Direct asymmetrie aldol reaction of aryl ketones with aryl aldehydes catalyzed by chiral BINOL-derived zincate catalyst

Article abstract of DOI:10.1021/jo801182n

(Chemical Equation Presented) Direct asymmetric aldol reaction of aryl ketones with aryl aldehydes catalyzed by chiral metal complex is reported for the first time herein. Two novel semicrown chiral ligands 1a and 1b were synthesized from (S)- and (R)-BIN

Full text of DOI:10.1021/jo801182n

reactions.1a,b There are three processes that have emerged. The
most developed methods are asymmetric organocatalytic direct
aldol reactions3 which have been fruitful since List, Lerner, and
Barbas4 reported the first remarkably successful case of direct
reaction of acetone with aryl aldehydes catalyzed by L-proline.
Another protocol is based on biological catalysts, i.e., enzymes
or abzymes.5 The third method is the protocol catalyzed by chiral
metal complexes.6-8 Among the chiral metal catalysts, Trost’s
dinuclear Zn catalysts8 and Shibasaki’s (S,S)-zinc-zinc-linked-
BINOL complex7c,d are especially efficient, which were broadly
applied to catalyze simple aldol addition of arylketones,7c,8a
methyl vinyl ketone,8f acetone,8c R-hydroxyl aryl ketones,8b,d
and methyl ynones8e to aldehydes as well as nitro aldol reactions
(the Henry reaction).8g-i These facts make zinc-containing chiral
catalysts more promising for various direct aldol additions. To
the best of our knowledge, however, direct asymmetric aldol
reaction between aryl ketones and aryl aldehydes catalyzed by
chiral organometallic complexes has not been reported to date.9
This reaction can generate versatile biologically active diaryl
ꢀ-hydroxyl ketones. Traditionally, these compounds are syn-
thesized by Mukaiyama-type aldol reactions,10 in which pre-
conversion of aryl ketones to more reactive intermediates is
indispensable.11 This situation makes it very interesting to
develop zinc-containing chiral ligands for direct aldol addition
of aryl ketones to aryl aldehydes today. Herein we report our
results on the design and synthesis of novel C2-symmetric
Direct Asymmetric Aldol Reaction of Aryl
Ketones with Aryl Aldehydes Catalyzed by
Chiral BINOL-Derived Zincate Catalyst
Hong Li, Chao-Shan Da,* Yu-Hua Xiao, Xiao Li, and
Ya-Ning Su
Institute of Biochemistry & Molecular Biology, School of
Life Sciences, Lanzhou UniVersity, Lanzhou 730000, China
dachaoshan@lzu.edu.cn
ReceiVed May 31, 2008
Direct asymmetric aldol reaction of aryl ketones with aryl
aldehydes catalyzed by chiral metal complex is reported for
the first time herein. Two novel semicrown chiral ligands
1a and 1b were synthesized from (S)- and (R)-BINOL,
respectively, and then employed to catalyze the direct
asymmetric aldol addition of aryl ketones to aryl aldehydes.
Introduced with 2.0 equiv of diethylzinc, 1b had higher
enantioselectivity than 1a. Up to 97% yield and up to 80%
enantioselectivity were achieved.
(4) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122,
2395.
(5) (a) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39,
1352. (b) Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C.-H. Chem. ReV. 1996,
96, 443. (c) Wagner, J.; Lerner, R. A.; Barbas, C. F., III Science 1995, 270,
1797. (d) Dean, S. M.; Greenberg, W. A.; Wong, C.-H. AdV. Synth. Catal. 2007,
349, 1308. (e) Kumagai, N.; Matsunaga, S.; Yoshikawa, N.; Ohshima, T.;
Shibasaki, M. Org. Lett. 2001, 3, 1539.
(6) (a) Kantam, M. L.; Ramani, T.; Chakrapani, L.; Kumar, K. V. Tetrahedron
Lett. 2008, 49, 1498. (b) Paradowska, J.; Stodulski, M.; Mlynarski, J. AdV. Synth.
Catal. 2007, 349, 1041. (c) Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am.
Chem. Soc. 2003, 125, 8706.
(7) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1871. (b) Yoshikawa, N.; Yamada, Y. M. A.;
Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168. (c)
Yoshikawa, N.; Kumagai, N.; Mutsunaga, S.; Moll, G.; Ohshima, T.; Suzuki,
T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2466. (d) Kumagai, N.;
Matsunaga, S.; Yoshikawa, N.; Ohshima, T.; Shibasaki, M. Org. Lett. 2001, 3,
1539.
The aldol reaction is one of the most important and useful
carbon-carbon bond formation reactions in organic chemistry,1
because it can produce versatile ꢀ-hydroxyl carbonyl com-
pounds, which are key intermediates or synthetic building blocks
of biologically active compounds.2 Therefore, many groups are
now focusing on catalytic asymmetric direct aldol addition
(1) (a) Modern Aldol reactions. Vol. 1: Enolates, Organocatalysis, Bioca-
talysis and Natural Product Synthesis; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, Germany, 2004. (b) Modern Aldol reactions. Vol. 2: Metal Catalysis;
Mahrwald, R., Ed.; Wiley-VCH: Weinheim, Germany, 2004. (c) Casiraghi, G.;
Zanardi, F.; Appendino, G.; Rassu, G. Chem. ReV. 2000, 100, 1929.
(2) (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (b) Marshall,
J. A. Chem. ReV. 1996, 96, 31. (c) Mahrwald, R. Chem. ReV. 1999, 99, 1095.
(d) Schinzer, D. In Modern Aldol reactions. Vol. 1: Enolates, Organocatalysis,
Biocatalysis and Natural Product Synthesis; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, Germany, 2004; p 311. (e) Fujii, K.; Maki, K.; Kanai, M.; Shibasaki,
M. Org. Lett. 2003, 5, 733.
(3) For reviews on asymmetric organocatalytic aldol reactions, see: (a)
Guillena, G.; Na´jera, C.; Ramo´n, D. J. Tetrahedron: Asymmetry 2007, 18, 2249.
(b) Tanaka, F.; Barbas, C. F.,III In EnantioselectiVe Organocatalysis; Dalko,
P. I., Ed.; Wiley-VCH: Weinheim,Germany, 2007; p 19. (c) Notz, W.; Tanaka,
F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580. (d) Berkessel, A.; Groger,
H. Asymmetric Organocatalysis - From Biomimetic Concepts to Applications in
Asymmetric Synthesis; Wiley-VCH: Weinheim, Germany, 2004; p 140. (e)
Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N.
Acc. Chem. Res. 2004, 37, 558. (f) Saito, S.; Yamamoto, H. Acc. Chem. Res.
2004, 37, 570. (g) Pellissier, H. Tetrahedron 2007, 63, 9267. (h) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007, 107, 5471. (i) Palomo,
C.; Oiarbide, M.; Garc´ıa, J. M. Chem. Soc. ReV. 2004, 33, 65.
(8) (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003. (b) Trost,
B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123, 3367. (c) Trost,
B. M.; Silcoff, E. R.; Ito, H. Org. Lett. 2001, 3, 2497. (d) Trost, B. M.; Yeh,
V. S. C. Org. Lett. 2002, 4, 3513. (e) Trost, B. M.; Fettes, A.; Shireman, B. T.
J. Am. Chem. Soc. 2004, 126, 2660. (f) Trost, B. M.; Shin, S.; Sclafani, J. A.
J. Am. Chem. Soc. 2005, 127, 8602. (g) Trost, B. M.; Yeh, V. S. C. Angew.
Chem., Int. Ed. 2002, 41, 861. (h) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer,
N. Org. Lett. 2002, 4, 2621. (i) Trost, B. M.; Lupton, D. W. Org. Lett. 2007, 9,
2023.
(9) Only recently was one case of organocatalytic asymmetric direct aldol
reaction of aryl ketone with aryl aldehydes disclosed: Mei, K.; Zhang, S.; He,
S.; Li, P.; Jin, M.; Xue, F.; Luo, G.; Zhang, H.; Song, L.; Duan, W.; Wang, W.
Tetrahedron Lett. 2008, 49, 2681.
(10) Mukaiyama reactions: (a) Mukaiyama, T.; Kobayashi, S.; Uchiro, H.;
Shina, I. Chem. Lett. 1990, 129; (b) Kobayashi, S.; Fujishita, Y.; Mukaiyama,
T. Chem. Lett. 1990, 1455.
(11) For recent Mukaiyama-type aldol reactions on aryl ketones with aryl
aldehydes, see: (a) Denmark, S. E.; Heemstra, J. R., Jr. Org. Lett. 2003, 5, 2303.
(b) Jankowska, J.; Mlynarski, J. J. Org. Chem. 2006, 71, 1317. (c) Li, H.-J.;
Tian, H.-Y.; Chen, Y.-J.; Liu, L.; Wang, D.; Li, C.-J. AdV. Synth. Catal. 2005,
347, 1247. (d) Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000, 65,
9125. (e) Kiyooka, S.; Takeshita, Y.; Tanaka, Y.; Higaki, T.; Wada, Y.
Tetrahedron Lett. 2006, 47, 4453.
7398 J. Org. Chem. 2008, 73, 7398–7401
10.1021/jo801182n CCC: $40.75 2008 American Chemical Society
Published on Web 08/14/2008

TABLE 1. Direct Aldol Reaction of Acetophenone and
Benzaldehyde Catalyzed by Chiral Zinc Catalystsa
SCHEME 1. Synthesis of Ligands 1
ligand (%)
Et2Znb
solvent
additive
ee (%)c
1a (5)
1a(20)
1b (5)
1b (5)
1b (5)
1b (5)
1b (5)
1b (5)
1b (5)
1b (5)
1b (5)
1b(10)
1b(10)
1b(10)
1b(10)
1b(10)
1b(20)
1b(20)
1/2.0
1/2.0
1/2.0
1/2.0
1/2.0
1/2.0
1/2.0
1/2.0
1/1.3
1/1.6
1/2.3
1/2.0
1/2.0
1/2.0
1/2.0
1/2.0
1/2.0
1/2.0
DMF
THF
THF
DMSO
CH2Cl2
Tol.
no
no
no
no
no
no
no
no
no
no
no
No
14d
13d
30
26
27
38
8
48
42
48
38
46 (45)
19
Et2O
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Et2Ne
Et3Ne
DIPEAe
DIPEAe
Et3Ne
Et3Ne
58 (43)
40
56f
58 (76)
70 (61)f
a The reaction was performed at room temperature under an argon
atmosphere, and 20 mg 4Å molecular sieves were added. b Data was the
ratio of ligand 1a or 1b to Et2Zn. c The ee was determined by the chiral
HPLC. Data in parentheses are yields. The configuration is R except for
entries 1 and 2, which was determined by the optical direction and retention
time on HPLC compared to the reported data.14 d Configuration of the
product is S. e 80% additive equiv to benzaldehyde was used. f The
reaction was performed under 0 °C.
semicrown zinc-containing catalysts derived from commercially
available chiral BINOL and their application in this challenging
asymmetric reaction.
Ligands 1a and 1b were designed and synthesized from chiral
BINOL and (S)-diphenylprolinol. The preparative course was
depicted in Scheme 1. Initially, (S)- or (R)-BINOL was routinely
protected with the MOM group according to the reported
processes.12 The dialdehyde derivatives 2a,b were achieved by
lithiation of the MOM-protected (S)- and (R)-BINOL with
n-BuLi and successive reaction with DMF. Dialdehydes 2a,b
were then reduced with NaBH4 to yield dialcohols 3a,b, which
were brominated in succession to give dibromo derivatives 4a,b.
Amination of 4a,b with (S)-diphenylprolinol and deprotection
of the MOM group afforded C2-symmetric semicrown ligands
(S,S,S)-1a and (R,S,S)-1b.
Activities of ligands 1a and 1b were evaluated by catalyzing
direct aldol addition of acetophenone to benzaldehyde (Table
1). (S,S,S)-1a yielded (S)-product whereas (R,S,S)-1b afforded
(R)-diaryl ꢀ-hydroxyl ketone. These phenomena implied that
the configuration of the aldol product should be determined by
the BINOL moiety rather than the amino alcohols’ parts. The
results showed that 1b was superior to 1a in enantioselectivity.
As for solvent, DMF gave the highest ee and yield among the
six screened solvents. The ratio of ligand to diethyl zinc was
crucial to the enantioselectivity. 1b/Et2Zn ) 1/2 gave the optimal
result. When the ratio was higher than 1:2, the enantioselectivity
dropped. Although the ratio of 1:1.6 yielded the same ee as 1:2
achieved, less Et2Zn made the reaction quite sluggish. And
further lowering this ratio also afforded the decreased enanti-
oselectivity. So 1b:Et2Zn ) 1:2 should be the optimal ratio.
This was consistent with results reported by Trost8a and
Shibasaki.7c When DMF was selected as solvent, we occasion-
ally found that organic amines could be beneficial to the
stereoseletion.13 Three amines were checked. It was shown that
TABLE 2. Direct Asymmetric Aldol Addition of Aryl Ketones to
Aryl Aldehydes
entry
Ar1
Ar2
yield (%)
ee (%)a
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
61
63
70
65
70
22
97
95
70
74
75
43
45
36
65
59
70
73
72
59
62
32
54
74
64
57
46
50
80
69
54
57
1-naphthyl
2-naphthyl
2-MeO-Ph
3-MeO-Ph
4-MeO-Ph
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
9
10
11
12
13
14
15
16
3-NO2-Ph
4-NO2-Ph
3-Me-Ph
furan-2-
thiophene-2-
Ph
1-naphthyl
2-naphthyl
Ph
a Determined by chiral HPLC.
tertiary amine could heighten the enantioselectivity whereas
secondary amine gave a sharply decreased ee. Triethylamine
was the best additive among them; it gave the obviously
heightened ee value. Enantioselectivity could be further im-
proved by lowering the temperature at the accompanying
expense of increasing the reaction time. When the amount of
1b was increased, no effect on the enantioselectivity was
observed, but a higher yield was achieved.
(12) (a) Hamashima, Y.; Sawada, D.; Nogami, H.; Kanai, M.; Shibasaki, M.
Tetrahedron 2001, 57, 805. (b) Matsunaga, S.; Das, J.; Roels, J.; Vogl, E. M.;
Yamomoto, N.; Iida, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2000,
122, 2252.
(13) The solvent DMF usually contains some little amines. When we initially
used simply dried DMF as solvent, we got varied results which could not be
easily duplicated. After carefully preparing dry DMF, however, a decreased ee
value was achieved. So we speculated that amines might be beneficial to higher
enantioselectivity.
Under the optimized reaction conditions (20% 1b, 40% Et2Zn,
4Å MS, DMF as solvent and triethylamine as an additive at 0
°C) direct aldol reactions of a brand of aryl aldehydes with aryl
(14) Mandal, S. K.; Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Org.
Chem. 2003, 68, 4600.
J. Org. Chem. Vol. 73, No. 18, 2008 7399

FIGURE 1. The proposed mechanism elucidates that the attack will occur from the Re-face of the benzaldehyde.
Preparation of (R)-3,3′-Bis(bromomethyl)-2,2′-bis(methoxy-
ketones were observed. The results were included in Table 2.
It could be found that this dinuclear zincate catalyst was effective
in this reaction. Up to 97% yield could be obtained. As for
enantioselectivity, moderate to high ee was achieved. Acetophe-
none yielded higher enantioselectivity than two acetonaphthones.
The catalyst could be employed to catalyze many sorts of aryl
aldehydes in this reaction. The sites of the substituent groups
on the phenyl ring could have great effects on the stereoselec-
tion. The meta-substituted substrates generated higher ee than
ortho- and para-substituted aldehydes. Big aryl rings such as
1-naphthyl and 2-naphthyl aldehydes both gave higher enanti-
oselectivity. Strong electron-withdrawing groups impaired the
enantioselectivity such as nitro, as did electron-donating groups
such as the methoxy group. When furan-2-carbaldehyde was
used as the substrate, the highest enantioselectivity up to 80%
was achieved. All products were R configuration, which was
determined by comparing their optical direction or retention time
on HPLC to the reported data.14,15
According to the mechanisms of Trost’s semicrown zincate
catalysts,7a Shibasaki’s zinc-zinc-linked BINOL catalyst,7c and
Pu’s speculation on their research,16 we envisioned that zincate-
1b should mainly adopt the steady transition state as depicted
in Figure 1. Thus the attack of zincate enol to benzaldehyde
should chiefly occur from the Re-face of benzaldehyde and yield
diaryl ꢀ-hydroxyl carbonyl compound 5a with R configuration.
In conclusion, we have successfully performed the first case
of direct enantioselective aldol reaction of aryl ketones with
aryl aldehydes catalyzed by chiral metal-containing complex.
Two novel C2-symmetric semicrown ligands 1a and 1b were
effectively synthesized from chiral BINOL and (S)-diphenyl-
prolinol. The zincate of 1b was found to be a more effective
catalyst, which could highly catalyze this topic reaction. Up to
97% yield and up to 80% enantioselectivity were achieved.
methyl)-1,1′-binaphthol (4b). To an ice-cooled solution of crude
3b (1.96 g, 4.5 mmol) in toluene (30 mL)/ethyl acetate (30 mL)
were successively added Et3N (5 mL, 36mmol) and MsCl (1.4 mL,
18 mmol). The mixture was stirred at 0 °C for 90 min. The resulting
suspension was filtered to remove solid salt Et3NH+Cl– and the
solid was washed with ethyl acetate (30 mL). The combined filtrate
and washings were cooled to 0 °C and then LiBr (7.82 g, 90 mmol)
in 75 mL of DMF was added. The mixture was stirred at room
temperature for a further 10 min. It was then diluted with ether
(120 mL) and washed with water (60 mL × 2), 1 mmol/L aqueous
HCl (30 mL × 2), saturated aqueous NaHCO3 (30 mL), and
saturated brine in succession, and finally dried over MgSO4 and
evaporated in vacuo to give 4b as yellow oil (5.568 g, 11.9 mmol,
and yield 91%) which was pure enough to be used in the next step
without further purification. [R]20 -36 (c 0.84, THF); IR (KBr)
D
2924, 2854, 1745, 1460, 1157, 968, 750 cm-1; 1H NMR (400 MHz,
CDCl3) δ 8.09 (s, 2H), 7.88 (d, J ) 8.0 Hz, 2H), 7.43 (t, J ) 7.8
Hz, 2H), 7.28-7.24 (m, 2H), 7.18-7.15 (m, 2H), 4.89 (d, J ) 9.6
Hz, 2H), 4.85 (d, J ) 10 Hz, 2H), 4.67 (d, J ) 6.0 Hz, 2H), 4.56
(d, J ) 5.2 Hz, 2H), 2.99 (s, 6H); 13C NMR (400 MHz, CDCl3) δ
152.3, 134.2, 131.5, 130.6, 129.0, 128.2, 127.3, 126.0, 125.6, 125.3,
99.3, 56.9, 29.3; HRMS calcd for C26H28Br2NO4 ([M + NH4]+)
576.0380, found 576.0382.
Preparation of (R,S,S)-3,3′-Bis[(N-diphenylprolinol)methyl]-2,2′-
bis(methoxymethyl)-1,1′-binaphthol (1b). To a mixture of 0.84 g
of (R)-4b (1.5 mmol) and 2.1 g of anhydrous K2CO3 (15 mmol) in
15 mL of dry DMF was introduced in one portion at room
temperature 0.84 g of solid (S)-diphenylprolinol (3.3 mmol). The
reaction was stirred for 24 h, and it was then quenched with 30
mL of water, extracted with ethyl acetate three times, combined
the organic layers, washed with water two times and a little saturated
brine, and condensed in vacuo to give yellow thick oil. This oil
was redissolved with 3.0 N HCl (5 mL) in 20 mL of THF. This
solution was refluxed for 6 h, and then the organic solvents were
removed by condensation in vacuo. Next 5 mL of water was added,
the solution pH was adjusted to 10.0 or so with concentrated
hydrous ammonia, and the solution was extracted with ethyl acetate
three times. The combined ethyl acetate layers were washed
successively with water and a little saturated brine, dried with
anhydrous Na2SO4, and condensed in vacuo to give a yellow solid.
Purification by a silica column afforded the product (R,S,S)-1b as
Experimental Section
3b was routinely synthesized from (R)-BINOL according to the
reported procedures.12
a white solid (0.98 g, yield 80%). [R]20 +82 (c 5.0, CHCl3); mp
D
(15) Two alkyl aldehydes, isovaleraldehyde and butyraldehyde, were also
used to replace aryl aldehydes as electrophilic acceptors, and both of them
afforded R-configurational products with moderate enantioselectivities of 44%
(5q) and 39% (5r), but with low yields of 22% (5q) and 21% (5r).
119-124 °C; IR (KBr) 3509, 2964, 1729, 1446, 1248, 1108, 748,
1
701 cm-1; H NMR (400 MHz, CDCl3) δ 7.76 (d, J ) 7.2 Hz,
1H), 7.58-7.51 (m, 5H), 7.37-7.07 (m, 9H), 4.14-4.09 (m, 1H),
3.98 (br, 1H), 3.52 (br, 2H), 3.13-3.10 (m, 1H), 2.54-2.52 (m,
(16) Wang, Q.; Chen, S.-Y.; Yu, X.-Q.; Pu, L. Tetrahedron 2007, 63, 4422.
7400 J. Org. Chem. Vol. 73, No. 18, 2008

1H), 2.08-2.04 (m, 2H), 1.85 (br, 1H), 1.71 (br, 2H), 1.27-1.23
(m, 1H); 13C NMR (400 MHz, CDCl3) δ 152.3, 128.5, 128.3, 128.1,
127.8, 127.0, 126.6, 125.9, 124.7, 123.3, 114.2, 79.0, 55.5, 29.5,
24.0, 14.2; HRMS calcd for C56H53N2O4 ([M + H]+) 817.4000,
found 817.3999.
Purification by column chromatography afforded the desired product
5a in 61% yield: mp 50-52 °C; [R]20D +60 (c 0.83, CHCl3) (lit.14
[R]20D -85.3 (c 1.3, CHCl3) for the S enantiomer); 1H NMR (200
MHz, CDCl3) δ 7.95 (d, J ) 7.0 Hz, 2H), 7.59-7.25 (m, 8H),
5.35 (t, J ) 6.0 Hz, 1H), 3.37 (d, J ) 6.0 Hz, 2H); ee was
determined by HPLC with a OD-H column (hexane:2-propanol )
85:15, 0.8 mL/min), major enantiomer tR ) 13.1 min, minor
enantiomer tS ) 11.8 min.
Typical Procedure of Direct Aldol Addition of Aryl Ketone to
Aryl Aldehyde (5a). Diethyl zinc (0.04 mmol, 1.123 mmol/mL in
n-hexane) was added dropwise into a solution of 1b (0.02 mmol,
16.35 mg) in 1.0 mL of DMF at 0 °C under an argon atmosphere.
The mixture was stirred for 40 min, and then 20 mg of 4Å molecular
seives and triethylamine (0.08 mmol, 11.2 µL) were successively
introduced. After 10 min, 0.1 mmol of aldehyde and 1.0 mmol of
ketone were successively added. The reaction was continued for 5
days. Cold diluted hydrous HCl was added dropwise and the
aqueous layer was extracted three times with ethyl acetate. The
organic layers were combined, washed successively with water and
a little brine, and dried with anhydrous Na2SO4. The salt was filtered
out and the solution was condensed under reduced pressure.
Acknowledgment. We thank the National Natural Science
Foundation of China for financial support (No. 20672051).
Supporting Information Available: Detailed preparation of
ligands 1a,b from (S)- and (R)-BINOL and data for the aldol
products 5a-r. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO801182N
J. Org. Chem. Vol. 73, No. 18, 2008 7401