Enantioselective conjugate addition of boronic acids to enones catalyzed by O-monoacyltartaric acids

Article abstract of DOI:10.1039/c0cc03076g

We have found that O-monoacyltartaric acids catalyze asymmetric conjugate addition of boronic acids to enones with good enantioselectivity, and the 3,5-di(tert-butyl)benzoyl group provides the best results among the acyl groups examined. The Royal Society

Full text of DOI:10.1039/c0cc03076g

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Enantioselective conjugate addition of boronic acids to enones catalyzed
by O-monoacyltartaric acidsw
Masaharu Sugiura,* Mirai Tokudomi and Makoto Nakajima
Received 5th August 2010, Accepted 31st August 2010
DOI: 10.1039/c0cc03076g
We have found that O-monoacyltartaric acids catalyze
asymmetric conjugate addition of boronic acids to enones with
good enantioselectivity, and the 3,5-di(tert-butyl)benzoyl group
provides the best results among the acyl groups examined.
(6%, 0% ee), O,O-dibenzoyl L-tartaric acid (14%, 4% ee)]. On
the other hand, an acceptable enantioselectivity (45% ee) was
obtained with O-monobenzoyl L-tartaric acid (1a), but the
yield was low (23%). Upon further examination, the addition
of methanol (2 equiv. relative to 3a) at a higher concentration
(toluene, 0.3 M) improved both the yield and selectivity
(38%, 59% ee; see Table 1, entry 1). Methanol suppressed
the non-catalyzed reaction (6%) because 4a was obtained in
35% yield in the absence of both 1a and methanol.10
Enantioselective 1,4- and 1,2-additions of boronic acids to
a,b-unsaturated carbonyl compounds, aldehydes, ketones, or
imines constitute effective C–C bond forming reactions
in organic synthesis.1 Although numerous efficient chiral
transition metal catalysts are known, few organocatalysts
(chiral biphenol derivatives,2–4 thioureas,5 and secondary
amines)6 have been successful in these transformations. Herein
we report a class of chiral catalysts, O-monoacyltartaric acids
1 (Fig. 1),7 capable of activating boronic acids.8
Under conditions using the methanol additive, various
monoacylated L-tartaric acids11 were investigated (Table 1).
1- and 2-Naphthoyl groups improved the chemical yield and
selectivity (entries 2 and 3). Additionally, meta-substitution
provided a superior selectivity compared to ortho- and
para-substitution of the methyl substituent in the benzoyl
group (entries 4–6). 3,5-Dimethylbenzoate 1g was more
selective than monomethylated 1e (entry 7). Introducing
electron-donating methoxy groups at the 3,5-positions
significantly decelerated the reaction (entry 8), whereas
electron-withdrawing trifluoromethyl groups exhibited
a
Fig. 1 O-Monoacyltartaric acids 1.
higher activity (entry 9). Moreover, bulkier alkyl substituents
at the 3,5-positions increased the selectivity (entries 7, 10 and
11). These results suggest that not only the electronic effect but
also the steric bulkiness of the substituent plays an important
role for the activity and selectivity of the catalyst. Meanwhile,
varying the reaction temperature with catalyst 1k did
not improve the selectivity (entries 12 and 13). Among the
O-monoacylated L-tartaric acids (1a–k) tested, 3,5-di(tert-
butyl)benzoate 1k gave the best results (entry 11).
Because a-hydroxycarboxylic acids are suitable scaffolds
for boronic acids,9 we hypothesized that they may activate
boronic acids. Thus, we initially examined the activity of
L-tartaric acid (10 mol%) for the conjugate addition of
(E)-styrylboronic acid (3a) to chalcone (2a) (eqn (1)). The
reaction in refluxing dichloromethane (0.05 M relative to 2a)
for 24 h gave the desired product 4a in 89% yield with 25% ee.
However, without L-tartaric acid under the same conditions,
4a was obtained in 31%. Changing the solvent to toluene
effectively suppressed the non-catalyzed reaction to 5% yield,
whereas the presence of L-tartaric acid resulted in a similar
yield and selectivity as the reaction in dichloromethane
(97%, 24% ee).
Table 1 Enantioselective conjugated addition of 3a to 2a catalyzed
by O-monoacyltartaric acid 1a
Entry
R in 1
%yield of 4a
%ee of 4ab
1
2
3
4
5
6
7
8
Ph (1a)
38
86
41
63
51
58
77
22
81
74
92
41
90
59
69
70
64
70
62
80
73
79
82
87
87
86
1-naphthyl (1b)
2-naphthyl (1c)
o-tolyl (1d)
m-tolyl (1e)
p-tolyl (1f)
3,5-Me2C6H3 (1g)
3,5-(MeO)2C6H3 (1h)
3,5-(F3C)2C6H3 (1i)
3,5-iPr2C6H3 (1j)
3,5-tBu2C6H3 (1k)
1k
ð1Þ
Using toluene, we then examined the activity of other tartaric
acid derivatives (10 mol%). For comparison, all reactions were
conducted in toluene at 50 1C for 24 h. Protecting either the
two carboxyl groups or the two hydroxy groups of L-tartaric
acid significantly decreased the activity [dimethyl L-tartrate
9
10
11
12c
13d
1k
a
Unless otherwise noted, reactions were carried out using
chalcone (2a) (0.3 mmol), (E)-styrylboronic acid (3a) (0.36 mmol),
O-monoacyltartaric acid (10 mol%), and methanol (0.72 mmol) in
Graduate School of Pharmaceutical Sciences, Kumamoto University,
5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
E-mail: msugiura@kumamoto-u.ac.jp
w Electronic supplementary information (ESI) available: General
procedures and spectroscopic data. See DOI: 10.1039/c0cc03076g
toluene (1 mL) at 50 1C for 24 h. All cases gave the (S)-isomer. c At
40 1C. At 60 1C.
b
d
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7799–7800 7799

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Notes and references
1 For reviews on 1,4- and 1,2-additions of organoboronic acids, see:
(a) K. Yoshida and T. Hayashi, in Boronic Acids, ed. D. G. Hall,
Wiley-VCH, Weinheim, 2005, ch. 4; (b) R. A. Batey, in Boronic
Acids, ed. D. G. Hall, Wiley-VCH, Weinheim, 2005, ch. 7.
2 For 1,4-addition to enones catalyzed by chiral biphenols, see:
(a) T. R. Wu and J. M. Chong, J. Am. Chem. Soc., 2005, 127,
3244; (b) T. R. Wu and J. M. Chong, J. Am. Chem. Soc., 2007, 129,
4908. For a theoretical study, see: ; (c) S. C. Pellegrinet and
J. M. Goodman, J. Am. Chem. Soc., 2006, 128, 3116;
(d) R. S. Paton, J. M. Goodman and S. C. Pellegrinet, J. Org.
Chem., 2008, 73, 5078.
3 For 1,2-addition to ketones catalyzed by chiral biphenols, see:
(a) S. Lou, P. N. Moquist and S. E. Schaus, J. Am. Chem. Soc.,
2006, 128, 12660; (b) D. S. Barnett, P. N. Moquist and
S. E. Schaus, Angew. Chem., Int. Ed., 2009, 48, 8679.
4 For 1,2-addition to imines or iminium ions catalyzed by chiral
biphenols, see: (a) S. Lou, P. N. Moquist and S. E. Schaus, J. Am.
Chem. Soc., 2007, 129, 15398; (b) S. Lou and S. E. Schaus, J. Am.
Chem. Soc., 2008, 130, 6922; (c) J. B. Bishop, S. Lou and
S. E. Schaus, Angew. Chem., Int. Ed., 2009, 48, 4337.
5 For reactions of boronic acids catalyzed by thioureas, see:
(a) Y. Yamaoka, H. Miyabe and Y. Takemoto, J. Am. Chem.
Soc., 2007, 129, 6686; (b) T. Inokuma, K. Takasu, T. Sakaeda and
Y. Takemoto, Org. Lett., 2009, 11, 2425.
6 For reactions of boronic acids and enals catalyzed by chiral
secondary amines, see: (a) S. Lee and D. W. C. MacMillan,
J. Am. Chem. Soc., 2007, 129, 15438; (b) S.-G. Kim, Tetrahedron
Lett., 2008, 49, 6148.
7 Yamamoto et al. employed boron complexes of O-monoacyltartaric
acids as asymmetric Lewis acid catalysts for Diels–Alder reactions,
aldol-type reactions, allylations, etc., and found 2,6-dialkoxy-
benzoyl derivatives to be effective. For leading references, see:
(a) K. Furuta, Y. Miwa, K. Iwanaga and H. Yamamoto, J. Am.
Chem. Soc., 1988, 110, 6254; (b) K. Furuta, T. Maruyama and
H. Yamamoto, J. Am. Chem. Soc., 1991, 113, 1041; (c) K. Ishihara,
Q. Gao and H. Yamamoto, J. Am. Chem. Soc., 1993, 115, 10412;
(d) K. Ishihara, M. Mouri, Q. Gao, K. Furuta and H. Yamamoto,
J. Am. Chem. Soc., 1993, 115, 11490.
Scheme
1
O-3,5-Di(tert-butyl)benzoyltartaric acid (1k)-catalyzed
conjugate addition. The values in parentheses indicate reaction
temperatures and times.
Then the reactions of other enones with boronic acids were
examined using catalyst 1k (Scheme 1). Although methyl
ketone-type enone 2b afforded adduct 4b in a low yield for
reactions with styrylboronic acid (3a), phenyl ketone-type
enones 2a and 2c–f showed good reactivities to give adducts
4a and 4c–f with good enantioselectivities (81–88% ee),
respectively. Enone 2e, which possessed p-MeOC6H4 as the
R2 group, reacted more smoothly than p-NO2-substituted
enone 2f.12 Furthermore, the effect of other boronic acids
was examined for the reaction with chalcone (2a). Although
alkenylboronic acid 3b was much less reactive than 3a, furan-
and benzofuranboronic acids 3c and 3d13 showed acceptable
reactivities to give adducts 4h and 4i with good selectivities,
respectively. These findings suggest that the enantioselectivity
depends on the structure of boronic acids rather than that of
enones. However, further studies are necessary to elucidate the
precise mechanism.14
8 Chiral carboxylic acids have been utilized as enantioselective
organocatalysts, see: (a) N. Momiyama and H. Yamamoto,
J. Am. Chem. Soc., 2005, 127, 1080; (b) T. Hashimoto and
K. Maruoka, J. Am. Chem. Soc., 2007, 129, 10054;
(c) T. Hashimoto and K. Maruoka, Synthesis, 2008, 3703;
(d) T. Hashimoto, M. Hirose and K. Maruoka, J. Am. Chem.
Soc., 2008, 130, 7556; (e) T. Hashimoto, N. Uchiyama and
K. Maruoka, J. Am. Chem. Soc., 2008, 130, 14380; (f) H. Ube,
S. Fukuchi and M. Terada, Tetrahedron: Asymmetry, 2010, 21,
1203.
9 D. G. Hall, Boronic Acids, ed. D. G. Hall, Wiley-VCH, Weinheim,
2005, ch. 1.
10 The addition of methanol (1 equiv.) or the use of water or tert-
butylalcohol (2 equiv.) instead of methanol afforded comparable-
results. However, methanol (4 equiv.) cut in the yield in half. It has
recently been reported that the presence of a small amount of
alcohol improves the outcome of binaphthol-catalyzed allyl-
boration of ketones, see ref. 3b.
11 O-Monoacylated L-tartaric acids were prepared via monoacylation
of dibenzyl L-tartarate and subsequent hydrogenolysis of the
benzyl esters, according to the reported procedure, see:
K. Furuta, Q.-Z. Gao and H. Yamamoto, Org. Synth., 1998,
Coll. Vol. 9, 722. See also ref. 7.
12 Due to the conjugation of the p-MeO group, enone 2e has a more
negatively charged carbonyl oxygen and a more positively charged
b-carbon than 2a, which may facilitate the coordination of the
catalyst–boronic acid complex and the migration of the R3 group.
13 For enantioselective conjugate additions of furanboronic acids to
enals, see ref. 6.
14 Rapid complexation between boronic acids and catalyst 1k could
be observed by 1H-NMR at room temperature. Catalysis by
the 1ꢀboron complex instead of 1 itself cannot be excluded at this
stage.
In summary, we have demonstrated for the first time that
O-monoacylated tartaric acids, particularly 3,5-di(tert-butyl)-
benzoyl derivative 1k, are effective enantioselective catalysts for
the asymmetric conjugate addition of boronic acids to enones.
Further investigations to improve the catalytic activity and to
extend the applicability to other reactions are underway.
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan.
c
7800 Chem. Commun., 2010, 46, 7799–7800
This journal is The Royal Society of Chemistry 2010