Asymmetric synthesis of propargylic alcohols catalyzed by (-)-MITH

Article abstract of DOI:10.1016/j.tetasy.2009.07.032

This investigation describes that in the presence of 2.5 mol % of (-)-2-exo-morpholinoisobornane-10-thiol (MITH) 1, catalytic asymmetric alkynylation of aldehydes gives enantioenriched propargylic alcohols with good enantioselectivities.

Full text of DOI:10.1016/j.tetasy.2009.07.032

Tetrahedron: Asymmetry 20 (2009) 1837–1841
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Tetrahedron: Asymmetry
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Asymmetric synthesis of propargylic alcohols catalyzed by (ꢀ)-MITH
*
Ping-Yu Wu, Hsyueh-Liang Wu, Ying-Ying Shen, Biing-Jiun Uang
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
This investigation describes that in the presence of 2.5 mol % of (ꢀ)-2-exo-morpholinoisobornane-10-
thiol (MITH) 1, catalytic asymmetric alkynylation of aldehydes gives enantioenriched propargylic alco-
hols with good enantioselectivities.
Received 23 May 2009
Accepted 22 July 2009
Available online 2 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
O
1. Introduction
OH
R''
1 (10 mol % )
+
R'ZnR''
R
H
R
O
Chiral propargylic alcohols are versatile building blocks for the
synthesis of optically active pharmaceutical ingredients and natu-
ral products.1 Among the several efficient procedures that have
been developed, such as Ti-mediated reactions,2,3 there is a partic-
ular emphasis on the asymmetric nucleophilic addition of Zn-alky-
nylides to carbonyl compounds to prepare enantioenriched
propargylic alcohols,4–8 which offer the advantages of the low-tox-
icity of zinc metal and the wide functional group tolerance of
organozinc reagents.9 In literature reports7,8 describing the asym-
metric addition of Zn-alkynylides to aldehydes, preparing the cor-
responding propargylic alcohols in high ee usually requires high
ligand loadings. Thus, it is desirable to develop an effective chiral
mediator that promotes the enantioselective alkynylation of alde-
hydes at lower ligand loading.
As part of our endeavors to develop camphor-derived chiral li-
gands in catalytic asymmetric reactions,10,11 (ꢀ)-2-exo-morpholi-
noisobornane-10-thiol (MITH) 1 has been demonstrated to be an
effective promoter for the asymmetric addition of diethylzinc, aryl-
zinc,11a and alkenylzinc11b species to aldehydes, affording the cor-
responding optically active alcohols with enantioselectivities
ranging from 95% to >99% ee. Recently, ligand 1 was employed as
a chiral promoter in the asymmetric addition of dimethylzinc to
N
R'' = ethyl, alkenyl, aryl
95 to >99% ee
SH
1
1 (20 mol %), Me2Zn
O
Me
OH
CO2Me
up to 89% ee
B(OEt)3 (25 mol %)
Ar
CO2Me
toluene−hexane, −50 o
C
Ar
Scheme 1. Asymmetric addition of organozincs to carbonyls catalyzed by ligand 1.
presence of ligand 1 (10 mol %), deprotonation of compound 2 at
70 °C in toluene, followed by the addition of benzaldehyde at
ꢀ30 °C, gave alkynylation product 3 (Table 1, entry 1) predomi-
nantly,7d albeit, with a modest yield and low ee. Deprotonation
at ambient temperature in either toluene or hexane led to unsatis-
factory yields, and the methylated adduct was obtained as the ma-
jor product (entries 2 and 3).7b,c Subsequently, using a mixed
toluene–THF solvent system showed a better yield with higher
ee, in which no methylation product was observed (entry 4).6a,c
The equivalents of zinc acetylide were subsequently optimized
to achieve a better enantioselectivity with the toluene–THF mixed
solvent system (Table 2). The reaction gave better ee when more
than 4 equiv of organozincs were used (entries 1 and 2 vs entries
3–7). Although it was reported that a 1:1 mixture of alkynyl and
dialkylzinc gave the propargylic alcohols in higher ee,6a adducts
with comparable ee’s were observed in our cases under different
ratios of dimethylzinc to phenylacetylene (entries 3, 5, and 6).
Alkylation product 4b was obtained when dimethylzinc was
substituted with diethylzinc (entry 7). Accordingly, 4 equiv of
methylalkynylzinc for economical concern were applied for further
optimization of solvents (entry 3).
a-ketoesters, providing the corresponding hydroxyl esters bearing
quaternary stereogenic centers with good yields and ee (Scheme
1).11c On the basis of these results, enantioselective addition of
alkynylzinc reagents was investigated in order to expand the reac-
tion scope. Herein, we report our recent developments in the cata-
lytic asymmetric alkynylation of aldehydes.
2. Results and discussion
Initially, the preparation of zinc acetylide from phenylacetylene
2 and dimethylzinc was examined for our catalytic system. In the
Over re-examination of the solvent effect was first focused on
the role of tetrahydrofuran. After the zinc acetylide was prepared
in toluene–THF (1.5:1), the solvents were removed and the
* Corresponding author. Tel.: +886 3 5721224; fax: +886 3 5711082.
E-mail address: bjuang@mx.nthu.edu.tw (B.-J. Uang).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.032

1838
P.-Y. Wu et al. / Tetrahedron: Asymmetry 20 (2009) 1837–1841
Table 1
The preparation of zinc phenylacetylide
OH
OH
Me
(1) Me2Zn, 1 (10 mol %)
0.25 M, (condition 1)
+
Ph
Ph
H
Ph
(2) PhCHO, (condition 2)
Ph
2
3
4a
Entry
Me2Zn (equiv)
2 (equiv)
Condition 1
Condition 2
3
4a
Solvent
Temp (°C)
Time (h)
Temp (°C)
Time (h)
Yielda (%)
eeb (%)
yieldc (%)
1d
2
3
6
3
3
3
7
3
3
3
Toluene
Hexane
Toluene
70
rt
rt
2.5
0.5
0.5
2
ꢀ30
0
0
24
13
13
28
66
37
39
80
39
68
62
81
<5
43
40
4
TOL–THFe
rt
0
NDf
a
b
c
d
e
f
Isolated yield after column chromatography.
Determination by chiral HPLC.
Yield determined by crude 1H NMR.
The reaction was conducted in 0.125 M.
TOL–THF = toluene/THF = 1.5:1 (v/v).
Not detected by 1H NMR.
Table 2
Table 3
Optimization of the reagent equivalents
Optimization of the solvent system
OH
(1) 1 (10 mol %)
OH
OH
Ph
(1) R2Zn (y equiv), 1 (10 mol %)
OH
Me2Zn (4.0 equiv), rt, 2 h
+
toluene-THF (1.5:1), rt, 2 h
(2) PhCHO, 0 oC, time
Ph
H
+
Ph
Ph
Me
Ph
H
Ph
R
(2) PhCHO, 0 oC, time
Ph
2 (4.0 equiv)
Ph
3
4a
2
(x equiv)
4a: R = Me
4b: R = Et
3
Entry
Solventsa
Time (h)
3
4a
Yieldb (%)
eec (%)
Yieldd (%)
Entry
R
x
y
Time (h)
3
4
Yielda (%)
eeb (%)
yieldc (%)
1
2e
3
4
5
6
7
8
Toluene
21
38
24
28
28
96
24
22
82
90
61
93
83
74
94
94
8
79
64
74
49
76
83
77
ND
ND
17
ND
12
ND
ND
5
HEX–THF (1.5:1)
TOL–DCM (1.5:1)
TOL–DOX (1.5:1)
TOL–DEE (1.5:1)
TOL–THF (1:2)
TOL–THF (3:1)
TOL–THF (9:1)
1
2
3
4
5
6
7
Me
Me
Me
Me
Me
Me
Et
1.5
2
4
8
4
1.5
2
4
8
8
36
36
28
36
21
48
22
93
98
85
94
91
85
80
70
69
82
81
80
81
79
ND
ND
ND
ND
ND
ND
19
4
4
2
4
a
Solvent abbreviations: TOL-toluene; THF-tetrahydrofuran; HEX-hexane; DCM-
dichloromethane; DOX-dioxane; and DEE-diethyl ether.
a
b
c
Isolated yield after column chromatography.
Determined by chiral HPLC.
b
Isolated yield after column chromatography.
Yield determined by crude 1H NMR. ND: not detected by 1H NMR.
c
Determined by chiral HPLC.
Yield determined by crude 1H NMR; ND: not detected by 1H NMR.
d
e
Me2Zn (0.7 M in hexane) was used; the reaction was conducted in 0.10 M with
respect to PhCHO.
addition reaction was performed in toluene since the ether solvent
was considered to promote the background reaction.11b However,
we found that the absence of tetrahydrofuran in the system deliv-
ered quite low ee (Table 3, entry 1 vs Table 2, entry 3). Changing
the reaction medium from toluene–THF to hexane-THF was not
beneficial to the ee and yield (entry 2). Using other solvents in
place of THF with toluene gave no better results (entries 3–5).
Thus, co-solvent mixtures of toluene and THF with different ratios
were tested; a ratio of 3:1 was found to be a better solvent system
for the asymmetric addition of phenylethynyl zinc to benzalde-
hyde, and (S)-1,3-diphenylprop-2-yn-1-ol 3 was isolated in 94%
yield and 83% ee (entry 7).
tives such as isopropanol (entries 1–6) and alkyl borates (entries
7–10) were investigated to improve the asymmetric induction, be-
cause they have been reported to accelerate similar catalytic
organozinc reactions.11c,12 However, the addition of isopropanol
as well as a variety of borates in catalytic to stoichiometric
amounts showed no improvement in the ee of the adduct. Further-
more, the ratio of the mixed solvent system was examined again at
ꢀ20 °C (entries 11–14), and it was found that a slightly lower per-
centage of THF in the co-solvent system could enhance the yield
without a loss of ee (entry 12).
Conducting the reactions at low temperature enhanced the
enantioselectivities (Table 4, entries 1-5) with the best result of
87% ee along with 75% yield (entry 4). A better enantioselectivity
(90% ee) was obtained at ꢀ30 °C (entry 5), but the yield was low
and a longer reaction time was necessary. However, as the ligand
loading decreased to 2.5 mol %, a slightly deteriorated enantio-
induction was observed. In general, 87–84% ee’s were observed
through 10–2.5 mol % of ligand 1 at ꢀ20 °C (entries 4 and 6ꢀ8).
After obtaining good enantioselectivity in the alkynylation of
benzaldehyde with only 2.5 mol % of ligand 1, our attention was
then turned to the effects of additives (Table 5). Accordingly, addi-
The scope of this catalytic system was investigated to include a
variety of aldehydes (Table 6). In the cases of substituted benzalde-
hydes bearing diverse functional groups on the para-, meta-, and
ortho-positions, asymmetric alkynylation gave the corresponding
propargylic alcohols with 80–87% ee (entries 1–8). Addition to cin-
namaldehyde provided a lower ee (61% ee) of the adduct (entry 9),
while in the case of the a-substituted analogues, higher ee (71% ee)
was observed (entry 10). Zinc alkynylides bearing substituents
were also utilized, and the corresponding propargylic alcohols
were obtained in 66–84% ee, although with unsatisfactory yields
(15–55%) (entries 12–15).

P.-Y. Wu et al. / Tetrahedron: Asymmetry 20 (2009) 1837–1841
1839
Table 4
Table 6
Optimization of temperatures and ligand loadings
Asymmetric alkynylation of various aldehydes catalyzed by 2.5 mol % of ligand 1
OH
OH
(1) 1, Me2Zn (4 equiv)
1 (2.5 mol %), Me2Zn (4.0 equiv)
toluene−THF (5:1), −20 oC
Ph
H
toluene-THF (3:1), rt, 2 h
(2) PhCHO
1
2
+
R1
R CHO
R
H
Ph
2
(4.0 equiv)
R2
(4.0 equiv)
Ph
3
5a−o
Entry
1 (mol %)
Temp (°C)
Time (h)
Yielda (%)
eeb (%)
Entry R1
R2
Time (h) Yielda (%) eeb (%)
1
2
3
4
5
6
7
8
10
10
10
10
10
5
rt
10
10
ꢀ20
ꢀ30
ꢀ20
ꢀ20
ꢀ20
6
16
24
24
72
42
48
72
91
99
91
75
61
73
61
73
76
79
84
87
90
86
84
51
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4-Tol
3-Tol
2-Tol
4-Cl–Ph
3-Cl–Ph
2-Cl–Ph
4-MeO–Ph
4-CF3–Ph
Cinnamyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
72
72
72
48
48
48
72
48
48
48
48
48
48
48
48
70
88
79
80
82
79
27c
84
41
21d
69
46
55
15
15
86
85
86
86
86
83
80
87
61
71
49
84
76
66
75
2.5
1
a
Isolated yield after column chromatography; methylation product was
a-Me-cinnamyl Ph
5j
5k
5l
observed in <5% yield by crude 1H NMR in all cases.
PhCH2CH2
Ph
4-CF3–Ph
4-MeO–Ph 5m
4-Cl–Ph
b
Determined by chiral HPLC.
Ph
Ph
Ph
Ph
5n
5o
n-Bu
Table 5
a
Isolated yield after column chromatography, and methylation product was
Optimization based on 2.5 mol % of ligand 1
observed in <5% yield in crude 1H NMR in all cases.
b
Determination by chiral HPLC.
The aldehyde was recovered in 68%.
The aldehyde was recovered in 59%.
OH
(1) 1 (2.5 mol %), Me2Zn (4 equiv)
c
toluene−THF, rt, 2 h
Ph
H
d
Ph
(2) PhCHO, −20 oC, 48 h
2 (4.0 equiv)
Ph
eec (%)
3
(667
lL), dimethylzinc (3.3 mL, 4 mmol, 1.2 M in toluene), and
Entry
Toluene–THF
Additivesa
Yieldb (%)
phenylacetylene (439
l
L, 4 mmol) were added sequentially in the
1
2
3
4
5
6
7
8
9
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
4:1
5:1
7:1
9:1
2.5 mol % i-PrOH
5 mol % i-PrOH
10 mol % i-PrOH
25 mol % i-PrOH
50 mol % i-PrOH
100 mol % i-PrOH
10 mol % B(OEt)3
10 mol % B(Oi-Pr)3
10 mol % B(Ot-Bu)3
10 mol % B(Ot-Bu)3
—
61
58
63
62
66
55
67
52
55
70
59
68
61
55
65
62
76
74
72
67
82
87
87
79
87
86
85
83
flask. The mixture was stirred at ambient temperature for two
hours before the system was cooled to ꢀ20 °C. The mixture was
stirred at ꢀ20 °C for 10 min, followed by the addition of the alde-
hyde (1 mmol). The reaction mixture was worked up after 48 h
by the addition of saturated aq NH4Cl. The mixture was diluted
with 1 M aq HCl (20 mL), and was extracted with dichloromethane
(20 mL ꢁ 3). The organic extracts were combined, dried over anhy-
drous Na2SO4, and concentrated to afford the crude product, which
was purified by column chromatography to give the corresponding
propargylic alcohol. The ee value was determined by HPLC on a
chiral stationary phase.
10d
11
12
13
14
—
—
—
a
Additives were added to the reaction mixture after step 1.
Isolated yield after column chromatography; methylation product was
b
4.1.1. (1S)-1,3-Diphenyl-prop-2-yn-1-ol 3
A colorless oil. ½a D27
ꢂ
¼ ꢀ2:4 (c 1.2, CHCl3); 1H NMR (400 MHz,
observed in <5% yield under crude 1H NMR in all cases.
c
Determined by chiral HPLC.
8 equiv of alkyne were used.
CDCl3): d 7.62ꢀ7.60 (m, 2H), 7.48ꢀ7.45 (m, 2H), 7.42ꢀ7.29 (m,
2H), 5.68 (d, J = 6.0 Hz, 1H), 2.32 (d, J = 6.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 140.6 (C), 131.6 (CH x2), 128.5 (CH ꢁ2),
128.4 (CH), 128.2 (CH), 128.2 (CH ꢁ2), 126.6 (CH ꢁ2), 122.3 (C),
88.8 (C), 86.5 (C), 64.9 (CH); IR (neat) 3365, 3062, 3032, 2872,
2229, 1955, 1885, 1809, 1749, 1598, 1490, 1455, 1031, 757,
692 cmꢀ1; HRMS calcd for C15H12O 208.0888, found 208.0882.
Chiral HPLC analysis: Chiralcel OD-H, 2-propanol/hexane (10:90),
1.0 mL/min, UV 254 nm; tR = 10.7 min (7.0%), 19.6 min (93.0%),
86% ee.
d
3. Conclusion
In conclusion, the asymmetric addition of zinc alkynylides to
aldehydes to give optically active propargylic alcohols catalyzed
by ligand 1 has been developed, affording the products in 49–
87% ee. Notably, this catalytic system required only 2.5 mol % of
the chiral ligand to afford propargylic alcohols derived from substi-
tuted benzaldehydes with >80% ee without additional additives. To
the best of our knowledge, ligand 1 is the first chiral mediator bear-
ing a b-amino thiol reported to catalyze the alkynylzinc addition
reaction with aldehydes.
4.1.2. (1S)-3-Phenyl-1-p-tolyl-prop-2-yn-1-ol 5a
A white solid (mp 58ꢀ62 °C). ½a D27
ꢂ
¼ ꢀ5:2 (c 1.2, CHCl3); 1H
NMR (400 MHz, CDCl3): d 7.50ꢀ7.43 (m, 4H), 7.32ꢀ7.27 (m, 3H),
7.20 (d, J = 8.0 Hz, 2H), 5.64 (d, J = 6.0 Hz, 1H), 2.36 (s, 3H), 2.21
(d, J = 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 137.9 (C), 137.7
(C), 131.6 (CH ꢁ2), 129.1 (CH ꢁ2), 128.3 (CH), 128.1 (CH ꢁ2),
126.6 (CH ꢁ2), 122.4 (C), 89.0 (C), 86.3 (C), 64.6 (CH), 21.0 (CH3);
IR (neat) 3369, 3053, 3024, 2921, 2864, 2228, 1949, 1904, 1803,
1597, 1489, 1178, 1031, 962, 757, 691 cmꢀ1; HRMS calcd for
C16H14O 222.1045, found 222.1049. Chiral HPLC analysis: Chiralcel
OD-H, 2-propanol/hexane (10:90), 1.0 mL/min, UV 254 nm;
tR = 8.5 min (7.0%), 17.4 min (93.0%), 86% ee.
4. Experimental
4.1. General experimental procedure for the catalytic,
asymmetric alkynylation with aldehydes
A
flame-dried 10-mL flask containing (ꢀ)-MITH (6.4 mg,
0.025 mmol, 2.5 mol %) was filled with argon. Tetrahydrofuran

1840
P.-Y. Wu et al. / Tetrahedron: Asymmetry 20 (2009) 1837–1841
4.1.3. (1S)-3-Phenyl-1-m-tolyl-prop-2-yn-1-ol 5b
4.1.8. (1S)-1-(4-Methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol 5g
A colorless, viscous oil. ½a D27
ꢂ
¼ ꢀ5:8 (c 1.3, CHCl3); 1H NMR
A colorless, viscous oil. ½a D27
ꢂ
¼ ꢀ4:2 (c 1.7, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.48ꢀ7.44 (m, 2H), 7.41ꢀ7.39 (m, 3H),
7.33ꢀ7.24 (m, 4H), 7.16ꢀ7.14 (m, 2H), 5.64 (d, J = 6.2 Hz, 1H),
2.38 (s, 3H), 2.24 (d, J = 6.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
140.5 (C), 138.1 (C), 131.6 (CH ꢁ2), 128.9 (CH), 128.4 (CH), 128.3
(CH), 128.1 (CH ꢁ2), 127.3 (CH), 123.7 (CH), 122.4 (C), 89.0 (C),
86.2 (C), 64.7 (CH), 21.2 (CH3); IR (neat) 3368, 3054, 3023, 2920,
2865, 2230, 1951, 1883, 1801, 1607, 1598, 1490, 1032, 757,
691 cmꢀ1; HRMS calcd for C16H14O 222.1045, found 222.1049. Chi-
ral HPLC analysis: Chiralcel OD-H, 2-propanol/hexane (10:90),
1.0 mL/min, UV 254 nm; tR = 9.7 min (7.6%), 23.3 min (92.4%),
85% ee.
(400 MHz, CDCl3): d 7.55ꢀ7.51 (m, 2H), 7.47ꢀ7.44 (m, 2H),
7.31ꢀ7.28 (m, 3H), 6.93ꢀ6.89 (m, 2H), 5.63 (d, J = 6.0 Hz,
1H), 3.81 (s, 3H), 2.21 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3):
d 159.4 (C), 132.9 (C), 131.6 (CH x2), 128.3 (CH),
128.1 (CH ꢁ2), 128.0 (CH ꢁ2), 122.4 (C), 113.8 (CH ꢁ2),
89.1 (C), 86.2 (C), 64.3 (CH), 55.1 (CH3); IR (neat) 3412,
3001, 2956, 2934, 2836, 2228, 1610, 1511, 1251, 1173, 1033,
834, 757, 692 cmꢀ1; HRMS calcd for C16H14O2 238.0994, found
238.0998. Chiral HPLC analysis: Chiralcel OD-H, 2-propanol/
hexane (10:90), 1.0 mL/min, UV 254 nm; tR = 11.9 min (10.1%),
26.4 min (89.9%), 80% ee.
4.1.4. (1S)-3-Phenyl-1-o-tolyl-prop-2-yn-1-ol 5c
4.1.9. (1S)-3-Phenyl-1-(4-trifluoromethyl-phenyl)-prop-2-yn-1-
A colorless, viscous oil. ½a D27
ꢂ
¼ þ12:2 (c 1.2, CHCl3); 1H NMR
ol 5h
(400 MHz, CDCl3): d 7.74ꢀ7.70 (m, 1H), 7.47ꢀ7.42 (m, 2H),
7.32ꢀ7.26 (m, 3H), 7.26ꢀ7.18 (m, 3H), 5.83 (d, J = 5.6 Hz, 1H),
2.49 (s, 3H), 2.18 (d, J = 5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
138.3 (C), 135.8 (C), 131.6 (CH ꢁ2), 130.6 (CH), 128.3 (CH), 128.2
(CH), 128.1 (CH ꢁ2), 126.5 (CH), 126.1 (CH), 122.4 (C), 88.6 (C),
86.2 (C), 62.7 (CH), 18.9 (CH3); IR (neat) 3367, 3062, 3023, 2955,
2923, 2862, 2229, 1953, 1886, 1809, 1598, 1489, 1177, 1034,
961, 756, 691 cmꢀ1; HRMS calcd for C16H14O 222.1045, found
222.1053. Chiral HPLC analysis: Chiralcel OD-H, 2-propanol/hex-
ane (10:90), 1.0 mL/min, UV 254 nm; tR = 8.3 min (7.0%), 17.8 min
(93.0%), 86% ee.
A colorless, viscous oil. ½a D27
ꢂ
¼ ꢀ6:9 (c 1.4, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.74ꢀ7.72 (m, 1H), 7.66ꢀ7.64 (m, 1H),
7.47ꢀ7.44 (m, 2H), 7.34ꢀ7.29 (m, 3H), 5.74 (d, J = 5.8 Hz, 1H),
2.39 (d, J = 5.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 144.3 (C),
131.7 (CH ꢁ2), 130.3 (q, J = 32 Hz, C), 128.8 (CH), 128.3 (CH ꢁ2),
126.9 (CH ꢁ2), 125.4 (q, J = 3.7 Hz, CH ꢁ2), 124.0 (q, J = 270 Hz,
C), 121.9 (C), 88.0 (C), 87.1 (C), 64.2 (CH); IR (neat) 3346, 3063,
2881, 2230, 1916, 1804, 1620, 1490, 1326, 1167, 1127, 1018,
850, 757, 691 cmꢀ1; HRMS calcd for C16H11F3O 276.0762, found
276.0756. Chiral HPLC analysis: Chiralcel OD-H, 2-propanol/hex-
ane (10:90), 1.0 mL/min, UV 254 nm; tR = 7.9 min (6.7%), 36.7 min
(93.3%), 87% ee.
4.1.5. (1S)-1-(4-Chloro-phenyl)-3-phenyl-prop-2-yn-1-ol 5d
A white solid (mp 46ꢀ48 °C). ½a D27
ꢂ
¼ ꢀ7:9 (c 1.4, CHCl3); 1H
4.1.10. (3S)-1,5-Diphenyl-pent-1-en-4-yn-3-ol 5i
NMR (400 MHz, CDCl3): d 7.56ꢀ7.53 (m, 2H), 7.46ꢀ7.44 (m,
2H), 7.37ꢀ7.28 (m, 5H), 5.66 (d, J = 6.0 Hz, 1H), 2.30 (d,
J = 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 139.0 (C), 134.0
(C), 131.6 (CH ꢁ2), 128.6 (CH), 128.6 (CH ꢁ2), 128.2 (CH ꢁ2),
128.0 (CH ꢁ2), 122.0 (C), 88.3 (C), 86.7 (C), 64.1 (CH); IR (neat)
3341, 3055, 2873, 2226, 1949, 1903, 1597, 1488, 1090, 1015,
963, 756, 691 cmꢀ1; HRMS calcd for C15H11ClO 242.0498, found
242.0505. Chiral HPLC analysis: Chiralcel OD-H, 2-propanol/
hexane (10:90), 1.0 mL/min, UV 254 nm; tR = 8.7 min (6.8%),
27.6 min (93.2%), 86% ee.
Colorless crystals (mp 64ꢀ65 °C). ½a D27
ꢂ
¼ ꢀ7:3 (c 0.5, CHCl3); 1H
NMR (400 MHz, CDCl3): d 7.50ꢀ7.24 (m, 10H), 6.83 (d, J = 15.6 Hz,
1H), 6.42ꢀ6.36 (m, 1H), 5.29 (d, J = 6.0 Hz, 1H), 2.47 (br, 1H); 13C
NMR (100 MHz, CDCl3): d 135.9 (C), 131.6 (CH), 131.6 (CH ꢁ2),
128.3 (CH ꢁ2), 128.3 (CH), 128.1 (CH ꢁ2), 127.9 (CH), 127.8
(CH), 126.6 (CH ꢁ2), 122.2 (C), 88.1 (C), 86.1 (C), 63.0 (CH); IR
(neat) 3349, 3058, 3028, 2914, 2850, 2225, 1952, 1597, 1489,
1443, 1006, 964, 755, 690 cmꢀ1
; HRMS calcd for C17H14O
234.1045, found 234.1045. Chiral HPLC analysis: Chiralcel OD-H,
2-propanol/hexane (10:90), 1.5 mL/min, UV 254 nm; tR = 9.6 min
(19.7%), 30.9 min (80.3%), 61% ee.
4.1.6. (1S)-1-(3-Chloro-phenyl)-3-phenyl-prop-2-yn-1-ol 5e
A colorless, viscous oil. ½a D27
ꢂ
¼ ꢀ14:2 (c 1.5, CHCl3); 1H NMR
4.1.11. (3S)-2-Methyl-1,5-diphenyl-pent-1-en-4-yn-3-ol 5j
(400 MHz, CDCl3): d 7.61ꢀ7.60 (m, 1H), 7.49ꢀ7.45 (m, 3H),
7.33ꢀ7.31 (m, 5H), 5.66 (d, J = 6.0 Hz, 1H), 2.37ꢀ2.35 (m, 1H);
13C NMR (100 MHz, CDCl3): d 142.4 (C), 134.2 (C), 131.6 (CH ꢁ2),
129.7 (CH), 128.6 (CH), 128.2 (CH), 128.2 (CH ꢁ2), 126.7 (CH),
124.7 (CH), 121.9 (C), 88.0 (C), 86.8 (C), 64.0 (CH); IR (neat) 3361,
3062, 3021, 2876, 2230, 1945, 1880, 1808, 1759, 1690, 1597,
1489, 1188, 969, 756 cmꢀ1; HRMS calcd for C15H11ClO 242.0498,
found 242.0505. Chiral HPLC analysis: Chiralcel OD-H, 2-propa-
nol/hexane (10:90), 1.0 mL/min, UV 254 nm; tR = 8.9 min (7.2%),
29.3 min (92.8%), 86% ee.
A colorless, viscous oil. ½a D27
ꢂ
¼ þ31:6 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.47ꢀ7.44 (m, 2H), 7.36ꢀ7.30 (m, 6H),
7.25ꢀ7.21 (m, 2H), 6.75 (s, 1H), 5.14 (d, J = 5.6 Hz, 1H), 2.09 (d,
J = 5.6 Hz, 1H), 2.06 (d, J = 1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 137.0 (C), 136.7 (C), 131.6 (CH x2), 128.9 (CH x2), 128.4 (CH),
128.2 (CH ꢁ2), 128.0 (CH ꢁ2), 127.1 (CH), 126.7 (CH), 122.4 (C),
88.1 (C), 86.1 (C), 68.6 (CH), 14.1 (CH3); IR (neat) 3415, 3057,
3025, 2917, 2853, 2200, 1616, 1600, 1489, 1443, 1278, 1062,
756, 691 cmꢀ1
; HRMS calcd for C18H16O 248.1201, found
248.1194. Chiral HPLC analysis: Chiralcel OD-H, 2-propanol/hex-
ane (10:90), 1.0 mL/min, UV 254 nm; tR = 9.0 min (14.4%),
38.6 min (85.6%), 71% ee.
4.1.7. (1S)-1-(2-Chloro-phenyl)-3-phenyl-prop-2-yn-1-ol 5f
A colorless, viscous oil. ½a D27
ꢂ
¼ þ46:2 (c 1.4, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.83ꢀ7.81 (m, 1H), 7.48ꢀ7.43 (m, 2H),
7.40ꢀ7.38 (m, 1H), 7.35ꢀ7.25 (m, 5H), 6.03 (d, J = 5.6 Hz, 1H),
2.54 (d, J = 5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 137.8 (C),
132.6 (C), 131.7 (CH ꢁ2), 129.6 (CH), 129.5 (CH), 128.5 (CH),
128.3 (CH), 128.2 (CH ꢁ2), 127.1 (CH), 122.2 (C), 87.6 (C), 86.4
(C), 62.2 (CH); IR (neat) 3371, 3064, 2928, 2854, 2230, 1953,
1923, 1811, 1597, 1574, 1490, 1442, 1032, 756, 691 cmꢀ1; HRMS
calcd for C15H11ClO 242.0498, found 242.0499. Chiral HPLC analy-
sis: Chiralcel OD-H, 2-propanol/hexane (10:90), 0.5 mL/min, UV
254 nm; tR = 8.2 min (8.5%), 9.7 min (91.5%), 83% ee.
4.1.12. (3S)-1,5-Diphenyl-pent-1-yn-3-ol 5k
A colorless, viscous oil. ½a D27
ꢂ
¼ þ28:4 (c 1.1, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.43ꢀ7.41 (m, 2H), 7.31ꢀ7.19 (m, 8H),
4.61ꢀ4.56 (m, 1H), 2.85 (t, J = 8.0 Hz, 2H), 2.14ꢀ2.03 (m,2H), 1.88
(d, J = 5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 141.2 (C), 131.6
(CH ꢁ2), 128.4 (CH ꢁ2), 128.3 (CH ꢁ2), 128.2 (CH), 128.1 (CH
ꢁ2), 125.8 (CH), 122.5 (C), 89.9 (C), 85.0 (C), 62.0 (CH), 39.1
(CH2), 31.4 (CH2); IR (neat) 3357, 3027, 2925, 2861, 2230, 1948,
1869, 1600, 1490, 1455, 1338, 1042, 756, 691 cmꢀ1; HRMS calcd
for C17H16O 236.1201, found 236.1200. Chiral HPLC analysis:

P.-Y. Wu et al. / Tetrahedron: Asymmetry 20 (2009) 1837–1841
1841
Chiralcel OD-H, 2-propanol/hexane (10:90), 1.0 mL/min, UV
hexane (10:90), 1.0 mL/min, UV 254 nm; tR = 11.0 min (87.5%),
254 nm; tR = 11.4 min (25.5%), 22.7 min (74.5%), 49% ee.
13.8 min (12.5%), 75% ee.
4.1.13. (1S)-1-Phenyl-3-(4-trifluoromethyl-phenyl)-prop-2-yn-1-
Acknowledgment
ol 5l
Colorless crystals (mp 50ꢀ54 °C). ½a D27
ꢂ
¼ þ1:3 (c 1.1, CHCl3); 1H
We thank the National Science Council, Republic of China, for
the financial support.
NMR (400 MHz, CDCl3): d 7.60ꢀ7.52 (m, 5H), 7.43ꢀ7.33 (m, 4H),
5.71 (br, 1H), 2.45 (br, 1H); 13C NMR (100 MHz, CDCl3): d 140.2
(C), 131.9 (CH ꢁ2), 130.3 (q, J = 33 Hz, C), 128.7 (CH ꢁ2), 128.6
(CH), 126.7 (CH ꢁ2), 126.2 (C), 125.2 (q, J = 3.7 Hz, CH ꢁ2), 123.7
(q, J = 271 Hz, C), 91.2 (C), 85.1 (C), 64.9 (CH); IR (neat) 3337,
3066, 3034, 2923, 2237, 1615, 1324, 1168, 1127, 1068, 1018,
References
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1990, 547; (b) Trost, B. M.; Weiss, A. H. Org. Lett. 2006, 8, 4461; (c) Dussault, P.
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Asano, Y.; Hara, K.; Ito, H.; Sawamura, M. Org. Lett. 2007, 9, 3901.
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5. For synthesis of chiral propargylic alcohols using zinc triflate and triethylamine
system: (a) Frantz, D. E.; Fässler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem.
Res. 2000, 33, 373; (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123,
9687; (c) Boyall, D.; López, F.; Sasaki, H.; Frantz, D.; Carreira, E. M. Org. Lett.
2000, 2, 4233; (d) El-Sayed, E.; Anand, N. K.; Carreira, E. M. Org. Lett. 2001, 3,
3017; (e) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4, 2605.
6. For leading references of the alkynylzinc addition to aldehydes using a zinc
system: (a) Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937; (b) Ishizaki,
M.; Hoshino, O. Tetrahedron: Asymmetry 1994, 5, 1901; (c) Xu, M.-H.; Pu, L. Org.
Lett. 2002, 4, 4555; (d) Lu, G.; Li, X.; Zhou, Z.; Chan, W. L.; Chan, A. S. C.
Tetrahedron: Asymmetry 2001, 12, 2147.
842, 698 cmꢀ1
; HRMS calcd for C16H11F3O 276.0762, found
276.0752. Chiral HPLC analysis: Chiralcel OD-H, 2-propanol/hex-
ane (10:90), 1.0 mL/min, UV 254 nm; tR = 6.9 min (91.9%), 8.3 min
(8.1%), 84% ee.
4.1.14. (1S)-3-(4-Methoxy-phenyl)-1-phenyl-prop-2-yn-1-ol 5m
A colorless, viscous oil. ½a D26
ꢂ
¼ þ1:9 (c 1.1, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.61ꢀ7.59 (m, 2H), 7.41ꢀ7.31 (m, 5H),
6.84ꢀ6.82 (m, 2H), 5.66 (d, J = 6.0 Hz, 1H), 3.79 (s, 3H), 2.27 (d,
J = 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d 159.3 (C), 140.7 (C),
132.9 (CH ꢁ2), 128.2 (CH ꢁ2), 127.9 (CH), 126.5 (CH ꢁ2), 114.3
(C), 113.6 (CH ꢁ2), 87.5 (C), 86.1 (C), 64.5 (CH), 54.9 (CH3); IR
(neat) 3401, 3033, 2936, 2838, 2226, 2048, 1890, 1606, 1510,
1249, 1032, 832, 701 cmꢀ1; HRMS calcd for C16H14O2 238.0994,
found 238.0995. Chiral HPLC analysis: Chiralcel OD-H, 2-propanol/
hexane (10:90), 1.0 mL/min, UV 254 nm; tR = 14.0 min (12.1%),
26.6 min (87.9%), 76% ee.
4.1.15. (1S)-3-(4-Chloro-phenyl)-1-phenyl-prop-2-yn-1-ol 5n
A colorless, viscous oil. ½a D26
ꢂ
¼ þ2:6 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.59ꢀ7.58 (m, 2H), 7.42ꢀ7.27 (m, 7H),
.67 (d, J = 6.0 Hz, 1H), 2.31 (d, J = 6.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d 140.3 (C), 134.3 (C), 132.8 (CH ꢁ2), 128.43 (CH ꢁ2),
128.38 (CH ꢁ2), 128.2 (CH), 126.5 (CH ꢁ2), 120.7 (C), 89.8 (C),
85.2 (C), 64.6 (CH); IR (neat) 3360, 3065, 2875, 2230, 1956, 1901,
1593, 1488, 1190, 1092, 1015, 963, 828 698 cmꢀ1; HRMS calcd
for C15H11ClO 242.0498, found 242.0500. Chiral HPLC analysis: Chi-
ralcel OD-H, 2-propanol/hexane (10:90), 0.5 mL/min, UV 254 nm;
tR = 17.3 min (82.8%), 19.0 min (17.2%), 66% ee.
7. For selected examples of the alkynylzinc addition to aldehydes using a zinc
system: (a) Dahmen, S. Org. Lett. 2004, 6, 2113; (b) Trost, B. M.; Weiss, A. H.;
von Wangelin, A. J. J. Am. Chem. Soc. 2006, 128, 8; (c) Wolf, C.; Liu, S. J. Am. Chem.
Soc. 2006, 128, 10996; (d) Blay, G.; Fernández, I.; Marco-Aleixandre, A.; Pedro, J.
R. J. Org. Chem. 2006, 71, 6674.
8. For recent advances of alkynylzinc addition to aldehydes using zinc system: (a)
Li, Z.-B.; Liu, T.-D.; Pu, L. J. Org. Chem. 2007, 72, 4340; (b) Wang, Q.; Chen, S.-Y.; Yu,
X.-Q.; Pu, L. Tetrahedron 2007, 63, 4422; (c) Yang, X.-F.; Hirose, T.; Zhang, G.-Y.
Tetrahedron: Asymmetry 2007, 18, 2668; (d) Ruan, J.; Lu, G.; Xu, L.; Li, Y.-M.; Chan,
A. S. C. Adv. Synth. Catal. 2008, 350, 76; (e) Li, H.; Huang, Y.; Jin, W.; Xue, F.; Wan, B.
Tetrahedron Lett. 2008, 49, 1686.
9. For reviews of organozinc reactions: (a) Noyori, R.; Kitamura, M. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 49; (b) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833; (c) Pu,
L.; Yu, H.-B. Chem. Rev. 2001, 101, 757.
10. (a) Chang, C.-W.; Yang, C.-T.; Hwang, C.-D.; Uang, B.-J. Chem. Commun. 2002,
54; (b) Wu, H.-L.; Uang, B.-J. Tetrahedron: Asymmetry 2002, 13, 2625; (c) Uang,
B.-J.; Fu, I.-P.; Hwang, C.-D.; Chang, C.-W.; Yang, C.-T.; Hwang, D.-R. Tetrahedron
2004, 60, 10479; (d) Wu, Z.-L.; Wu, H.-L.; Wu, P.-Y.; Uang, B.-J. Tetrahedron:
Assymmetry 2009, 20, 1556.
11. (a) Wu, P.-Y.; Wu, H.-L.; Uang, B.-J. J. Org. Chem. 2006, 71, 833; (b) Wu, H.-L.;
Wu, P.-Y.; Uang, B.-J. J. Org. Chem. 2007, 72, 5935; (c) Wu, H.-L.; Wu, P.-Y.;
Uang, B.-J. J. Org. Chem. 2008, 73, 6445.
12. (a) Vogl, E. M.; Gröger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 1570;
(b) Funabashi, K.; Jachmann, M.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed.
2003, 42, 5489; (c) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445.
4.1.16. (1S)-1-Phenyl-hept-2-yn-1-ol 5o
A colorless oil. ½a D25
ꢂ
¼ ꢀ18:1 (c 1.3, CHCl3); 1H NMR (400 MHz,
CDCl3): d 7.54–7.52 (m, 2H), 7.38ꢀ7.28 (m, 3H), 5.43 (d, J = 5.6 Hz,
1H), 2.26 (td, J = 7.2, 2.0 Hz, 2H), 2.13 (d, J = 5.6 Hz, 1H), 1.55ꢀ1.36
(m, 4H), 0.898 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
141.2 (C), 128.3 (CH ꢁ2), 127.9 (CH), 126.5 (CH ꢁ2), 87.3 (C), 79.9
(C), 64.5 (CH), 30.5 (CH2), 21.8 (CH2), 18.3 (CH2), 13.4 (CH3); IR (neat)
3397, 3031, 2958, 2933, 2873, 2227, 1950, 1884, 1809, 1603, 1494,
1455, 1135, 1002, 698 cmꢀ1; HRMS calcd for C13H16O 188.1201,
found 188.1192. Chiral HPLC analysis: Chiralcel OD-H, 2-propanol/