Construction of optically active quaternary propargyl amines by highly enantioselective zinc/BINOL-catalyzed alkynylation of ketoimines

Article abstract of DOI:10.1002/chem.201301479

A general and efficient method for the highly enantioselective alkynylation of ketoimines through a zinc/1,1-bi-2-naphthol (BINOL)-catalyzed process has been developed. A variety of ketoimines, including α-fluoroalkyl α-imine esters, α-aryl α-imine esters, and trifluoromethyl aryl ketoimines, are applicable and provide their corresponding quaternary propargyl amines in excellent yields with high ee values (up to 99 % ee). Both the steric and electronic effects of substituents at the 3,3 positions of BINOL are critical for the reaction efficiency and enantioselectivity. To demonstrate the usefulness of the method, (R)-α-CF₃ α-proline has been prepared in a highly efficient manner. The notable features of this protocol are its broad substrate scope, high reaction efficiency (up to 99 %) and enantioselectivity (up to 99 % ee), low catalyst loading (5 mol % of BINOL derivative), and mild reaction conditions. Copyright

Full text of DOI:10.1002/chem.201301479

FULL PAPER
Enantioselectivity
G. Huang, Z. Yin,
X. Zhang* ..................... &&&& — &&&&
Construction of Optically Active
Quaternary Propargyl Amines by
Highly Enantioselective Zinc/BINOL-
Catalyzed Alkynylation of Ketoimines
Propped up: A Zn/BINOL-catalyzed
method for the enantioselective alky-
nylation of ketoimines, including a-flu-
oroalkyl a-imine esters, a-aryl a-imine
esters, and trifluoromethyl aryl ketoi-
mines, is described (see scheme;
PG=protecting group, TMS=trime-
thylsilyl, Tf=triflyl). The correspond-
ing quaternary propargyl amines are
produced in excellent yields with high
ee values (up to 99% ee).
Chinese mythology…… was used to describe the
challenges involved in the catalytic enantioselective
alkynylation of ketoimines. The arrow shows the
alkynylzinc reagent generated from alkyne and
Me2Zn; BINOL, an accelerator for the reaction, is
the bow. The substrates ketoimines are the suns.
The three suns shot down in the sea are the three
types of products, chiral quaternary propargyl
amines. For more details, see the Full Paper by X.
Zhang et al. on page &&ff.
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DOI: 10.1002/chem.201301479
Construction of Optically Active Quaternary Propargyl Amines by Highly
Enantioselective Zinc/BINOL-Catalyzed Alkynylation of Ketoimines
Gaochao Huang, Zengsheng Yin, and Xingang Zhang*[a]
Abstract:
A
general and efficient
amines in excellent yields with high ee
values (up to 99% ee). Both the steric
and electronic effects of substituents at
the 3,3’ positions of BINOL are critical
for the reaction efficiency and enantio-
selectivity. To demonstrate the useful-
ness of the method, (R)-a-CF3 a-pro-
line has been prepared in a highly effi-
cient manner. The notable features of
this protocol are its broad substrate
scope, high reaction efficiency (up to
99%) and enantioselectivity (up to
99% ee), low catalyst loading (5 mol%
of BINOL derivative), and mild reac-
tion conditions.
method for the highly enantioselective
alkynylation of ketoimines through a
zinc/1,1’-bi-2-naphthol (BINOL)-cata-
lyzed process has been developed. A
variety of ketoimines, including a-fluo-
roalkyl a-imine esters, a-aryl a-imine
esters, and trifluoromethyl aryl ketoi-
mines, are applicable and provide their
corresponding quaternary propargyl
Keywords: alkynylation
·
amino
acids · BINOL · ketoimines · prop-
argyl amines · zinc
Introduction
permeability through certain body barriers.[10] Hence, it is of
great interest to prepare these valuable building blocks.
Very recently, we reported a first example of the catalytic
enantioselective alkynylation of ketoimine (a-CF3 ketoimine
Developing new methods to prepare optically active prop-
argyl amines, including quaternary propargyl amino acids
and related derivatives, is of great importance due to the
synthetic utility of chiral propargyl amines in the total syn-
thesis of natural products and pharmaceutical compounds.[1]
The most widely used approaches to these important syn-
thetic building blocks rely on the asymmetric alkynylation
of imines.[2] Over the past several years, great endeavors
have been devoted to this area and some impressive proto-
cols with high enantioselectivities and yields resulting from
the addition of terminal alkynes to aldimines have been re-
ported.[3,4] To date, however, the catalytic enantioselective
alkynylation of ketoimines is still a challenge because of the
low reactivity and difficulties in enantiofacial discrimination
of ketoimines.[5,6] Thus, new methods that meet these chal-
lenges for widespread synthetic application are highly desir-
able.[7]
Meanwhile, enantiomerically enriched quaternary a-
amino acids or related derivatives are found in many biolog-
ically active compounds[8] and lend conformational rigidity
to biologically active peptides.[9] In particular, the incorpora-
tion of a-fluorinated amino acids into peptides leads to
great changes in their biological activity by improving enzy-
matic stability and enhancing in vivo absorption and drug
ester) by
a
zinc/1,1’-bi-2-naphthol[11] (BINOL)-catalyzed
process (Table 1, entries 1 and 2).[7a] As part of our contin-
ued efforts in this area,[12] we herein describe a general
method for the catalytic enantioselective alkynylation of
acyclic ketoimines by
a zinc/BINOL-catalyzed process
(Scheme 1). The advantages of this protocol are a broad
Table 1. Catalytic enantioselective addition of terminal alkynes 2 to a-
ketoimine esters 1.[a]
Entry
1
R1
2
R
4 Yield
ee
[%][b]
[%][c]
1
2
3
1a
1a
1b
F
2a
2b
2a
Ph
Ph
4a, 90
4b, 91
4c, 94
97
98
94
F
Br
4
1b
Br
2c
4d, 91
89
5
1b
Br
2b
4e, 86
96
6[d]
7
8
1b
1c
1d
Br
Cl
CF3
2d
2a
2a
BnOCH2
Ph
Ph
4 f, 88
4g, 83
4h, 95
92
96
95
[a] G. Huang, Dr. Z. Yin, Prof. Dr. X. Zhang
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
9
1d
1e
CF3
2b
2a
4i, 76
4j, 92
96
95
10
allyl
Ph
345 Lingling Lu, Shanghai 200032 (P.R. China)
E-mail: xgzhang@mail.sioc.ac.cn
[a] Reaction conditions unless otherwise specified:
1
(0.3 mmol),
2
(1.7 equiv), Me2Zn (1.2 equiv), L*3a (5 mol%), toluene (1.2 mL), 19–
48 h, RT. [b] Yield of isolated product. [c] Determined by chiral HPLC
analysis. [d] With 2.5 equiv of 2.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301479.
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Enantioselective Zinc/BINOL-Catalyzed Alkynylation of Ketoimines
FULL PAPER
obtained when perfluoroalkylated substrate 1d was tested
(Table 1, entries 8 and 9). The functionalized allyl-substitut-
ed a-ketoimine ester 1e also underwent the reaction
smoothly to provide a good yield and high ee value (Table 1,
entry 10). It should be pointed out that these resulting di-
fluorinated propargyl amines can also serve as a class of im-
portant building blocks for the synthesis of biologically
active compounds; the incorporation of a geminal difluoro-
methlene group (CF2) into an organic molecule can not only
enhance the acidity of its neighboring groups, but also act as
an isopolar–isosteric substitute for oxygen.[16] The configura-
tion of 4 was determined to be R by X-ray crystal structure
analysis of 4d (Figure 1).[17]
Scheme 1. Zinc/BINOL-catalyzed alkynylation of acyclic ketoimines;
PG=protecting group.
substrate scope for both terminal alkynes and acyclic keto-
ACHTUNGTRENNUNGimines, a high reaction efficiency and enantioselectivity (up
to 99% ee), low catalyst loading (5 mol% of BINOL deriva-
tive), and mild reaction conditions (room temperature). This
protocol provides an efficient method for the preparation of
optically active quaternary a-amino acids, including a-fluo-
roalkyl amino acids.
Results and Discussion
Enantioselective alkynylation of a-fluoroalkyl a-imine
esters: Fluorinated amino acids are important building
blocks in the field of peptide design and protein engineering
due to the unique properties of fluorine atom(s). However,
limited methods for the enantioselective synthesis of fluori-
nated amino acids have been developed so far.[13] In particu-
lar, few examples of the catalytic enantioselective synthesis
of a-fluoroalkyl a-amino acids have been reported.[14] In-
spired by our recent work, a variety of fluorinated a-ketoi-
mine esters 1, including functionalized difluoromethyl and
perfluoroalkyl a-ketoimine esters,[15] were investigated. As
illustrated in Table 1, different optically active a-fluoroalkyl
a-amino acids were obtained by reaction of 1 (1.0 equiv)
with alkynes 2 (1.7 equiv) and Me2Zn (1.2 equiv) in the
presence of (R)-3,3’-TMS2-BINOL (3a, TMS=trimethylsil-
yl; 5 mol%) in toluene at room temperature. Generally, the
nature of the substituent R1 did not influence the reaction
efficiency and enantioselectivity. Ketoimines 1b–c, contain-
ing bromo- and chloro- difluoromethyl groups, were tolerat-
ed in the reaction systems with Br and Cl atoms remaining
intact, and gave alkynylated products 4c–g in good yields
with excellent ee values of up to 96% (Table 1, entries 3–7).
This allowed for the further formation of carbon–carbon
bonds or carbon–heteroatom bonds by transition-metal-
mediated coupling and other reactions (i.e., radical reac-
tions). High ee values (95–97%) and good yields were also
Figure 1. X-ray crystal structure of compound 4d. Hydrogen atoms have
been removed for clarity, ellipsoids are shown at the 30% probability
level.
Catalytic enantioselective alkynylation of a-aryl a-imine
esters:[17,18] To further probe the applicability of this method,
we turned our attention to the relatively less reactive a-aryl
a-imine esters. A dramatically decreased yield and enantio-
selectivity were observed when the a-phenyl a-imine ester
5a was subjected to the same reaction conditions (Table 2,
entry 1). To address the issue, an electron-withdrawing
group NO2 was introduced into the N-protecting group to
enhance the electrophilicity of 5a. As expected, the yield
was significantly increased, although no enantioselectivity
was observed (Table 2, entry 2). Considering that the steric
effect of both substituents in ketoimine plays a critical role
in the enantioselectivity of the reaction, and that different
sizes of these two substituents benefit the enantiofacial dis-
crimination of ketomine, we then tuned the size of the ester
group to improve the reaction enantioselectivity (Table 2,
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X. Zhang et al.
Table 2. Optimization of catalytic enantioselective addition of terminal
electronic effects of the substituents at positions 3,3’ of
BINOL are critical to the enantioselectivity. For instance,
the CF3-containing ligand 3g provided a much higher ee
value than its nonfluorinated counterpart 3 f (Table 3, en-
tries 6 and 7), suggesting that an electron-withdrawing group
benefits the enantioselectivity. But bulky substituents were
less effective, low ee values were observed (Table 3, en-
tries 2, 3 and 8). With these findings in mind, CF3- and Tf-
substituted ligands 3i and 3j were further evaluated
(Table 3, entries 9 and 10). To our delight, an excellent ee
(98%) and yield (98%) were obtained when 3j was used
(Table 3, entry 10).
With the optimized reaction conditions established
(Table 3, entry 10), the substrate scope of the catalytic enan-
tioselective alkynylation of a-aryl a-imine esters 5 with al-
kynes 2 was investigated (Table 4). Generally, imine esters 5
containing different aryl groups underwent the reaction
smoothly with excellent yields (92–98%) and high ee values
(86–98%; Table 4, entries 1–6). Notably, the bromide-con-
taining substrate 5j successfully furnished the corresponding
propargyl amine in excellent yield with high enantioselectiv-
ity (97% ee; Table 4, entry 5). Naphthyl groups were also
tolerated in the catalytic system (Table 4, entry 6). A variety
of terminal alkynes, including aryl-, alkyl-, and silyl-substi-
tuted alkynes, were also examined (Table 4, entries 7–13).
For aromatic and conjugated terminal alkynes, excellent
yields and high ee values were obtained (Table 4, entries 7–
10). In particular, aliphatic and silyl-substituted terminal al-
kynes gave high ee values, providing opportunities for fur-
ther transformations (Table 4, entries 11–13). The configura-
tion of 6 was determined to be S by X-ray crystal structure
analysis of 6j (Figure 2).[17]
alkyne 2a to a-aryl a-imine esters 5.[a]
Entry
Imine 5
R2
R3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
5a
5b
5c
5d
5e
5 f
Me
Me
Cy
iPr
1-Ad
tBu
H
6a, 19
6b, 82
6c, 90
6d, 78
6e, 96
6 f, 82
19
0
34
43
72
77
NO2
NO2
NO2
NO2
NO2
[a] Reaction conditions unless otherwise specified:
5
(0.3 mmol), 2a
(1.7 equiv), Me2Zn (1.2 equiv), 3a (5 mol%), toluene (1.2 mL), 19–48 h,
RT. [b] Yield of isolated product. [c] Determined by chiral HPLC analy-
sis.
entries 3–6). It turned out that a tert-butyl group was the
best choice, providing a good yield (82%) and moderate ee
(77%; Table 2, entry 6). Changing the tert-butyl group to a
cyclohexyl (Cy) or 1-adamantyl (1-Ad) group led to higher
yields but lower enantioselectivities (Table 2, entries 3 and
5).
After identification of the suitable a-phenyl a-imine ester
substrate 5 f, different BINOL-type ligands L*3, modified at
the 3,3’ positions, were evaluated in an effort to further im-
prove the enantioselectivity (Table 3). We found that the
Table 3. Screening of chiral ligands for the catalytic enantioselective ad-
dition of terminal alkyne 2a to a-phenyl a-imine ester 5 f.[a]
Catalytic enantioselective alkynylation of trifluoromethyl
aryl ketoimines:[17,19] Chiral fluorinated amines have re-
Entry
L*3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3 f
3g
3h
3i
82
93
93
99
99
80
99
75
99
98
77
19
88
60
74
19
96
55
81
98
10
3j
[a] Reaction conditions unless otherwise specified: 5 f (0.3 mmol), 2a
(1.7 equiv), Me2Zn (1.2 equiv), L*3 (5 mol%), toluene (1.2 mL), 19–48 h,
RT. [b] Yield of isolated product. [c] Determined by chiral HPLC analy-
sis.
Figure 2. X-ray crystal structure of compound 6j. Hydrogen atoms have
been removed for clarity, ellipsoids are shown at the 30% probability
level.
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Enantioselective Zinc/BINOL-Catalyzed Alkynylation of Ketoimines
FULL PAPER
Table 4. Catalytic enantioselective addition of terminal alkynes 2 to a-phenyl a-imine
esters 5.[a]
10). We found that even when the BINOL 3d was
used, a good enantioselectivity could still be ob-
tained (Table 5, entry 10). In contrast, a low enan-
tiomeric excess was observed when (R)-3,3’-F2-
BINOL was examined, suggesting that the electron-
ic effect of the substituents at the 3,3’ positions of
BINOL is also critical to the reaction enantioselec-
tivity (Table 5, entry 9). Interestingly, when the
BINOL-type ligands with electron-deficient sub-
stituents CF3 or Tf were explored, an enantiomer
with the opposite configuration was obtained as the
major product (Table 5, entries 4 and 5). A similar
finding was also observed when (R)-8H-BINOL
(3p) was investigated (Table 5, entry 11), demon-
strating that we can obtain both enantiomers enan-
tioselectively by choosing a suitable ligand.
To further optimize the reaction conditions, the
reaction temperature was examined (Table 6). It
was found that the enantioselectivity was sensitive
to the reaction temperature; different temperatures
led to different enantioselectivities. To our delight,
the highest ee value (94%) was obtained when the
reaction was performed at 308C (Table 6, entry 4).
However, higher or lower reaction temperatures re-
sulted in lower ee values (Table 6, entries 1–3, 5,
and 6). Unexpectedly, when the reaction tempera-
ture was cooled to 0–58C, an opposite enantiomeric
excess was obtained (Table 6, entry 1). Thus, both
enantiomers of 8 can be selectively synthesized by
tuning the reaction temperature.
Entry
Imine 5
R4
Ph
Alkyne
2
R
6, Yield
ee
[%][b]
[%][c]
1
2
5 f
5g
2a
2a
Ph
Ph
6 f, 98
6g, 92
98
89
3
4
5h
5i
2a
2a
Ph
Ph
6h, 95
6i, 98
86
99
5
6
5j
2a
2a
Ph
Ph
6j, 96
6k, 98
97
96
5k
7
5 f
Ph
2e
6l, 97
99
8
5 f
5 f
5 f
Ph
Ph
Ph
2 f
2g
2h
6m, 96
6n, 97
6o, 98
91
93
98
9
10[d]
11
5 f
5 f
5 f
Ph
Ph
Ph
2b
2i
6p, 97
6q, 92
6r, 84
89
87
91
12[d]
13[e]
2j
[a] Reaction conditions unless otherwise specified: 5 (0.3 mmol), 2 (1.7 equiv), Me2Zn
(1.2 equiv), 3j (5 mol%), toluene (1.2 mL), 19–48 h, RT. [b] Yield of isolated product.
[c] Determined by chiral HPLC analysis. [d] With 2.5 equiv of 2. [e] With 5.0 equiv of
2.
With the optimal reaction conditions in hand, the
scope of the catalytic enantioselective addition of
terminal alkynes 2 to trifluoromethyl aryl ketoi-
mines 7 was explored. As shown in Table 7, ketoi-
ceived considerable interest due to their importance in phar-
maceuticals and materials science.[14a] Although many syn-
thetic methods to produce these valuable fluorinated com-
pounds have been developed, few catalytic enantioselective
approaches have been reported.[20] To further extend the
substrate scope of this method, the zinc/BINOL-catalyzed
alkynylation of trifluoromethyl aryl ketoimines was investi-
gated (Table 5). Unexpectedly, none of the desired product
8a was observed when ketoimine 7a was treated with
alkyne 2a under the standard reaction conditions identified
previously for the synthesis of compounds 4 (Table 5,
entry 1). We surmised that the negative result may arise
from the use of the bulky ligand (R)-3,3’-(TMS)2-BINOL
(3a), which blocks the attack of the alkynyl-Zn/BINOL
complex to the ketoimine 7a. Accordingly, the TMS groups
at the 3,3’ positions of BINOL were changed to smaller
phenyl groups. To our delight, a 62% yield of 8a was ob-
tained, albeit in low enantiomeric excess (Table 5, entry 2).
Further investigation of the ligand 3 with a much smaller
methyl group resulted in a dramatically improved enantiose-
lectivity and reaction efficiency. Encouraged by these re-
sults, a series of BINOL-type ligands 3 with small substitu-
ents at the 3,3’ positions were examined (Table 5, entries 3–
mines 7 possessing different aryl groups gave chiral proparg-
yl amines 8 in excellent yields with good enantioselectivities
(Table 7, entries 2–5). In the case of para-trifluoromethyl-
phenyl-substituted 7c, only a modest ee value was achieved
(Table 7, entry 3). Thiophenyl-substituted 7 f also furnished
the corresponding product 8 f in excellent yield and good
enantioselectivity (Table 7, entry 6). Importantly, vinyl tri-
fluoromethyl ketoimine 7h underwent the reaction smoothly
without 1,4-addition byproducts being observed (Table 7,
entry 8). A variety of terminal alkynes, including those with
aryl- and alkyl-substituents, are all suitable substrates, pro-
viding their corresponding chiral propargyl amines 8 in ex-
cellent yields and enantioselectivities (Table 7, entries 9–15).
The configuration of 8 was determined to be S by X-ray
crystal structure analysis of 9, which was synthesized from
8o (Scheme 2a).[17] Further transformation of compound 9
with a Sonogashia reaction gave compound 10 in good yield,
thus providing an efficient way to access diverse optically
active fluorinated quaternary propargyl amines.
The protecting group on the nitrogen of propargyl amines
can be easily removed. As shown in Scheme 2b, hydrogena-
tion of 8a provided compound 11 in quantitative yield. The
resulting amine 11 was then treated with cerium (IV) diam-
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X. Zhang et al.
Table 5. Screening chiral ligands for catalytic enantioselective addition of
Table 6. Investigation of reaction temperature of enantioselective addi-
terminal alkyne 2a to trifluoromethyl aryl ketoimine 7a.[a]
tion of terminal alkynes 2a to trifluoromethyl aryl ketoimine 7a.[a]
Entry
T [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
0–5
17–25
25
30
35
100
100
100
98
98
97
À44
59
88
94
87
Entry
L*3
Yield [%][b]
ee [%][c]
40
87
1
2
3
4
5
6
7
3a
3k
3o
3i
3j
3e
3l
NR
62
100
100
21
–
27
88
À43
À72
77
[a] Reaction conditions unless otherwise specified: 7a (0.3 mmol), 2a
(1.7 equiv), Me2Zn (1.2 equiv), L*3o (5 mol%), toluene (1.2 mL), 19–
48 h. [b] Yield of isolated product. [c] Determined by chiral HPLC analy-
sis.
57
99
71
quaternary propargyl amines to the optically active a-fluo-
roalkyl a-amino acid was performed. As illustrated in
Scheme 3, (R)-a-CF3 a-proline (15), an important building
block in the conformation of peptides and proteins, can be
easily obtained in four steps with high efficiency from the
chiral propargyl amine 4k. To the best of our knowledge,
this is the first example of the enantioselectively catalyzed
synthesis of 15 so far.[21]
8
9
10
11
3n
3m
3d
3p
90
100
83
60
25
86
À83
97
[a] Reaction conditions unless otherwise specified: 7a (0.3 mmol), 2a
(1.7 equiv), Me2Zn (1.2 equiv), L*3 (5 mol%), toluene (1.2 mL), 19–48 h,
RT. [b] Yield of isolated product. [c] Determined by chiral HPLC analy-
sis.
monium nitrate (CAN) in the presence of H2SO4 to give op-
tically acitve quaternary amine 12 in 80% yield.
Conclusion
Transformation of chiral quaternary propargyl amines to op-
tically active a-fluoroalkyl a-amino acids: To demonstrate
the usefulness of this method, the transformation of chiral
A general and efficient method for the enantioselective al-
kynylation of ketoimines has been developed by using a
zinc/BINOL-catalyzed process.
Both the electronic and steric
effects of substituents at the 3,3’
positions of BINOL-type ligand
are critical for the reaction
enantioselectivity. Notably, both
enantiomers of the quaternary
propargyl amines can be enan-
tioselectively
obtained
by
tuning the electronic properties
of the BINOL-type ligand or
the reaction temperature, pro-
viding
a convenient way to
access these important building
blocks. This method led to the
synthesis of the important a-
fluoroalkyl a-amino acid in a
highly efficient manner, thus
demonstrating the usefulness of
the protocol. Because of its
broad substrate scope, high re-
action efficiency and enantiose-
lectivity, low catalyst loading
(5 mol% BINOL derivative),
Scheme 2. Determination of the absolute configuration of 8o by X-ray crystal structure analysis of compound
9 and synthesis of compounds 10 and 12.
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Enantioselective Zinc/BINOL-Catalyzed Alkynylation of Ketoimines
FULL PAPER
Experimental Section
General procedure for the catalytic
enantioselective addition of terminal
alkynes
to
ketoimines:
Me2Zn
(1.2 equiv) was added to a solution of
terminal alkyne 2 (1.7 equiv) in anhy-
drous toluene (1.2 mL) under argon at
room temperature. After stirring for
1 h, the BINOL-type ligand (5 mol%)
was added. The reaction mixture was
stirred for 2.5 h at room temperature.
The ketoimine (0.3 mmol) was then
added. The reaction mixture was stir-
Scheme 3. Synthesis of compound 12 and (R)-a-trifluoromethyl proline (15).
red at the same temperature until the
starting material was fully consumed,
as indicated by TLC. The reaction
mixture was quenched with a solution
of saturated NH4Cl then diluted with EtOAc. The aqueous
layer was extracted with EtOAc. The combined organic ex-
tracts were dried over anhydrous sodium sulfate, and the sol-
vent was removed. The residue was purified with column chro-
matography on silica gel to give the pure products.
Table 7. Catalytic enantioselective addition of terminal alkynes 2 to trifluoromethyl
aryl ketoimines 7.[a]
Acknowledgements
Entry
Imine
7
R1
Ph
Alkyne
2
R
8, Yield
ee
[%][b]
[%][c]
The National Basic Research Program of China (973 Program;
No. 2012CB821600), the NSFC (Nos. 20902100, 21172242), and
SIOC are greatly acknowledged for funding this work.
1
2
7a
7b
2a
2a
Ph
Ph
8a, 98
8b, 92
94
90
3
4
7c
7d
2a
2a
Ph
Ph
8c, 96
8d, 98
55
91
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5
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8 f, 95
86
84
7
8
7g
7h
2a
2a
Ph
Ph
8g, 95
8h, 97
92
86
9
7a
Ph
2e
8i, 96
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7a
7a
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2 f
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2h
8j, 94
8k, 98
8l, 95
85
89
93
11
12[d]
13[d]
14
15[e]
7a
7a
7a
Ph
Ph
Ph
2i
8m, 91
8n, 94
8o, 85
88
90
90
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[a] Reaction conditions unless otherwise specified: 7 (0.3 mmol), 2 (1.7 equiv), Me2Zn
(1.2 equiv), 3o (5 mol%), toluene (1.2 mL), 19–48 h, 308C. [b] Yield of isolated prod-
uct. [c] Determined by chiral HPLC analysis. [d] With 2.5 equiv of 2. [e] With
5.0 equiv of 2.
and mild reaction conditions, we believe that this protocol
will find applications in the synthesis of biologically active
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Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!

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[22] Editorial Note (further details to the inside cover graphic): The
drawing depicts a well-known folklore in China named Houyi She
Ri or Houyi Shot Down Nine Suns. In Chinese mythology, at around
2170 BC, there were ten suns in the sky. As a result, crops shriveled
in the fields, lakes and ponds dried up, human and animals cowered
in shelters or collapsed from exhaustion. Yao, the Emperor of China
that time, decided to plead for divine intervention and to ask
Houyi–the God of Archery–for help. So Houyi went to the shore of
the East China Sea, lifted up his bow and shot down nine of the ten
suns. As order was restored to the Earth, Houyi was hailed as a
hero for mankind.
Received: April 18, 2013
Published online: && &&, 0000
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ÝÝ
These are not the final page numbers!