Highly enantioselective addition of methyl propiolate to aldehydes catalyzed by a titanium(IV) complex of a β-hydroxy amide

Article abstract of DOI:10.1016/j.tetasy.2009.11.022

Three chiral β-hydroxy amide ligands were prepared by the reaction of benzyl chloride with amino alcohols derived from l-tyrosine. The titanium(IV) complex of chiral ligand 4a was found to be an effective catalyst for the asymmetric addition of methyl propiolate to aliphatic and aromatic aldehydes. The γ-hydroxy-α,β-acetylenic esters were obtained in excellent enantiomeric excesses (up to 94% ee) under optimized conditions. Crown Copyright

Full text of DOI:10.1016/j.tetasy.2009.11.022

Tetrahedron: Asymmetry 20 (2009) 2733–2736
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective addition of methyl propiolate to aldehydes catalyzed
by a titanium(IV) complex of a b-hydroxy amide
*
Tao Xu, Chao Liang, Yan Cai, Jian Li, Ya-Min Li, Xin-Ping Hui
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 chiral b-hydroxy amide ligands were prepared by the reaction of benzyl chloride with amino alco-
Received 12 October 2009
Accepted 24 November 2009
Available online 6 January 2010
hols derived from
catalyst for the asymmetric addition of methyl propiolate to aliphatic and aromatic aldehydes. The
-hydroxy- ,b-acetylenic esters were obtained in excellent enantiomeric excesses (up to 94% ee) under
optimized conditions.
L-tyrosine. The titanium(IV) complex of chiral ligand 4a was found to be an effective
c
a
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
1. Introduction
proved to be an excellent enantioselective catalyst system for the
asymmetric addition of methyl propiolate to aromatic aldehydes
under mild conditions.10 Recently, good enantioselectivities have
been observed for the alkyl propiolate addition to aliphatic alde-
hydes when a novel H8-BINOL-based chiral ligand was used as an
effective catalyst in the presence of diethylzinc and titanium tetra-
isopropoxide, alleviating the need for any Lewis base additive.11
Among the catalytic methods developed, fewer excellent chiral li-
gands have been disclosed in the efficient catalytic asymmetric
addition of methyl propiolate to both aliphatic and aromatic
aldehydes.
Due to the potential coordination and H-bond donor ability of b-
hydroxy amides, some of them have been applied to asymmetric
catalysis. In our group, we have already developed chiral b-hydroxy
amide ligands, and successfully introduced them into the asym-
metric addition of phenylacetylene to aliphatic, vinyl, and aromatic
aldehydes to obtain high enantioselectivities.12 As part of the devel-
opment of b-hydroxy amide chiral ligands, we synthesized chiral
b-hydroxy amides 4a–c from (S)-tyrosine. Herein, we report the
addition of asymmetric methyl propiolate to aliphatic and aromatic
aldehydes catalyzed by the titanium(IV) complex of ligand 4a.
The catalytic enantioselective addition of terminal alkynes to
aldehydes is one of the most useful procedures for the formation
of carbon–carbon bonds because this process can produce synthet-
ically very useful chiral propargyl alcohols.1 Although many stud-
ies have been reported in this area, most of them focus on the
asymmetric addition of monoaryl or monoalkyl alkynes to alde-
hydes.2–6 The product resulting from the addition of propiolate to
an aldehyde is a c-hydroxy-a,b-acetylenic ester, an extremely ver-
satile synthetic intermediate. Functional group transformations
can elaborate the adduct into a variety of useful building blocks.
The direct asymmetric addition of an alkyl propiolate to aldehydes
has proven to be a challenge. This may be due to the greater sen-
sitivity and different reactivity of alkynoates in contrast with sim-
ple alkyl and aryl alkynes. The asymmetric reaction of alkynoates
to aldehydes was first reported by Pu et al.7a Pu discovered that
in the presence of diethylzinc, hexamethylphosphoramide (HMPA),
and titanium tetraisopropoxide, (S)-1,10-bi-2-naphthol (BINOL) can
efficiently catalyze the enantioselective reaction of methyl propio-
late with aromatic aldehydes with high enantioselectivity at room
temperature.7 However, HMPA is a strong carcinogen. Since then,
the studies of other catalytic systems were quickly reported. Trost
2. Results and discussion
demonstrated a practical and general alkynylation of
a,b-unsatu-
rated aldehydes using a proline-derived dinuclear zinc catalytic
system in high ee values and yields.8 Wang reported with the
use of a b-sulfonamide alcohol as a ligand, the asymmetric addition
of methyl propiolate to aromatic aldehydes, which proceeded
smoothly in combination with diethylzinc, 1,2-dimethoxyethane
and titanium tetraisopropoxide.9 Without titanium tetraisoprop-
oxide, the cyclopropane-based amino alcohol–zinc complex
Chiral ligands 4a–c were conveniently synthesized using inex-
pensive (S)-tyrosine as the starting material (Scheme 1). We initi-
ated the reaction of methyl propiolate with isovaleraldehyde in the
presence of 0.25 equiv chiral ligand 4a, diethylzinc, and titanium
tetraisopropoxide in toluene, the expected propargylic alcohol
was obtained in 75% ee (Table 1, entry 1). Some reports have
shown that the Lewis bases can enhance the reaction of alkynoates
with aldehydes4c,9,13 and that the Lewis base played an important
role in this reaction. In comparison with the Lewis bases HMPA and
1,2-dimethoxyethane (DME), tertiary amine N-methylimidozole
* Corresponding author. Fax: +86 931 8915557.
E-mail address: huixp@lzu.edu.cn (X.-P. Hui).
0957-4166/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.022

2734
T. Xu et al. / Tetrahedron: Asymmetry 20 (2009) 2733–2736
Et
HO
HO
HO
SOCl2
MeOH
EtMgBr
THF
Et
COOMe
COOH
R
H2N
OH
HCl H2N
H2N
1
2
R
ArCOCl
Et3N, CH2Cl2
4-RC6H4CH2Cl
NaH, DMF
Et
O
Et
O
Et
Et
HN
Ar
OH
O
H2N
OH
3a-b
R = H, Ar = C6H5 4a
R = MeO, Ar = C6H5 4b
R = H, Ar = 2-CH3OC6H4 4c
Scheme 1. Synthesis of chiral ligands 4a–c.
Table 1
Optimization of reaction conditionsa
OH
ligand 4, additive
COOMe
CHO
+
Ti(OiPr)4, ZnEt2
COOMe
Entry
Ligand
L (mol %)
Solvent
Additive (equiv)
L/Ti(OiPr)4
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15d
16
4a
4a
4a
4a
4a
4a
4b
4c
4a
4a
4a
4a
4a
4a
4a
4a
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
30
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
—
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/2
1/3
1/1
1/1
88
90
65
69
71
88
82
84
76
73
84
Trace
82
80
73
88
75
77
68
71
74
85
81
75
79
84
76
—
HMPA (1)
NMI (0.05)
TEA (0.05)
TMEDA (0.05)
DME (1)
DME (1)
DME (1)
DME (0.75)
DME (1.5)
DME (1)
DME (1)
DME (1)
DME (1)
DME (1)
DME (1)
THF
Toluene
Toluene
Toluene
Toluene
81
80
79
88
a
b
c
Methyl propiolate/ZnEt2/isovaleraldehyde = 3:3:1 (molar ratio); reaction time: 12 h; reaction temperature: rt.
Isolated yield.
Determined by HPLC analysis of its acetate ester.
Reaction temperature: 0 °C.
d
(NMI), triethylamine (TEA) and N,N,N,N-tetramethylethane-1,2-
diamine (TMEDA) are stronger bases. To improve the enantioselec-
tivity, HMPA (1 equiv),4c NMI (0.05 equiv),13 TEA (0.05 equiv),
TMEDA (0.05 equiv), and DME (1 equiv)9 were used as additives;
DME was found to be the best choice (Table 1, entries 2–6). Methyl
4-hydroxy-6-methylhept-2-ynoate was afforded in 88% yield and
85% ee (Table 1, entry 6). Using ligands 4b and 4c, which have a
methoxy group, resulted in a lower enantioselectivity than ligand
4a (Table 1, entries 7 and 8). Hence, ligand 4a was chosen to be
the optimal chiral ligand to facilitate this alkynoate addition
reaction.
Further optimization studies were carried out using ligand 4a in
combination with diethylzinc, DME, and titanium tetraisopropox-
ide. The enantioselectivities of the reaction were strongly affected
by the reaction conditions. Changing the amount of DME from
1 equiv to 0.75 equiv afforded a lower enantioselectivity (Table 1,
entry 9). Subsequently, when 1.5 equiv of DME were used, the
reaction retained a good ee of 84% (Table 1, entry 10). Other sol-
vents such as CH2Cl2 and THF were also examined (Table 1, entries
11 and 12). We were unable to detect the excepted product when
THF was used as a solvent. Hence toluene was found to be a
suitable solvent. Increasing the amount of Ti(OiPr)4 resulted in a
decrease in enantioselectivity (Table 1, entries 13 and 14). To
further improve the enantioselectivity, the temperature effect
was also observed. The result showed that only 79% ee was ob-
tained under 0 °C (Table 1, entry 15). Subsequently, by increasing
the catalyst loading to 30 mol %, the ee value of methyl 4-hydro-
xy-6-methylhept-2-ynoate was improved to 88%, while the yield
remained high at 88% (Table 1, entry 16). Thus, entry 16 in Table 1
was identified as the optimized reaction procedure.
The generality of this catalytic system for methyl propiolate
asymmetric addition to aliphatic, trans-cinnamaldehyde, and aro-
matic aldehydes was examined using the titanium(IV) complex
of ligand 4a under the optimized reaction conditions. As shown
in Table 2, for aliphatic aldehydes, and enantiomerically active
c-hydroxy-a,b-acetylenic esters could be obtained in 78–91% ee
in the presence of chiral ligand 4a. The less sterically hindered ali-
phatic aldehydes resulted in good enantioselectivities ranging from
86% to 88% ee (Table 2, entries 1–5). It is noteworthy that for 2-
phenylacetaldehyde, an excellent enantioselectivity of 91% ee
was obtained (Table 2, entry 6). The aldehydes with bulky groups
gave lower enantioselectivities (Table 2, entries 7 and 8). We also
examined
a,b-unsaturated aldehydes as electrophiles to produce
chiral propargylic allylic alcohols, recently shown to be an efficient
substrate in a metal-catalyzed cyclization reactions. The ee value
was 85% for trans-cinnamaldehyde. As the results summarized in

T. Xu et al. / Tetrahedron: Asymmetry 20 (2009) 2733–2736
2735
Table 2
excesses (up to 94% ee). Currently, we are further expanding the
applicability of this b-hydroxy amide to other kinds of asymmetric
catalytic reaction.
Asymmetric addition of methyl propiolate to aliphatic aldehydes promoted by ligand
4aa
OH
ligand 4a, Ti(OiPr)4
R
4. Experimental
4.1. General
+
RCHO
COOMe
ZnEt2, DME
COOMe
5a-h
Product Yieldb (%) eec (%) (Config.)d
½ ꢁ
a 2D0
Entry Aldehyde
All reactions were carried out under a nitrogen atmosphere. All
solvents used were dried and the aldehydes were purified by stan-
dard methods. Ti(OiPr)4 was freshly distilled prior to use. Melting
points were taken on an XT-4 melting point apparatus and are
uncorrected. 1H NMR and 13C NMR spectra were recorded on Var-
ian Bruker-400 MHz spectrometers with TMS as an internal stan-
dard. IR spectra were obtained on NEXUS 670 FT-IR spectrometer
in KBr disc. HRMS data were measured with ESI techniques (Bruker
Apex II). Optical rotations were measured on a Perkin–Elmer 341
polarimeter. Enantiomeric excess values were determined by HPLC
with Chiralcel column on Waters 600 Delta.
1
2
3
4
5
6
7
8
9
CH3CH2CHO
5a
5b
5c
5d
5e
5f
5g
5h
5i
89
87
90
88
76
70
86
82
68
87
87
86
88
86
91
78
81 (R)
85
+8
+3
+7
+3
+3
+4
+4
+2
+3
CH3CH2CH2CHO
(CH3)2CHCHO
(CH3)2CHCH2CHO
CH3(CH2)5CHO
PhCH2CHO
(CH3)3CCHO
c-C6H11CHO
(E)-PhCH@CHCHO
Methyl propiolate/ZnEt2/aldehyde/Ti(OiPr)4/4a = 3:3:1:0.3:0.3 (molar ratio);
reaction time: 12 h; reaction temperature: rt.
a
b
Isolated yield.
c
Amino alcohols 3a–b,12c chiral ligands 4a–b,12c and diethyl-
zinc14 (0.9 M solution in toluene) were prepared according to the
literature methods.
Ee values of 5a–g were determined by HPLC analysis of acetate esters using
Chiralcel column.
d
Absolute configuration of the products was based on measurement of the HPLC
and comparison with the literature values (Ref. 6).
4.2. Synthesis of chiral ligand b-hydroxy amide 4c
Table 3, excellent enantioselectivities (90–93% ee) were achieved
for the reaction of methyl propiolate with aromatic aldehydes con-
taining electron-donating or electron-withdrawing substituents at
the para-position. The best enantioselectivity of 94% ee was
obtained for the 2-naphthaldehyde. On the other hand, the large
sterically hindered ortho-chlorobenzaldehyde resulted in lower
enantioselectivity (Table 3, entry 3). The results showed that this
catalytic system has a broad generality for aliphatic and aromatic
aldehydes.
A solution of 2-methoxybenzoyl chloride (5.5 mmol) in CH2Cl2
(20 mL) was added to a cold (0 °C) solution of amino alcohol 3
(5.00 mmol) and NEt3 (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 M
HCl (3 ꢀ 10 mL), saturated aqueous NaHCO3 (3 ꢀ 10 mL), and brine
(3 ꢀ 10 mL). The organic layer was dried over anhydrous MgSO4
and concentrated in vacuo. The yellow residue was purified by col-
umn chromatography to afford b-hydroxy amide 4c.
Table 3
Asymmetric addition of methyl propiolate to aromatic aldehydes promoted by ligand
4.2.1. N-((S)-1-(4-(Benzyloxy)phenyl)-3-ethyl-3-hydroxypentan-
4aa
2-yl)-2-methoxybenzamide 4c
OH
White needle solid, yield 42%; mp 116–117 °C; ½a D20
¼ ꢂ115 (c
ꢁ
1.00, acetone). 1H NMR (400 MHz, CDCl3) d: 0.93–1.00 (m, 6H),
1.57–1.68 (m, 3H), 1.73–1.79 (m, 1H), 2.82 (dd, J = 14.4, 10.8 Hz,
1H), 3.06 (dd, J = 14.4, 3.2 Hz, 1H), 3.17 (br, 1H), 3.81 (s, 3H),
4.23–4.29 (m, 1H), 5.00 (s, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.92 (d,
J = 8.4 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H),
7.31–7.45 (m, 6H), 7.94 (d, J = 8.4 Hz, 1H), 8.08 (dd, J = 7.6, 1.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) d: 7.72, 8.00, 27.94, 28.47, 34.36,
55.90, 57.69, 69.99, 76.87, 111.40, 114.80, 121.29, 121.59, 127.43,
127.86, 128.52, 130.04, 131.56, 132.29, 132.68, 137.15, 157.26,
ligand 4a, Ti(OiPr)4
Ar
+
ArCHO
COOMe
COOMe
ZnEt2, DME
5j-r
Entry
Aldehyde
Product
Yieldb (%)
eec (%) (Config.)d
½ ꢁ
a 2D0
1
2
3
4
5
6
7
8
9
C6H5CHO
5j
5k
5l
5m
5n
5o
5p
5q
5r
88
82
85
77
83
79
81
72
78
93 (R)
90
87
90
91
90
94
92
92
+4
+8
4-FC6H4CHO
2-ClC6H4CHO
4-ClC6H4CHO
4-BrC6H4CHO
1-C10H7CHO
2-C10H7CHO
4-CH3C6H4CHO
4-CH3OC6H4CHO
ꢂ27
+4
+7
ꢂ22
ꢂ4
+4
157.41, 166.13. IR (KBr)
mmax: 3359, 2974, 2937, 1632, 1548,
1512, 1299, 1241, 1178 cmꢂ1; HRMS (ESI) calcd for C28H33NO4
(M+H): 448.2482; Found: 448.2472.
+6
a
Methyl propiolate/ZnEt2/aldehyde/Ti(OiPr)4/4a = 3:3:1:0.3:0.3 (molar ratio);
4.3. General procedure for the asymmetric addition of methyl
propiolate to aldehydes
reaction time: 12 h; reaction temperature: rt.
b
Isolated yield.
Determined by HPLC analysis using a Chiralcel column.
Absolute configuration of the products was based on measurement of the HPLC
c
d
Under a nitrogen atmosphere, to a solution of 4a (0.09 mmol),
and comparison with the literature value (Ref. 4a).
DME (0.3 mmol, 32.5
ene, 0.9 mmol) in 5 mL anhydrous toluene, methyl propiolate
(0.9 mmol, 80.1 L) was added in one portion. After the solution
was stirred at room temperature for 6 h, Ti(OiPr)4 (0.09 mmol,
26.6 L) was added and stirred for half an hour. Then, the aldehyde
lL), and diethylzinc (1 mL, 0.9 mol/L in tolu-
l
3. Conclusions
l
In conclusion, the chiral b-hydroxy amide ligands were synthe-
sized and used in the reaction of catalytic asymmetric addition of
methyl propiolate to aliphatic and aromatic aldehydes under mild
conditions. The titanium(IV) complex of chiral ligand 4a was pro-
(0.3 mmol) was added in one portion and the reaction was allowed
to proceed at room temperature for 12 h. The mixture was treated
with saturated ammonia chloride and extracted with diethyl ether.
The combined organic layer was dried over anhydrous sodium sul-
fate and concentrated in vacuo. The crude product was purified by
ven to be an effective catalyst for this reaction and the
c-hydro-
xy- ,b-acetylenic esters were obtained in high enantiomeric
a

2736
T. Xu et al. / Tetrahedron: Asymmetry 20 (2009) 2733–2736
flash column chromatography (silica gel, 12.5–15% EtOAc in petro-
leum ether) to give the -hydroxy- ,b-acetylenic esters 5a–r.
4.4.7. Methyl 4-acetoxy-5,5-dimethylhex-2-ynoate 6g
Yield 86%, 78% ee determined by HPLC analysis of its acetate es-
ter (AS-H column, hexane/i-PrOH = 99/1, l mL/min); retention
time: tmajor= 5.822 min, tminor= 5.002 min.
c
a
4.4. General procedure for the acetylation of
acetylenic ester 5a–g
c-hydroxy-a,b-
Acknowledgment
To a solution of c-hydroxy-a,b-acetylenic esters 5a–g in 2 mL
dichloromethane, triethylamine (1.1 equiv), and acetyl chloride
(1.1 equiv) were added and stirred for half an hour at room tem-
perature. The mixture was quenched with water and extracted
with ethyl acetate. The combined organic layer was dried over
anhydrous sodium sulfate and concentrated in vacuo. The crude
products were purified by flash column chromatography (silica
gel, 6% EtOAc in petroleum ether) to give the products 6a–g for
HPLC analysis.
This work was supported by National Natural Science Founda-
tion of China (NSFC 20702022, 20621091 and J0730425).
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C.; Huang, L.-N.; Xu, P.-F.; Fan, G.-F. Tetrahedron 2008, 64, 2553–2558; (c) Li,
Y.-M.; Tang, Y.-Q.; Hui, X.-P.; Huang, L.-N.; Xu, P.-F. Tetrahedron 2009, 65,
3611–3614.
4.4.6. Methyl 4-acetoxy-5-phenylpent-2-ynoate 6f
Yield 70%, 91% ee determined by HPLC analysis of its acetate es-
ter (OD-H column, hexane/i-PrOH = 99/1, l mL/min); retention
time: tmajor = 12.217 min, tminor= 16.422 min.
13. Yang, F.; Xi, P.; Yang, L.; Lan, J.; Xie, R.; You, J. J. Org. Chem. 2007, 72,
5457–5460.
14. Noller, C. R. Org. Synth. 1943, Collect. Vol. 2, 184–187.