Hydroxyl group-directed organocatalytic asymmetric michael addition of α,β-unsaturated ketones with alkenylboronic acids

Article abstract of DOI:10.1021/ol9006053

The organocatalytic asymmetric Michael addition of organoboronic acids to ?-hydroxy enones in the presence of an iminophenol-type thiourea catalyst is demonstrated. The hydroxyl group in the substrates plays a critical role in this reaction.

Full text of DOI:10.1021/ol9006053

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2425-2428
Hydroxyl Group-Directed
Organocatalytic Asymmetric Michael
Addition of r,ꢀ-Unsaturated Ketones
with Alkenylboronic Acids
Tsubasa Inokuma, Kiyosei Takasu, Toshiyuki Sakaeda, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity,
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
takemoto@pharm.kyoto-u.ac.jp
Received March 23, 2009
ABSTRACT
The organocatalytic asymmetric Michael addition of organoboronic acids to γ-hydroxy enones in the presence of an iminophenol-type thiourea
catalyst is demonstrated. The hydroxyl group in the substrates plays a critical role in this reaction.
Asymmetric catalytic Michael addition of organoboronic
acids to various electrophiles is a powerful tool for the
construction of the carbon-carbon bonds.1 Due to their
stability toward air and moisture relative to other typical
organometallic reagents such as Grignard reagents2 and
organolithium compounds,3 organoboronic acids are con-
sidered to be some of the most useful carbon nucleophiles
in organic chemistry. Most of the reported asymmetric
catalytic Michael additions with organoboronic acids are in
the presence of metallic catalysts such as rhodium and chiral
phosphine ligands.1 On the other hand, at the beginning of
our research to achieve the organocatalytic asymmetric
Michael addition of organoboronic acids, there were only
two reported nonmetallic versions4 of these reactions.5 Chong
et al. reported the Michael addition of alkenyl and alkynyl
boronates to R,ꢀ-unsaturated ketones catalyzed by the
(1) For reviews, see: (a) Miyaura, N. Bull. Chem. Soc. Jpn. 2008, 81,
1535. (b) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829. For recent
examples, see: (c) Navarro, C.; Moreno, A.; Csaky, A. G. J. Org. Chem.
2009, 74, 466. (d) Nishikawa, T.; Kiyomura, S.; Yamamoto, Y.; Miyaura,
N. Synlett 2008, 2487. (e) Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet,
J. P.; Darses, S. Angew. Chem., Int. Ed. 2008, 47, 7669. (f) Nishimura, T.;
Nagaosa, M.; Hayashi, T. Chem. Lett. 2008, 37, 860.
(4) For recent reviews of organocatalysts, see: (a) Yu, X.; Wang, W.
Chem. Asian J. 2008, 3, 516. (b) Doyle, A. G.; Jacobsen, E. N. Chem. ReV.
2007, 107, 5713. (c) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (d)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5318. (e) Dalko,
P. I. EnantioselectiVe Organocatalysis; Wiley-VCH: Weinheim, 2007. (f)
Brekessel, H.; Groger, H. Asymmetric Organocatalysis, Wiley-VCH:
Weinheim, 2004.
(2) For recent examples, see: (a) Biswas, K.; Woodward, S. Tetrahedron:
Asymmetry 2008, 19, 1702. (b) Wang, S.; Ji, S.; Loh, T. J. Am. Chem. Soc.
2007, 129, 276. (c) Wang, S.-Y.; Ji, S.-J.; Loh, T.-P. J. Am. Chem. Soc.
2007, 129, 276.
(3) For recent examples, see: (a) Yamamoto, Y.; Suzuki, H.; Yasuda,
Y.; Iida, A.; Tomioka, K. Tetrahedron Lett. 2008, 49, 4582. (b) Duguet,
N.; Harrison-Marchand, A.; Maddaluno, J.; Tomioka, K. Org. Lett. 2006,
8, 5745.
(5) (a) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2007, 129, 4908. (b)
Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2005, 127, 3244.
10.1021/ol9006053 CCC: $40.75
Published on Web 04/29/2009
 2009 American Chemical Society

electron-deficient BINOL catalyst.5 Recently, we reported
that the bifunctional amino alcohol thiourea 1a could be used
for the 1,2-addition of organoboronic acids to acylquinolium
species.6,7 According to our and Chong’s reports, it seemed
that boronic acids were activated by the hydroxyl groups of
the catalysts. Therefore, we speculate that if a hydroxyl group
is added to the substrates, dual coordination of the substrate
and the catalyst to the organoboronic acid should enhance
the reactivity (Scheme 1).8,9
H2O2 and Na2CO3, diol 5 was isolated in 22% yield with
64% ee (Table 1, entry 1). The same reaction with 1b11 gave
Table 1. Catalyst Screening of the Michael Additiona
Scheme 1
Furthermore, the hydroxyl group of the products could be
used for further transformations. We report here an organo-
catalytic asymmetric Michael addition of organoboronic acid
to R,ꢀ-unsaturated ketones bearing a hydroxyl group at the
γ-position together with its transformation to obtain unique
cyclic compounds. Based on our hypothesis, we investigated
the Michael addition of p-methoxyphenylvinyl boronic acid
3a to γ-hydroxyenone 2a in the presence of amino alcohol
thiourea 1a which had been developed previously.6 Although
the desired Michael adduct 4a was indeed obtained in
moderate yield, the enantiomeric excess of 4a was somewhat
low (36% ee). Recently, the oxy-Michael addition of
arylboronic acids to 2a catalyzed by the thiourea derived
from a cinchona alkaloid was reported by Falck et al.10 The
obtained Michael adduct was converted to diol 5 under
oxidative workup. When we treated the reaction mixture with
4a
5
entry catalyst time (h) yieldb (%) eec (%) yieldb (%) eec (%)
1
2
3
4
5
6
7
8
9e
1a
1b
1cd
1d
1e
1f
1g
1h
1f
36
24
72
72
36
24
72
72
36
52
<1
20
38
91
92
36
16
0
36
22
88
0
0
0
0
16
0
64
88
8
47
95
97
26
14
33
0
a Reactions were carried out with 2a (1.0 equiv), 3a (2.0 equiv), and
catalyst 1a-h (10 mol %) in toluene at room temperature. b Isolated yield.
c Determined by chiral HPLC. d Catalyst loading was 20 mol %. e 6 was
used instead of 2a.
(6) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007,
129, 6686
.
(7) Similar BINOL catalysts such as Chong’s could be applied for the
asymmetric 1,2-addition of organoboronic acids; see: (a) Lou, S.; Schaus,
S. E. J. Am. Chem. Soc. 2008, 130, 6922. (b) Lou, S.; Moquist, P. M.;
Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398. (c) Lou, S.; Moquist,
the diol 5 exclusively in high yield with 88% ee (entry 2).
These results suggest that the basic amine might promote
the production of diol, while the alcohol moieties promote
the production of vinyl adduct 4a. Therefore, we examined
several thioureas bearing a hydroxyl group and no basic
P. M.; Schaus, S. E. J. Am. Chem. Soc. 2006, 128, 12660
(8) During the course of our investigation, a related report has appeared
in the literature; see: (a) Kim, S.-G. Tetrahedron Lett. 2008, 49, 6148
.
.
(9) (a) Petasis, N. A.; Akrltopoulou, I. Tetrahedron Lett. 1993, 34, 583.
(b) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445. (c)
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798. (d)
Prakash, G. K. S.; Mandal, M.; Schweized, S.; Petasis, N. A.; Olah, G. A.
Org. Lett. 2000, 2, 3173
(10) Li, D. R.; Murugan, A.; Falck, J. R. J. Am. Chem. Soc. 2008, 130,
46.
.
(11) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672. (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119.
2426
Org. Lett., Vol. 11, No. 11, 2009

amino group. Alcoholic catalyst 1c showed poor reactivity
for the Michael addition of the vinylboronic acid, but the
production of 5 was completely suppressed (entry 3). The
use of thiourea 1d, which has a more acidic phenol group,
resulted in an increase in the chemical yield of 4a with no
production of diol 5 (entry 4). Based on these results, we
next screened the phenol thiourea catalysts. As a result, we
found that iminothiourea 1e provided the desired vinyl adduct
4a in good yield and high ee (entry 5). Thiourea 1f, which
is derived from 2-hydroxy-5-methoxybenzaldehyde, showed
increased reactivity in this reaction (entry 6). To investigate
the role of the hydroxyl group and thiourea moiety of the
catalyst, we synthesized catalysts 1g and 1h. These catalysts
gave diminished yield and ee (entries 7 and 8). In addition,
substrate 6 (X ) H) gave neither the Michael adduct 4a nor
the diol 5 under the same conditions as in entry 5 (entry 9).
Therefore, the hydroxyl groups of both the substrate and
catalysts must participate in this reaction.
and 1f gave slightly diminished enantioselectivity (94% yield,
77% ee, data not shown). After several examinations, we
found that the use of ethylboronate 3b6a instead of 3a
improved the stereoselectivity (entry 5). The substrate with
a bulky naphthyl group 2g also gave a good result (entry 6).
With regard to the boronic acids, the electrodensity of the
reagents significantly affected the yield. When relatively
electron-deficient nucleophiles 3c and 3f were used in this
reaction, 20 mol % of the catalyst 1f and a prolonged reaction
time were necessary to achieve a good yield (entries 7 and
10).12 In contrast, electron-rich nucleophiles 3d and 3e gave
good results under the same reaction conditions as with 3a
(entries 8 and 9). In addition, the heteroaromatic vinylboronic
acid 3g6 could be used for this transformation (entry 11).
The absolute configuration of the Michael adduct 4 was
determined by the conversion of 4h into known compound
7,13 as shown in Scheme 2. Dess-Martin oxidation14 of 4h
Having established the optimized catalyst for this Michael
addition, we next screened several substrates 2b-g and
organoboronic acids 3a-g (Table 2). First, the four substrates
Scheme 2
.
Determination of the Absolute Configuration of the
Michael Adduct 4h
Table 2. Substrate Scope of the Michael Additiona
was followed by Pinnick oxidation15and condensation with
morpholine in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-
2-yl)-4-methylmorpholinium chloride (DMTMM)16 to give
ketone 7 in 45% yield in three steps. Comparison of the
specific rotation of synthetic 7 with that reported in the
literature showed that the Michael adduct 4h has an S-
configuration.
We explored the transformation of the Michael adduct 4a
into unique cyclic compounds (Scheme 3). Unexpectedly, the
entry
2
3
time (h)
product
yieldb (%)
eec (%)
1
2
3
4
2b
2c
2d
2e
2f
2g
2a
2a
2a
2a
2a
3a
3a
3a
3a
3b
3a
3c
3d
3e
3f
24
24
24
24
24
36
72
24
36
72
24
4b
4c
4d
4e
4f
4g
4h
4i
81
84
86
95
82
91
79
99
87
64
84
97
94
95
94
97
92
92
98
92
93
91
Scheme 3. Transformations of the Michael Adduct 4a
5
6
7d
8
9
4j
4k
4l
10d
11
3g
a Reactions were carried out with 2 (1.0 equiv), 3 (2.0 equiv) and catalyst
1h (10 mol %) in toluene at room temperature. b Isolated yield. c Determined
by chiral HPLC. d Catalyst loading was 20 mol %.
with several substituents at the para position of the phenyl
groups were treated with p-methoxyphenylvinylboronic acid
3a in the presence of iminothiourea 1f to give the desired
products 4b-e in good yields and ee’s (entries 1-4). In the
case of meta-substituted substrate 2f, the reaction with 3a
Org. Lett., Vol. 11, No. 11, 2009
2427

reaction of Michael adduct 4a with o-nitrobenzenesulfonamide
under Mitsunobu conditions17 produced the cyclopropyl ketone
8 in 72% yield with high diastereoselectivity. In addition,
successive treatment of 4a with N-bromosuccinimide and
t-BuOK provided the bicycle [3.1.0] compound 9 in 57% yield.
Proteins Research Program” from the Ministry of Education,
Culture, Sports, Science and Technology of Japan, JSPS
KAKENHI (3316). T.I. thanks the JSPS for a Fellowship.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for catalysts 1d-h, substrates
2a-g, products 4a-l, 8, and 9. This material is available
free of charge via the Internet at http://pubs.acs.org.
In summary, we have developed a novel catalyst 1f for
the asymmetric Michael addition of various organoboronic
acids or organoboronates to γ-hydroxyenones. The Michael
adducts obtained were successfully transformed into cyclo-
propyl and bicyclic compounds. Further studies are currently
underway to clarify the precise mechanism of the thiourea-
catalyzed asymmetric Michael addition of organoboronic
acids.
OL9006053
(12) When less reactive nucleophiles were used, 2-phenylfuran was
produced as the byproduct, and the yield of the desired products had been
decreased. For the reactions of γ-hydroxy enones, see: Greatrex, B. W.;
Kimber, M. C.; Taylor, D. K.; Tiekink, T. K. J. Org. Chem. 2003, 68,
4239.
(13) Zigterman, J. L.; Woo, J. C. S.; Walker, S. D.; Tedrow, J. S.; Borths,
C. J.; Bunnel, E. E.; Faul, M. M. J. Org. Chem. 2007, 72, 8870.
(14) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(15) Krause, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825.
(16) Kunishima, K.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S.
Tetrahedron Lett. 1999, 40, 5327.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research (B) (Y.T.) and Scientific
Research on Priority Areas: Advanced Molecular Transfor-
mations of Carbon Resources (Y.T. and K.T.), “Targeted
(17) Mitsunobu, O. Synthesis 1981, 1.
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