A mild and efficient asymmetric hetero-diels-alder reaction of the brassard diene with aldehydes

Article abstract of DOI:10.1002/ejoc.200500126

This paper describes the successful development of the hetero-Diels-Alder (HDA) reaction of the Brassard diene with aldehydes in the presence of a series of titanium(IV) tridentate Schiff-base complexes under mild conditions. The influence of the substituent of the chiral Schiff-base ligands on the enantioselectivities of the reaction was studied. It was found that ligand L13 is a highly enantioselective ligand for the Ti-catalyzed HDA reaction, affording 6-substituted 4-ethoxy-5,6-dihydropyran-2-one in up to 99 % ee. The mechanism of the HDA reaction between the Brassard diene and benzaldehyde in the presence of the (Schiff base)Ti^IV complex was investigated. The results indicate that the reaction pathway is influenced by reaction temperature: at higher temperature (0°C), the reaction is mostly a Diels-Alder process, whereas at lower temperature (-78°C) it is a Mukaiyama aldol process. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500126

FULL PAPER
A Mild and Efficient Asymmetric Hetero-Diels–Alder Reaction of the Brassard
Diene with Aldehydes
Qian Fan,[a,b] Lili Lin,[a] Jie Liu,[a] Yaozong Huang,[a] and Xiaoming Feng*[a]
Keywords: Brassard diene / Cycloaddition / Diels–Alder reaction / Schiff bases / Lactones
This paper describes the successful development of the het-
ero-Diels–Alder (HDA) reaction of the Brassard diene with
aldehydes in the presence of a series of titanium(IV) triden-
tate Schiff-base complexes under mild conditions. The influ-
ence of the substituent of the chiral Schiff-base ligands on
the enantioselectivities of the reaction was studied. It was
found that ligand L13 is a highly enantioselective ligand for
the Ti-catalyzed HDA reaction, affording 6-substituted 4-
ethoxy-5,6-dihydropyran-2-one in up to 99% ee. The mecha-
nism of the HDA reaction between the Brassard diene and
benzaldehyde in the presence of the (Schiff base)TiIV com-
plex was investigated. The results indicate that the reaction
pathway is influenced by reaction temperature: at higher
temperature (0 °C), the reaction is mostly a Diels–Alder pro-
cess, whereas at lower temperature (–78 °C) it is a Mukai-
yama aldol process.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Two mechanistic pathways are generally taken into ac-
count for the HDA reaction when Lewis acid catalyzed re-
actions are considered. The two pathways (Scheme 1) are
formulated as a Mukaiyama aldol reaction (stepwise
mechanism) and a [4+2] Diels–Alder cycloaddition (con-
certed mechanism).[2c] The actual reaction mechanism is
usually demonstrated by separation of the reaction interme-
diates[6a] or semiempirical calculations.[8]
Introduction
The catalytic asymmetric synthesis of enantiomerically
enriched products is of importance to modern synthetic and
pharmaceutical chemistry.[1] The catalytic asymmetric het-
ero-Diels–Alder (HDA) reaction,[2] which is one of the most
important asymmetric C–C bond-forming reactions, pro-
vides a highly effective protocol for preparing optically
active six-membered ring compounds such as dihydropy-
rans, dihydropyranones, etc.[3] The chiral Lewis acid cata-
lyzed HDA reaction is easy to perform. BINOL and its de-
rivatives,[3d,3e,3i–3m,4] chiral C2-symmetric bis(oxazolines),[5]
and Schiff-base ligands,[3f,3g,6] such as salen, aminoindanol-
derived Schiff-base ligands, and Nobin-derived Schiff-base
ligands, complexed with suitable metals such as copper, alu-
minum, chromium, titanium, and other transition metals or
nonmetals, such as boron, have been successfully applied to
the enantioselective HDA reaction. Recently, organocata-
lytic enantioselective HDA reactions have been devel-
oped.[7] Rawal et al. have found that the enantioselective
HDA reaction of a nitrogen-containing diene with alde-
hydes occurs smoothly with 52–97% yield and 86–98% ee
in the presence of α,α,αЈ,αЈ-tetra(1-naphthyl)-2,2-dimethyl-
1,3-dioxolan-4,5-dimethanol (TADDOL) without any met-
als,[7a] and Jørgensen and co-workers have reported the first
example of an inverse-electron-demand HDA reaction cata-
lyzed by proline derivatives (up to 94% ee).[7b]
Scheme 1. Two possible mechanisms of the hetero-Diels–Alder re-
action.
Chiral 5,6-dihydropyran-2-one or α,β-unsaturated δ-lac-
tone derivatives are key structural subunits of some natural
products with a wide range of biological activity, such as
antifungal and antitumor.[9] Thus, the synthesis of δ-lac-
tones has been an area of intense research efforts. Many
methods have been developed, such as the annulation of
open-chained precursors,[10] the derivatization from a 2,3-
dihydropyran-4-one,[9d,10e] and the two-step addition reac-
tion of ene to dicarbonyl compounds.[10e] From the view-
point of synthesis, one of the most convenient accesses to
δ-lactones is based on the HDA reaction of the Brassard
[a] Key Laboratory of Green Chemistry & Technology (Sichuan
University), Ministry of Education, College of Chemistry,
Sichuan University,
Chengdu 610064, China
Fax: +86-28-85418249
E-mail: xmfeng@scu.edu.cn
[b] Institute of Chemical Materials, CAEP,
Mianyang 621900, China
3542
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500126
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Asymmetric Hetero-Diels–Alder Reaction of the Brassard Diene with Aldehydes
FULL PAPER
diene[11] (1a) with suitable aldehydes or ketones. The reac-
tion of the Brassard diene with aliphatic aldehydes in the
presence of Eu(hfc)3 occurs smoothly with high enantio-
selectivity.[12a–12d] However, the enantioselective approach
with the Brassard diene and aromatic aldehydes only gave a
disappointing result, in which the enantiomeric excess value
obtained was less than 5%.[12e] Very recently, we reported
the first example of the highly enantioselective synthesis of
optically active δ-lactones in the presence of chiral titani-
um(iv) tridentate Schiff-base complexes.[13] Ding and co-
workers subsequently reported the same reaction with
TADDOL.[14] This paper describes our studies of the rela-
tionships between catalyst structure and activity, substrate
generality, mechanism, and limitations.
Results and Discussion
Considering the stability of the Brassard diene, the meth-
oxy group of 1a was replaced with an ethoxy group to give
diene 1b. Although this results in only a small change in the
structure, diene 1b is more stable and easier to purify than
1a. Diene 1b is easily synthesized according to Brassard’s
procedures.[11] As the ethyl group is larger than the methyl
group, we speculated that the enantioselectivity of the pro-
duct from diene 1b would be higher than that from diene
1a. In our initial attempts, diene 1a gave the corresponding
product with 86% ee, and diene 1b gave the corresponding
product with 90% ee, thus confirming our speculation.
Scheme 2. Ligands used in this paper.
Preliminary Trials
Table 1. Preliminary trials of the asymmetric HDA reaction be-
tween benzaldehyde and 1b catalyzed by some easily accessible chi-
ral ligands.[a]
A variety of different ligands complexed with [Ti(OiPr)4]
were tested as catalysts for the HDA reaction of the Brass-
ard diene 1b with benzaldehyde in our initial attempts
(Scheme 2). The ligands were prepared according to litera-
ture procedures.[15] The catalyst was prepared in situ by stir-
ring a solution of the chiral ligand and [Ti(OiPr)4] in a mo-
lar ratio of 1:1 in toluene. The reaction procedure is as fol-
lows: benzaldehyde and the Brassard diene 1b were success-
ively added to the catalyst solution at 0 °C. After 72 h, the
system was treated with trifluoroacetic acid (TFA), and the
desired product was obtained by flash chromatography on
silica gel. The enantiomeric excess of the product was as-
sayed by HPLC with a Chiralpak AD-H column. The re-
sults are summarized in Table 1.
Entry
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L13
n.d.
n.d.
trace
23
trace
32
–
–
–
65
–
63
90
The initial studies revealed that the HDA reaction pro-
duct, which is formed in high enantioselectivity, depends on
the ligand structures. No product was obtained with tetra-
dentate ligands (L1–2) complexed with [Ti(OiPr)4], proba-
bly because benzaldehyde coordinates to the catalyst to
46
[a] All reactions were performed with benzaldehyde (1 mmol) and
1b (1.2 mmol) in 1 mL of toluene at 0 °C for 48 h. Catalysts: 1:1
molar ratio of ligand/[Ti(OiPr)4]. Catalyst loading was 20 mol-%.
[b] Isolated yield. [c] Enantioselectivities were determined by HPLC
form an intermediate with greater steric hindrance, which with a Chiralpak AD-H column.
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Q. Fan, L. Lin, J. Liu, Y. Huang, X. Feng
FULL PAPER
prevents 1b approaching benzaldehyde. Diisopropyl tartrate withdrawing group reduce the reactivity. A bulkier ortho
(L3) also has little catalytic capability. The bidentate ligand group, like tert-butyl, gives a higher ee (Table 2, Entry 8).
(R)-BINOL (L4) promotes this conversion with 23% yield However, when the ortho group was adamantyl, the large
and 65% ee. The multidentate ligand L5, with larger hin- steric hindrance resulted in a lower enantioselectivity
drance, also shows very little catalytic activity. Fortunately, (Table 2, Entry 10). When the two substituents were Cl or
tridentate ligands derived from (1R,2S)-2-amino-1,2-di- Br, the reactions afforded the products in good to excellent
phenylethanol (L6 and L13) exhibit better chiral induction enantioselectivities with moderate yields (Table 2, En-
for this reaction, especially L13 (90% ee).
tries 11 and 12). It therefore became obvious that a suitable
group on the phenol ring of the ligand can enhance the
match between substrate and catalyst and result in higher
enantioselectivity. Some other ligands with different chiral
moieties were also examined, although the results were dis-
appointing (Table 2, Entries 13 and 14). The L18–Ti(OiPr)4
complex, for instance, promoted the reaction with very low
enantioselectivity. This may be partly attributed to its less
flexible five-membered ring structure; moreover, TiIV is an
inappropriate metal for the Jacobsen catalyst[3f,3g] in which
the central metal is Cr. Ligand L13 is therefore the optimal
one.
Ligand and Lewis Acid Effects
A group of tridentate Schiff-base ligands and Lewis acids
was examined as catalysts for the HDA reaction of 1b with
benzaldehyde. The ligands were prepared according to lit-
erature procedures.[15] This ligand screening revealed that
the HDA product is formed in diverse yields and enantio-
selectivities depending on the ligand’s structure. Some rep-
resentative results are shown in Table 2.
Besides [Ti(OiPr)4], other Lewis acids were also screened
Table 2. Influence of different ligands on the hetero-Diels–Alder in the HDA reaction of 1b with benzaldehyde. The results
reaction of benzaldehyde with 1b.[a]
are shown in Table 3. Among the Lewis acid complexes
screened, the AlIII–L13 complex afforded a racemic product
(Table 3, Entries 1–3), the ZrIV–L13 complex provided the
product in low yield with 29% ee (Table 3, Entry 7), and
the TiIV–L13 complex promoted the reaction to give a mod-
erate yield (Table 3, Entries 4–6). However, only [Ti(OiPr)4]
achieved a high enantioselectivity of up to 92% ee (Table 3,
Entry 6).
Entry
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
L6
L7
35
35
42
n.d.
n.d.
45
43
58
trace
54
43
64
63
71
–
L8
L9
L10
L11
L12
L13
L14
L15
L16
L17
L18
L19
–
76
81
92
–
85
82
90
47
–
Table 3. Influence of the Lewis acid on the hetero-Diels–Alder reac-
tion of benzaldehyde with 1b.[a]
Entry
Lewis acid
Yield [%][b]
ee [%][c]
31
48
trace
1
2
3
4
5
6
7
Al(OiPr)3
AlEt3
AlEt2Cl
trace
43
52
63
48
58
Ͻ5
–
0
0
26
33
92
29
[a] All reactions were performed with benzaldehyde (1 mmol) and
1b (1.2 mmol) in 1 mL of toluene at 0 °C for 48 h. Catalysts: 1:1
molar ratio of ligand/[Ti(OiPr)4]. Catalyst loading was 20 mol-%.
[b] Isolated yield. [c] Enantioselectivities were determined by HPLC
with a Chiralpak AD-H column.
TiCl4
[TiCl2(OiPr)2]
[Ti(OiPr)4]
[Zr(OiPr)4]
[a] All reactions were performed with benzaldehyde (1 mmol) and
1b (1.5 mmol) in 1 mL of toluene at 0 °C for 72 h. Catalysts: 1.1:1
molar ratio of ligand L13/Lewis acid, with a catalyst loading of
20 mol-%. [b] Isolated yield. [c] Enantioselectivities were deter-
mined by HPLC with a Chiralpak AD-H column.
The chiral induction of ligands L6–19 was surveyed. The
results (Table 2) show that both electronic and steric effects
of the substituents on the aromatic ring have an influence
on the enantiomeric excess of the product. Substituents or-
tho to the phenol hydroxy group in the ligands influence
the enantioselectivity more strongly than para substituents.
When substituent R1 was H and the R2 group was varied
from H and methyl to tert-butyl, the group’s electron-do-
nating capability and the reactivity increased slightly
Solvent Effects
The performance of the TiIV–L13 complex in various sol-
(Table 2, entries 1–3). However, when R2 was methoxy or vents was determined by applying the standard procedure.
nitro, the reaction did not proceed (Table 2, Entries 4,5). This solvent survey revealed that toluene, benzene, Et2O,
When R1 was tert-butyl and R2 was changed from H and and CH2Cl2 gave the product of the HDA reaction with
methyl to tert-butyl, the group’s electron-donating capa- high enantioselectivity and 58%, 37%, 42%, and 76% yield,
bility and both the reactivity and the enantioselectivity im- respectively (Table 4). THF showed a strong solvent effect
proved (Table 2, Entries 6–8). When R2 was nitro, the reac- in which a rather low ee was obtained. From these results,
tion hardly proceeded (Table 2, Entry 9). Thus, a rather CH2Cl2 was determined to be the appropriate solvent for
strong electron-donating group or a rather strong electron- this reaction.
3544
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Asymmetric Hetero-Diels–Alder Reaction of the Brassard Diene with Aldehydes
FULL PAPER
Table 4. Influence of solvent on the TiIV–L13-catalyzed hetero- zoic acid, and p-nitrobenzoic acid, the ee of the product
Diels–Alder reaction of benzaldehyde with 1b.[a]
decreased sharply from 93% to 76%, 74%, and 65%,
Entry
Solvent
Yield [%][b]
ee [%][c]
respectively. Perhaps the structure discrimination of the
Brassard diene with Danishefsky’s diene is the key to ex-
plain these results, as Togni has speculated that double sub-
stitution at the terminus has deleterious consequences upon
the enantioselectivity of this cycloaddition reaction.[12e]
1
2
3
4
5
toluene
benzene
Et2O
CH2Cl2
THF
58
37
42
76
46
92
93
89
93
61
[a] All reactions were performed with benzaldehyde (1 mmol) and
1b (1.5 mmol) in 1 mL of solvent at 0 °C for 72 h. Catalysts: 1.1:1
molar ratio of ligand L13/[Ti(OiPr)4], with a catalyst loading of
20 mol-%. [b] Isolated yield. [c] Enantioselectivities were deter-
mined by HPLC with a Chiralpak AD-H column.
Ratio of Ligand/Metal
To further optimize the reaction conditions, the effects
of the molar ratio of ligand L13/[Ti(OiPr)4] on yield and
enantioselectivity were examined in detail. When the molar
ratio of ligand L13/[Ti(OiPr)4] was 1.1:1, the optimal
enantioselectivity and yield were obtained (Table 7, En-
try 3). The yield varied appreciably with a change of the
molar ratio. An insufficiency or excess of ligand both gave
worse results (Table 7, Entries 1 and 5).
Temperature Effect
The influence of the temperature of the HDA reaction
of 1b with benzaldehyde was investigated in the presence of
TiIV–L13 (Table 5). A temperature dependence on the yield
and enantioselectivity was found. At 0 °C, both the yield
and the enantioselectivity had the optimal values (Table 3,
Entry 2). A higher temperature (23 °C) gave lower enantio-
selectivity (Table 3, Entry 1), and a lower temperature
brought about a sharp drop in the reactivity and, at –40
and –78 °C, also a drop in the enantioselectivity (Table 3,
Entries 3–5).
Table 7. The effect of the ratio of ligand/metal on the asymmetric
HDA reaction.[a]
Entry
Ratio of ligand/metal
Yield [%][b]
ee [%][c]
1
2
3
4
5
0.8:1
1:1
1.1:1
1.5:1
2:1
48
63
76
68
52
89
90
93
92
94
Table 5. Temperature effects on the asymmetric HDA reaction be-
tween 1b and benzaldehyde.[a]
[a] All reactions were performed with benzaldehyde (1 mmol) and
1b (1.5 mmol) in 1 mL of CH2Cl2 at 0 °C for 72 h. Catalysts: ligand
L13/[Ti(OiPr)4] with a catalyst loading of 20 mol-%. [b] Isolated
yield. [c] Enantioselectivities were determined by HPLC with a Chi-
ralpak AD-H column.
Entry
Temperature [°C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
23
0
–20
–40
–78
74
76
48
38
41
81
93
94[d]
51[d]
43[d]
[a] All reactions were performed with benzaldehyde (1 mmol) and
1b (1.5 mmol) in 1 mL of CH2Cl2 for 72 h. Catalysts: 1.1:1 molar
ratio of ligand L13/[Ti(OiPr)4] with a catalyst loading of 20 mol-
%. [b] Isolated yield. [c] Enantioselectivities were determined by
HPLC with a Chiralpak AD-H column. [d] The reaction time was
prolonged to 7 d due to the lower reaction rate.
Concentration of Substrate
The concentration of the substrate was examined to de-
termine the optimal reaction conditions (Table 8). The sol-
vent volume used in the reaction was changed and the other
conditions were kept fixed. Maintaining a sufficient concen-
tration is important for the HDA reaction, and a low con-
centration of catalyst and substrate leads to a sharp drop
Additive Effects
To investigate the effect of an additive on the reaction, in the yield and enantioselectivity (Table 8, Entry 1). When
some representative additives, such as 4 Å molecular sieves the concentration of substrate was 0.25 m, the optimal yield
(MS) and acids that have been applied successfully in the and enantioselectivity were achieved (up to 78% yield and
HDA reaction previously,[6d,6e] were added to the system,
but gave much worse results (Table 6). With 4 Å MS, ben-
Table 8. The effect of the catalyst concentration on the asymmetric
HDA reaction.[a]
Table 6. The effect of an additive on the asymmetric HDA reac-
tion.[a]
Entry Solvent volume Concentration of sub- Yield
ee [%]
[c]
[mL]
strate [m]
[%][b]
Entry
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
8
4
2
1
0.5
0.125
0.25
0.5
1
52
78
75
76
74
83
94
93
93
92
1
2
3
4
100 mg 4 Å MS
Benzoic acid
p-Nitrobenzoic acid
3,5-Dinitrosalicylic acid
58
43
68
76
74
65
–
trace
2
[a] All reactions were performed with benzaldehyde (1 mmol) and
1b (1.5 mmol) in 1 mL of CH2Cl2 for 72 h. Catalysts: 1.1:1 molar
ratio of ligand L13/[Ti(OiPr)4] with a catalyst loading of 20 mol-
%. [b] Isolated yield. [c] Enantioselectivities were determined by
HPLC with a Chiralpak AD-H column.
[a] All reactions were performed with benzaldehyde (1 mmol) and
1b (1.5 mmol) in CH2Cl2 at 0 °C for 72 h. Catalysts: 1.1:1 molar
ratio of ligand L13 and [Ti(OiPr)4] with a catalyst loading of
20 mol-%. [b] Isolated yield. [c] Enantioselectivities were deter-
mined by HPLC with a Chiralpak AD-H column.
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Q. Fan, L. Lin, J. Liu, Y. Huang, X. Feng
FULL PAPER
94% ee, Table 8, Entry 2). The corresponding concentration Entries 2–7). The reactions of chloro-substituted benzalde-
of catalyst was 0.05 m.
hydes with diene 1b occurred smoothly (Table 10, Entries 8–
Catalyst Loading
The amount of catalyst was found to be an important
factor that influences the enantioselectivity and yield of the
HDA reaction. The catalyst loading was changed from
40 mol-% to 1 mol-%; the results are listed in Table 9. A
higher amount of catalyst gave a worse result, probably due
to the high concentration causing aggregation of the cata-
lyst (Table 9, Entry 1). There was no difference in the
enantioselectivity and no significant loss in the yield with
catalyst loadings between 20 mol-% and 5 mol-% (Table 9,
Entries 2–4). However, when the catalyst loading was re-
duced to 2 mol-% and 1 mol-%, the enantioselectivities and
yields decreased sharply (Table 9, Entries 5 and 6). The op-
timal catalyst loading was 5 mol-%, at this point, with a
concentration of catalyst of 0.05 m, which is the same value
determined earlier (Table 8, Entry 2). This extensive screen-
ing showed that the optimized catalytic system is 5 mol-%
TiIV–L13, 0.25 m aldehyde with 1.5 equiv. of 1b in 1 mL of
CH2Cl2 at 0 °C for 72 h.
Table 9. The effect of catalyst loading on the asymmetric HDA
reaction.[a]
Entry
Catalyst loading [mol-%]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
40
20
10
5
2
1
56
76
73
71
43
20
84
93
93
93
82
78
Scheme 3. Substrates applied to the HDA reaction of the Brassard
diene.
[a] All reactions were performed with benzaldehyde (0.25 mmol)
and 1b (0.375 mmol) in 1 mL of CH2Cl2 at 0 °C for 72 h. Catalysts:
1.1:1 molar ratio of ligand L13 and [Ti(OiPr)4]. [b] Isolated yield.
[c] Enantioselectivities were determined by HPLC, using Chiralpak
AD-H column.
Table 10. Asymmetric hetero-Diels–Alder reaction of 1b with alde-
hydes promoted by Ti–L13.[a]
Entry
Substrate
Yield [%] ee [%][c]
[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
benzaldehyde (2a)
piperonal (2b)
71
21
45
24
53
36
46
70
70
87
67
N.D.
54
53
61
56
61
48(54)
26
93
88
96
92
93
90
95
99
90
97
95
–
87
93
90
91
96
m-anisaldehyde (2c)
o-tolualdehyde (2d)
Substrate Generality
m-tolualdehyde (2e)
Encouraged by the results obtained with benzaldehyde,
we investigated the enantioselective HDA reaction of 1b
with a variety of other aldehydes (Scheme 3), most of which
gave products with high enantioselectivities (up to 99% ee,
Table 10). As can be seen from these data, there are signifi-
cant electronic and steric effects of the aromatic ring’s
groups on the reactivity. With an enhancement of the
groups’ electron-donating capability from Cl to CH3 and
OCH3, the reactivity was reduced (Table 10, Entries 9, 5,
and 3), and with an enhancement of the groups’ electron-
withdrawing capability from Cl to CN and NO2 the reactiv-
ity was also reduced (Table 10, Entries 10, 15, and 16). Ap-
propriate electron-withdrawing groups on the substituted
benzaldehydes did, however, give higher enantioselectivities
and yields (Table 10, Entries 8 and 10), although the
stronger electron-withdrawing and -donating groups gen-
p-tolualdehyde (2f)
p-phenylbenzaldehyde (2g)
o-chlorobenzaldehyde (2h)
m-chlorobenzaldehyde (2i)
p-chlorobenzaldehyde (2j)
2,4-dichlorobenzaldehyde (2k)
2,6-dichlorobenzaldehyde (2l)
3,4-dichlorobenzaldehyde (2m)
p-fluorobenzaldehyde (2n)
p-cyanobenzaldehyde (2o)
p-nitrobenzaldehyde (2p)
2-naphthylbenzaldehyde (2q)
isobutyral (2r)
21(75)[16]
7
n-hexanal (2s)
p-nitroacetophenone (2t)
66
7
[a] All reactions were performed with aldehyde (0.25 mmol) and 1b
(0.375 mmol) in 1 mL of toluene at 0 °C for 72 h. Catalysts: 1.1:1
molar ratio of ligand/[Ti(OiPr)4], with a catalyst loading of 5 mol-
%. [b] Isolated yield. [c] Enantioselectivities were determined by
erally show lower reactivity (Table 10, Entries 14–16 and HPLC with a Chiralpak AD-H column.
3546 © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
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Asymmetric Hetero-Diels–Alder Reaction of the Brassard Diene with Aldehydes
FULL PAPER
10). Dichloro-substituted benzaldehydes were also used in with TFA, which transforms 4 into 3a by a cyclization reac-
this reaction: 2,4- and 3,4-substituted benzaldehydes gave tion, the final enantiomeric excess of 3a was reduced
good results (Table 10, Entries 11 and 13), but the 2,6-sub- sharply to 43%. These results indicate that the reaction
stituted benzaldehyde gave no product (Table 10, Entry 12). temperature has an influence on the reaction pathway: at
This could be due to larger steric hindrance than in the higher temperature (0 °C), the reaction mostly follows the
others, as the carbon atom of the carbonyl moiety is sur- Diels–Alder pathway, and at lower temperature (–78 °C) it
rounded by the two chlorine atoms and catalyst. Moreover, follows the Mukaiyama aldol pathway.
the meta position of the substituted benzaldehydes has
more influence on both reactivity and enantioselectivity
Conclusions
than the ortho or para position (Table 10, Entries 3, 5, and
9). A condensed-ring aldehyde also gives high enantio-
selectivity (Table 10, Entriy 17). All in all, the reactions of
1b with aromatic aldehydes proceed smoothly to give the
desired lactones in high enantioselectivities. However, when
isobutyral, n-hexanal, and p-nitroacetophenone were exam-
ined in this HDA reaction, the results were disappointing,
with very low enantioselective excess (Table 10, Entries 18–
20). The HDA reaction between isobutyral and the Brass-
ard diene was promoted by (R)-BINOL–Ti(OiPr)4, and an
enantiomeric excess of 75% could be achieved.[16] This
shows that the TiIV–L13 complex is an excellent catalyst for
the conversion of the Brassard diene with aromatic alde-
hydes but not with aliphatic aldehydes.
In conclusion, we have developed a series of titanium(iv)
tridentate Schiff-base complexes that promote the synthesis
of δ-lactones by the HDA reaction. The titanium(iv) com-
plex with ligand L13 exhibits excellent chiral induction in
the reaction of 1b with aromatic aldehydes under mild con-
ditions. However, this complex gives worse enantio-
selectivities with aliphatic aldehydes. The substituents on
the chiral Schiff-base ligands have a strong influence on the
yield and enantioselectivity of the reaction. Ligand L13 ex-
hibits a high chiral induction in the TiIV-catalyzed HDA
reaction, affording 6-substituted 4-ethoxy-5,6-dihydropy-
ran-2-one in up to 99% ee. The mechanism of the HDA
reaction between the Brassard diene and benzaldehyde in
the presence of the (Schiff base)TiIV complex was studied.
The results indicate that the reaction temperature influences
the reaction pathway: at higher temperature (0 °C), the re-
Mechanism Studies
Finally, to determine the mechanism of this kind of action mostly follows the Diels–Alder pathway, and at
HDA reaction, we performed some experiments to clarify lower temperature (–78 °C) it follows the Mukaiyama aldol
whether the reaction proceeds by the Mukaiyama aldol pathway. Further efforts will be devoted to the understand-
pathway or the Diels–Alder pathway (Scheme 4). When the ing of the difference between the Brassard diene and Brass-
reaction was performed at 0 or –20 °C, 3a (94% ee) and a ard diene-type derivatives, and searching for effective cata-
trace of 4 could be directly obtained by purification through lysts for aliphatic aldehydes.
a silica gel column at the end of the reaction without treat-
ment with TFA or other workup. However, when the reac-
Experimental Section
tion was carried out at –78 °C, most of the product ob-
tained by the same procedure was 4 in 35% yield and 30%
ee. Its structure was confirmed by NMR as the aldol pro-
duct. The enantiomeric excess of 3a was up to 99% with
General Method: Unless otherwise noted, all non-aqueous reac-
tions were carried out under dry nitrogen in dried glassware. All
manipulations involving [Ti(OiPr)4] were performed using standard
12% yield. When the reaction mixture above was treated Schlenk techniques. The H and 13C NMR spectra were recorded
1
Scheme 4. Mechanism of HDA reaction between 1b and aldehyde.
Eur. J. Org. Chem. 2005, 3542–3552
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3547

Q. Fan, L. Lin, J. Liu, Y. Huang, X. Feng
FULL PAPER
at 600 MHz and 150 MHz (Bruker Avance), respectively. The
chemical shifts are reported in ppm downfield from CDCl3 (δ =
7.27 ppm) for 1H NMR and relative to the the central CDCl3 reso-
nance (δ = 77.0 ppm) for 13C NMR spectroscopy. Coupling con-
stants in 1H NMR are given in Hz. HR mass spectra were recorded
with a BRUKER-APEX-2 (SIMS). Optical rotation data were re-
corded with a Perkin–Elmer Polarimeter-341. The enantiomeric ex-
cess (ee) of the products was determined by HPLC using Chiralpak
AD-H or Chiralcel OJ columns with hexane/2-propanol as eluent,
and the retention times were compared to corresponding racemic
samples.
(d, J = 1.4 Hz, 1 H, =CH), 4.00 (m, 2 H, OCH2), 2.80 (ddd, J =
17.1, 12.2, 1.4 Hz, 1 H, CHAHB), 2.53 (dd, J = 17.1, 3.8 Hz, 1 H,
CHAHB), 1.40 (t, J = 7.1 Hz, 3 H, CH3) ppm. 13C NMR (150 MHz,
CDCl3): δ = 171.9, 167.2, 148.2, 148.0, 132.4, 120.0, 108.5, 106.9,
101.5, 90.9, 77.3, 65.2, 35.6, 14.2 ppm. HRMS: calcd. for [M + H]+
263.0914; found 263.0918.
4-Ethoxy-6-(3-methoxyphenyl)-5,6-dihydropyran-2-one (3c): The ee
was determined by HPLC using a Chiralcel OJ column (90:10 hex-
ane/2-propanol; flow rate: 1.0 mLmin–1; tminor = 23.7 min, tmajor
=
27.0 min). Pale-yellow solid; m.p. 78–80 °C. [α]2D0 = +142.9 (c =
1
0.112, CH2Cl2, 96% ee; 45% yield). H NMR (600 MHz, CDCl3):
δ = 7.32–6.89 (m, 5 H, Ph-H), 5.42 (dd, J = 12.2, 3.8 Hz, 1 H,
PhCH-O), 5.22 (s, 1 H, =CH), 4.00 (m, 2 H, OCH2), 3.83 (s, 3 H,
OCH3), 2.82 (dd, J = 17.2, 12.2 Hz, 1 H, CHAHB), 2.60 (dd, J =
17.2, 3.8 Hz, 1 H, CHAHB), 1.41 (t, J = 7.1 Hz, 3 H, CH3) ppm.
13C NMR (150 MHz, CDCl3): δ = 172.0, 167.3, 160.1, 140.1, 129.9,
118.3, 114.4, 111.6, 91.0, 65.2, 55.5, 35.5, 14.2 ppm. HRMS: calcd.
for [M + H]+ 249.1121; found 249.1125.
Materials: Toluene, THF, and Et2O were freshly distilled from so-
dium/benzophenone ketyl. CH2Cl2 was distilled freshly from CaH2.
Brassard diene 1b was prepared from ethyl 3-ethoxybut-2-enoate[17]
according to a literature procedure.[11] Ligands L5–19 were pre-
pared[15] from aminoethanol and substituted salicylaldehydes, pur-
chased from Aldrich, or prepared from the corresponding phenols.
[Ti(OiPr)4] was distilled and stored as a 1.0 m solution in toluene.
All aldehydes were purchased from Acros, Aldrich, or Fluka. Li-
quid aldehydes were distilled in vacuo prior to use, and solid alde-
hydes were used directly without further purification. Racemic
samples of 3a–t were prepared with anhydrous ZnCl2 or Et2AlCl
as the catalyst.
4-Ethoxy-6-(2-methylphenyl)-5,6-dihydropyran-2-one (3d): The ee
was determined by HPLC using a Chiralpak AD-H column (96:4
hexane/2-propanol; flow rate: 1.0 mLmin–1; tmajor = 20.3 min, tminor
= 23.0 min). Pale-yellow solid; m.p. 59–60 °C. [α]2D0 = +169.6 (c =
1
0.112, CH2Cl2, 92% ee; 24% yield). H NMR (600 MHz, CDCl3):
δ = 7.53–7.19 (m, 5 H, Ph-H), 5.63 (dd, J = 12.6, 3.6 Hz, 1 H,
PhCH-O), 5.24 (d, J = 1.3 Hz, 1 H, =CH), 4.02 (m, 2 H, OCH2),
2.82 (ddd, J = 17.2, 12.7, 1.4 Hz, 1 H, CHAHB), 2.52 (dd, J = 17.3,
3.6 Hz, 1 H, CHAHB), 2.38 (s, 3 H, PhCH3), 1.42 (t, J = 7.1 Hz, 3
H, CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 172.2, 167.5,
136.5, 135.0, 130.9, 128.7, 126.7, 126.3, 90.9, 74.8, 65.2, 34.4, 19.3,
14.3 ppm. HRMS: calcd. for [M + H]+ 233.1172; found 233.1175.
Typical Procedure: [Ti(OiPr)4] (12.5 μL, 1 m in toluene,
0.0125 mmol) was stirred with 2a (5.9 mg, 0.01375 mmol) in
CH2Cl2 (0.5 mL) at 35 °C for 1 h under nitrogen. The mixture was
then cooled to room temperature, and benzaldehyde (25 μL,
0.25 mmol) and 0.5 mL of dry CH2Cl2 were added. The reaction
solution was stirred for 0.5 h, then cooled to –20 °C, and Brassard
diene 1b (85 μL, 0.375 mmol) added. The reaction mixture was
stirred at 0 °C for 72 h before quenched with five drops of TFA.
After stirring for an additional 2 h, the mixture was neutralized
with saturated NaHCO3 (2 mL) and partitioned between Et2O and
water twice. The combined organic layers were washed with satu-
rated brine and then dried with anhydrous Na2SO4 and concen-
trated in vacuo. The residue was purified by flash chromatography
on silica gel (eluent 3:1 petroleum ether/ethyl acetate) to afford the
cycloadduct 3a in 71% yield with 93% ee [determined by HPLC
on Chiralpak AD-H Column, hexane/2-propanol (95:5), flow rate
1.0 mLmin–1, tmajor = 19.83 min, tminor = 23.11 min]. [α]2D0 = +160
(c = 0.16, CH2Cl2).
4-Ethoxy-6-(3-methylphenyl)-5,6-dihydropyran-2-one (3e): The ee
was determined by HPLC using a Chiralpak AD-H column (95:5
hexane/2-propanol; flow rate: 1.0 mLmin–1; tmajor = 15.6 min, tminor
= 18.0 min). Pale-yellow solid; m.p. 87–88 °C. [α]2D0 = +173.2 (c =
1
0.112, CH2Cl2, 93% ee; 53% yield). H NMR (600 MHz, CDCl3):
δ = 7.30–7.26 (m, 2 H, Ph-H), 7.20–7.17 (m, 2 H, Ph-H), 5.40 (dd,
J = 12.2, 3.8 Hz, 1 H, PhCH-O), 5.22 (d, J = 1.2 Hz, 1 H, =CH),
4.00 (m, 2 H, OCH2), 2.82 (ddd, J = 17.2, 12.3, 1.3 Hz, 1 H,
CHAHB), 2.59 (dd, J = 17.2, 3.8 Hz, 1 H, CHAHB), 2.38 (s, 3 H,
PhCH3), 1.41 (t, J = 7.1 Hz, 3 H, CH3) ppm. 13C NMR (150 MHz,
CDCl3): δ = 172.0, 167.4, 138.7, 138.5, 129.5, 128.7, 126.9, 123.2,
91.0, 77.4, 65.1, 35.5, 21.6, 14.2 ppm. HRMS: calcd. for [M + H]+
233.1172; found 233.1171.
4-Ethoxy-6-phenyl-5,6-dihydropyran-2-one (3a): The ee was deter-
mined by HPLC using a Chiralpak AD-H column (95:5 hexane/2-
propanol; flow rate: 1.0 mLmin–1; tmajor = 19.8 min, tminor
=
4-Ethoxy-6-(4-methylphenyl)-5,6-dihydropyran-2-one (3f): The ee
23.1 min). Colorless needle crystals (after recrystallization from
ethyl acetate/hexane); m.p. 76–77 °C. [α]2D0 = +160.0 (c = 0.160,
CH2Cl2, 93% ee; 71% yield). 1H NMR (600 MHz, CDCl3): δ =
7.43–7.35 (m, 5 H, Ph-H), 5.44 (dd, J = 12.2, 3.8 Hz, 1 H, PhCH-
O), 5.23 (d, J = 1.4 Hz, 1 H, =CH), 4.01 (m, 2 H, OCH2), 2.83
(ddd, J = 17.2, 12.2, 1.4 Hz, 1 H, CHAHB), 2.60 (dd, J = 17.2,
4.0 Hz, 1 H, CHAHB), 1.41 (t, J = 7.1 Hz, 3 H, CH3) ppm. 13C
NMR (150 MHz, CDCl3): δ = 172.0, 167.3, 138.5, 128.9, 128.8,
126.2, 91.0, 77.4, 65.2, 35.5, 14.2 ppm. HRMS: calcd. for
[M + H]+ 219.1016; found 219.1018.
was determined by HPLC using a Chiralcel OJ column (94:6 hex-
ane/2-propanol; flow rate: 1.0 mLmin–1; tmajor = 30.0 min, tminor
=
36.8 min). Pale-yellow solid; m.p. 58–60 °C. [α]2D0 = +154.6 (c =
1
0.126, CH2Cl2, 90% ee; 36% yield). H NMR (600 MHz, CDCl3):
δ = 7.31–7.20 (m, 4 H, Ph-H), 5.40 (dd, J = 12.2, 3.8 Hz, 1 H,
PhCH-O), 5.22 (s, 1 H, =CH), 4.00 (m, 2 H, OCH2), 2.82 (dd, J =
17.2, 12.3 Hz, 1 H, CHAHB), 2.57 (dd, J = 17.2, 3.8 Hz, 1 H,
CHAHB), 2.37 (s, 3 H, PhCH3), 1.42 (t, J = 7.1 Hz, 3 H, CH3)
ppm. 13C NMR (150 MHz, CDCl3): δ = 172.0, 167.5, 138.6, 135.6,
129.5, 126.2, 91.0, 77.4, 65.1, 35.5, 21.4, 14.2 ppm. HRMS: calcd.
for [M + H]+ 233.1172; found 233.1176.
6-(Benzo[d][1,3]dioxol-5-yl)-4-ethoxy-5,6-dihydropyran-2-one (3b):
The ee was determined by HPLC using a Chiralcel OJ column
4-Ethoxy-6-(4-phenylphenyl)-5,6-dihydropyran-2-one (3g): The ee
(90:10 hexane/2-propanol; flow rate: 1.0 mLmin–1; tminor
43.3 min, tmajor = 47.4 min). White solid; m.p. 128–129 °C. [α]2D0
=
=
was determined by HPLC using a Chiralcel OJ column (80:20 hex-
ane/2-propanol; flow rate: 1.0 mLmin–1; tminor = 30.5 min, tmajor
=
+114.7 (c = 0.068, CH2Cl2, 88% ee; 21% yield). 1H NMR
(600 MHz, CDCl3): δ = 6.92 (d, J = 1.5 Hz, 1 H, Ph-H), 6.86 (dd,
J = 8.0, 1.1 Hz, 1 H, Ph-H), 6.81 (d, J = 8.0 Hz, 1 H, Ph-H), 5.98
(s, 2 H, OCH2O), 5.33 (dd, J = 12.2, 3.8 Hz, 1 H, PhCH-O), 5.20
36.0 min). Yellow solid; m.p. 123–124 °C. [α]2D0 = +148.1 (c = 0.104,
CH2Cl2, 95% ee; 46% yield). 1H NMR (600 MHz, CDCl3): δ =
7.64–7.60 (m, 4 H, Ph-H), 7.51–7.45 (m, 4 H, Ph-H), 7.37 (m, 1 H,
Ph-H), 5.49 (dd, J = 12.1, 3.8 Hz, 1 H, PhCH-O), 5.24 (d, J =
3548
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 3542–3552

Asymmetric Hetero-Diels–Alder Reaction of the Brassard Diene with Aldehydes
1.4 Hz, 1 H, =CH), 4.01 (m, 2 H, OCH2), 2.87 (ddd, J = 17.1, 12.2, = 1.7 Hz, 1 H, =CH), 4.03 (m, 2 H, OCH2), 3.46 (ddd, J = 17.3,
FULL PAPER
1.4 Hz, 1 H, CHAHB), 2.64 (dd, J = 17.2, 3.8 Hz, 1 H, CHAHB), 13.5, 1.6 Hz, 1 H, CHAHB), 2.40 (dd, J = 17.3, 4.6 Hz, 1 H,
1.42 (t, J = 7.0 Hz, 3 H, CH3) ppm. 13C NMR (150 MHz, CDCl3):
δ = 171.9, 167.2, 141.7, 140.7, 137.5, 129.0, 127.7, 127.6, 127.3,
CHAHB), 1.42 (t, J = 7.1 Hz, 3 H, CH3) ppm. 13C NMR (150 MHz,
CDCl3): δ = 171.6, 166.6, 135.5, 132.3, 130.5, 129.7, 90.9, 73.7,
126.7, 91.0, 77.4, 65.2, 35.4, 14.2 ppm. HRMS: calcd. for [M + H]+ 65.2, 30.6, 14.2 ppm. HRMS: calcd. for [M + H]+ 287.0236; found
295.1329; found 295.1325.
287.0240.
6-(2-Chlorophenyl)-4-ethoxy-5,6-dihydropyran-2-one (3h): The ee
was determined by HPLC using a Chiralpak AD-H column (98:2
hexane/2-propanol; flow rate: 1.0 mLmin–1; tmajor = 26.1 min, tminor
= 29.9 min). Pale-yellow solid; m.p. 85–86 °C. [α]2D0 = +270.2 (c =
6-(3,4-Dichlorophenyl)-4-ethoxy-5,6-dihydropyran-2-one (3m): The
ee was determined by HPLC using a Chiralpak AD-H column
(95:5 hexane/2-propanol; flow rate: 1.0 mLmin–1; tmajor = 20.0 min,
tminor = 28.9 min). White solid; m.p. 74–75 °C. [α]2D0 = +139.1 (c =
1
1
0.124, CH2Cl2, 99% ee; 70% yield). H NMR (600 MHz, CDCl3):
0.11, CH2Cl2, 87% ee, 54% yield). H NMR (600 MHz, CDCl3): δ
δ = 7.69–7.67 (m, 1 H, Ph-H), 7.39–7.35 (m, 2 H, Ph-H), 7.32–7.29 = 7.54 (d, J = 2.0 Hz, 1 H, Ph-H), 7.47 (d, J = 8.4 Hz, 1 H, Ph-
(m, 1 H, Ph-H), 5.80 (dd, J = 12.3, 3.8 Hz, 1 H, PhCH-O), 5.24
(d, J = 1.3 Hz, 1 H, =CH), 4.02 (m, 2 H, OCH2), 2.78 (ddd, J =
17.2, 12.2, 3.8 Hz, 2 H, CHAHB), 2.62 (ddd, J = 17.2, 12.2, 1.4 Hz,
H), 7.25 (dd, J = 8.4, 2.0 Hz, 1 H, Ph-H), 5.39 (dd, J = 12.1, 3.9 Hz,
1 H, PhCH-O), 5.21 (d, J = 1.3 Hz, 1 H, =CH), 4.00 (m, 2 H,
OCH2), 2.75 (ddd, J = 17.1, 12.1, 1.3 Hz, 1 H, CHAHB), 2.60 (dd,
1 H, CHAHB), 1.42 (t, J = 7.1 Hz, 3 H, CH3) ppm. 13C NMR J = 17.1, 3.9 Hz, 1 H, CHAHB), 1.41 (t, J = 7.1 Hz, 3 H, CH3)
(150 MHz, CDCl3): δ = 172.0, 167.2, 136.5, 131.5, 129.8, 127.7, ppm. 13C NMR (150 MHz, CDCl3): δ = 171.5, 166.6, 138.8, 133.2,
127.6, 90.8, 74.4, 65.3, 34.1, 14.2 ppm. HRMS: calcd. for [M + H]+ 132.9, 130.9, 128.2, 125.4, 91.0, 75.8, 65.3, 35.3, 14.2 ppm. HRMS:
253.0626; found 253.0632.
calcd. for [M + H]+ 287.0236; found 287.0240.
6-(3-Chlorophenyl)-4-ethoxy-5,6-dihydropyran-2-one (3i): The ee 4-Ethoxy-6-(4-fluorophenyl)-5,6-dihydropyran-2-one (3n): The ee
was determined by HPLC using a Chiralpak AD-H column (95:5
hexane/2-propanol; flow rate: 1.0 mLmin–1; tmajor = 17.9 min, tminor
= 21.7 min). Pale-yellow solid; m.p. 114–116 °C. [α]2D0 = +161.0 (c
= 0.118, CH2Cl2, 90% ee; 70% yield). 1H NMR (600 MHz,
was determined by HPLC using a Chiralpak AD-H column (93:7
hexane/2-propanol; flow rate: 1.0 mLmin–1; tmajor = 16.8 min, tminor
= 20.3 min). Pale-yellow solid; m.p. 64–65 °C. [α]2D0 = +164.5 (c =
1
0.104, CH2Cl2, 93% ee; 53% yield). H NMR (600 MHz, CDCl3):
CDCl3): δ = 7.44 (s, 1 H, Ph-H), 7.34–7.29 (m, 3 H, Ph-H), 5.41 δ = 7.41–7.39 (m, 2 H, Ph-H), 7.10–7.07 (m, 2 H, Ph-H), 5.41 (dd,
(dd, J = 12.2, 3.9 Hz, 1 H, PhCH-O), 5.22 (d, J = 1.5 Hz, 1 H,
=CH), 4.01 (m, 2 H, OCH2), 2.79 (ddd, J = 17.2, 12.2, 1.4 Hz, 1
H, CHAHB), 2.61 (dd, J = 17.1, 4.0 Hz, 1 H, CHAHB), 1.41 (t, J
J = 12.2, 3.8 Hz, 1 H, PhCH-O), 5.21 (d, J = 1.5 Hz, 1 H, =CH),
4.00 (m, 2 H, OCH2), 2.79 (ddd, J = 17.1, 12.2, 1.5 Hz, 1 H,
CHAHB), 2.57 (dd, J = 17.1, 3.8 Hz, 1 H, CHAHB), 1.40 (t, J =
= 7.1 Hz, 1 H, CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 171.7, 7.0 Hz, 3 H, CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 171.83,
166.8, 140.6, 134.9, 130.2, 128.9, 126.4, 124.2, 91.0, 76.4, 65.3, 35.4,
167.08, 163.75, 162.11, 134.41, 134.38, 128.10, 128.76, 115.91,
115.76, 90.96, 76.72, 65.22, 35.51, 14.21 ppm. HRMS: calcd. for
[M + H]+ 237.0921; found 237.0916.
14.2 ppm. HRMS: calcd. for [M + H]+ 253.0626; found 253.0624.
6-(4-Chlorophenyl)-4-ethoxy-5,6-dihydropyran-2-one (3j): The ee
was determined by HPLC using a Chiralpak AD-H column (95:5
hexane/2-propanol; flow rate: 1.0 mLmin–1; tmajor = 23.9 min, tminor
= 29.1 min). Pale-yellow solid; m.p. 103–104 °C. [α]2D0 = +151.9 (c
= 0.104, CH2Cl2, 97% ee; 87% yield). 1H NMR (600 MHz,
6-(4-Cyanophenyl)-4-ethoxy-5,6-dihydropyran-2-one (3o): The ee
was determined by HPLC using a Chiralpak AD-H column (85:15
hexane/2-propanol; flow rate: 1.0 mLmin–1; tmajor = 19.2 min, tminor
= 22.8 min). Pale-yellow solid; m.p. 71–72 °C. [α]2D0 = +181.9 (c =
1
CDCl3): δ = 7.39–7.35 (m, 4 H, Ph-H), 5.41 (dd, J = 12.1, 3.8 Hz, 0.116, CH2Cl2, 90% ee; 61% yield). H NMR (600 MHz, CDCl3):
1 H, PhCH-O), 5.22 (s, 1 H, =CH), 4.00 (m, 2 H, OCH2), 2.77 (dd,
J = 17.2, 12.1 Hz, 1 H, CHAHB), 2.59 (dd, J = 17.2, 3.9 Hz, 1 H,
CHAHB), 1.40 (t, J = 7.0 Hz, 3 H, CH3) ppm. 13C NMR (150 MHz,
CDCl3): δ = 171.7, 167.0, 137.1, 134.6, 129.1, 127.6, 91.0, 76.6,
65.3, 35.4, 14.2 ppm. HRMS: calcd. for [M + H]+ 253.0626; found
253.0630.
δ = 7.72, (d, J = 8.4 Hz, 2 H, Ph-H), 7.56 (d, J = 8.2 Hz, 2 H, Ph-
H), 5.49 (dd, J = 12.0 Hz, 3.9, 1 H, PhCH-O), 5.24 (d, J = 1.3 Hz,
1 H, =CH), 4.02 (m, 2 H, OCH2), 2.76 (ddd, J = 17.1, 12.0, 1.3 Hz,
1 H, CHAHB), 2.64 (dd, J = 17.1, 3.9 Hz, 1 H, CHAHB), 1.42 (t, J
= 7.1 Hz, 3 H, CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 171.4,
166.4, 143.7, 132.8, 126.8, 118.5, 112.7, 91.0, 76.2, 65.4, 35.3,
14.2 ppm. HRMS: calcd. for [M + H]+ 244.0968; found 244.0976.
6-(2,4-Dichlorophenyl)-4-ethoxy-5,6-dihydropyran-2-one (3k): The
ee was determined by HPLC using a Chiralpak AD-H column
(98:2 hexane/2-propanol; flow rate: 1.0 mLmin–1; tmajor = 26.6 min,
tminor = 30.8 min). White solid; m.p. 100–101 °C. [α]2D0 = +243.4 (c
= 0.12, CH2Cl2, 95% ee, 67% yield). 1H NMR (600 MHz, CDCl3):
4-Ethoxy-6-(4-nitrophenyl)-5,6-dihydropyran-2-one (3p): The ee was
determined by HPLC using a Chiralpak AD-H column (85:15 hex-
ane/2-propanol; flow rate: 1.0 mLmin–1; tmajor = 20.2 min, tminor
=
26.1 min). Yellow solid; m.p. 92–93 °C. [α]2D0 = +159.3 (c = 0.108,
δ = 7.62 (d, J = 8.5 Hz, 1 H, Ph-H), 7.41 (d, J = 2.1 Hz, 1 H, Ph- CH2Cl2, 91% ee; 56% yield). 1H NMR (600 MHz, CDCl3): δ =
H), 7.35 (dd, J = 8.5, 2.0 Hz, 1 H, Ph-H), 5.74 (dd, J = 12.4, 3.8 Hz,
1 H, PhCH-O), 5.23 (d, J = 1.4 Hz, 1 H, =CH), 4.02 (m, 2 H,
OCH2), 2.76 (dd, J = 17.2, 3.8 Hz, 1 H, CHAHB), 2.58 (ddd, J =
17.2, 12.4, 1.4 Hz, 1 H, CHAHB), 1.42 (t, J = 7.1 Hz, 3 H, CH3)
ppm. 13C NMR (150 MHz, CDCl3): δ = 171.8, 166.8, 135.1, 135.0,
132.2, 129.6, 128.7, 128.0, 90.8, 73.9, 65.4, 34.1, 14.2 ppm. HRMS:
calcd. for [M + H]+ 287.0236; found 287.0235.
8.28 (d, J = 8.8 Hz, 2 H, Ph-H), 7.63 (d, J = 8.7 Hz, 2 H, Ph-H),
5.55 (dd, J = 12.1, 4.1 Hz, 1 H, PhCH-O), 5.25 (d, J = 1.1 Hz, 1
H, =CH), 4.03 (m, 2 H, OCH2), 2.78 (ddd, J = 17.1, 12.1, 1.2 Hz,
1 H, CHAHB), 2.67 (dd, J = 17.1, 4.1 Hz, 1 H, CHAHB), 1.42 (t, J
= 7.0 Hz, 3 H, CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 171.3,
166.3, 148.2, 145.5, 126.9, 124.2, 91.0, 76.0, 65.5, 35.3, 14.2 ppm.
HRMS: calcd. for [M + H]+ 264.0866; found 264.0874.
6-(2,6-Dichlorophenyl)-4-ethoxy-5,6-dihydropyran-2-one (3l): The
racemic mixture of enantiomers was separated by HPLC using a
4-Ethoxy-6-(naphthalen-3-yl)-5,6-dihydropyran-2-one (3q): The ee
was determined by HPLC using a Chiralpak AD-H column (92:8
hexane/2-propanol; flow rate: 1.0 mLmin–1; tmajor = 19.5 min, tminor
Chiralpak AD-H column (90:10 hexane/2-propanol; flow rate:
1
1.0 mLmin–1; t1 = 13.0 min, t2 = 13.7 min). H NMR (600 MHz, = 24.5 min). White solid; m.p. 125–126 °C. [α]2D0 = +145.5 (c =
1
CDCl3): δ = 7.36 (d, J = 8.0 Hz, 2 H, Ph-H), 7.24 (t, J = 8.0 Hz,
0.176, CH2Cl2, 96% ee; 61% yield). H NMR (600 MHz, CDCl3):
1 H, Ph-H), 6.21 (dd, J = 13.5, 4.6 Hz, 1 H, PhCH-O), 5.24 (d, J δ = 7.91–7.86 (m, 4 H, Ar-H), 7.63 (m, 3 H, Ar-H), 5.61 (dd, J =
Eur. J. Org. Chem. 2005, 3542–3552
www.eurjoc.org © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3549

Q. Fan, L. Lin, J. Liu, Y. Huang, X. Feng
FULL PAPER
12.1, 3.8 Hz, 1 H, ArCH-O), 5.26 (s, 1 H, =CH), 4.02 (m, 2 H, 2-{[(1S,2R)-2-Hydroxy-1,2-diphenylethylimino]methyl}-4-methyl-
OCH2), 2.91 (dd, J = 17.2, 12.1 Hz, 1 H, CHAHB), 2.70 (dd, J =
phenol (L7): M.p. 123–124 °C. 1H NMR (400 MHz, CDCl3): δ =
17.2, 3.8 Hz, 1 H, CHAHB), 1.42 (t, J = 7.0 Hz, 3 H, CH3) ppm. 12.92 (s, 1 H, PhO-H), 8.02 (s, 1 H, N=CH), 7.38–7.25 (m, 10 H,
13C NMR (150 MHz, CDCl3): δ = 171.92, 167.27, 135.92, 133.46,
133.32, 128.79, 128.35, 127.93, 126.69, 126.66, 125.32, 123.69,
91.04, 65.18, 35.53, 14.23 ppm. HRMS: calcd. for [M + H]+
269.1172; found 269.1165.
Ph-H), 7.09 (d, 8 Hz, 1 H, Ph-H), 6.85 (m, 2 H, Ph-H), 5.04 (dd,
7.2 Hz, 2 Hz, 1 H, HOC-H), 4.49 (d, J = 7.2 Hz, 1 H, C=NC-H),
2.22 (s, 3 H, Me), 2.11 (d, 2 Hz, 1 H, CO-H) ppm.
4-tert-Butyl-2-{[(1S,2R)-2-hydroxy-1,2-diphenylethylimino]-
methyl}phenol (L8): M.p. 168–170 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.13 (s, 1 H, N=CH), 7.37–7.25 (m, 11 H, Ph-H), 7.07
(d, J = 2.4 Hz, 1 H, Ph-H), 6.88 (d, J = 8.8 Hz, 1 H, Ph-H), 5.06
(dd, J = 7.2, 2.8 Hz, 1 H, HOC-H), 4.53 (d, J = 7.2 Hz, 1 H,
C=NC-H), 2.04 (d, J = 2.8 Hz, 1 H, CO-H), 1.24 (s, 9 H, tBu)
ppm.
4-Ethoxy-6-isopropyl-5,6-dihydropyran-2-one (3r): The ee was deter-
mined by GC using a Chiralsil DEX CB column (150 °C; tmajor
=
24.2 min, tminor = 25.3 min). Yellow oil; 21% ee; 48% yield. 1H
NMR (600 MHz, CDCl3): δ = 5.11 (d, J = 1.7 Hz, 1 H, =CH),
4.13 (m, 1 H, -CH-O), 3.95 (m, 2 H, OCH2), 2.51 (ddd, J = 17.0,
12.8, 1.6 Hz, 1 H, CHAHB), 2.26 (dd, J = 17.0, 3.6 Hz, 1 H,
CHAHB), 1.97 (m, 1 H, CH), 1.38 (t, J = 7.0 Hz, 3 H, CH3), 1.04
(d, J = 6.7 Hz, 3 H, isopropyl-CH3), 1.00 (d, J = 6.87 Hz, 3 H,
isopropyl-CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 172.5,
168.0, 90.7, 80.7, 64.9, 32.1, 30.6, 18.2, 18.0, 14.2 ppm. HRMS:
calcd. for [M + H]+ 185.1178; found 185.1017.
2-{[(1S,2R)-2-Hydroxy-1,2-diphenylethylimino]methyl}-4-methoxy-
phenol (L9): M.p. 98–99 °C. 1H NMR (400 MHz, CDCl3): δ =
12.65 (s, 1 H, PhO-H), 8.03 (S, 1 H, N=CH), 7.40–7.27 (m, 10 H,
Ph-H), 6.89 (m, 2 H, Ph-H), 6.59 (d, J = 1.6 Hz, 1 H, Ph-H), 5.05
(dd, J = 7.2, 2.8 Hz, 1 H, HOC-H), 4.50 (d, J = 7.2 Hz, 1 H,
C=NC-H), 3.72 (s, 3 H, OMe), 2.04 (d, J = 2.8 Hz, 1 H, CO-H)
ppm.
4-Ethoxy-6-pentyl-5,6-dihydropyran-2-one (3s): The ee was deter-
mined by GC using a Chiralsil DEX CB column (170 °C; tminor
=
29.3 min, tmajor = 29.9 min). Yellow oil; 7% ee; 26% yield. 1H
NMR (600 MHz, CDCl3): δ = 5.09 (d, J = 1.2 Hz, 1 H, =CH),
4.36 (m, 1 H, -CH-O), 3.95 (m, 2 H, OCH2), 2.46 (ddd, J = 17.0,
12.0, 1.2 Hz, 1 H, CHAHB), 2.31 (dd, J = 17.0, 3.7 Hz, 1 H,
CHAHB), 1.79 (m, 1 H, pentyl-H), 1.62 (m, 1 H, pentyl-H), 1.51
(m, 1 H, pentyl-H), 1.40 (m, 1 H, pentyl-H), 1.38 (t, J = 7.0 Hz, 3
H, OCH2CH3), 1.32 (m, 4 H, pentyl-H), 0.89 (t, J = 6.7 Hz, 3 H,
pentyl-H) ppm. 13C NMR (150 MHz, CDCl3): δ = 172.2, 167.9,
90.7, 76.1, 64.9, 34.9, 33.4, 31.7, 24.7, 22.7, 14.21, 14.16.
2-{[(1S,2R)-2-Hydroxy-1,2-diphenylethylimino]methyl}-4-nitrophen-
ol (L10): M.p. 188–190 °C. 1H NMR (400 MHz, CDCl3): δ = 14.40
(s, 1 H, Ph-H), 8.19 (dd, J = 9.2, 5.6 Hz, 1 H, Ph-H), 8.10 (s, 1 H,
N=CH), 8.07 (d, J = 2.8 Hz, 1 H, Ph-H), 7.42–7.23 (m, 10 H, Ph-
H), 6.99 (d, J = 9.2 Hz, 1 H, Ph-H), 5.06 (dd, J = 7.2, 2.4 Hz, 1
H, HOC-H), 4.61 (d, J = 7.2 Hz, 1 H, C=NC-H), 2.08 (d, J =
2.4 Hz, 1 H, CO-H) ppm.
6-tert-Butyl-2-{[(1S,2R)-2-hydroxy-1,2-diphenylethyl-
1
imino]methyl}phenol (L11): M.p. 47–49 °C. H NMR (600 MHz,
4-Ethoxy-6-methyl-6-(4-nitrophenyl)-5,6-dihydropyran-2-one
The ee was determined by HPLC using a Chiralcel OD column
(80:20 hexane/2-propanol; flow rate: 1.0 mLmin–1; tminor
(3t):
CDCl3): δ = 13.66 (s, 1 H, PhO-H), 8.09 (s, 1 H, N=CH), 7.43–
7.25 (m,11 H), 6.95 (dd, J = 7.6, 1.4 Hz, 1 H, Ph-H), 6.75 (t, J =
7.6 Hz, 1 H, Ph-H), 5.08 (d, J = 7.2 Hz, 1 H, HOC-H), 4.50 (d, J
= 7.2 Hz, 1 H, C=NC-H), 2.08 (d, J = 2.0 Hz, 1 H, CO-H), 1.45
(s, 9 H, tBu) ppm. 13C NMR (150 MHz, CDCl3): δ = 166.8, 160.4,
140.4, 139.6, 137.5, 130.2, 129.9, 128.9, 128.3, 128.2, 127.4, 118.8,
118.0, 80.4, 78.6, 76.8, 35.0, 29.5 ppm. HRMS: calcd. for [M + H]+
374.2115; found 374.2122.
=
13.6 min, tmajor = 21.5 min). Yellow solid; m.p. 144–145 °C; 7% ee;
1
66% yield. H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 8.8 Hz,
2 H, Ph-H), 7.59 (d, J = 8.8 Hz, 2 H, Ph-H), 5.09 (s, 1 H, =CH),
3.90 (m, 2 H, OCH2), 2.98 (m, 2 H, cyclic-CH2), 1.73 (s, 3 H, CH3),
1.35 (t, J = 7.2 Hz, 3 H, OCH2CH3) ppm. HRMS: calcd. for [M
+ H]+ 278.1023; found 278.1024.
6-tert-Butyl-2-{[(1S,2R)-2-hydroxy-1,2-diphenylethylimino]methyl}-
4-methylphenol (L12): M.p. 47–48 °C. 1H NMR (600 MHz,
CDCl3): δ = 13.40 (s, 1 H, PhO-H), 8.05 (s, 1 H, N=CH), 7.42–
7.26 (m, 10 H, Ph-H), 7.11 (s, 1 H, Ph-H), 6.75 (s, 1 H, Ph-H), 5.06
(d, J = 7.0 Hz, 1 H, HOC-H), 4.49 (d, J = 7.0 Hz, 1 H, C=NC-H),
2.23 (s, 3 H, Me), 1.45 (s, 9 H, tBu) ppm. HRMS: calcd. for [M +
H]+ 388.2271; found 388.2275.
Ethyl 3-Ethoxy-5-hydroxy-5-phenylpent-2-enoate (4): The ee was de-
termined by HPLC using a Chiralpak AD-H column (92:8 hexane/
2-propanol; flow rate: 1.0 mLmin–1; tmajor = 19.5 min, tminor
=
24.5 min). Colorless oil; 30% ee; 35% yield.1H NMR (600 MHz,
CDCl3): δ = 7.39–7.37 (m, 4 H, Ph-H), 7.31 (m, 1 H, Ph-H), 5.10
(s, =CH), 4.96 (m, 1 H, HOC-H), 4.21 (m, 2 H, =COCH2), 4.13
(q, J = 7.1 Hz, 2 H, COOCH2), 2.59 (m, 2 H, =CCH2), 2.35 (d, J
= 2.9 Hz, 1 H, CO-H), 1.35 (t, J = 7.0 Hz, 3 H, =COCH2CH3),
1.27 (t, J = 7.1 Hz, 3 H, COOCH2CH3) ppm. 13C NMR (150 MHz,
CDCl3): δ = 167.2, 165.1, 143.2, 128.6, 127.9, 125.6, 99.0, 72.2,
67.8, 59.6, 45.2, 15.4, 14.3 ppm.
4,6-Di-tert-butyl-2-{[(1S,2R)-2-hydroxy-1,2-diphenylethyl-
1
imino]methyl}phenol (L13): M.p. 59–61 °C. H NMR (600 MHz,
CDCl3): δ = 13.40 (s, 1 H, PhO-H), 8.15 (s, 1 H, N=CH), 7.37–
7.25 (m, 11 H, Ph-H), 6.92 (d, J = 2.4 Hz, 1 H, Ph-H), 5.08 (dd, J
= 6.7, 3.0 Hz, 1 H, HOC-H), 4.51 (d, J = 6.7 Hz, 1 H, C=NC-H),
2.06 (d, J = 3.0 Hz, 1 H, CO-H), 1.44 (s, 9 H, tBu), 1.25 (s, 9 H,
tBu) ppm. 13C NMR (150 MHz, CDCl3): δ = 167.3,158.1, 140.4,
140.3, 139.8, 136.8, 128.9, 128.3, 128.2, 128.1, 127.4, 126.5, 118.0,
80.2, 78.6, 35.2, 34.3, 31.6, 29.6 ppm. HRMS: calcd. for [M + H]+
430.2741; found 430.2742.
(R)-3-{(E)-[(1S,2R)-2-Hydroxy-1,2-diphenylethylimino]methyl}-1-(2-
{(E)-[(1S,2R)-2-hydroxy-1,2-diphenylethylimino]methyl}-3-hydroxy-
naphth-4-yl)naphthalen-2-ol (L5): M.p. 104–105 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.35 (s, 2 H, N=CH), 7.81 (m, 4 H, Ph-
H), 7.4–7.42 (m, 4 H, Ph-H), 7.36–7.20 (m, 20 H, Ph-H), 7.07 (d,
J = 8.0 Hz, 2 H, Ph-H), 5.06 (d, 7.2 hz, 2 H, HOC-H), 4.55 (d, J
= 7.2 Hz, 2 H, C=NC-H), 2.10 (br., 2 H, CO-H) ppm.
6-tert-Butyl-2-{[(1S,2R)-2-Hydroxy-1,2-diphenylethylimino]methyl}-
1
2-{[(1S,2R)-2-Hydroxy-1,2-diphenylethylimino]methyl}phenol (L6):
M.p. 82–84 °C. 1H NMR (600 MHz, CDCl3): δ = 13.15 (s, 1 H,
4-nitrophenol (L14): M.p. 66–67 °C. H NMR (600 MHz, CDCl3):
δ = 15.03 (s, 1 H, PhO-H), 8.20 (d, J = 2.7 Hz, 1 H, Ph-H), 8.12
PhO-H), 8.08 (s, 1 H, N=CH), 7.40–7.26 (m, 10 H, Ph-H), 7.09 (d, (s, 1 H, N=CH)7.95 (d, J = 2.7 Hz, 1 H, Ph-H), 7.45–7.23 (m, 10
J = 7.9 Hz,1 H, Ph-H), 6.95 (d, J = 7.9 Hz, 1 H, Ph-H), 6.82 (s, 1
H, Ph-H), 5.06 (d, J = 7.0 Hz, 1 H, HOC-H), 4.53 (d, J = 7.0 Hz,
1 H, C=NC-H), 2.06 (d, J = 2.0 Hz, 1 H, CO-H) ppm.
H, Ph-H), 5.10 (d, J = 6.7 Hz, 1 H, HOC-H), 4.61 (d, J = 6.7 Hz,
1 H, C=NC-H), 2.10 (d, J = 2.2 Hz, 1 H, CO-H), 1.47 (s, 9 H, tBu)
ppm. HRMS: calcd. for [M + H]+ 419.1965; found 419.1976.
3550
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3542–3552

Asymmetric Hetero-Diels–Alder Reaction of the Brassard Diene with Aldehydes
FULL PAPER
K. A. Jørgensen, Angew. Chem. 2000, 112, 3702–3733; Angew.
Chem. Int. Ed. 2000, 39, 3558–3588; d) J. S. Johnson, D. A.
Evans, Acc. Chem. Res. 2000, 33, 325–335; e) H. B. Kagan, O.
Riant, Chem. Rev. 1992, 92, 1007–1019.
6-Adamantyl-4-tert-butyl-2-{[(1S,2R)-2-hydroxy-1,2-diphenylethyl-
imino]methyl}phenol (L15): M.p. 101–103 °C. H NMR (600 MHz,
1
CDCl3): δ = 13.37 (s, 1 H, PhO-H), 8.14 (s, 1 H, N=C-H), 7.44–
7.27 (m, 11 H, Ph-H), 6.90 (d, 2.2HZ, 1 H, Ph-H), 5.09 (dd, J =
6.8, 3.0 Hz, 1 H, HOC-H), 4.50 (d, J = 6.8 Hz, 1 H, C=NC-H),
2.30–2.11 (m, 9 H, adamantyl-H), 2.06 (d, J = 3.0 Hz, 1 H, CO-
H), 1.82 (m, 6 H, adamantyl-H), 1.25 (s, 9 H, tBu) ppm. 13C NMR
(150 MHz, CDCl3): δ = 167.4, 158.4, 140.5, 140.3, 139.8, 137.1,
128.9, 128.4, 128.3, 128.1, 127.4, 126.4, 118.0, 80.4, 78.5, 40.5,
37.45, 37.40, 34.3, 31.7, 29.4 ppm. HRMS: calcd. for [M + H]+
508.3210; found 508.3203.
[3]
For some recent works on hetero-Diels–Alder reaction, see: a)
K. Juhl, K. A. Jørgensen, Angew. Chem. 2003, 115, 1536–1539;
Angew. Chem. Int. Ed. 2003, 42, 1498–1501; b) H. Audrain, J.
Thorhauge, R. G. Hazell, K. A. Jørgensen, J. Org. Chem. 2000,
65, 4487–4497; c) J. Thorhauge, M. Johannsen, K. A.
Jørgensen, Angew. Chem. 1998, 110, 2543–2546; Angew. Chem.
Int. Ed. 1998, 37, 2404–2406; d) Y. Yamashita, S. Saito, H.
Ishitani, S. Kobayashi, J. Am. Chem. Soc. 2003, 125, 3793–
3798; e) Y. Yamashita, S. Saito, H. Ishitani, S. Kobayashi, Org.
Lett. 2002, 4, 1221–1223; f) D. E. Chavez, E. N. Jacobsen, Org.
Lett. 2003, 5, 2563–2565; g) G. D. Joly, E. N. Jacobsen, Org.
Lett. 2002, 4, 1795–1798; h) H.-F. Du, K.-L. Ding, Org. Lett.
2003, 5, 1091–1093; i) J. Long, J.-Y. Hu, X.-Q. Shen, B.-M. Ji,
K.-L. Ding, J. Am. Chem. Soc. 2002, 124, 10–11; j) Y. Yuan,
X. Li, K.-L. Ding, Org. Lett. 2002, 4, 3309–3311; k) B. Wang,
X.-M. Feng, X. Cui, H. Liu, Y.-Z. Jiang, Chem. Commun.
2000, 1605–1606; l) B. Wang, X.-M. Feng, Y.-Z. Huang, H.
Liu, X. Cui, Y.-Z. Jiang, J. Org. Chem. 2002, 67, 2175–2182;
m) Y.-Z. Huang, X.-M. Feng, B. Wang, G.-L. Zhang, Y.-Z.
Jiang, Tetrahedron Lett. 2002, 43, 2122–2125.
For the use of BINOL derivatives in the HDA reaction see, for
example: a) K. Maruoka, T. Itoh, Y. Araki, T. Shirasaka, H.
Yamamoto, Bull. Chem. Soc. Jpn. 1988, 61, 2975–2976; b) K.
Maruoka, T. Itoh, T. Shirasaka, H. Yamamoto, J. Am. Chem.
Soc. 1988, 110, 310–312; c) T. Ooi, D. Uraguchi, N. Kagosh-
ima, K. Maruoka, J. Am. Chem. Soc. 1998, 120, 5327–5328; d)
K. B. Simonsen, N. Svenstrup, M. Roberson, K. A. Jørgensen,
Chem. Eur. J. 2000, 6, 123–128; e) Q.-Z. Gao, T. Maruyama,
M. Mouri, H. Yamamoto, J. Org. Chem. 1992, 57, 1951–1952.
For the use of chiral bis(oxazolines) in the HDA reaction see,
for example: a) D. A. Evans, D. M. Barnes, J. S. Johnson, T.
Lectka, P. Matt, S. J. Miller, J. A. Murry, R. D. Norcross, E. A.
Shaughnessy, K. R. Campos, J. Am. Chem. Soc. 1999, 121,
7582–7594, and references cited therein; b) H. Audrian, J.
Thorhauge, R. G. Hazell, K. A. Jørgensen, J. Org. Chem. 2000,
65, 4487–4497, and references cited therein; c) D. A. Evans,
J. S. Johnson, E. J. Olhava, J. Am. Chem. Soc. 2000,122, 1635–
1649.
For the use of Schiff-base ligands in the HDA reaction see, for
example: a) S. E. Schaus, J. Brånalt, E. N. Jacobsen, J. Org.
Chem. 1998, 63, 403–405; b) K. Gademann, D. E. Chavez,
E. N. Jacobsen, Angew. Chem. Int. Ed. 2002, 41, 3059–3061; c)
R. T. Ruck, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124,
2882–2883; d) Y. Yuan, J. Long, J. Sun, K.-L. Ding, Chem. Eur.
J. 2002, 8, 5033–5042; e) B.-M. Ji, Y. Yuan, K.-L. Ding, J.-B.
Meng, Chem. Eur. J. 2003, 9, 5989–5996.
4,6-Dichloro-2-{[(1S,2R)-2-hydroxy-1,2-diphenylethylimino]-
methyl}phenol (L16): M.p. 59–61 °C. 1H NMR (400 MHz, CDCl3):
δ = 7.92 (s, 1 H, N=CH), 7.40–7.23 (m, 11 H, Ph-H), 6.96 (d, J =
2.4 Hz, 1 H, Ph-H), 5.03 (d, J = 7.2 Hz, 1 H, HOC-H), 4.51 (d, J
= 7.2 Hz, 1 H, C=NC-H), 2.04 (br., 1 H, CO-H) ppm. HRMS:
calcd. for [M + H]+ 386.0709; found 386.0718.
4,6-Dibromo-2-{[(1S,2R)-2-hydroxy-1,2-diphenylethylimino]-
methyl}phenol (L17): M.p. 70–72 °C. 1H NMR (400 MHz, CDCl3):
δ = 7.89 (s, 1 H, N=CH), 7.66 (d, J = 2.4 Hz, 1 H, Ph-H), 7.41–
7.24 (m, 10 H, Ph-H), 7.14 (d, J = 2.4 Hz, 1 H, Ph-H), 5.03 (d, J
= 7.2 Hz, 1 H, HOC-H), 4.51 (d, J = 7.2 Hz, 1 H, C=NC-H), 2.04
(s, 1 H, CO-H) ppm. HRMS: calcd. for [M + H]+ 473.9699; found
473.9702.
[4]
[5]
[6]
(1R,2S)-1-(3,5-Di-tert-butyl-2-hydroxybenzylideneamino)-2,3-di-
1
hydro-1H-inden-2-ol (L18): M.p. 62–63 °C. H NMR (600 MHz,
CDCl3): δ = 13.12 (s, 1 H, PhO-H), 8.64 (s, 1 H, N=C-H), 7.43–
7.19 (m, 6 H, Ph-H), 4.81 (d, J = 5.1 Hz, 1 H, C=NC-H), 4.70 (m,
1 H, HOC-H), 3.26 (dd, 15.8, 5.8 Hz, 1 H, CH2), 3.14 (dd, 15.8,
4.8 Hz, 1 H, CH2), 2.17 (d, J = 7.0 Hz, 1 H, CO-H), 1.42 (s, 9 H,
tBu), 1.33 (s, 9 H, tBu) ppm. HRMS: calcd. for [M + H]+ 366.2428;
found 366.2436.
4,6-Di-tert-butyl-2-{[(S)-2-hydroxy-1-phenylethylimino]-
methyl}phenol (L19): M.p. 48–49 °C. 1H NMR (400 MHz, CDCl3):
δ = 13.51 (s, 1 H, PhO-H), 8.51 (s, 1 H, N=CH), 7.43–7.29 (m, 6
H, Ph-H), 7.12(d, J = 2.0 Hz, 1 H, Ph-H), 4.47 (dd, J = 7.6, 5.6 Hz,
1 H, C=NC-H), 3.93 (m, 2 H, HOC-H), 2.17 (s, 1 H, CO-H), 1.46
(s, 9 H, tBu), 1.30 (s, 9 H, tBu) ppm. HRMS: calcd. for [M + H]+
354.2428; found 354.2434.
Acknowledgments
The authors thank the National Natural Science Foundation of
China (grant nos. 20225206, 20472056, and 20390055), the Minis-
try of Education, P. R. China (grant nos. 104209, 20030610021, and
others), and the Foundation of Institute of Chemical Materials (SJ
20040309) for financial support. We are also grateful to Prof. Guo-
lin Zhang of Chengdu Institute of Biology, Chinese Academy of
Sciences, China, for fruitful discussion.
[7]
[8]
a) Y. Huang, A. K. Unni, A. N. Thadani, V. H. Rawal, Nature
2003, 424, 146–146; b) K. Juhl, K. A. Jørgensen, Angew. Chem.
Int. Ed. 2003, 42, 1498–1501.
a) M. A. McCarrick, Y.-D. Wu, K. N. Houk, J. Am. Chem.
Soc. 1992, 114, 1499–1500; b) M. A. McCarrick, Y.-D. Wu,
K. N. Houk, J. Org. Chem. 1993, 58, 3330–3343; c) G. Ujaque,
P. S. Lee, K. N. Houk, M. F. Hentemann, S. J. Danishefsky,
Chem. Eur. J. 2002, 8, 3423–3430; d) L. F. Tietze, A. Schuffen-
hauer, P. R. Schreiner, J. Am. Chem. Soc. 1998, 120, 7952–7958;
e) M. Roberson, A. S. Jepsen, K. A. Jørgensen, Tetrahedron
2001, 57, 907–913.
a) K. U. Bindeseil, A. Zeeck, Helv. Chim. Acta 1993, 76, 150–
157; b) F. E. Boyer, J. V. N. V. Prasad, J. M. Domagala, E. L.
Ellsworth, C. Gajda, S. E. Hagen, L. J. Markoski, B. D. Tait,
E. A. Lunney, A. Palovsky, D. Ferguson, N. Graham, T. Holler,
D. Hupe, C. Nouhan, P. J. Tummino, A. Urumov, E. Zeikus,
G. Zeikus, S. J. Gracheck, J. M. Sanders, S. V. Roest, J. Brod-
fuehrer, K. Iyer, M. Sinz, S. V. Gulnik, J. W. Erickson, J. Med.
Chem. 2000, 43, 843–858; c) J. M. Harris, G. A. O’Doherty,
Tetrahedron Lett. 2000, 41, 183–187; d) K. Yasui, Y. Tamura,
[1] a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley,
New York, 1994; b) Catalysis Asymmetric Synthesis (Ed.: I.
Ojima), 2nd ed., Wiley-VCH, New York, 2000; c) H. B. Kagan,
Comprehensive Organic Chemistry, Pergamon, Oxford, 1992,
vol. 8; d) Comprehensive Asymmetric Catalysis (Eds.: E. N. Ja-
cobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999, vols.
I–III.
[2] For some reviews on the hetero-Diels–Alder reaction, see: a)
E. J. Corey, Angew. Chem. 2002, 114, 1724–1741; Angew. Chem.
Int. Ed. 2002, 41, 1650–1667; b) K. C. Nicolaou, S. A. Snyder,
T. Montagnon, G. Vassilikogiannakis, Angew. Chem. 2002, 114,
1742–1773; Angew. Chem. Int. Ed. 2002, 41, 1668–1698; c)
[9]
Eur. J. Org. Chem. 2005, 3542–3552
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3551

Q. Fan, L. Lin, J. Liu, Y. Huang, X. Feng
FULL PAPER
T. Nakatani, K. Kawada, M. Ohtani, J. Org. Chem. 1995, 60,
7567–7574; e) X.-P. Fang, J. E. Anderson, C.-J. Chang, J. L.
McLaughlin, P. E. Fanwick, J. Nat. Prod. 1991, 54, 1034–1043;
f) A. D. Argoudelis, J. F. Zieserl, Tetrahedron Lett. 1966, 7,
1969–1975; g) S. Takano, T. kamikubo, T. Sugihara, K. Ogasa-
wara, Tetrahedron: Asymmetry 1992, 3, 853–856; h) Y. Kato, Y.
Ogawa, T. Imada, S. Iwasaki, N. Shimazaki, H. Kobayashi, T.
Komai, J. Antibiot. 1991, 44, 66–75.
[15] a) Y.-Z. Jiang, X.-G. Zhou, W.-H. Hu, L.-J. Wu, A.-Q. Mi,
Tetrahedron: Asymmetry 1995, 6, 405–408; b) D. A. Cogan, G.-
C. Liu, K. Kim, B. J. Backes, J. A. Ellman, J. Am. Chem. Soc.
1998, 120, 8011–8019.
[16] The reaction procedure is as follows: [Ti(OiPr)4] (50 μL, 1 m
in toluene, 0.05 mmol) was stirred with (R)-BINOL (28.6 mg,
0.1 mmol) in TBME (0.5 mL) at 35 °C under nitrogen for 1 h.
The mixture was then cooled to room temperature, and isobu-
tyral (22 μL, 0.25 mmol) and 0.5 mL of dry TBME were added.
The reaction solution was stirred for 0.5 h, then cooled to
–20 °C, and Brassard diene 1b (85 μL, 0.375 mmol) added. The
reaction mixture was then stirred at 0 °C for 72 h before being
quenched with five drops of TFA. After stirring for an ad-
ditional 2 h, the mixture was neutralized with saturated
NaHCO3 (2 mL), and partitioned between Et2O and water
twice. The combined organic layers were washed with saturated
brine and then dried with anhydrous Na2SO4 and concentrated
in vacuo. The residue was purified by flash chromatography on
silica gel (eluent 3:1 petroleum ether/ethyl acetate) to afford the
cycloadduct 3r in 54% yield with 75% ee [determined by GC
using a Chiralsil DEX CB column (150 °C; tmajor = 24.2 min,
tminor = 25.3 min)].
[10] For some recent work on the synthesis of δ-lactones, see: a) J.
Mulzer, E. Ohler, Chem. Rev. 2003, 103, 3753–3786; b) M.-A.
N’Zoutani, A. Pancrazi, J. Ardisson, Synlett 2001, 769–772; c)
T. K. Chakraborty, S. Tapadar, Tetrahedron Lett. 2003, 44,
2541–2543; d) U. Hanefeld, A. M. Hooper, J. Staunton, Syn-
thesis 1999, 401–403; e) H. Audrain, K. A. Jørgensen, J. Am.
Chem. Soc. 2000, 122, 11543–11544.
[11] J. Savard, P. Brassard, Tetrahedron Lett. 1979, 20, 4911–4914.
[12] a) M. M. Midland, R. S. Graham, J. Am. Chem. Soc. 1984,
106, 4294–4296; b) M. M. Midland, R. W. Koops, J. Org.
Chem. 1990, 55, 4647–4650; c) M. M. Midland, R. W. Koops,
J. Org. Chem. 1990, 55, 5058–5065; d) M. M. Midland, M. M.
Afonso, J. Am. Chem. Soc. 1989, 111, 4368–4371; e) A. Togni,
Organometallics 1990, 9, 3106–3113.
[13] Q. Fan, L.-L. Lin, J. Liu, Y.-Z. Huang, X.-M. Feng, G.-L.
Zhang, Org. Lett. 2004, 6, 2185–2188.
[14] H.-F. Du, D.-B. Zhao, K.-L. Ding, Chem. Eur. J. 2004, 10,
5964–5970.
[17] E. E. Smissman, A. N. Voldeng, J. Org. Chem. 1964, 29, 3161–
3165.
Received: February 18, 2005
Published Online: June 28, 2005
3552
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3542–3552