Organocatalytic asymmetric 1,4-addition of organoboronic acids to γ-hydroxy α,β-unsaturated aldehyde: facile synthesis of chiral β-substituted γ-lactones

Article abstract of DOI:10.1016/j.tetlet.2008.08.025

Catalytic asymmetric 1,4-addition of arylvinyl- and arylboronic acids to a γ-hydroxy α,β-unsaturated aldehyde, which affords β-substituted γ-lactols, has been established using a diarylprolinol silyl ether as an organocatalyst. The β-substituted γ-lactols have been obtained in good yields and with up to 91% ee, which lead to chiral β-substituted γ-lactones followed by oxidation.

Full text of DOI:10.1016/j.tetlet.2008.08.025

Tetrahedron Letters 49 (2008) 6148–6151
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic asymmetric 1,4-addition of organoboronic acids to
c-hydroxy
a,b-unsaturated aldehyde: facile synthesis of chiral b-substituted c-lactones
*
Sung-Gon Kim
Department of Chemistry, College of Natural Science, Kyonggi University, San 94-6, Iui-dong, Yeongtong-gu, Suwon 443-760, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Catalytic asymmetric 1,4-addition of arylvinyl- and arylboronic acids to a
c-hydroxy a,b-unsaturated
Received 4 July 2008
Revised 3 August 2008
Accepted 7 August 2008
Available online 23 August 2008
aldehyde, which affords b-substituted
as an organocatalyst. The b-substituted
91% ee, which lead to chiral b-substituted
c
-lactols, has been established using a diarylprolinol silyl ether
-lactols have been obtained in good yields and with up to
-lactones followed by oxidation.
Ó 2008 Elsevier Ltd. All rights reserved.
c
c
Keywords:
Organocatalyst
Asymmetric 1,4-addition
Organoboronic acid
c
c
-Lactol
-Lactone
R2
R3
O
Enantiomerically pure
ure and in many biologically active compounds.1 In addition,
tone chemistry plays a very important role in the synthesis of
natural products.2 Among them, chiral
-butyrolactones possess-
c
-lactones are widely distributed in nat-
N
B
c
-lac-
O
R2
R1
R3
R2
R3
OH
N
N
H
2
+
+
B
H
R1
OH
R1
HO
c
OH
OH
ing a b-stereocenter are found in a number of biologically active
1
3
5
OH
natural products such as lignans (À)-trachelogenin and (À)-entero-
4
lactone.3 They also serve as key precursors to the synthesis of
c-
aminobutyric acid (GABA) derivatives such as (À)-baclofen and
pregabalin, which are neurotransmitter inhibitors in the central
nervous system.4
Scheme 1. Petasis one-step three-component coupling.
Owing to the importance of this class of compounds, numerous
mechanism in mind, we envisioned that 1,4-iminium addition
might be possible if a -hydroxy ,b-unsaturated aldehyde was
used instead of an -hydroxy aldehyde, wherein an amine compo-
nent would also be changed from a coupling partner to a catalyst
(Scheme 2).
synthetic approaches to chiral b-substituted c-lactones have been
c
a
reported.5 Some of the strategies include enzymatic resolution,6
synthesis using a chiral auxiliary,7 catalytic enantioselective Bae-
yer–Villiger oxidation,8 C–H insertion reaction,9 hydrogenation,10
1,4-reduction11 and 1,4-addition reaction.12 In this Letter, we de-
a
scribe the facile synthetic strategy of chiral b-substituted
tones by the oxidation of chiral b-substituted -lactols, which are
prepared by new catalytic asymmetric 1,4-addition of arylvinyl-
c-lac-
R2
R3
R2
R2
c
N
H
N
O
OH
B
OH
B
O
R1
+
OH
OH
and arylboronic acids to a
c-hydroxy a,b-unsaturated aldehyde
R1
OH
H
chiral amine
catalyst
using an organocatalyst.13,14
Petasis and co-workers elegantly demonstrated a one-step
three-component process involving the condensation of aryl- and
OH
O
*
vinylboronic acids with amines and
a
-hydroxy aldehydes leading
O
R1
*
oxidation
to b-amino alcohols;15,16 this mechanism involves a transient spe-
cies such as 4, leading to the product 5 (Scheme 1). With this
O
O
OH
H
*
R1
R1
* Tel.: +82 31 249 9631; fax: +82 31 249 9639.
E-mail address: sgkim123@kgu.ac.kr
Scheme 2. Organocatalytic 1,4-addition of organoboronic acid to
,b-unsaturated aldehyde.
c-hydroxy
a
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.025

S.-G. Kim / Tetrahedron Letters 49 (2008) 6148–6151
6149
Table 1
In this process, arylvinyl boronic acids are able to perform 1,4-
addition on -hydroxy ,b-unsaturated aldehydes to give chiral
hydroxy b-substituted aldehydes, which are equilibrated or shifted
to chiral b-substituted -lactols, when chiral amine catalysts are
used. The resulting b-substituted -lactols might be easily con-
verted to b-substituted -lactones by oxidation.
The 1,4-addition of styrylboronic acid 6 to 4-hydroxy-but-2-
Asymmetric 1,4-addition of styrylboronic acid to 4-hydroxy-but-2-enal by organo-
c
a
c-
cataysta
OH
c
c
20 mol % Cat.
Ph
OH
O
HO
c
B
+
O
OH
enal 717 was selected as a model reaction.
L-Proline I (Fig. 1) was
6
7
8
Ph
initially examined in this reaction with H2O (2 equiv)18 in CH2Cl2
at room temperature. The reaction proceeded to furnish the corre-
Entry
Catalyst
Solvent
Temp (°C)
Time (h)
Yieldb (%)
erc
1
2
3
I
II
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
24
24
24
24
24
24
24
24
24
24
48
48
59
89
23
28
88
64
99
53
64
88
60
98
63:37
65:35
88:12
83:17
87:13
86:14
92:8
89:11
92:8
92:8
sponding b-styryl
c-lactol (diastereomeric ratio, 0.6:0.4) without
detection of -hydroxy b-styryl aldehyde, though the yield was
c
III CF3CO2H
IV CF3CO2H
V
V
VI
VI
VI
VI
VI
VI
moderate and its enantioselectivity was not as high as desired
(Table 1, entry 1).
4
5
Encouraged by this result, we investigated other organocata-
lysts for the 1,4-addition of styrylboronic acid 6 to 4-hydroxy-
but-2-enal 7 to improve both reactivity and enantioselectivity.
(S)-5-Pyrrolidin-2-yl-1H-tetrazole II afforded good reactivity (89%
yield, entry 2), but a poor level of enantioselectivity was observed.
Imidazolidinone catalyst III and IV showed increased enantioselec-
tivities (88:12 er and 83:17 er, respectively) but in low yields (en-
tries 3 and 4). However, we were pleased to discover that
diphenylprolinol silyl ether V provided the product in good yield
with high enantioselectivity (88% yield, 87:13 er, entry 5). Further-
more, trifluoromethyl-substituted diarylprolinol silyl ether VI
afforded excellent reactivity and improved enantioselectivity
(99% yield, 92:8 er, entry 7).
6d
7
8
9
10
11e
12
95:5
95.5:4.5
a
Reactions were carried out in solvent (0.3 M) with 2.0 equiv of H2O and
2.0 equiv of 4-hydroxy-but-2-enal relative to the styrylboronic acid in the presence
of 20 mol % catalyst.
b
Isolated yield after chromatographic purification.
Determined by HPLC analysis.
Reactions were carried out with 1.1 equiv of styrylboronic acid relative to the
c
d
4-hydroxy-but-2-enal.
e
10 mol % of PhCO2H was added.
After the reaction conditions were optimized, we found that the
superior levels of enantioselectivity and yield were exhibited by
catalyst VI in CH2Cl2 at 0 °C (98% yield, 95.5:4.5 er, entry 12). An
acid additive diminished the reaction efficiency in this reaction,
though it slightly increased the enantioselectivity (entry 11).
Having established the optimal reaction conditions, we next
probed the generality of this asymmetric catalytic reaction with
various arylvinyl- and arylboronic acids to 4-hydroxy-but-2-enal
7. In the first, arylvinylboronic acids were examined in this reac-
tion (Table 2). The results showed that high levels of enantioselec-
tivity (>93:7 er’s) were obtained with arylvinylboronic acids,
regardless of electron-donating (4-MeO, entry 2) and electron-
withdrawing substituents (4-Cl, 4-F, entries 3 and 4). It was noted
O
N
N
CO2H
N
H
N
H
N
Bn
that the resulting
c-lactols provided chiral b-substituted c-lac-
N
H
III
HN
N
tones with good yields (61-86%) after treatment of pyridium chlo-
rochromate (PCC).
I
II
F3C
CF3
CF3
We next expanded our substrates to include aromatic boronic
acids. However, we discerned that aryl substrates have less reac-
tion efficiency than arylvinylboronic acids in this 1,4-addition reac-
tion. In the case of phenylboronic acid, the reaction was inert even
under severe reaction conditions such as high temperature and
increased catalyst loading. To circumvent this limitation, we sought
reaction conditions which would further accelerate the feasibility
of this class of substrates. As such, we determined that catalyst V
O
N
Ph
Ph
OTMS
N
H
Bn
N
N
H
H
CF3
OTMS
IV
V
VI
Figure 1. Chiral amine organocatalysts.
Table 2
Catalytic asymmetric 1,4-addition of arylvinylboronic acids to 4-hydroxy-but-2-enala
OH
O
20 mol % VI
R
OH
O
O
PCC
HO
B
+
O
CH2Cl2, 0 ºC
CH2Cl2
OH
7
6
8
9
R
R
Entry
Time (h)
Ph
4-MeOC6H4
4-ClC6H4
4-FC6H4
R
Yield of 8b (%)
Yield of 9b (%)
erc,d (%)
1
2
3
4
48
48
36
24
98
77
30
99
86
61
75
85
95.5:4.5
93:7
93:7
93:7
a
Reactions were carried out in CH2Cl2 (0.3 M) at 0 °C with 2.0 equiv of H2O and 2.0 equiv of 4-hydroxy-but-2-enal relative to the arylvinylboronic acid in the presence of
20 mol% catalyst.
b
Isolated yield after chromatographic purification.
Determined by HPLC analysis.
Absolute stereochemistry assigned by chemical correlation.
c
d

6150
S.-G. Kim / Tetrahedron Letters 49 (2008) 6148–6151
Table 3
Catalytic Asymmetric 1,4-Addition of Arylboronic Acids to 4-Hydroxy-but-2-enala
OH
O
20 mol % V
R
OH
O
O
PCC
CH2Cl2
HO
B
+
O
*
*
CH2Cl2, r.t.
OH
R
R
7
8
9
6
Entry
1
R
Time (h)
36
Yield of 8b (%)
Yield of 9b (%)
erc (%)
52:48
MeO
75
65
60
84
MeO
MeO
2
3
24
3
75
97
59:41
52:48
O
4
5
48
36
61
71
74
80
55:45
55:45
O
S
S
6
7
48
48
45
51
65
83
61:39
55:45
N
Boc
N
d
8
2
99
—
—
a
Reactions were carried out in CH2Cl2 (0.3 M) with 10 equiv of 0.5 M NaOH in H2O and 2.0 equiv of 4-hydroxy-but-2-enal relative to the arylboronic acid in the presence of
20 mol % catalyst.
b
Isolated yield after chromatographic purification.
Determined by HPLC analysis.
The desired product was not obtained.
c
d
promoted the 1,4-addition of arylboronic acid to 4-hydroxy-but-
2-enal by adding sodium hydroxide. The results are summarized
in Table 3. Though phenylboronic acid was still inert under these
conditions, electron-donating substituted phenyboronic acids
Acknowledgments
Generous support by Korea Research Institute of Chemical
Technology (KRICT) is gratefully acknowledged. We thank Dr. Joel
Austin, Bristol-Myers Squibb, for making critical editorial com-
ments about the manuscript.
(4-MeO, 3,4-diMeO) provided the corresponding c-lactol with high
efficiency (65% yield and 60% yield, respectively, entries 1 and 2). In
particular, 4-N,N-dimethylamino substituent accelerated the reac-
tion rate and the reaction proceeded to completion (entry 8). We
have also found that this process works well with heteroarylboron-
ic acids including furan, benzofuran, thiophen, benzothiophen and
N-Boc-pyrrole (entries 3–7). However, unfortunately in all cases,
poor levels of enantioselection were observed (3–22% ee). Though
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.08.025.
the resulting
the lactols were readily converted to
c
-lactols did not show high enantioselectivity,
-lactones by PCC oxi-
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c
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