Asymmetric Mukaiyama aldol reaction of nonactivated ketones catalyzed by allo-threonine-derived oxazaborolidinone

Article abstract of DOI:10.1021/ol802087u

(Chemical Equation Presented) Asymmetric Mukaiyama aldol reaction of nonactivated ketones is realized for the first time by using an oxazaborolidinone catalyst derived from O-benzoyl-N-tosyl-allo-threonine. By employing a dimethylsilyl ketene S,O-acetal as a nucleophile, a variety of acetophenone derivatives afford the corresponding tertiary β-hydroxy carbonyl compounds with high enantioselectivity up to 98% ee.

Full text of DOI:10.1021/ol802087u

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4999-5001
Asymmetric Mukaiyama Aldol Reaction
of Nonactivated Ketones Catalyzed by
allo-Threonine-Derived
Oxazaborolidinone
Shinya Adachi and Toshiro Harada*
Department of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
harada@chem.kit.ac.jp
Received September 5, 2008
ABSTRACT
Asymmetric Mukaiyama aldol reaction of nonactivated ketones is realized for the first time by using an oxazaborolidinone catalyst derived
from O-benzoyl-N-tosyl-allo-threonine. By employing a dimethylsilyl ketene S,O-acetal as a nucleophile, a variety of acetophenone derivatives
afford the corresponding tertiary ꢀ-hydroxy carbonyl compounds with high enantioselectivity up to 98% ee.
Chiral tertiary alcohols are important subunits frequently
found in biologically active compounds. Recently, catalytic
asymmetric aldol addition to ketone acceptors has received
growing attention since the resulting tertiary aldols are
valuable building blocks for these subunits. A number of
efficient Lewis acid catalysts have been developed for the
asymmetric Mukaiyama aldol reaction of aldehyde accep-
tors.1 However, for the reaction of ketones, successful
examples are so far limited to those of highly reactive
R-ketoesters and R-diketones.2,3 The catalytic asymmetric
reaction of simple ketones has been realized based upon
different approaches.4-8 The first successful reaction was
reported by Denmark and co-workers,4 employing a trichlo-
rosilyl ketene acetals with chiral Lewis base catalysts.
Shibasaki and co-workers5 have developed an efficient
catalytic reaction involving a chiral copper enolate interme-
diate, by using trimethylsilyl ketene acetals with chiral
copper(I) fluoride-phosphine catalysts.6 Very recently, a new
strategy that relies on domino reduction/aldol reaction
(4) (a) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233–
4235. (b) Denmark, S. E.; Fan, Y.; Eastgate, M. D. J. Org. Chem. 2005,
70, 5235–5248.
(5) (a) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2003, 125, 5644–5645. (c) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2006, 128, 7164–7165.
(6) For relevant asymmetric vinylogous aldol reactions of ketones, see:
Moreau, X.; Baza´n-Tejeda, B.; Campagne, J.-M. J. Am. Chem. Soc. 2005,
127, 7288–7289.
(1) Carreira, E. M. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima,
I., Ed.; Wiley-VCH: Weinheim, 2000; Chapter 8B2.
(2) (a) Evans, D. A.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W.
J. Am. Chem. Soc. 1999, 121, 686–699. (b) Langner, M.; Re´my, P.; Bolm,
C. Chem. Eur. J. 2005, 11, 6254–6265. (c) Akullian, L. C.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 6532–6533. (d) Sedelmeier,
(7) (a) Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225–4228. (b)
Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew. Chem., Int.
Ed. 2006, 45, 1292–1297. (c) Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2006, 128, 14440–14441. (d) Oisaki, K.; Zhao, D.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 7439–7443. (e)
Shiomi, T.; Nishiyama, H. Org. Lett. 2007, 9, 1651–1654.
(8) For asymmetric Reformatsky reaction to ketones, see: (a) Cozzi, P. G.
Angew. Chem., Int. Ed. 2006, 45, 2951–2954. (b) Ferna´ndez-Iba´nez, M. A.;
Macia´, B.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2008, 2571–
2573.
J.; Hammerer, T.; Bolm, C. Org. Lett. 2008, 10, 917–920
.
(3) For organocatalytic asymmetric aldol reaction of activate ketones,
see: (a) Bøgevig, A.; Kumaragurubaran, N.; Jørgensen, K. A. Chem.
Commun. 2002, 620–621. (b) Liu, J.; Yang, Z.; Wang, Z.; Wang, F.; Chen,
X.; Liu, X.; Feng, X.; Su, Z.; Hu, C. J. Am. Chem. Soc. 2008, 130, 5654–
5655
.
10.1021/ol802087u CCC: $40.75
Published on Web 09/26/2008
2008 American Chemical Society

by the improvement in conversion and enantioselectivity,
reaction conditions were surveyed for the reaction with 3b.10
The reactions in diethyl ether and in toluene exhibited
enhanced selectivity at -40 °C (entries 3 and 6). While
byproduct formation of 7 became significant at -10 °C in
diethyl ether (entry 4), the combined yield of the aldol
derivatives 4a, 5, and 6 was improved without degrading
high enantioselectivity by carrying out the reaction in toluene
at -10 °C (entry 7) and at higher concentration (entry 8).
Upon treatment with aqueous 1 N HCl in THF, silyl deriv-
atives 5 and 6 were cleanly converted into 4a without
lowering the enantioselectivity. Thus, the reaction mixture
of entry 8, after such treatment, afforded 4a of 94% ee in
68% yield (entry 9).
sequence between R,ꢀ-unsaturated esters and ketones has
been developed for the preparation of tertiary aldols with
an R-methyl group.7
We have recently reported that allo-threonine-derived
oxazaborolidinone (OXB) 1 is an efficient catalyst for the
asymmetric Michael reaction9a-c and Diels-Alder reac-
tion9d,e of acyclic R,ꢀ-unsaturated ketones.9f The character-
istic feature of the OXB catalyst for the enantioselective
activation of the less reactive ketone carbonyl groups
prompted us to employ it in the ketone aldol reaction. Herein,
we wish to report the first example of the asymmetric
Mukaiyama aldol reaction of nonactivated ketones by
employing a dimethylsilyl ketene S,O-acetal as a nucleophile
with OXB 1.
The scope of the OXB-catalyzed ketone aldol reaction was
examined in toluene at -10 °C (eq 2, Table 2). A variety of
The potential of OXB catalyst 1 in ketone aldol reaction
was first evaluated in the reaction of p-bromoacetophenone
(2a) with silyl ketene S,O-acetals 3a,b (eq 1). The reaction
Table 2. Asymmetric Aldol Reaction of Ketones 2a-q with 3ba
entry
ketone R1
R2 product yield (%) ee (%)
1
2a
p-BrC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
68
61
76
78
36
65
65
68
65
68
53
53
54
44
40
51
23
94
91
91
94
92
93
95
92
94
94
98
92
81
97
55
52
66
2
2b C6H5
2c
2d 3,5-Br2C6H3
2e
2f
3b
m-BrC6H4
4b c
,
5
o-BrC6H4
p-ClC6H4
m-ClC6H4
6b d
with trimethylsilyl derivative 3a in the presence of 1 (20
mol %) in dichloromethane at -40 °C for 24 h gave aldol
product 4a in 20% yield and 84% ee (Table 1, entry 1). When
,
7b d
2g
,
8b d
2h p-CF3C6H4
2i m-CF3C6H4
,
9b d
,
10b d 2j
p-EtOCOC6H4 Me
,
11e
12
13
14
15
16
17
2k p-NO2C6H4
2l p-MeC6H4
2m p-MeOC6H4
2n 2-naphthyl
Me
Me
Me
Me
Me
Me
Et
Table 1. Asymmetric Aldol Reaction of p-Bromoacetophenone
(2a) with Silyl Ketene S,O-Acetals 3a,b Catalyzed by OXB 1a
yield (%) (ee (%))
2o
2-thienyl
entry solvent time (h) temp (°C)
4aa
5
6
7
2p C6H5CH2CH2
2q C6H5
1b
2
3
4
5
CH2Cl2
CH2Cl2
Et2O
24
24
24
97
2
24
48
48
48
48
-40
-40
-40
-10
-40
-40
-10
-10
-10
-10
20 (84)
19 (90)
23 (94) 18
17 (96)
21 (94)
25 (93)
28 (94) 17
27 (93) 27 14 15
68 (94)
19 (94)
a Unless otherwise noted, reactions were carried out with 2 (1.0 mmol),
3b (1.5 mmol), and 1 (0.2 mmol) in toluene (0.5 mL) at -10 °C for 48 h.
b 1.5 mL of toluene was used. c The reaction was carried out for 9 h. d The
reaction was carried out for 21 h. e The reaction was carried out at room
temperature.
9c 8d 17
5
6
Et2O
0
0
0
15 31
toluene
toluene
toluene
toluenee
toluenee
toluene
0
0
4
0
0
5
6
7
8
acetophenone derivatives bearing substituents at the para-,
meta-, or ortho-position underwent reaction with 3b to give
the corresponding aldol products 4 in high enantioselectivity
(91-98% ee) and in satisfactory yield (entries 1-12).
Specifically, aldol products 4j and 4k bearing ethoxycaro-
bonyl and nitro groups, respectively, could be prepared
9f
13g
10b
a Unless otherwise noted, reactions were carried out by using 2a (1.0
mmol), 3b (1.5 equiv), and OXB 1 (20 mol %) in a solvent (2 mL). b 3a
was used as a nucleophile. c 91% ee. d 90% ee. e 0.5 mL of toluene was
used. f The crude products were treated with aqueous 1 N HCl in THF at
room temperature. g 44% ee. The absolute configuration was determined
to be S (see Supporting Information).
(9) (a) Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo,
M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68, 10046–10057. (b) Harada,
T.; Adachi, S.; Wang, X. Org. Lett. 2004, 6, 4877–4879. (c) Harada, T.;
Yamauchi, T.; Adachi, S. Synlett 2005, 2151–2154. (d) Singh, R. S.; Harada,
T. Eur. J. Org. Chem. 2005, 3433–3435. (e) Singh, R. S.; Adachi, S.;
Tanaka, F.; Yamauchi, T.; Inui, C.; Harada, T. J. Org. Chem. 2008, 73,
212–218. (f) Harada, T.; Kusukawa, T. Synlett 2007, 1823–1835.
(10) For the advantageous use of dimethylsilyl enolates, see ref 9b and
references therein.
dimethylsilyl derivative 3b was used as a nucleophile under
similar conditions, 4a (90% ee) and its silyl derivatives, 5
(91% ee) and 6 (90% ee), were obtained in 36% combined
yield, together with reduction product 7 (entry 2). Encouraged
5000
Org. Lett., Vol. 10, No. 21, 2008

enantioselectively (entries 10 and 11). High selectivity was
also obtained in the reaction of 2-naphthophenone (2n) (entry
14), while on the other hand the reactions of heteroaromatic
ketone 2o, aliphatic ketone 2p, and ethyl ketone 2q resulted
in lower selectivity (entries 15-17). The reactions were
sluggish for o-bromo derivative 2e (entry 5) and 2l and 2m
with electron-donating substituents at the para-position
(entries 12 and 13).
The absolute stereochemical course of the present reac-
tion11 is rationalized in terms of an activated complex model
8, in which nucleophile 3b attacks selectively from the open
re face of a ketone (Scheme 1). The attack of ketene silyl
and 6 as well as 4a (entries 7 and 8). The result can be
rationalized by assuming a stepwise silyl-group migration
via silyl ester 10;12 initial rapid migration to form 10
followed by slow formation of 5′ with regeneration of OXB
1. According to this pathway, at the low temperature, the
reaction stopped at 10 to give 4 after hydrolysis as an
exclusive aldol product. At higher temperature, transforma-
tion of 10 to 5′ proceeded slowly to afford the observed
mixture of products after workup.13 In the reaction with
trimethylsilyl derivative 3a, the formation of the correspond-
ing silyl product 5′ was not observed even at -10 °C after
48 h (entry 10). The result suggests that the crucial
conversion of silyl ester 10 into 5′ is accelerated significantly
for the dimethylsilyl derivative in comparison with the
trimethylsilyl derivative.
Scheme 1. Plausible Reaction Pathway
In summary, we have developed an OXB-catalyzed
asymmetric aldol reaction of nonactivated aromatic ketones,
providing tertiary ꢀ-hydroxy carbonyl compounds with high
enantioselectivity. The use of dimethylsilyl ketene S,O-acetal
3b, in place of the conventional trimethylsilyl derivative 3a,
is shown to be essential to achieve catalytic reaction and
high selectivity.
Acknowledgment. This work was supported partially by
a grant from the Ministry of Education, Science, Sports and
Culture of the Japanese Government (Grant-in-Aid for
Scientific Research no. 17550101).
Supporting Information Available: Experimental pro-
cedures and characterization of the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
acetal 3a,b to activated enone 8 first generates unstable
intermediate 9. A pathway involving direct silyl-group
migration of 9 to give 5′ is less likely from the following
observation. In the reaction of 2a with 3b, the formation of
4a (21%) was relatively fast at -40 °C (entry 5 in Table 1).
However, prolonged reaction time and higher temperature
were required for the reaction to proceed in a catalytic
manner, leading to the formation of the silyl derivatives 5
OL802087U
(12) An analogous silyl ester intermediate was proposed previously for
a oxazaborolidinone-catalyzed aldol reaction: Parmee, E. R.; Tempkin, O.;
Masamune, S.; Abiko, A. J. Am. Chem. Soc. 1991, 113, 9365–9366.
(13) Treatment of 5 (93% ee) with an equimolar amount each of 2a
and 1 in toluene at -10 °C for 18 h gave 6 (30% yield, 93% ee) and 7
(28% yield, 34% ee). The result suggests that, during the reaction, a part
of 5 is converted into the hydroxydimethylsilyl derivative by the reaction
with 2a.
(11) For the absolute structure determination of 4b and 4q, see
Supporting Information.
Org. Lett., Vol. 10, No. 21, 2008
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