Mucohalic acid in Lewis acid catalyzed Mukaiyama aldol reaction: A concise method for highly functionalized γ-substituted γ-butenolides

Article abstract of DOI:10.1016/j.tetlet.2005.01.147

The first Mukaiyama aldol reaction on mucohalic acid (1a/b) has been achieved. Reaction of 1 with various ketene silyl acetals or silyl enol ethers in the presence of a Lewis acid provides the γ-substituted γ-butenolides in good to excellent yield.

Full text of DOI:10.1016/j.tetlet.2005.01.147

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2029–2032
Mucohalic acid in Lewis acid catalyzed Mukaiyama
aldol reaction: a concise method for highly functionalized
c-substituted c-butenolides
Paul Angell, Ji Zhang,* Daniel Belmont, Timothy Curran and James G. Davidson
Chemical Research and Development, Pfizer Global Research and Development, Michigan Laboratories, Pfizer, Inc.,
2800 Plymouth Road, Ann Arbor, MI 48105, USA
Received 4 October 2004; accepted 27 January 2005
Abstract—The first Mukaiyama aldol reaction on mucohalic acid (1a/b) has been achieved. Reaction of 1 with various ketene silyl
acetals or silyl enol ethers in the presence of a Lewis acid provides the c-substituted c-butenolides in good to excellent yield.
Ó 2005 Elsevier Ltd. All rights reserved.
The great importance of substituted c-butyrolactones
O
O
(c-butanolides or c-lactones)1 and a,b-unsaturated c-
lactones (c-butenolides)2 has attracted much attention
for synthetic organic and medicinal chemists. Both
c-butyrolactones and c-butenolides appear in a large
variety of biologically active natural products, such as
(À)-roccellaric acid,3,4b phaseolinic acid,4 asimicin,5a
bullatacin,5a squamotacin,5b trilobin,5c and enrollment
as pharmaceuticals, for example, Vioxx6 and endothelin
antagonists.7 Meanwhile, they are prominent moieties in
the building of natural flavors and odors, including sex
attractant pheromones of some species of insects,8 which
may prove beneficial for developing environmentally
friendly insecticides. Furthermore c-butenolides have
been employed to make some functionalized open-chain
molecules, such as 1,4-solfanylalcohols,9 compounds
found in fruits and vegetables and have been the subject
of intense research in flavor chemistry. On the other
hand, c-butyrolactones also serve as precursors to fused
bicyclic lactones, such as dihydrocanadensolide, isoave-
nociolide, ethisolide,10 and avenaciolide.10,11 Mucohalic
acids 1a/b (Fig. 1) are two highly functionalized mole-
cules and can be viewed as a,b-unsaturated aldehydes
and pseudo unsaturated c-lactones which make them
ideal as the building blocks to access highly functional-
ized c-substituted c-butenolides.12
O
O
X
X
X
X
OH
H
OTMS
O
O
R2
R3
OH
1a X=Cl
1b X=Br
O
OR*
2
R*=menthyl
3
R2=H, Me
R3=H, Me
1a' X=Cl
1b' X=Br
Figure 1. Mucohalic acid (1) and some related compounds used in
Mukaiyama aldol reaction.
It is unlikely for the Grignard reagents attacking the
aldehyde C@O functional group of mucohalic acid to
form the c-substituted c-butenolides since the other
functional groups, vinyl halides are sensitive to nucleo-
philes.13 Additionally, it is very unlikely to apply the
classic aldol reaction to 1a/b, the base catalyzed conden-
sation of one carbonyl compound with the enolate/enol
of another, to generate a c-butenolide since mucohalic
acids have poor stability under basic conditions. Under-
standing the stability issues of mucohalic acid allowed us
to rapidly focus our attention to investigate the Lewis
acid catalyzed Mukaiyama aldol reaction.14 We rea-
soned these conditions would enable aldehyde C@O
bond activation and its aldol reaction rather than the
nucleophilic replacement of the halogen atoms in a- or
b-positions. To our best knowledge, there are very few
reports regarding the use of this approach to form c-
butenolides. van Oeveren and Feringa15a reported
the asymmetric synthesis of c-substituted c-buten-
olides via Mukaiyama aldol type reaction where
Keywords: Mucohalic acid; Mukaiyama aldol; Butenolides; Lewis acid.
*
Corresponding author. Tel.: +1 734 622 3940; fax: +1 734 622
3294; e-mail: ji.zhang@pfizer.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.147

2030
P. Angell et al. / Tetrahedron Letters 46 (2005) 2029–2032
Table 1. Mukaiyama aldol reaction-Lewis acid studya
5(R)-(menthyloxy)-2(5H)-furanone 2 was the chiral syn-
thon; Evans et al.15b described the synthesis of enantio-
merically pure c-substituted c-butenolides using silox-
yfuran 3 and C2-symmetric Cu(II) complexes. van der
O
O
OTMS
R1
Cl
Cl
Cl
Cl
R2
O
O
LA
Ohe and Bruckner reported a Mukaiyama aldol addi-
¨
tion/anti-elimination route to c-alkylidenebutenolides
+
O
R3
R2
OH
where siloxyfuran 3 was the starting material (Fig. 1).16
4a, R1=OMe
R2=R3=Me
4d, R1=Ph
R2=R3=H
R1
R3
5a or 5d
1a
In this letter, we describe our results of Lewis acid cata-
lyzed Mukaiyama aldol reaction where mucohalic acids
1a/b, inexpensive and commercially available starting
materials act as aldehydes (Scheme 1). Having easy
access to c-substituted c-butenolide with a- and b-acti-
vated functional groups should enable the preparation
of potentially more complex molecules containing this
skeleton.
Entry (1a+4a)
Catalyst
1ab
5ab
1
La(OTf)3
Mg(OTf)2
Sc(OTf)3
TiCl4
92
95
14
39
7
3
1
2
3
84
58
88
52
7
4
5
ZnCl2
Zn(OTf)2
InCl3
6
41
89
28
Ã72
7
Mucohalic acid 1a/b can exist either as the open or cyclic
form; however, it is accepted and confirmed that 1 exists
predominantly in the lactone form. Thus, the Lewis
acid-promoted reaction between ketene silyl acetal
(KSA) or silyl enol ether (SEE) and mucohalic acid
can be viewed as a nucleophilic reaction of a hemiacetal.
8
Sn(OTf)2
BF3ÆOEt2
None
70
17
ND
1
9
10
11
Pd(CF3CO2)2
97
* Only silylated 1a was observed.
a Reaction conditions: 1 mmol scale; 0.25 M in PhMe (KSA) or Et2O
(SEE), 2.0 equiv 4, 10 mol % catalyst; reactions were stirred at
À20 °C for 2 h then at rt for 3 h.
Lewis acid screening work was carried out using methyl
trimethylsilyldimethyl ketene acetal 4a for a representa-
tive KSA and the SEE 1-phenyl-1-(trimethylsilyl-
oxy)ethylene 4d. These two nucleophiles were chosen
because both are commercially available. Initial applica-
tion of Mukaiyama-aldol conditions toward mucochlo-
ric acid (1a) led to a key observation—the reaction is
catalyzed by Lewis acid in substoichiometric levels.
The catalyst screening for the representative KSA is
shown in Table 1. Among the Lewis acids screened,
ZnCl2 and Sc(OTf)3 were superior providing 88% and
84%, respectively, of the desired lactone 5a.17 Three
other catalysts, Sn(OTf)2, TiCl4, and Zn(OTf)2 provided
70%, 58%, and 52% of 5a, respectively. Although the
remaining catalysts, provided small amounts of 5a, they
were not synthetically useful at this substoichiometric
level.18
b Yield was determined by HPLC (215 nm). ND (none detected).
In order to find appropriate and reliable conditions for
the Mukaiyama aldol reaction on mucohalic acid 1a/b,
further studies were undertaken to determine two other
reaction parameters: temperature and solvent. Since
ZnCl2 and Sc(OTf)3 were shown to be highly effective
catalysts in initial screening experiments they were used
in determining the temperature/solvent semi-optimiza-
tion conditions.
The result of the temperature screen showed very little
effect from À30 < T < 20 °C for either KSA or SEE
(Table 2). Only slightly better conversions were observed
Table 2. Mukaiyama aldol with KSA/SEE-temperature studya
Surprisingly, ZnCl2 is not an efficient catalyst for the
reaction between SEE 4d and mucohalic acid, providing
only 43% product 5d. The result of the catalyst screening
for SEE 4d (see Supporting material) shows that
Sc(OTf)3 was superior providing 79% of the desired lac-
tone 5d. Other catalysts, InCl3 and Sn(OTf)2, provided
5d in 64% and 61% yield, respectively. The remaining
catalysts were inferior at this substoichiometric level.
Based on these results, we decided to use ZnCl2 as the
Lewis acid when KSA was the nucleophile and Sc(OTf)3
when SEE was used.
O
O
OTMS
R1
Cl
Cl
Cl
Cl
R2
O
O
LA
+
O
R3
CH2Cl2
R2
OH
4a, R1=OMe
R2=R3=Me
4d, R1=Ph
R2=R3=H
R1
R3
5a or 5d
1a
Entry
T (°C)
5ab (%)
Entry
T (°C)
5db (%)
1
2
3
4
5
À30
À10
0
94
94
92
89
84
6
7
À30
À10
0
78
78
77
74
73
O
O
X
X
8
X
X
SiMe3
R1
O
Lewis Acid
Solvent
10
20
9
10
10
20
O
O
+
R2
O
OH
R2
a Reaction conditions: 1 mmol scale; 0.25 M (CH2Cl2), 2.0 equiv 4,
10 mol % ZnCl2 (4a) or Sc(OTf)3 (4d), 16 h.
b Yield was determined by HPLC and represents the total conversion
of 1a to 5 and its presumed hydrated open form (seco-acid form; 0–
8%) after 16 h.
R3
R3
5, X=Cl; 6, X=Br
1a X=Cl; 1b X=Br
R1
4
Scheme 1. Mukaiyama aldol reaction on mucohalic acid.

P. Angell et al. / Tetrahedron Letters 46 (2005) 2029–2032
Table 3. Mukaiyama aldol with KSA-solvent studya Table 4. Mukaiyama aldol with KSA and SEEa
2031
KSA
Product (yield)b
KSA/SEE Product (yield)b
O
O
Cl
Cl
O
O
OTMS
OMe
4a
Cl
Cl
Cl
Cl
O
Cl
OTMS
OMe
O
ZnCl2
OTMS
St-Bu
4c
+
O
O
CO2Me
Cl
OH
St-Bu
1a
CO2Me
4a
5a
5c
(56%)
5a
(80%)
O
Entry
Solvent
1ab (%)
5ab,c (%)
1
2
3
4
5
6
7
8
PhMe
Et2O
THF
6
6
94
94
O
O
Cl
Cl
Br
Br
OTMS
76
8
24
92
OTMS
O
O
CH2Cl2
CHCl3
MeNO2
EtCN
DME
OMe
O
Ph
4d
29
3
71
CO2Me
>96
44
4a
5d
Ph
(79%)c
6a
56
33
(75%)
67
a Reaction conditions: 1 mmol scale; 0.25 M, 2.0 equiv 4a, 10 mol %
ZnCl2; reactions were stirred at À20 °C for 2 h then at rt for 14 h (no
further consumption of 1a was observed with longer reaction time).
b Yield was determined by HPLC (215 nm).
O
O
Cl
Cl
Br
Br
O
OTMS
OTMS
Ph
O
O
c Represents the total conversion of 1a to 5 and its presumed hydrated
O
open form (0–8%).
O
O
4b
4d
6d
(73%)
5b
(48%)
Ph
at À30 < T < 0 °C. With this data we determined to
complete the remainder of the study at À20 °C for both
the KSAꢀs and the SEEꢀs.
a Reaction conditions: 1 mmol scale; 0.25 M in PhMe (4a–c) or Et2O
(4d), 2.0 equiv 4, 10 mol % ZnCl2 (4a–c) or Sc(OTf)3 (4d); reactions
were stirred at À20 °C for 2 h then at rt for 16 h.
b Isolated yield; products passed elemental analysis or HRMS.
c A 35 mmol scale also provided 5d in 79% yield.
During the Lewis acid catalyst screen, we observed that
ZnCl2, InCl3, and Sn(OTf)2 showed essentially no reac-
tion at T = À20 °C with 1a and 4d; however, HPLC
analysis after 16 h at rt showed significant amounts of
lactone 5d were produced. This observation, in contrast
to the Sc(OTf)3 result, clearly indicates that temperature
optimization is catalyst dependant.
was treated with various KSAꢀs (4a–c) and SEE 4d to ex-
plore the generality of the reaction (Table 4). All provide
the expected lactones 5a–d, 6a, and 6d in moderate to
good yields. The reactions are generally clean, but some
difficulty is encountered in obtaining complete con-
sumption of mucohalic acid 1a/b; this obstacle is likely
a result of silylation of 1a/b before the reaction occurs.
After finding suitable temperature conditions, a solvent
screen was initiated (Table 3). In the case of KSA 4a,
four of the eight solvents screened—PhMe, Et2O,
CH2Cl2, and MeNO2 gave excellent results with conver-
sions of 92% or higher. Although MeNO2 provides the
fastest/highest conversion (1 h at À20 °C provided
>96% conversion), for environmental and safery rea-
sons, PhMe (94% conversion) was chosen to complete
the subsequent substrate study. Moderate-performing
solvents include CHCl3 and DME (71% and 67%
conversion, respectively) while EtCN and THF are
poor-performing solvents (44% and 24% conversion,
respectively).
Using this method, butenolide 5b, a core structure found
in some important natural products, such as biatractylo-
lide, biepiasterolide, and others,19 was prepared. With-
out purification, 1a and 2b gave predominantly (90%)
syn-5b and 10% anti-5b.20 After crystallization, NMR
analysis indicated a single stereoisomer; X-ray crystal
structure analysis of 5b confirmed the syn racemate
(Fig. 2).
The SEE solvent screen provided similar results (see
Supporting material). Again, PhMe, Et2O, CH2Cl2,
and MeNO2 were found to be the best-performing sol-
vents with 72–83% conversions; Et2O provided the high-
est production of 5d and was used in the substrate study.
Mid-performing solvents were CHCl3 and DME. They
provided 62% and 43% of 5d, respectively; however,
EtCN is a poor-performing solvent providing only 8%
of 5d with 13% of a double-aldol product. THF is
incompatible with Sc(OTf)3.
Finally, using the semi-optimized reaction conditions
(temperature, solvent, and Lewis acid) mucohalic acid
Figure 2. X-ray crystal structure for c-butenolide 5b.

2032
P. Angell et al. / Tetrahedron Letters 46 (2005) 2029–2032
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Unlike the normal Mukaiyama aldol reaction that gen-
erates a b-hydroxy carbonyl compound, this approach
gives predominantly the c-butenolides as the product.
Therefore, the possible mechanism (see Supporting
material) is more complicated since two carbonyl groups
in mucohalic acid may be activated. Meanwhile, both
cyclic and open forms of mucohalic acid are likely
involved in the formation of final c-butenolides.
This latest methodology has several advantages: (1) both
starting materials are cheap, commercially available or
easily prepared; (2) the reaction occurs under mild con-
ditions with good to excellent yield; (3) the products are
highly functionalized, allowing further transformation;
(4) since the Lewis acid requirement is catalytic (10%
or lower)21 practical asymmetric Mukaiyama aldol reac-
tion conditions offer opportunity to prepare optically-
active c-butenolides.22
6. Zhang, J.; Blazecka, P. G.; Belmont, D.; Davidson, J. G.
Org. Lett. 2002, 4, 4559.
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In summary, we have developed a simple, efficient, and
selective method to prepare a variety of highly function-
alized, c-substituted c-butenolides using the Mukaiyama
aldol reaction. Further investigations, including exten-
sion of the use of these synthons will be reported in
due course.
Acknowledgements
We thank Brian Samas for obtaining the X-ray crystal-
lographic structure, Dr. Wei Wang for NMR interpreta-
tion and Professors Tarek Sammakia and Richard
Hsung for providing valuable mechanistic input during
visits to our laboratory.
10. Chen, M.-J.; Narkunan, K.; Liu, R.-S. J. Org. Chem.
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12. Zhang, J.; Blazecka, P. G.; Berven, H.; Belmont, D.
Tetrahedron Lett. 2003, 44, 5579.
Supplementary data
13. Beska, E.; Rapos, P. J. Chem. Soc., Perkin Trans. 1 1976,
23, 2470.
14. (a) Heathcock, C. H. Comput. Org. Synth. 1991, 2, 133;
(b) Mukaiyama, T. Org. React. 1982, 28, 203.
Supplemetary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.01.147.
15. (a) van Oeveren, A.; Feringa, B. L. J. Org. Chem. 1996, 61,
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17. The overall desired aldol reaction may be slightly higher—
for simplicity of discussion, any remaining uncyclized
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without purification, in 79% ee; unpublished result.
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