One catalyst for two distinct reactions: Sequential asymmetric hetero Diels-Alder reaction and diethylzinc addition

Article abstract of DOI:10.1016/j.tet.2005.08.007

This paper describes the successful development of a series of chiral zinc catalysts containing (R)-3,3′-Br₂-BINOL ligand and various diimine activators for enantioselective HDA reaction of Danishefsky's diene with aldehydes through a combinato

Full text of DOI:10.1016/j.tet.2005.08.007

Tetrahedron 61 (2005) 9465–9477
One catalyst for two distinct reactions: sequential asymmetric
hetero Diels–Alder reaction and diethylzinc addition
*
Haifeng Du, Xue Zhang, Zheng Wang and Kuiling Ding
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, People’s Republic of China
Received 22 June 2005; revised 1 August 2005; accepted 2 August 2005
Abstract—This paper describes the successful development of a series of chiral zinc catalysts containing (R)-3,30-Br2-BINOL ligand and
various diimine activators for enantioselective HDA reaction of Danishefsky’s diene with aldehydes through a combinatorial approach,
affording the corresponding 2,3-dihydro-4H-pyran-4-one derivatives in excellent yields and enantioselectivities. The application of this type
of catalysts was also extended to the diethylzinc addition to the benzaldehyde, affording the corresponding secondary alcohol with up to
94.5% ee under optimized conditions. On the basis of these facts, the integration of two distinct enantioselective reactions, HDA and
diethylzinc addition reactions, has been realized in one-pot with the promotion of a single chiral zinc catalyst in a sequential manner. The
impact of diimine additive on the catalytic system of HDA reaction was also investigated by probing the nonlinear effect of reaction system.
The positive nonlinear effect exhibited in the catalytic system could be attributed to the poor solubility of the heterochiral zinc species. On the
basis of various experimental findings disclosed in this research, a possible mechanism for the asymmetric induction in the 3,30-Br2-BINOL/
Zn/diimine catalyzed enantioselective HDA reaction of Danishefsky’s diene with aldehydes was outlined.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
most important methods for the construction of optically
active six-membered oxo heterocycles with extensive
synthetic applications in natural or unnatural products.5,6
Since the first HDA reaction of Danishefsky’s diene and
aldehydes was achieved with the catalysis of ZnCl2,7
various chiral Lewis acids, such as aluminum, boron,
transition and lanthanide metal complexes, and so on, have
been employed for this type of reaction.5,6 However, the use
of chiral zinc catalysts for this reaction has been less
explored although the chiral zinc complexes of ligands 18
and 29 have been recently reported to be efficient catalysts
for a variety of catalytic asymmetric reactions. The Lewis
acid 3 obtained from the reaction of diethylzinc and 1,10-bi-
2-naphthol (BINOL) was reported by Yamamoto to catalyze
the enantioselective cyclization of unsaturated aldehydes.10
Very recently, Yamamoto’s Zn–BINOL complex 3 was
found to be an enantioselective catalyst for asymmetric
Diels–Alder reaction of N-alkoxyacrylamides with cyclo-
pentadiene or aza-Diels–Alder reaction of Danishefsky’s
diene with imines by Renaud and Whiting.11 However,
stoichiometric amount of Zn–BINOL complex was required
in order to ensure an acceptable enantioselectivity and
reactivity of the reactions. A successful application of
catalytic amount of BINOLate–zinc complex as efficient
chiral Lewis acid for HDA was reported in our previous
communication.12 The Zn–BINOLate complex (4) prepared
in situ from the reaction of 3,30-dibromo-1,10-bi-2-naphthol
Organometallic catalysts are traditionally designed and
optimized to promote a single reaction.1 However, the
increasing demand for expedient synthetic processes
requires the development of more efficient organometallic
catalysts that are capable of catalyzing multiple, mecha-
nistically distinct reactions directly or by simple modifi-
cation.2 Asymmetric catalysis of organic reactions has
provided a powerful strategy for amplification of chirality to
get optically active compounds. So far there were only very
few reports on the sequential catalysis of two distinct
enantioselective reactions using a single chiral catalyst.3
Therefore, integration of two or more reactions in one-pot
with the promotion of a single catalyst is still a great
challenge for chemists. As an effort to exemplify such a
system,4 herein, we demonstrate the ability of a single
catalyst to promote two different reactions in one-pot
through a sequential approach.
The enantioselective hetero-Diels–Alder (HDA) reaction of
Danishefsky’s diene with aldehydes represents one of the
Keywords: Alkylation; Asymmetric catalysis; Combinatorial chemistry;
Hetero Diels–Alder; High-throughput screening; Sequential catalysis; Zinc.
Corresponding author. Tel.: C86 21 64163300; fax: C86 21 6416 6128;
e-mail: kding@mail.sioc.ac.cn
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.007

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H. Du et al. / Tetrahedron 61 (2005) 9465–9477
(3,30-Br2-BINOL) with Et2Zn was found to be highly
efficient for the catalysis of enantioselective reaction of
Danishefsky’s diene and aldehydes, affording 2-substituted
2,3-dihydro-4H-pyran-4-one in up to quantitative yield an0d
98% ee. Moreover, the asymmetric activation of 3,3 -
Ph2BINOL–Zn (5) complex with diimine has been found to
be a useful strategy for achieving high efficiency and
enantioselectivity in catalytic asymmetric diethylzinc
addition to aldehydes.13,14 Accordingly, if the enantio-
selective catalysis of HDA reaction can be realized with the
catalysis of diimine-activated Zn–binolate complexes, it
would be possible to carry out both HDA and diethylzinc
addition reactions in one-pot with a single catalyst.
reactivity of the reaction were significantly influenced by
both the electronic effect and steric hindrance of the
substituents at 3,30-positions of BINOL. The serious steric
hindrance of phenyl groups at 3,30-positions of BINOL (L9,
L10) was found to be unfavorable for the reaction.
Moreover, the absolute configuration of product was mainly
controlled by the chirality of diol ligands, and the level of
enantioselectivity of the reaction could be affected by the
chirality and steric environment of diimine activators.
The effect of binaphthyl backbone was not evident in the
cases of L4–6. However, in the asymmetric induction of
3,30-substituted BINOL derivatives, partially reduced
binaphthyl ligands L11, L10 are inferior to their parent
2. Results and discussion
ligands L12 and L9 in terms of both enantioselectivity and
reactivi0ty. Among the 0chiral diols screened for this reaction,
(S)-3,3 -dibromo-1,1 -bi-2-naphthol (3,30-Br2-BINOL,
L12) turns out to be the most efficient one in the presence
of various diimines, affording the product in up to
quantitative yield and 93.8% ee.
As an effort to explore the potential application of diimine-
activated Zn–binolate complexes with the structures like 5
as catalysts for two distinct asymmetric reactions such as
diethylzinc addition and hetero-Diels–Alder reaction, we
first investigated the possibility of using this type of
complexes for the promotion of hetero Diels–Alder
(HDA) reaction of Danishefsky’s diene (6) with benz-
aldehyde (7a).5,6 The initial trials using complex 3 in
combination with diimine S1 (Scheme 1) as the catalyst for
HDA reaction between 6 and 7a (Eq. 1) showed that the
reaction proceeded smoothly at 0 8C to give (S)-2-phenyl-
2,3-dihydro-4H-pyran-4-one 8a in 78% yield with moderate
enantioselectivity (63.6%). This result prompted us to
further improve the enantioselectivity of the reaction by
tuning the steric and electronic features in the diol ligands
and diimine activators through a combinatorial approach.15
Accordingly, a library of chiral diol ligands including
commercially available or easily prepared BINOL and
biphenol derivatives (L1–L12) and a library of diimines
(S1–S20) derived from enantiopure 1,2-diaminocyclo-
hexane were created, respectively (Scheme 1). High
throughput screening of the chiral Zn catalyst library with
240 members generated by combining the members of diol
ligand (L1–L12) and diimine activator (S1–S20) libraries
with Et2Zn showed that all of the catalysts could promote
the HDA reaction of 6 with 7a at 0 8C to give the desired
product 8a. The results were summarized in Figure 1, which
clearly demonstrated that the enantioselectivity and
(1)
The reaction catalyzed by the lead combinations (L12 with
S2–3, S6–7, S10–S13, S15, or S20) was further optimized
by lowering the reaction temperature to K20 8C. It was
found that 8a could be obtained in up to 98.7% ee and
quantitative yield with the catalysis of Zn complex of L12/
S13 or L12/S20 combination (entries 8 and 10, Table 1).
Accordingly, the optimized catalysts L12/Zn/S2, L12/Zn/
S7, L12/Zn/S13, and L12/Zn/S20 were submitted to the
catalysis of the reactions of the Danishefsky’s diene with a
variety of aldehydes (7a–k) in order to examine their
substrate scope adaptability. As shown in Table 2, the
optimized catalysts were applicable for the promotion of
HDA reaction of 6 with a variety of aldehydes 7a–k,
including aromatic and olefinic derivatives, to give
corresponding 2-substituted 2,3-dihydro-4H-pyran-4-ones
in excellent yields and enantioselectivities with the

H. Du et al. / Tetrahedron 61 (2005) 9465–9477
9467
Scheme 1. Libraries of chiral diol ligands (L1–L12) and diimine activators (S1–S20).
exception of the cases of aliphatic (entry 3) and sterically
demanding aromatic aldehydes (entry 11). It is obvious that
all these results obtained in the presence of diimine
activators are comparable or even superior to those achieved
by the catalysis of 4 in the absence of activator. Particularly,
the reaction of cinnamic aldehyde (7d) catalyzed by various
diimine activated L12/Zn catalysts (entry 4, Table 2)
afforded the corresponding cycloadduct 8d in 91–O99%
yields with 94.4–96.4% ee’s, which are significantly higher
Table 1. Enantioselective catalysis of the reaction between 6 and 7a with
the lead catalystsa
Entry
Catalyst
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
L12/Zn/S2
L12/Zn/S3
L12/Zn/S6
L12/Zn/S7
L12/Zn/S10
L12/Zn/S11
L12/Zn/S12
L12/Zn/S13
L12/Zn/S15
L12/Zn/S20
O99
O99
O99
93.8
96.9
O99
O99
O99
92.9
O99
98.6
98.3
97.9
98.6
97.2
97.8
98.2
98.7
98.0
98.7
9
10
a All of the reactions were carried out at K20 8C.
b Determined by HPLC with biphenyl as an internal standard.
c Enantiomeric excesses of product 8a were determined by HPLC on
Chiralcel OD column.
Figure 1. Screening of Zn catalyst library generated by assembling chiral
diol ligands (L1–L12) and chiral diimine activators (S1–S20) with Zn for
HDA reaction of 6 with 7a.

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H. Du et al. / Tetrahedron 61 (2005) 9465–9477
Table 2. The investigation of substrate scope for the reactions of Danishefsky’s diene (6) with various aldehydes (7a–k) under the catalysis of optimized
catalysts
Entry
R in 7
ee (%)a
L12/Zn/S13
L12/Zn/S2
L12/Zn/S7
L12/Zn/S20
1
2
3
4
5
6
7
8
Ph (7a)
98.6 (O99)
93.8 (O99)
58.8 (60.6)
96.4 (91.2)
95.7 (O99)
97.0 (O99)
98.0 (O99)
96.6 (O99)
96.6 (94.9)
95.8 (81.3)
88.5 (O99)
98.6 (93.8)
92.7 (O99)
56.6 (25.5)
96.4 (O99)
96.4 (O99)
95.7 (O99)
96.7 (O99)
54.5 (O99)
96.6(O99)
96.0 (91.4)
82.7 (O99)
98.7 (O99)
93.1 (O99)
51.8 (53.6)
95.3 (O99)
90.4 (O99)
97.2 (O99)
96.3 (O99)
97.0 (O99)
95.8 (O99)
97.6 (92.8)
71.8 (O99)
98.7 (O99)
88.4 (O99)
43.7 (56.1)
94.4 (O99)
93.4 (O99)
96.2 (O99)
95.9 (O99)
70.1 (O99)
94.9 (O99)
96.1 (O99)
83.5 (O99)
3-MeOPh (7b)
3-Ph(CH2)2 (7c)
E-Stylryl (7d)
2-Furfuryl (7e)
4-NCPh (7f)
3-BrPh (7g)
3-ClPh (7h)
4-BrPh (7i)
9
10
11
4-ClPh (7j)
2,6-Cl2Ph (7k)
a Enantiomeric excesses of products were determined by HPLC on Chiralcel OD or Chiralpak AD column, and the data shown in parentheses are isolated
yields.
than those obtained with L12/Zn (4) (33% yield and
86.7% ee).12
So far, we have discovered that catalyst (L12/Zn/S26) is
highly efficient and enantioselective in both HDA reaction
and diethyl zinc addition of benzaldehyde. This catalyst
system has provided an excellent opportunity to conduct
two asymmetric reactions in one-pot using a single catalyst.
Thus, terephthalaldehyde 10a was taken as a substrate for
sequential asymmetric HDA reaction and diethylzinc
addition to generate dihydropyranone and secondary
alcohol moieties in one molecule (Scheme 3). The HDA
reaction was first carried out in the presence of 10 mol% of
L12/S26 combined with 14 mol% of diethyl zinc for 30 h at
K20 8C in toluene, and subsequently, 3 equiv of diethyl
zinc was introduced directly to the reaction mixture for the
second-step asymmetric addition under the same experi-
mental conditions without workup of the first HDA reaction
product. As shown in Table 4, the two asymmetric reactions
proceeded efficiently and selectively to give product 11a in
92% yield. It was found that the ee for the HDA reaction
was 97.4%, and the de for the diethylzinc addition step was
95.0%, which were essentially identical to those obtained
using benzaldehyde substrate. Similarly, the sequential
asymmetric HDA reaction and diethylzinc addition of
isophthalaldehyde 10b using the same catalyst also
demonstrated the excellent stereoselectivity for the forma-
tion of product 11b (82% yield, entry 2, Table 4). The
With these leading results in hand, we switched our
attention to the screening of highly efficient and enantio-
selective catalysts for diethylzinc addition to benzaldehyde
by combining L12 with a variety of diimine activators. The
literature results showed that in the catalysis of diethylzinc
addition to aldehydes, the steric hindrance of diimine
activators were critical for getting maximum activation of
BINOL-Zn catalyst.13 Accordingly, a library of diimines
with eight members (Scheme 2) was created by conden-
sation of enantiopure 1,2-diphenylethylenediamine or
1,2-diaminocyclohexane with 2 equiv of 2,6-disubstituted
or 2,4,6-trisubstituted benzaldehydes. A rapid screening of
the chiral catalyst library composed of L12 and the chiral
activators shown in Scheme 2 for diethylzinc addition to
benzaldehyde at 0 8C disclosed that L12/S26 was the best
combination, affording (S)-1-phenylpropanol ((S)-9) with
72% ee (Table 3). The enantioselectivity of the reaction
could be improved to 94.5% at a lower reaction temperature
(K20 8C) with the catalysis of L12/S26. Reexamination of
L12/S26 catalyst system for HDA reaction at K20 8C
resulted in the formation of (R)-5 with 97.4% ee and
quantitative yield.
Scheme 2. A library of diimine activators for asymmetric diethylzinc addition to benzaldehyde.

H. Du et al. / Tetrahedron 61 (2005) 9465–9477
9469
Scheme 3. Sequential asymmetric catalysis of hetero Diels–Alder reaction and diethylzinc addition using a single catalyst.
configurations of two chiral centers formed through HDA
and diethylzinc reactions in product 11a and 11b were
tentatively assigned to be R and S, respectively, as shown
in Scheme 3 on the basis of the results obtained using
benzaldehyde as substrate mentioned above. The
conversion and chemical selectivity for the first HDA step
was found to be very high (monoadduct:diadductO96:4) in
the reaction of 10a. The high chemoselectivity of the first-
step reaction is probably due to the fact that strong electron-
withdrawing formyl group can make the dienophile more
electrophilic to better interact with diene, and as a result to
facilitate the first HDA reaction. After HDA reaction, the
remaining second formyl group becomes much less reactive
than the starting dialdehyde because of electron-donating
property of a-dihydropyranyl moiety in the monoadduct.
The significant decrease of chemoselectivity in the reaction
of dialdehyde 10c (entry 3, Table 4) further supports the
explanation mentioned above, because the bridging oxygen
atom between two benzaldehyde will block the electronic
communication of two formyl groups in 10c.
Table 3. Screening of activated catalysts for diethylzinc addition to
benzaldehyde by combining L12 with a variety of diimine activators
Entry
Diimine
Yield (%)a
ee (%)b
Configurationc
1
2
3
4
5
6
7
8
S10
S20
S21
S22
S23
S24
S25
S26
O99
O99
91.2
97.0
75.5
62.4
76.3
55.5
45.6
34.1
48.1
21.1
45.7
4.6
S
S
S
R
S
S
R
S
2.1. Mechanistic investigation of L12/Zn/diimine
promoted HDA reaction
The search for nonlinear effects (NLE) in a given system has
become a useful probe for analyzing the nature of the
catalytic species or the nonreacting species involved in an
asymmetric synthesis.16 In our previous work, we have
disclosed that there exists a very unusual and interesting
NLE in the catalytic system with L12/Zn (Fig. 2a).12 The
14.2
72.0
a Isolated yields.
b Determined with HPLC on Chiralcel OD column.
c Determined by comparison of the retention time with that of an authentic
sample.

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H. Du et al. / Tetrahedron 61 (2005) 9465–9477
Figure 2. Enantioselectivity for the reaction of 6 with 7a catalyzed by the Zn complexes of partially resolved (R)-L12 in the absence (a), and in the presence of
S27 (b), S28 (c) or S29 (d). The broken lines indicate the expected values when the reactivity difference between (R)-L12/Zn/diimine and (S)-L12/Zn/diimine
was not considered.
sign of product configuration was found to be dependent on
the enantiopurity of L12, which implies that a variety of
aggregated catalytic species might be involved in the
catalytic system and the catalytic system may not be
behaved in one particular model. The change of the
catalytically active species might occur along with the
variation of ligand enantiopurity. On the other hand, upon
addition of achiral (S27–28) or meso (S29) diimines
(Scheme 4) to the BINOLate-Zn catalyst system, the NLE
patterns were dramatically changed in comparison with the
case in the absence of diimine additive. These facts clearly
indicated that the diimine additives indeed have some
impact on the catalytic process. As shown in Figure 2c–d,
when the ee value of L12 was less than 20%, very week
(K)-NLE could be observed in the presence of S28 or S29.
However, the catalytic systems demonstrated obvious (C)-
NLE with the increase of enantiopurity of L12. This is
apparently different from that observed by Walsh in
the diethylzinc addition reaction, in which only linear
relationship between the ee’s of ligand and product was
observed.13c
In order to further understand the origin of (C)-NLE
observed in the present catalytic system, an experiment was
carried out to isolate the precipitates formed during the
catalyst preparation using 40% ee of L12 in the presence of
achiral diimine S27 (Scheme 5). The enantiomeric excesses
of L12 in the isolated solids and in the supernatant were
determined to be 19.2% and O99%, respectively, which
implies that the enantiopurity of the catalytic species in the
liquid phase of the reaction system could be significantly
enriched due to the poor solubility of heterochiral zinc
species. Employing this supernatant for the catalysis of the
reaction between 6 and 7a under the otherwise identical
conditions afforded 8a in 47% yield with 85% ee, which is
higher than that obtained with in situ prepared catalyst using
S27 and L12 having 40% ee. On the basis of these
observations and the impact of diimine additives on the
Scheme 4. Achiral and meso-diimine activators.

H. Du et al. / Tetrahedron 61 (2005) 9465–9477
9471
interaction with diimine to give the monomeric species
that is responsible for the catalysis (Scheme 6).
As to the reaction pathway for the catalytic addition of
Danishefsky’s diene to aldehydes, two posibilities have
been reported: Mukaiyama aldol condensation versus
concerted [4C2] cycloaddition.5,7,17 In our reaction system,
1H NMR determination of primary reaction product before
CF3COOH treatment revealed that [4C2] cycloadduct were
formed exclusively, which supported a concerted cyclo-
addition mechanism. The possible asymmetric induction
pathway can be illustrated by using the schematic
representation depicted in Figure 3 (the interaction pattern
between catalyst and benzaldehyde was obtained by
geometrical optimization using universal force field (UFF)
implemented in GAUSSIAN 98) on the basis of experi-
mental evidence disclosed above, the sense of asymmetric
induction observed in the products, as well as the nonlinear
effects in the catalytic systems. It can be assumed that the
catalytically active species should be a monomeric zinc
Scheme 5. Experimental probing the origin of (C)-NLE.
reaction, as well as the discovery by Walsh,13c we can
conclude that the heterochirally aggregated Zn complexes
might be much more stable than the homochiral species, and
as a result, only trace amount of heterochiral aggregated Zn
complexes in the reaction system could be dissociated by
the coordination of diimine (Scheme 6). On the contrary, the
homochiral species will be readily cleaved by the
Scheme 6. Interaction of homochiral and heterochiral dimeric zinc complexes with diimine additive.
Table 4. Sequential asymmetric reactions of dialdehydes in the presence of L12/Zn/S26a
Entry
1
Substrate
Et2Zn (%)
Yield (%)b
ee (%)c,d
De (%)d,e
10a
14cC300e
11a (92)
12a (!3)
13a (!3)
11b (82)
12b (6)
13b (10)
11c (74)
12c (17)
13c (8)
11a (97.4)
12a (O99)
13a (nd)
11b (95.9)
12b (O99)
13b (nd)
11c (94.1)
12c (O99)
13c (nd)
11a (95.0)
12a (96.9)
13a (nd)
11b (94.9)
12b (96.6)
13b (nd)
11c (92)
12c (94.5)
13c (nd)
2
3
10b
10c
14cC300e
14cC300e
a All of the reactions were carried out at K20 8C in toluene with a molar ratio of dialdehyde: Danishefsky’s diene:L12:S26Z1:1.3:0.1:0.1.
b Isolated yields.
c For the first step HDA reaction.
d Determined by HPLC on Chiralcel OD or AD column. The de is the enantioselectivity of the second alkylation step.
e For diethylzinc addition.

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H. Du et al. / Tetrahedron 61 (2005) 9465–9477
induction mechanism and design of new catalytic asym-
metric reaction systems using activated Zn catalysts.
4. Experimental
4.1. General considerations
NMR spectra were recorded in deuteriochloroform on a
Varian Mercury 300 (1H 300 MHz; 13C 75 MHz) spectro-
meter. Chemical shifts are reported in ppm relative to an
1
internal standard: tetramethylsilane (0 ppm) for H NMR
and deuteriocholorform (77.0 ppm) for 13C NMR. Coupling
constants, J, are listed in Hertz. EI mass (70 ev) and ESI
spectra were obtained on HP5989A and Mariner LC-TOF
spectrometers, respectively. HRMS spectra were deter-
mined on a Kratos Concept instrument, Q-Tof micro
instrument or APEXIII 7.0 TESLA FTMS. Elemental
analysis was performed with an Elemental VARIO EL
apparatus. Optical rotations were measured on a Perkin-
Elmer 341 automatic polarimeter. Infrared spectra were
obtained on a BIO-RAD FTS-185 Fourier transform
spectrometer in KBr pellelts or neat. Liquid chromato-
graphic analyses were conducted on a JASCO 1580 system.
All the experiments sensitive to moisture or air were carried
out under argon atmosphere using standard Schlenk
techniques. Commercial reagents were used as received
without further purification unless otherwise noted.
Dichloromethane, chloroform, and tetrachloromethane
were freshly distilled from calcium hydride and THF,
diethyl ether and toluene from sodium benzophenone ketyl.
Figure 3. Schematic representation of the proposed asymmetric induction
pathway for L12/Zn/diimine catalyzed enantioselective HDA reaction.
complex containing both binolate and diimine moieties.
Upon the attaching of carbonyl group of aldehyde to the
central zinc ion, one of the coordinated imino N will
dissociate from zinc atom. Due to the steric shielding of
naphthyl ring and bromo atom from the Si face of
coordinated carbonyl group, the bound aldehyde is ready
to accept the attack of Danishefsky’s diene from Re face
(Fig. 3) to give the product in R configuration.
4.2. Ligand library
All the members of ligand library were prepared according
to the following literature methods: L1, L2, L9, L10, L12;18
L3;19 L5;20 L4, L6;6d L7, L8;21 L11.22 The diimine
activators S1–S20 were prepared by simple condensation of
tatarate salt of (R,R)- or (S,S)-cyclohexane-1,2-diamine,
which was synthesized according to the procedure reported
by Jacobsen23 with corresponding aldehyde in methanol in
the presence of K2CO3, and the following known diimines
were characterized by comparing the analytical data with
those reported in the literatures: S1, S11;24 S2, S10, S12,
S20;25 S3, S13;26 S4, S14;27 S8, S18;28 S21, S22;29 S23,
S24;13a S25, S26.30 The achiral diimine activators S27–28
were prepared by the condensation of 2,4,6-trimethylbenz-
aldehyde with corresponding diamines in refluxing toluene
or methanol.13c Danishefsky’s diene,31 diethylzinc,32 and
dialdehyde 9c33 were prepared following the literature
procedures.
3. Conclusion
In summary, a series of new type of chiral zinc catalysts
containing (R)-3,30-Br2-BINOL ligand and diimine activa-
tors have been discovered based on the combinatorial
approach, and were found to be highly efficient and
enantioselective for HDA reaction of Danishefsky’s diene
with aldehydes, affording the corresponding 2,3-dihydro-
4H-pyran-4-one derivatives in excellent yields and up to
98.7% ee. The application of this type of catalysts was also
extended to the diethylzinc addition to the benzaldehyde,
affording the corresponding secondary alcohol with up to
94.5% ee after optimization. On the basis of these facts, the
integration of enantioselective HDA and diethylzinc
addition reactions has been realized in one-pot with the
promotion of a single chiral zinc catalyst in a sequential
manner. The strategy described in the present work
demonstrated the ability of a single catalyst to promote
two distinct enantioselective reactions in one-pot, which
might provide an important direction to the design of chiral
catalysts for asymmetric synthesis. The impact of diimine
additive on the catalytic system of HDA reaction was also
investigated by probing the nonlinear effect of reaction
system. The positive nonlinear effect exhibited in the
catalytic system could be attributed to the poor solubility of
the heterochiral zinc species. We hope these findings will be
helpful for the further understanding of the asymmetric
4.2.1. (R,R)-N,N0-Di(3-bromobenzylidene)cyclohexane-1,
2-diamine (S5) and (S,S)-N,N0-di(3-bromobenzylidene)-
cyclohexane-1,2-diamine (S15). S5; [a]2D0K268.2 (c 0.4 in
MeOH). S15; [a]2D0C271.0 (c 0.4 in MeOH); mp 128–
130 8C; 1H NMR (300 MHz, CDCl3): dZ8.13 (s, 2H), 7.79
(t, JZ1.8 Hz, 2H), 7.56–7.52 (m, 4H), 7.21–7.16 (m, 2H),
3.42–3.40 (m, 2H), 1.88–1.78 (m, 6H), 1.52–1.45 (m, 2H);
FT-IR (KBr): nZ2927, 2854, 1647, 1560, 1477, 1372, 1339,
1278, 1200, 1065, 939, 891, 794, 687 cmK1; EI-MS (70 ev)
(m/z): 448 (MC, 2), 184 (100), 186 (94), 265 (37), 264 (29),
267 (25), 89 (20), 81 (16). Anal. Calcd for C20H20Br2N2: C,

H. Du et al. / Tetrahedron 61 (2005) 9465–9477
9473
53.66; H, 4.50; N, 6.25%. Found: C, 53.53; H, 4.63; N,
6.12%.
after 24 h. Internal standard biphenyl (10 mg) in toluene and
saturated sodium bicarbonate aqueous solution (0.5 mL)
were added to the quenched mixture. The organic layer was
separated and submitted to HPLC analysis for the
determination of yields and enantiomeric excesses (ee).
The yields were determined with a JASCO HPLC1500
with autosampler on Intersil CN-3 column: eluent hexane/
2-propanol 97:3, flow rateZ0.5 mL/min; UV detection at
lZ254 nm; tR of biphenyl, 7.6 min (factor 1.000); tR of
benzaldehyde, 11.4 min (factor 1.208); tR of 2-phenyl-2,
3-dihydro-4H-pyran-4-one, 23.0 min (factor 1.742). The
enantiomeric excesses were determined by using the same
HPLC analytical system on Chiralcel OD column: eluent
hexane/2-propanol 90:10, flow rateZ1.0 mL/min; UV
detection at lZ254 nm; tRZ13.0 min (S enantiomer),
15.2 min (R enantiomer). The results for the catalyst library
screening were summarized in Figure 1.
4.2.2. (R,R)-N,N0-Di(3-chlorobenzylidene)cyclohexane-1,
2-diamine (S6) and (S,S)-N,N0-di(3-chlorobenzylidene)-
cyclohexane-1,2-diamine (S16). S6; [a]2D0K300.9 (c 0.4 in
MeOH). S16; [a]2D0C297.0 (c 0.4 in MeOH); mp 110–
112 8C; 1H NMR (300 MHz, CDCl3): dZ8.14 (s, 2H), 7.64
(t, JZ1.5 Hz, 2H), 7.44–7.40 (m, 2H), 7.34–7.12 (m, 4H),
3.42–3.40 (m, 2H), 1.90–1.71 (m, 6H), 1.52–1.46 (m, 2H);
FT-IR (KBr): nZ2931, 2928, 1646, 1568, 1480, 1373, 1340,
1280, 1214, 1098, 1071, 939, 891, 796, 687, 426 cmK1
;
EI-MS (70 ev) (m/z): 358 (MC, 1), 140 (100), 186 (94), 142
(32), 221 (30), 220 (23), 138 (20), 89 (19). Anal. Calcd for
C20H20Cl2N2: C, 66.86; H, 5.61; N, 7.79%. Found: C, 66.67;
H, 5.72; N, 7.73%.
4.2.3. (R,R)-N,N0-Di(3-methoxybenzylidene)cyclohexane-
1,2-diamine (S7) and (S,S)-N,N0-di(3-methoxybenzyl-
idene)cyclohexane-1,2-diamine (S17). S7; [a]2D0K306.2
(c 0.5 in MeOH). S17; [a]2D0C303.3 (c 0.5 in MeOH); mp
100–102 8C; 1H NMR (300 MHz, CDCl3): dZ8.24 (s, 2H),
7.32–7.26 (m, 2H), 7.22–7.18 (m, 4H), 6.96–6.93 (m, 2H),
3.84 (s, 2H), 3.49–3.45 (m, 2H), 1.94–1.83 (m, 6H), 1.52–
1.50 (m, 2H); FT-IR (KBr): nZ2936, 2859, 1647, 1640,
1596, 1558, 1491, 1465, 1431, 1378, 1321, 1264, 1168,
1155, 1035, 802, 690, 429 cmK1; EI-MS (70 ev) (m/z): 350
(MC, 2), 136 (100), 135 (96), 134 (74), 217 (73), 214 (25),
186 (23), 121 (21). Anal. Calcd for C22H24O2N2: C, 75.40;
H, 7.48; N, 7.99%. Found: C, 75.18; H, 7.53; N, 7.89%.
4.3.1. A typical procedure for asymmetric catalysis of
HDA reaction of Danishefsky’s diene (6) with aldehydes
(7) under optimized conditions. To a 1.5 mL polypropyl-
ene microtube were added 0.05 M toluene solution of L12
(0.01 mmol, 0.2 mL), 0.050 M toluene solution of S13
(0.01 mmol, 0.2 mL), and 1 M solution of Et2Zn in hexane
(0.014 mmol, 14 mL, 1 M in hexane). The mixture was kept
at room temperature for 0.5 h and then freshly distilled
benzaldehyde (7a) (10.6 mg, 0.10 mmol) was added.
Danishefsky’s diene (6) (34.4 mg, 0.2 mmol) was charged
when the reaction temperature was kept constant at K20 8C.
The reaction was quenched by introducing 10 drops of
trifluoroacetic acid after 24 h. Saturated sodium bicarbonate
aqueous solution (0.8 mL) was added to the quenched
mixture. The aqueous layer was extracted with diethyl ether
(3!15 mL), and the combined organic layers were dried
over Na2SO4 and concentrated. The crude material was
purified by flash chromatography on silcal gel with hexane/
ethyl acetate 4:1 as eluent to afford 17.4 mg (O99% yield)
of (R)-2-phenyl-2,3-dihydro-4H-pyran-4-one (8a) as color-
4.2.4. (R,R)-N,N0-Di(2-methoxybenzylidene)cyclohexane-
1,2-diamine (S9) and (S,S)-N,N0-di(2-methoxybenzyl-
idene)cyclohexane-1,2-diamine (S19). S9; [a]2D0K250.8
(c 0.4 in MeOH). S19; [a]2D0C252.3 (c 0.4 in MeOH); mp
112–114 8C; 1H NMR (300 MHz, CDCl3): dZ8.08 (s, 2H),
7.48 (d, JZ1.8 Hz, 4H), 7.34 (t, JZ2.1 Hz, 2H), 3.42–3.89
(m, 2H), 1.90–1.67 (m, 6H), 1.53–1.47 (m, 2H); FT-IR
(KBr): nZ3092, 3078, 2929, 2862, 2858, 1645, 1589, 1565,
1
less oil with 98.7% ee; H NMR (300 MHz, CDCl3): dZ
1420, 1375, 1341, 1217, 1039, 862, 803, 604, 468 cmK1
;
7.46 (d, JZ6.6 Hz, 1H), 7.42–7.36 (m, 5H), 5.51 (dd, JZ
5.7, 1.2 Hz, 1H), 5.41 (dd, JZ14.18, 3.4 Hz, 1H), 2.95–2.84
(m, 1H), 2.68–2.60 (m, 1H); FT-IR (neet): nmaxZ3064,
1676, 1596, 1402, 1272, 1228, 1210, 1040, 990, 934, 864,
826, 796, 760, 732, 720, 640, 612 cmK1. The results were
summarized in Table 1.
EI-MS (70 ev) (m/z): 426 (MC, 0.4), 174 (100), 176 (62),
255 (62), 257 (33), 256 (30), 254 (29), 173 (26). Anal. Calcd
for C20H18Cl4N2: C, 56.10; H, 4.24; N, 6.49%. Found: C,
56.13; H, 4.38; N, 6.49%.
4.3. High throughput screening of the chiral Zn catalyst
library generated by assembling the member of diol
ligand (L1–L12) and diimine activator (S1–S20) libraries
with Zn for HDA reaction of Danishefsky’s diene (7)
with benzaldehyde (8a)
Following the optimized procedure described above, the
scope of the substrate was investigated under the catalysis of
L12/Zn/diimine. The results were shown in Table 2.
4.4. Procedure for screening of enantioselective catalysts
for diethylzinc addition to benzaldehyde by combining
L12 with a variety of diimine activators
To each member of an array of 1.5 mL polypropylene
microtubes were added 0.050 M toluene solution of Lm
(0.01 mmol, 0.2 mL) and 0.050 M toluene solution of Sn
(0.01 mmol, 0.2 mL), and then 1 M solution of Et2Zn in
hexane (0.012 mmol, 12 mL) was added. The mixtures were
kept at room temperature for 0.5 h and then to each
microtube freshly distilled benzaldehyde 8a (10.6 mg,
0.10 mmol) was added. The microtubes were then set up
in a cooling bath to maintain the temperature at 0 8C for
30 min, and finally Danishefsky’s diene (17.2 mg,
0.1 mmol) was quickly added to each tube. The reaction
was quenched by introducing 5 drops of trifluoroacetic acid
To each member of an array of 1.5 mL polypropylene
microtubes were added 0.10 M toluene solution of L12
(0.02 mmol, 0.2 mL) and 0.10 M toluene solution of
diimine activators (shown in Scheme 2) (0.02 mmol,
0.2 mL), then freshly distilled benzaldehyde (21.2 mg,
0.20 mmol) was added. The microtubes were then set up
in a cooling bath to maintain the temperature at 0 8C for
30 min, and finally Et2Zn (0.4 mL, 1 M in toluene,
0.4 mmol) was quickly added. After standing at 0 8C for

9474
H. Du et al. / Tetrahedron 61 (2005) 9465–9477
4 h, the reaction mixture was quenched with saturated
ammonium chloride solution and extracted with diethyl
ether. The organic phase was washed with brine and dried
over anhydrous sodium sulfate. After removal of the
solvent, the crude product was purified by flash chroma-
tography on silica gel with EtOAc/hexane 1:7 as eluent to
give 1-phenyl-1-propanol as a colorless liquid. Its enantio-
meric excess was determined with HPLC on Chiralcel OD
column: eluent hexane/2-propanol 98.5:1.5, flow rateZ
1.0 mL/min; UV detection at lZ254 nm; tRZ18.6 min (R
enantiomer), 22.9 min (S enantiomer). The results of
screening were summarized in Table 3.
0.93 (t, JZ7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): dZ
192.3, 163.3, 145.6, 136.7, 126.4, 126.1, 107.2, 80.8, 75.4,
43.1, 31.9, 10.0; MS (EI, 70 ev) (m/z %): 232 (2), 203 (61),
133 (100), 105 (41), 77 (25); HRMS: calcd for C14H16O3:
232.1099; found: 232.1092. The enantiomeric excess and
diastereoselectivity were determined by HPLC on Chiralcel
OD column with hexane/isopropanol 80:20 as eluent, flow
rateZ1.0 mL/min, tR1Z12.8 min, tR2Z14.0 min, tR3
16.3 min, tR4Z18.1 min.
Z
4.5.2. Compound 12a. Yield 3%, 1.7 mg, O99% ee. Mp
170–172 8C; [a]D20K179 (c 0.3 in CHCl3); 1H NMR
(300 MHz, DMSO-d6): dZ7.52 (d, JZ5.7 Hz, 2H), 7.34
(s, 4H), 5.39 (d, JZ13.5 Hz, 2H), 5.24 (d, JZ8.1 Hz, 2H),
2.69–2.79 (m, 2H), 2.32 (d, JZ12 Hz, 2H); 13C NMR
(75 MHz, DMSO-d6): dZ191.3, 173.7, 138.6, 126.6, 106.7,
79.8, 42.4; FT-IR (KBr): nZ2971, 1667, 1592, 1579, 1403,
1374, 1274, 1230, 1214, 1172, 1403, 976, 937, 841,
798 cmK1; EI-MS m/z (relative intensity): 270 (MC,
1.76), 130 (100), 241 (21.88), 128 (15.65), 131 (15.01),
115 (12.25), 171 (11.03), 182 (10.36); HRMS (EI): calcd for
C16H14O4: 270.0892; found: 270.0856. The enantiomeric
excess and diastereoselectivity were determined by HPLC
on Chiralcel OD column, hexane:isopropanol 65:35, flow
4.4.1. The optimized procedure for diethylzinc addition
to benzaldehyde under the catalysis of L12/S26. To a
1.5 mL polypropylene microtubes were added 0.10 M
toluene solution of L12 (0.02 mmol, 0.2 mL), 0.10 M
toluene solution of S26 (0.02 mmol, 0.2 mL) and freshly
distilled benzaldehyde (21.2 mg, 0.20 mmol) was added.
Et2Zn (0.4 mmol, 0.4 mL, 1 M in toluene) was introduced to
the reaction system after the microtube was kept at K20 8C
for 30 min. The reaction was continued for 24 h at K20 8C
before it was quenched with saturated ammonium chloride
solution and extracted with diethyl ether. The organic phase
was washed with brine and dried over anhydrous sodium
sulfate. After removal of the solvent, the crude product was
purified by flash chromatography on silica gel with EtOAc/
hexane 1:7 as eluent to give 1-phenyl-1-propanol 24.0 mg
rateZ1.0 mL/min, tRRZ26.88 min; tSSZ21.72 min; tmeso
23.93 min.
Z
1
4.5.3. Compound 11b. Colorless oil, 38.2 mg, 95.0% ee,
(87.6% yield, 94.5% ee (S)) as colorless liquid; H NMR
95.0% de, 82% yield; [a]2D0K90.5 (c 1.9 in CHCl3); H
1
(300 MHz, CDCl3): dZ0.92 (t, 3H, JZ7.8 Hz), 1.65–1.84
(m, 2H), 1.88 (br s, 1H), 4.58 (t, 1H, JZ7.5 Hz), 7.23–7.38
(m, 5H).
NMR (300 MHz, CDCl3): dZ7.48 (d, JZ6.0 Hz, 1H),
7.28–7.40 (m, 4H), 5.53 (dd, JZ5.7, 1.2 Hz, 1H), 5.43 (dd,
JZ14.1, 3.3 Hz, 1H), 4.64 (t, JZ6.6 Hz, 1H), 2.84–2.94 (m,
1H), 2.61–2.67 (m, 1H), 2.20 (s, 1H), 1.75–1.83 (m, 2H),
0.93 (t, JZ7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): dZ
192.3, 163.3, 145.6, 137.9, 128.9, 126.6, 125.1, 123.7,
107.3, 81.1, 75.6, 43.3, 32.0, 10.1; FT-IR (neat): nZ3423,
2966, 2933, 2877, 2248, 1673, 1591, 1405, 1276, 1221,
1041, 991, 912, 799, 734, 706 cmK1; EI-MS m/z (relative
intensity): 232 (MC, 5.57), 133 (100), 105 (55.59), 203
(48.46), 77 (29.04), 159 (23.18), 103 (19.04), 79 (16.59);
HRMS (EI): calcd for C14H16O3: 232.1099; found:
232.1103. The enantiomeric excess and diastereoselectivity
were determined by HPLC on Chiralcel OD column,
4.5. General procedure for sequential asymmetric
catalysis
All of the experiments were carried out under argon.
Weighed amounts of chiral ligand L12 (8.9 mg, 0.02 mmol)
and chiral activator S26 (9.4 mg, 0.02 mmol) were
introduced into a 1.5 mL polypropylene microtube. Toluene
(0.8 mL), Et2Zn (0.28 mmol, 28 mL, 1 M in hexane) and
aldehyde 10 (0.2 mmol) were added to the microtube in
glove box with a microsyringe. The microtube was then set
up in a cooling bath to maintain the temperature at K20 8C
for 30 min, and finally Danishefsky’s diene 6 (41.2 mg,
0.26 mmol) was quickly added. After agitation at K20 8C
for 30 h, Et2Zn (0.6 mmol, 0.2 mL, 3 M in toluene) was
introduced to the reaction system. After the reaction was
continued for additional 24 h, the microtube was opened and
trifluoacetic acid was added to quench the reaction. The
aqueous layer was neutralized with NaHCO3 aqueous
solution and extracted with ethyl acetate for three times.
The combined organic phase was washed with brine and
then dried over anhydrous Na2SO4. After removal of the
solvent, the residue was purified by flash column chroma-
tography on silica gel with EtOAc/hexane 1:2 as eluent to
give 11 as colorless oil.
hexane:isopropanol 85:15, flow rateZ1.0 mL/min, tR1
12.2 min, tR2Z13.1 min, tR3Z15.8 min, tR4Z30.9 min.
Z
4.5.4. Compound 12b. Yield 6%, 3.5 mg, O99% ee, 3%
1
meso. Mp 118–120 8C; [a]2D0K145 (c 0.5 in CHCl3); H
NMR (300 MHz, DMSO-d6): dZ7.60 (d, JZ5.7 Hz, 2H),
7.49 (s, 1H), 7.35 (s, 3H), 5.44 (dd, JZ14.1, 2.4 Hz, 2H),
5.30 (d, JZ6.0 Hz, 2H), 2.77–2.89 (m, 2H), 2.38 (d, JZ
14.1 Hz); 13C NMR (75 MHz, DMSO-d6): dZ191.4, 163.8,
138.7, 128.8, 126.7, 124.7, 106.7, 80.0, 42.4; FT-IR (KBr):
nZ3070, 3062, 2908, 1666, 1599, 1591, 1411, 1353, 1284,
1272, 1230, 1218, 1039, 994, 940, 796, 707 cmK1; EI-MS
m/z (relative intensity): 270 (MC, 2.16), 149 (100), 130
(95.17), 129 (26.92), 171 (21.35), 182 (18.33), 128 (17.08),
131 (15.49); HRMS (EI): calcd for C16H14O4: 270.0892;
found: 270.08882; The enantiomeric excess and diastereo-
selectivity were determined by HPLC on Chiralcel AD
column, hexane:isopropanol 80:20, flow rateZ1.0 mL/min,
tRRZ19.82 min; tSSZ28.74 min; tmesoZ21.00 min.
4.5.1. Compound 11a. Yield 92%, 42.8 mg; [a]2D5K110 (c
1
2.0 in CHCl3); H NMR (300 MHz, CDCl3): dZ7.48 (d,
JZ6.0 Hz, 1H), 7.40 (s, 4H), 5.53 (dd, JZ6.0, 1.2 Hz, 1H),
5.43 (dd, JZ14.1, 3.9 Hz, 1H), 4.65 (t, JZ6.3 Hz, 1H),
2.86–2.97 (m, 1H), 2.62–2.69 (m, 1H), 1.70–1.83 (m, 3H),

H. Du et al. / Tetrahedron 61 (2005) 9465–9477
9475
4.5.5. Compound 11c. Colorless oil, 47.7 mg, 74% yield,
Acknowledgements
94.1% ee, 92.1% de; [a]2D0K84.9 (c 2.9 in CHCl3); 1H NMR
(300 MHz, CDCl3): dZ7.49 (d, JZ6.3 Hz, 1H), 7.36 (t, JZ
8.4 Hz, 4H), 7.03 (t, JZ7.8 Hz, 4H), 5.54 (d, JZ5.7 Hz,
1H), 5.39 (dd, JZ14.1, 3.0 Hz, 1H), 4.61 (t, JZ6.6 Hz, 1H),
2.98–2.88 (m, 1H), 2.69–2.62 (m, 1H), 2.25 (br s, 1H), 1.87–
1.73 (m, 2H), 0.94 (t, JZ7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3): dZ192.2, 163.3, 158.0, 155.7, 140.1, 132.2, 127.8,
127.5, 119.1, 118.5, 107.2, 80.6, 75.4, 43.1, 31.9, 10.3; IR
(neat): nZ3421, 3062, 2966, 2932, 2876, 1674, 1599,
1504 1404, 1274, 1233, 1211, 1170, 1041, 987, 934, 837,
797 cmK1; EI-MS m/z (relative intensity): 324 (MC, 10.02),
257 (100), 225 (83.89), 211 (51.99), 295 (51.61), 49 (44.51),
84 (40.63), 77 (32.72); HRMS (EI): calcd for C20H20O4:
324.1356; found: 324.1354. The enantiomeric excess and
diastereoselectivity were determined by HPLC on Chiralcel
OD column, hexane:isopropanol 80:20, flow rateZ1.0 mL/
Financial support from the National Natural Science
Foundation of China, the Chinese Academy of Sciences,
the Major Basic Research Development Program of China
(Grant no. G2000077506), and the Commission of Science
and Technology, Shanghai Municipality is gratefully
acknowledged.
References and notes
1. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley-Interscience: New York, 1994. (b) Catalysis Asym-
metric Synthesis; Ojima, I., Ed. 2nd ed.; Wiley-VCH: New
York, 2000. (c) Kagan, H. B.; Comprehensive Organic
Chemistry; Pergamon: Oxford, 1992; Vol. 8. (d) Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Comprehensive
Asymmetric Catalysis; Springer: Berlin, 1999; Vol. I–III.
(e) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.;
Wiley-VCH: New York, 2001.
min, tR1Z17.2 min, tR2Z19.3 min, tR3Z21.8 min, tR4
Z
24.5 min.
4.5.6. Compound 12c. Colorless oil, 12.6 mg, 17% yield,
1
O99% ee, 5% meso; [a]2D0K128.0 (c 1.1 in CHCl3); H
2. For reviews on tandem catalysis, see: (a) Wasilke, J.-C.;
Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105,
1001–1020. (b) Ajamian, A.; Gleason, J. L. Angew. Chem., Int.
Ed. 2004, 43, 3754–3760. (c) Fogg, D. E.; dos Santos, E. N.
Coord. Chem. Rev. 2004, 248, 2365–2379. For leading
examples of one catalyst for two different reactions, see:
(d) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 11312–11313. (e) Bielawski, C. W.; Louie, J.;
Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 12872–12873.
(f) Drouin, S. D.; Zamanian, F.; Fogg, D. E. Organometallics
2001, 20, 5495–5497. (g) Orita, A.; Nagano, Y.; Nakazawa,
K.; Otera, J. Adv. Synth. Catal. 2002, 344, 548–555. (h) Chen,
J.; Otera, J. Angew. Chem., Int. Ed. 1998, 37, 91–93. (i) Sutton,
A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am.
Chem. Soc. 2002, 124, 13390–13391. (j) Periana, R. A.;
Mironov, O.; Taube, D.; Bhalla, G.; Jones, C. J. Science 2003,
301, 814–818. (k) de Wet-Roos, D.; Dixon, J. T. Macro-
molecules 2004, 37, 9314–9320. (l) Evans, P. A.; Robinson,
J. E. J. Am. Chem. Soc. 2001, 123, 4609–4610.
NMR (300 MHz, CDCl3): dZ7.49 (d, JZ6.0 Hz, 2H),
7.42–7.38 (m, 4H), 7.10–7.06 (m, 4H), 5.54 (dd, JZ6.0,
0.9 Hz, 2H), 5.43 (dd, JZ14.1, 3.3 Hz, 2H), 2.99–2.88 (m,
2H), 2.71–2.63 (m, 2H); 13C NMR (75 MHz, CDCl3): dZ
1192.1, 163.2, 157.3, 132.8, 127.9, 119.1, 107.3, 80.6, 43.2;
FT-IR (neat): nZ3071, 1684, 1668, 1603, 1588, 1506, 1405,
1272, 1243, 1231, 1209, 1172, 1049, 1038, 988, 933,
836 cmK1; EI-MS m/z (relative intensity): 362 (MC, 1.0),
225 (100), 295 (75.39), 211 (66.18), 77 (21.25), 226 (17.05),
91 (16.33), 296 (15.26), 324 (15.15); HRMS (EI): calcd for
C22H18O5: 362.1149; found: 362.1144. The enantiomeric
excess and diastereoselectivity were determined by HPLC
on Chiralcel OD column, hexane:isopropanol 80:20, flow
rateZ1.0 mL/min, tRRZ22.3 min; tSSZ39.2 min; tmeso
Z
28.1 min.
4.6. Investigation of nonlinear effects
3. For leading examples of one catalyst for two different
asymmetric reactions, see: (a) Yu, H.-B.; Hu, Q.-S.; Pu, L.
J. Am. Chem. Soc. 2000, 122, 6500–6501. (b) Tian, J.;
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The examination of NLE was carried out following the
similar procedure mentioned above at 0 8C with 10 mol% of
L12 with specified enantiopurity in the absence of or in the
presence of achiral diimine activators (S27–S29). The
enantiomeric excesses of the L12 employed for the reaction
were measured by HPLC on Chiralpak AD column (hexane/
isopropanol 60:40, flow rateZ1.0 mL/min, tR1Z13.9 min
(R), tR2Z19.4 min (S)) before they were submitted to the
catalysis. The yields were determined with a JASCO
HPLC1500 with autosampler on Intersil CN-3 column:
eluent hexane/2-propanol 97:3, flow rateZ0.5 mL/min; UV
detection at lZ254 nm; tR of biphenyl, 7.6 min (factor
1.000); tR of benzaldehyde, 11.4 min (factor 1.208); tR of
2-phenyl-2, 3-dihydro-4H-pyran-4-one, 23.0 min (factor
1.742). The enantiomeric excesses were determined by
using the same HPLC analytical system on Chiralcel OD
column: eluent hexane/2-propanol 90:10, flow rateZ
1.0 mL/min; UV detection at lZ254 nm; tR 13.0 min
(S enantiomer), 15.2 min (R enantiomer). The results were
shown in Figure 2a–d.
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