Organocatalytic approach to 3,5,6-trisubstituted and 4,6-disubstituted tetrahydropyran-2-ones

Article abstract of DOI:10.1016/j.tetlet.2010.05.077

The diarylprolinol ether-catalyzed Michael addition and subsequent cyclization of ethyl 3-methyl-2-oxobut-3-enoate with aldehydes, and γ-substituted β,γ-unsaturated-α-ketoesters with acetaldehyde, afforded the corresponding lactals, which were subjected t

Full text of DOI:10.1016/j.tetlet.2010.05.077

Tetrahedron Letters 51 (2010) 3827–3829
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Organocatalytic approach to 3,5,6-trisubstituted and 4,6-disubstituted
tetrahydropyran-2-ones
b,
Danhua Xu a, Yihua Zhang a, , Dawei Ma
*
*
a Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The diarylprolinol ether-catalyzed Michael addition and subsequent cyclization of ethyl 3-methyl-2-oxo-
Received 21 April 2010
Revised 17 May 2010
Accepted 18 May 2010
but-3-enoate with aldehydes, and c-substituted b,c-unsaturated-a-ketoesters with acetaldehyde, affor-
ded the corresponding lactals, which were subjected to oxidation and stereocontrolled hydrogenation
to provide 3,5,6-trisubstituted and 4,6-disubstituted tetrahydropyran-2-ones with excellent
enantioselectivities.
Ó 2010 Elsevier Ltd. All rights reserved.
The syn-1,3-dimethyl moiety has been frequently found in nat-
ural products, particularly the deoxypolyketides.1 This fact has
stimulated numerous investigations for developing new methods
tions, this molecule is obviously useful for assembling some known
syn-1,3-dimethyl building blocks.2–10
We initialed our experiment by screening suitable conditions for
the organocatalytic reaction of 2a and 3. As summarized in Table 1,
under our previous conditions,12b this reaction completed in 8.5 h,
affording 4a in 92% yield and 90% ee (entry 1). Changing solvent to
methanol, DMF, 1,4-dioxane, or THF did not improve the results
(entries 2–5). However, better enantioselectivities were observed
by using chloroform and toluene as the solvent, although the reac-
tion yields dropped slightly (entries 6 and 7). Switching the catalyst
from 1a to 1b gave a similar result, but prolonging the reaction time
was required (entry 8). When catalyst 1c was utilized, the reaction
turned to be more sluggish (entry 9). Using acids as the additives
is beneficial for this reaction, as evident from that a longer reaction
time was needed in the absence of the additives (compare entries 6,
to construct functionalized chirons with
a syn-1,3-dimethyl
unit.2–10 The typical approaches to these building blocks were
heavily relied on chiral auxiliary-induced stereoselective enolate
alkylations and conjugate additions,2,3 asymmetric allylic substitu-
tion,2,4 as well as enzymatic resolution of the corresponding meso-
diols.5 Recently, some catalytic methods have been developed,
which include copper-catalyzed hetero Diels–Alder reaction of
(Z)-1-ethoxyprop-1-ene with ethyl 3-methyl-2-oxobut-3-enoate,6
asymmetric carboalumination–vinylation tandem process of sty-
rene,7 catalytic organocuprate addition of
a,b-unsaturated thioes-
ters,8 enantioselective hydrogenation of polyene compounds9,
and desymmetrization of meso-3,5-dimethyl glutaric anhydride.10
In the past decade great progress has been achieved in the
development of organocatalytic asymmetric reactions, which pro-
vide new opportunity for elaborating a variety of chiral building
blocks in a more efficient and inexpensive manner.11 During the
investigations on the enamine-based Michael reactions,12 we be-
came interested in the assembly of syn-1,3-dimethyl chiron 6a
by using a cascade Michael addition and cyclization12b (or het-
ero-Diels–Alder reaction as proposed by Juhl and Jørgensen13) pro-
cess. As depicted in Scheme 1, we envisaged that if the reaction of
propionaldehyde 2a and ethyl 3-methyl-2-oxobut-3-enoate 3 pro-
ceeded well to afford cyclic semi-acetal 4a with high enantioselec-
tivity, 6a could be obtained after oxidation of its semi-acetal unit
and subsequent diastereoselective hydrogenation of its C–C double
bond. Since its two ester groups are ready for further transforma-
O
HO
O
CO2Et
CHO
O
1/additive
oxidation
OEt
+
2a
4a
3
O
O
CO2Et
O
O
CO2Et
hydrogenation
6a
5a
OTMS
Ar
N
H
Ar
1a: Ar = Ph
1b: Ar = 2-naphtyl
1c: Ar = 3,5-(CF3)2C6H3
* Corresponding authors.
E-mail address: madw@mail.sioc.ac.cn (D. Ma).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.077

3828
D. Xu et al. / Tetrahedron Letters 51 (2010) 3827–3829
Table 1
Table 2
Organocatalytic reaction of propionaldehyde 2a and enone 3 under different reaction
Synthesis of 3,5,6-trisubstituted tetrahydropyran-2-onesa
conditionsa
O
1. RCH2CHO, 1a, PhCO2H, CHCl3
O
R
O
CO2Et
O
Entry
Solvent
Catalyst/additive
t (h)
Yieldb (%)
eec (%)
OEt
2. Dess-Martin periodinane
3. Pd/C, H2
1
2
3
4
5
6
7
8
9
H2O
MeOH
DMF
1,4-Dioxane
THF
CHCl3
Toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
1a/PhCO2H
1a/PhCO2H
1a/PhCO2H
1a/PhCO2H
1a/PhCO2H
1a/PhCO2H
1a/PhCO2H
1b/PhCO2H
1c/PhCO2H
1a/—d
8.5
14
72
15
72
20
16
33
48
47
24
72
92
85
63
77
77
78
72
72
50
77
87
38
90
87
75
91
90
96
95
95
97
89
88
94
3
6
Entry
R (product)
Et (6b)
n-Pr (6c)
i-Pr (6d)
Bn (6e)
Yieldb (%)
eec (%)
drd
1
2
3
4
5
48
41
29
30
25
>99
99
96
98
99
89:11
96:2:2
89:7:2:2
94:6
10
11
12
n-C9H19 (6f)
98:1.5:0.5
1a/AcOH
1a/AcONa
a
Reaction conditions:
1
(0.06 mmol), aldehyde 2 (1.2 mmol), enone 3
(0.6 mmol), PhCO2H (0.12 mmol), CHCl3 (0.6 mL), 0 °C for 1 h, and then rt for about
a
Reaction conditions: 1 (0.06 mmol), propionaldehyde 2a (1.2 mmol), enone 3
30 h.
(0.6 mmol), additive (0.12 mmol), solvent (0. 6 mL), 0 °C for 1 h, and then rt for
b
Isolated overall yield for three steps.
Determined by chiral-phase HPLC analysis of 5.
Determined by GC.
indicated time.
c
b
Isolated yield for 4a.
Determined by chiral-phase HPLC analysis of 5a.
No additive was used.
d
c
d
Table 3
Organocatalytic reaction of acetaldehyde and enone 7a under different reaction
10 and 11). Switching the additives from benzoic acid to acetic acid
or sodium acetate led to a decrease in enantioselectivity (entry 11)
or yield (entry 12).
conditionsa
O
CH3CHO
10 mol % 1a
HO
O
CO2Et
O
O
CO2Et
O
PCC
After identifying 1a, benzoic acid, and CHCl3 as the optimized
combination, a gram-scale reaction was conducted (Scheme 2). In
this case 4a was isolated with almost the same yield and enanti-
oselectivity. After oxidation of 4a with Dess–Martin periodinane,
we were pleased to observe that Pd/C-catalyzed hydrogenation of
5a took place in a highly diastereoselective manner. The ratio for
6a and its two detectable isomers was about 99:0.3:0.7 as deter-
mined by GC–MS analysis. The stereochemistry of 6a was proposed
by mechanism analysis and further confirmed by NOESY studies.
Other aldehydes were then examined for synthesizing 3,5,6-tri-
substituted tetrahydropyran-2-ones. As shown in Table 2, they all
gave the desired products with excellent enantioselectivities. How-
ever, diastereoselectivities at the hydrogenation step are slightly
different, although the reason is not yet clear.
OEt
7a
9a
8a
Entry
Solvent
Additive
t (h)
Yieldb(%)
eec (%)
d
1
2
3
4
5
6
7
8
1,4-Dioxane
MeCN
n-Hexane
Toluene
CHCl3
CHCl3
CHCl3
CHCl3
—
—
—
45
17
24
69
24
12
25
10
43
41
52
44
63
43
43
45
95
94
92
95
96
94
96
96
d
d
d
—
d
—
PhCO2H
AcOH
AcONa
a
Reaction conditions:
1 (0.06 mmol), acetaldehyde (6 mmol), enone 7a
(0.6 mmol), additive (0.12 mmol), solvent (0.12 mL), 0 °C for 1 h, and then rt for
We next explored the possibility of diarylprolinol ether-cata-
lyzed reaction between acetaldehyde and (E)-ethyl 2-oxopent-3-
enoate 7a. The purpose for this attempt is to develop a facile route
to 4-methyl tetrahydropyran-2-one 10a. This is a challenging task
because some side reactions may occur due to the high reactivity of
acetaldehyde as both a nucleophile and an electrophile. Only very
recently this special aldehyde was identified as a suitable substrate
for organocatalytic asymmetric reactions.14 To our delight, reaction
of 7a with acetaldehyde proceeded smoothly under the same con-
ditions used for Michael addition of nitroolefins with acetaldehyde
by Hayashi et al.14c (Table 3, entry 1) and List and co-workers14d
(entry 2), delivering the desired lactal 8a with 94–95% ee. How-
ever, reaction yields were not satisfactory in these cases. Changing
solvent to less polar n-hexane and toluene gave similar results (en-
tries 3 and 4). The best result was observed by using chloroform as
the solvent (entry 5). Interestingly, introduction of additives led to
decrease in reaction yields (entries 6–8).
indicated time.
b
Isolated yield for 8a.
Determined by chiral-phase HPLC analysis of 9a.
No additive was used.
c
d
Table 4
Synthesis of 4,6-disubstituted tetrahydropyran-2-onesa
O
1. CH3CHO, 1a, CHCl3
O
O
R
CO2Et
O
OEt
2. PCC or Dess-Martin periodinane
3. Pd/C, H2
10
7
R
Entry
R (product)
Yield (%) 1st/2nd/3rd stepb
eec (%)
drd
1
2
3
4
Me (10a)
Ph (10b)
i-Pr (10c)
n-Bu (10d)
63/67/49e
64/57/66e
78/55/48e
77/31/56e
96
97
96
96
5:1
4:1
4:1
4:1
Oxidation of 8a with PCC afforded lactone 9a in 67% yield,
which was hydrogenated to give a mixture of 10a and its trans-iso-
a
Reaction conditions:
1 (0.06 mmol), acetaldehyde (6 mmol), enone 7 (0.6
mmol), CHCl3 (0.12 mL), 0 °C for 1 h, and then rt for about 30 h.
b
Isolated yield.
c
Determined by chiral-phase HPLC analysis of 9.
d
Determined by 1H NMR.
HO
O
CO2Et
O
O
CO2Et
1. Dess-Martin oxidation
e
For pure cis-isomer.
2. Pd/C, H2
69%
4a
6a
gram scale, dr 99:0.3:0.7
mer in a ratio of 5:1. The pure 10a could be isolated by column
chromatography with 49% yield (Table 4, entry 1). Starting from
Scheme 2.

D. Xu et al. / Tetrahedron Letters 51 (2010) 3827–3829
3829
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The authors are grateful to the Ministry of Science and Technol-
ogy (Grant 2009ZX09501-00), Chinese Academy of Sciences, and
National Natural Science Foundation of China (Grant 20632050 &
20921091) for their financial support.
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