Synthesis of new β-hydroxy amide ligands and their Ti(IV) complex-catalyzed enantioselective alkynylation of aliphatic and vinyl aldehydes

Article abstract of DOI:10.1016/j.tet.2009.03.005

Three new chiral β-hydroxy amide ligands were synthesized via the reaction of benzyl chloride and amino alcohols derived from l-tyrosine. The titanium(IV) complex of chiral ligand 8b was found to be an effective catalyst for the asymmetric alkynylation of aliphatic, vinyl and aromatic aldehydes. The propargyl alcohols were obtained in highly enantiomeric excesses (up to 96% ee) under optimized conditions.

Full text of DOI:10.1016/j.tet.2009.03.005

Tetrahedron 65 (2009) 3611–3614
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of new
b-hydroxy amide ligands and their Ti(IV) complex-catalyzed
enantioselective alkynylation of aliphatic and vinyl aldehydes
*
Ya-Min Li, Yi-Quan Tang, Xin-Ping Hui , Lu-Ning Huang, Peng-Fei Xu
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Three new chiral
amino alcohols derived from
effective catalyst for the asymmetric alkynylation of aliphatic, vinyl and aromatic aldehydes. The prop-
argyl alcohols were obtained in highly enantiomeric excesses (up to 96% ee) under optimized conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
b
-hydroxy amide ligands were synthesized via the reaction of benzyl chloride and
-tyrosine. The titanium(IV) complex of chiral ligand 8b was found to be an
Received 19 December 2008
Received in revised form 2 March 2009
Accepted 3 March 2009
L
Available online 6 March 2009
Keywords:
Asymmetric addition
b
-Hydroxy amide
Phenylacetylene
Titanium tetraisopropoxide
1. Introduction
The alkynylation of aldehydes is one of the most useful car-
bon–carbon bond-forming reactions because this process can
produce the synthetically very useful chiral propargyl alcohols.1
Since the first efficient asymmetric alkynes addition to aldehydes
was demonstrated by Corey and Cimprich2 using chiral oxaza-
borolidines, many highly enantioselective catalysts have been
developed for this reaction.3–7 Among the catalytic methods
developed, the addition of terminal acetylene to aromatic alde-
hydes is currently considered to be the most practical. However,
fewer excellent chiral ligands have been disclosed in efficiently
catalytic asymmetric alkynylation of aliphatic and vinyl alde-
hydes. Carreira and co-workers reported that a system using
Zn(OTf)2 and catalytic amount (þ)-N-methyl ephedrine (1) with
triethylamine afforded high yields and enantioselectivities in the
addition of terminal acetylide to aliphatic aldehydes.8 For tita-
nium complex-catalyzed alkynylation reaction, (S)-1,10-bi-2-
naphthol (BINOL) (2) was demonstrated to be an excellent ligand
by Pu’s group.5a Shibasaki and co-workers developed a new
catalytic system for alkynylation of aliphatic and aromatic alde-
hydes with the combination of indium(III)/(S)-BINOL complex
and Cy2NMe.9 Recently, 1,10-binaphthyl macrocycle 3 was found
to be an excellent catalyst for the alkynes addition to aliphatic
and vinyl aldehydes.10
N
N
N
N
Ph
Me
HO
HO
OH
OH
OH
OH
HO
NMe2
1
2
3
In our laboratory, we have developed chiral b-hydroxy amide
ligands, and successfully introduced it into the asymmetric addi-
tion of phenylacetylene to aromatic aldehydes to obtain excellent
enantioselectivities.11 To further develop efficient catalysts for the
asymmetric alkynes addition to aliphatic and vinyl aldehydes, we
here report the synthesis of new b-hydroxy amides 8a–c. The best
performed titanium(IV) catalyst of 8b catalyzes asymmetric phe-
nylacetylene addition to aliphatic and vinyl aldehydes in good
yields and excellent enantioselectivities (up to 96% ee).
2. Results and discussion
Recently, we have reported that the C2-symmetric bis(b-hy-
droxy amide) 4 in combination with ZnEt2 and Ti(O-i-Pr)4 could
catalyze the reaction of phenylacetylene with aromatic aldehydes
with high enantioselectivities. However, when the C2-symmetric
* Corresponding author. Fax: þ86 931 8915557.
E-mail address: huixp@lzu.edu.cn (X.-P. Hui).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.005

3612
Y.-M. Li et al. / Tetrahedron 65 (2009) 3611–3614
Table 1
bis(b-hydroxy amide) 4 was used to catalyze the reaction of phe-
Optimization of reaction conditionsa
nylacetylene with n-butylaldehyde at room temperature, only 52%
ee was obtained.11a To further develop efficient catalysts for the
asymmetric alkyne addition to aliphatic and vinyl aldehydes, we
chose cheap (S)-tyrosine as chiral source and conveniently syn-
thesized new ligands 8a–c (Scheme 1). Coupling of benzyl chloride
with amino alcohols 6a and 6b, which were prepared by (S)-tyro-
sine methyl ester hydrochloride with Grignard reagents, in the
presence of sodium hydride and DMF gave compounds 7a–c.
Compounds 7a–c reacted with benzoyl chloride in the presence of
OH
ligand 8, Ti(O-i-Pr)4
ZnEt2
CHO
+
Ph
Ph
Entry Catalyst L (mol %) Solvent L/Ti(O-i-Pr)4 Yieldb (%) eec (%) (Config.)
1
2
3
4
8a
8b
8c
8b
8b
8b
8b
8b
8b
8b
8b
8b
8b
8b
20
20
20
20
20
20
20
20
20
20
20
30
10
20
Toluene 1/3
Toluene 1/3
Toluene 1/3
Toluene 1/2
Toluene 1/4
Toluene 1/3
Toluene 1/3
Hexane 1/3
78
85
87
64
79
80
83
77
79
71
74
85
80
76
39 (R)
91
81
80
86
87
84
82
80
65
82
91
triethylamine afforded new
b
-hydroxy amide ligands 8a–c.
5
6d
7e
8
O
O
C
C
9
CH2Cl2
THF
1/3
1/3
1/3
10
11
12
13
14f
NH
HN
Et2O
Ph
Et
Ph
Et
Toluene 1/3
Toluene 1/3
Toluene 1/3
OH
HO
73
72
Et
Et
4
a
Phenylacetylene/ZnEt2/n-butyraldehyde¼3:3:1 (molar ratio); reaction time:
18 h; reaction temperature: rt.
b
The addition of phenylacetylene to n-butyraldehyde was first
examined in the presence of 0.2 equiv chiral ligands 8a and 8b,
ZnEt2 and Ti(O-i-Pr)4 in toluene and the results are summarized in
Table 1. Ligand 8a, which has two benzyl substituents at the hy-
droxyl-bearing carbon atom, resulted in a lower enantioselectivity
(Table 1, entry 1). To our delight, when 8b was used and the cor-
responding propargyl alcohol was given in 85% yield and 91% ee
(Table 1, entry 2). It is obviously that ligand 8a, which has the
bulkier, less flexible benzyl substituents at the hydroxy-bearing
carbon atom, resulted in a lower enantioselectivity than ligand 8b,
which has the more flexible ethyl substituents. For further explor-
ing the chiral ligand effect of titanium(IV) complex in asymmetric
addition reactions of phenylacetylene to n-butyraldehyde, ligand
8c, which having 4-methoxybenzyl group instead of benzyl group
in 8b, was synthesized. For ligand 8c, the propargyl alcohol was
obtained in a slightly lower selectivity than 8b (Table 1, entry 3). So,
ligand 8b was chosen to be the best overall chiral ligand to facilitate
this alkynyl addition reaction.
Further optimization studies were carried out using ligand 8b in
combination with ZnEt2 and Ti(O-i-Pr)4. The enantioselectivities of
the reaction were strongly affected by different conditions. In-
creasing the amount of Ti(O-i-Pr)4 from 2:1 to 3:1 relative to chiral
ligand 8b afforded obviously increased enantioselectivity (Table 1,
entries 2 and 4). Further increase in the amount of Ti(O-i-Pr)4
resulted in decrease in enantioselectivity (Table 1, entry 5). The
amount of diethylzinc was also important. When the amount of
ZnEt2 was increased, the ee value decreased from 91 to 84% (Table 1,
entry 7). Four solvents were also examined and toluene was found
to be the best choice (Table 1, entries 8–11). The ee value of
Isolated yield.
c
Determined by HPLC analysis using Chiralcel OD-H column.
d
Phenylacetylene/ZnEt2/n-butyraldehyde¼2:2:1 (molar ratio).
e
Phenylacetylene/ZnEt2/n-butyraldehyde¼4:4:1 (molar ratio).
f
Reaction temperature: 0 ꢀC.
propargyl alcohol decreased when the amount of chiral ligand 8b
was reduced from 20 to 10% (Table 1, entry 13). To further improve
the enantioselectivity in this reaction, temperature effect was ob-
served. The result showed that temperature effect was obvious and
only 72% ee was obtained under 0 ꢀC (Table 1, entry 14). Thus, entry
2 in Table 1 was identified as the optimized reaction procedure.
The generality of this catalytic system for phenylacetylene
asymmetric addition to aliphatic and vinyl aldehydes was examined
using the titanium complex of ligand 8b under the optimized re-
action conditions and the results are summarized in Table 2. The
chiral propargyl alcohols could be obtained in 88–96% ee for ali-
phatic and vinyl aldehydes (Table 2, entries 1–11). For aliphatic
aldehydes, the one with bulky group gave a slightly lower
enantioselectivities (Table 2, entries 6 and 7). It is worth noting that
for 2-phenylacetaldehyde, excellentenantioselectivityof 94% eewas
obtained (Table 2, entry 8). For vinyl aldehydes, trans-cinnamalde-
hyde afforded excellent enantioselectivity of 96% ee (Table 2, entry
9). Furthermore, the optimized conditions were also applicable to
benzaldehyde. The addition of phenylacetylene to benzaldehyde
proceeded smoothly to give the product in 85% yield and 92% ee
(Table 2, entry 12). It is noteworthy that this catalytic system has
broad generality for both aliphatic, vinyl and aromatic aldehydes.
R1
HO
R1MgBr
THF
HO
R1
SOCl2
MeOH
HO
COOMe
COOH
R2
H2N
6a-b
OH
HCl H2N
5
H2N
R2
R1
4-R2C6H4CH2Cl
NaH, DMF
PhCOCl
Et3N, CH2Cl2
R1
O
R1
O
R1
HN
Ph
OH
O
H2N
OH
7a-c
R1=Bn, R2=H (8a)
R1=Et, R2=H (8b)
R1=Et, R2=MeO (8c)
Scheme 1. Synthesis of chiral ligands 8a–c.

Y.-M. Li et al. / Tetrahedron 65 (2009) 3611–3614
3613
Table 2
aqueous layer was extracted with ethyl acetate (3ꢁ25 mL). The
combined organic fractions were washed with saturated aqueous
NaHCO3 (20 mL) and brine (20 mL), then dried with anhydrous
MgSO4. After filtration and evaporation of the solvent, the crude
product was obtained. The crude product was dissolved in
dichloromethane, dry hydrogen chloride was bubbled. The solvent
was removed and the solid was recrystallized from ethyl acetate–
petroleum ether to give a white solid. The white solid was neu-
tralized by ammonia, extracted with chloroform, and the solvent
was removed to give pure 6a and 6b.
Asymmetric addition of phenylacetylene to aliphatic and vinyl aldehydes promoted
by ligand 8ba
OH
ligand 8b, Ti(O-i-Pr)4
R
RCHO
+
Ph
ZnEt2
Ph
Entry
Aldehydes
Yieldb (%)
eec (%)
Config.d
1
2
3
4
5
6
7
8
Propionaldehyde
n-Butyraldehyde
Isobutyraldehyde
3-Methylbutanal
n-Heptanal
75
85
87
83
80
81
81
79
83
71
86
85
90
91
92
90
91
88
88
94
96
90
90
92
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(ꢂ)
(R)
(R)
(R)
(R)
4.2.1.1. 4-[(S)-2-Amino-3-ethyl-3-hydroxypentyl]phenol hydro-
20
chloride. Mp 166–170 ꢀC. [
a]
ꢂ42 (c 1.0, H2O). 1H NMR (400 MHz,
D
Pivalaldehyde
D2O)
d
: 0.74–0.86 (m, 6H), 1.48–1.59 (m, 4H), 2.48 (t, J¼12.9 Hz, 1H),
Cyclohexanecarbaldehyde
2-Phenylacetaldehyde
trans-Cinnamaldehyde
Acrylaldehyde
2.95 (d, J¼8.0 Hz, 1H), 3.35 (dd, J¼3.0, 12.0 Hz, 1H), 6.75 (d,
J¼8.4 Hz, 2H), 7.06 (d, J¼8.4 Hz, 2H). IR (KBr): 3399, 3101, 2968,
9
10
11
12
2684, 2571, 1619, 1515, 1448, 1249, 1136, 969 cmꢂ1
.
(E)-But-2-enal
Benzaldehyde
4.2.1.2. 4-[(S)-2-Amino-3-benzyl-3-hydroxy-4-phenylbutyl]phenol
a
Phenylacetylene/ZnEt2/aldehyde/Ti(O-i-Pr)4/8b¼3:3:1:0.6:0.2 (molar ratio);
20
hydrochloride. Mp 168–170 ꢀC. [
(300 MHz, D2O)
a]
ꢂ4 (c 1.0, H2O). 1H NMR
D
reaction time: 18 h; reaction temperature: rt.
b
d
: 2.77 (dd, J¼12.3, 14.7 Hz, 1H, CH2), 2.93–3.04 (m,
Isolated yield.
c
Determined by HPLC analysis using Chiralcel OD-H column.
Absolute configuration of the products was based on measurement of the optical
3H, CH, CH2), 3.17 (dd, J¼2.1, 12.6 Hz, 2H, CH2), 3.34 (dd, J¼3.6,
14.7 Hz, 1H, CH2), 6.84 (d, J¼8.7 Hz, 2H, ArH), 7.01 (d, J¼8.7 Hz, 2H,
d
rotation and comparison with the literature values.4a,5a,7b,10
ArH), 7.31–7.48 (m, 10H, ArH). 13C NMR (75 MHz, D2O)
d: 32.73,
40.46, 41.81, 59.45, 74.16, 116.07, 127.40, 127.47, 128.75, 128.83,
130.51, 130.70, 131.52, 135.12, 135.60, 155.04.
3. Conclusions
4.2.2. Preparation of amino alcohols 7a–c
In conclusion, the new chiral
b-hydroxy amide ligands were
A solution of 6a or 6b (10 mmol) in dry DMF (15 mL) was added
dropwise at room temperature to NaH (60%, 0.40 g, 10 mmol). After
the evolution of hydrogen was complete, benzyl chloride/
4-methoxybenzyl chloride (10 mmol) was added dropwise. The
resulting mixture was stirred at room temperature under nitrogen
for 10 h. The solution was then poured into a mixture of water and
ethyl acetate. The aqueous layer was extracted with ethyl acetate
(3ꢁ20 mL) and the combined organic fractions were washed with
water (20 mL) and brine (20 mL), then dried with anhydrous
MgSO4. The solvent was removed and the crude product was
recrystallized from ethyl acetate/petroleum ether to afford amino
alcohols 7a–c.
synthesized and used in the reaction of catalytic asymmetric ad-
dition of phenylacetylene to aliphatic, vinyl and aromatic alde-
hydes. Ligand 8b was found to be an effective catalyst for this
reaction and the propargyl alcohols were obtained in highly en-
antiomeric excesses (up to 96% ee). The application of these ligands
supported by cross-linked polystyrene backbone in this asymmet-
ric addition is ongoing.
4. Experimental
4.1. General
All reactions were carried out under nitrogen atmosphere. All
solvents used were dried and aldehydes were purified by standard
methods. Ti(O-i-Pr)4 was freshly distilled prior to use. Reactions
were monitored by thin layer chromatography (TLC). Melting
points were taken on an X-4 melting point apparatus and are un-
corrected. 1H NMR and 13C NMR spectra were recorded on Varian
Mercury-300 MHz spectrometers with TMS as an internal standard.
IR spectra were obtained on NEXUS 670 FT-IR spectrometer in KBr
disc. HRMS data were measured with ESI techniques (Bruker Apex
II). Optical rotation value was measured on Perkin–Elmer 341 po-
larimeter. Enantiomeric excess values were determined by HPLC
with Chiralcel OD-H column on Waters 600 Delta.
4.2.2.1. (S)-3-Amino-2-benzyl-4-(4-(benzyloxy)phenyl)-1-phenyl-
20
butan-2-ol (7a). White powder, yield 45%; mp 119–120 ꢀC. [
a]
D
ꢂ11 (c 1.00, acetone). 1H NMR (300 MHz, CDCl3)
d: 2.34–2.42 (m,
1H), 2.63–2.83 (m, 3H), 2.97 (dd, J¼3.9, 12.9 Hz, 2H), 3.21 (d,
J¼13.5 Hz, 1H), 3.85 (br, 1H), 5.01 (s, 2H), 6.84–6.92 (m, 4H), 7.24–
7.40 (m, 15H). 13C NMR (75 MHz, CDCl3)
d: 38.25, 42.03, 42.66,
58.22, 69.93, 75.05, 114.86, 126.32, 127.38, 127.90, 127.96, 128.08,
128.53, 129.88, 130.69, 130.87, 131.75, 136.96, 137.58, 137.64, 157.32.
HRMS (ESI) calcd for C30H31NO2 (MþH): 438.2428; found:
438.2431.
4.2.2.2. (S)-2-Amino-1-(4-(benzyloxy)phenyl)-3-ethylpentan-3-ol
20
Diethylzinc (1.0 M solution in CH2Cl2) was prepared according to
the literature method.12 (S)-Tyrosine methyl ester hydrochloride (5)
was synthesized according to the literature method.13
(7b). Light yellow powder, yield 47%; mp 63–65 ꢀC. [
a
]
ꢂ27 (c
D
1.00, acetone). 1H NMR (300 MHz, CDCl3)
d: 0.92–0.98 (m, 6H),
1.39–1.69 (m, 4H), 2.26 (dd, J¼13.5, 3.4 Hz, 1H), 2.90–2.94 (m, 2H),
5.05 (s, 2H), 6.94 (d, J¼8.1 Hz, 2H), 7.11 (d, J¼8.1 Hz, 2H), 7.31–7.46
4.2. Synthesis of chiral ligands
(m, 5H). 13C NMR (75 MHz, CDCl3)
d: 7.60, 7.64, 26.39, 27.76, 36.92,
57.15, 69.87, 74.22, 114.85, 127.37, 127.86, 128.47, 129.96, 132.09,
136.89, 157.24. HRMS (ESI) calcd for C20H27NO2 (MþH): 314.2115;
found: 314.2119.
4.2.1. Preparation of amino alcohols 6a and 6b
(S)-Tyrosine methyl ester hydrochloride (2.8 g, 12.0 mmol) was
added portion wise to a THF solution of ethylmagnesium bromide
(96.0 mmol) at 0 ꢀC. The mixture was allowed to warm to room
temperature and stirred overnight. After the reaction was com-
pleted, the reaction solution was cooled to 0 ꢀC and quenched by
saturated aqueous NH4Cl. The organic layer was separated, the
4.2.2.3. (S)-1-(4-(4-Methoxybenzyloxy)phenyl)-2-amino-3-ethyl-
pentan-3-ol (7c). Light yellow powder, yield 54%; mp 81–83 ꢀC.
20
[a
]
ꢂ20 (c 1.00, acetone). 1H NMR (300 MHz, CDCl3)
d: 0.85–0.98
D
(m, 6H), 1.39–1.69 (m, 4H), 2.25 (dd, J¼14.1, 11.7 Hz, 1H), 2.89–2.93

3614
Y.-M. Li et al. / Tetrahedron 65 (2009) 3611–3614
(m, 2H), 3.82 (s, 3H), 4.97 (s, 2H), 6.91 (d, J¼1.8 Hz, 2H), 6.94 (d,
J¼1.8 Hz, 2H), 7.10 (d, J¼8.4 Hz, 2H), 7.36 (d, J¼8.4 Hz, 2H). 13C NMR
157.29, 159.28, 168.05. IR (KBr): 3403, 3364, 3033, 2964, 1623, 1535,
1516, 1491, 1244, 1176, 1033, 692 cmꢂ1. HRMS (ESI) calcd for
C28H33NO4 (MþNa): 470.2302; found: 470.2302.
(75 MHz, CDCl3) d: 7.59, 7.62, 26.40, 27.77, 36.96, 55.14, 57.17, 69.66,
74.18, 113.84, 114.86, 128.89, 129.12, 129.92, 132.02, 157.30, 159.29.
HRMS (ESI) calcd for C21H29NO3 (MþH): 344.2220; found:
344.2223.
4.3. General procedure for the asymmetric addition
of phenylacetylene to aldehydes
4.2.3. General procedures for preparation of b-hydroxy
amides 8a–c
Under dry nitrogen, the ligand 8b (0.05 mmol) and Ti(O-i-Pr)4
(45 mL, 0.15 mmol) were mixed in anhydrous toluene (1.5 mL) at
A solution of benzoyl chloride (5.5 mmol) in CH2Cl2 (20 mL) was
added to a cold (0 ꢀC) solution of amino alcohol 7 (5.00 mmol) and
Et3N (0.77 mL, 5.5 mmol) in CH2Cl2 (20 mL). The reaction mixture
was allowed to warm to room temperature and stirred overnight.
The reaction mixture was washed with 1 N HCl (2ꢁ10 mL), satu-
rated aqueous NaHCO3 (2ꢁ10 mL), and brine (2ꢁ10 mL). The or-
ganic layer was dried over anhydrous MgSO4, concentrated under
vacuum. The yellow residue was purified by column chromatog-
room temperature and stirred for 1 h. Then a solution of ZnEt2
(0.75 mL, 1.0 M in CH2Cl2, 0.75 mmol) was added. After the mixture
was stirred at room temperature for 2 h, phenylacetylene (82.4 mL,
0.75 mmol) was added and stirred for another 1 h. Aldehyde
(0.25 mmol) was then added, and the reaction mixture was stirred
at room temperature for 18 h. Aqueous HCl (5%) was added to
quench the reaction, and the mixture was extracted with diethyl
ether. The organic layer was washed with brine, dried with anhy-
drous MgSO4, 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.
raphy to afford b-hydroxy amides.
4.2.3.1. N-((S)-3-Benzyl-1-(4-(benzyloxy)phenyl)-3-hydroxy-4-phe-
nylbutan-2-yl)benzamide (8a). White needle solid, yield 72%; mp
20
169–170 ꢀC. [
d
a]
ꢂ48 (c 1.00, acetone). 1H NMR (300 MHz, CDCl3)
D
Acknowledgements
: 2.83 (dd, J¼11.4, 14.4 Hz, 1H), 2.95 (dd, J¼8.7, 13.8 Hz, 2H), 3.05
(dd, J¼6.6, 13.8 Hz, 2H), 3.33 (dd, J¼3.3, 14.4 Hz, 1H), 3.77 (s, 1H),
4.25–4.33 (m, 1H), 4.96 (s, 2H), 5.53 (d, J¼8.7 Hz, 1H), 6.81 (d,
J¼8.7 Hz, 2H), 6.95 (d, J¼8.7 Hz, 2H), 7.13–7.44 (m, 20H). 13C NMR
This work was supported by National Natural Science Founda-
tion of China (NSFC 20702022 and 20621091).
(75 MHz, CDCl3) d: 35.35, 42.71, 45.10, 58.28, 69.83, 77.49, 114.90,
References and notes
126.54, 126.63, 126.73, 127.36, 127.84, 128.18, 128.32, 128.41, 128.47,
129.59, 130.04, 130.61, 130.64, 131.39, 133.59, 136.74, 136.86, 137.66,
157.39, 168.70. IR (KBr): 3414, 3373, 3028, 2940, 1630, 1531, 1514,
1490, 1450, 1247, 1024, 709 cmꢂ1. HRMS (ESI) calcd for C37H35NO3
(MþNa): 564.2509; found: 564.2504.
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U.S.A. 2004, 101, 5417; (d) Gao, G.; Wang, Q.; Yu, X.-Q.; Xie, R.-G.; Pu, L. Angew.
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4.2.3.2. N-((S)-1-(4-(Benzyloxy)phenyl)-3-ethyl-3-hydroxypentan-
2-yl)benzamide (8b). White needle solid, yield 76%; mp 156–
20
157 ꢀC. [
a
]
ꢂ139 (c 1.00, acetone). 1H NMR (300 MHz, CDCl3)
d:
D
0.90–1.00 (m, 6H), 1.57–1.78 (m, 4H), 2.56 (br, 1H), 2.79 (dd, J¼14.1,
10.5 Hz, 1H), 3.08 (dd, J¼14.1, 3.6 Hz, 1H), 4.23–4.30 (m, 1H), 4.99 (s,
2H), 6.17 (d, J¼9.3 Hz, 1H), 6.84 (d, J¼8.7 Hz, 2H), 7.12 (d, J¼8.7 Hz,
2H), 7.28–7.55 (m, 10H). 13C NMR (75 MHz, CDCl3)
d: 7.62, 7.98,
27.72, 28.07, 34.21, 56.67, 69.83, 76.89, 114.74, 126.77, 127.35, 127.76,
128.32, 128.41, 130.04, 131.15, 134.64, 136.99, 157.24, 168.03. IR
6. (a) Li, X.-S.; Lu, G.; Kwok, W. H.; Chan, A. S. C. J. Am. Chem. Soc. 2002, 124, 12636;
(b) Lu, G.; Li, X.; Chan, W. L.; Chan, A. S. C. Chem. Commun. 2002, 172; (c) Lu, G.;
Li, X.; Chen, G.; Chan, W. L.; Chan, A. S. C. Tetrahedron: Asymmetry 2003, 14, 449.
(KBr): 3446, 3352, 2967, 1630, 1540, 1511, 1237, 1012, 694 cmꢂ1
.
HRMS (ESI) calcd for C27H31NO3 (MþNa): 440.2196; found:
¨
7. (a) Koyuncu, H.; Dogan, O Org. Lett. 2007, 9, 3477; (b) Emmerson, D. P. G.; Hems,
440.2192.
W. P.; Davis, B. G. Org. Lett. 2006, 8, 207; (c) Wolf, C.; Liu, S. J. Am. Chem. Soc.
2006, 128, 10996; (d) Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am. Chem.
Soc. 2006, 128, 8; (e) Xu, Z.; Chen, C.; Xu, J.; Miao, M.; Yan, W.; Wang, R. Org. Lett.
2004, 6, 1193; (f) Dahmen, S. Org. Lett. 2004, 6, 2113; (g) Xu, Z. Q.; Wang, R.; Xu,
J. K.; Da, C. S.; Yan, W. J.; Chen, C. Angew. Chem., Int. Ed. 2003, 42, 5747.
8. Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
9. Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
13760.
4.2.3.3. N-((S)-1-(4-(4-Methoxybenzyloxy)phenyl)-3-ethyl-3-hy-
droxypentan-2-yl)benzamide (8c). White needle solid, yield 79%;
20
mp 167–168 ꢀC. [
a]
ꢂ128 (c 1.00, acetone). 1H NMR (300 MHz,
D
CDCl3) d: 0.90–1.00 (m, 6H), 1.56–1.76 (m, 4H), 2.69 (br, 1H), 2.80
(dd, J¼14.1, 10.5 Hz, 1H), 3.08 (dd, J¼14.1, 3.6 Hz, 1H), 3.80 (s, 3H),
4.25–4.30 (m, 1H), 4.91 (s, 2H), 6.22 (d, J¼6.9 Hz, 1H), 6.85 (d,
J¼8.7 Hz, 2H), 6.89 (d, J¼8.7 Hz, 2H), 7.14 (d, J¼8.1 Hz, 2H), 7.30–
10. Li, Z.-B.; Liu, T.-D.; Pu, L. J. Org. Chem. 2007, 72, 4340.
11. (a) Hui, X.-P.; Yin, C.; Chen, Z.-C.; Huang, L.-N.; Xu, P.-F.; Fan, G.-F. Tetrahedron
2008, 64, 2553; (b) Chen, Z.-C.; Hui, X.-P.; Yin, C.; Huang, L.-N.; Xu, P.-F.; Yu,
X.-X.; Cheng, S.-Y. J. Mol. Catal. A: Chem. 2007, 269, 179.
12. Noller, C. R. Org. Synth. 1951, Collect. Vol. 2, 184.
13. Shinichi, I.; Michio, N.; Koichi, I.; Akira, H.; Masaki, O.; Naoki, K.; Seiichi, N.
J. Chem. Soc., Perkin Trans. 1 1985, 2615.
7.48 (m, 4H), 7.54 (d, J¼8.1 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d:
7.65, 8.02, 27.76, 28.08, 34.16, 55.21, 56.76, 69.62, 76.92, 113.85,
114.75, 126.78, 128.37, 128.96, 129.18, 130.02, 130.93, 131.24, 134.60,