Asymmetric hetero Diels-Alder reaction using chiral cationic metallosalen complexes as catalysts

Article abstract of DOI:10.1016/S0040-4020(00)01048-6

Chiral cationic (R,S)- or (R,R)-(salen)-manganese(III) and -chromium(III) complexes served as the catalysts for asymmetric hetero Diels-Alder reaction of Danishefsky's diene with aldehydes, achieving high enantioselectivity (up to 97% ee at 0°C). The reac

Full text of DOI:10.1016/S0040-4020(00)01048-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 845±851
Asymmetric hetero Diels±Alder reaction using chiral cationic
metallosalen complexes as catalysts
Kohsuke Aikawa, Ryo Irie and Tsutomu Katsukip
Department of Chemistry, Faculty of Science, Graduate School, Kyushu University 33, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
Received 28 April 2000; accepted 21 August 2000
AbstractÐChiral cationic (R,S)- or (R,R)-(salen)±manganese(III) and ±chromium(III) complexes served as the catalysts for asymmetric
hetero Diels±Alder reaction of Danishefsky's diene with aldehydes, achieving high enantioselectivity (up to 97% ee at 08C). The reactions of
aldehydes bearing no precoordinating functional group were well effected by using (R,R)-complexes as catalysts, while those of aldehydes
bearing a precoordinating functionality were better effected by using (R,S)-complexes. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Furthermore, we recently found that second-generation
(salen)±manganese(III) complexes that bear binaphthyl
subunit as a chiral auxiliary catalyze a wide range of asym-
metric reactions with excellent enantioselectivity4a and that
some attractive interaction exists between the second-
generation salen ligand and substrates.8a Based on these
®ndings, we expected that cationic second-generation
metallosalen complexes would serve as effective Lewis
acid catalysts. Hence, we studied about asymmetric HDA
reaction of Danishefsky's diene with cationic second-
generation (salen)±manganese(III) and ±chromium(III)
complexes (hereafter referred to as second-generation Mn-
and Cr±salen complexes) as the catalysts.
Chiral Lewis acid-catalyzed asymmetric hetero Diels±
Alder (HDA) reaction of Danishefsky's diene (1-methoxy-
3-trimethylsilyloxy-1,3-butadiene) and various aldehydes
provides versatile building blocks for natural product
synthesis.1 Thus, many chiral Lewis acid catalysts have
been applied for this reaction2 and excellent level of
enantioselectivity has been realized with several chiral
catalysts.3
On the other hand, optically active salen ligands are now
recognized as ef®cient chiral auxiliaries and many metallo-
salen complexes have been found to serve as excellent
catalysts for various asymmetric reactions.4 For example,
(salen)-manganese, ±ruthenium, and ±cobalt complexes
catalyze asymmetric oxene or its isoelectronic nitrene and
carbene transfer reactions with high enantioselectivity.
Besides, they serve as excellent Lewis acid catalysts.
Several years ago, we found that a high valent (salen)-
manganese complexes served as the Lewis acid catalyst
for asymmetric Diels±Alder reaction even at 2788C.5 In
concurrence with this, (salen)-cobalt and -chromium
complexes were found to be excellent Lewis acid catalysts
by Jacobsen et al.6 and more recently we found that (salen)-
ruthenium complex was also ef®cient Lewis acid catalyst.7
Among them, (salen)-chromium (1b)6a and -ruthenium7
complexes have been reported to be good catalysts for
asymmetric HDA reaction, showing high enantioselectivity
up to 93% ee.6a Although high valent (salen)±manganese
complex shows potent Lewis acidity, cationic (salen)±
manganese(III) complexes also show some Lewis acidity.
2. Results and discussion
2.1. Mn±salen catalyzed HDA reaction
We ®rst examined the reaction between benzaldehyde and
Danishefsky's diene with cationic Mn±salen complexes
1±3 as catalysts (Table 1). Since it had been reported that
the apical sites of cationic Mn±salen complexes are ligated
by aqua ligands which might show Brùnsted-acidity,8 the
reaction was performed in the presence of molecular sieves
Ê 6a
3 A to favor the coordination of benzaldehyde and to mini-
mize the undesired Brùnsted-acid catalysis. Differing from
the reported reaction with Cr±salen complex as a catalyst
(1b, 87% ee, 2308C),6a the reaction with the corresponding
cationic Mn±salen complex 1a showed only moderate
enantioselectivity (51% ee, 08C, entry 1). The reaction
with second-generation (R,S)-Mn±salen complex 2a also
showed moderate enantioselectivity (entry 2), but the
reaction with its diastereomeric (R,R)-Mn±salen complex
3 proceeded with good enantioselectivity of 88% ee at
08C as well as good chemical yield (entry 3). Lowering
the reaction temperature enhanced the enantioselectivity
Keywords: cationic metallosalen complex; asymmetric catalysis; hetero
Diels±Alder reaction; Danishefsky's diene.
* Corresponding author. Fax: 181-92-642-2607;
e-mail: katsuscc@mbox.nc.kyushu-u.ac.jp
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01048-6

846
K. Aikawa et al. / Tetrahedron 57 (2001) 845±851
Table 1. Asymmetric HDA reaction with chiral (salen)manganese(III) complexes as catalysts (a solution of aldehyde (0.2 mmol), Danishefsky's diene
Ê
(0.36 mmol), and catalyst (5 mmol) in dichloromethane (0.5 ml) was stirred in the presence of MS 3 A for 24 h at 08C under N2, unless otherwise mentioned)
Entry
Catalyst
Temp. (8C)
Yield (%)a
% Eeb
Con®gnc
1
2
(R)-1a
0
0
0
230
0
50
88
95
42
88
51
60
88
92
76
R
S
R
R
R
(R,S)-2a
(R,R)-3a
(R,R)-3a
(R,R)-3a
3
4d
5e
a Yield was calculated on the basis of the amount of aldehyde used.
b Determined by HPLC using Chiralcel OD±H (hexane/i-propanolˆ9:1).
c Determined by comparison of the elution order in HPLC analysis (Ref. 6c).
d Reaction time was 48 h.
e Reaction was carried out in the absence of molecular sieves.
to 92% ee, though the reaction became slow (entry 4). The
reaction in the absence of molecular sieves suffered in
enantioselectivity and chemical yield (entry 5).
more, some metallosalen complexes bearing a bidentate
counter anion have been reported to take cis-b-structure.10
These results suggested that (R,R)- and (R,S)-complexes
might change their ligand-conformation in different ways
upon coordination of the o-polar substituent. Thus, we
examined the reaction with (R,S)-Mn±salen complex 2a
as the catalyst. Although introduction of o-methyl sub-
stituent only slightly improved enantioselectivity (cf,
Table 1, entry 2 and Table 2, entry 1), that of an o-coordi-
nating substituent remarkably enhanced enantioselectivity.
The reactions of o-chloro- and methoxy-benzaldehydes
showed high enantioselectivity of 91 and 96% ee, respec-
tively (entries 2 and 4). In contrast to this, the reaction of
p-chlorobenzaldehyde with 2a showed only moderate
enantioselectivity of 59% ee, suggesting that chelation of
the o-coordinating substituent with manganese ion is essen-
tial for high enantioselection by (R,S)-2a (entry 3).
The above results suggested that (R,R)-Mn±salen complex
3a is a catalyst suitable for the reaction of aldehydes bearing
no coordinating substituent and small in size, while (R,S)-
Mn±salen complex 2a for the reaction of substrates bearing
a chelating group. On the basis of this knowledge, we
examined the reaction of heptanal with complex 3a as the
catalyst. As expected, the reaction at 08C exhibited high
enantioselectivity of 93% ee and the reaction at 2408C
showed the enantioselectivity of 98% ee, though the chemi-
cal yield suffered (Scheme 1).
Encouraged by these results, we next examined the reaction
of o-substituted benzaldehydes by using (R,R)-Mn±salen
complex 3a as the catalyst (Table 2). Introduction of
o-substituent, however, generally reduced enantioselectivity
of the reactions (entries 5, 6 and 8). In particular, intro-
duction of a polar substituent such as chloro or methoxy
group badly reduced enantioselectivity (entries 6 and 8).
The adverse effect by the polar groups was considered to
be caused by its coordination to the manganese ion which
might change the conformation of the salen ligand and affect
enantioselectivity. In accord with this consideration, the
reaction of p-chlorobenzaldehyde showed enantioselectivity
as good as that of benzaldehyde (entry 7). We recently
revealed that diastereomeric second-generation (R,S)- and
(R,R)-Mn±salen complexes have the ligand-conformation
considerably different to each other7a and also proposed
that the epoxidation with (R,S)-Mn±salen complex as a
catalyst proceeded through a metallaoxetane intermediate,
the ligand of which should adopt cis-b-structure.9 Further-
2.2. Cr±salen catalyzed HDA reaction
As described in the beginning of this paper, asymmetric
catalysis of cationic Cr(III)±salen complex has been
reported by Jacobsen et al.6a Since chromium and manga-
nese ions show similar catalytic activity in many respects,11
we also examined HDA reaction with second-generation
cationic Cr(III)±salen complexes as the catalyst (Table 3).
Likewise the reaction with Mn(III)±salen complexes,
Cr(III)±salen complexes also showed an interesting
substrate-speci®city. The reaction of benzaldehyde with
(R,R)-complex 3b showed high enantioselectivity of 93%
ee even at 08C (entry 3) which is better than that observed
with (R,R)-Mn-complex 3a, while the same reaction with
(R,S)-complex 2b exhibited moderate enantioselectivity of

K. Aikawa et al. / Tetrahedron 57 (2001) 845±851
847
Table 2. Asymmetric HDA reaction of various aldehydes with Mn±salen complexes as catalysts (a solution of aldehyde (0.2 mmol), Danishefsky's diene
Ê
(0.36 mmol), and catalyst (5 mmol) in dichloromethane (0.5 ml) was stirred in the presence of MS 3 A for 24 h at 08C under N2. Yield was calculated on the
basis of the amount of aldehyde used)
Entry
Catalyst
Aldehyde
Yield (%)
% Eea
R1
Me
Cl
H
MeO
Me
Cl
H
MeO
R2
1
2
3
4
5
6
7
8
(R,S)-2a
(R,S)-2a
(R,S)-2a
(R,S)-2a
(R,R)-3a
(R,R)-3a
(R,R)-3a
(R,R)-3a
H
61
99
95
98
60
99
97
97
266
291b
259
296b
82
H
Cl
H
H
H
Cl
H
41b
88
68b
a Determined by HPLC analysis using Chiralcel OD±H (hexane/i-propanolˆ9:1), unless otherwise mentioned. Con®guration of the products obtained with 2a
was opposite to that obtained with 3a.
b Determined by HPLC analysis using Chiralcel OJ (hexane/i-propanolˆ9:1).
Scheme 1.
78% ee (entry 1). In contrast to this, the reaction of
o-methoxybenzaldehyde with complex 3b was moderately
enantioselective (entry 5) but the reaction of o-methoxy-
benzaldehyde with 2b showed excellent enantioselectivity
of 96% ee (entry 2). It is noteworthy that addition of
molecular sieves did not affect enantioselectivity and
chemical yield, when Cr±salen complexes were used as
catalysts (cf entries 3 and 4). Thus, all the Cr±salen
catalyzed reactions were performed in the absence of
molecular sieves.
reaction of aliphatic aldehydes (Table 4). Actually, the
reaction of cyclohexanecarbaldehyde proceeded with enan-
tioselectivity of 96% ee and that of heptanal with enantio-
selectivity of 97% ee at 08C as well as good chemical yields.
HDA reaction of a,b-unsaturated aldehyde was also
effected with a slightly diminished enantioselectivity
(entry 3).
It is worth while to note that, in all the reactions examined,
(R,S)- and (R,R)-complexes showed opposite sense of
enantioselectivity (see, Tables 1±3), suggesting that
ligand-conformation of complexes which was dictated by
the chirality of the ethylenediamine unit8a plays an
Based on these results, (R,R)-Cr±salen complex 3b was
expected to be the most suitable catalyst for the HDA
Table 3. Asymmetric HDA reaction with Cr±salen complexes as catalysts (a solution of aldehyde (0.2 mmol), Danishefsky's diene (0.36 mmol), and catalyst
(5 mmol) in dichloromethane (0.5 ml) was stirred for 24 h at 08C under N2. Yield was calculated on the basis of the amount of aldehyde used)
Entry
Catalyst
Aldehyde (R)
Yield (%)
% Eea
1
2
(R,S)-2b
(R,S)-2b
(R,R)-3b
(R,R)-3b
(R,R)-3b
H
MeO
H
H
MeO
96
88
93
92
90
278
296b
93
93
63b
3
4c
5
a Determined by HPLC using Chiralcel OD±H (hexane/i-propanolˆ9:1), unless otherwise mentioned.
b Determined by HPLC using Chiralcel OJ (hexane/i-propanolˆ9:1).
c Reaction was carried out in the presence of molecular sieves 4A.

848
K. Aikawa et al. / Tetrahedron 57 (2001) 845±851
Table 4. Asymmetric HDA reaction of aliphatic and a,b-unsaturated aldehydes with (R,R)-Cr±salen complex 3b as the catalyst (a solution of aldehyde
(0.2 mmol), Danishefsky's diene (0.36 mmol), and catalyst (5 mmol) in dichloromethane (0.5 ml) was stirred for 24 h at 08C under N2. Yield was calculated on
the basis of the amount of aldehyde used)
Entry
Aldehyde (R)
c-C6H11
n-C6H13
Yield (%)
% Eea
1
2
3
92
98
96
97
(E)-C6H5CHvCH
Quantitative (75%)b
91 (98% ee)b,c
a Determined by HPLC using Chiralcel OD±H (hexane/ i-propanolˆ 9:1), unless otherwise mentioned.
b Number in the parentheses is the value after recrystallization.
c Determined by HPLC using Chiralcel OD (hexane/i-propanolˆ9:1).
important role in asymmetric induction by the complexes,
though the detailed mechanism of asymmetric induction is
unclear at present. Despite the ambiguity of the mechanism
of asymmetric induction, the present reaction is considered
to proceed via [412] cycloaddition pathway for the follow-
VP equipped with an appropriate optically active column
as described in the footnotes of the corresponding Tables.
Reagents and solvents were used as received unless other-
wise mentioned below. Commercially available methanol-
free dichloromethane was dried and distilled over calcium
hydride before use. Tetrahydrofuran (THF) was dried and
deoxygenated by treatment with sodium benzophenone±
ketyl and distilled shortly before use. Heptanal, o-tolu-
aldehyde, and o-chlorobenzaldehyde (Tokyo Kasei Kogyo
Co., Ltd), benzaldehyde, o-methoxybenzaldehyde, and
p-chlorobenzaldehyde (Nacalai Tesque, Inc.), and cyclo-
hexanecarbaldehyde and 1-methoxy-3-trimethylsilyloxy-
1,3-butadiene (Danishefsky's diene) (Aldrich) were also
puri®ed by distillation prior to use. Chiral Mn(III)±salen
complexes 1a,14 2a,15 and 3a15 were prepared as previously
reported. Reactions were carried out under an atmosphere of
nitrogen if necessary. All the products were fully analyzed
but only the spectroscopic data are given here for known
compounds.
1
ing reasons: H NMR analysis of HDA reaction of benzal-
dehyde in CD2Cl2 showed that the primary product was the
corresponding silylated cycloaduct and neither the
trimethylsilyloxy dienone (Mukaiyama aldol condensation
adduct) nor the desilylated compound was detected.
Furthermore, the Mukaiyama aldol condensation adduct
which was separately synthesized according to the litera-
ture,12 was not converted to the cyclic compound under
the present reaction conditions. We also examined HDA
reaction with (R,S)- and (R,R)-(salen)titanium dichloride
complexes.13 Although Ti-complexes show the same
substrate speci®city as described above, enantioselectivity
and chemical yield were inferior to those by Mn± and Cr±
salen complexes. For example, HDA reaction of benzalde-
hyde with (R,R)-(salen)titanium dichloride complex at 08C
provided the corresponding product of 80% ee in 36%.
3.1.1. (R,R)-(Salen)chromium(III) tetra¯uoroborate 3b.
The parent (R,R)-salen ligand was prepared from a 2:1
mixture of its chiral (R)-salycilaldehyde16 and (R,R)-
diamine units in ethanol as described in Ref. 15a. Without
further puri®cation, the ligand (397 mg, 0.48 mmol) was
added to a solution of anhydrous Cr(II)Cl2 (67 mg,
0.55 mmol) in dry, deoxygenated THF (15 ml) under nitro-
gen atmosphere. The resulting brown solution was stirred
for 3 h and then exposed to air. Stirring was continued over
night to give a dark brown solution, which was diluted with
CH2Cl2 (60 ml) followed by washing with sat. NH4Cl
(3£50 ml) and aq. NaCl (3£50 ml). The organic phase was
dried over Na2SO4 and concentrated under reduced pressure
to afford the corresponding (R,R)-(salen)chromium(III) chlo-
ride as a brown solid (356 mg, 74%). IR (KBr): 3487 (br),
3051, 2934, 2858, 1632, 1612, 1582, 1551, 1493, 1448,
1425, 1394, 1350, 1331, 1294, 1271, 1246, 1227, 1190,
1146, 1123, 1026, 953, 912, 864, 762, 746, 702, 579, 548,
536 cm21. Anal. Calcd for C60H44N2O2CrClH2OTHF: C,
76.67; H, 5.43; N, 2.79%. Found: C, 76.63; H, 5.47; N,
3.11%. Without further puri®cation, a part of this complex
(104 mg, 0.10 mmol) was dissolved in dry CH2Cl2 (2.0 ml)
and AgBF4 (22.1 mg, 0.11 mmol) was added to the solution
in the dark. After 5.5 h of stirring at room temperature, the
mixture was ®ltered through a pad of Celite and washed
with CH2Cl2. Concentration of the combined ®ltrate gave
the titled complex as a brown solid (98.9 mg, 94%). IR
In conclusion, we were able to disclose that second-genera-
tion cationic Mn(III)± and Cr(III)±salen complexes are
ef®cient Lewis acid catalysts for asymmetric HDA reaction.
Further studies on the mechanism of their asymmetric
induction of the present reactions and their application to
natural product synthesis are now proceeding in our
laboratory.
3. Experimental
3.1. General procedures
1H NMR spectra were recorded at 400 MHz on a BRUKER
DPX-400. All signals were expressed as ppm down ®eld
from tetramethylsilane used as an internal standard
(d-value in CDCl3). IR spectra were obtained with a
SHIMADZU FTIR-8600 instrument. Optical rotations
were measured with a JASCO P-1020 polarimeter. Column
chromatography was conducted on silica gel BW-820MH,
70±200 mesh ASTM, available from FUJI SILYSIA
CHEMICAL LTD. Preparative thin layer chromatography
was performed on 0.5 mm£20 cm£20 cm E. Merck silica
gel plate (60 F-254). Enantiomeric excesses were deter-
mined by HPLC analysis using SHIMADZU LC-10AT-

K. Aikawa et al. / Tetrahedron 57 (2001) 845±851
849
(KBr): 3487 (br), 3051, 2936, 2860, 1632, 1612, 1582,
1555, 1493, 1448, 1425, 1394, 1352, 1329, 1294, 1271,
1246, 1226, 1190, 1146, 1122, ca. 1050 (br), 1026, 953,
866, 822, 764, 748, 702, 581, 534, 527 cm21. Anal. Calcd
for C60H44N2O2CrBF4H2OTHF: C, 72.94; H, 5.16; N,
2.66%. Found: C, 72.95; H, 5.26; N, 2.93%. The complex
thus obtained was used as the catalyst in this study without
further puri®cation.
ture, the reaction mixture was treated with a drop of
tri¯uoroacetic acid and further stirred for another 5 min.
The mixture was concentrated in vacuo and the residue
was chromatographed on silica gel (hexane/ethyl acetateˆ
8/2) to give the corresponding 2,3-dihydropyran-4-one
derivative. The enantiomeric excess of the product was
determined by HPLC analysis using optically active column
as described below.
3.1.2. (R,S)-(Salen)chromium(III) tetra¯uoroborate 2b.
The corresponding (R,S)-(salen)chromium(III) chloride
was synthesized as a brown solid (511 mg, 73%) from the
parent (R,S)-salen ligand15b (538 mg, 0.65 mmol) and anhy-
drous Cr(II)Cl2 (88 mg, 0.72 mmol) under the same condi-
tions as descried for complex 3b. IR (KBr): 3485 (br), 3049,
2932, 2856, 1632, 1612, 1582, 1551, 1491, 1448, 1425,
1393, 1350, 1329, 1294, 1263, 1246, 1225, 1188, 1146,
1123, 1026, 951, 912, 866, 759, 746, 702, 577, 550,
536 cm21. Anal. Calcd for C60H44N2O2CrClH2O2THF: C,
76.00; H, 5.81; N, 2.61%. Found: C, 75.84; H, 5.81; N,
2.61%. Without further puri®cation, a part of this complex
(93 mg, 0.087 mmol) was dissolved in THF (2.0 ml) and
AgBF4 (19 mg, 0.11 mmol) was added to the solution in
the dark. After being stirred at room temperature overnight,
the mixture was ®ltered through a pad of Celite and washed
with THF. Concentration of the combined ®ltrate gave the
titled complex as a brown solid (92 mg, quantitative). IR
(KBr): 3474 (br), 3049, 2961, 2932, 2856, 1634, 1614,
1582, 1553, 1491, 1448, 1425, 1394, 1348, 1329, 1294,
1261, 1227, 1190, 1146, 1123, ca. 1070 (br), 1043, 1028,
3.3.1. (R)-2,3-Dihydro-2-phenyl-4H-pyran-4-one. (Table
3, entry 3) Colorless oil. 93% ee [Chiralcel OD±H, hexane:
i-propanolˆ9:1, 0.5 mL/min, tR (major) 24.0 min, tR
24
(minor) 28.8 min]. [a]D ˆ288.98 (c 1.07, CHCl3) [Lit.17
23
[a]D ˆ296.38 (c 0.87, CHCl3) for optically pure material].
1H NMR (400 MHz): d 7.49 (d, Jˆ6.4 Hz, 1H), 7.46±7.36
(m, 5H), 5.54 (dd, Jˆ1.5, 6.4 Hz, 1H), 5.44 (dd, Jˆ3.4,
14.7 Hz, 1H), 2.92 (dd, Jˆ14.7, 16.5 Hz, 1H), 2.67 (ddd,
Jˆ1.5, 3.4, 16.5 Hz, 1H). IR (KBr): 1678, 1595, 1497, 1454,
1404, 1369, 1271, 1229, 1209, 1173, 1040, 989, 934, 797,
758, 698, 638, 611, 476, 446 cm21. The absolute con-
®guration was determined to be (R) based on comparison
of the measured speci®c rotation with the literature
value.17
3.3.2. 2,3-Dihydro-2-(o-tolyl)-4H-pyran-4-one. (Table 2,
entry 5) Colorless oil. 82% ee [Chiralcel OD, hexane:
i-propanolˆ9:1, 0.5 mL/min, tR (major) 22.0 min, tR
25
(minor) 32.2 min]. [a]D ˆ2588 (c 0.13, CHCl3). 1H
NMR (400 MHz): d 7.51 (d, Jˆ5.9 Hz, 1H), 7.45 (m,
1H), 7.31±7.27 (m, 2H), 7.22 (m, 1H), 5.64 (dd, Jˆ2.9,
14.7 Hz, 1H), 5.54 (dd, Jˆ1.5, 5.9 Hz, 1H), 2.90 (dd,
Jˆ14.1, 17.1 Hz, 1H), 2.61 (ddd, Jˆ1.5, 2.9, 17.1 Hz,
1H), 2.37 (s, 3H). IR (KBr): 3063, 3028 2966, 2924,
1678, 1593, 1494, 1462, 1404, 1367, 1271, 1223, 1188,
1040, 989, 932, 868, 795, 760, 727, 484 cm21. HRFABMS.
Calcd for C12H13O2 [M1H]1: 189.0915. Found: 189.0920.
The absolute con®guration has not been determined.
951, 914, 866, 818, 799, 760, 702, 611, 579, 550, 521 cm21
.
Anal. Calcd for C60H44N2O2CrBF4H2OTHF: C, 72.94; H,
5.16; N, 2.66%. Found: C, 72.86; H, 5.40; N, 2.69%. The
complex thus obtained was used as the catalyst in this study
without further puri®cation.
3.2. Typical experimental procedure of the asymmetric
hetero Diels±Alder reaction catalyzed by Mn(III)±salen
complex
3.3.3. 2-(o-Chlorophenyl)-2,3-dihydro-4H-pyran-4-one.
(Table 2, entry 2) Colorless oil. 91% ee [Chiralcel OJ,
hexane:i-propanolˆ9:1, 0.5 mL/min, tR (major) 28.7 min,
To a suspension of Mn±salen complex (5.1 mg, 5 mmol)
Ê
and freshly dried powdered 3 A molecular sieves (50 mg)
25
1
tR (minor) 35.6 min]. [a]D ˆ21408 (c 0.82, CHCl3). H
NMR (400 MHz): d 7.60 (dd, Jˆ1.5, 7.5 Hz, 1H), 7.52 (d,
Jˆ6.0 Hz, 1H), 7.41 (dd, Jˆ2.0, 7.5 Hz, 1H), 7.37 (ddd,
Jˆ2.0, 7.5, 7.5 Hz, 1H), 7.32 (ddd, Jˆ2.0, 7.5, 7.5 Hz,
1H), 5.83 (dd, Jˆ4.0, 14.1 Hz, 1H), 5.56 (dd, Jˆ1.0,
6.0 Hz, 1H), 2.81 (ddd, Jˆ1.0, 4.0, 17.1 Hz, 1H), 2.72
(dd, Jˆ14.1, 17.1 Hz, 1H). IR (KBr): 3094, 3083, 3032,
2966, 2907, 1668, 1587, 1483, 1441, 1414, 1364, 1340,
1283, 1229, 1173, 1128, 1045, 997, 966, 934, 870, 826,
799, 770, 746, 723, 692, 638, 611, 550, 509, 486, 473,
448, 421 cm21. Anal. Calcd for C11H9O2Cl: C, 63.32; H,
4.35%. Found: C, 63.43; H, 4.40%. The absolute con®gura-
tion has not been determined.
in dry dichloromethane (0.5 ml) were successively added
aldehyde and 1-methoxy-3-trimethylsilyloxy-1,3-butadiene
(70 ml, 0.36 mmol) at 08C under nitrogen atmosphere. After
stirring for 24 h at the temperature, the mixture was treated
with a drop of tri¯uoroacetic acid and stirred for another
5 min. The mixture was concentrated in vacuo and the
residue was chromatographed on silica gel (hexane/ethyl
acetateˆ8/2) to give the corresponding 2,3-dihydropyran-
4-one derivative. The enantiomeric excess of the product
was determined by HPLC analysis using optically active
column as described below.
3.3. Typical experimental procedure of the asymmetric
hetero Diels±Alder reaction catalyzed by Cr(III)±salen
complex
3.3.4. 2-(p-Chlorophenyl)-2,3-dihydro-4H-pyran-4-one.
(Table 2, entry 7) Colorless oil. 88% ee [Chiralcel OD±H,
hexane:i-propanolˆ9:1, 0.5 mL/min, tR (major) 26.5 min,
25
1
tR (minor) 32.9 min]. [a]D ˆ276.38 (c 1.17, CHCl3). H
NMR (400 MHz): d 7.47 (d, Jˆ5.9 Hz, 1H), 7.40 and 7.34
(psuedo ABq, JABˆ8.6 Hz, 4H), 5.54 (dd, Jˆ1.0, 6.4 Hz,
1H), 5.41 (dd, Jˆ3.9, 14.2 Hz, 1H), 2.86 (dd, Jˆ14.2,
16.6 Hz, 1H), 2.65 (ddd, Jˆ1.0, 3.4, 16.6 Hz, 1H). IR
To a solution of (R,R)-Cr(III)±salen complex (4.8 mg,
5 mmol) in dry dichloromethane (0.5 ml) were successively
added aldehyde (0.2 mmol) and 1-methoxy-3-trimethyl-
silyloxy-1,3-butadiene (70 ml, 0.36 mmol) at 08C under
nitrogen atmosphere. After stirring for 24 h at the tempera-

850
K. Aikawa et al. / Tetrahedron 57 (2001) 845±851
(KBr): 3081, 3058, 3036, 1666, 1595, 1491, 1402, 1362,
1308, 1265, 1227, 1209, 1171, 1088, 1057, 1038, 1015,
988, 984, 953, 862, 839, 816, 791, 746, 718, 675, 642,
544, 527, 480, 457 cm21. Anal. Calcd for C11H9O2Cl: C,
63.32; H, 4.35%. Found: C, 63.62; H, 4.53%. The absolute
con®guration has not been determined.
Jˆ1.0, 5.9 Hz, 1H), 5.07 (ddd, Jˆ4.2, 6.5, 13.2 Hz, 1H),
2.74 (dd, Jˆ13.2, 16.6 Hz, 1H), 2.62 (ddd, Jˆ1.0, 4.2,
16.6 Hz, 1H). IR (KBr): 3063, 3024, 2964, 2907, 1678,
1593, 1493, 1450, 1414, 1377, 1306, 1273, 1250, 1221,
1171, 1126, 1057, 1043, 989, 974, 897, 864, 841, 827,
802, 746, 692, 529, 488, 446 cm21. The absolute con®gura-
tion has not been determined.
3.3.5. 2,3-Dihydro-2-(o-methoxyphenyl)-4H-pyran-4-one.
(Table 2, entry 4) Colorless oil. 96% ee [Chiralcel OJ,
hexane:i-propanolˆ9:1, 0.5 mL/min, tR (major) 32.8 min,
Acknowledgements
25
1
tR (minor) 38.7 min]. [a]D ˆ2638 (c 0.45, CHCl3). H
NMR (400 MHz): d 7.54 (d, Jˆ5.5 Hz, 1H), 7.46 (dd,
Jˆ1.5, 7.5 Hz, 1H), 7.34 (ddd, Jˆ1.5, 8.0, 9.5 Hz, 1H),
7.03 (pseudo t, Jˆ7.5 Hz, 1H), 6.92 (pseudo d, Jˆ8.0 Hz,
1H), 5.81 (dd, Jˆ5.5, 12.0 Hz, 1H), 5.54 (d, Jˆ5.5 Hz,
1H), 3.84 (s, 3H), 2.81±2.69 (m, 2H). IR (KBr): 3072,
3007, 2964, 2941, 2907, 2839, 1680, 1603, 1589, 1497,
1464, 1441, 1404, 1367, 1273, 1250, 1225, 1202, 1181,
1165, 1111, 1040, 1026, 991, 934, 870, 827, 787, 756, 638,
613, 577, 559, 519, 480, 449, 434 cm21. HRFABMS. Calcd
for C13H13O3 [M1H]1: 205.0865. Found: 205.0868. The
absolute con®guration has not been determined.
Financial support from a Grant-in-Aid for Scienti®c
Research on Priority Areas, No. 706: Dynamic Control of
Stereochemistry, from the Ministry of Education, Science,
Sports and Culture, Japan, is gratefully acknowledged.
References
1. (a) For reviews, see: Danishefsky, S. J. Chemtracts 1989,
273±297. (b) Danishefsky, S. J.; De Ninno, M. P. Angew.
Chem., Int. Ed. Engl. 1987, 26, 15±23. (c) Danishefsky, S. J.
Aldrichimica Acta 1986, 19, 59±69.
3.3.6. 2-Hexyl-2,3-dihydro-4H-pyran-4-one. (Table 4,
entry 2) Colorless oil. 99% ee [Chiralcel OD±H, hexane:
i-propanolˆ9:1, 0.5 mL/min, tR (minor) 11.0 min, tR
2. Bednarski, M.; Danishefsky, S. Tetrahedron Lett. 1983, 24,
3451±3454.
3. (a) Hanamoto, H.; Furuno, H.; Sugimoto, Y.; Inanaga, J.
Synlett 1997, 79±80. (b) Ghosh, A. K.; Mathivanan, P.;
Cappiello, J. Tetrahedron Lett. 1997, 38, 2427±2430. (c)
Ghosh, A. K.; Mathivanan, P.; Cappiello, J.; Krishnan, K.
Tetrahedron: Asymmetry 1997, 8, 815±816. (d)
Matsukawa, S.; Mikami, K. Tetrahedron: Asymmetry 1996,
7, 2165±2168. (e) Mikami, K.; Kotera, O.; Motoyama, Y.;
Sakaguchi, H. Synlett 1995, 975±977. (f) Keck, E.;
Krishnamurthy, D. J. Org. Chem. 1995, 60, 5998±5999. (g)
Motoyama, Y.; Mikami, K. Chem. Commun. 1994, 1563±
1564. (h) Gao, Q.; Ishihara, K.; Maruyama, T.; Mouri, M.;
Yamamoto, H. Tetrahedron 1994, 50, 979±988. (i) Gao, Q.;
Maruyama, T.; Mouri, M.; Yamamoto, H. J. Org. Chem. 1992,
57, 1951±1952. (j) Corey, E. J.; Cywin, L.; Roper, T. D.
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Organometallics 1990, 9, 3106±3113.
(major) 11.8 min]. [a]D ˆ21728 (c 0.192, CHCl3). 1H
25
NMR (400 MHz): d 7.36 (d, Jˆ6.0 Hz, 1H), 5.40 (dd,
Jˆ1.0, 6.0 Hz, 1H), 4.40 (ddt, Jˆ4.0, 7.5, 9.0 Hz, 1H),
2.52 (dd, Jˆ13.1, 16.6 Hz, 1H), 2.43 (ddd, Jˆ1.0, 4.0,
16.6 Hz, 1H), 1.82 (m, 1H), 1.65 (m, 1H), 1.52±1.26 (m,
8H), 0.91±0.87 (m 3H). IR (KBr): 2959, 2926, 2856, 1722,
1682, 1597, 1464, 1406, 1379, 1275, 1229, 1198, 1121,
1040, 905, 791 725, 488, 438 cm21. Anal. Calcd for
C11H18O2: C, 72.49; H, 9.95. Found: C, 72.52; H, 10.09%.
The absolute con®guration has not been determined.
3.3.7. (R)-2-Cyclohexyl-2,3-dihydro-4H-pyran-4-one.
(Table 4, entry 1) Colorless oil. 96% ee [Chiralcel OD±H,
hexane:i-propanolˆ9:1, 0.5 mL/min, tR (minor) 12.2 min,
25
tR (major) 13.5 min]. [a]D ˆ21648 (c 1.13, CHCl3) [Lit.
[a]D ˆ21598 for 76% ee material (c 0.5, CHCl3)3j);
23
4. (a) Ito, Y. N.; Katsuki, T. Bull. Chem. Soc. Jpn. 1999, 72,
603±619. (b) Katsuki, T. Coord. Chem. Rev. 1995, 140,
189±214. (c) Jacobsen, E. N. In Catalytic Asymmetric
Synthesis, Ojima, I., Ed.; VCH: New York, 1993; pp 159±202.
5. Yamashita, Y.; Katsuki, T. Synlett 1995, 829±830.
6. (a) Schaus, E.; Jacobsen, N. J. Org. Chem. 1998, 63, 403±405.
(b) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121,
6086±6087. (c) Jacobsen, E. N.; Wu, M. H. In Comprehensive
Asymmetric Catalysis, Jacobsen, E. N., Pfaltz, A., Yamamoto,
H., Eds., Springer: Berlin, 1999; Vol. III, pp 1309±1326. (d)
Li, L.-S.; Wu, Y.; Hu, Y.-J.; Xia, L.-J.; Wu, Y.-L. Tetrahe-
dron: Asymmetry 1998, 9, 2271±2277.
[a]D ˆ21578 for 93% ee material (c 1.03, CH2Cl2)6a].
26
1H NMR (400 MHz): d 7.38 (d, Jˆ5.9 Hz, 1H), 5.39 (dd,
Jˆ1.0, 5.9 Hz, 1H), 4.17 (ddd, Jˆ3.4, 5.4, 8.8 Hz, 1H), 2.56
(dd, Jˆ14.2, 16.6 Hz, 1H), 2.39 (ddd, Jˆ1.0, 3.4, 16.6 Hz,
1H), 1.91±1.62 (m, 5H), 1.34±1.01 (m, 6H). IR (neat):
3049, 2930, 2855, 1680, 1595, 1450, 1406, 1279, 1240,
1217, 1188, 1038, 993, 910, 889, 876, 837, 797, 750, 640,
525, 488, 463 cm21. The absolute con®guration was
determined to be (R) based on comparison of the measured
speci®c rotation with the literature value.3j
3.3.8.
(R)-2,3-Dihydro-2-[(E)-styryl]-4H-pyran-4-one.
7. Mihara, J.; Hamada, T.; Takeda, T.; Irie, R.; Katsuki, T.
Synlett 1999, 1160±1162.
(Table 4, entry 3) The isolated material was recrystallized
from a minimum amount of a 5:1 mixture of Et2O and
hexane to give colorless needlelike crystals (75%) in 98%
ee [Chiralcel OD, hexane:i-propanolˆ9:1, 0.5 mL/min, tR
8. (a) Hashihayata, T.; Punniyamurthy, T.; Irie, R.; Katsuki, T.;
Akita, M.; Moro-oka, Y. Tetrahedron 1999, 55, 14599±
14610. (b) Pospisil, P. J.; Carsten, D. H.; Jacobsen, E. N.
Chem. Eur. J. 1996, 2, 974±980.
24
(minor) 30.3 min, tR (major) 63.0 min]. [a]D ˆ22138 (c
26
0.38, CHCl3) [Lit. [a]D ˆ22158 for 99% ee material (c
9. Hamada, T.; Fukuda, T.; Imanishi, H.; Katsuki, T.
Tetrahedron 1996, 52, 515±530.
0.36, CH2Cl2)6a]. Mp 55±568C. H NMR (400 MHz): d
7.42±7.39 (m, 3H), 7.37±7.27 (m, 3H), 6.72 (d,
1
10. (a) Lloret, F.; Julve, M.; Mollar, M.; Castro, I.; Lattore, J.;
Faus, J.; Solans, X.; Morgenstern-Badarau, I. J. Chem. Soc.
Jˆ16.1 Hz, 1H), 6.33 (dd, Jˆ6.5, 16.1 Hz, 1H), 5.47 (dd,

K. Aikawa et al. / Tetrahedron 57 (2001) 845±851
851
Dalton Trans. 1989, 729±738. (b) Nakamura, M.; Itoh, T.;
Okawa, H.; Kida, S. J. Inorg. Nucl. Chem. 1981, 43, 2281±
2284. (c) Lauffer, R. B.; Heistand, R. H.; Que, Jr., L. Inorg.
Chem. 1983, 22, 50±55. (d) Calligaris, M.; Manzini, G.;
Nardin, G.; Randaccio, L. J. Chem. Soc. Dalton 1972,
543±547. (e) Bailey, N. A.; Higson, B. M.; McKenzie, E. D.
J. Chem. Soc. Dalton 1972, 503±507.
1171, 1151, 1123, 1072, 1045, 1024, 957, 910, 891, 862, 818,
797, 789, 770, 758, 708, 694, 648, 619, 598, 554, 496, 473,
459, 422 cm21. Anal. Calcd for C60H44N2O2Cl2Ti´0.5. H2O: C,
75.63; H, 4.76; N, 2.94%. Found: C, 75.61; H, 4.71; N, 2.92%.
(R,S)-Ti±salen complex. 1H NMR (400 MHz): d 8.29 (s, 1H),
8.10 (d, Jˆ8.8 Hz, 1H), 7.96±7.94 (m, 2H), 7.78±7.72 (m
1H), 7.76±7.73 (m, 1H), 7.41±7.37 (m, 2H), 7.31±7.28 (m,
8H), 6.82 (t, Jˆ7.3 Hz, 1H), 6.61 (t, Jˆ7.3 Hz, 1H), 6.38 (d,
Jˆ7.3 Hz, 1H), 4.07±4.00 (m, 1H), 2.49 (br d, Jˆ11.2 Hz,
1H), 2.00 (br d, Jˆ10.3 Hz, 1H), 1.53±1.46 (br m, 1H),
1.40±1.29 (br m, 1H). IR (KBr): 3452, 3051, 2934, 2856,
1609, 1583, 1493, 1445, 1425, 1393, 1352, 1292, 1267,
1246, 1221, 1188, 1171, 1151, 1123, 1072, 1043, 1024, 959,
910, 889, 862, 818, 797, 789, 770, 756, 708, 694, 648, 619,
598, 554, 496, 473, 459, 422 cm21. Anal. Calcd for
C60H44N2O2Cl2Ti´1.5 H2O: C, 74.23; H, 4.88; N, 2.89%.
Found: C, 74.10; H, 4.70; N, 2.99%.
11. (a) Samsel, E. G.; Srinivasan, K.; Kochi, J. K. J. Am. Chem.
Soc. 1985, 107, 7606±7617. (b) Srinivasan, K.; Michaud, P.;
Kochi, J. K. J. Am. Chem. Soc. 1986, 108, 2309±2320. (c)
Katsuki, T. In Catalytic Asymmetric Synthesis, Ojima, I., Ed.;
2nd Edn., Wiley-VCH: New York, 2000; pp 287±325.
12. Danishefsky, S. J.; Larson, E.; Askin, D.; Kato, N. J. Am.
Chem. Soc. 1985, 107, 1246.
13. Ti(IV)±salen complexes were synthesized by treatment of the
corresponding salen ligands with equimolar titanium(IV)
tetrachloride in dichloromethane at room temperature and
puri®ed by recrystallization from dichloromethane and aceto-
nitrile. (R,R)-Ti±salen complex. 1H NMR (400 MHz): d 8.36
(s, 1H), 8.20 (d, Jˆ8.8 Hz, 1H), 8.08 (s, 1H), 7.98 (d,
Jˆ8.3 Hz, 1H), 7.86±7.81 (m, 1H), 7.58 (d, Jˆ8.3 Hz, 1H),
7.45±7.41 (m, 1H), 7.36±7.31 (m, 2H), 7.28±7.23 (m, 2H),
7.05 (d, Jˆ8.3 Hz, 1H), 6.72 (dt, Jˆ2.4, 6.8 Hz, 1H), 6.37±
6.31 (m, 4H), 4.03±3.95 (m, 1H), 2.46 (br d, Jˆ11.7 Hz, 1H),
2.04 (br d, Jˆ8.8 Hz, 1H), 1.53±1.46 (br m, 1H), 1.42±1.30
(br m, 1H). IR (KBr): 3447, 3051, 2936, 2856, 1609, 1583,
1493, 1445, 1425, 1393, 1352, 1292, 1265, 1246, 1221, 1188,
14. Hamada, T.; Irie, R.; Mihara, J.; Hamachi, K.; Katsuki, T.
Tetrahedron 1998, 54, 10017±10028.
15. (a) Miyafuji, A.; Katsuki, T. Tetrahedron 1998, 54, 10339±
10348. (b) Hamada, T.; Irie, R.; Mihara, J.; Hamachi, K.;
Katsuki, T. Tetrahedron 1998, 54, 10017±10028.
16. Sasaki, H.; Irie, R.; Hamada, T.; Suzuki, K.; Katsuki, T.
Tetrahedron 1994, 50, 11827±11838.
17. Bednarski, M.; Danishefsky, S. J. J. Am. Chem. Soc. 1986,
108, 7060±7067.