Synthesis of new C2-symmetric bis(β-hydroxy amide) ligands and their applications in the enantioselective addition of alkynylzinc to aldehydes

Article abstract of DOI:10.1016/j.tet.2008.01.036

A series of chiral C₂-symmetric bis(β-hydroxy amide) ligands was synthesized via the reaction of isophthaloyl dichloride and amino alcohols derived from l-amino acid. The titanium(IV) complex of C₂-symmetric chiral ligand 3b was effe

Full text of DOI:10.1016/j.tet.2008.01.036

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Tetrahedron 64 (2008) 2553e2558
www.elsevier.com/locate/tet
Synthesis of new C2-symmetric bis(b-hydroxy amide) ligands and
their applications in the enantioselective addition
of alkynylzinc to aldehydes
a
a
a
a,
Xin-Ping Hui a, , Chao Yin , Zhi-Ce Chen , Lu-Ning Huang , Peng-Fei Xu
*
*
,
Gui-Fang Fan b
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
b Jinchuan Nickel & Cobalt New Product Company, JNMC, Jinchang, China
Received 31 October 2007; received in revised form 9 January 2008; accepted 11 January 2008
Available online 13 January 2008
Abstract
A series of chiral C2-symmetric bis(b-hydroxy amide) ligands was synthesized via the reaction of isophthaloyl dichloride and amino alcohols
derived from L-amino acid. The titanium(IV) complex of C2-symmetric chiral ligand 3b was effective for the asymmetric alkynylation of alde-
hydes and the propargyl alcohols were obtained in high yields (up to 94%) and high enantiomeric excesses (up to 98%) under optimized con-
ditions. The results obtained using ligand 3h support that the two b-hydroxy amide moieties in these ligands behave as two independent ligands
in the catalytic system.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Asymmetric addition; b-Hydroxy amide; Phenylacetylene; Titanium tetraisopropoxide
1. Introduction
the addition of terminal acetylide to aliphatic aldehydes.
For titanium complex-catalyzed alkynylation reaction, BI-
NOLs and H8-BINOLs were demonstrated to be excellent li-
gands by Chan et al.,6 Pu et al.,7 and Gong et al..8 Wang
et al.9 described a highly enantioselective addition of phenyl-
acetylene to aldehydes catalyzed by b-sulfonamide alcohols
in combination with Ti(O-i-Pr)4.
C2-Symmetry is interesting in chemistry, and compounds
with C2-symmetry have also received much attention for their
utilities as asymmetric ligands in stereoselective reactions.10
Development of new types of C2-symmetric ligands for asym-
metric reaction is an intriguing research area. Recently, we
have developed a new b-hydroxy amide chiral ligand 1b,
which was successfully used in the asymmetric addition of
phenylacetylene to aldehydes with excellent enantioselectiv-
ities (up to 97% ee).11 For further exploring chiral ligand
effects of titanium(IV) complexes in this addition, we herein
describe the synthesis of a series of new C2-symmetric b-hy-
droxy amide ligands 3aef and their applications in enantiose-
lective additions of phenylacetylene to aldehydes.
The asymmetric alkyne addition to carbonyl compounds is
very useful for the synthesis of chiral propargyl alcohols,
which are valuable building blocks for fine chemicals, pharma-
ceuticals, and natural products.1 Since the first efficient asym-
metric alkyne addition to aldehydes was demonstrated by
Corey and Cimprich2 using chiral oxazaborolidines, the devel-
opment of new and efficient catalysts for alkynylation of alde-
hydes is of current interest and many highly enantioselective
catalysts have been disclosed to this reaction.3,4 Among the
catalytic methods developed, several of them are currently con-
sidered to be the most practical. Carreira and coworkers5 re-
ported that a system using Zn(OTf)2 and chiral ephedrine with
triethylamine afforded high yields and enantioselectivities in
* Corresponding authors. Tel.: þ86 931 8912281; fax: þ86 931 8915557.
E-mail addresses: huixp@lzu.edu.cn (X.-P. Hui), xupf@lzu.edu.cn (P.-F.
Xu).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.036

2554
X.-P. Hui et al. / Tetrahedron 64 (2008) 2553e2558
R2
R1
Table 1
Asymmetric addition of phenylacetylene to benzaldehyde catalyzed by ligands
3aeha
R2
O
NH OH
Ph
1a R1 = R2 = Ph
OH
1a-c
Et2Zn
ligand, Ti(O-i-Pr)4
1b R1 = Ph, R2 = Et
1c R1 = i-Pr, R2 = Et
PhCHO
+
Ph
Ph
Ph
Entry
Ligand
Ligand/Ti(O-i-Pr)4
Yieldb (%)
eec (%)
2. Results and discussion
1
3a
3b
3c
3d
3e
3f
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:1.5
1:3
1:4
1:5
88
92
89
88
87
86
87
85
83
89
93
91
56
95
88
62
26
23
85
11
74
78
94
81
2
Reaction of isophthalyl chloride with amino alcohols
2aef12e14 in the presence of triethylamine afforded new C2-
symmetric bis(b-hydroxy amide) ligands 3aef (Scheme 1). The
addition of phenylacetylene to benzaldehyde in the presence
of chiral ligands 3aef, Et2Zn, and Ti(O-i-Pr)4 in toluene was
first examined and the results are summarized in Table 1.
Ligand 3a, which has two benzyl substituents at the hydroxy-
bearing carbon atom, resulted in a low enantioselectivity
(Table 1, entry 1). When 3b was used, which possesses small
and more flexible ethyl substituents, the corresponding prop-
argyl alcohol was given in 92% yield and 95% ee (Table 1, en-
try 2). For ligands 3c and 3d, having a-phenylethyl or isobutyl
group instead of benzyl group, the enantioselectivity dropped
to 88 and 62% ee, respectively (Table 1, entries 3 and 4).
When ligands 3e and 3f were used, the propargyl alcohol
was only obtained in 26 and 23% ee, respectively (Table 1, en-
tries 5 and 6). The ee value decreased when the amount of chi-
ral ligand 3b was reduced from 10 to 7.5% (Table 1, entry 7).
To improve the enantioselectivity, the reaction conditions
were optimized with ligand 3b. The results are summarized
in Table 2. The enantioselectivity of the reaction was strongly
affected by different conditions. Increasing the amount of
Ti(O-i-Pr)4 from 2:1 to 3:1 relative to chiral ligand 3b in-
creased the enantioselectivity (Table 2, entries 1 and 2). How-
ever, the enantioselectivity decreased obviously when the ratio
of Ti(O-i-Pr)4 to chiral ligand 3b was increased to 4:1 (Table
2, entry 3). So the ratio in entry 2 was found to be the best. The
amount of diethylzinc is also important. When the amount of
ZnEt2 was increased, the ee value decreased from 95 to 84%
(Table 2, entry 5). When the reaction was carried out in vari-
ous solvents, such as n-hexane, dichloromethane, diethyl ether,
3
4
5
6
7d
8
3b
3g
3h
3h
3h
3h
9
10
11
12
a
ZnEt2/phenylacetylene/PhCHO/ligand¼3:3:1:0.1; solvent: toluene; reac-
tion time: 18 h; reaction temperature: rt.
b
Isolated yield.
Determined by HPLC analysis using Chiracel OD-H column.
Ligand was 7.5 mol %.
c
d
and THF, lower ee values were obtained (Table 2, entries 6e
9). So toluene is the best choice of the solvent.
In this study, ligand 3b contains two b-hydroxy amide moi-
eties and each b-hydroxy amide moiety resembles a bidentate
ligand. In order to support our proposal, a ligand with one
b-hydroxy amide moiety blocked is required to demonstrate
that the remaining unblocked b-hydroxy amide moiety is still
an effective ligand for this addition reaction. Thus, b-hydroxy
amide 2b was first converted to 4. Compound 4 was deproto-
nated with n-BuLi followed by the addition of 1.0 equiv of iso-
phthalyl chloride to give a mixture of 5 and 3g. Without
purification, the mixture was treated with 1.65 equiv of 2b in
the presence of NEt3 and a catalytic amount of DMAP to af-
ford the target compound 3h (Scheme 2). Both compounds
3g and 3h were examined for alkynylzinc addition to benz-
aldehyde. For ligand 3g, the desired product was obtained in
85% yield and only 11% ee (Table 1, entry 8). For ligand
R2
R1
R1
R2
OH
(i) SOCl2, MeOH
(ii) R2MgBr, Et2O
COOH
H2N
H2N
2a-d
O
O
R2
C
C
R1
Et3N
R3
OH
R1 NH
HN
R1
R2
R3
+
CH2Cl2
ClOC
COCl
R2
H2N
OH
R3
HO
2a-f
3a-f
R1 = R2 = R3 = PhCH2 (3a)
R1 = PhCH2, R2 = R3 = CH2CH3 (3b)
R1 = PhCH2CH2, R2 = R3 = CH2CH3 (3c)
R1 = i-Bu, R2 = R3 = CH2CH3 (3d)
R1 = PhCH2, R2 = R3 = H (3e)
R
1 = PhCH2, R2 = H, R3=Ph (3f)
Scheme 1. Synthesis of chiral ligands 3aef.

X.-P. Hui et al. / Tetrahedron 64 (2008) 2553e2558
2555
Table 2
Asymmetric addition of phenylacetylene to benzaldehyde catalyzed by ligand
Table 3
Asymmetric addition of phenylacetylene to aldehydes promoted by ligand 3ba
3ba
OH
*
Et2Zn
OH
RCHO
+
Ph
Et2Zn
R
ligand 3b, Ti(O-i-Pr)4
PhCHO
+
Ph
ligand 3b, Ti(O-i-Pr)4
Ph
Ph
Ph
Entry
Aldehyde
Yieldb (%)
eec (%)
Entry Solvent
Ligand/Ti(O-i-Pr)4 ZnEt2 (mmol) Yieldb (%) eec (%)
1
Benzaldehyde
2-Anisaldehyde
92
93
90
91
94
89
93
89
91
87
82
85
83
87
95
88
93
90
98
93
92
94
96
89
94
87
52
67
1
2
3
4
5
6
7
8
9
10d
a
Toluene
Toluene
Toluene
Toluene
Toluene
1:2
1:3
1:4
1:3
1:3
0.75
0.75
0.75
0.50
1.00
0.75
0.75
0.75
0.75
0.75
84
92
92
80
85
88
84
79
86
81
81
95
82
74
84
87
87
58
29
89
2
3
4-Anisaldehyde
2-Tolualdehyde
4-Tolualdehyde
4
5
6
2-Chlorobenzaldehyde
2-Flourobenzaldehyde
3-Chlorobenzaldehyde
4-Chlorobenzaldehyde
1-Naphthaldehyde
2-Naphthaldehyde
Cinnamaldehyde
n-Hexane 1:3
7
CH2Cl2
Et2O
THF
1:3
1:3
1:3
1:3
8
9
10
11
12
13
14
a
Toluene
PhCHO/ligand¼1: 0.1; reaction time: 18 h; reaction temperature: rt.
Isolated yield.
b
n-Butylaldehyde
Cyclohexanecarbaldehyde
c
Determined by HPLC analysis using Chiracel OD-H column.
Reaction was performed under 0 ꢀC.
d
Aldehyde/phenylacetylene/ZnEt2/Ti(O-i-Pr)4/3b¼1:3:3:0.3:0.1; solvent:
toluene; reaction time: 18 h; reaction temperature: rt.
b
Isolated yield.
Determined by HPLC analysis using Chiracel OD-H column.
c
3h with one b-hydroxy amide moiety blocked, a half-amount
of Ti(O-i-Pr)4 is expected to be enough to catalyze the reaction
with comparable enantioselectivity which was obtained from
the catalytic system of ligand 3b. In fact, ligand 3h gave the
desired propargylic alcohol in good yield and 78% ee (Table
1, entry 10) in the same conditions.
To demonstrate the generality of the ligand for phenylace-
tylene asymmetric addition to aldehydes, various aldehydes
were examined using the titanium complex of ligand 3b under
the optimized reaction conditions and the results are listed in
Table 3. The chiral propargyl alcohols could be obtained
in good isolated yields of 82e94% and excellent
enantioselectivities of 88e98% ee for aromatic aldehydes (Ta-
ble 3, entries 1e11). For para-substituted benzaldehydes, the
one with strong electron-donating group gave a slightly lower
enantioselectivity (Table 3, entry 3, p-CH3O, ee 93%), while
the aldehydes with moderate electron-withdrawing and elec-
tron-donating groups gave a little higher enatioselectivities
(Table 3, entry 5, p-CH3, ee 98%; entry 9, p-Cl, ee 96%). a,b-
Unsaturated trans-cinnamaldehyde afforded 87% enantioselec-
tivity (Table 3, entry 12). However, aliphatic n-butylaldehyde
and cyclohexanecarbaldehyde gave the products in low
O
(i) BuLi
C
Et
Ph
H2N
HN
O
(ii) isophthaloyl dichloride
(i) ClCO2Et, NEt3, THF
(ii) NaH, THF, reflux
Et
Et
OH
Ph
Et
4
2b
O
O
O
O
C
C
C
C
Ph
+
Ph
Cl
N
O
N
O
N
O
Ph
Et
O C
C O O
C
Et
Et
Et
Et
Et
3g
5
DMAP, NEt3
2b
O
O
C
C
N
NH
Ph
Ph
O C
Et
Et
O
OH
Et
Et
3h
Scheme 2. Synthesis of chiral ligands 3geh.

2556
X.-P. Hui et al. / Tetrahedron 64 (2008) 2553e2558
enantioselectivities of only52 and 67% ee, respectively (Table 3,
entries 13 and 14).
(3ꢁ10 mL), and brine (3ꢁ10 mL). The organic layer was
dried over anhydrous MgSO4, and the solvent was removed
under reduced pressure to give a yellow residue. The crude
product was purified by flash column chromatography to
give 3aef.
3. Conclusions
We have described new C2-symmetric chiral bis(b-hydroxy
amide) ligands, which could be prepared easily from isophthalyl
chlorideandchiralaminoalcohols. Theenantioselectiveaddition
of phenylacetylene to aldehydes catalyzed by 3b/Ti(O-i-Pr)4 was
demonstrated with excellent enantioselectivity (up to 98% ee).
The reaction catalyzed by blocked ligand 3h/Ti(O-i-Pr)4 system
supports that the two b-hydroxy amide moieties in these C2-sym-
metrical ligands behave as two independent ligands in the cata-
lytic system. The application of these ligands supported by
cross-linked polystyrene backbone in this asymmetric addition
is currently under the way and will be reported in due course.
4.2.2.1. N1,N3-Bis[(S)-3-benzyl-3-hydroxy-1,4-diphenylbutan-
2-yl]isophthalamide (3a). White powder, yield 55%, mp 150e
151 ꢀC. [a]D25 ꢂ16 (c 1.00, CH2Cl2). 1H NMR (400 MHz,
CDCl3) d: 7.42e7.00 (m, 34H, ArH), 5.57 (d, J¼8.8 Hz, 2H,
NH), 4.38e4.30 (m, 2H, CH), 3.54 (br, 2H, OH), 3.38 (d,
J¼14.4 Hz, 2H, CH), 3.06e2.84 (m, 10H, CH2). 13C NMR
(100 MHz, CDCl3) d: 167.63, 137.78, 137.33, 136.62,
133.80, 130.61, 129.47, 128.63, 128.53, 128.44, 128.37,
128.18, 126.79, 126.74, 126.56, 124.99, 77.37, 58.24, 44.81,
42.65, 36.09. IR (KBr): 3409, 3344, 3060, 3027, 2941,
1641, 1541, 1496, 1451, 733 cmꢂ1
. Anal. Calcd for
4. Experimental
C54H52N2O4 (%): C, 81.79; H, 6.61; N, 3.53. Found: C,
81.58; H, 6.63; N, 3.55.
4.1. General information
4.2.2.2. N1,N3-Bis[(S)-3-ethyl-3-hydroxy-1-phenylpentan-2-yl]-
All the reactions were carried out under a dry nitrogen atmo-
sphere. Melting points were taken on an X-4 melting point ap-
paratus and were uncorrected. 1H NMR and 13C NMR spectra
were recorded on Varian Mercury-400 or 300 MHz spectrome-
ter with TMS as an internal standard. IR spectra were obtained
on a Nicolet NEXUS 670 FT-IR instrument. Mass spectra were
performed on Thermo DSQ mass instrument (EI at 70 eV). Op-
tical rotation was measured on a PerkineElmer 341 polarime-
ter. Elemental analyses were determined by Elemental vario EL
instrument. Enantiomeric excess values were determined by
HPLC with a Chiralcel OD-H column. Ti(O-i-Pr)4 was freshly
distilled prior to use. Triethylamine was distilled over KOH
pellets and stored in a sealed flask. All solvents used were dried
by heating under reflux for at least 12 h over P2O5 (dichlorome-
thane) or sodium/benzophenone (diethyl ether, THF, toluene or
n-hexane), and were freshly distilled prior to use. Aldehydes
were purchased from Aldrich and used directly. Reactions
were monitored by thin layer chromatography (TLC). Diethyl-
zinc (1.0 M solution in CH2Cl2) was prepared following the
literature method15 and then diluted with CH2Cl2 to 1.0 M.
isophthalamide (3b). White powder, yield 57%, mp 144e
1
145 ꢀC. [a]D25 ꢂ126 (c 1.00, CH2Cl2). H NMR (300 MHz,
CDCl3) d: 7.60 (s, 1H, ArH), 7.43 (d, J¼8.4 Hz, 2H, ArH),
7.26e7.11 (m, 11H, ArH), 6.35 (d, J¼8.7 Hz, 2H, NH),
4.37e4.29 (m, 2H, CH), 3.13 (dd, J¼14.1, 3.6 Hz, 2H,
PhCH2), 2.83 (dd, J¼14.1, 11.1 Hz, 2H, PhCH2), 2.63 (br,
2H, OH), 1.79e1.52 (m, 8H, CH2), 1.00e0.92 (m, 12H,
CH3). 13C NMR (75 MHz, CDCl3) d: 167.36, 138.82,
134.76, 129.48, 129.15, 128.43, 128.28, 126.23, 124.99,
56.52, 35.04, 28.02, 27.62, 7.97, 7.67. IR (KBr): 3403,
2967, 2940, 1639, 1541, 1452, 741 cmꢂ1. Anal. Calcd for
C34H44N2O4: C, 74.97; H, 8.14; N, 5.14. Found: C, 74.69;
H, 7.94; N, 5.32.
4.2.2.3. N1,N3-Bis[(S)-4-ethyl-4-hydroxy-1-phenylhexan-3-yl]-
isophthalamide (3c). White powder, yield 58%, mp 81e
82 ꢀC. [a]D25 ꢂ40 (c 1.00, CH2Cl2). 1H NMR (300 MHz,
CDCl3) d: 8.28 (s, 1H, ArH), 7.91 (d, J¼7.8 Hz, 2H, ArH),
7.48 (t, J¼7.5 Hz, 1H, ArH), 7.27e7.12 (m, 10H, ArH),
6.64 (d, J¼9.6 Hz, 2H, NH), 4.30e4.23 (m, 2H, CH), 2.78e
2.65 (m, 4H, CH2), 2.09 (br, 2H, OH), 2.02e1.82 (m, 4H,
CH2), 1.66e1.47 (m, 8H, CH2), 0.85 (t, J¼7.2 Hz, 12H,
CH3). 13C NMR (75 MHz, CDCl3) d: 166.95, 141.87,
134.80, 129.88, 128.80, 128.34, 128.31, 125.81, 125.58,
77.06, 54.60, 32.80, 31.30, 27.86, 27.70, 7.77, 7.57. IR
(KBr): 3419, 3062, 2967, 2939, 2882, 1644, 1519, 1454,
728 cmꢂ1. Anal. Calcd for C36H48N2O4: C, 75.49; H, 8.45;
N, 4.89. Found: C, 75.42; H, 8.15; N, 4.83.
4.2. Synthesis of chiral ligands
4.2.1. Amino alcohols
Amino alcohols 2aed, 2e, and 2f were synthesized accord-
ing to literature procedures,12e14 respectively.
4.2.2. General procedures for preparation of C2-
symmetrical b-hydroxy amides (3aef)
A solution of isophthalyl chloride (5.00 mmol) in CH2Cl2
(10 mL) was added to a solution of the corresponding amino
alcohol (10.0 mmol) and Et3N (4.18 mL, 30 mmol) in
CH2Cl2 (20 mL) at 0 ꢀC. The reaction mixture was allowed
to warm to room temperature and stirred overnight. The reac-
tion mixture was diluted with CH2Cl2 (10 mL) and washed
with 1 M HCl (2ꢁ10 mL), saturated aqueous NaHCO3
4.2.2.4. N1,N3-Bis[(S)-5-ethyl-5-hydroxy-2-methylheptan-4-yl]-
isophthalamide (3d). White powder, yield 53%, mp 206e
208 ꢀC. [a]2D5 ꢂ43 (c 1.00, DMSO). 1H NMR (400 MHz,
CDCl3) d: 8.23 (s, 1H, ArH), 7.91 (d, J¼8.0 Hz, 2H, ArH),
7.49 (t, J¼7.6 Hz, 1H, ArH), 6.40 (d, J¼9.2 Hz, 2H, NH),
4.27 (t, J¼9.6 Hz, 2H, CH), 1.95 (br, 2H, OH), 1.68e1.47
(m, 12H, CH2, CH), 1.39e1.33 (m, 2H, CH), 0.99e0.87 (m,

X.-P. Hui et al. / Tetrahedron 64 (2008) 2553e2558
2557
24H, CH3). 13C NMR (100 MHz, CDCl3) d: 166.85, 134.89,
129.83, 128.74, 125.52, 77.16, 52.94, 38.37, 27.86, 27.71,
24.96, 24.14, 21.55, 7.85, 7.51. IR (KBr): 3432, 3315, 2964,
2878, 1640, 1583, 1531, 1467, 718 cmꢂ1. Anal. Calcd for
C28H48N2O4: C, 70.55; H, 10.15; N, 5.88. Found: C, 70.31;
H, 9.83; N, 5.58.
4.2.4. Synthesis of chiral ligands 3g and 3h
To a solution of 4 (1.03 g, 4.41 mmol) in CH2Cl2 (25 mL)
at ꢂ78 ꢀC, n-butyllithium solution (2.5 M, 2.11 mL,
5.3 mmol) was added and the mixture was stirred for 0.5 h.
A solution of isophthalyl chloride (0.90 g, 4.41 mmol) in
CH2Cl2 (25 mL) was added to the above solution. The result-
ing solution was allowed to warm to room temperature and
stirred for 18 h. This mixture was added slowly in 0.5 h to a so-
lution of NEt3 (1.85 mL, 13.2 mmol), a catalytic amount of
DMAP, and amino alcohol 2b (1.09 g, 5.29 mmol) in
CH2Cl2 (20 mL) at room temperature. The solution was stirred
overnight and then washed with 1 M HCl (3ꢁ25 mL), and
brine (3ꢁ25 mL). The organic phase was dried over anhydrous
MgSO4 and the solvent was removed under reduced pressure
to give a yellow residue. The crude product was purified by
flash column chromatography to afford 3g and 3h.
4.2.2.5. N1,N3-Bis[(S)-1-hydroxy-3-phenylpropan-2-yl]isoph-
thalamide (3e). White powder, yield 53%, mp 151e152 ꢀC.
[a]2D5 ꢂ129 (c 1.00, DMSO). H NMR (300 MHz, DMSO-
1
d6) d: 8.29 (d, J¼9.0 Hz, 2H, NH), 8.16 (s, 1H, ArH), 7.85
(d, J¼7.5 Hz, 2H, ArH), 7.48 (t, J¼7.5 Hz, 1H, ArH), 7.24e
7.12 (m, 10H, ArH), 4.89 (t, J¼5.7 Hz, 2H, OH), 4.16e4.14
(m, 2H, CH), 3.55e3.28 (m, 4H, CH2), 2.93 (dd, J¼13.5,
4.8 Hz, 2H, PhCH2), 2.77 (dd, J¼13.5, 8.7 Hz, 2H, PhCH2).
13C NMR (75 MHz, DMSO-d6) d: 166.63, 139.84, 135.42,
130.28, 129.73, 128.83, 126.99, 126.68, 63.49, 53.96, 37.10.
IR (KBr): 3414, 3343, 2958, 1633, 1547, 1452, 730 cmꢂ1
.
4.2.4.1. 1,3-Bis[(S)-4-benzyl-5,5-diethyloxooxazolidin-3-formyl]-
Anal. Calcd for C26H28N2O4: C, 72.20; H, 6.53; N, 6.48.
Found: C, 72.01; H, 6.84; N, 6.48.
benzene (3g). White powder, yield 21%, mp 61e62 ꢀC. [a]D25
1
þ29 (c 1.00, CH2Cl2). H NMR (400 MHz, CDCl3) d: 7.90
(s, 1H, ArH), 7.73 (d, J¼8.0 Hz, 2H, ArH), 7.39 (t, J¼8.0 Hz,
1H, ArH), 7.27e7.13 (m, 10H, ArH), 4.77e4.74 (m, 2H, CH),
3.23 (dd, J¼14.0, 5.2 Hz, 2H, PhCH2), 2.91 (dd, J¼14.0,
8.4 Hz, 2H, PhCH2), 1.98e1.92 (m, 2H, CH2), 1.66e1.58 (m,
4H, CH2), 1.50e1.43 (m, 2H, CH2), 0.95 (t, J¼7.6 Hz, 6H,
CH3), 0.75 (t, J¼7.6 Hz, 6H, CH3). 13C NMR (100 MHz,
CDCl3) d: 168.71, 152.40, 136.49, 133.12, 132.77, 130.63,
129.07, 128.64, 127.00, 126.90, 86.67, 61.75, 34.62, 29.12,
25.65, 7.74, 7.24. IR (KBr): 2975, 2944, 2885, 1781, 1683,
1458, 1356, 1301, 724 cmꢂ1. Anal. Calcd for C36H40N2O6: C,
72.46; H, 6.76; N, 4.69. Found: C, 72.27; H, 6.81; N, 4.74.
4.2.2.6. N1,N3-Bis[(1R,2S)-1-hydroxy-1,3-diphenylpropan-2-
yl]isophthalamide (3f). White powder, yield 84%, mp 110e
111 ꢀC. [a]D25 ꢂ91 (c 1.00, CH2Cl2). 1H NMR (300 MHz,
CDCl3) d: 7.69 (s, 1H, ArH), 7.39e7.01 (m, 23H, ArH),
6.38 (d, J¼8.1 Hz, 2H, NH), 5.06 (d, J¼2.7 Hz, 2H, CH),
4.60e4.52 (m, 2H, CH), 2.80e2.77 (m, 4H, CH2). 13C
NMR (75 MHz, CDCl3) d: 167.74, 141.27, 138.70, 134.35,
129.27, 129.11, 128.66, 128.37, 127.74, 126.60, 126.34,
125.90, 75.29, 57.68, 33.15. IR (KBr): 3409, 3061, 3028,
1643, 1519, 1450, 749 cmꢂ1. Anal. Calcd for C38H36N2O4:
C, 78.06; H, 6.21; N, 4.79. Found: C, 77.77; H, 6.31;
N, 4.72.
4.2.4.2. 3-[(S)-4-Benzyl-5,5-diethyloxooxazolidin-3-formyl]-N-
[(S)-3-ethyl-3-hydroxy-1-phenylpentan-2-yl]-benzamide (3h).
White powder, yield 25%, mp 63e64 ꢀC. [a]D25ꢂ54 (c 1.00,
4.2.3. Preparation of (S)-4-benzyl-5,5-diethyloxazolidin-2-
one (4)
1
CH2Cl2). H NMR (400 MHz, CDCl3) d: 7.76 (s, 1H, ArH),
To a solution of 2b (1.03 g, 5.0 mmol) and triethylamine
(3.48 mL, 25 mmol) in THF (25 mL), ethyl chloroformate
(0.48 mL, 5.0 mmol) was added at room temperature and
the mixture was allowed to react for 3 h. The solution was
7.66 (d, J¼8.0 Hz, 2H, ArH), 7.39 (t, J¼8.0, 1H, ArH),
7.34e7.14 (m, 10H, ArH), 6.22 (d, J¼9.2 Hz, 1H, NH),
4.83e4.79 (m, 1H, CH), 4.33e4.29 (m, 1H, CH), 3.27 (dd,
J¼5.2, 14.0 Hz, 1H, PhCH2), 3.14 (dd, J¼14.0, 3.6 Hz, 1H,
PhCH2), 2.98 (dd, J¼14.0, 8.8 Hz, 1H, PhCH2), 2.87 (dd,
J¼14.0, 10.4 Hz, 1H, PhCH2), 2.51 (br, 1H, OH), 1.79e1.50
(m, 8H, CH2), 1.04e0.80 (m, 12H, CH3). 13C NMR
(100 MHz, CDCl3) d: 169.01, 166.89, 152.48, 138.73,
136.48, 134.47, 133.52, 131.77, 130.55, 129.17, 129.13,
128.68, 128.46, 127.89, 127.59, 126.99, 126.37, 86.90,
76.95, 61.65, 56.82, 35.11, 34.67, 29.12, 28.11, 27.82,
25.57, 8.03, 7.77, 7.67, 7.28. IR (KBr): 3383, 2970, 2941,
2882, 1781, 1684, 1642, 1536, 1357, 729 cmꢂ1. Anal. Calcd
for C35H42N2O5: C, 73.66; H, 7.42; N, 4.91. Found: C,
73.63; H, 7.38; N, 4.80.
then added slowly to
a suspension of NaH (1.20 g,
50 mmol) in THF (25 mL) during a period of 0.5 h and the re-
sulting mixture was refluxed for 12 h. The solution was cooled
down and washed with 1 M HCl (3ꢁ50 mL) and brine
(3ꢁ50 mL), then the organic phase was dried over anhydrous
MgSO4, and the solvent was removed to give yellowish oil 4
in 88% yield. [a]2D5 ꢂ66 (c 1.00, CH2Cl2). 1H NMR
(300 MHz, CDCl3) d: 7.37e7.16 (m, 5H, ArH), 4.96 (br,
1H, NH), 3.76 (dd, J¼11.1, 3.6 Hz, 1H, CH), 2.86 (dd,
J¼3.0, 14.4 Hz, 1H, PhCH2), 2.70 (dd, J¼14.4, 12.9 Hz,
1H, PhCH2), 1.98e1.91 (m, 1H, CH2), 1.84e1.68 (m, 3H,
CH2), 1.06 (t, J¼7.5 Hz, 3H, CH3), 0.97 (t, J¼7.5 Hz, 3H,
CH3). 13C NMR (75 MHz, CDCl3) d: 157.99, 137.10,
128.88, 128.74, 126.95, 87.22, 60.86, 37.08, 28.99, 24.89,
7.65, 7.37. IR (KBr): 3272, 2973, 1747, 1604, 1495, 1457,
1388, 739 cmꢂ1. MS (EI) m/z: 234.0 (47.5), 141.8 (72.7),
97.8 (100), 90.8 (63.1).
4.3. General procedure for asymmetric addition of
phenylacetylene to aldehydes
Under dry nitrogen, the ligand (0.025 mmol) and Ti-
(O-i-Pr)4 (0.075 mmol) were mixed in the solvent (1.5 mL)

2558
X.-P. Hui et al. / Tetrahedron 64 (2008) 2553e2558
lin, A. J. Am. Chem. Soc. 2006, 128, 8; (f) Hsieh, S.-H.; Gau, H.-M.
Synlett 2006, 1871; (g) Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2005, 127, 13760; (h) Fang, T.; Du, D.-M.; Lu,
S.-F.; Xu, J.-X. Org. Lett. 2005, 7, 2081; (i) Yamashita, M.; Yamada,
K.; Tomioka, K. Adv. Synth. Catal. 2005, 347, 1649; (j) Li, M.; Zhu,
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15, 219; (k) Dahmen, S. Org. Lett. 2004, 6, 2113.
at room temperature. Then diethylzinc (0.75 mL, 1.0 M solution
in CH2Cl2) was added. After the mixture was stirred at room
temperature for 2 h, phenylacetylene (82.4 mL, 0.75 mmol)
was added and the mixture was stirred for 1 h. Then the solution
was treated with aldehyde (0.25 mmol). After the reaction was
completed (TLC), the reaction solution was cooled to 0 ꢀC and
quenched by 5% aqueous HCl. The mixture was extracted with
diethyl ether (3ꢁ10 mL). The extract was washed with brine
(3ꢁ15 mL), dried over anhydrous Na2SO4, and concentrated
under vacuum. The crude product was purified by flash column
chromatography (silica gel, 12.5% EtOAc in petroleum ether) to
give the propargyl alcohol.
5. (a) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687; (b)
Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4, 2605; (c) Frantz,
D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806.
6. (a) Lu, G.; Li, X.; Chen, G.; Chan, W. L.; Chan, A. S. C. Tetrahedron:
Asymmetry 2003, 14, 449; (b) Li, X. S.; Lu, G.; Kwok, W. H.; Chan,
A. S. C. J. Am. Chem. Soc. 2002, 124, 12636; (c) Lu, G.; Li, X.; Chan,
W. L.; Chan, A. S. C. Chem. Commun. 2002, 172.
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Acknowledgements
8. Liu, Q.-Z.; Xie, N.-S.; Luo, Z.-B.; Cui, X.; Cun, L.-F.; Gong, L.-Z.; Mi,
A.-Q.; Jiang, Y.-Z. J. Org. Chem. 2003, 68, 7921.
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Chem., Int. Ed. 2003, 42, 5747; (b) Xu, Z.; Chen, C.; Xu, J.; Miao, M.;
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This work was supported by National Natural Science
Foundation of China (NSFC 20572039, 20621091,
20702022), the Program (NCET-05-0880) and the Doctoral
Funds from Chinese Ministry of Education of P.R. China.
10. (a) Jiang, B.; Feng, Y. Tetrahedron Lett. 2002, 43, 2975; (b) Yus, M.;
´
Ramon, D. J.; Prieto, O. Tetrahedron: Asymmetry 2002, 13, 1573; (c)
Yus, M.; Ramon, D. J.; Prieto, O. Tetrahedron: Asymmetry 2003, 14,
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