Asymmetric cyclization-carbonylation of 2-propargyl-1,3-dione

Article abstract of DOI:10.1016/S0040-4039(03)00547-1

The first example of asymmetric cyclization-carbonylation of 2-propargyl-1,3-dione 1 catalyzed by palladium(II) with chiral bisoxazolines (C.H.-BOX) was investigated. The use of bulky alcohols increased the ee of the products 2. The product 2d was converted into bicyclic enones 7 and 8, a useful intermediate for the synthesis of natural products.

Full text of DOI:10.1016/S0040-4039(03)00547-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3089–3092
Asymmetric cyclization–carbonylation of 2-propargyl-1,3-dione
Keisuke Kato,a,* Maki Tanaka,a Shigeo Yamamura,a Yasuhiro Yamamotob and Hiroyuki Akitaa,*
aSchool of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
bDepartment of Chemistry, Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
Received 29 January 2003; revised 21 February 2003; accepted 21 February 2003
Abstract—The first example of asymmetric cyclization–carbonylation of 2-propargyl-1,3-dione 1 catalyzed by palladium(II) with
chiral bisoxazolines (C.H.-BOX) was investigated. The use of bulky alcohols increased the ee of the products 2. The product 2d
was converted into bicyclic enones 7 and 8, a useful intermediate for the synthesis of natural products. © 2003 Elsevier Science
Ltd. All rights reserved.
Palladium(II)-catalyzed intramolecular oxycarbonyla-
tion of alkynols is an important transformation of
alkynes into b-ketoesters or b-alkoxyacrylates.1
Recently, we have reported that the oxidative cycliza-
tion–methoxycarbonylation of 4-yn-1-ones2 and
propargylic acetates3 is also a useful reaction for the
above transformation. An asymmetric version of this
type reaction has not been reported so far.4 Now we
wish to report here the first example of asymmetric
cyclization–carbonylation of 2-propargyl-1,3-dione 1
catalyzed by palladium(II) with chiral bisoxazoline lig-
ands (Scheme 1).
Pd(CH3CN)4(BF4)2, the chiral palladium complex did
not dissolve in i-BuOH; the reaction proceeded by
addition of CH2Cl2 to afford 25% ee of 2d in 48% yield
(entry 5). On addition of Cu(OTf)2 and LiClO4, the
yields improved but the ee values were lowered (entries
6 and 7). Next, we examined the use of seven types of
mixed solvents (DMF, DMSO, benzene, THF, 1,2-
dichloroetane, CCl4, CH2Cl2) containing 10 equiv. of
i-BuOH. Among them, only CH2Cl2 is effective for the
present reaction; the ee of 2d was slightly increased,
though the yield was reduced (entry 8). The use of
i-BuOH/CH2Cl2=1/1 gave a similar result (entry 9) to
that obtained by using only i-BuOH (entry 4). The use
of 1:1 ratio of the ligand and Pd(CF3CO2)2 gave 43% ee
of 2d in 49% yield (entry 10), which was comparable to
the result using 2:1 ratio of the ligand and palladium
catalyst (entry 4). Thus, the following reactions were
performed in i-BuOH using 1:1 ratio of the ligand and
Pd(CF3CO2)2. The palladium catalyst with ligands D
and E did not show any catalytic activity. When the
reaction was performed in the presence of ligands B, C,
F4b, G, H and I6, the product 2 was obtained in low
yields with low enantioselectivities, although these chi-
ral oxazolines have been successfully used for some
other asymmetric reactions (entries 11–16). These mis-
As shown in Table 1 (entry 1), asymmetric cyclization–
methoxycarbonylation of 2-propargyl-1,3-diketone 1 in
the presence of Pd(CF3CO2)2/ligand A/p-benzoquinone
in methanol at −30°C under carbon monoxide atmo-
sphere (balloon) afforded 8% ee of cis-2a as a single
diastereomer in 90% yield.5 As a preliminary experi-
ment, many kinds of ligands (A to I) were examined in
MeOH; however the ee of the product 2a was not
improved. The bulkiness of alcohol affected the enan-
tioselectivity and yield of the products 2 as shown in
entries 2–4. When the reaction was performed in bulky
alcohols, ee of 2b–d was increased (n-BuOH 27% ee<i-
PrOH 33% ee<i-BuOH 43% ee). The use of
Scheme 1.
* Corresponding authors. Fax: +047-472-1825; e-mail: kkk@phar.toho-u.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00547-1

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K. Kato et al. / Tetrahedron Letters 44 (2003) 3089–3092
Table 1. Asymmetric cyclization–carbonylation of 2-propargyl-1,3-dione 1
Entry
Pd cat.
Ligand (mol%)
Conditions
Yield (%)
Solvent
% ee (config.)a
1
2
3
4
5
6
7
8
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
(CH3CN)4Pd(BF4)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
A (10)
A (10)
A (10)
A (10)
A (10)
A (10)b
A (10)c
A (10)
A (10)
A (5)
B (5)
C (5)
F (5)
G (5)
H (5)
I (5)
J (5)
K (5)
−30°C, 24 h
0–10°C, 20 h
0°C, 23 h
0°C, 20 h
r.t., 72 h
0°C, 12 h
0°C, 15 h
r.t., 16 h
0°C, 24 h
90
54
62
48
48
71
54
29
49
49
25
47
36
40
42
21
27
54
MeOH
i-PrOH
n-BuOH
i-BuOH
i-BuOH/CH2Cl2=2/1
i-BuOH
i-BuOH
i-BuOH in CH2Cl2
i-BuOH/CH2Cl2=1/1
i-BuOH
i-BuOH
i-BuOH
i-BuOH
i-BuOH
i-BuOH
i-BuOH
i-BuOH
i-BuOH
8 (R)
33 (S)
27 (S)
43 (S)
25 (S)
25 (S)
9 (R)
48 (S)
43 (S)
43 (S)
31 (S)
0
6 (R)
24 (S)
19 (R)
3 (R)
11 (R)
59 (R)
9
10
11
12
13
14
15
16
17
18
0°C, 20 h
0°C, 23 h
0°C–r.t., 26 h
0°C, 23 h
0°C–r.t., 24 h
0°C–r.t., 24 h
0°C–r.t., 23 h
r.t., 72 h
0°C, 22 h
a Absolute configuration of quaternary carbon bearing a methyl group is only presented.
b Cu(OTf)2 (5 mol%) and ligand A (10 mol%) were used.
c LiClO4 (50 mol%) was used.
with monoamide 3 (69%). The ligand K was obtained
by treatment of 4 with Ph3P/CCl4/Et3N in 96% yield.
The monoamide 3 was also converted into ligand K.
Formation of an oxazoline ring followed by hydrolysis
of the ester group and subsequent condensation with
(S)-phenylglycinol afforded monoamide 5 having the
oxazoline ring in 33% overall yield. The ligand K was
obtained by treatment of 5 with Ph3P/CCl4/Et3N in
76% yield. The ligand J was also prepared in a similar
manner to that described above. Next, we examined the
present reaction in the presence of ligand J/
Pd(OCOCF3)2 and ligand K/Pd(OCOCF3)2 catalysts.
Although the use of ligand J did not give good result
(27%, 11% ee), that of ligand K bearing the (S,S)-1,2-
cyclohexane skeleton ((S,S)-ph-C.H.-BOX) gave the
erable results prompt us to the synthesis of another
kind of chiral ligand. In recent years, a number of
conformationally constrained box ligands were pre-
pared.4b,c,f,7 For example, Takacs et al. reported box
ligands built around bicyclo[2.2.1] and bicyclo[2.2.2]-
backbones.7a We were puzzled by the absence of box
ligands based on simple trans-1,2-cyclohexane frag-
ment. The cyclohexane template is present in a number
of useful chiral ligands8 and chiral auxiliary9 as a result
of its ability to rigidify the trans configuration of sub-
stituents. We therefore prepared chiral box ligand based
on trans-1,2-cyclohexane skeleton (C.H.-BOX) as
shown in Scheme 2. Condensation of (S)-phenylgly-
cinol with (S,S)-cyclohexanedicarboxylic acid10 fol-
lowed by esterification afforded diamide 4 (15%) along
Scheme 2.

K. Kato et al. / Tetrahedron Letters 44 (2003) 3089–3092
3091
Scheme 3.
Scheme 4.
suggested that a specific hydroxyl group bearing cis-
relationship against the propargyl group was more
reactive than that of a ‘trans’-hydroxyl group. At first,
two kinds of hemiacetal intermediates X and Y which
have a ‘trans’ and a ‘cis’ hydroxyl group against the
propargyl group should be produced, respectively. The
coordination of the alkyne to Pd(II) could be induced
by attack of the ‘cis’ hydroxyl group in intermediate Y
to produce the vinyl palladium intermediate followed
by CO insertion and subsequent reaction with ROH to
provide cis-2 as a single diastereomer (Scheme 4). Actu-
ally, the cyclization–carbonylation of non-cyclic sub-
strate 11 using the same reaction conditions as that of
entry 10 in Table 1 afforded 12 as an inseparable 1:2
mixture of diastereomers in 54% yield (Scheme 6).13
best result (54%, 59% ee) in Table 1 (entries 17 and
18).11
As shown in Scheme 3, the absolute stereochemistry of
2d was determined by conversion into authentic
bicyclic-diketone 8. The authentic 8 was synthesized
from authentic 6 (65% ee) which has (S)-configuration
of the quaternary carbon bearing a methyl group.4g
Oxidation of the secondary alcohol group in 6 gave the
ketone which was treated with 10%HCl/THF to give a
b-keto ester. Knoevenagel condensation of the b-keto
ester followed by oxidation afforded authentic (+)-7 in
75% overall yield. Treatment of (+)-7 with Ti(i-PrO)4/i-
BuOH in benzene gave authentic (+)-8 in 74% yield. On
the other hand, the product 2d was also converted to
(+)-8 by the following four-step sequence. Reduction of
ketone in 2d followed by acid hydrolysis and subse-
quent Knoevenagel condensation afforded bicyclic alco-
hol which was treated with Dess-Martin reagent to give
(+)-8. Thus, the absolute configuration of the quater-
nary carbon bearing a methyl group in 2d was deter-
mined to be R.
In summary, we have presented the first example of an
asymmetric cyclization-carbonylation of 2-propargyl-
A conceivable mechanism of the present reaction would
be proposed as shown in Scheme 4 based on the
following experimental results. (I) The bulkiness of
alcohols affected enantioselectivity and yield of 2 as
shown in Table 1 (entries 1–4), which suggested that the
alcohol incorporated into the substrate as a hemiacetal
before cyclization.12 (II) The addition of Lewis acid
might accelerate the hemiacetal formation, and the
yields were increased (entries 6 and 7). (III) We have
recently reported that the cyclization carbonylation of
2-propargyl-1,3-diol 9 afforded the product 10 in 98%
yield as a single diastereomer (Scheme 5).4g This result
Scheme 5.
Scheme 6.

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K. Kato et al. / Tetrahedron Letters 44 (2003) 3089–3092
1,3-dione 1 catalyzed by palladium(II) with chiral
bisoxazolines. Chiral bisoxazoline ligand K based on
the 1,2-cyclohexane skeleton ((S,S)-ph-C.H.-BOX) was
more effective than ligands A–J. Optically active
bicyclic enones 7 and 8, being a useful intermediate of
natural products, was synthesized.
5. The structure of racemic-2a was unequivocally deter-
mined by X-ray analysis. X-ray data for 2a has been
deposited at the Cambridge Crystallographic Data Centre
as supplementary material. General procedure: A 30 mL
two-necked round-bottomed flask, containing a magnetic
stirring bar, Pd(CF3CO2)2 (0.015 mmol), Chiral ligand
(0.03 mmol), p-benzoquinone (0.33 mmol) and MeOH (6
mL) was fitted with a rubber septum and three-way
stopcock connected to a balloon filled with carbon
monoxide. The apparatus was purged with carbon
monoxide by pumping-filling via the three-way stopcock.
A solution of the substrate 1 (0.3 mmol) in MeOH (2
mL) was added dropwise to the stirred mixture via a
syringe. After being stirred for the period of time and at
a temperature, CH2Cl2 (30 mL) was added dropwise to
the stirred mixture, washed with 5% NaOH aq (40 mL),
and dried over MgSO4. The crude product was purified
by column chromatography on silica gel. The fraction
eluted with hexane/ethyl acetate (50/1) containing Et3N
(1%) afforded 2 as a colorless oil or colorless needles. The
ee was determined by HPLC analysis using a chiral
column.
Acknowledgements
We are grateful to Dr. M. Seki and Dr. T. Furutani,
Tanabe Seiyaku Co., Ltd. for providing binaphthyl
dicarboxylic acid for the preparation of (S,S)-ph-
boxax.
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