Asymmetric Mukaiyama-Michael Addition of Acyclic Enones Catalyzed by allo-Threonine-Derived B-Aryloxazaborolidinones

Article abstract of DOI:10.1021/ol016062r

(Formula Presented) O-(2-Naphthoyl)-N-tosyl-L-allo-threonine-derived B-phenyloxazaborolidinone catalyzes the asymmetric Mukaiyama-Michael addition of simple acyclic enones to give adducts of 54-85% ee. 2,6-Diisopropylphenol as an additive is demonstrated

Full text of DOI:10.1021/ol016062r

ORGANIC
LETTERS
2001
Vol. 3, No. 13
2101-2103
Asymmetric Mukaiyama−Michael
Addition of Acyclic Enones Catalyzed
by allo-Threonine-Derived
B-Aryloxazaborolidinones
Toshiro Harada,* Hiroyoshi Iwai, Hiroshi Takatsuki, Katsuhiro Fujita,
Mikako Kubo, and Akira Oku
Department of Chemistry, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto, 606-8585, Japan
harada@chem.kit.ac.jp
Received May 3, 2001
ABSTRACT
O-(2-Naphthoyl)-N-tosyl-L-allo-threonine-derived B-phenyloxazaborolidinone catalyzes the asymmetric Mukaiyama−Michael addition of simple
acyclic enones to give adducts of 54−85% ee. 2,6-Diisopropylphenol as an additive is demonstrated to effectively retard the undesirable
Si+-catalyzed racemic pathway.
The Lewis acid-promoted conjugate addition of silyl ketene
acetals and enolsilanes to R,â-unsaturated carbonyl com-
pounds, the Mukaiyama-Michael addition,1 has become a
powerful method for the preparation of 1,5-dicarbonyl
compounds. However, only limited advances have been made
toward the enantioselective version of the reaction using a
chiral Lewis acid catalyst.2 Most recently, Evans et al.
demonstrated the utility of C2-symmetric chiral Cu(II) Lewis
acids for the reaction of bidentate Michael acceptors such
as alkylidene malonates and alkenoyl oxazolidinones.3 Herein
we wish to report that L-allo-threonine-derived oxazaboro-
lidinones 1 are efficient catalysts for the asymmetric
Mukaiyama-Michael addition of simple acyclic enones. The
use of 2,6-diisopropylphenol as an additive to retard the
undesirable Si+-catalyzed racemic pathway is also described.
Oxazaborolidinone 1a was prepared by the reaction of
O-benzoyl-N-tosyl-L-allo-threonine4,5 with dichlorophenyl-
boron in CH2Cl2. Slow addition of benzalacetone (2) during
4 h to a solution of TBS ketene S,O-acetal 3a (1.5 equiv)
and 1a (0.4 equiv) in CH2Cl2 at -78 °C afforded enantio-
merically enriched Michael adduct (S)-4a6,7 (83% ee) and
(3) (a) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am.
Chem. Soc. 1999, 121, 1994-1995. (b) Evans, D. A.; Willis, M. C.;
Johnston, J. N. Org. Lett. 1999, 1, 865-868. (c) Evans, D. A.; Johnston, J.
S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635-1649. (d) Evans, D.
A.; Rovis, T.; Kozlowski, M. C.; Downey, C. W.; Tedrow, J. S. J. Am.
Chem. Soc. 2000, 122, 9134-9142.
(4) O-Acyl-N-sulfonyl-L-allo-threonines 1a-i were prepared from L-allo-
threonine5 by the following sequence: (1) R1SO2Cl, ether, aqueous NaHCO3,
(2) BnOH, TsOH, toluene reflux, (3) R2COCl, pyridine, (4) H2, Pd/C.
(5) Elliot, D. F. J. Chem. Soc. 1950, 62-68.
(6) The absolute configuration of 2a was determined by converting to
the methyl ester derivative7 on treatment of 2a with silver trifluoroacetate
in methanol.
(1) Narasaka, T.; Soai, K.; Mukaiyama, T. Chem. Lett. 1974, 1223-
1224.
(2) (a) Kobayashi, S.; Suda, S.; Yamada, M.; Mukaiyama, T. Chem. Lett.
1994, 97-100. (b) Bernardi, A.; Colombo, G.; Scolastico, C. Tetrahedron
Lett. 1996, 37, 8921-8924. (c) Bernardi, A.; Karamfilova, K.; Sanguinetti,
S. Scolastico, C. Tetrahedron 1997, 53, 13009-13026. (d) Kitajima, H.;
Ito, K.; Katsuki, T. Tetrahedron 1997, 53, 17015-17028. (e) Nishikori,
H.; Ito, K.; Katsuki, T. Tetrahedron: Asymmetry 1998, 9, 1165-1170.
10.1021/ol016062r CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/05/2001

racemic enolsilane 5a (2% ee) in 6% and 71% yield,
respectively (eq 1). The result implies the intrinsically high
It was anticipated that a phenol as an additive would react
with intermediate 6b (Si ) TMS) to give adduct 4a and the
corresponding aryl silyl ether with simultaneous regeneration
of the catalyst 1a.9 Indeed, slow addition (4 h) of a mixture
of enone 2 and 2,6-diisopropylphenol (1.0 equiv) to a solution
of 3b and oxazaborolidinone 1a (0.4 equiv) in CH2Cl2 at
-78 °C afforded 4a in 50% ee (80% yield) together with
the formation of diisopropylphenyl trimethylsilyl ether.
Examination of a variety of substituted phenols as additives
revealed that steric environment around the hydroxy group
is crucial. 2,6-Dimethylphenol, for example, did not give a
good result (25% ee) probably due to the complexation of
the phenol with 1a. On the other hand, sterically hindered
2,6-di(tert-butyl)phenol could not trap the TMS group,
resulting in a low ee (24%) of the adduct.
We then focused our attention to the optimization of the
structure of allo-threonine-derived oxazaborolidinones. For
this purpose, the reaction of 2 with TBS ketene S,O-acetal
3a was chosen because the ee of 4a in this reaction might
tell us the intrinsic enantioselectivity of the catalyst not
obscured by the racemic pathway. As shown in the results
summarized in Table 1, the modification of the aryl group
enantioselectivity of oxazaborolidinone 1a. Thus, plausible
intermediate 6 (Si ) TBS) might undergo intermolecular silyl
group transfer to enone 2 to catalyze a nonenantioselective
reaction (path b),8 rather than undergoing intramolecular
transfer to the enolate oxygen atom to regenerate 1a (path
a) (Scheme 1). The adduct (S)-4a of high ee might be derived
from boron enolate 7, thus formed.
Scheme 1. Chiral Lewis Acid- vs Si+-Promoted Pathways
Table 1. Asymmetric Michael Addition of 2 and 3a with
Oxazaborolidinones 1a-ia
1
R1
R2SO2
R3
ee (%) of 4a b
1a
1b
1c
1d
1e
1f
1g
1h
1i
C6H5
C6H5
C6H5
C6H5
CH3
3,5-(MeO)2C6H3
2-naphthyl
2-naphthyl
Ts
Ts
Ts
Ms
Ts
Ts
Ts
Ts
Ts
C6H5
83
83
82
82
67
87
88
89
89
p-ClC6H4
m-ClC6H4
C6H5
C6H5
C6H5
C6H5
m-ClC6H4
p-ClC6H4
2-naphthyl
a The reaction was carried out by adding a solution of 2 in CH2Cl2 to a
solution of 3a (1.5 equiv) and 1a-i (0.4 equiv) in CH2Cl2 during 4 h at
-78 °C. The yields of (S)-4a were 6-36%. b Determined by chiral HPLC
using a Chirapak AD column.
Under similar conditions, the reaction of the enone with
TMS ketene S,O-acetal 3b in the presence of 1a (0.4 equiv)
afforded the corresponding enolsilane 5b exclusively, which
was hydrolyzed with 1 N HCl to give adduct (S)-4a of 32%
ee in 76% yield (eq 2). The formation of nonracemic
attached to the boron atom of O-benzoyl derivative 1a did
not affect the enantioselectivity of the resulting oxazaboro-
lidinones (1b,c).10,11 N-Methanesulfonyl derivative 1d also
exhibited a similar ee of 82%. On the other hand, the
enantioselectivity was influenced by the structure of the
O-acyl group. An improved enantioselectivity was observed
for 3,5-dimethoxybenzoyl derivative 1f and 2-naphthoyl
derivatives 1g-i. The later exhibited high ee values (88-
89%) irrespective of the structures of the B-aryl group.
enolsilane 5b as an initial product suggests the regeneration
of the catalyst from the intermediate 6b (Si ) TMS) (path
a). However, the Si+-catalyzed racemic pathway (path b)
might still be predominant, lowering the enantioselectivity
of the adduct.
(7) Enders, D.; Papadopoulos, K. Tetrahedron Lett. 1983, 24, 4967-
4970.
(8) (a) Carreira, E. M.; Singer, R. A. Tetrahedron Lett. 1994, 35, 4323-
4326. (b) Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994,
116, 8837-8838. (c) Hollis, T. K.; Bosnich, B. J. Am. Chem. Soc. 1995,
117, 4570-4581.
The reaction of enone 2 with TMS ketene acetal 3b was
examined by using O-(2-naphthoyl) derivatives 1g,h in the
2102
Org. Lett., Vol. 3, No. 13, 2001

Table 2. Asymmetric Michael Addition of 2 and 3b with
Oxazaborolidinones 1a,g,h in the Presence of
2,6-Diisopropylphenola
Table 3. Asymmetric Michael Addition of Acyclic Enonesa
product
3b
entry catalyst (equiv) (equiv)
additive concnb
(M)
yield (%) ee (%)c
1
2
3
4
5
6d
7
8
1a
1g
1.5
1.5
1.5
3.0
3.0
3.0
1.5
3.0
1.0
1.0
1.0
3.0
3.0
3.0
1.0
3.0
0.1
0.2
0.1
0.1
0.2
0.1
0.1
0.1
80
64
89
81
77
88
66
67
50
59
64
74
81
79
63
80
enone 2
3g
yield
(%)
eeb,c
(%)
entry
R1
R2
CH3
p-MeC6H4 CH3
(equiv)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
Ph
0.2
0.2
0.2
0.2
0.4
0.4
0.4
0.4
88
57
94
69
93
71
72
60
79
54
85
69
61
81
16
84
p-ClC6H4
m-ClC6H4
Ph
CH3
CH3
CH3CH2
(CH3)2CH
(CH3)3C
CH3
1h
Ph
Ph
a Unless otherwise noted, 0.4 equiv of a catalyst was used. b The initial
concentration of a catalyst in CH2Cl2. c Determined by chiral HPLC using
a Chirapak AD column eluting with hexane-2-propanol mixtures. d 0.2
equiv of a catalyst was used.
2g
2h d
CH3
a The reaction was carried out by using 3b (3.0 equiv) and 2,6-
diisopropylphenol (3.0 equiv) at -78 °C in CH2Cl2. b ee was determined
by chiral HPLC using a Chirapak AD or a Chirapak ADH column eluting
with hexane-2-propanol mixtures. c The absolute configurations of 4a,e
and 4h were determined by specific rotation of the methyl ester derivative7
and 1H NMR analysis of the (R)-1-(R-naphthyl)ethylamide derivative,13
respectively. d Contains 30% mesityl oxide.
presence of 2,6-diisopropylphenol (Table 2). These oxaza-
borolidinones exhibited higher ee values than O-benzoyl
derivative 1a under the reaction conditions in which 1.5 equiv
of 3b and 1.0 equiv of the additive were used at 0.1 M in
CH2Cl2 (entries 3 and 7 vs entry 1). B-(m-Chlorophenyl)
derivative 1h of higher Lewis acidity promoted the
Mukaiyama-aldol reaction of the adduct as well, resulting
in its lower chemical yield. The use of the additive in excess
(3 equiv) considerably improved the enantioselectivity
(entries 4 and 8). The best result of 81% ee was obtained
when the reaction was conducted with 1g at higher concen-
tration (0.2 M) (entry 5). The reaction using 0.2 equiv of
the catalyst afforded a comparable ee (79%) as well as a
high chemical yield (entry 6).12
substituted benzalacetones, the p-chloro derivative exhibited
the highest enantioselectivity of 85% ee (entry 3). The
structure of the alkyl group attached to the carbonyl
influences the enantioselectivity. Although the reaction of
the tert-butyl derivative was nonselective (entry 7), an
enantioselectivity comparable to that of benzalacetone was
obtained for the isopropyl derivative (entry 6). It should be
noted that the present reaction could be equally applicable
to a simple aliphatic enone (entry 8).
Asymmetric Michael addition of other acyclic enones was
examined by using 1g as a catalyst (Table 3). Of the
In summary, we have developed O-aroyl-L-allo-threonine-
derived oxazaborolidinones 1 as Lewis acid catalysts for the
asymmetric Mukaiyama-Michael addition. The enantio-
selective reaction of simple acyclic enones has been achieved
for the first time by using O-(2-naphthoyl) derivative 1g.
2,6-Diisopropylphenol as an additive was demonstrated to
effectively retard the undesirable Si+-catalyzed racemic
pathway.
(9) Hexafluoro-2-propanol which has been reported to be an effective
additive for a similar purpose2d,3b did not give us improved enantioselectivity.
(10) The oxazaborolidinones were prepared by using the corresponding
aryldibromoboranes.11
(11) Haubold, W.; Herdtle, J.; Gollinger, W.; Einholz, W. J. Organomet.
Chem. 1986, 315, 1-8.
(12) Experimental procedure for the preparation of (S)-4a (Table 2,
entry 6). To a solution of O-(2-naphthoyl)-N-tosyl-L-allo-threonine (85 mg,
0.20 mmol) in CH2Cl2 (2 mL) under a nitrogen atmosphere at room
temperature was added dichlorophenylborane (26 µL, 0.20 mmol). After
being stirred for 1 h, the mixture was concentrated in vacuo. To a solution
of the resulting oxazaborolidinone 1g and silyl ketene acetal 3b (612 mg,
3.0 mmol) in CH2Cl2 (2 mL) at -78 °C were added a CH2Cl2 (2 mL)
solution of enone 2a (146 mg, 1.0 mmol) and 2,6-diisopropylphenol (535
mg, 3.0 mmol) during 4 h by using a syringe pump. After completion of
the addition, the reaction was quenched by the addition of saturated aqueous
NaHCO3 and the solution was filtered. The filtrate was extracted three times
with hexane, dried (Na2SO4), and concentrated in vacuo. The residue was
dissolved in 1 N HCl (4 mL)-THF (20 mL), and the resulting solution
was stirred at room temperature for 30 min. The mixture was poured into
aqueous NaHCO3 and extracted three times with ether. The organic layers
were dried (Na2SO4) and concentrated in vacuo. Purification of the residue
by flash chromatography (SiO2, 5% ethyl acetate in hexane) gave 245 mg
(88%) of adduct (S)-4a (79% ee).
Acknowledgment. Financial support from the Ministry
of Education, Science, Sports and Culture of the Japanese
Government [Grant-in-Aid for Scientific Research (Priority
Areas, No. 706: Dynamic Control of Stereochemistry)] is
gratefully acknowledged.
Supporting Information Available: Preparation of O-(2-
naphthoyl)-N-tosyl-L-allo-threonine and characterization data
for the products in Table 3. This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) Hoye, T. R.; Koltun, D. O. J. Am. Chem. Soc. 1998, 120, 4638-
4643.
OL016062R
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2103