Enantioselective addition of alkynylzinc to arylaldehydes catalyzed by azetidino amino alcohols bearing an additional stereogenic center

Article abstract of DOI:10.1016/j.tetasy.2009.10.031

Chiral azetidino amino alcohol ligands bearing an additional stereogenic center were readily prepared and used as catalysts for the asymmetric addition of alkynylzinc to aromatic aldehydes with enantioselectivities of up to 87% ee. The relationship betwee

Full text of DOI:10.1016/j.tetasy.2009.10.031

Tetrahedron: Asymmetry 20 (2009) 2616–2621
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective addition of alkynylzinc to arylaldehydes catalyzed
by azetidino amino alcohols bearing an additional stereogenic center
*
*
Jun-Long Niu, Min-Can Wang , Liu-jie Lu, Guo-Liang Ding, Hui-Jie Lu, Qing-Tao Chen, Mao-Ping Song
Department of Chemistry, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Zhengzhou University, Zhengzhou, Henan 450052, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral azetidino amino alcohol ligands bearing an additional stereogenic center were readily prepared
and used as catalysts for the asymmetric addition of alkynylzinc to aromatic aldehydes with enantiose-
lectivities of up to 87% ee. The relationship between the reaction enantioselectivity and the structure of
the chiral ligands was also evaluated in this reaction. The experimental results showed that the enanti-
oselectivity level of the reaction was greatly influenced by the second stereogenic center attached to
azetidine ring, but the stereochemical sense was only determined by the configuration of the azetidine
ring. A possible transition structure for the catalytic asymmetric addition was also proposed.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 8 September 2009
Accepted 16 October 2009
Available online 22 November 2009
1. Introduction
In previous reports on the asymmetric addition of alkynylzinc
reagents to aldehydes,10 an interesting phenomenon was that the
Chiral propargylic alcohols are useful and versatile building
blocks for the synthesis of a wide range of natural products and
pharmaceuticals.1 Asymmetric additions of organometallic
reagents to aldehydes have a strategic synthetic advantage because
a new C–C bond is formed. The asymmetric addition of alkynylzinc
reagents to aldehydes has received special attention in the pres-
ence of either stoichiometric or catalytic quantities of chiral
ligands in recent years because of their good tolerance of various
functionalities.2 A variety of chiral catalysts based on N-methyl-
ephedrine,3 BINOL and its derivatives,4 b-hydroxy amides,5
bisoxazolidines,6 imino alcohols,7 and other amino alcohol com-
pounds8 have been used successfully for the asymmetric addition
of alkynylzinc to aldehydes. Chiral b-amino alcohols, which can
introduction of an additional chiral element into the nitrogen atom
on the same framework greatly influenced the enantioselectivity of
the alkynylation reaction. That is, a remarkable improvement in
the enantioselectivity resulted if an additional chiral element
matched the stereogenic center on skeleton. For example, Chan
et al. described the relationship between ligand structure based
on 1,2-diphenyl amino alcohols and enantioselectivity by the
means of an additional axial chirality element, and their results
suggested that the effective match of the (R)-binaphthyl moiety
with the (1R,2S)-amino alcohol unit gave good enantioselectivity
in the asymmetric addition of alkynylzinc to aldehydes (Fig. 1, 2
vs 1 or 3).10a Recently, Wan et al. reported similar results based
on N-methylephedrine structure via the introduction of an addi-
tional stereogenic center into nitrogen atom (Fig. 1, 5 vs 4 or 6).10b
In recent years,11 we have been exploring the use of chiral aza-
heterocycle-based ligands in catalytic asymmetric synthesis.
Recently,12 we found that the four-membered heterocycle-based
backbone was a good potential unit for the enantioselective addi-
tion of various organozincs to aldehydes, and the highly enantiose-
lective ethylation, methylation, and arylation of aldehydes were
realized in the presence of catalytic amounts of chiral N-ferroce-
nylmethyl azetidin-2-yl(diphenyl)methanol. However, asymmetric
addition of alkynylzinc to aldehydes gave relatively lower enanti-
oselectivities (71–85% ee). In addition, the synthesis of the chiral
be easily prepared from chiral
a-amino acids or other sources,
are one of the most widely employed types of ligands in asymmet-
ric synthesis, especially in the asymmetric addition of alkylzinc to
aldehydes,9 where amino alcohol ligands have been shown to exhi-
bit excellent enantioselectivity. By contrast, to date chiral b-amino
alcohols have not been extensively applied to similar asymmetric
addition of alkynylzinc to aldehydes.3,8 The main reason for the
lack of broad application of b-amino alcohols in the alkynylation
of aldehydes may be the lower enantioselectivity of alkynylation
than of the corresponding alkylation in the presence of a catalytic
amount of ligands. Therefore, it seems highly desirable to explore
the application of new and effective chiral b-amino alcohol ligands
in the asymmetric addition of alkynylzinc to aldehydes.
ligands from L-(+)-methionine was very inconvenient, and involved
a multistep synthesis. Therefore, the search for the easily available
and new chiral ligand for the asymmetric addition of alkynylzinc to
aldehydes will continue. Herein, we report the synthesis of some
chiral ligands with an additional stereogenic center on nitrogen
atom, and their application in the asymmetric addition of alkynyl-
zinc to aldehydes.
* Corresponding authors. Tel./fax: +86 371 67767895.
E-mail addresses: wangmincan@zzu.edu.cn (M.-C. Wang), mpsong9350@zzu.
edu.cn (M.-P. Song).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.10.031

J.-L. Niu et al. / Tetrahedron: Asymmetry 20 (2009) 2616–2621
2617
enantiomerically pure form. The treatment of the four esters with
phenylmagnesiumbromide afforded the chiral ligands (S,2R)-9a,
(S,2S)-9b, (R,2S)-11a, and (R,2R)-11b, respectively. The chiral li-
gands (R,2S)-11a and (R,2R)-11b were new compounds. In addi-
tion, the absolute configuration of the chiral ligand (R,2S)-11a
was further determined by X-ray diffraction (Fig. 1).14
2. Results and discussion
The chiral ligands 9 and 11 were easily synthesized from com-
mercially available (S)- or (R)-a-methylbenzylamine and methyl
2,4-dibromobutanoate 7 according to the previously reported pro-
cedure (Scheme 1).13 First methyl 2,4-dibromobutanoate 7 was re-
In order to examine the catalytic behavior of the ligands and
seek the influence of a second stereogenic center, the addition of
alkynylzinc to benzaldehyde was first investigated under our pre-
vious reaction conditions (10 mol % of ligands, 200 mol % of dieth-
ylzinc, 10 mol % of DiMPEG 2000 and toluene as solvent).12 The
alkynylzinc reagent was formed in situ by deprotonation of phen-
acted with enantiomerically pure (S)- or (R)-a-methylbenzyl
amine to produce the corresponding mixture of diastereomeric
N-alkylazetidine esters 8 (75%) and 10 (81%), respectively. Then
the chromatographic separation of the diastereomeric esters 8
and 10 by the preparative silica gel TLC gave the desired esters
(S,2R)-8a, (S,2S)-8b, (R,2S)-10a, and (R,2R)-10b, respectively, in
Ph
Ph
OH
Ph
Ph
OH
N
N
+
Ph
Ph
Me
(S,2R)-9a
PhMgBr
Ph
Me
(S,2S)-9b
PhMgBr
THF
78%
83%
NH2
THF
CO2Me
CO2Me
Ph
Me
N
N
+
K2CO3,
CH3CN/H2O
Br
Me
(S,2R)-8a
Ph
Me
(S,2S)-8b
OMe
75%
Br
(1:1)
O
NH2
7
CO2Me
CO2Me
Me
Ph
N
N
+
K2CO3,
CH3CN/H2O
Me
Ph
(R,2S)-10a
Me
Ph
(R,2R)-10b
81%
(1:1)
PhMgBr
PhMgBr
THF
79%
80%
THF
Ph
Ph
OH
Ph
Ph
OH
N
N
Me
Ph
Me
Ph
(R,2S)-11a
(R,2R)-11b
Scheme 1. Synthesis of the chiral ligands 9 and 11.
Ph
Ph
Ph
N
Ph
Ph
Ph
HO
N
OH
OH
N
10 mol%
68% ee
10 mol%
79% ee
10 mol%
26% ee
1
3
2
Ph
HO
Ph
HO
Me
Me
N
Ph
Me
Ph
Ph
N
HO
NMe2
Me NHTf
Me NHTf
10 mol%
42% ee
10 mol%
10 mol%
92% ee
45% ee
4
6
5
Figure 1. The structure of some b-amino alcohols.

2618
J.-L. Niu et al. / Tetrahedron: Asymmetry 20 (2009) 2616–2621
ylacetylene with diethylzinc at room temperature. Two pairs of
enantiomers (S,2R)-9a, (R,2S)-11a, and (S,2S)-9b (R,2R)-11b were
tested, and the results are summarized in Table 1 (entries 1–4).
Ph
Ph
Ph
Ph
OH
Ph
Ph
N
OH
N
N
OH
Table 1
Asymmetric addition of alkynylzinc to benzaldehyde catalyzed by ligands 9 and 11a
Fc
Ph
OH
10 mol%
84.6% ee
20 mol%
77% ee
20 mol%
65% ee
O
ZnEt2, Ligand (10 mol%)
Ph
*
+
Ph
Ph
H
DiMPEG (10 mol%),
toluene, -10ºC, 20 h
12
13
14
Ph
Figure 3. The structure of some b-amino alcohols.
Entry
Ligand
Yieldb (%)
eec (%)
Config.d
1
2
3
4
(S,2R)-9a
(S,2S)-9b
(R,2S)-11a
(R,2R)-11b
66
76
70
82
65
82
64
82
S
R
R
S
metric addition of alkynylzinc to benzaldehyde catalyzed by ligand
11a can be proposed (Scheme 2).
The reaction of diethylzinc with the ligand 11a first yielded the
corresponding zinc aminoalkoxide 15, which acted as a bifunc-
tional catalyst. The lone pair electrons of oxygen atom of benzalde-
hyde coordinated with the Lewis acidic Zn atom at the less
hindered face of the five-membered ring chelate 15, and then the
adjacent basic oxygen accepted alkynylzinc at Zn to form the prod-
uct-forming, mixed-ligand complex 16. The phenylacetylene group
transfer from the alkynylzinc to the aldehyde from both the Si-face
and the Re-face resulted in the anti-5/4/4-fused tricyclic transition
states 17 and 18, respectively. In the transition state 17, a non-
bonded repulsion between Et and Ph is absent, but steric repulsive
interaction between the Et and Ph groups disfavors the transition
state 18. As a result, the transition state 17 is the favored structure,
and the addition product with (R)-configuration was afforded.
Therefore, if the absolute configuration of azetidine ring was S,
the configuration of the addition product was R. Conversely, if
the absolute configuration of azetidine ring was R, the result would
be opposite to the above statement. These were in good agreement
with the experimentally observed results.
a
b
c
The mol ratio of phenylacetylene/Et2Zn/benzaldehyde was 2:2:1.
Isolated yields.
Determined by HPLC using a chiralcel OD column. The product chromatograms
were compared against a known racemic mixture.
Absolute configuration assigned by known elution order from a chiralcel OD
column according to the literature.
d
As can be seen from Table 1, the asymmetric addition of phen-
ylacetylene to benzaldehyde led to the desired products in 66–84%
yields with 62–82% ee (entries 1–4). It was shown that both the
enantioselectivity and the reactivity were very sensitive to the
structure of the chiral ligands. When the ligand (S,2S)-9b and its
enantiomer (R,2R)-11b were employed, the alkynylation of benzal-
dehyde afforded high ee values (82% ee) and good chemical yields
(76%, 81%, Table 1, entries 2 and 4). The ligand (S,2R)-9a and its
antipode (R,2S)-11a not only showed relatively low catalytic activ-
ity (66–70%), but also gave the product with relatively low ee val-
ues (64-65% ee, Table 1, entries 1 and 3). It was interesting to
compare the results obtained from the chiral compounds (S,2S)-
9b and (R,2R)-11b with those from their diastereomers (S,2R)-9a
and (R,2S)-11a, respectively. For example, the ligand (S,2S)-9b gave
the product with an (R)-configuration with 82% ee while its diaste-
reomers (S,2R)-9a and (R,2S)-11a afforded the product with an (S)-
configuration with 65% ee, (R)-configuration with 64% ee, respec-
tively. These results suggested that the absolute configuration of
the addition products was only determined by the configuration
of the azetidine ring. At the same time, these results also indicated
that the match of the configuration of the azetidine ring with the
configuration of the additional stereogenic center was crucial to
obtain high enantioselectivity.
Recently, we described the synthesis of the ferrocenyl azetidino
alcohol 12 (Fig. 3) and its application as a catalyst.12 We observed
that the hindrance of the bulky ferrocenyl group relative to the
phenyl group was essential for obtaining higher enantioselectivity.
A similar phenomenon was observed by Zhang et al. in the asym-
metric addition of alkynylzinc to aldehydes.15 In their experience,
replacement of the phenyl group on the nitrogen atom of the
five-membered heterocycle-based skeleton with a bulky 2,4,6-tri-
methylphenyl substituent led to an increase in the enantioselectiv-
ity from 65% ee (the ligand 14 (Fig. 3)) to 77% ee (the ligand 13
(Fig. 3)). A comparison of the results (82% ee) obtained by the li-
gand (S,2S)-9b with those (84.6% ee) by 12 demonstrates that the
same effect, which was resulted by the large ferrocenyl group,
was achieved by the means of the match of the second stereogenic
center on nitrogen atom with the stereogenic center of the azeti-
dine ring. In addition, the chiral ligand (S,2S)-9b was easily pre-
pared in two steps in contrast to the compound 12.
O
Et
Ph
Ph
Zn
sp2
N
Ph
Me
19
The X-ray structures of the non-complexed ligands did not pro-
vide direct information about the structure of the catalytically ac-
tive metal complex, but they did help in understanding the
reaction mechanism and the effect of free ligands on reaction
enantioselectivity. The X-ray structure analysis of 11a revealed
that the N-methylbenzyl group on the nitrogen atom of the hetero-
cycle is positioned anti to the diphenylhydroxymethyl group on the
heterocycle (Fig. 2). The four-membered N1, C9, C10, C11 ring
moiety is almost a planar structure with the sum of the four bond
angles being 353.2°. The N(1)–C(9)–C(10), C(9)–C(10)–C(11),
N(1)–C(11)–C(10), and C(9)–N(1)–C(11) bond angles are 88.8°,
86.6°, 88.3°, and 89.5°, respectively. The values of the torsion
angles C(10)–C(11)–C(12)–C(19) and C(9)–N(1)–C(7)–C(6) were
ꢀ167.1(4)° and ꢀ174.5(4)°, respectively, indicating that two phe-
nyl substituents point in the same direction. The replacement of
the hydrogen atom on the hydroxyl group in 11a by an ethylzinc
moiety gave the catalyst 15. Compared with free ligand 11a, the
catalyst 15 should not lead to any significant structural distortion
because ground-state conformation in free ligand 11a resembles
that in the complex 15. Thus, two phenyl groups pointing in the
same direction with respect to the five-membered ring can inhibit
cooperatively one face of the catalyst 15. If the configuration of the
second stereogenic center on the nitrogen atom is S, the methyl
group on the additional chiral carbon atom and one phenyl
Based on a great number of previous theoretical studies on the
mechanism of the asymmetric addition of alkylzinc to aldehydes16
and our experimental results, a plausible mechanism for the asym-

J.-L. Niu et al. / Tetrahedron: Asymmetry 20 (2009) 2616–2621
2619
O
Ph
Ph
Et
Ph
Ph
HO
Zn
sp2
ZnEt2
PhC CZnEt
PhCHO
_ CH3CH3
N
N
Me
Ph
11a
Me
Ph
Ph
15
Ph
Ph
O
Ph
Ph
H
H
H
Zn
Ph
Et
Zn
Et
Et
O
Zn
O
Et
Zn
Et
Ph
Ph
Et
O
O
Ph
Ph
Ph
O
Zn
Zn
Ph
+
N
N
N
Me
Ph
Me
Me
Ph
Ph
16
18
17
Scheme 2. Transition structures derived from b-amino alcohol (R,2S)-11a.
uents. As a result, two relatively parallel phenyl groups provided
much room for the approach of benzaldehyde and alkynylzinc from
this face compared with methyl and phenyl substituents. There-
fore, the catalyst 15 is less effective in stereodifferentiation than
19, giving lower enantioselectivity.
To examine substrate generality under the above-mentioned
reaction conditions, the most successful enantiomer (R,2R)-11b
was tested for the asymmetric addition of phenylactylene to vari-
ous aromatic aldehydes, and the results are presented in Table 2.
As can be seen from Table 2, the chiral ligand (R,2R)-11b was effec-
tive in various substituted aromatic aldehydes, including ortho-,
para-, and meta-substituted benzaldehydes (Table 2, entries 1–
14). The presence of electron-donating or electron-withdrawing
substituents on the aromatic ring is also compatible with these
Table 2
Asymmetric addition of alkynylzinc to aldehydes catalyzed by ligand (R,2R)-11ba
OH
O
ZnEt2, (R,2R)-11b (10 mol%)
Ar
*
+
Ph
R
H
Ph
DiMPEG (10 mol%),
toluene, -10ºC, 20 h
Entry
R
Yieldb (%)
eec (%)
Config.d
Figure 2. ORTEP drawing of the X-ray crystallographic structure of ligand (R,2S)-
11a. Selected bond lengths (Å) and angles (°): N(1)–C(9) 1.499(6); N(1)–C(11)
1.500(6); C(9)–C(10) 1.532(8); C(10)–C(11) 1.546(7); C(9)–N(1)–C(11) 89.5(3);
N(1)–C(9)–C(10) 88.8(4); C(9)–C(10)–C(11) 86.6(4); N(1)–C(11)–C(10) 88.3(3).
N(1)–C(11)–C(12)–C(19) 91.2(5); N(1)–C(11)–C(12)–C(13) –147.5(4); N(1)–C
(11)–C(12)–O(1) –31.5(5); C(10)–C(11)–C(12)–C(19) –167.1(4); C(9)–N(1)–C(7)–
C(6) –174.5(4); C(12)–C(19)–C(24)–C(23) –176.0(5); C(4)–C(5)–C(6)–C(7) 178.2(5).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
o-MeOC6H4
m-MeOC6H4
p-MeOC6H4
m-PhOC6H4
o-MeC6H4
m-MeC6H4
p-MeC6H4
o-ClC6H4
m-ClC6H4
p-ClC6H4
o-BrC6H4
m-BrC6H4
p-BrC6H4
3,4-OCH2OC6H3
2-Naph
56
68
56
77
80
66
75
59
70
80
76
78
77
76
75
76
80
87
79
78
84
69
68
80
80
72
75
84
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
substituent in diphenylhydroxymethyl group will be located on the
cis side of the coordination five-membered ring, as in 19, blocking
more effectively one face of the catalyst 19 and resulting in enanti-
oselectivity higher than that of 11a. This result indicated that the
steric hindrance effect of the methyl group was more effective than
that of the phenyl substituent. This point may be explained from
the X-ray structures of 11a (Fig. 2). The values of the torsion
angles C(12)–C(19)–C(24)–C(23) and C(4)–C(5)–C(6)–C(7) were
72
49
16
PhCH2CH2
51
18
(S)
a
b
c
The mol ratio of phenylacetylene/Et2Zn/aldehydes was 2:2:1.
Isolated yields.
Determined by HPLC using a chiralcel OD column. In all cases, the product
ꢀ176.0(5)° and 178.2(5)°, respectively, indicating that a
p–p inter-
chromatograms were compared against a known racemic mixture.
d
action exists between two phenyl groups pointing toward the
Absolute configuration assigned by known elution order from a chiralcel OD
column according to the literature.
same direction, which may inhibit free rotation of phenyl substit-

2620
J.-L. Niu et al. / Tetrahedron: Asymmetry 20 (2009) 2616–2621
reaction conditions. High enantioselectivity was also observed for
the addition to 2-naphthaldehyde (Table 2, entry 15). The best
asymmetric induction (as high as 87% ee) was found by using an
aldehyde bearing a 2-MeC6H4 group as the substrate (Table 2, entry
5). The chiral ligand (R,2R)-11b is comparable to the existing b-
amino alcohol ligands for alkynyl addition using a terminal alkyne
and diethylzinc in the presence of catalytic amounts of chiral li-
gands8 although the maximum asymmetric induction obtained
was 87% ee.
The chiral ligand 11b was also tested with aliphatic aldehyde
3-phenylpropionaldehyde, but very low enantioselectivity (only
18% ee) was obtained under the same reaction conditions as
arylaldehydes (Table 2, entry 15). Therefore, further extension of
the substrate scope for aliphatic aldehydes was not performed.
compound 10 dissolved in 1 mL THF at ꢀ20 °C over a period of
30 min. The mixture was then allowed to reach room temperature.
After stirring for 24 h, the reaction was quenched with saturated
aqueous NH4Cl (10 mL) at 0 °C. The product was separated and
the aqueous phase extracted with Et2O (3 ꢁ 10 mL). The combined
organic phases were washed with brine (15 mL), dried over
Na2SO4, and concentrated under reduced pressure. The resulting
residue was purified by the preparative TLC with hexane/EtOAc
(8:1, v/v) as the developing solvent to give the ligand up to 80%
yield.
4.2.1. Diphenyl-(l-((1R)-phenylethyl)azetidin-(2S)-yl)-methanol
(R,2S)-11a
White solid, yield 79%, mp 95–97 °C. ½a D20
¼ þ63:6 (c 1.00,
ꢂ
CHCl3). 1H NMR (400 MHz, CDCl3) d 7.57–7.05 (m, 15H), 5.32 (br
s, 1H), 4.65 (t, 1H, J = 7.7 Hz), 3.32–3.26 (m, 1H), 3.08–3.03 (m,
1H), 2.94–2.90 (m, 1H), 2.04–1.87 (m, 2H), 1.17 (d, 3H,
J = 6.8 Hz). 13C NMR (100 MHz, CD3Cl): d 147.5, 144.7, 142.9,
128.1, 128.0, 127.0, 126.7, 126.5, 126.4, 125.5, 75.5, 68.4, 57.8,
42.7, 19.1, 12.8. IR (KBr pellet): 3028, 2970, 2844, 1490, 1448,
1397, 1167, 998, 747, 702. MS: m/z (ESI) 344 (M++1). HRMS-ESI
m/z calcd for C24H25NO+H+ 344.2014, found 344.2022.
3. Conclusion
In conclusion, we described the preparation of a series of chiral
azetidino amino alcohol ligands with an additional stereogenic
center, and their catalytic capabilities in the asymmetric addition
of alkynylzinc to aldehydes. The chiral ligand (R,2R)-11b was found
to be highly effective in the enantioselective alkynylation of alde-
hydes. Studies on the structure-relationship showed that the abso-
lute configuration of the addition products was only determined by
the configuration of the azetidine ring, and the match of the config-
uration of the azetidine ring with the configuration of the addi-
tional chiral center was crucial to obtain high enantioselectivity.
Efforts to extend the application of these ligands to other enantio-
selective metal-catalyzed reactions are also in progress.
4.2.2. Diphenyl-(l-((1R)-phenylethyl)azetidin-(2R)-yl)-metha-
nol(R,2R)-11b
White solid, yield 80%, mp 98–100 °C. ½a D20
¼ þ22:4 (c 1.00,
ꢂ
CHCl3). 1H NMR (400 MHz, CDCl3) d 7.64–6.85 (m, 15H), 5.31 (br
s, 1H), 4.28 (t, 1H, J = 7.8 Hz), 3.22–3.17 (m, 1H), 3.10–3.06 (m,
1H), 3.00–2.94 (m, 1H), 1.92–1.80 (m, 2H), 0.86 (d, 3H,
J = 6.9 Hz). 13C NMR (100 MHz, CD3Cl): d 148.0, 145.1, 140.5,
128.1, 128.0, 127.1, 126.5, 126.4, 125.9, 125.6, 75.7, 69.8, 61.1,
44.9, 19.7, 19.4. IR (KBr pellet): 3025, 2970, 2843, 1491, 1448,
1395, 1180, 973, 747, 702. MS: m/z (ESI) 344 (M++1). HRMS-ESI
m/z calcd for C24H25NO+H+ 344.2014, found 344.2021.
4. Experimental
4.1. General
Unless otherwise noted, all reactions were carried out under
argon or nitrogen using standard Schlenk and vacuum line tech-
niques. Toluene was freshly distilled over calcium hydride prior
to use. Other reagents were obtained from commercial sources
and used as received without further purification. Melting points
were determined using YRT-3 melting point apparatus and are
uncorrected. Optical rotations were measured with Perkin Elmer,
model 341 Polarimeter at 20 °C in CHCl3. The enantiomeric purity
was determined by HPLC using a chiral column with hexane/pro-
pan-2-ol (ratio as indicated) as the eluent. The chromatographic
system consisted of a JASCO model PU-1580 intelligent HPLC
pump and a JASCO model UV-1575 intelligent UV–vis detector
4.3. General procedure for the asymmetric alkynylation of aryl
aldehydes
Under a nitrogen atmosphere, diethylzinc (1.0 mL, 200 mol %,
1.0 mol/L in hexane) and phenylacetylene (110 lL, 200 mol %)
were added to a dried Schlenk tube containing toluene (2 mL),
the chiral ligand (R,2R)-11b (22 mg, 10 mol %), and DiMPEG
(100 mg, 10 mol %, mw = 2000). The resulting mixture was stirred
for 2 h at room temperature. After the mixture was cooled to
ꢀ10 °C, aldehyde (0.5 mmol) was added under nitrogen atmo-
sphere. The reaction mixture was stirred for 20 h at ꢀ10 °C. The
reaction was quenched by the addition of saturated aqueous NH4Cl
(8 mL). The mixture was extracted with CH2Cl2 (3 ꢁ 10 mL). The
combined organic layers were washed with brine, dried over anhy-
drous Na2SO4, and evaporated under reduced pressure. Purification
of the residue by the preparative silica gel TLC plate (hexane/
EtOAc) afforded the pure propargylic alcohol. The ee was deter-
mined by HPLC analyses using a chiralcel OD column. In all cases,
the product chromatograms were compared against a known race-
mic mixture.
(254 nm). The injection loop had a 20 lL capacity. The column
used was a Chiralcel OD (250 ꢁ 4.6 mm) from Daicel Chemical
Ind., Ltd (Japan). The column was operated at ambient tempera-
ture. NMR spectra (1H and 13C) were performed on a Bruker DPX
400 (400 MHz) spectrometer using solutions in CDCl3 (referenced
internally to Me4Si); J values are given in hertz. TLC was per-
formed on dry silica gel plates developed with hexane/ethyl ace-
tate. Mass spectra were obtained using a Bruker esquire-3000
instrument with an electrospray ionization source (ESIMS). All
the ESIMS spectra were performed using MeOH as the solvent.
Methanol was dried with Mg(OCH3)2.
4.4. X-ray crystallographic study14
Complexes 8–10 were synthesized according to the literature
A prismatic crystal of (R,2S)-11a (0.20 ꢁ 0.18 ꢁ 0.16 mm) was
selected and mounted on a glass fiber. Crystallographic data was
measured on a Rigaku RAXIS-IV imaging plate area detector. The
data were collected at 291(2) K using graphite-monochromated
procedure.12,13
4.2. Synthesis of the azetidine-carbinol
Mo Ka (k = 0.71073 Å), 2.13° < h < 25.48°. The structures were
To the Grignard reagent solution prepared from 817 mg
(5.2 mmol) bromobenzene in 3 mL THF and 124 mg (5.2 mmol)
magnesium in 5 mL THF was gradually added 278 mg (1.27 mmol)
solved by a direct method, and expanded by using Fourier tech-
niques. The non-hydrogen atoms were refined anisotropically.
Hydrogen atoms were included but not refined. All calculations

J.-L. Niu et al. / Tetrahedron: Asymmetry 20 (2009) 2616–2621
2621
5. (a) Xu, Z.; Wang, R.; Xu, J.; Da, C.-S.; Yan, W.-J.; Chen, C. Angew. Chem., Int. Ed.
2003, 42, 5747–5749; (b) Xu, Z.; Chen, C.; Xu, J.; Miao, M.; Yan, W.; Wang, R.
Org. Lett. 2004, 6, 1193–1195; (c) Fang, T.; Du, D.-M.; Lu, S.-F.; Xu, J. Org. Lett.
2005, 7, 2081–2084; (d) Mao, J. C.; Wan, B. S.; Wu, F.; Wang, R. L.; Lu, S. W. J.
Mol. Catal. A: Chem. 2005, 232, 9–12; (e) Hui, X.-P.; Yin, C.; Chen, Z.-C.; Huang,
L.-N.; Xu, P.-F.; Fan, G.-F. Tetrahedron 2008, 64, 2553–2558; (f) Li, Y.-M.; Tang,
Y.-Q.; Hui, X.-P.; Huang, L.-N.; Xu, P.-F. Tetrahedron 2009, 65, 3611–3614.
6. Wolf, C.; Liu, S. J. Am. Chem. Soc. 2006, 128, 10996–10997.
were performed using the teXsan crystallographic software pack-
age. Crystal data for (R,2S)-11a: triclinic P1, a = 6.0146(12) Å,
a
c
= 94.11(3)°, b = 8.6987(17) Å, b = 98.46(3)°, c = 9.7283(19) Å,
= 102.49(3)°, V = 488.70(17) Å3; formula unit C24H25NO with
Z = 1, Dcalcd = 1.167 g cmꢀ3
, F (0 0 0) = 184, l(Mo Ka) = 0.070
mmꢀ1. Full-matrix least-squares refinement on F2 based on 1650
independent reflections (Rint = 0.0000) converged with 1650
7. (a) Dahmen, S. Org. Lett. 2004, 6, 2113–2116; (b) Omote, M.; Eto, Y.; Tarui, A.;
Sato, K.; Ando, A. Tetrahedron: Asymmetry 2009, 20, 602–604.
parameters. Final R indices [I > 2r (I)]: R1 = 0.0731, wR2 = 0.2004;
8. (a) Li, Z.; Upadhyay, V.; DeCamp, A.; DiMichele, L.; Reider, P. J. Synthesis 1999,
1453–1458; (b) Jiang, B.; Chen, Z.; Xiong, W. Chem. Commun. 2002, 1524–1525;
(c) Kamble, R. M.; Singh, V. K. Tetrahedron Lett. 2003, 44, 5347–5349; (d) Kang,
Y.-F.; Liu, L.; Wang, R.; Yan, W.-J.; Zhou, Y.-F. Tetrahedron: Asymmetry 2004, 15,
3155–3159; (e) Li, M.; Zhu, X.-Z.; Yuan, K.; Cao, B.-X.; Hou, X.-L. Tetrahedron:
Asymmetry 2004, 15, 219–222; (f) Kang, Y.-F.; Wang, R.; Liu, L.; Da, C.-S.; Yan,
W.-J.; Xu, Z.-Q. Tetrahedron Lett. 2005, 46, 863–865; (g) Pizzuti, M. G.; Superch,
S. Tetrahedron: Asymmetry 2005, 16, 2263–2269; (h) Watts, C. C.; Thoniyot, P.;
Hirayama, L. C.; Tomano, T.; Singaram, B. Tetrahedron: Asymmetry 2005, 16,
1829–1835; (i) Trost, B. M.; Weiss, A. H.; Jacobi von Wangelin, A. J. Am. Chem.
Soc. 2006, 128, 8–9; (j) Koyuncu, H.; Dogan, Ö. Org. Lett. 2007, 9, 3477–3479; (k)
Zhong, J.-C.; Hou, S.-C.; Bian, Q.-H.; Yin, M.-M.; Na, R.-S.; Zheng, B.; Li, Z.-Y.; Liu,
S.-Z.; Wang, M. Chem. Eur. J. 2009, 15, 3069–3071.
R indices (all data): R1 = 0.0797, wR2 = 0.2140; GoF = 1.033.
Acknowledgments
We are grateful to the Innovation Fund for Outstanding Scholar
of Henan Province (074200510005), the National Natural Sciences
Foundation of China (NNSFC: 20672102), and Henan Outstanding
Youth Program (084100410001).
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