Scope and limitations of chiral B-[3,5-bis(trifluoromethyl)phenyl]oxazaborolidine catalyst for use in the Mukaiyama aldol reaction

Article abstract of DOI:10.1021/jo001271v

A new chiral oxazaborolidine catalyst was prepared in situ from 3,5-bis(trifluoromethyl)phenylboron dichloride and N-(p-toluenesulfonyl)-(S)-tryptophan. This catalyst is much more active than Corey's original catalyst for the Mukaiyama aldol reaction of a

Full text of DOI:10.1021/jo001271v

J . Org. Chem. 2000, 65, 9125-9128
9125
Scop e a n d Lim ita tion s of Ch ir a l
B-[3,5-Bis(tr iflu or om eth yl)p h en yl]oxa za bor olid in e Ca ta lyst for Use
in th e Mu k a iya m a Ald ol Rea ction
Kazuaki Ishihara,† Shoichi Kondo,‡ and Hisashi Yamamoto*,‡
Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, J apan,
CREST, J apan Science and Technology Corporation (J ST), and Research Center for Advanced Waste and
Emission Management (ResCWE), Furo-cho, Chikusa, Nagoya 464-8603, J apan
yamamoto@cc.nagoya-u.ac.jp
Received August 22, 2000
A new chiral oxazaborolidine catalyst was prepared in situ from 3,5-bis(trifluoromethyl)phenylboron
dichloride and N-(p-toluenesulfonyl)-(S)-tryptophan. This catalyst is much more active than Corey’s
original catalyst for the Mukaiyama aldol reaction of aldehydes with silyl enol ethers. The observed
syn selectivities and re-face attack of silyl enol ethers on carbonyl carbon of aldehydes imply that
the extended-transition state model is applicable.
In tr od u ction
of aldehydes with silyl enol ethers5d but also the Diels-
Alder reaction of R-substituted R,â-enals with dienes (eq
Ever since we1 and Helmchen’s group2a independently
announced a new class of chiral acyloxyboranes (CAB)3
derived from N-sulfonylamino acids and borane‚THF,
chiral 1,3,2-oxazaborolidines, their utility as chiral Lewis
acid catalysts in enantioselective synthesis has been
convincingly demonstrated.4-9 In particular, Corey’s tryp-
tophan-derived chiral oxazaborolidines 2a and 2b are
highly effective for not only the Mukaiyama aldol reaction
1).5a-c,e However, more than 20 mol % of 2b is required
* To whom correspondence should be addressed.
† ResCWE, Nagoya University.
‡ Graduate School of Engineering, CREST, J ST, Nagoya University.
(1) Takasu, M.; Yamamoto, H. Synlett 1990, 194.
(2) (a) Sartor, D.; Saffrich, J .; Helmchen, G. Synlett 1990, 197. (b)
Sartor, D.; Saffrich, J .; Helmchen, G.; Richards, C. J .; Lambert, H.
Tetrahedron: Asymmetry 1991, 2, 639.
(3) CAB is a general name for chiral Lewis acids prepared from
boron reagents and chiral carboxylic acids such as R-hydroxycarboxylic
acids and R-amino acid.
(4) (a) Itsuno, S.; Kamahori, K.; Watanabe, K.; Koizumi, T.; Ito, K.
Tetrahedron: Asymmetry 1994, 5, 523. (b) Charette, A. B.; Chua, P.
Mol. Online 1998, 2, 63.
(5) (a) Corey, E. J .; Loh, T.-P. J . Am. Chem. Soc. 1991, 113, 8966.
(b) Marshall, J . A.; Xie, S. J . Org. Chem. 1992, 57, 2987. (c) Corey, E.
J .; Loh, T.-P.; Roper, T. D.; Azimioara, M. D.; Noe, M. C. J . Am. Chem.
Soc. 1992, 114, 8290. (d) Corey, E. J .; Cywin, C. L.; Roper, T. D.
Tetrahedron Lett. 1992, 33, 6907. (e) Corey, E. J .; Loh, T.-P. Tetrahe-
dron Lett. 1993, 34, 3979. (f) Corey, E. J .; Guzman-Perez, A.; Loh, T.-
P. J . Am. Chem. Soc. 1994, 116, 3611.
for the former reaction. Other chiral oxazaborolidines
that have been developed for the enantioselective aldol
reaction of aldehydes with relatively more reactive ketene
silyl acetals also require large amounts (more than 20
mol %) to give aldol adducts in good yield.6,7 We recently
succeeded in enhancing the catalytic activities of CAB
derived from 2,6-di(isopropoxy)benzoyltartaric acid and
borane‚THF and Brønsted acid-assisted chiral Lewis acid
(BLA) derived from chiral tetrol and borane‚THF by
using 3,5-bis(trifluoromethyl)phenylboronic acid (3) in-
(6) (a) Kiyooka, S.-i.; Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano,
M. J . Org. Chem. 1991, 56, 2276. (b) Kiyooka, S.-i.; Kaneko, Y.; Kume,
K.-i. Tetrahedron Lett. 1992, 33, 4927. (c) Kaneko, Y.; Matsuo, T.;
Kiyooka, S.-i. Tetrahedron Lett. 1994, 35, 4107. (d) Kiyooka, S.-i.; Kido,
Y.; Kaneko, Y. Tetrahedron Lett. 1994, 35, 5243. (e) Kiyooka, S.-i.;
Kaneko, Y.; Harada, Y.; Matsuo, T. Tetrahedron Lett. 1995, 36, 2821.
(f) Kiyooka, S.-i.; Hena, M. A. Tetrahedron: Asymmetry 1996, 7, 2181.
(g) Kiyooka, S.-i.; Kira, H.; Hena, M. A. Tetrahedron Lett. 1996, 37,
2597. (h) Uggla, R.; Nevalainen, V.; Sundberg, M. R. Tetrahedron:
Asymmetry 1996, 7, 2725. (i) Kiyooka, S.-i.; Yamagichi, T.; Maeda, H.;
Kira, H.; Hena, M. A.; Horiike, M. Tetrahedron Lett. 1997, 38, 3553.
(j) Corey, E. J .; Barnes-Seeman, D.; Lee, T. W. Tetrahedron Lett. 1997,
38, 4351. (k) Kiyooka, S.-i.; Maeda, H. Tetrahedron: Asymmetry 1997,
8, 3371. (l) Kiyooka, S.-i. Rev. Heteroatom Chem. 1997, 17, 245. (m)
Wu, G.; Tormos, W. J . Org. Chem. 1997, 62, 6412. (n) Hena, M. A.;
Terauchi, S.; Kim, C.-S.; Horiike, M.; Kiyooka, S. Tetrahedron: Asym-
metry 1998, 9, 1883. (o) Kiyooka, S.-i.; Maeda, H.; Hena, M. A.; Uchida,
M.; Kim, C.-S.; Horiike, M. Tetrahedron Lett. 1998, 39, 8287. (p)
Nevalainen, V.; Mansikka, T.; Kostiainen, R.; Simpura, I.; Kokkonen,
J . Tetrahedron: Asymmetry 1999, 10, 1. (q) Simpura, I.; Nevalainen,
V. Tetrahedron: Asymmetry 1999, 10, 7. (r) Hena, M. A.; Kim, C.-S.;
Horiike, M.; Kiyooka, S.-i. Tetrahedron Lett. 1999, 40, 1161.
(7) (a) Parmee, E. R.; Tempkin, O.; Masamune, S.; Abiko, A. J . Am.
Chem. Soc. 1991, 113, 9365. (b) Parmee, E. R.; Hong, Y.; Tempkin, O.;
Masamune, S. Tetrahedron Lett. 1992, 33, 1729. (c) Iseki, K.; Kuroki,
Y.; Kobayashi, Y. Tetrahedron 1999, 55, 2225.
(8) (a) Seerden, J .-P. G.; Scheeren, H. W. Tetrahedron Lett. 1993,
34, 2669. (b) Seerden, J .-P. G.; Scholte op Reimer, A. W. A.; Scheeren,
H. W. Tetrahedron Lett. 1994, 35, 4419. (c) Seerden, J .-P. G.; Kurpers,
M. M. M.; Scheeren, H. W. Tetrahedron: Asymmetry 1995, 6, 1441.
(d) Seerden, J .-P. G.; Boeren, M. M. M.; Scheeren, H. W. Tetrahedron
1997, 53, 11843.
(9) (a) Reilly, M.; Oh, T. Tetrahedron Lett. 1995, 36, 221. (b)
Kinugasa, M.; Harada, T.; Fujita, K.; Oku, A. Synlett 1996, 43. (c)
Kinugasa, M.; Harada, T.; Egusa, T.; Fujita, K.; Oku, A. Bull. Chem.
Soc. J pn. 1996, 69, 3639. (d) Kinugasa, M.; Harada, T.; Oku, A. J .
Org. Chem. 1996, 61, 6772. (e) Kinugasa, M.; Harada, T.; Oku, A. J .
Am. Chem. Soc. 1997, 119, 9067. (f) Kinugasa, M.; Harada, T.; Oku,
A. Tetrahedron Lett. 1998, 39, 4529. (g) Harada, T.; Egusa, T.;
Kinugasa, M.; Oku, A. Tetrahedron Lett. 1998, 39, 5531. (h) Harada,
T.; Egusa, T.; Oku, A. Tetrahedron Lett. 1998, 39, 5535. (i) Harada,
T.; Nakamura, T.; Kinugasa, M.; Oku, A. Tetrahedron Lett. 1999, 40,
503.
10.1021/jo001271v CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/02/2000

9126 J . Org. Chem., Vol. 65, No. 26, 2000
Ishihara et al.
Ta ble 1. En a n tioselective Mu k a iya m a Ald ol Rea ction of
Ben za ld eh yd e w ith Tr im eth ylsilyl En ol Eth er Der ived
fr om Acetop h en on e Ca ta lyzed by 2a
Sch em e 1. Syn th esis of
3,5-Bis(tr iflu or om eth yl)p h en ylbor on Dich lor id e (5)
a n d P r ep a r a tion of Ca ta lyst 2d
6
7
catalyst
(mol%)
time
(h)
yield (%)b
ee (%)c
yield (%)b
ee (%)c
d
d
2b (20)
2b (10)
2c (10)
2d (10)
2d ( 6)
2d ( 4)
14
13
3
3
7
-
38
88
91
96
94
-
82d
15
11
4
4
4
89d
82
76
68
76
72
82
79
93
91
91
15
a
The silyl enol ether was added to a mixed solution of 2 and
benzaldehyde in propionitrile. Isolated yield. c Determined by
HPLC. Data from reference 5d. The data after treatment of
b
d
stead of borane‚THF.10,11 The utility of 3 in the design of
more active boron catalysts encouraged us to seek a new
and extremely active Corey’s catalyst 2d . This paper
describes a successful example of a designer chiral Lewis
acid catalyst modified using arylboron dichlorides bearing
electron-withdrawing substituents as Lewis acid compo-
nents.12
products with 1 M HCl are indicated.
ether derived from acetophenone at -78 °C in propioni-
trile as a solvent in the presence of 2 as a catalyst.
Following Corey’s procedure using 10 mol % of 2b, we
obtained the trimethylsilyl ether of aldol 6 and the free
aldol 7 in respective yields of only 38% and 15%.
However, when the B-phenyl analogue 2c was used as a
catalyst, the chemical yield was dramatically improved.
Furthermore, when the B-3,5-bis(trifluoromethyl)phenyl
analogue 2d was used, catalytic activity and enantio-
selectivity were increased to a turnover of 25 and 91-
93% ee, respectively. The absolute configuration of the
aldol adducts indicated in Table 1 was uniformly R.
Resu lts a n d Discu ssion
A new chiral oxazaborolidine catalyst 2d was prepared
by treating N-(p-toluenesulfonyl)-(S)-tryptophan (1) with
an equimolar amount of 3,5-bis(trifluoromethyl)phenyl-
boron dichloride (5a ) in dichloromethane and subsequent
removal of the resulting HCl and the solvent in vacuo
(Scheme 1). Moisture-sensitive boron dichloride 5a and
boron dibromide 5b were synthesized by dehydration of
3 to trimeric anhydride 4 and subsequent halogenation
of 4 with 2 equiv of boron trichloride and boron tribro-
mide, respectively. The preparation of oxazaborolidines
from arylboron dichlorides was previously reported by
Reilly and Oh9a and Harada et al.9b-i Although B-
butyloxazaborolidine 2b has been prepared from 1 and
butylboronic acid by dehydration,5 B-aryloxazaborolidine
could not be prepared from arylboronic acid, as observed
by Nevalainen et al.6p and Harada et al.9c In contrast,
CAB derived from 2,6-di(isopropoxy)benzoyltartaric acid
in place of N-sulfonylamino acids has been easily pre-
pared by adding an equimolar amount of the correspond-
ing arylboronic acid at room temperature.10
Next, the reaction of several aldehydes with trisubsti-
tuted (E)-trimethylsilyl enol ethers was conducted at -78
°C in propionitrile in the presence of 10 mol % of 2d as
a catalyst. The results of these experiments are sum-
marized in Table 2. In the reaction of benzaldehyde with
the trimethylsilyl enol ether of cyclohexanone, both
substrates were sequentially added to a solution of 2d
in propionitrile at -78 °C according to Corey’s procedure
(method A).5d The reaction proceeded quantitatively to
give only the aldol products in a 78:22 syn-anti ratio,
and the optical yield of the syn isomer 8 was 89% ee. In
contrast, the reaction of isobutyraldehyde with the same
silyl enol ether did not proceed well, probably due to the
decomposition of isobutyraldehyde in the presence of the
strong Lewis acid 2d before addition of the trimethylsilyl
enol ether. Nevertheless, the aldol adducts were obtained
with 96% ee. On the other hand, the sequential addition
of silyl enol ethers and aldehydes to a solution of catalyst
2d (method B) gave the aldol adducts in higher yield, but
the enantioselectivity was relatively low. Unfortunately,
catalyst 2d was less effective for the enantioselective
reaction with silyl enol ethers derived from cyclopen-
tanone and cycloheptanone. High enantioselectivity was
also observed in the reaction with acyclic (E)-silyl enol
ether derived from 3-pentanone. The use of 3,5-bis-
(trifluoromethyl)phenylboron dibromide 5b in place of 5a
in the in situ preparation of 2d slightly diminished the
enantioselectivity (method A′).
According to Corey,5d terminal trimethylsilyloxy (vin-
ylidene) olefins appear to be the most favorable sub-
strates for enantioselective Mukaiyama aldol coupling
catalyzed by 2b, compared to more highly substituted
olefins such as RCHdC(OSiMe3)R′ or R2CdC(OSiMe3)-
R′. In fact, the reaction of trimethylsilyl enol ether
derived from cyclopentanone with benzaldehyde afforded
the aldol products in only 71% yield even in the presence
of 40 mol % of 2b.5d
Our initial studies, summarized in Table 1, were
conducted with benzaldehyde and trimethylsilyl enol
(10) (a) Ishihara, K.; Mouri, M.; Gao, Q.; Maruyama, T.; Furuta,
K.; Yamamoto, H. J . Am. Chem. Soc. 1993, 115, 11490. (b) Ishihara,
K.; Maruyama, T.; Mouri, M.; Gao, Q.; Furuta, K.; Yamamoto, H. Bull.
Chem. Soc. J pn. 1993, 66, 3483.
(11) (a) Ishihara, K.; Kurihara, H.; Yamamoto, H. J . Am. Chem. Soc.
1996, 118, 3049. (b) Ishihara, K.; Kondo, S.; Kurihara, H.; Yamamoto,
H. J . Org. Chem. 1997, 62, 3026. (c) Ishihara, K.; Kurihara, H.;
Matsumoto, M.; Yamamoto, H. J . Am. Chem. Soc. 1998, 120, 6920.
(12) Part of this work has been published as a preliminary com-
munication: Ishihara, K.; Kondo, S.; Yamamoto, H. Synlett 1999, 1283.
Similar experiments were examined for the reaction
of aldehydes with (Z)-silyl enol ethers (Table 3). As
expected, the reaction of aliphatic aldehydes with (Z)-
trimethylsilyl enol ethers using method A did not proceed
well, probably for the same reason as above. Fortunately,
the reaction proceeded cleanly by adding trimethylsilyl

Chiral Catalyst for the Mukaiyama Aldol Reaction
J . Org. Chem., Vol. 65, No. 26, 2000 9127
Ta ble 2. Mu k a iya m a Ald ol Rea ction of Ald eh yd es w ith
has been observed in the reaction of aldehydes with (E)-
ketene trimethylsilyl acetals catalyzed by other chiral
oxazaborolidines.6,7a,b Thus, we were able to expand the
scope of the substrates that could be used in the enan-
tioselective Mukaiyama-aldol reaction by developing
B-3,5-bis(trifluoromethyl)phenyloxazaborolidine 2d .
In summary, these results demonstrate that the in-
troduction of an electron-withdrawing substituent such
as 3,5-bis(trifluoromethyl)phenyl group to the B atom of
chiral boron catalysts is an effective method for enhanc-
ing their catalytic activity. The present method is espe-
cially attractive for large-scale synthesis (eq 2).
(E)-Silyl En ol Eth er s
Exp er im en ta l Section
P r ep a r a tion of Silyl En ol Eth er s. 1-Phenyl-1-(trimeth-
ylsilyloxy)ethylene, 1-(trimethylsilyloxy)cyclopentene, and 1-(t-
rimethylsilyloxy)cyclohexene were purchased from Aldrich. (Z)-
3-Trimethylsilyloxy-2-pentene was prepared by heating 3-penta-
none and chlorotrimethylsilane in dichloromethane in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).13a Other
silyl enol ethers were prepared by quenching the corresponding
lithium enolates, derived from ketones with lithium N,N-
diisopropylamide (LDA) in THF, with chlorotrimethylsilane.13b
P r ep a r a tion of 3,5-Bis(tr iflu or om eth yl)p h en ylbor on
Dih a lid e (5). After a suspension of 3,5-bis(trifluoromethyl)-
phenylboronic acid (3) (3.86 g, 15 mmol) in benzene (30 mL)
was heated at reflux with removal of water (CaH2 in a Soxhlet
thimble) for 2-5 h (oil bath: 100-105 °C), the solution was
cooled to room temperature and concentrated in vacuo to give
trimeric anhydride 4 as white solid. Each of 1 M solution of
boron trichloride (30 mL, 30 mmol) in hexane and a 1 M
solution of boron tribromide (30 mL, 30 mmol) in heptane was
added to 4 at room temperature under argon. After the two
reaction mixtures were heated at reflux for 4 h (oil bath: 100-
105 °C) and 56 h (oil bath: 105-110 °C), respectively, solvents
were removed by distillation. Dihaloboron compounds 5a and
5b were isolated as colorless oils by distillation under reduced
pressure from the residues, respectively, in ca. 40-50% yield.
3: Purchased from Lancaster Synthesis Ltd.; 1H NMR (C6D6,
300 MHz) δ 7.81 (s, 1H), 8.01 (s, 2H).
a
Method A: A solution of silyl enol ether (0.96 mmol) in
propionitrile (0.32 mL) was added over 2 min to a mixed solution
of 2d (0.08 mmol) and an aldehyde (0.8 mmol) in propionitrile (0.65
mL). Method A′: Catalyst 2d , prepared in situ from 1 and 5b in
place of 5a , was used under the conditions in Method A. Method
B: A solution of aldehyde (0.8 mmol) in propionitrile (0.32 mL)
was added over 10 min to a mixed solution of the silyl enol ether
(0.96 mmol) and 2d (0.08 mmol) in propionitrile (0.65 mL).
Isolated yield. c Determined by 1H NMR analysis. Determined
b
d
by HPLC. e 5 mol % of 2d was used. E:Z ) 70:30.
f
Ta ble 3. Mu k a iya m a Ald ol Rea ction of Ald eh yd es w ith
(Z)-Silyl En ol Eth er s
1
4: H NMR (C6D6, 300 MHz) δ 8.01 (s, 1H), 8.46 (s, 2H).
5a : 38-40 °C (0.05-0.06 Torr); 1H NMR (C6D6, 300 MHz) δ
7.80 (s, 1H), 8.12 (s, 2H); 11B NMR (C6D6, 96 MHz) δ 53.2; 13
C
NMR (C6D6, 75.5 MHz) δ 123.1 (q, J ) 272.8 Hz, 2C), 127.1
(s, 1C), 131.0 (q, J ) 33.5 Hz, 2C), 134.8-135.2 (m, 1C), 135.5
(s, 2C); 19F NMR (C6D6, 282 MHz) δ -64.3.
ee (%)d
5b: 48-50 °C (0.015 Torr); 1H NMR (C6D6, 300 MHz) δ 7.83
(s, 1H), 8.27 (s, 2H); 11B NMR (C6D6, 96 MHz) δ 56.6; 13C NMR
(C6D6, 75.5 MHz) δ 123.0 (q, J ) 273.2 Hz, 2C), 127.3 (s, 1C),
131.1 (q, J ) 33.6 Hz, 2C), 135.0-135.8 (m, 1C), 136.2 (s, 2C);
19F NMR (C6D6, 282 MHz) δ -64.0.
silyl enol ether
yield
R1
R2 (Z:E)
methoda (%)b
8:9c
8
9
Pr
Pr
Pr
i-Pr
i-Pr
Ph (>99:1)
Ph (>99:1)
Et (97:3)
Ph (>99:1)
Et (97:3)
Ph (>99:1)
Ph (>99:1)
A
B
B
B
Be
B
B
23 >99:1
>99 >99:1
>99
>99
94
96
>99
-
-
62:38
97:3
83:17
95:5
92 77
98
92 91
97
90 58
P r ep a r a tion of Ch ir a l Oxa za bor olid in e Ca ta lyst 2d .
To a suspension of 15a (32.3 mg, 0.09 mmol) in dichloromethane
(0.75 mL) was added 5a (22.1 mg, 0.075 mmol) at room
temperature under argon. After being stirred for 1 h, the
mixture was concentrated in vacuo to give 2d as a white solid,
which was dissolved in propionitrile and used for Mukaiyama
aldol reactions.
-
(E)-MeCHdCH
PhCtC
85
92
-
89:11
See footnote a in Table 2. Isolated yield. c Determined by 1H
a
b
NMR analysis. Determined by HPLC. e 5 mol % of 2d was used.
d
1
2d : H NMR (CD2Cl2, 300 MHz) δ 2.37 (s, 3H), 3.56 (dd, J
enol ether followed by butyraldehyde to give only the syn
aldol adduct with more than 99% ee.7a
) 2.6, 15.0 Hz, 1H), 3.83 (dd, J ) 4.5, 15.0 Hz, 1H), 4.56-4.59
(m, 1H), 7.08-7.30 (m, 4H), 7.26 (d, J ) 8.1 Hz, 2H), 7.54 (d,
J ) 8.1 Hz, 2H), 7.82 (d, J ) 7.5 Hz, 1H), 7.95 (s, 1H), 8.04 (s,
The syn preference and the absolute preference for
carbonyl re-face attack observed in the reactions of
aldehydes with (E)- and (Z)-trimethylsilyl enol ethers
suggests that the reaction occurs via an extended-
transition state assembly (Figure 1).5,10 Anti preference
(13) (a) Taniguchi, Y.; Inanaga, J .; Yamaguchi, M. Bull. Chem. Soc.
J pn. 1981, 54, 3229. (b) Colvin, E. W. Silicon Reagents in Organic
Synthesis; Academic Press: London, 1988; pp 99-105.

9128 J . Org. Chem., Vol. 65, No. 26, 2000
Ishihara et al.
F igu r e 1. Proposed extended-transition state assembly.
2H), 8.22 (brs, 1H); 11B NMR (CD2Cl2, 96 MHz) δ 33.8; 19F
NMR (C6D6, 282 MHz) δ -64.2.
La r ge Sca le En a n tioselective Syn th eis of (R)-7. To a
suspension of 15a (215.0 mg, 0.60 mmol) in dichloromethane
(2.0 mL) was added 5a (147.4 mg, 0.50 mmol) at room
temperature under argon. After being stirred for 1 h, the
mixture was concentrated in vacuo to give 2d as a white solid,
which was dissolved in propionitrile and used for Mukaiyama
aldol reactions. To 2d (0.50 mmol, 5 mol %) prepared by the
preceding procedure was added propionitrile (5 mL) at room
temperature. After being cooled to -78 °C, benzaldehyde (1.01
mL, 10 mmol) was added, and a solution of 1-phenyl-1-
(trimethylsiloxy)ethylene (2.46 mL, 12 mmol) in propionitrile
(5 mL) was subsequently added dropwise over 1 h. The reaction
mixture was stirred at -78 °C for 5 h and then quenched by
the addition of saturated aqueous NaHCO3. The mixture was
extracted with ether, and then the combined organic phases
were dried over MgSO4 and evaporated. The residue was
dissolved in THF (5 mL) and 1 M aqueous HCl (5 mL), and
the resulting solution was allowed to stand for 30 min.
Saturated aqueous NaHCO3 was added, and the mixture was
extracted with ether. The combined organic phases were dried
over MgSO4 and evaporated to an oily residue. Silica gel
chromatography (hexanes-ethyl acetate ) 4:1) afforded 2.23
g (99% yield) of the known aldol product 7 [94% ee (R)].
Rep r esen ta tive P r oced u r e for th e Mu k a iya m a Ald ol
Rea ction Ca ta lyzed by 2d (Meth od A, Ta ble 1). To 2d
(0.075 mmol, 6 mol %) prepared by the preceding procedure
was added propionitrile (1 mL) at room temperature. After
being cooled to -78 °C, benzaldehyde (127 µL, 1.25 mmol) was
added, and a solution of 1-phenyl-1-(trimethylsiloxy)ethylene
(308 µL, 1.5 mmol) in propionitrile (0.5 mL) was subsequently
added dropwise over 2 min. The reaction mixture was stirred
at -78 °C for 12 h and then quenched by the addition of
saturated aqueous NaHCO3. The mixture was extracted with
ether, and then the combined organic phases were dried over
MgSO4 and evaporated. The residue was dissolved in THF (2
mL) and 1 M aqueous HCl (2 mL), and the resulting solution
was allowed to stand for 30 min. Saturated aqueous NaHCO3
was added, and the mixture was extracted with ether. The
combined organic phases were dried over MgSO4 and evapo-
rated to an oily residue. Silica gel chromatography (hexanes-
ethyl acetate ) 4:1) afforded 282 mg (>99% yield) of the known
aldol product 7. 1H NMR, 13C NMR, and IR spectroscopic data
are in agreement with those reported in the literature.10b The
enantiomeric ratio and the absolute configuration were deter-
mined by HPLC analysis (Daicel OD-H column with hexane-
i-PrOH ) 20:1, flow rate ) 1.0 mL/min):16c tR ) 21.2 ((S), minor
enantiomer), 24.4 ((R), major enantiomer) min.
For the determination of the syn/anti ratios, enantiomeric
ratios, and absolute configurations of other aldol adducts 8
synthesized by the similar procedure A or B (Tables 2 and 3),
see Supporting Information.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data of aldols 8 (Tables 2 and 3) and HPLC traces of the optical
and diastereomeric purity. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O001271V
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