Mild and highly enantioselective vinylogous aldol reaction of brassards diene with aromatic aldehydes by combined lewis acid catalyst

Article abstract of DOI:10.1021/jo100674f

(Figure presented) The combined Lewis acid catalytic system, generated from (R)-1,1′-bi-2-naphthol [(R)-BINOL], Ti(O-i-Pr)₄, H ₂O, and lithium chloride, effectively catalyzed the enantioselective vinylogous aldol reaction of Brassard

Full text of DOI:10.1021/jo100674f

pubs.acs.org/joc
assisted Lewis acid, could enhance the inherent acid reacti-
Mild and Highly Enantioselective Vinylogous Aldol
Reaction of Brassard’s Diene with Aromatic
Aldehydes by Combined Lewis Acid Catalyst
vity by associative interaction, while reorganized structure
provides a more efficient chiral induction.1 Recently, some
successful applications of this concept in the asymmetric
catalyst design have been reported.2 For instance, Maruoka
and co-workers designed a novel mono-oxygen bridged bis-
Ti oxide with strong activation of aldehydes promoting a
catalytic enantioselective allylation of aldehydes with allyl-
tributyltin.2e The authors proposed that the high reactivity
might be ascribed to the intramolecular coordination of one
isopropoxy oxygen atom to the other titanium center, there-
by allowing a stronger carbonyl activation caused by enhan-
ced Lewis acidity of the original Ti center.
Guowei Wang, Jinfeng Zhao, Yuhan Zhou, Baomin Wang,
and Jingping Qu*
State Key Laboratory of Fine Chemicals, School of Chemical
Engineering, Dalian University of Technology,
Dalian 116012, People’s Republic of China
qujp@dlut.edu.cn
Received April 15, 2010
The design and use of chiral homo- or heterobimetallic
complexes, especially those in which the two metal centers
work synergistically in a catalytic process, constitute another
promising approach in asymmetric catalyst design.3,4 For
example, the rare earth-alkali heterobimetallic complexes
developed by Shibasaki’s group have been successfully used
as Lewis acid-Brønsted base bifunctional catalysts in a
variety of transformations with high selectivities.5 This
catalyst functions as not only a Lewis acid to activate the
electrophiles but also a Brønsted base to deprotonate the
nucleophiles to form active metal species. In this paper, we
wish to report a combination of the two concepts mentioned
above to develop a novel BINOL-Ti catalyst assisted by
weak Lewis acid LiCl which may work as a Lewis acid-
Lewis acid bifunctional reagent to promote the enantiose-
lective vinylogous aldol reaction of Brassard’s diene with
aromatic aldehydes.
The asymmetric vinylogous aldol (AVA) reaction has
been one of the versatile C-C bond-forming reactions with
extensive application in the synthesis of natural polyketides
producuts.6 In the last two decades, several asymmetric cata-
lysts have been successfully developed for the AVA reactions
between aldehydes and preformed silyl dienol ether donors.7
However, among most of these successful examples, low-
temperature or stoichiometric additives was usually required
The combined Lewis acid catalytic system, generated
from (R)-1,10-bi-2-naphthol [(R)-BINOL], Ti(O-i-Pr)4,
H2O, and lithium chloride, effectively catalyzed the en-
antioselective vinylogous aldol reaction of Brassard’s
diene with aromatic aldehydes affording the (Z)-δ-hydro-
xyl-R,β-unsaturated esters exclusively in good yields with
excellent enantioselectivities (90-99% ee) under mild
conditions. A Lewis acid-Lewis acid bifunctional work-
ing model was proposed for the catalytic process based on
some control experiments.
€
(3) For reviews on the concept of bifuntional catalysis, see: (a) Groger, H.
Chem.;Eur. J. 2001, 7, 5246. (b) Rowlands, G. J. Tetrahedron 2001, 57,
1865. (c) Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002,
1989. (d) Ma, J. A.; Cahard, D. Angew. Chem., Int. Ed. 2004, 43, 4566.
(e) Shibasaki, M.; Matsunaga, S.; Kumagai, N. Synlett. 2008, 1583.
(f) Shibasaki, M.; Kanai, M.; Matsunaga, S.; Kumagai, N. Acc. Chem.
Res. 2009, 42, 1117.
(4) For selected examples, see: (a) Yoshikawa, N.; Yamada, Y. M. A.;
Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168.
(b) Ichikawa, E.; Suzuki, M.; Yabu, K.; Albert, M.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2004, 126, 11808. (c) Trost, B. M.; Ito, H. J. Am. Chem.
Soc. 2000, 122, 12003. (d) Belokon, Y. N.; North, M.; Maleev, V. I.;
Voskoboev, N. V.; Moskalenko, M. A.; Peregudov, A. S.; Dmitriev, A. V.;
Ikonnikov, N. S.; Kagan, H. B. Angew. Chem., Int. Ed. 2004, 43, 4085.
(e) Handa, S.; Nagawa, K.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2008, 47, 3230. (f) Chen, Z.; Morimoto, H.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170.
(5) For reviews, see: (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1236. (b) Shibasaki, M.; Yoshikawa, N. Chem. Rev.
2002, 102, 2187.
The development of novel chiral metal complexes for the
catalytic production of optically active compounds is among
the most important tasks in current organic chemistry. In
this context, the strategy of combined Lewis acid has att-
racted much attention in the design of asymmetric catalyst.
Combination of Lewis acids, also referred as Lewis acid
(1) For review of combined acid, see: Yamamoto, H.; Futatsugi, K.
Angew. Chem., Int. Ed. 2005, 44, 1924.
(2) For selected examples of combined Lewis acid in asymmetric catalysis,
see: (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc.
1986, 108, 6071. (b) Oishi, M.; Aratake, S.; Yamamoto, H. J. Am. Chem. Soc.
1998, 120, 8271. (c) Ishihara, K.; Kobayashi, J.; Inanaga, K.; Yamamoto, H.
Synlett 2001, 393. (d) Ishitani, H.; Komiyama, S.; Kobayashi, S. Angew.
Chem., Int. Ed. 1998, 37, 3186. (e) Hanawa, H.; Hashimoto, T.; Maruoka, K.
J. Am. Chem. Soc. 2003, 125, 1708. (f) Li, P.; Yamamoto, H. J. Am. Chem.
Soc. 2009, 131, 16628.
(6) For reviews, see: (a) Casiraghi, G.; Zanardi, F.; Appendino, G.;
Rassu, G. Chem. Rev. 2000, 100, 1929. (b) Denmark, S. E.; Heemstra, J. R.,
Jr.; Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682. (c) Schetter, B.;
Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506. (d) Brodmann, T.;
Lorenz, M.; Schackel, R.; Simsek, S.; Kalesse, M. Synlett 2009, 174.
5326 J. Org. Chem. 2010, 75, 5326–5329
Published on Web 06/30/2010
DOI: 10.1021/jo100674f
r
2010 American Chemical Society

Wang et al.
JOCNote
SCHEME 1. Two Competitive Reactions between Benzalde-
hyde and Brassard’s Diene
TABLE 1. AVA Reaction of Brassard’s Diene 4 with Benzaldehyde by
(R)-BTHLa
BINOL/Ti/
H2O/LiCl
diene 4
(mmol)
cat.d
(mol %)
yielde
(%)
eef
(%)
entry
1
2
3
4
1:1:0.5:1
1:1:1:1
1:1:1.5:1
1:1:1:1
1:1:1:1
1:1:1:1
1:1:1:1
1:1:1:1
1:1:1:1
1.5
1.5
1.5
2.5
2.5
2.5
2.5
2.5
2.5
10
10
10
10
10
10
5
48
60
50
72
78
80
55
74
41
88
96
95
96
97
97
96
96
92
5b
6b,c
7b
8b,c
9b
SCHEME 2. Preparation of the Novel Catalyst (R)-BTHL
5
2.5
aUnless specially noted, all reactions were performed with 1 mmol of
benzaldehyde and Brassard’s diene 4 in 4 mL of THF at 25 °C over 16 h.
bConcentration of substrate was 0.125 M. cTime extended to 40 h.
dBased on bis-Ti complex. eIsolated yield. fThe enantiomeric excess was
determined by HPLC analysis with the E isomer of 5a.
BTHL. Using 10 mol % of BTHL as catalyst, we initially
tested the reaction between benzaldehyde and Brassard’s
diene 4 (1.5 equiv) in THF at room temperature. To our
delight, the reaction proceeded through an aldol pathway to
give the linear product exclusively instead of the cyclopro-
duct after workup with 1 M HCl.11 The (Z)-δ-hydroxyl-R,β-
unsaturated ester 5a was obtained in 60% yield with 96% ee.
To the best of our knowledge, this is the first example of
highly enantioselective catalytic AVA reaction of Brassard’s
diene with benzaldehyde.
As is well known, water has a dramatic and sensitive effect
on the structure and catalytic performance of BINOL-Ti
species.10,12 Thus, we investigated what effect the amount of
water exerted on the performance of the catalytic system. It
turned out that increase or decrease of the amount of water
would causedecreased results (Table1, entries1 and 3). Utiliz-
ing the BTHL (1:1:1:1) as catalyst, the reaction conditions
werethenoptimized,andtheresultsaresummarizedinTable1
(entries 4-9). Solvent effect was not investigated as a result
of the bad solubility of BTHL in other solvents except THF.
Chemical yield was increased to 72% with 2.5 equiv of
Brassard’s diene 4, while the enantioselectivity was still
maintained (entry 4). When the concentration of the sub-
strate was reduced to 0.125 M, both the yield and enantio-
selectivity were increased (78% yield and 97% ee, entry 5),
and we speculated that reduced aggregate of the active titan-
ium species at lower concentration was responsible for the
improved chemical yield.13 Over a prolonged time of 40 h,
the result did not made a substantial difference (80% yield
and 97% ee, entry 6). Next, we reduced the catalyst loading
to obtain high enantioselectivity. In addition, effective cat-
alytic system for AVA reaction of Brassard’s diene with
aldehydes is still undeveloped. The main challenge lies in the
competition between the aldol pathway and the HDA
pathway (Scheme 1), and most concerned reports to date
proceeded through the HDA-concerted pathway to give
the cycloadducts directly.8,9 Consequently, considering the
potential utility of the δ-hydroxyl-R,β-unsaturated esters in
natural product synthesis, it would be an interesting task to
investigate the AVA reaction of Brassard’s diene with alde-
hydes via an efficient and practical catalyst under mild
conditions.
This novel combined-acid catalyst is easily available. As
shown in Scheme 2, the in situ prepared (R)-BINOL-Ti(O-i-
Pr)2 (R)-1 was hydrolyzed with 1 equiv of water to give the
precatalyst μ-oxo bititanium species (R,R)-2,10 and then 2
equiv of lithium chloride was added to afford the catalyst
(7) For selected examples, see: (a) Singer, R. A.; Carreira, E. M. J. Am.
€
Chem. Soc. 1995, 117, 12360. (b) Kruger, J.; Carreira, E. M. J. Am. Chem.
Soc. 1998, 120, 837. (c) Evans, D. A.; Kozlowski, J. A.; Christopher, S. B.;
Campos, K. R.; Connell, B. T.; Staples, R. J. Am. Chem. Soc. 1999, 121, 669.
(d) Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125, 7800.
(e) Denmark, S. E.; Heemstra, J. R., Jr. J. Am. Chem. Soc. 2006, 128, 1038.
(f) Rosa, M. D.; Acocella, M. R.; Rega, M. F.; Scettri, A. Tetrahedron:
Asymmetry 2004, 15, 3029. (g) Gondi, V. B.; Gravel, M.; Rawal, V. H. Org.
Lett. 2005, 7, 5757.
(8) (a) Togni, A. Organometallics 1990, 9, 3106. (b) Fan, Q.; Lin, L.; Liu,
J.; Huang, Y.; Feng, X.; Zhang, G. Org. Lett. 2004, 6, 2185. (c) Fan, Q.; Lin,
L.; Liu, J.; Huang, Y.; Feng, X. Eur. J. Org. Chem. 2005, 3542. (d) Du, H.;
Zhao, D.; Ding, K. Chem.;Eur. J. 2004, 10, 5964. (e) Lin, L.; Fan, Q.; Qin,
B.; Feng, X. J. Org. Chem. 2006, 71, 4141. (f) Lin, L.; Chen, Z.; Yang, X.; Liu,
X.; Feng, X. Org. Lett. 2008, 10, 1311.
(11) The configuration of the product was identified as (Z) by an NOE
experiment.
(12) For selected examples, see: (a) Terada, M.; Matsumoto, Y.;
Nakamura, Y.; Mikami, K. Inorg. Chim. Acta 1999, 296, 267. (b) Mikami,
K.; Matsumoto, Y.; Xu, L. Inorg. Chim. Acta 2006, 359, 4159. (c) Kurosu,
M.; Lorca, M. Synlett 2005, 1109. (d) Komatsu, N.; Hashizume, M.; Sugita,
T.; Uemura, S. J. Org. Chem. 1993, 58, 4529. (e) Komatsu, N.; Hashizume,
M.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58, 7624. (f) Bao, H.; Zhou, J.;
Wang, Z.; Guo, Y.; You, T.; Ding, K. J. Am. Chem. Soc. 2008, 130, 10116.
(13) (a) Corey, E. J.; Letavic, M. A.; Noe, M. C.; Sarshar, S. Tetrahedron
Lett. 1994, 35, 7553. (b) Terada, M.; Mikami, K.; Nakai, T. Chem. Commun.
1990, 1623. (c) Terada, M.; Mikami, K. Chem. Commun. 1994, 833.
(9) Vinylogous aldol reaction of N-oxypyridine aldehyde with Brassard’s
€
diene was reported: (a) Landa, A.; Richter, B.; Johansen., R. L.; Minkkila,
A.; Jørgensen, K. A. J. Org. Chem. 2007, 72, 240. For a diastereoselective
report, see: (b) Midland, M.; Afonso, M. M. J. Am. Chem. Soc. 1989, 111,
4368.
(10) (a) Kitamoto, D.; Imma, H.; Nakai, T. Tetrahedron Lett. 1995, 36,
1861. (b) Takizawa, S.; Somei, H.; Jayaprakash, D.; Sasai, H. Angew. Chem.,
Int. Ed. 2003, 42, 5711.
J. Org. Chem. Vol. 75, No. 15, 2010 5327

Wang et al.
JOCNote
TABLE 2. AVA Reaction of Brassard’s Diene 4 with Various Aromatic
TABLE 3. Control Experiments of AVA Reaction of Benzaldehyde with
Aldehydes by (R)-BTHLa
Brassard’s Diene 4 by Various (R)-BINOL-Ti Speciesa
entry
R
product
yieldb (%)
eec (%)
entry
BINOL/Ti/H2O/LiCl
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H5 (3a)
5a
5b
5c
5d
5e
5f
5g
5h
5i
74
69
61
58
64
73
73
75
77
49
75
71
16
96
94
93
99
92
90
91
1
2
3
4
5
6
7
8
9
10
1:1:0:0
1:1:0:1
2:1:0:0
2:1:0:1
1:1:1:0
1:1:1:1
1:1:1:2
1:1:1:1 (NaCl)
1:1:1:1 (LiBr)
1:1:1:1 (LiOTf)
48
51
40
50
16
60
58
14
27
38
67
91
84
91
16
96
96
20
70
95
p-CH3C6H4 (3b)
o-CH3OC6H4 (3c)
p-CH3OC6H4 (3d)
3,4,5-(CH3O)3C6H2 (3e)
o-ClC6H4 (3f)
p-ClC6H4 (3g)
p-BrC6H4 (3h)
p-FC6H4 (3i)
m-NO2C6H4 (3j)
2-furyl (3k)
91 (R)d
96
91
5j
5k
5l
95
90
aAll reactions were performed with 1 mmol of benzaldehyde and 1.5
mmol of diene 4 in 4 mL of THF at 25 °C over 16 h, and catalyst loading
was based on mono-Ti complex. Isolated yield. Enantiomeric excess
was determined by HPLC analysis with the (E) isomer of 5a.
C6H5CHdCH (3l)
(CH3)2CH (3m)
5m
96e
b
c
aAll reactions were performed with 1 mmol of aldehyde and 2.5 mmol
of diene 4 in 8 mL of THF at 25 °C over 40 h. bIsolated yield. The
c
enantiomeric excess was determined by HPLC analysis with the (E)
isomer of 5a-l. dThe absolute configuration was determined by X-ray
crystal structure analysis (see the Supporting Information for details).
eDetermined with 5m by HPLC analysis.
from 10 to 5 mol %, the yield sharply dropped to 55% while
the enantiomeric excess only dropped slightly (96% ee, enry
7). However, over extended time to 40 h, the reaction gave
74% yield with 5 mol % of catalyst (entry 8). Further reduced
catalyst loading to 2.5 mol % caused an obvious decrease in
both the chemical yield and enantioselectivity (41% yield,
92% ee, entry 9). From the viewpoint of catalyst efficiency,
we took entry 8 as the optimal conditions for further sub-
strate generality investigation.
With the optimized conditions in hand, the aldol reaction
of Brassard’s diene with various substituted aromatic alde-
hydes was investigated. As shown in Table 2, a wide substrate
generality was tolerated, and various substituted aromatic
aldehydes underwent the vinylogous aldol reaction to afford
the target products in high enantiomeric excess (90-99% ee)
with moderate to good yields (49-77%). A significant
electronic effect was observed that electron-withdrawing
groups caused enhanced reactivity and slightly reduced
enantioselectivity. An extension to aliphatic aldehyde was
also investigated with isobutylaldehyde (entry 13), and 96% ee
was obtained with obviously decreased reactivity (yield 16%).
Several control experiments were performed to gain pre-
liminary mechanistic insight into the catalytic system. As
shown in Table 3, the simple combinations of (R)-BINOL
and Ti(O-i-Pr)4 with a molar ratio of 1:1 and 2:1 both gave
unsatisfactory results (entries 1 and 3). When LiCl was added
as additive, both the yields and enantioselectivities were
improved, which implied that LiCl was a potentially power-
ful additive (entries 2 and 4). When the precatalyst (R,R)-2
was used in our model reaction, poor results were obtained
(entry 5). However, when LiCl was added to this hydrolyzed
(R)-BINOL-Ti species, the best result was obtained in terms
of chemical yield and enantioselectivity (entry 6). An increase
of the amount of LiCl gave exactly the same result (entry 7).
Other chloride represented by NaCl was also examined in
place of LiCl. However, the added NaCl was totally insoluble
in the solution, and this catalyst gave identically poor results
FIGURE 1. (a) Proposed structure of the active catalyst. (b) Pos-
sible bifunctional working model for the catalytic process.
as (R,R)-2 (entry 8 vs entry 5). The anionic effect of lithium
salts was also investigated with LiBr and LiOTf, and both the
results (entries 9 and 10) were inferior to LiCl. The results
manifest that the Lewis acids Ti and Li work cooperatively in
the catalytic process while H2O and chlorine anion facilitated
the formation of high-performance catalyst.
Though the structure of the active catalyst species and the
details of the catalytic mechanism are still ambiguous, we
proposed a Lewis acid assisted Lewis acid model for this cat-
alytic system based on the control experiments (Figure 1a).
When LiCl was added to the precatalyst μ-oxo bititanium
complex, the lithium should coordinate to oxygen owing to
its strong oxygen affinity,14 thereby enhancing the acidity of
the Ti center through associative interaction (Table 3, entry 5
vs entry 6). For the catalytic process, a possible Lewis acid-
Lewis acid bifunctional working model is depicted based
on Shibasaki’s outstanding work15 (Figure 1b). The strong
(14) Olsher, U. Chem. Rev. 1991, 91, 137.
(15) A Lewis acid-Lewis acid bifunctional catalytic manner was de-
scribed: (a) Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2003, 125, 16178. (b) Yamagiwa, N.; Qin, H.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2005, 127, 13419.
5328 J. Org. Chem. Vol. 75, No. 15, 2010

Wang et al.
JOCNote
SCHEME 3. Transformation of the Aldol Producta
FIGURE 2. Nonlinear effect (NLE) in the AVA reaction of benz-
aldehyde with Brassard’s diene 4.
aReagents and conditions: (a) TFA, THF, 0 °C, 4 h; (b) 1 M NaOH,
MeOH, 0 °C, 15 min.
Lewis acid Ti activates the carbonyl group and discrimi-
nates the prochiral face. Meanwhile, the diene would
coordinate to the weak Lewis acid Li center in a chelating
manner and be positioned close to the aldehyde. The two
metal centers function differently and both are essential
for high selectivity.
combined Lewis acid would provide a convenient and effective
approach for screening of high-performance asymmetric catalysts.
Further research will be devoted to elucidation of the structural
details of the catalyst and application to other transformations.
We also carried out the nonlinear effect (NLE) experiment
for this catalytic system using partially racemic BINOL while
keeping the other conditions unchanged. As shown in Figure 2,
a strong positive NLE implied that an oligomeric titanium
structure may work as the active species to promote the
reaction,16 which also provides an evidence for the proposed
bis-Ti structure.
We also found that after the indicated time if the reaction
solution was treated with TFA and stirred for several hours,
the (E) isomer 6a would be obtained with sustained chemical
yield and enantioselectivity (Scheme 3). Alternatively, the
isolated (Z) product could be readily converted to the (E)
isomer when treated with TFA in THF. It seemed that (Z)-δ-
hydroxy-R,β-unsaturated esters 5a would isomerize to a
more thermodynamically stable (E) isomer under acid
conditions. Further treatment of the (E) isomer 6a with
NaOH would afford δ-lactone 7a, which shares the same
cyclic subunit with many biologically active products.17
These transformations broaden the utility of this developed
methodology.
Experimental Section
General Procedure for the Vinylogous Aldol Reaction of
Brassard’S Diene 4 and Benzaldehyde. Under N2 atmosphere
in a dry Schlenk tube, a mixture of Ti(O-i-Pr)4 (0.2 mmol) and
(R)-BINOL (0.2 mmol) was stirred in THF (16 mL) at room
temperature for 20 min. Then to this mixture was added H2O
(7.2 μL, 0.2 mmol) with a syringe. After another 20 min,
anhydrous LiCl (8.6 mg, 0.2 mmol) kept in a Schlenk tube was
quickly added bottle to bottle under N2 atmosphere. After the
mixture was stirred over 30 min, 8 mL of the catalyst solution
was transferred to another Schlenk tube and the benzaldehyde
(1 mmol) and Brassard’s diene 4 (2.5 mmol) were added suc-
cessively by a syringe. After being stirred for 40 h at 25 °C, the
reaction solution was cooled to 0 °C and quenched with five
drops of 1 M HCl. After an additional 15 min, the mixture was
neutralized with saturated NaHCO3. After usual workup, the
residue was purified by chromatography on silica gel (acetone/
petroleum ether =1/12) to afford 5a as a colorless oil in 74%
yield: [R]25D 39.5 (c 0.08, CH2Cl2); 1H NMR (400 MHz, CDCl3)
δ 7.29-7.37 (m, 5H), 5.08 (s, 1H), 4.93-4.97 (m, 1H), 4.14-4.22
(m, 2H), 4.12 (q, J = 7.2 Hz, 2H), 2.59 (s, 1H), 2.57 (s, 1H), 2.49
(d, J = 3.2 Hz, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 167.4, 165.4, 143.5, 128.7,
127.9, 125.8, 99.0, 72.3, 67.8, 59.7, 45.2, 15.5, 14.4; ESI-HRMS
(M þ Na)þ calcd for C15H20O4Na 287.1259, found 287.1263.
Enantiomeric excess was determined to be 96% with the (E) iso-
mer of 5a (determined by HPLC using chiralcel OD-H column,
hexane/2-propanol = 9/1, λ = 254 nm, 30 °C, 0.7 mL/min,
In summary, we have demonstrated that a combination of
the weak Lewis acid LiCl with hydrolyzed (R)-BINOL-Ti
complex would generate a novel bimetallic catalytic system.
Employing this catalyst, highly enantioselective vinylogous
aldol reaction between Brassard’s diene and aromatic alde-
hydes was first realized with high enantioselectivities and good
yields at room temperature. We believe that this strategy of
t
major = 7.6 min, tminor = 8.3 min).
(16) For reviews of nonlinear effect, see: (a) Girard, C.; Kagan, H. B.
Angew. Chem., Int. Ed. 1998, 37, 2922. (b) Soriente, A.; De, R. M.; Villano,
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Abraham, S.; Kagan, H. B. Angew. Chem., Int. Ed. 2009, 48, 456.
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Palovsky, A.; Ferguson, D.; Graham, N.; Holler, T.; Hupe, D.; Nouhan,
C.; Tummino, P. J.; Urumov, A.; Zeikum, E.; Zeikum, G.; Gracheck, S. J.;
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Erickson, J. W. J. Med. Chem. 2000, 43, 843. (c) Harris, J. M.; O’Doherty,
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Acknowledgment. We appreciate the financial support
from the National Natural Science Foundation of China
(No. 20572011) and the Program for Changjiang Scholars
and Innovative Research Team in University (No.
IRT0711).
Supporting Information Available: Experimental details and
characterization and analytical data for the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 15, 2010 5329