An efficient and enantioselective approach to 2,5-disubstituted dihydropyrones

Article abstract of DOI:10.1055/s-2004-830869

A highly efficient method for the formation of optically active 2,5-disubstituted dihydropyrones using catalytic enantioselective hetero-Diels-Alder reaction of (E)-3-methyl-4-methoxy-2-[(trimethylsilyl)oxy]-1, 3-butadiene with aldehydes is presented. In the presence of 5 mol% chiral titanium(IV) complex, this catalytic reaction proceeded smoothly to afford corresponding dihydropyrones in moderate to excellent yields with high enantioselectivities (up to 99% ee).

Full text of DOI:10.1055/s-2004-830869

1772
LETTER
An Efficient and Enantioselective Approach to 2,5-Disubstituted
Dihydropyrones
Efficient
a
nd En
h
antioselectiv
e
e
A
pproach
n
to 2,5-Disu
g
bstituted
D
ih
y
ydropyrone
s
an Fu,a Bo Gao,a Zhipeng Yu,a Lan Yu,a Yaozhong Huang,a Xiaoming Feng,*a,b Guolin Zhangc
a
Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, P. R. of China
Fax +86(28)85418249; E-mail: xmfeng@scu.edu.cn
b
c
State Key Laboratory of Applied Organic Chemistry, Lanzhou 730000, P. R. of China
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Received 19 April 2004
electron demand hetero-Diels–Alder reaction,5a–e respec-
tively. Many chiral diol titanium(IV) complexes were
found to be efficient for solvent-free enantioselective het-
ero-Diels–Alder reaction of Danishfsky’s diene through
Abstract: A highly efficient method for the formation of optically
active 2,5-disubstituted dihydropyrones using catalytic enantiose-
lective hetero-Diels–Alder reaction of (E)-3-methyl-4-methoxy-2-
[(trimethylsilyl)oxy]-1,3-butadiene with aldehydes is presented. In
the presence of 5 mol% chiral titanium(IV) complex, this catalytic high-throughput screening by Ding et al.3s Recently,
reaction proceeded smoothly to afford corresponding dihydropy-
Jørgensen et al. presented chiral pyrrolidines catalyzed
rones in moderate to excellent yields with high enantioselectivities
(up to 99% ee).
hetero-Diels–Alder reactions of aldehydes with enones to
give highly functionalized, optically active molecules
with excellent diastereo- and enantioselectivity.5g
Key words: hetero-Diels–Alder reaction, titanium complex, asym-
metric catalysis, dihydropyrones
Although, chiral 2,5-disubstituted dihydropyrone deriva-
tives (up to 84% ee) have been prepared by Danishefsky
et al. using the chiral auxiliary–chiral catalyst combina-
The interest in developing efficient synthetic methods for
tion strategy,1a the asymmetric synthesis of this series has
the formation of optically active dihydropyrones is due to
not been fully studied. Herein, we report our preliminary
the importance of these compounds in organic synthesis,
study on the highly enantioselective synthesis of these
especially in carbohydrate synthesis.1 These compounds
compounds by hetero-Diels–Alder reaction using chiral
are usually prepared by hetero-Diels–Alder reactions of
BINOL–Ti(IV) complex.
activated dienes (such as Danishefsky’s diene) with alde-
hydes or ketones.2 During the last two decades, asymmet-
ric catalysis of this reaction has been reported by a number
of groups.3–7 Corey et al. found that the tryptophan-de-
rived oxazaborolidine catalyst gave good yields and mod-
erate enantioselectivities for the reaction of Danishefsky’s
diene with representative aldehydes.3e Keck et al. reported
that catalyst generated using 2:1 BINOL-Ti(Oi-Pr)4 in the
presence of 4 Å MS and 0.003 equivalents of TFA led to
2-substituted dihydropyrones with good to excellent
enantiomeric excesses.3h Ghosh’s group demonstrated the
utility of bisoxazoline-derived chiral catalysts in hetero-
Diels–Alder reactions with glyoxylate esters.3i Mikami
and co-workers described the critical importance of the
chiral activators for the titanium(IV) catalysis of Diels–
Alder reactions of the Danishefsky’s diene and glyoxy-
late.3j Jacobsen’s group developed a series of chiral tet-
radentate and tridentate Schiff base chromium(III)
complexes, which could afford hetero-Diels–Alder
products3l,m and inverse electron demand hetero-Diels–
Alder products5f with good to excellent enantioselectivi-
ties. In the studies of Jørgensen’s group and Evans’ group,
C2-symmetric bisoxazoline-metal complexes were widely
used in hetero-Diels–Alder reaction4a,b,6a,c,d and inverse
At first, diene 3 was prepared according to the reported
procedure (Scheme 1).8 The initial material butan-2-one
(1) was treated with 1.5 equivalents of NaH (60% disper-
sion in mineral oil) and 3.0 equivalents of methyl formate
in THF at –10 °C to give off-white solid, which was treat-
ed, after the solvent was replaced by DMF, with dimethyl
sulfate to give (E)-3-methyl-4-methoxy-3-buten-2-one
(2). After being purified by column chromatography over
activated aluminum oxide (neutral), the butenone 2 was
transformed into (E)-3-methyl-4-methoxy-2-[(trimethyl-
silyl)oxy]-1,3-butadiene (3) by treatment with 1.1 equiva-
lents of LDA in THF at –78 °C followed by addition of
Me3SiCl. The crude diene 3 was purified by vacuum
distillation, bp 68 °C (14 mmHg).9
OMe
(1) HCO2Me, NaH, THF, –10 °C
(2) (MeO)2SO2, DMF, 0 °C
O
O
2
1
OMe
(1) LDA, THF, –78 °C
(2) TMSCl, –78 °C to r.t.
Me3SiO
SYNLETT 2004, No. 10, pp 1772–1775
Advanced online publication: 28.07.2004
0
9
.0
8
.2
0
0
4
3
DOI: 10.1055/s-2004-830869; Art ID: U11204ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 The synthesis of diene 3

LETTER
Efficient and Enantioselective Approach to 2,5-Disubstituted Dihydropyrones
1773
Then, benzaldehyde was chosen as test substrate. A Encouraged by the results above, the generality of this cat-
BINOL–Ti(Oi-Pr)4–4 Å MS system was found to be the alyst in catalyzing hetero-Diels–Alder reactions with a va-
most promising catalyst for this reaction. Further studies riety of aldehydes was examined (Table 2). Unsubstituted
showed that several parameters influenced the reactivity aromatic and heteroaromatic aldehydes such as benzalde-
and enantioselectivity of this cycloaddition. The results hyde (entry 1), 2-pyridinecarboxaldehyde (entry 8), 3-py-
are summarized in Table 1. Catalyst generated using 1:1 ridinecarboxaldehyde (entry 9) and 2-furaldehyde (entry
(R)-BINOL–Ti(Oi-Pr)4 stoichiometry promoted this reac- 10) afforded the corresponding dihydropyrones with
tion with moderate enantioselectivity (entry 1). When the higher enantioselectivities. While substituted benzalde-
ratio of (R)-BINOL to Ti(Oi-Pr)4 increased to 1.1:1, good hydes afforded dihydropyrones with lower enantiomeric
enantiomeric excess was achieved (entry 2). And higher excesses (entries 2–7). It should also be noted that 2-sub-
enantiomeric excess was obtained by using a 2:1 ratio (en- stituted benzaldehydes revealed lower enantioselectivities
try 3). This indicates that the activity of this catalyst is (entries 2, 3) than those 4-substituted benzaldehydes (en-
greatly affected by the ratio of ligand to central metal. tries 5–7). These results are consistent with our previous
Considering the hexacoordinated titanium atom, the actu- reports.7
al catalyst might be a BINOL2–Ti(Oi-Pr)2 complex or its
aggregates. Upon the decrease of catalyst loading, the
Table 2 Asymmetric Hetero-Diels–Alder Reactions of Aldehydes10
OMe
yield was somewhat sacrificed, but the enantioselectivity
increased (entries 3, 4). A temperature examination
showed that the reactivity and enantioselectivity were de-
O
(1) 5 mol% (R)-BINOL-Ti(IV),
O
4 Å MS, THF, 0 °C, 48 h
+
R
H
(2) TFA, 12 h
pendent on temperature. The optimal reaction temperature
was 0 °C (entries 4–6). Further, solvent effect study re-
vealed that the reaction performed in the more coordina-
tive THF afforded the product in much higher
enantioselectivity (99% ee, entry 10) than in other sol-
vents (entries 4, 7–9). This might attribute to the geomet-
rical structure of this catalyst, which was changed by the
appropriate solvent.2
Me3SiO
O
R
3
Entry
1
Substrate
Yield (%)a ee (%)b
Benzaldehyde
86
>99
>99
>99
95
99
90
91
91
92
94
96
98
96
97
85
87
2
2-Chlorobenzaldehyde
2-Nitrobenzaldehyde
3-Methoxybenzaldehyde
4-Cyanobenzaldehyde
4-Fluorobenzaldehyde
4-Chlorobenzaldehyde
2-Pyridinecarboxaldehyde
3-Pyridinecarboxaldehyde
2-Furaldehyde
3
Table 1 Asymmetric Hetero-Diels–Alder Reaction of Diene 3 with
Benzaldehyde Promoted by (R)-BINOL–Ti(IV) Complexa
4
5
Entry
Catalyst
loading
(mol%)b
Temp.
(°C)
Solvent
Yield
(%)c
ee
(%)d
6
73
7
66
1
2
10e
10f
10
5
0
0
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
Et2O
93
87
77
82
87
90
91
66
92
89
81
99
8
>99
98
9
3
0
>99
97
10
11
12
>99
47
4
0
(E)-3-Phenyl-2-propenal
n-Hexanal
5
5
–20
25
0
92
41
6
5
60
a Isolated yields.
b Determined by HPLC.
7
5
69
8
5
0
>99
98
In conclusion, we have presented an efficient synthetic
method for the formation of 2,5-disubstituted dihydropy-
rones. The simplicity of the experimental procedure and
the easy availability of the chiral ligand thus render this an
experimentally attractive method for the preparation of
these compounds. In the presence of 5 mol% catalyst, ex-
cellent enantioselectivities of 85–99% ee and high yields
were obtained for aromatic, heteroaromatic, aliphatic and
a,b-unsaturated aldehydes. The mechanism of this system
and methods for the preparation of other kinds of dihydro-
pyrones are now underway.
9
5
0
t-BuOMe
THF
10
5
0
86
a These reactions were carried out in corresponding solvent with a
concentration of 0.25 M, in the presence of 120 mg 4 Å MS for 48 h.
b The ratio of (R)-BINOL to Ti(Oi-Pr)4 was 2:1, unless noted other-
wise.
c Isolated yields.
d The ee values were determined by HPLC using Daicel Chiralcel OJ
column.
e The ratio of (R)-BINOL to Ti(Oi-Pr)4 was 1:1.
f The ratio of (R)-BINOL to Ti(Oi-Pr)4 was 1.1:1.
Synlett 2004, No. 10, 1772–1775 © Thieme Stuttgart · New York

1774
Z. Fu et al.
LETTER
Figure 1
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Acknowledgment
The authors thank the National Natural Science Foundation of
China (NO.20225206, 20390050) and the Ministry of Education,
P. R. China (NO.01144, 104209, 20030610021 and others) for
financial support.
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Synlett 2004, No. 10, 1772–1775 © Thieme Stuttgart · New York

LETTER
Efficient and Enantioselective Approach to 2,5-Disubstituted Dihydropyrones
1775
(7) For recent progresses on asymmetric catalytic hetero-Diels–
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(9) The following are the NMR data of diene 3: 1H NMR (300
MHz, CDCl3): d = 6.52 (s, 1 H), 4.24 (s, 1 H), 4.13 (s, 1 H),
3.68 (s, 3 H), 1.70 (s, 3 H), 0.25 (s, 9 H).
(10) A Typical Experimental Procedure is Given for the
Synthesis of 2,3-Dihydro-5-methyl-2-phenylpyran-4-
one: A mixture of (R)-BINOL (7.2 mg, 0.025 mmol), Ti(Oi-
Pr)4 (1 M in toluene, 12.5 mL, 0.0125 mmol) and finely
powdered 4 Å MS (120 mg) in THF (0.5 mL) was heated at
35 °C for 1 h. After the brown mixture was cooled to –18 °C,
benzaldehyde (26 mL, 0.25 mmol), diene (84 mL) and THF
(0.5 mL) were added successively. The reaction was allowed
to stir at 0 °C for 48 h, after this time it was removed from
the bath, and treated with TFA (100 mL). After stirring 12 h
at r.t., the reaction was quenched with sat. NaHCO3 (5 mL),
filtered through a plug of Celite, extracted with Et2O (10 × 5
mL). The organic layer was dried over Na2SO4 and
concentrated. The crude residue was purified by flash
chromatography (9:1 PEa: Et2O) to yield 2,3-dihydro-5-
methyl-2-phenylpyran-4-one (40.6 mg, 86% yield) as white
crystals. The isolated material was determined to be in 99%
ee by HPLC analysis (Daicel Chiralcel OJ, 254 nm UV
detector, 90:10 hexane:2-propanol, tR(minor) = 15.40 min,
tR(major) = 21.15 min). 1H NMR (600 MHz, CDCl3): d =
7.40–7.46 (m, 5 H), 7.39 (s, 1 H), 5.39–5.42 (m, 1 H), 2.88–
2.94 (m, 1 H), 2.69–2.73 (m, 1 H), 1.76 (s, 3 H). 13C NMR
(150 MHz, CDCl3): d = 192.59, 159.49, 138.27, 128.80,
128.78, 126.05, 114.14, 80.99, 43.21, 10.51. The
chromatograms are illustrated in Figure 1.
Synlett 2004, No. 10, 1772–1775 © Thieme Stuttgart · New York