Highly enantioselective catalytic methyl propiolate addition to both aromatic and aliphatic aldehydes

Article abstract of DOI:10.1016/j.tetasy.2016.03.009

The excellent catalytic effect on methyl propiolate addition to a wide range of aromatic and aliphatic aldehydes promoted by inexpensive and commercially available BINOL-based ligand is reported. The catalyst systems showed high yields and excellent enantioselectivities for aromatic aldehydes, and excellent yields and high enantioselectivities for aliphatic aldehydes.

Full text of DOI:10.1016/j.tetasy.2016.03.009

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective catalytic methyl propiolate addition to both
aromatic and aliphatic aldehydes
Jian Huang a,y, Siping Wei a,y, Li Wang a, Chun Zhang a, Shuangxun Li a, Pingxian Liu a, Xi Du a,
Qin Wang a,b,
⇑
a Department of Medicinal Chemistry, Sichuan Medical University, Luzhou 646000, PR China
b Key Laboratory of Medicinal Electrophysiology of Ministry of Education, Sichuan Medical University, Luzhou 646000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The excellent catalytic effect on methyl propiolate addition to a wide range of aromatic and aliphatic
aldehydes promoted by inexpensive and commercially available BINOL-based ligand is reported. The cat-
alyst systems showed high yields and excellent enantioselectivities for aromatic aldehydes, and excellent
yields and high enantioselectivities for aliphatic aldehydes.
Received 10 January 2016
Revised 11 March 2016
Accepted 15 March 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
to a,b-chiral amino alcohol ligand in combination with ZnEt2 and
Ti(OiPr)4 for the addition of unsaturated aldehydes using a pro-
line-derived catalyst and ZnMe2 in 2006.7 Later, Wang and Hui
reported the use of methyl propiolate to aromatic and aliphatic
aldehydes, independently.8 Recently, Wang and Kojima indepen-
dently reported the use of ZnMe2 and a chiral amino alcohol for
the asymmetric addition of methyl propiolate to aromatic and
aliphatic aldehydes without Ti(OiPr)4.9
Chiral propargylic alcohols have found extensive applications in
yjr synthesis of fine chemicals, pharmaceuticals, and natural prod-
ucts.1 Over the past few years, we have focused on the develop-
ment of the use of 1,10-binaphthol (BINOL) in combination with a
Ti(IV) complex to catalyze the asymmetric alkyne addition to alde-
hydes as well as the application of chiral propargylic alcohols in
the synthesis of cyclic organic compounds.2 Chiral
b-acetylenic esters represent a class of functional propargylic alco-
hols that are very useful and versatile structural subunits in many
biologically active compounds.1–3
Only a small number of catalysts are applicable for the asym-
metric propiolate addition to aldehydes, due to the high sensitivity
and very different reactivity of the propiolate in comparison with
normal terminal alkyl and aryl alkynes.4–9 Previously, we reported
the first highly enantioselective catalyst for the asymmetric reac-
tion of methyl propiolate with aromatic aldehydes to generate
c
-hydroxy-
a,
In spite of the significant progress in this area, there are still a
number of limitations in the scope of the substrates for the
reported catalyst systems. Our BINOL or H8BINOL-based chiral cat-
alytic systems were independently shown to achieve excellent
enantioselectivities and yields for the addition of methyl propio-
late to aromatic or aliphatic aldehydes; however, the different cat-
alytic systems require multiple syntheses for the special efficient
ligands.4,6,10 The amino alcohol–Zn catalytic system, reported by
Wang and Hui, also requires the design and synthesis of the indi-
vidual ligands, respectively.8,9a Kojima’s amino alcohol–Zn system
afforded good yield and excellent enantioselectivity for only a
small range of aromatic and aliphatic aldehydes.9b Herein, we
report our work on the development of an easily available
BINOL-based catalyst to catalyze the reaction of methyl
propiolate with a wide range of aromatic and aliphatic aldehydes
c
-hydroxy-a,b-acetylenic esters by using a BINOL-Ti(IV)-HMPA
catalyst system.4 Later, You et al. modified the BINOL-Ti system
by substituting HMPA with NMI, which reduced the amount of
the base and BINOL required for the catalysis.5 We further devel-
oped the BINOL-based catalyst system by using a catalytic amount
of Cy2NH in place of HMPA for the asymmetric alkyne addition to
aldehydes and achieved excellent enantioselectivity.6 Trost et al.
reported on a highly enantioselective addition of methyl propiolate
to generate various
c-hydroxy-a,b-acetylenic esters.
2. Results and discussions
Previously, we reported that BINOL in combination with Cy2NH,
ZnEt2 and Ti(OiPr)4 can catalyze the addition of various alkynes to
aldehydes with high enantioselectivity. However, when we tested
the application of this catalyst for the reaction of methyl propiolate
⇑
Corresponding author. Tel./fax: +86 830 3162292.
E-mail address: wq_ring@hotmail.com (Q. Wang).
These authors contributed equally to this work.
y
http://dx.doi.org/10.1016/j.tetasy.2016.03.009
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
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J. Huang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
with aldehydes, only a low yield (<20%) of the product was
obtained. Similar results were obtained when H8BINOL and (R)-
3,30-dibromo-1,10-bi-2-naphthol ((R)-2) were used. When using
(R)-6,60-dibromo-1,10-bi-2-naphthol (R)-1 as the catalyst for the
asymmetric addition of methyl propiolate to benzaldehyde, a good
yield and excellent enantioselectivity were achieved (for detailed
results of the catalyst screening see Supplementary material,
Table S1).
containing an electron-withdrawing substituent were better than
those of benzaldehydes containing an electron-donating sub-
stituent except for ortho-methylbenzaldehyde, due to the
electron-withdrawing effect. The heteroaromatic aldehydes,
furan-2-carbaldehyde
and
thiophene-2-carbaldehyde,
and
1-naphthaldehyde showed good yields and high enantioselectiv-
ities (up to 97%, entry 10–12). As is evident in entries 13–24,
the linear (n-butyraldehyde, n-pentanal, n-octanal and
Br
Br
Br
OH
OH
OH
OH
OH
OH
OH
OH
Br
(R)-2
(R)-1
The results from the (R)-1 survey in combination with Ti(OiPr)4
are summarized in Table 1. As shown in entries 1–4, when the sol-
vent changed from THF to CH2Cl2, the yield of the desired product
increased with high enantioselectivity. The catalytic effects of var-
ious amounts of Cy2NH were also investigated. As shown in entries
4–8, when the amount of Cy2NH was increased from 2.5 mol % to
30 mol %, the yields were simultaneously increased but the enan-
tioselectivities remained the same. Increasing the amount of Cy2-
NH to 60 mol % reduced the yield (entry 9). Therefore, this
catalysis system was found to be inferior to 30 mol % Cy2NH in
CH2Cl2. Further optimization of reaction conditions revealed that
an increase in the amount of (R)-1 (40 mol %) and Ti(OiPr)4
(100 mol %) led to an excellent enantioselectivity of 94% ee and
65% yield while the amount of Cy2NH was 30 mol %. The absolute
configuration of the product was determined to be (S) by studying
the 19F NMR spectra of its Mosher ester, which is consistent with
other studies.4,10
With the optimized conditions in hand, the asymmetric reac-
tion of methyl propiolate with various aromatic and aliphatic
aldehydes was screened. The results shown in Table 2 demon-
strate that our catalytic system was capable of tolerating both
aromatic aldehydes (entries 1–12) and aliphatic aldehydes
(entries 13–24) with good yields and excellent enantioselectivi-
ties. As can be seen from entries 2–9, the yields of benzaldehydes
n-decanal),
and 2-ethylbutanal), and
the addition reaction in excellent yields (up to 99%) and with
high enantioselectivities. The b-branched aliphatic aldehyde
3-methylbutanal, and bulky trimethyl acetaldehyde showed low
reactivity with good yields and moderate enantioselectivities.
a
-branched aliphatic aldehydes (isobutyraldehyde
a
-cyclopropanecarbaldehyde underwent
Functionalized
aldehydes,
such
as
phenylacetaldehyde,
cinnamaldehyde, and trans-2-pentenal, are also examined with
good yields and enantioselectivities. These results demonstrate
that this catalytic system has
aromatic and aliphatic aldehydes.
a broad generality for both
3. Conclusion
In conclusion, we have described a highly effective method for
the asymmetric catalysis of methyl propiolates to various aromatic
and aliphatic aldehydes with high enantioselectivities and yields
using a commercially available BINOL-based catalyst. By using
the inexpensive and easily available ligand (R)-1, it is possible
to conveniently prepare structurally diverse optically active
c-hydroxy-a,b-acetylenic esters under very mild reaction
conditions. Further research on the application of these chiral
propargylic alcohols in the synthesis of pharmaceutical compound
currently in process.
Table 1
Optimization of the reaction conditionsa
OH
CHO
(R)-1, Cy2NH
COOMe
Et2Zn, Ti(OiPr)4
COOMe
Entry
(R)-1/Ti(OiPr)4 (mol %)
Solvent
Cy2NH (mol %)
Yield (%)
eeb (%)
1
2
3
4
20/50
20/50
20/50
20/50
20/50
20/50
20/50
20/50
20/50
40/100
THF
Et2O
5
5
5
Trace
38
48
45
36
52
51
65
50
85
83
87
87
87
87
87
87
94
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5
5
2.5
10
10
30
60
30
6
7c
8
9
10d
65
a
The following conditions were used unless otherwise indicated: methyl propiolate:Et2Zn:Ti(OiPr)4:(R)-1:aldehyde = 3:3:0.5:0.2:1. A mixture of (R)-1, methyl propiolate,
solvent, Cy2NH and Et2Zn was stirred at room temperature for 24 h. Ti(OiPr)4 was then added with stirring for 2 h at room temperature. Benzaldehyde was added and the
mixture was stirred for 24 h at room temperature.
b
Enantiomeric excess determined by chiral HPLC.
c
After the aldehyde was added, the reaction solution was stirred for 48 h.
d
Methyl propiolate:Et2Zn:Ti(OiPr)4:(R)-1:aldehyde = 4:4:1:0.4:1.
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J. Huang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 2
Enantioselective addition of methyl propiolate to aromatic aldehydesa
OH
CHO
1
(R)- , Cy2NH
COOMe
Et2Zn, Ti(OiPr)4
COOMe
Entry
1
Product
Yield (%)
65
eeb (%)
94
OH
OH
COOMe
COOMe
2
3
4
79
47
60
90
93
90
OH
OH
COOMe
COOMe
OH
5
55
90
COOMe
OMe OH
6
7
8
66
67
80
87
87
89
COOMe
F
OH
OH
COOMe
COOMe
Cl
OH
9
76
88
94
97
COOMe
COOMe
Cl
HO
10
OH
OH
OH
11
12
13
14
15
73
52
73
79
90
88
94
80
84
O
S
COOMe
COOMe
COOMe
OH
COOMe
OH
83
6
COOMe
(continued on next page)
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J. Huang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 2 (continued)
Entry
Product
OH
Yield (%)
eeb (%)
85
16
17
18
19
20
21
22
23
98
96
95
98
85
82
67
61
68
8
COOMe
COOMe
OH
87
85
78
51
74
87
89
84
OH
COOMe
OH
OH
COOMe
COOMe
OH
COOMe
OH
Ph
Ph
COOMe
OH
COOMe
OH
24
4
COOMe
a
Methyl propiolate:Et2Zn:Cy2NH:Ti(OiPr)4:(R)-1:aldehyde = 4:4:0.3:1:0.4:1.
Determined by the HPLC.
b
and the organic phase was dried over Na2SO4. After filtration, the
solvent was removed by rotary evaporation and the residue was
purified by column chromatography on silica gel eluted with pet-
roleum ether/ethyl acetate (10:1) to give the product. The ee val-
ues were determined by HPLC.
4. Experimental
4.1. General
All reactions were carried out under a nitrogen atmosphere.
CH2Cl2 was distilled from CaH2 under nitrogen before use. THF
was distilled from sodium benzophenone ketyl under nitrogen.
Aldehydes and dicyclohexylamine were distilled according to stan-
dard methods prior to use. 1H NMR spectra and 13C NMR spectra
were tested on Bruker-400 MHz and Bruker-100 MHz with TMS
as an internal standard. Enantiomeric excesses were measured by
HPLC using corresponding chiralcel column. Mass analysis data
were acquired on Agilent 6890–5973 N mass spectroscopy. Optical
rotations were detected on PerkinElmer-341 automatic
polarimeter.
4.3. Preparation of racemic propargylic alcohols
Under nitrogen, a solution of methyl propiolate (1 mmol) in THF
(6 mL) was cooled to ꢀ78 °C in a liquid nitrogen/acetone bath, and
n-BuLi (0.5 mL, 2.5 M in hexane) was added. The solution was stir-
red for 30 min after which the aldehyde (0. 5 mmol) was added.
The reaction mixture was stirred for 1 h. Ice water was then added
to quench the reaction and CH2Cl2 was used for extraction. The
organic phase was dried over magnesium sulfate. The solvent
was removed by rotoevaporation and the residue was purified by
flash column chromatography on silica gel eluted with petroleum
ether/ethyl acetate (10/1) to afford the product.
4.2. General procedure for the asymmetric addition of methyl
propiolate to aldehydes
4.4. Characterization of the propargylic alcohols
4.4.1. Methyl 4-hydroxy-4-phenylbut-2-ynoate4
Under nitrogen, (R)-1 (0.2 mmol, 88.8 mg) was dissolved in a
10 mL flask, which contained 6 mL of CH2Cl2. Next, Cy2NH
(0.15 mmol, 28.8 lL), methyl propiolate (2 mmol, 178.9 lL), and
Et2Zn (2 mmol, 1 mL, 2 mol/L in toluene) were added successively
and the reacting mixture was stirred at room temperature for 24 h.
To the resulting solution was added Ti(OiPr)4 (0.5 mmol, 148 lL)
OH
and stirred for another 2 h. Next the aldehyde (0.5 mmol) was
added to the reaction mixture at room temperature. After 24 h,
the reaction was quenched by adding saturated aqueous ammo-
nium chloride. The liquor was extracted with CH2Cl2 three times
O
O
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J. Huang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
Yield 65%, 94% ee determined by HPLC analysis: Chiracel AD-H
(101 MHz, DMSO)
d
153.66, 137.84, 137.70, 129.43, 126.76,
column, 95:5 hexanes:iPrOH, flow rate = 1 mL/min, k = 254 nm,
retention time: tmajor = 16.037 min, and tminor = 17.453 min;
89.57, 76.34, 62.40, 53.33, 21.14. GC–MS (EI) m/z (%) 204 (M+,
90), 189(100), 115(88), 91(93).
[
a]
20 = ꢀ1.8 (c 0.950, CH2Cl2); 1H NMR (400 MHz, DMSO-d6) d
D
7.61–7.22 (m, 5H), 6.49 (d, J = 6.0 Hz, 1H), 5.62 (d, J = 6.0 Hz, 1H),
3.72 (s, 3H). 13C NMR (100 MHz, DMSO-d6) d 153.63, 140.59,
128.93, 128.56, 126.79, 89.38, 76.44, 62.55, 53.36. GC–MS (EI)
m/z (%) 190 (M+, 60), 175(55), 105(100), 77(98).
4.4.5. Methyl 4-(4-(tert-butyl)phenyl)-4-hydroxybut-2-ynoate
OH
4.4.2. Methyl 4-hydroxy-4-(o-tolyl)but-2-ynoate4
O
O
OH
Yield 55%, 90% ee determined by HPLC analysis: Chiracel AD-H
column, 90:10 hexanes:iPrOH, flow rate = 1 mL/min, k = 254 nm,
retention time: tmajor = 8.234 min, and tminor = 8.989 min;
O
O
[a
]
D
20 = ꢀ0.6 (c 1.13, CH2Cl2); 1H NMR (400 MHz, DMSO) d 7.40 (q,
J = 8.5 Hz, 4H), 6.38 (d, J = 5.9 Hz, 1H), 5.56 (d, J = 5.9 Hz, 1H),
3.71 (s, 3H), 1.28 (s, 9H). 13C NMR (101 MHz, DMSO) d 153.66,
151.07, 137.68, 126.58, 125.68, 89.58, 76.33, 62.36, 53.33, 34.72,
31.52. GC–MS (EI) m/z (%) 246 (M+, 20), 231(100), 190(52).
Yield 79%, 90% ee determined by HPLC analysis: Chiracel AS-H
column, 98:2 hexanes:iPrOH, flow rate = 1 mL/min, k = 254 nm,
retention time: tmajor = 45.703 min, and tminor = 43.662 min;
[a]
20 = +10.1 (c 1.0, CH2Cl2); 1H NMR (400 MHz, DMSO) d 7.55–
D
4.4.6. Methyl 4-hydroxy-4-(2-methoxyphenyl)but-2-ynoate
7.47 (m, 1H), 7.27–7.16 (m, 3H), 6.40 (d, J = 5.6 Hz, 1H), 5.69 (d,
J = 5.6 Hz, 1H), 3.71 (s, 3H), 2.36 (s, 3H). 13C NMR (101 MHz, DMSO)
d 138.26, 135.74, 130.92, 128.53, 126.69, 126.40, 88.90, 76.31,
60.66, 53.33, 18.96. GC–MS (EI) m/z (%) 156 (49), 115(100),
91(79), 65(40).
O
OH
O
4.4.3. Methyl 4-hydroxy-4-(m-tolyl)but-2-ynoate4
O
OH
Yield 66%, 87% ee determined by HPLC analysis: Chiracel AS-H
column, 95:5 hexanes:iPrOH, flow rate = 1 mL/min, k = 254 nm,
retention time: tmajor = 34.113 min, and tminor = 28.439 min;
O
O
[a
]
D
20 = ꢀ2.1 (c 1.22, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 7.44
(dd, J = 7.5, 1.7 Hz, 1H), 7.34 (ddd, J = 8.2, 7.6, 1.7 Hz, 1H), 7.06–
6.86 (m, 2H), 5.72 (d, J = 7.6 Hz, 1H), 3.91 (s, 3H), 3.78 (s, 3H),
3.18 (t, J = 6.2 Hz, 1H). 13C NMR (101 MHz, DMSO) d 156.09,
153.75, 129.98, 128.38, 127.33, 120.99, 111.64, 89.55, 75.19,
57.13, 56.09, 53.32. GC–MS (EI) m/z (%) 220 (M+, 60), 173(100),
135(88), 77(80).
Yield 47%, 93% ee determined by HPLC analysis: Chiracel AD-H
column, 90:10 hexanes:iPrOH, flow rate = 1 mL/min, k = 254 nm,
retention time: tmajor = 8.618 min, and tminor = 9.072 min;
[
a]
D
20 = ꢀ1.7 (c 0.35, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 7.28
(dd, J = 14.6, 7.9 Hz, 3H), 7.17 (d, J = 6.6 Hz, 1H), 5.52 (d,
J = 6.2 Hz, 1H), 3.78 (s, 3H), 2.71 (d, J = 6.3 Hz, 1H), 2.37 (s, 3H).
13C NMR (101 MHz, CDCl3) d 153.81, 138.71, 138.43, 129.74,
128.78, 127.31, 123.73, 86.71, 77.53, 64.32, 52.92, 21.41. GC–MS
(EI) m/z (%) 204 (M+, 85), 189(78), 119(90), 91(100).
4.4.7. Methyl 4-(2-fluorophenyl)-4-hydroxybut-2-ynoate
F
OH
4.4.4. Methyl 4-hydroxy-4-(p-tolyl)but-2-ynoate4
O
O
OH
Yield 67%, 87% ee determined by HPLC analysis: Chiracel OD-3
column, 95:5 hexanes:iPrOH, flow rate = 1 mL/min, k = 254 nm,
retention time: tmajor = 14.377 min, and tminor = 18.561 min;
O
O
[a]
20 = +8.1 (c 1.105, CH2Cl2); 1H NMR (400 MHz,CDCl3) d 7.60
D
(td, J = 7.6, 1.8 Hz, 1H), 7.36 (dddd, J = 8.2, 7.3, 5.3, 1.8 Hz, 1H),
7.19 (td, J = 7.6, 1.1 Hz, 1H), 7.09 (ddd, J = 10.1, 8.3, 1.0 Hz, 1H),
5.83 (d, J = 6.3 Hz, 1H), 3.79 (s, 3H), 2.81 (dd, J = 6.3, 0.8 Hz, 1H).
13C NMR (101 MHz, CDCl3) d 161.20, 158.73, 153.61, 130.82 (d,
J = 8.3 Hz), 128.33 (d, J = 3.2 Hz), 124.58 (d, J = 3.7 Hz), 115.77 (d,
J = 20.9 Hz), 85.35, 77.27, 58.73 (d, J = 5.1 Hz). 52.91. GC–MS (EI)
m/z (%) 208 (M+, 35), 179(40), 148(60), 123(100), 95(50).
Yield 60%, 90% ee determined by HPLC analysis: Chiracel AD-H
column, 90:10 hexanes:iPrOH, flow rate = 1 mL/min, k = 254 nm,
retention time: tmajor = 9.972 min, and tminor = 11.365 min;
[
a]
D
20 = ꢀ1.62 (c 0.985, CH2Cl2); 1H NMR (400 MHz, DMSO) d 7.34
(d, J = 7.8 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.39 (dd, J = 6.0, 0.7 Hz,
1H), 5.55 (d, J = 5.9 Hz, 1H), 3.71 (s, 1H), 2.30 (s, 1H). 13C NMR
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J. Huang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4.4.8. Methyl 4-(2-chlorophenyl)-4-hydroxybut-2-ynoate4
Yield 73%, 88% ee determined by HPLC analysis: Chiracel OD-H
column, 90:10 hexanes:iPrOH, flow rate = 1 mL/min, k = 220 nm,
retention time: tminor = 14.018 min, and tmajor = 15.064 min;
[a]
20 = ꢀ3.3 (c 1, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 7.45 (s,
D
Cl
OH
1H), 6.50 (s, 1H), 6.38 (s, 1H), 5.59 (s, 1H), 3.81 (s, 3H), 2.59 (s,
1H). 13C NMR (101 MHz, CDCl3) d 153.54, 150.64, 143.63, 110.67,
108.83, 83.77, 77.27, 57.95, 53.06.
O
O
4.4.12. Methyl 4-hydroxy-4-(thiophen-2-yl)but-2-ynoate
Yield 80%, 89% ee determined by HPLC analysis: Chiracel AD-H
column, 95:5 hexanes:iPrOH, flow rate = 1 mL/min, k = 254 nm,
retention time: tmajor = 15.499 min, and tminor = 16.202 min;
HO
S
[a]
20 = +35.5 (c 1.15, CH2Cl2); 1H NMR (400 MHz, DMSO) d 7.73–
D
O
7.66 (m, 1H), 7.54–7.32 (m, 3H), 6.75 (d, J = 5.8 Hz, 1H), 5.78 (d,
J = 5.8 Hz, 1H), 3.71 (s, 3H). 13C NMR (101 MHz, DMSO) d 153.47,
137.64, 131.58, 130.43, 129.92, 128.36, 128.07, 87.68, 75.94,
59.98, 53.41. GC–MS (EI) m/z (%) 224 (M+, 25), 195(100), 164(83),
139(85).
O
Yield 52%, 94% ee determined by HPLC analysis: Chiracel OD-H
column, 95:5 hexanes:iPrOH, flow rate = 1 mL/min, k = 220 nm,
retention time: tminor = 27.424 min, and tmajor = 29.325 min;
4.4.9. Methyl 4-(4-chlorophenyl)-4-hydroxybut-2-ynoate4
[a]
20 = ꢀ22.8 (c 1.01, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 7.35
D
(s, 1H), 7.21 (s, 1H), 7.00 (s, 1H), 5.79 (s, 1H), 3.81 (s, 3H), 2.76
(s, 1H). 13C NMR (101 MHz, CDCl3) d 153.63, 141.79, 126.98,
126.90, 126.34, 85.34, 77.00, 60.06, 53.08.
OH
O
Cl
4.4.13. Methyl 4-hydroxyhept-2-ynoate
O
OH
Yield 76%, 94% ee determined by HPLC analysis: Chiracel AD-H
column, 95:5 hexanes:iPrOH, flow rate = 1 mL/min, k = 254 nm,
retention time: tmajor = 16.647 min, and tminor = 19.271 min;
O
O
[a
]
D
20 = ꢀ2.1 (c 0.235, CH2Cl2); 1H NMR (400 MHz, DMSO) d 7.48
(s, 4H), 6.58 (d, J = 6.0 Hz, 1H), 5.65 (d, J = 6.0 Hz, 1H), 3.72 (s,
3H). 13C NMR (101 MHz, DMSO) d 153.54, 139.61, 133.13, 128.96,
128.65, 88.81, 76.55, 61.85, 53.42. GC–MS (EI) m/z (%) 224 (M+,
35), 139(100), 111(40), 75(37).
Yield 73%, 80% ee determined by HPLC analysis: Chiracel AS-H
column, 98:2 hexanes:iPrOH, flow rate = 0.8 mL/min, k = 220 nm,
retention time: tmajor = 31.248 min, and tminor = 28.938 min;
4.4.10. Methyl 4-(naphthalen-1-yl)4-hydroxybut-2-ynoate4
[a]
20 = ꢀ4.85 (c 1.05, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 4.51
D
(dd, J = 12.6, 6.6 Hz, 1H), 3.79 (s, 3H), 2.24 (d, J = 5.9 Hz, 1H), 1.79
– 1.72 (m, 2H), 1.66 – 1.38 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C
NMR (101 MHz, CDCl3) d 153.87, 88.31, 77.36, 77.04, 76.73,
76.23, 61.90, 52.85, 38.87, 18.24, 13.62. GC–MS (EI) m/z (%) 125
(44), 113(70), 96(50), 81(66). 65(40).
OH
O
O
4.4.14. Methyl 4-hydroxyoct-2-ynoate10a
Yield 88%, 97% ee determined by HPLC analysis: Chiracel OD-H
column, 90:10 hexanes:iPrOH, flow rate = 1 mL/min, k = 220 nm,
retention time: tminor = 20.539 min, and tmajor = 27.440 min;
OH
O
O
[a]
20 = +5.2 (c 1.07, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 8.21 (d,
D
J = 8.0 Hz, 1H), 8.01–7.72 (m, 3H), 7.64–7.39 (m, 3H), 6.20 (s, 1H),
3.78 (s, 3H), 2.84 (s, 1H). 13C NMR (101 MHz, CDCl3) d 153.83,
134.02, 133.57, 130.32, 130.03, 128.90, 126.87, 126.19, 125.26,
125.11, 123.58, 86.34, 78.28, 62.72, 53.00.
Yield 79%, 84% ee determined by HPLC analysis: Chiracel OD-3
column, 98:2 hexanes:iPrOH, flow rate = 0.8 mL/min, k = 220 nm,
retention time: tmajor = 28.361 min, and tminor = 26.764 min;
4.4.11. Methyl 4-(furan-2-yl)-4-hydroxybut-2-ynoate4
[a]
20 = ꢀ2.2 (c 1.05, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 4.58–
D
4.15 (m, 1H), 3.79 (s, 3H), 2.13 (d, J = 5.9 Hz, 1H), 1.86–1.72 (m,
2H), 1.50 – 1.29 (m, 4H), 0.91 (dt, J = 9.4, 6.5 Hz, 3H). 13C NMR
(101 MHz, CDCl3) d 153.84, 88.28, 76.25, 62.15, 52.83, 36.59,
27.02, 22.27, 13.90. GC–MS (EI) m/z (%) 139 (35), 114(100), 82
(60), 53(90).
HO
O
O
O
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J. Huang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
4.4.15. Methyl 4-hydroxyundec-2-ynoate11
Yield 95%, 85% ee determined by HPLC analysis: Chiracel AS-H
column, 98:2 hexanes:iPrOH, flow rate = 1 mL/min, k = 220 nm,
retention time: tmajor = 15.537 min, and tminor = 14.690 min;
[a]
20 = +3.0 (c 1.09, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 4.53 (t,
D
OH
J = 4.7 Hz, 1H), 3.78 (s, 1H), 1.91 (d, J = 5.9 Hz, 1H), 1.57–1.34 (m,
1H), 0.95 (ddd, J = 7.4, 4.8, 1.0 Hz, 1H). 13C NMR (101 MHz, DMSO)
d 153.68, 90.25, 76.13, 62.85, 53.22, 46.88, 40.56, 40.35, 40.14,
39.93, 39.72, 39.51, 39.31, 21.91, 21.81, 11.78, 11.58. GC–MS (EI)
m/z (%) 153(15), 114(100), 82(20), 52(25).
O
O
Yield 90%, 83% ee determined by HPLC analysis: Chiracel OD-3
column, 98:2 hexanes:iPrOH, flow rate = 1 mL/min, k = 220 nm,
retention time: tmajor = 19.047 min, and tminor = 17.979 min;
4.4.19. Methyl 4-cyclopropyl-4-hydroxybut-2-ynoate11
[a]
20 = +1.7 (c 1.06, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 4.49 (q,
D
J = 6.3 Hz, 1H), 3.79 (s, 1H), 1.99 (d, J = 5.9 Hz, 1H), 1.77 (ddd,
J = 13.1, 8.6, 4.3 Hz, 2H), 1.50–1.23 (m, 10H), 0.88 (t, J = 6.7 Hz,
3H). 13C NMR (101 MHz, CDCl3) d 153.84, 88.32, 77.35, 77.03,
76.71, 76.22, 62.14, 52.82, 36.86, 31.73, 29.11, 29.10, 24.91,
22.62, 14.07. GC–MS (EI) m/z (%) 151(20), 123(30), 114(100), 81
(40), 57(60).
OH
O
O
4.4.16. Methyl 4-hydroxytridec-2-ynoate
Yield 99%, 78% ee determined by HPLC analysis: Chiracel AS-H
column, 95:5 hexanes:iPrOH, flow rate = 1 mL/min, k = 220 nm,
retention time: tmajor = 17.229 min, and tminor = 15.455 min;
[a]
20 = +35.3 (c 1.12, CH2Cl2); 1H NMR (400 MHz, DMSO) d 5.78
D
OH
(d, J = 6.1 Hz, 1H), 4.08–4.01 (m, 1H), 3.72 (s, 3H), 1.19–1.09 (m,
1H), 0.52–0.43 (m, 2H), 0.38–0.31 (m, 2H). 13C NMR (101 MHz,
DMSO) d 153.71, 89.74, 74.90, 63.56, 53.26, 40.56, 40.35, 40.15,
39.94, 39.73, 39.52, 39.31, 17.28, 3.58, 2.14. GC–MS (EI) m/z (%)
141(30), 126(60), 94(100), 75(80), 53(70).
O
O
Yield 99%, 85% ee determined by HPLC analysis: Chiracel OD-H
column, 99:1 hexanes:iPrOH, flow rate = 1 mL/min, k = 220 nm,
retention time: tmajor = 50.452 min, and tminor = 43.946 min;
4.4.20. Methyl 4-hydroxy-5,5-dimethylhex-2-ynoate11
[a]
20 = +1.8 (c 1.08, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 4.49
D
(dd, J = 12.7, 6.5 Hz, 1H), 3.79 (s, 3H), 2.15 (d, J = 5.9 Hz, 1H), 1.82
– 1.72 (m, 2H), 1.56 – 1.21 (m, 14H), 0.88 (t, J = 6.8 Hz, 3H). 13C
NMR (101 MHz, CDCl3) d 153.83, 88.30, 76.23, 62.15, 52.82,
36.87, 31.87, 29.49, 29.43, 29.27, 29.15, 24.91, 22.67, 14.11. GC–
MS (EI) m/z (%) 123(40), 114(100), 81(56), 55(77).
OH
O
O
4.4.17. Methyl 4-hydroxy-5-methylhex-2-ynoate11
Yield 85%, 51% ee determined by HPLC analysis: Chiracel AS-H
column, 95:5 hexanes:iPrOH, flow rate = 1 mL/min, k = 220 nm,
retention time: tmajor = 8.284 min, and tminor = 7.707 min;
OH
[a
]
D
20 = ꢀ1.0 (c 1.07, CH2Cl2); 1H NMR (400 MHz, DMSO) d 5.81 (d,
J = 5.7 Hz, 1H), 4.06 (d, J = 5.7 Hz, 1H), 3.72 (s, 3H), 0.92 (s, 9H).
13C NMR (101 MHz, DMSO) d 153.71, 89.72, 76.33, 69.31, 53.23,
36.01, 25.61. GC–MS (EI) m/z (%) 114(100), 57(80), 53(30).
O
O
4.4.21. Methyl 4-hydroxy-6-methylhept-2-ynoate11
Yield 96%, 87% ee determined by HPLC analysis: Chiracel AS-H
column, 98:2 hexanes:iPrOH, flow rate = 0.8 mL/min, k = 220 nm,
retention time: tmajor = 27.720 min, and tminor = 24.109 min;
[
a]
D
20 = ꢀ0.4 (c 1.03, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 4.29 (t,
OH
J = 5.8 Hz, 1H), 3.79 (s, 3H), 2.23 (d, J = 5.9 Hz, 1H), 1.96 (qt,
J = 13.5, 6.8 Hz, 1H), 1.04 (dd, J = 6.7, 5.8 Hz, 6H). 13C NMR
(101 MHz, DMSO) d 153.69, 89.77, 76.07, 65.98, 53.23, 34.15,
18.38, 17.91. GC–MS (EI) m/z (%) 125(25), 99(20), 82(40), 53(48).
O
O
4.4.18. Methyl 5-ethyl-4-hydroxyhept-2-ynoate11
Yield 82%, 74% ee determined by HPLC analysis: Chiracel AS-H
column, 98:2 hexanes:iPrOH, flow rate = 1 mL/min, k = 220 nm,
retention time: tmajor = 21.186 min, and tminor = 19.680 min;
OH
[a
]
D
20 = ꢀ8.5 (c 1.07, CH2Cl2); 1H NMR (400 MHz, acetone) d 4.72
O
O
(d, J = 6.0 Hz, 1H), 4.55 (dt, J = 8.0, 6.2 Hz, 1H), 3.74 (s, 3H), 1.86
(td, J = 13.5, 6.7 Hz, 1H), 1.71 – 1.51 (m, 2H), 0.94 (dd, J = 6.7,
Please cite this article in press as: Huang, J.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.03.009

8
J. Huang et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
2.8 Hz, 6H). 13C NMR (101 MHz, acetone) d 153.42, 89.42, 75.01,
59.45, 51.97, 45.85, 24.37, 21.98, 21.54. GC–MS (EI) m/z (%) 114
(100), 81(40), 57(45), 53(55).
4.5. Preparation of the Mosher esters of methyl 4-hydroxy-4-
phenylbut-2-ynoate
To a 5 mL round-bottom flask, methyl 4-hydroxy-4-phenylbut-
2-ynoate (95 mg, 0.5 mmol), DCC (206 mg, 1 mmol), DMPA
(61 mg, 1 mmol), and (R)-Mosher acid or (S)-Mosher acid
(234 mg, 1 mmol) were added. After the solution was stirred at
room temperature for 30 min, the crude mixture was passed
through a short silica gel column to afford the desired (R)-Mosher
ester or (S)-Mosher ester (ꢁ80 mg, 39% yield) as a light yellow oil.
Characterization of the Mosher esters: Proton chemical shifts
are referenced to residual CHCl3 (d 7.26); 19F NMR spectra are
recorded in CDCl3 with TFA (d: ꢀ75.77) as an external standard.
(R)-Mosher ester: 1HNMR (400 MHz, CDCl3) d 3.45 (s, 3H), 3.79
(s, 3H), 6.67 (s, 1H), 7.35–7.42 (m, 6H), 7.44–7.47 (m, 2H), 7.49–
7.53 (m, 2H); 19F NMR (282 MHz, CDCl3) d ꢀ71.76. (S)-Mosher
ester: 1HNMR (400 MHz, CDCl3) d 3.59 (s, 3H), 3.82 (s, 3H), 6.75
(s, 1H), 7.32–7.37 (m, 5H), 7.39–7.44 (m, 5H); 19F NMR
(282 MHz, CDCl3) d ꢀ71.62. On the basis of the 19F NMR, methyl
4-hydroxy-4-phenylbut-2-ynoate, prepared by using (R)-1 as the
catalyst, was determined to have an (S)-configuration.12
4.4.22. Methyl 4-hydroxy-5-phenylpent-2-ynoate8b
OH
O
O
Yield 67%, 87% ee determined by HPLC analysis: Chiracel AD-H
column, 95:5 hexanes:iPrOH, flow rate = 1 mL/min, k = 220 nm,
retention time: tmajor = 20.029 min, and tminor = 17.597 min;
[
a
]
20 = ꢀ0.4 (c 1.09, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 7.48–
D
7.15 (m, 5H), 4.70 (q, J = 6.2 Hz, 1H), 3.78 (s, 2H), 3.25–2.86 (m,
2H), 2.14 (d, J = 6.2 Hz, 1H). 13C NMR (101 MHz, DMSO) d 153.63,
137.25, 130.00, 128.48, 126.93, 90.31, 75.89, 61.91, 53.27, 43.11.
GC–MS (EI) m/z (%) 116(30), 91(100), 65(33).
Acknowledgments
This work was supported the National Natural Science Founda-
tion of China (No. 21302081), the Key Project (211160) and the
Project Sponsored by the Scientific Research Foundation for
the Returned Overseas Chinese Scholars (2012-1707) from State
Ministry of Education, the Scientific Fund of Sichuan Province, China
(2014JQ0052, 14JC0139), the Program of the Education Department
of Sichuan Province (14TD0017, 13ZB0254), and Science and
technology project of Luzhou City (2013LZLY-K58, 2013LZLY-K71).
Q.W. gives thanks to Professor Lin Pu (Department of Chemistry,
University of Virginia) for assistance in preparing this manuscript.
4.4.23. (E)-Methyl 4-hydroxy-6-phenylhex-5-en-2-ynoate8b
OH
O
O
Yield 61%, 89% ee determined by HPLC analysis: Chiracel AD-H
column, 95:5 hexanes:iPrOH, flow rate = 1 mL/min, k = 254 nm,
retention time: tmajor = 28.275 min, and tminor = 30.606 min;
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.03.
009.
[a
]
D
20 = ꢀ1.6 (c 0.51, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 7.55–
7.26 (m, 5H), 6.80 (d, J = 15.8 Hz, 1H), 6.28 (dd, J = 15.8, 6.1 Hz,
1H), 5.18 (t, J = 6.0 Hz, 1H), 3.81 (s, 3H), 2.28 (d, J = 6.5 Hz, 1H).
13C NMR (101 MHz, CDCl3) d 153.70, 135.53, 133.38, 128.69,
128.52, 126.89, 125.66, 85.70, 77.48, 62.65, 52.94. GC–MS (EI) m/
z (%) 215 (M+, 88), 201(84), 131(80), 103(100), 77(82).
References and notes
1. (a) Lu, G.; Li, Y.-M.; Li, X.-S.; Chan, A. S. C. Coord. Chem. Rev. 2005, 249, 1736–
1744; (b) Turlington, M.; Du, Y.-H.; Ostrum, S. G.; Santosh, V.; Wren, K.; Lin, T.;
Sabat, M.; Pu, L. J. Am. Chem. Soc. 2011, 133, 11780–11794; (c) Yue, Y.;
Turlington, M.; Yu, X.-Q.; Pu, L. J. Org. Chem. 2009, 74, 8681–8689; (d) Trost, B.
M.; Weiss, A. H. Adv. Synth. Catal. 2009, 351, 963–983.
4.4.24. (E)-Methyl 4-hydroxydodec-5-en-2-ynoate
2. (a) Qin, Y.-C.; Liu, L.; Sabat, M.; Pu, L. Tetrahedron 2006, 62, 9335–9348; (b)
Rajaram, A. R.; Pu, L. Org. Lett. 2006, 8, 2019–2021; (c) Zhou, L.-H.; Yu, X.-Q.; Pu,
L. J. Org. Chem. 2009, 74, 2013–2017; (d) Chen, W.; Tay, J.-H.; Ying, J.; Yu, X.-Q.;
Pu, L. J. Org. Chem. 2013, 78, 2256–2265; (e) Wang, Q.; Pu, L. Synlett 2013, 1340–
1363; (f) Pu, L. Acc. Chem. Res. 2014, 47, 1523–1535.
3. (a) Guillarme, S.; Ple, K.; Banchet, A.; Liard, A.; Haudrechy, A. Chem. Rev. 2006,
106, 2355–2403; (b) Gao, G.; Pu, L. Sci. China Chem. 2010, 53, 21–35.
4. Gao, G.; Wang, Q.; Yu, X. Q.; Xie, R. G.; Pu, L. Angew. Chem., Int. Ed. 2006, 45,
122–125.
OH
O
O
5. Yang, F.; Xi, P.; Yang, L.; Lan, J.; Xie, R.; You, J. J. Org. Chem. 2007, 72, 5457–5460.
6. Du, Y.-H.; Turlington, M.; Zhou, X.; Pu, L. Tetrahedron Lett. 2010, 51, 5024–5027.
7. Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am. Chem. Soc. 2006, 128, 8–9.
8. (a) Lin, L.; Jiang, X.; Liu, W.; Qui, L.; Xu, Z.; Xu, J.; Chan, A. S. C.; Wang, R. Org.
Lett. 2007, 9, 2329–2332; (b) Xu, T.; Liang, C.; Cai, Y.; Li, J.; Li, Y.-M.; Hui, X.-P.
Tetrahedron: Asymmetry 2009, 20, 2733–2736.
9. (a) Zhong, J.-C.; Hou, S.-C.; Bian, Q.-H.; Yin, M.-M.; Na, R.-S.; Zheng, B.; Li, Z.-Y.;
Liu, S.-Z.; Wang, M. Chem. Eur. J. 2009, 15, 3069–3071; (b) Kojima, N.;
Nishijima, S.; Tsuge, K.; Tanaka, T. Org. Biomol. Chem. 2011, 9, 4425–4428.
10. (a) Turlington, M.; DeBerardinis, A. M.; Pu, L. Org. Lett. 2009, 11, 2441–2444; (b)
Chen, Xi.; Chen, W.; Wang, L.; Yu, X.-Q.; Huang, D.-S.; Pu, L. Tetrahedron 2010,
66, 1990–1993.
Yield 68%, 84% ee determined by HPLC analysis: Chiracel AD-H
column, 97:3 hexanes:iPrOH, flow rate = 1 mL/min, k = 220 nm,
retention time: tmajor = 15.542 min, and tminor = 16.891 min;
[a]
20 = +40.2 (c 1.05, CH2Cl2); 1H NMR (400 MHz, CDCl3) d 5.93
D
(dtd, J = 14.9, 6.8, 1.1 Hz, 1H), 5.59 (ddt, J = 15.3, 6.2, 1.5 Hz, 1H),
4.95 (t, J = 6.0 Hz, 1H), 3.79 (s, 3H), 2.14 (d, J = 6.4 Hz, 1H), 1.32
(dddd, J = 12.7, 10.9, 10.3, 5.3 Hz, 6H), 0.89 (t, J = 6.9 Hz, 3H). 13C
NMR (101 MHz, DMSO) d 153.68, 133.20, 128.76, 89.17, 75.99,
61.13, 53.28, 31.63, 31.20, 28.47, 22.34, 14.31. GC–MS (EI) m/z
(%) 181(35), 136(55), 107(80), 79(70), 55(100).
11. Trost, Barry M.; Bartlett, Mark J.; Weiss, Andrew H.; vonWangelin, Axel Jacobi;
Vincent, S. Chan. Chem. Eur. J. 2012, 18, 16498–16509.
12. Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143–2147.
Please cite this article in press as: Huang, J.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.03.009