A TBAF-mediated chemoselective method for synthesis of 4-methylbutenolides and 4-hydroxy-4-methylbutenolides from 3-hydroxy-4-(tert-butyldimethylsilyloxy) pentanoates

Article abstract of DOI:10.1246/cl.2007.1058

A chemoselective synthesis of butenolides was found based on TBAF-mediated deprotection, cyclization, dehydration, and oxidation of 3-hydroxy-4-(tert- butyldimethylsilyloxy)-pentanoates, which yielded either 4-methylbutenolides or 4-hydroxy-4-methylbuteno

Full text of DOI:10.1246/cl.2007.1058

1058
Chemistry Letters Vol.36, No.8 (2007)
A TBAF-mediated Chemoselective Method for Synthesis
of 4-Methylbutenolides and 4-Hydroxy-4-methylbutenolides
from 3-Hydroxy-4-(tert-butyldimethylsilyloxy)pentanoates
Chunhong Li, Jijun Xue, Baiyan Xu, Zhixiang Xie, and Ying Liꢀ
State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, Gansu 730000, P. R. China
(Received May 10, 2007; CL-070508; E-mail: liying@lzu.du.cn)
A chemoselective synthesis of butenolides was found
Table 1. Investigation of chemoselectivity of the reaction
based on TBAF-mediated deprotection, cyclization, dehydra-
tion, and oxidation of 3-hydroxy-4-(tert-butyldimethylsilyloxy)-
pentanoates, which yielded either 4-methylbutenolides or 4-hy-
droxy-4-methylbutenolides in moderate to good yields. The
selectivity depends on the quantity of TBAF. This method was
applied to the synthesis of several 4-butenolide compounds.
Fluoride
HO
OH
HO
OTBS
OMe
reagent
+
+
O
O
O
THF
O
O
O
O
1a
4a
3a
2a
Fluoride Amount Temp Time Main product
/ꢂC /min
Entry
reagents
/equiv.
(yielda/%)
1
2
3
4
5
6
7
8
9
TBAF
TBAF
TBAF
TBAF
TBAF
1.2
1.2
2.0
2.5
4.0
1.0
4.0
1.0
4.0
20b
0b
30
55
30
30
30
30
30
30
30
2a (75)
2a (75)
3a (59)
3a (70)
4a (67)
2a (56)
2a (78)
2a (56)
2a (87)
Annonaceous acetogenins belong to the family of natural
polyketides, which contain either 4-methylbutenolides or 4-hy-
droxy-4-methylbutenolides at one terminal of the linear struc-
ture.1 A broadened spectrum of activities caused by annonaceous
acetogenins has been reported, including anticancer, immuno-
suppressant, anti-malarial, pestitcidal, and so on. Many acetoge-
nins present good to excellent toxicity against various tumor
cells. For example, asiminacin, a 4-methylbutenolide acetoge-
nin, showed IC50 in the 10ꢁ12 mg/mL range against KB cell.2a
And anmontanins B, C have highly potent anti-influenza and
anti-insomnia activities.2b
Although there are many strategies established for the
construction of 4-methylbutenolides3 and 4-hydroxy-4-methyl-
butenolides,4 to our knowledge, chemoselective synthesis of 4-
methylbutenolide and 4-hydroxy-4-methylbutenolides from the
same substrate based on one-pot reactions has not been reported.
When we investigated the deprotection of TBS on 1a by
TBAF,5 interestingly, besides the desired lactone 2a, two
unexpected products 3a and 4a were also isolated. After a detail
exploration on this discovery, we will report a new method
to chemoselectively synthesize 4-methylbutenolides and 4-
20
20
20
20
20
20
20
.
BF3 Et2O
.
BF3 Et2O
PyꢃHF
PyꢃHF
b
aIsolated yield. Reaction temperature has no obvious influ-
ence on the selectivity and yield, but the reaction rate increas-
ed with the raising of temperature.
Table 2. Chemoselectivity investigation with different sub-
stratesa
OH
HO
R
HO
R
TBAF
OTBS
O
O
+
O
+
OMe THF, r.t.
R
R
O
O
O
O
hydroxy-4-methylbutenolides based on
one-pot reaction.
a TBAF-mediated
1
3
4
2
d: R=
e:
c: R=
O
b: R=
OTBS
Using compound 1a as substrate, we examined the effects of
different temperature, fluoride reagents and their quantities on
the yield of 4-methylbutenolide 3a and 4-hydroxy-4-methyl-bu-
tenolides 4a (Table 1). The chemo-selectivity depends on the
quantity of TBAF. 2a was the main product when less than 2
equiv. of TBAF was used (Entries 1 and 2, Table 1). 3a was ob-
tained in more than 50% yield when 1a was treated with more
than 2 equiv. of TBAF (Entries 3 and 4, Table 1). And more than
4 equiv. of TBAF caused mainly the formation of 4a (Entry 5,
*
*
R=Ph
8
7
O
TBAF
/equiv.
Main product
(yieldb/%)
Entry
Substrate
1
2
3
4
5
6
7
8
9
1b
1b
1b
1c
1c
1d
1d
1e
1e
1.5
2.5
4.0
2.5
4.0
3.5
5.0
1.2
3.0
2b (72) and 3b (9)
3b (66)
4b (60)
3c (78)
4c (76)
3d (85)
4d (69)
3e (83)
4e (72)
6
7
.
.
Table 1). Different from TBAF, BF3 Et2O, and Py HF only
gave cyclization product 2a in moderate to good yields when
the amounts of reagents were varied from 1 to 4 equiv. (Entries
6–9, Table 1).
To further demonstrate the application of this reaction, more
substrates were examined under the modified reaction condition.
Very good results were obtained (Table 2). Using 1.5 equiv. of
aReaction temperature is 20 ꢂC and reaction time is 30 min.
bIsolated yield.
Copyright ꢀ 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.8 (2007)
1059
R
amounts of TBAF. The mechanism was also suggested and
TBAF functionalized as both desilylative reagents and Lewis
base. This method will serve as a complement to the existing
methodologies and find wide applications in organic synthesis.
R
R
R
1O2
NBu4
O
O
O
NBu4
O
O
O
O
O
O
O
O
H
7
6
OH
3
5
OH
R
PPh3
Project 20672050 supported by the National Natural Science
Foundation of China.
HO
Ph3PO
O
O
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4
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Scheme 1. Supposed mechanism of the formation of 4a–4e.
TBAF, 1b was mainly converted to 2b along with a little of 3b
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converted to 3e easily. This is due to the phenyl group of 3e.
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and the released free hydroxy group attacked the ester group
intramolecularly to established lactone 2a. Subsequently, the
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4
5
6
When total 4.5 equiv. of TBAF were used to treat compound
1a in three portions (1.5 equiv. Every 30 min), 2a, 3a, and 4a
were observed as major products in turn by TLC. This showed
that compound 3a came from 2a and converted to 4a. So the
mechanism of the formation of 4a was supposed as following
(Scheme 1): 3a was enolized by TBAF11 to form a furan
intermediate 5,12 which sensitized O2 as that Hart and Young13
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atmosphere. Under dark to avoid light, also no 4 obtained. These
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In conclusion, a cost-effective and convenient method was
found for chemoselectivity form the corresponding products:
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hydroxy-4-methylbutenolides, respectively depending on the
7
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Published on the web (Advance View) July 21, 2007; doi:10.1246/cl.2007.1058