nitrogen and 2d (7.5 mg, 0.025 mmol)
was added followed by CH2Cl2 (1.5 mL). The mixture was
stirred for 1 h and the dienophile 7 (35 mg, 0.25 mmol) was
added. After stirring for 30 min cyclopentadiene (6; 115 mg,
1.75 mmol) was added at –78 °C. After 1 h, the solvent was
removed under reduced pressure and the product was
purified by column chromatography to give compound 8;
yield: 50.5 mg (98%); [a]D25 –149.0 (c = 1.0, CHCl3; for a
90% ee and 98:2 endo/exo mixture). 1H NMR (300 MHz,
CDCl3): d = 6.23 (dd, J = 3.1, 5.6 Hz, 1 H), 5.86 (dd, J = 2.8,
5.6 Hz, 1 H), 4.40 (m, 2 H), 3.95 (m, 3 H), 3.30 (br s, 1 H),
2.93 (br s, 1 H), 1.94 (ddd, J = 3.7, 9.2, 12.1 Hz, 1 H), 1.50–
1.38 (m, 3 H). Chiral HPLC: Chiralpak AD-H, hexane–i-
PrOH (93:7), flow rate: 1 mL/min, exominor tR = 16.5 min,
endo(S)major tR = 17.6 min, exomajor tR = 21.5 min, endo(R)minor
tR = 22.5 min.
A solution of 4d (2.49 g, 7.9 mmol) and
(NH4)6Mo7O24·4H2O (988 mg, 0.8 mmol) in toluene (160
mL) was refluxed with a Dean–Stark trap for 4 h. The
reaction mixture was filtered through a short pad of silica gel
(2 cm), concentrated and the residue was chromatographed
on silica gel using hexane–EtOAc mixtures to give 5d; yield:
1.60 g (64%); mp 118–121 °C; [a]D25 +228.3 (c = 0.69,
CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.47 (m, 1 H), 7.21
(m, 3 H), 5.53 (d, J = 7.9 Hz, 1 H), 5.39 (ddd, J = 1.8, 6.8,
8.5 Hz, 1 H), 3.41 (dd, J = 6.8, 17.8 Hz, 1 H), 3.18 (dd, J =
1.5, 17.8 Hz, 1 H), 2.39–2.54 (m, 2 H), 2.06 (dd, J = 4.4, 4.4
Hz, 1 H), 1.96 (m, 1 H), 1.91 (d, J = 18.3 Hz, 1 H), 1.74 (ddd,
Synlett 2007, No. 17, 2659–2662 © Thieme Stuttgart · New York

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