Lithium binaphtholate-catalyzed asymmetric addition of lithium acetylides to carbonyl compounds

Article abstract of DOI:10.1021/jo5005394

The asymmetric addition of lithium acetylides to carbonyl compounds in the presence of a chiral lithium binaphtholate catalyst was developed. A procedure involving the slow addition of carbonyl compounds to lithium acetylides improved the enantioselectivi

Full text of DOI:10.1021/jo5005394

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Lithium Binaphtholate-Catalyzed Asymmetric Addition of Lithium
Acetylides to Carbonyl Compounds
Shunsuke Kotani,† Kenji Kukita,‡ Kana Tanaka,‡ Tomonori Ichibakase,‡ and Makoto Nakajima*,‡,§
‡
†Priority Organization for Innovation and Excellence and Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1
Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
S
* Supporting Information
ABSTRACT: The asymmetric addition of lithium acetylides to carbonyl compounds in the presence of a chiral lithium
binaphtholate catalyst was developed. A procedure involving the slow addition of carbonyl compounds to lithium acetylides
improved the enantioselectivity. This reaction afforded diverse chiral secondary and tertiary propargylic alcohols in high yields
and with good to high enantioselectivities.
lective alkynylation of ketones was applied to synthesize
efavirenz, an HIV-1 reverse transcriptase inhibitor.10,11 In both
cases, more than stoichiometric amounts of acetylide and ligand
were required to achieve high enantioselectivity. Recently, we
reported that a catalytic amount of chiral lithium binaphtholate
complex efficiently catalyzed the asymmetric alkynylation of
ketones with lithium acetylides, affording the corresponding
tertiary propargylic alcohols with high enantioselectivity.12 In
this paper, we report the details of lithium binaphtholate-
catalyzed enantioselective alkynylation of carbonyl compounds
using a slow addition procedure, thus dramatically increasing
the enantioselectivity.
INTRODUCTION
■
Organolithiums are versatile reagents and commonly used as
nucleophiles or bases in organic synthesis.1 The cationic
property of lithium leads to higher reactivity than Grignard or
organozinc reagents; however, this property is simultaneously
disadvantageous for achieving high stereoselectivity. Lithium
acetylide, an organolithium reagent, is used in alkynylations of
carbonyl compounds to afford the corresponding propargylic
alcohols that are useful building blocks in the synthesis of
pharmaceuticals, agrochemicals, and natural products.1 There-
fore, asymmetric alkynylations have been developed.2,3 Because
of recent significant progress in asymmetric catalysis, highly
stereoselective alkynylations of terminal alkynes have been
achieved using other metal cocatalysts such as Zn,4,5 Ti,6 Cu,7
and several other metals.8 However, the asymmetric
alkynylation using lithium acetylides without other metals has
been rarely examined despite the high reactivity of
alkynyllithiums (Scheme 1). In 1979, Mukaiyama and co-
workers developed the first enantioselective alkynylation with
lithium acetylide in the absence of other metals.9 They used
lithium acetylides and chiral ligands, affording propargylic
alcohols with high enantioselectivity. In 1995, the enantiose-
RESULTS AND DISCUSSION
■
Survey of Substrates and Catalysts for Enantioselec-
tive Alkynylations. First, we investigated the addition of
lithium phenylacetylide (4u) to benzaldehyde (2a) or
acetophenone (3a) in the presence of 10 mol % of lithium
binaphtholate (1b) (Table 1). Both the lithium reagents 1b and
4u were prepared in situ by adding n-butyllithium to a solution
of (R)-3,3′-diphenyl-2,2′-binaphthol (1b′) and phenylacetylene
(4u′) (Scheme 2). To the resulting solution was added a
solution of carbonyl compound 2a or 3a, affording the
corresponding propargylic alcohols 5au or 6au, respectively.
In the toluene solution, no selectivity was observed in the
alkynylation of 2a and 3a (Table 1, entries 1 and 3). In
contrast, the reaction in THF afforded 5au with moderate
enantioselectivity (32% ee, Table 1, entry 2). Furthermore, the
alkynylation of ketone 3a afforded the corresponding tertiary
Scheme 1. Methods for Asymmetric Alkynylation of
Carbonyl Compounds
Received: March 6, 2014
Published: April 21, 2014
© 2014 American Chemical Society
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a
Table 1. Asymmetric Alkynylation of Carbonyl Compounds
with Lithium Binaphtholate 1b
Table 2. Screening of Catalysts
a
(R)-Li2-BINOLs
b
b
entry
carbonyl compd
solvent
yield (%)
ee (%)
entry
1
R
yield (%)
ee (%)
1
2
3
4
PhCHO (2a)
toluene
THF
89
95
72
87
1
32
3
1
1a
1b
1c
1d
1e
1f
H
90
87
78
94
90
77
81
80
95
96
96
95
91
96
2
67
17
15
60
28
63
57
0
2
Ph
Br
Me
PhCOCH3 (3a)
toluene
THF
3
67
4
a
5
4-tolyl
The reaction was conducted by adding a solution of carbonyl
compound 2a or 3a over 1 min to a solution of acetylene 4u′ (2.0
equiv), (R)-Ph2-BINOL 1b′ (10 mol%), and n-BuLi (2.0 equiv) in the
above-mentioned solvent at 0 °C (entries 1 and 2) or at 23 °C (entries
6
3,5-xylyl
4-FC6H4
7
1g
1h
7
8
4-MeOC6H4
b
3 and 4). Determined by chiral HPLC.
9
Ph
Ph
Ph
Ph
Ph
Ph
10
11
12
13
14
8
0
c
c
c
c
Scheme 2. In Situ Generation of Lithium Binaphtholate and
Lithium Acetylide
1b
1b
1b
1b
92
96
96
96
,
,
,
d
e
d
,f
a
The reaction was conducted by adding a THF solution of ketone 3a
over 1 min to a THF solution of 4u′ (2.0 equiv), (R)-BINOL 1′ (10
b
c
mol%), and n-BuLi (2.0 equiv) at rt. Determined by chiral HPLC. At
d
e
−78 °C for 2 h. A THF solution of ketone 3a was added over 1 h. A
THF solution of ketone 3a was added over 3 h. 2 mol % of 1b was
f
used.
alcohol 6au with good enantioselectivity (67% ee, Table 1,
entry 4).
Screening of BINOLs for the Asymmetric Alkynylation
of Ketones. We investigated the alkynylation of ketone 3a
with lithium acetylide 4u using diverse BINOLs 1 because the
alkynylations of ketones have not been well established
compared to those of aldehydes (Table 2). The parent
BINOL (R = H, 1a) was ineffective (Table 2, entry 1).
Introduction of bromo, methyl, or different substituents on the
phenyl group did not improve the enantioselectivity. The best
result was obtained with 1b (R = Ph). Since no
enantioselectivity was achieved by using O-methylated
BINOL derivatives 7 and 8 (structures shown below Table
2), a bisphenol motif is absolutely essential for the asymmetric
alkynylation (Table 2, entries 9 and 10). When the reaction was
performed at −78 °C, both the product yield and
enantioselectivity dramatically increased (Table 2, entry 11).
We reported these reaction conditions (standard conditions:
catalyst, 1b; solvent, THF; reaction temperature, −78 °C) in
our previous communication.12 After further detailed inves-
tigation, we discovered that a slow addition of a solution of
ketone 3a over 1 h (slow addition procedure) improved the
enantioselectivity to 96% ee (Table 2, entry 12). A further
increase in the addition time did not improve the
enantioselectivity (Table 2, entry 13). Even when the catalyst
loading was reduced to 2 mol %, the product was obtained
without loss of both yield and enantioselectivity (Table 2, entry
14).
(addition over 1 min) are also listed in Table 3 for comparison
with those of the slow addition procedure (addition over 1 h).
Ethyl ketone 3b still afforded good enantioselectivity (Table 3,
entry 2), whereas isopropyl ketone 3c decreased the selectivity
because of less enantiodifferentiation by ketone 3c (Table 3,
entry 3). Although ortho-substituted ketone 3d slightly
decreased the yield, high enantioselectivity was achieved in
the reaction of tolylaldehydes 3d−f irrespective of the
substituent position (Table 3, entries 4−6). Aryl methyl
ketones 3g−m also afforded the corresponding tertiary
propargylic alcohols in both high chemical and optical yields
(Table 3, entries 7−13). In the reactions of ketones 3l and 3m,
the slow addition procedure decreased the product yields
(Table 3, entries 12 and 13). When the reactions were
quenched with deuterium oxide, deuterated ketones 3l-dα and
3m-dα could be obtained. The observation indicated that the
enolization of ketones was preferred over alkynylation because
of low electrophilicity of the carbonyl groups (Figure 1).13 Even
the alkynylation of ketone 3n, with a small steric difference
between the carbonyl substituents, afforded good enantiose-
lectivity (Table 3, entry 14). The alkynylation of aliphatic
ketone 3o was successful, affording good enantioselectivity
(Table 3, entry 15). Notably, ketones bearing heteroaromatic
rings afforded high yields and enantioselectivity because other
metal catalysts were less selective (Table 3, entries 16−18).
Propargylic alcohol 6qu, which exhibits antifungal activity,
Asymmetric Alkynylation of Ketones with Alkynes.
With the optimized reaction conditions and catalyst 1b, we
performed the asymmetric alkynylation of various ketones 3
(Table 3). The results obtained by using standard conditiosn12
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a
Table 3. Asymmetric Alkynylation of Ketones
b
ketone
R1
standard conditions
yield (%)
slow addition procedure
c
c
entry
3
R2
6
ee (%)
yield (%)
ee (%)
1
2
3a
3b
3c
3d
3e
3f
Ph
Ph
Ph
Me
Et
6au
6bu
6cu
6du
6eu
6fu
96
93
99
53
97
93
95
95
89
93
73
7
95
95
95
66
90
94
92
92
93
94
93
21
21
96
89
92
96
90
96
89
8
d
3
iPr
4
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-CF3C6H4
4-FC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
87
94
88
92
76
91
91
96
96
95
95
95
94
93
78
98
55
81
95
94
92
5
6
7
3g
3h
3i
6gu
6hu
6iu
8
9
10
11
3j
4-BrC6H4
2-naphthyl
1-naphthyl
3,4,5-(MeO)3C6H2
PhCH2CH2
iPr
6ju
3k
3l
6ku
6lu
94
76
90
99
95
85
70
97
39
33
d
12
d
13
3m
3n
3o
3p
3q
3r
6mu
6nu
6ou
6pu
6qu
6ru
14
15
16
17
18
2-thienyl
3-pyridyl
96
90
87
71
4-pyridyl
a
The reaction was conducted by adding a THF solution of ketone 3 to a THF solution of alkyne 4u′ (2.0 equiv), (R)-1b′ (10 mol%), and n-BuLi
b
c
d
(2.0 equiv) at −78 °C. A THF solution of ketone 3 was added over 1 h. Determined by chiral HPLC. For 6 h.
Table 4. Asymmetric Alkynylation of Acetophenone with
a
Alkynes
Figure 1. Enolization of 3m with lithium acetylide.
slow addition
b
could be readily synthesized.14 The slow addition procedure
was quite efficient for diverse substrates, affording the
corresponding products with improved enantioselectivity.
The alkynylations of diverse alkynes with acetophenone (3a)
are summarized in Table 4. n-Alkynes such as 1-hexyne (4v)
and 1-decyne (4w) afforded the corresponding tertiary
propargylic alcohols in high yields and with good enantiose-
lectivities (Table 4, entries 2 and 3). In the reaction of
cyclohexenylacetylene (4x), excellent selectivity was obtained
(Table 4, entry 4). Alkynes containing an oxygen or a silicon
atom also afforded the corresponding products with high
enantioselectivity (Table 4, entries 5 and 6). In the reaction
with alkyne 4z, the slow addition procedure dramatically
improved the enantioselectivity from 44% to 91% ee. This
alkynylation method of ketones has a broad substrate scope in
terms of both ketones and alkynes.
Determination of the Absolute Configuration of
Chiral Tertiary Propargylic Alcohols. Several asymmetric
alkynylations of ketones have been reported; however, the
determination of the absolute configurations of tertiary
propargylic alcohols has not been well established. This is
because the volume of the optical rotation data of this series of
compounds is small. To determine the absolute configurations,
the derivatives of product 6 were prepared by following the
procedure as shown in Scheme 3.15 Propargylic alcohol 6bu
lithium acetylide
R3
standard conditions
procedure
c
c
yield
(%)
ee
(%)
yield
(%)
ee
entry
4
6
(%)
1
2
3
4
5
6
4u
4v
4w
4x
4y
4z
Ph
6au
6av
6aw
6ax
6ay
6az
96
89
92
80
97
88
93
87
86
84
86
44
95
95
99
99
99
93
96
90
92
95
87
91
nBu
noctyl
cyclohexenyl
BnOCH2
TMS
a
The reaction was conducted by adding a THF solution of ketone 3a
to a THF solution of alkyne 4′ (2.0 equiv), (R)-1b′ (10 mol%), and n-
b
BuLi (2.0 equiv) at −78 °C. A THF solution of ketone 3 was added
c
over 1 h. Determined by chiral HPLC.
was reduced with Red-Al to afford the corresponding allylic
alcohol, followed by the ozonolysis and oxidation to afford the
corresponding ester 7b. The optical rotation of 7b was
compared with the reported value in the literature,16 and the
absolute configuration of 4bu was determined to be S.
Following the same procedure, the absolute configurations of
several products were determined, resulting in the S
configuration in all the cases.17
Asymmetric Alkynylation of Aldehydes with Alkynes.
Because the slow addition procedure was quite efficient for the
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Scheme 3. Derivatization of 6
alkynylation of ketones, we applied this procedure to the
asymmetric alkynylation of aldehydes (Table 5). When the
Table 6. Asymmetric Alkynylation of Aldehydes with
Alkynes
a
Table 5. Effect of Slow Addition Procedure for the
a
Alkynylation of Benzaldehyde 2a
lithium acetylide
R2
secondary propargylic alcohol
b
entry
4
5
yield (%)
ee (%)
1
2
3
4
5
4u
4v
4w
4x
4y
4z
Ph
5au
5av
5aw
5ax
5ay
5az
97
99
94
92
98
91
75
15
21
61
42
44
b
entry
addition time
yield (%)
ee (%)
nBu
noctyl
1
2
3
1 min
10 min
1 h
96
97
91
49
75
74
1-cyclohexenyl
BnOCH2
TMS
a
The reaction was conducted by adding a THF solution of aldehyde
6
2a over the above-mentioned addition time to a THF solution of
alkyne 4u′ (2.0 equiv), (R)- 1b′ (10 mol %), and n-BuLi (2.0 equiv) at
a
The reaction was conducted by adding a THF solution of aldehyde
2a over 10 min to a THF solution of an acetylene 4′ (2.0 equiv), (R)-
b
−78 °C. Determined by chiral HPLC.
b
1b′ (10 mol%), and n-BuLi (2.0 equiv) at −78 °C. Determined by
chiral HPLC.
asymmetric alkynylation of aldehyde 2a was performed with
lithium acetylide 4u at −78 °C, the standard conditions
afforded the corresponding product with only 49% ee (Table 5,
entry 1). The slow addition procedure dramatically improved
the enantioselectivity (Table 5, entries 2 and 3), and the best
result was obtained by the addition over 10 min (Table 5, entry
2).
Table 7. Asymmetric Alkynylation of Aldehydes with
Alkynes
a
The reactions of diverse alkynes 4 with benzaldehyde (2a)
were conducted (Table 6). The reactions of 1-hexyne (4v) and
1-decyne (4w) afforded almost racemic products (Table 6,
entries 2 and 3). Moderate enantioselectivity was observed in
the reaction with 1-cyclohexenylacetylene (4x) (Table 6, entry
4). The enantioselectivities of 3-(benzyloxy)prop-1-yne (4y)
and (trimethylsilyl)acetylene (4z) were moderate (Table 6,
entries 5 and 6).
Next, we investigated the alkynylation of diverse aldehydes 2
(Table 7). The nucleophilicity of lithium acetylide severely
affected the product selectivity. The enantioselectivity of
aromatic aldehydes depends on the steric and electronic effects
of the substituents on the phenyl groups (Table 7, entries 2−
5). Although the aldehydes with electron-withdrawing groups
decreased the enantioselectivity, the aldehydes with electron-
donating groups afforded good to high enantioselectivity. The
best enantioselectivity was achieved in the reaction with 3,4,5-
trimethoxybenzaldehyde (Table 7, entry 5). Aliphatic aldehyde
2f was less selective, affording moderate enantioselectivity
(Table 7, entry 6).
aldehyde
R1
secondary propargylic alcohol
b
entry
2
5
yield (%)
ee (%)
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
Ph
5au
5bu
5cu
5du
5eu
5fu
97
99
98
96
95
90
75
75
71
65
82
58
4-MeOC6H4
4-ClC6H4
2-naphthyl
3,4,5-(MeO)3C6H2
chex
a
The reaction was conducted by adding a THF solution of aldehyde
2a over 10 min to a THF solution of an acetylene 4u′ (2.0 equiv), (R)-
b
1b′ (10 mol%), and n-BuLi (2.0 equiv) at −78 °C. Determined by
chiral HPLC.
addition, we showed that the slow addition procedure
efficiently improved the enantioselectivity. This procedure
was useful for the alkynylation of carbonyl compounds with
lithium acetylide without using other metals. The study paved
the path to develop enantioselective reactions of organolithium
reagents.
Conclusion. The chiral lithium binaphtholate-catalyzed
enantioselective alkynylation of ketones and aldehydes with
lithium acetylides afforded the corresponding optically active
tertiary propargylic alcohols with high enantioselectivity. In
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2H), 7.62 (d, 2H, J = 8.2 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ
21.0, 33.2, 70.2, 84.8, 92.6, 122.6, 124.9, 128.3, 128.4, 129.0, 131.7,
137.5, 142.8. HPLC: Daicel Chiralcel OD-H, hexane/IPA = 19:1, 1.0
mL/min, 254 nm, tR = 8.1 min (R), tR = 10.9 min (S).
(−)-2-(4-Methoxyphenyl)-4-phenylbut-3-yn-2-ol (6gu). The ex-
perimental data are in accordance with those reported in the previous
literature.4h 104.5 mg (92% yield). [α]30D −6.9 (c 1.3, CHCl3) for 95%
ee. 1H NMR (CDCl3, 500 MHz): δ 1.86 (s, 3H), 2.39 (s, 1H), 3.82 (s,
3H), 6.91 (m, 2H, J = 9.2 Hz), 7.32−7.35 (m, 3H), 7.47−7.49 (m,
2H), 7.64−7.67 (d, 2H, J = 9.2 Hz). 13C{1H} NMR (CDCl3, 125
MHz): δ 33.2, 55.3, 70.1, 84.8, 92.6, 113.6, 122.6, 126.3, 128.3, 128.5,
131.7, 137.9, 159.2. HPLC: Daicel Chiralcel OD-H, hexane/IPA =
19:1, 1.0 mL/min, 254 nm, tR = 12.4 min (minor), tR = 19.8 min
(major).
EXPERIMENTAL SECTION
■
Representative Procedure for Asymmetric Alkynylations of
Ketones. Lithium acetylide 4u and lithium binaphtholate 1b were
prepared by the addition of n-BuLi (1.65 M in hexane, 0.52 mL, 0.86
mmol) to the solution of (R)-3,3′-diphenyl-1,1′-binaphthalene-2,2′-
diol (19 mg, 0.043 mmol) and phenylacetylene (0.10 mL, 0.86 mmol)
in THF (1.0 mL) at −78 °C. To the resulting solution was added
acetophenone (3a) (0.05 mL, 0.43 mmol) in THF (1.0 mL) over 1 h
at the same temperature, and the resulting solution was stirred for an
additional 3 h. After being quenched with saturated aq NH4Cl, the
reaction mixture was extracted with EtOAc. The organic layer was
washed with saturated aq NaHCO3 and saturated aq NaCl. After
drying over Na2SO4, the solvent was removed under vacuum, and the
residue was purified by silica gel column chromatography (hexane/
CH2Cl2 = 1/1) to afford 6au (90.2 mg, 95% yield) as an oil. The
enantiomeric excess (ee) was determined to be 96% by chiral HPLC
with Daicel Chiralcel OD-H column.
(S)-(−)-2-[(4-Trifluoromethyl)phenyl]-4-phenylbut-3-yn-2-ol
(6hu). The experimental data are in accordance with those reported in
the previous literature.7c 114.2 mg (92% yield). [α]16 −12.1 (c 0.65,
D
CHCl3) for 95% ee. 1H NMR (CDCl3, 500 MHz): δ 1.87 (s, 3H), 2.57
(s, 1H), 7.31−7.36 (m, 3H), 7.47−7.49 (m, 2H), 7.65 (d, 2H, J = 8.3
Hz), 7.85 (d, 2H, J = 8.3 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ
33.5, 70.1, 85.5, 91.6, 122.1, 124.1 (q, J = 269 Hz), 125.3 (q, J = 39
Hz), 128.3, 128.8, 130.4 (q, J = 3 Hz), 131.7, 149.5. HPLC: Daicel
Chiralcel OD-H, hexane/IPA = 19:1, 1.0 mL/min, 254 nm), tR = 7.6
min (R), tR = 9.0 min (S).
(S)-(−)-2,4-Diphenylbut-3-yn-2-ol (6au). The experimental data
are in accordance with those reported in the previous literature.15 90.2
mg (95% yield). [α]30 −7.4 (c 1.3, CHCl3) for 96% ee [lit. [α]22
D
D
−6.6 (c 1.0, CHCl3) for 82% ee, (S)]. 1H NMR (CDCl3, 500 MHz): δ
1.87 (s, 3H), 2.46 (s, 1H), 7.30−7.50 (m, 8H), 7.73−7.75 (d, 2H, J =
7.3 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ 33.3, 70.4, 84.9, 92.4,
122.5, 125.0, 127.7, 128.29, 128.34, 128.5, 131.7, 145,6. HPLC: Daicel
Chiralcel OD-H, hexane/isopropyl alcohol (IPA) = 19:1, 1.0 mL/min,
254 nm, tR = 8.8 min (R), tR = 10.9 min (S).
(−)-2-(4-Fluorophenyl)-4-phenylbut-3-yn-2-ol (6iu). The exper-
imental data are in accordance with those reported in the previous
literature.4m 93.4 mg (93% yield). [α]30D −8.3 (c 1.6, CHCl3) for 95%
ee. 1H NMR (CDCl3, 500 MHz): δ 1.85 (s, 3H), 2.48 (s, 1H), 7.04−
7.08 (m, 2H), 7.31−7.35 (m, 3H), 7.47−7.49 (m, 2H), 7.68−7.71 (m,
2H). 13C{1H} NMR (CDCl3, 125 MHz): δ 33.5, 70.0, 85.1, 92.1,
115.1 (d, J = 21 Hz), 122.4, 126.8 (d, J = 7 Hz), 128.4, 128.6, 131.7,
141.5 (d, J = 4 Hz), 162.2 (d, J = 244 Hz). HPLC: Daicel Chiralcel
OD-H, hexane/IPA = 19:1, 1.0 mL/min, 254 nm, tR = 8.3 min
(minor), tR = 10.4 min (major).
(S)-(−)-1,3-Diphenylpent-1-yn-3-ol (6bu). The experimental data
are in accordance with those reported in the previous literature:7c 84.4
mg (95% yield). [α]30 −10.9 (c 3.3, CHCl3) for 89% ee. H NMR
1
D
(CDCl3, 500 MHz): δ 1.03 (t, 3H, J = 7.3 Hz), 1.95−2.13 (m, 2H),
2.45 (s, 1H), 7.30−7.40 (m, 6H), 7.48−7.51 (m, 2H), 7.68−7.77 (m,
2H). 13C{1H} NMR (CDCl3, 125 MHz): δ 9.2, 38.4, 74.3, 86.1, 91.3,
122.6, 125.6, 127.7, 128.2, 128.3, 128.5, 131.7, 144.5. HPLC: Daicel
Chiralcel OD-H, hexane/IPA = 49:1, 1.0 mL/min, 254 nm, tR = 13.5
min (R), tR = 17.0 min (S).
(−)-2-(4-Bromophenyl)-4-phenyl-but-3-yn-2-ol (6ju). The exper-
imental data are in accordance with those reported in the previous
literature.18 128.5 mg (94% yield). [α]29 −5.9 (c 0.88, CHCl3) for
(−)-4-Methyl-1,3-diphenylpent-1-yn-3-ol (6cu). The experimental
data are in accordance with those reported in the previous literature.15
79.0 mg (95% yield). [α]30D −1.8 (c 0.90, CHCl3) for 8% ee. 1H NMR
(CDCl3, 500 MHz): δ 0.89 (d, 3H, J = 7.2 Hz), 1.14 (d, 3H, J = 6.7
Hz), 2.14−2.23 (qq, 1H, J = 6.7, 7.2 Hz), 2.41 (s, 1H), 7.28−7.39 (m,
6H), 7.47−7.53 (m, 2H), 7.66−7.71 (m, 2H). 13C{1H} NMR (CDCl3,
125 MHz): δ 17.5, 18.1, 40.5, 77.5, 86.9, 90.3, 122.7, 126.2, 127.6,
127.9, 128.3, 128.4, 131.7, 143.9. HPLC: Daicel Chiralpak AD-H,
hexane/IPA = 19:1, 1.0 mL/min, 254 nm, tR = 9.9 min (minor), tR =
14.6 min (major).
(−)-2-(2-Methylphenyl)-4-phenylbut-3-yn-2-ol (6du). The exper-
imental data are in accordance with those reported in the previous
literature.7c 59.6 mg (66% yield). [α]30D −9.4 (c 1.4, CHCl3) for 91%
ee. 1H NMR (CDCl3, 500 MHz): δ 1.94 (s, 3H), 2.40 (s, 1H), 2.69 (s,
3H), 7.19−7.33 (m, 6H), 7.41−7.46 (m, 2H), 7.74−7.77 (m, 1H).
13C{1H} NMR (CDCl3, 125 MHz): δ 21.3, 31.0, 70.0, 84.6, 92.8,
122.7, 125.0, 125.8, 127.7, 128.3, 128.4, 131.6, 132.3, 135.7, 142.3.
HPLC: Daicel Chiralcel OD-H, hexane/IPA = 19:1, 1.0 mL/min, 254
nm, tR = 9.6 min (minor), tR = 10.7 min (major).
D
1
94% ee. H NMR (CDCl3, 500 MHz): δ 1.84 (s, 3H), 2.42 (s, 1H),
7.30−7.35 (m, 3H), 7.45−7.52 (m, 4H), 7.58−7.61 (m, 2H). 13C{1H}
NMR (CDCl3, 125 MHz): δ 33.5, 70.0, 85.2, 91.8, 121.7, 122.2, 126.9,
128.3, 128.7, 131.4, 131.7, 144.8. HPLC: Daicel Chiralcel OD-H,
hexane/IPA = 19:1, 1.0 mL/min, 254 nm, tR = 9.3 min (minor), tR =
11.4 min (major).
(S)-(−)-2-(2-Naphthyl)-4-phenylbut-3-yn-2-ol (6ku). The exper-
imental data are in accordance with those reported in the previous
literature.4m 109.1 mg (93% yield). [α]29 −16.5 (c 1.4, CHCl3) for
D
1
93% ee. H NMR (CDCl3, 500 MHz): δ 1.95 (s, 3H), 2.58 (s, 1H),
7.31−7.35 (m, 3H), 7.46−7.52 (m, 4H), 7.78−7.88 (m, 4H), 8.18 (s,
1H). 13C{1H} NMR (CDCl3, 125 MHz): δ 33.2, 70.5, 85.1, 92.4,
122.5, 123.4, 123.5, 126.1, 126.2, 127.6, 128.2, 128.3, 128.5, 131.8,
132.9, 133.0, 142.9. HPLC: Daicel Chiralcel OD-H, hexane/IPA = 9:1,
1.0 mL/min, 254 nm, tR = 8.6 min (R), tR = 11.1 min (S).
(+)-2-(1-Naphthyl)-4-phenylbut-3-yn-2-ol (6lu). The experimental
data are in accordance with those reported in the previous literature.4m
1
27.0 mg (21% yield). [α]29 +17.8 (c 0.73, CHCl3) for 78% ee. H
D
(−)-2-(3-Methylphenyl)-4-phenylbut-3-yn-2-ol (6eu). The exper-
NMR (CDCl3, 500 MHz): δ 2.15 (s, 3H), 2.67 (s, 1H), 7.24−7.29 (m,
3H), 7.42−7.55 (m, 5H), 7.83 (d, 1H, J = 8.2 Hz), 7.89 (d, 1H, J = 8.0
Hz), 7.98 (dd, 1H, J = 1.2, 7.3 Hz), 8.86 (d, 1H, J = 8.9 Hz). 13C{1H}
NMR (CDCl3, 125 MHz): δ 31.8, 70.4, 85.5, 93.2, 122.6, 122.9, 124.9,
125.4, 125.5, 126.3, 128.3, 128.4, 129.0, 129.2, 130.1, 131.6, 134.7,
140.0. HPLC: Daicel Chiralcel OD-H, hexane/IPA = 19:1, 1.0 mL/
min, 254 nm, tR = 12.5 min (minor), tR = 15.8 min (major).
imental data are in accordance with those reported in the previous
literature.7c 78.2 mg, (90% yield). [α]30 −5.6 (c 0.86, CHCl3) for
D
96% ee. [lit. [α]20 +5.8 (c 1.21, CHCl3) for 86% ee]. 1H NMR
D
(CDCl3, 500 MHz): δ 1.86 (s, 3H), 2.39 (s, 3H), 2.45 (s, 1H), 7.12 (d,
1H, J = 7.3 Hz), 7.25−7.35 (m, 4H), 7.47−7.54 (m, 4H). 13C{1H}
NMR (CDCl3, 125 MHz): δ 21.6, 33.3, 70.3, 84.8, 92.6, 122.1, 122.6,
125.6, 128.2, 128.3, 128.4, 128.5, 131.7, 138.0, 145.6. HPLC: Daicel
Chiralcel OD-H, hexane/IPA = 19:1, 1.0 mL/min, 254 nm, tR = 8.2
min (minor), tR = 9.9 min (major).
(S)-(−)-2-(4-Methylphenyl)-4-phenylbut-3-yn-2-ol (6fu). The ex-
perimental data are in accordance with those reported in the previous
literature.7c 83.4 mg (94% yield). [α]28D −5.8 (c 0.65, CHCl3) for 96%
ee. 1H NMR (CDCl3, 500 MHz): δ 1.86 (s, 3H), 2.36 (s, 3H), 2.41 (s,
1H), 7.19 (d, 2H, J = 8.2 Hz), 7.28−7.33 (m, 3H), 7.47−7.49 (m,
(+)-4-Phenyl-2-(3,4,5-trimethoxyphenyl)but-3-yn-2-ol (6mu).
37.0 mg (26% yield). [α]30 +7.0 (c 1.2, CHCl3) for 98% ee. IR
D
(neat): ν (cm−1) 3431, 2935, 2835, 1593. 1H NMR (CDCl3, 500
MHz): δ 1.87 (s, 3H), 2.50 (s, 1H), 3.86 (s, 3H), 3.90 (s, 6H), 6.98 (s,
2H), 7.31−7.35 (m, 3H), 7.46−7.48 (m, 2H). 13C{1H} NMR (CDCl3,
125 MHz): δ 33.3, 56.1, 60.8, 70.5, 84.9, 92.3, 102.3, 122.4, 128.4,
128.6, 131.6, 137.4, 141.4, 153.0. LRMS (FAB): m/z 335 (M + Na)+,
312, 129, 77. HRMS: calcd for C19H20O4Na 335.1259, found
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The Journal of Organic Chemistry
Featured Article
335.1269. HPLC: Daicel Chiralcel OD-H, hexane/IPA = 9:1, 1.0 mL/
min, 254 nm, tR = 10.6 min (minor), tR = 14.1 min (major).
(S)-(+)-3-Methyl-1,5-diphenylpent-1-yn-3-ol (6nu). The experi-
mental data are in accordance with those reported in the previous
ee. 1H NMR (CDCl3, 500 MHz): δ 1.56−1.68 (m, 4H), 1.77 (s, 3H),
2.07−2.17 (m, 4H), 2.34 (s, 1H), 6.16 (t, 1H, J = 1.9 Hz), 7.25−7.39
(m, 3H), 7.65−7.67 (m, 2H). 13C{1H} NMR (CDCl3, 125 MHz): δ
21.4, 22.2, 25.6, 29.2, 33.4, 70.3, 86.7, 89.8, 120.1, 125.0, 127.5, 128.2,
135.4, 146.0. HPLC: Daicel Chiralcel OD-H, hexane/IPA = 99:1, 1.0
mL/min, 254 nm, tR = 16.1 min (minor), tR = 17.5 min (major).
(−)-1-(Benzyloxy)-4-phenylpent-2-yn-4-ol (6ay). The experimen-
tal data are in accordance with those reported in the previous
literature.24 115.0 mg (99% yield). [α]31D −4.5 (c 2.0, CHCl3) for 87%
ee. 1H NMR (CDCl3, 500 MHz): δ 1.76 (s, 3H), 2.51 (s, 1H), 4.23 (s,
2H), 4.61 (s, 2H), 7.24−7.36 (m, 8H), 7.63−7.65 (m, 2H). 13C{1H}
NMR (CDCl3, 125 MHz): δ 33.1, 57.4, 69.9, 71.7, 80.8, 90.0, 124.8,
127.7, 127.9, 128.1, 128.3, 128.4, 137.3, 145.3. HPLC: Daicel Chiralcel
OD-H, hexane/IPA = 19:1, 1.0 mL/min, 254 nm, tR = 14.2 min
(minor), tR = 16.0 min (major).
literature.4e 80.3 mg (96% yield). [α]28 +7.4 (c 1.9, CHCl3) for 55%
D
ee. 1H NMR (CDCl3, 500 MHz): δ 1.63 (s, 3H), 2.01−2.10 (m, 3H),
2.91−2.95 (m, 2H), 7,18−7.32 (m, 8H), 7.43−7.46 (m, 2H). 13C{1H}
NMR (CDCl3, 125 MHz): δ 30.1, 31.3, 45.4, 68.5, 83.9, 92.4, 122.6,
125.9, 128.27, 128.33, 128.4, 131.7, 141.9. HPLC: Daicel Chiralcel
OD-H, hexane/IPA = 19:1, 1.0 mL/min, 254 nm, tR = 11.5 min (R), tR
= 15.6 min (S).
(+)-3,4-Dimethyl-1-phenylpent-1-yn-3-ol (6ou). The experimental
data are in accordance with those reported in the previous literature.4e
1
78.6 mg (81% yield). [α]30 +5.9 (c 0.98, CHCl3) for 81% ee. H
D
NMR (CDCl3, 500 MHz): δ 1.07 (d, 3H, J = 6.7 Hz), 1.11 (d, 3H, J =
6.7 Hz), 1.54 (s, 3H), 1.90 (qq, 1H, J = 6.7, 6.7 Hz), 2.02 (s, 1H),
7.28−7.31 (m, 3H), 7.40−7.44 (m, 2H). 13C{1H} NMR (CDCl3, 125
MHz): δ 17.5, 18.0, 27.2, 39.1, 72.1, 84.0, 92.0, 122.9, 128.17, 128.21,
131.6. HPLC: Daicel Chiralcel OD-H, hexane/IPA = 19:1, 1.0 mL/
min, 254 nm, tR = 6.0 min (minor), tR = 8.2 min (major).
(+)-2-Phenyl-4-(trimethylsilyl)but-3-yn-2-ol (6az). The experimen-
tal data are in accordance with those reported in the previous
literature.25 88.7 mg (91% yield). [α]28 +6.1 (c 1.5, CHCl3) for 91%
D
ee. 1H NMR (CDCl3, 500 MHz): δ 0.21 (s, 9H), 1.76 (s, 3H), 2.33 (s,
1H), 7.27−7.31 (m, 1H), 7.34−7.38 (m, 2H), 7.64−7.66 (m, 2H).
13C{1H} NMR (CDCl3, 125 MHz): δ −0.1, 33.3, 70.2, 89.3, 108.7,
124.9, 127.7, 128.3, 145.4. HPLC: Daicel Chiralpak AS-H, hexane/IPA
= 99:1, 0.5 mL/min, 254 nm, tR = 24.0 min (minor), tR = 26.2 min
(major).
(−)-2-(2-Thienyl)-3-phenylbut-3-yn-2-ol (6pu). The experimental
data are in accordance with those reported in the previous literature.19
1
98.3 mg (92% yield). [α]22 −7.7 (c 0.65, CHCl3) for 95% ee. H
D
NMR (CDCl3, 500 MHz): δ 1.99 (s, 3H), 2.66 (s, 1H), 6.96−6.98 (m,
1H), 7.25−7.35 (m, 5H), 7.47−7.50 (m, 2H). 13C{1H} NMR (CDCl3,
125 MHz): δ 33.1, 67.7, 84.3, 91.7, 122.3, 124.0, 125.1, 126.7, 128.3,
128.7, 131.8, 150.6. HPLC: Daicel Chiralcel OD-H, hexane/IPA =
19:1, 1.0 mL/min, 254 nm, tR = 10.6 min (minor), tR = 13.4 min
(major).
Representative Procedure for Preparation of Esters 7a.
Reduction of alkynes to alkenes: A solution of Red-Al in toluene (65%,
4.0 equiv) was added to a solution of propargyl alcohol 6bu in
anhydrous Et2O at 0 °C via a syringe. The reaction mixture was
allowed to warm slowly to room temperature and stirred for 4 h. Then,
the mixture was cooled to 0 °C and quenched by dropwise addition of
MeOH. The resulting solution was allowed to warm to rt and diluted
with EtOAc. The solution was washed with saturated aq Rochelle’s salt
(sodium potassium tartrate), and the organic layer was dried over
MgSO4. After filtration and concentration, the resulting yellowish oil
was purified by column chromatography (eluent: hexane/EtOAc =
8:1) to afford the corresponding alkene.
Ozonolysis of alkenes to aldehydes: Ozone was bubbled into a
solution of the alkene in CH2Cl2 at −78 °C until a blue color persisted.
Oxygen was then passed through the solution to remove the ozone,
and then triphenylphosphine (1 equiv) was added at −78 °C. The
resulting mixture was stirred for 1 h at rt. The mixture was
concentrated under reduced pressure to afford an oil, which was
purified by column chromatography (eluent: hexane/EtOAc = 6:1) to
afford the corresponding aldehyde as an oil.
Oxidation of aldehyde to ester: NaHCO3 (33 equiv) was added to a
solution of the aldehyde in MeOH/water (9:1 v/v), followed by the
addition of bromine (7.5 equiv) over 30 min under vigorous stirring at
rt. After the solution was stirred for 2 h, the excess bromine was
decomposed with Na2S2O3. The resulting solution was filtered, and the
filtrate was extracted with EtOAc. The organic layer was washed with
brine and dried over Na2SO4. After concentration in vacuo, the crude
product obtained was purified by column chromatography (eluent:
hexane/CH2Cl2 = 3:2 to 1:3) to afford 7b (38 yield from 6bu) as a
colorless oil.
(−)-4-Phenyl-2-(3-pyridinyl)but-3-yn-2-ol (6qu). The experimental
data are in accordance with those reported in the previous literature.20
97.9 mg (96% yield). [α]33 −2.5 (c 0.89, CHCl3) for 94% ee [lit.
D
1
[α]24 −0.9 (c 1.0, CHCl3) for 75% ee, (S)]. H NMR (CDCl3, 500
D
MHz): δ 1.88 (s, 3H), 3.51 (s, 1H), 7.27−7.35 (m, 4H), 7.46−7.51
(m, 2H), 8.01−8.03 (m, 1H), 8.54−8.56 (m, 1H), 8.97 (m, 1H).
13C{1H} NMR (CDCl3, 125 MHz): δ 33.4, 68.7, 85.6, 91.4, 122.1,
123.1, 128.4, 128.7, 131.7, 132.9, 141.3, 147.0, 148.8. HPLC: Daicel
Chiralcel OD-H, hexane/IPA = 9:1, 1.0 mL/min, 254 nm, tR = 9.9 min
(minor), tR = 12.3 min (major).
(−)-4-Phenyl-2-(4-pyridinyl)but-3-yn-2-ol (6ru). The experimental
data are in accordance with those reported in the previous literature.21
1
85.7 mg (90% yield). [α]30 −4.3 (c 0.52, CHCl3) for 92% ee. H
D
NMR (CDCl3, 500 MHz): δ 1.82 (s, 3H), 4.01−6.21 (brs, 1H), 7.27−
7.35 (m, 3H), 7.41−7.44 (m, 2H), 7.62 (d, 2H, J = 6.1 Hz), 8.59 (d,
2H, J = 6.1 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ 33.1, 68.9, 85.0,
91.6, 120.2, 122.1, 128.3, 128.6, 131.6, 149.2, 155.6. HPLC: Daicel
Chiralcel OD-H, hexane/IPA = 4:1, 1.0 mL/min, 254 nm, tR = 7.2 min
(minor), tR = 11.0 min (major).
2-Phenyloct-3-yn-2-ol (6av). The experimental data are in
accordance with those reported in the previous literature.22 82.3 mg
(95% yield). [α]30 −0.3 (c 1.2, CHCl3) for 90% ee. 1H NMR
D
(CDCl3, 500 MHz): δ 0.93 (t, 3H, J = 7.3 Hz), 1.39−1.58 (m, 4H),
1.74 (s, 3H), 2.25−2.34 (m, 3H), 7.26−7.37 (m, 3H), 7.65−7.67 (m,
2H). 13C{1H} NMR (CDCl3, 125 MHz): δ 13.6, 18.4, 22.0, 30.7, 33.6,
70.1, 83.7, 85.7, 125.0, 127.5, 128.2, 146.2. HPLC: Daicel Chiralcel
OD-H, hexane/IPA = 200:1, 1.0 mL/min, 254 nm: tR = 20.7 min
(minor), tR = 22.5 min (major).
(S)-(+)-Methyl 2-hydroxy-2-phenylbutanoate (7b). The exper-
imental data are in accordance with those reported in the previous
literature.16 38% yield from 6bu. [α]24D +21.5 (c 0.50, CHCl3) for 71%
25
1
(−)-2-Phenyldodec-3-yn-2-ol (6aw). The experimental data are in
ee [lit. [α]D +34.1 (c 0.49, CHCl3) for 83% ee, (S)]. H NMR
(CDCl3, 400 MHz): δ 0.92 (t, 3H, J = 7.2 Hz), 1.99−2.12 (m, 1H),
2.19−2.28 (m, 2H), 3.72 (s, 1H), 3.78 (s, 3H), 7.26−7.37 (m, 3H),
7.59 (d, 2H, J = 8.2 Hz). HPLC: Daicel Chiralpak AD-H, hexane/IPA
= 19:1, 1.0 mL/min, 254 nm: tR = 7.8 min (S), tR = 8.5 min (R).
(S)-(+)-Methyl 2-hydroxy-2-(4-methylphenyl)propanoate. (7f).
The experimental data are in accordance with those reported in the
previous literature.17 11% yield from 6fu. [α]24D +25.3 (c 0.16, CHCl3)
for 81% ee [lit. [α]25D +54 (c 1.6, CHCl3) for 85% ee, (S)]. 1H NMR
(CDCl3, 400 MHz): δ 1.77 (s, 3H), 2.34 (s, 3H) 3.68 (s, 1H), 3.77 (s,
3H), 7.16 (d, 2H, J = 8.2 Hz), 7.42 (d, 2H, J = 8.2 Hz). HPLC: Daicel
Chiralcel OD-H, hexane/IPA = 9:1, 0.5 mL/min, 254 nm, tR = 15.0
min (S), tR = 18.3 min (R).
accordance with those reported in the previous literature.23 110.1 mg
(99% yield). [α]32 −2.3 (c 0.95, CHCl3) for 92% ee. 1H NMR
D
(CDCl3, 500 MHz): δ 0.88 (t, 3H, J = 6.7 Hz), 1.28−1.42 (m, 10H),
1.51−1.58 (m, 2H), 1.74 (s, 3H), 2.25−2.29 (m, 3H), 7.25−7.39 (m,
3H), 7.64−7.67 (m, 2H). 13C{1H} NMR (CDCl3, 125 MHz): δ 14.1,
18.7, 22.7, 28.6, 28.9, 29.1, 29.2, 31.8, 33.5, 70.1, 83.7, 85.8, 125.0,
127.5, 128.2, 146.2. HPLC: Daicel Chiralcel OD-H, hexane/IPA =
99:1, 1.0 mL/min, 254 nm, tR = 12.3 min (minor), tR = 13.3 min
(major).
(−)-4-(1-Cyclohexenyl)-2-phenylbut-3-yn-2-ol (6ax). The exper-
imental data are in accordance with those reported in the previous
literature.19 101.2 mg (99% yield). [α]25D −2.0 (c 1.3, CHCl3) for 95%
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Featured Article
(S)-(+)-Methyl 2-Hydroxy-2-[4-(trifluoromethyl)phenyl]-
propanoate (7h). The experimental data are in accordance with
previous literature.8b 96.0 mg (61% yield). [α]24D −2.8 (c 1.1, CHCl3)
1
for 61% ee [lit. [α]15 +6.7 (c 1.31, CHCl3) for 95% ee, (R)]. H
D
those reported in the previous literature.17 21% yield from 6hu. [α]24
NMR (CDCl3, 500 MHz): δ 1.55−1.67 (m, 4H), 2.09−2.15 (m, 5H),
5.57 (d, 1H, J = 6.4 Hz), 6.15−6.17 (m, 1H), 7.30−7.40 (m, 3H),
7.55−7.57 (m, 2H). 13C{1H} NMR (CDCl3, 125 MHz): δ 21.4, 22.2,
25.6, 29.0, 65.0, 86.0, 88.6, 120.0, 126.7, 128.2, 128.5, 135.7, 141.0.
HPLC: Daicel Chiralcel OD-H, hexane/IPA = 19:1, 1.0 mL/min, 254
nm, tR = 11.9 min (major), tR = 16.9 min (minor).
D
+28.9 (c 0.36, CHCl3) for 71% ee [lit. [α]24 +6.1 (c 1.8, CHCl3) for
D
1
16% ee, (S)]. H NMR (CDCl3, 400 MHz): δ 1.80 (s, 3H), 3.80 (s,
3H), 3.82 (s, 1H), 7.60−7.62 (m, 2H), 7.69−7.71 (m, 2H). HPLC:
Daicel Chiralcel OD-H, hexane/IPA = 49:1, 0.5 mL/min, 254 nm, tR =
16.5 min (R), tR = 17.8 min (S).
(S)-(+)-Methyl 2-Hydroxy-2-(2-naphthyl)propanoate. (7k). The
(−)-4-(Benzyloxy)-1-phenylbut-2-yn-1-ol (5ay). The experimental
data are in accordance with those reported in the previous literature.28
experimental data are in accordance with those reported in the
previous literature.17 31% yield from 6ku. [α]18 +43.4 (c 0.90,
1
121.9 mg (98% yield). [α]25 −4.8 (c 0.15, CHCl3) for 42% ee. H
D
D
CHCl3) for 88% ee [lit. [α]26 +45 (c 1.7, CHCl3) for 82% ee, (S)].
NMR (CDCl3, 500 MHz): δ 2.23 (d, 1H, J = 5.8 Hz), 4.26 (s, 2H),
4.60 (s, 2H), 5.53 (d, 1H, J = 5.8 Hz), 7.28−7.41 (m, 8H), 7.54 (d,
2H, J = 7.3 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ 57.4, 64.6, 71.8,
82.7, 86.3, 126.6, 127.9, 128.1, 128.2, 128.4, 128.6, 137.3, 140.4.
HPLC: Daicel Chiralpak AD-H, hexane/IPA = 9:1, 1.0 mL/min, 254
nm, tR = 14.2 min (major), tR = 16.3 min (minor).
D
1H NMR (CDCl3, 400 MHz): δ 1.89 (s, 3H), 3.79 (s, 3H), 3.86 (s,
1H), 7.46−7.51 (m, 2H), 7.64 (dd, 1H, J = 1.8, 8.7 Hz), 7.81−7.87
(m, 3H), 8.01−8.07 (m, 1H). HPLC: Daicel Chiralcel OJ-H, hexane/
IPA = 9:1, 0.5 mL/min, 254 nm, tR = 52.2 min (S), tR = 67.3 min (R).
(S)-(+)-Methyl 2-Hydroxy-2-methyl-4-phenylbutanoate. (7n).
The experimental data are in accordance with those reported in the
previous literature.17 59% yield from 6nu. [α]25D +17.7 (c 1.5, CHCl3)
for 39% ee [lit. [α]25D +7.2 (c 1.5, CHCl3) for 19% ee, (S)]. 1H NMR
(CDCl3, 400 MHz): δ 1.45 (s, 3H), 1.94−2.10 (m, 2H), 2.42−2.50
(m, 1H), 2.75−2.83 (m, 1H), 3.25 (s, 1H), 3.73 (s, 3H), 7.15−7.19
(m, 3H), 7.25−7.30 (m, 2H). HPLC: Daicel Chiralcel OJ-H, hexane/
IPA = 49:1, 0.5 mL/min, 254 nm, tR = 25.8 min (R), tR = 27.1 min (S).
Representative Procedure for Asymmetric Alkynylations of
Aldehydes. Lithium acetylide 4u and lithium binaphtholate 1b were
prepared by the addition of n-BuLi (1.65 M in hexane, 0.59 mL, 0.98
mmol) to the solution of (R)-3,3′-diphenyl-1,1′-binaphthalene-2,2′-
diol (22 mg, 0.049 mmol) and phenylacetylene (0.11 mL, 0.98 mmol)
in THF (1.0 mL) at −78 °C. A solution of benzaldehyde 2a (0.050
mL, 0.49 mmol) in THF (1.0 mL) was added to the reaction mixture
over 10 min at the same temperature and stirred for an additional 1 h.
After quenching with saturated aq NH4Cl, the resulting solution was
extracted with EtOAc. The organic layer was washed with saturated aq
NaHCO3 and brine. After drying over Na2SO4, the solvent was
removed under vacuum, and the residue was purified by silica gel
column chromatography (hexane/CH2Cl2 = 1:1 v/v), affording 5au
(99.2 mg, 97%) as an oil. The ee was determined to be 75% by chiral
HPLC with Daicel Chiralcel OD-H column.
(S)-1,3-Diphenylprop-2-yn-1-ol (5au). The experimental data are
in accordance with those reported in the previous literature.26 99.2 mg
(97% yield). [α]19D −1.8 (c 2.0, CHCl3) for 75% ee [lit. [α]27D −2.4 (c
1.2, CHCl3) for 86% ee, (S)]. 1H NMR (CDCl3, 500 MHz): δ 2.29 (d,
1H, J = 6.1 Hz), 5.69 (d, 1H, J = 6.1 Hz), 7.28−7.48 (m, 8H), 7.61 (d,
2H, J = 7.3 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ 65.1, 86.7, 88.7,
122.4, 126.7, 128.3, 128.4, 128.6, 128.7, 131.7, 140.6. HPLC: Daicel
Chiralcel OD-H, hexane/IPA = 9:1, 1.0 mL/min, 254 nm, tR = 14.5
min (R), tR = 23.6 min (S).
(S)-(−)-1-Phenylhept-2-yn-1-ol (5av). The experimental data are in
accordance with those reported in the previous literature.26 91.3 mg
(99% yield). [α]24D −2.5 (c 1.0, CHCl3) for 15% ee [lit. [α]25D −18.1
(c 1.3, CHCl3) for 75% ee, (S)]. 1H NMR (CDCl3, 500 MHz): δ 0.92
(t, 3H, J = 7.3 Hz), 1.40−1.57 (m, 4H), 2.06 (d, 1H, J = 6.1 Hz),
2.26−2.31 (m, 2H), 5.45 (d, 1H, J = 6.1 Hz), 7.30−7.40 (m, 3H), 7.55
(d, 2H, J = 7.0 Hz). 13C{1H} NMR (CDCl3, 125 MHz): δ 13.7, 18.5,
22.0, 30.6, 64.9, 79.9, 87.7, 126.6, 128.2, 128.5, 141.3. HPLC: Daicel
Chiralcel OD-H, hexane/IPA = 19:1, 1.0 mL/min, 254 nm, tR = 8.9
min (S), tR = 14.1 min (R).
(S)-(−)-1-Phenyl-3-(trimethylsilyl)but-2-yn-1-ol (5az). The exper-
imental data are in accordance with those reported in the previous
literature.29 91.3 mg (91% yield). [α]25 −11.6 (c 0.13, CHCl3) for
D
1
44% ee [lit. [α]25 +11.2 (c 0.58, CHCl3) for 52% ee, (R)]. H NMR
D
(CDCl3, 500 MHz): δ 0.21 (s, 9H), 2.18 (d, 1H, J = 6.4 Hz), 5.46 (d,
1H, J = 6.4 Hz), 7.31−7.41 (m, 3H), 7.53−7.56 (m, 2H). 13C{1H}
NMR (CDCl3, 125 MHz): δ −0.2, 65.0, 91.6, 104.9, 126.7, 128.3,
128.6, 140.3. HPLC: Daicel Chiralcel OD-H, hexane/IPA = 19:1, 1.0
mL/min, 254 nm, tR = 4.6 min (S), tR = 6.3 min (R).
(S)-(−)-1-(4-Methoxyphenyl)-3-phenylprop-2-yn-1-ol (5bu). The
experimental data are in accordance with those reported in the
previous literature.26 97.7 mg (99% yield). [α]24D −8.8 (c 1.2, CHCl3)
for 75% ee [lit. [α]27D −4.2 (c 1.7, CHCl3) for 80% ee, (S)]. 1H NMR
(CDCl3, 500 MHz): δ 2.21 (d, 1H, J = 6.1 Hz), 3.83 (s, 3H), 5.64 (d,
1H, J = 6.1 Hz), 6.91−6.94 (m, 2H), 7.28−7.32 (m, 3H), 7.45−7.48
(m, 2H), 7.52−7.56 (m, 2H). 13C{1H} NMR (CDCl3, 125 MHz): δ
55.3, 64.8, 86.5, 88.9, 114.0, 122.5, 128.2, 128.3, 128.6, 131.7, 133.0,
159.8. HPLC: Daicel Chiralcel OD-H, hexane/IPA = 4:1, 1.0 mL/min,
254 nm, tR = 8.6 min (R), tR = 13.6 min (S).
(S)-(−)-1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-ol (5cu). The
experimental data are in accordance with those reported in the
previous literature.26 116.4 mg (98% yield). [α]22 −5.9 (c 0.98,
D
CHCl3) for 71% ee [lit. [α]27 −7.9 (c 1.4, CHCl3) for 84% ee, (S)].
D
1H NMR (CDCl3, 500 MHz): δ 2.33 (d, 1H, J = 6.1 Hz), 5.66 (d, 1H,
J = 6.1 Hz), 7.29−7.58 (m, 9H). 13C{1H} NMR (CDCl3, 125 MHz): δ
64.4, 87.0, 88.2, 122.1, 128.1, 128.3, 128.8, 131.7, 134.2, 139.1. HPLC:
Daicel Chiralcel OD-H, hexane/IPA = 9:1, 1.0 mL/min, 254 nm, tR =
9.5 min (R), tR = 28.3 min (S).
(S)-(+)-1-(2-Naphthyl)-3-phenylprop-2-yn-1-ol (5du). The exper-
imental data are in accordance with those reported in the previous
literature.30 124.3 mg (98% yield). [α]18D +7.0 (c 1.6, CHCl3), 65% ee
1
[lit. [α]27 −7.8 (c 0.5, CHCl3) for 87% ee, (R)]. H NMR (CDCl3,
D
500 MHz): 2.35 (d, 1H, J = 6.1 Hz), 5.86 (d, 1H, J = 6.1 Hz), 7.32−
7.33 (m, 3H), 7.48−7.51 (m, 4H), 7.71−7.73 (m, 1H), 7.84−7.89 (m,
3H), 8.04 (s, 1H). 13C{1H} NMR (CDCl3, 125 MHz): δ 65.3, 87.0,
88.6, 122.4, 124.6, 125.5, 126.3, 127.7, 128.2, 128.3, 128.61, 128.64,
131.8, 133.2, 133.3, 138.0. HPLC: Daicel Chiralcel OD-H, hexane/IPA
= 4:1, 1.0 mL/min, 254 nm, tR = 9.6 min (R), tR = 23.5 min (S).
(−)-3-Phenyl-1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol (5eu).
The experimental data are in accordance with those reported in the
previous literature.31 139.4 mg (95% yield). [α]19 −6.1 (c 1.3,
D
CHCl3) for 82% ee. 1H NMR (CDCl3, 500 MHz): δ 2.26 (d, 1H, J =
6.1 Hz), 3.86 (s, 3H), 3.91 (s, 6H), 5.64 (d, 1H, J = 6.1 Hz), 6.87 (s,
2H), 7.33−7.36 (m, 3H), 7.47−7.49 (m, 2H). 13C{1H} NMR (CDCl3,
125 MHz): δ 56.2, 60.9, 65.3, 86.7, 88.5, 103.8, 128.4, 128.7, 131.7,
136.2, 153.4. HPLC: Daicel Chiralcel OD-H, hexane/IPA = 2:1, 1.0
mL/min, 254 nm, tR = 7.0 min (minor), tR = 15.9 min (major).
(S)-(+)-1-Cyclohexyl-3-phenylprop-2-yn-1-ol (5fu). The experi-
mental data are in accordance with those reported in the previous
(−)-1-Phenylundec-2-yn-1-ol (5aw). The experimental data are in
accordance with those reported in the previous literature.27 112.2 mg
(94% yield). [α]33 −2.5 (c 0.81, CHCl3) for 21% ee. 1H NMR
D
(CDCl3, 500 MHz): δ 0.88 (t, 3H, J = 6.7 Hz), 1.23−1.58 (m, 12H),
2.07 (d, 1H, J = 6.1 Hz), 2.24−2.29 (m, 2H), 5.44 (d, 1H, J = 6.1 Hz),
7.30−7.39 (m, 3H), 7.54 (d, 2H, J = 7.0 Hz). 13C{1H} NMR (CDCl3,
125 MHz): δ 14.1, 18.8, 22.7, 28.6, 28.9, 29.1, 29.2, 31.8, 64.9, 79.9,
87.8, 126.6, 128.1, 128.5, 141.3. HPLC: Daicel Chiralcel OD-H,
hexane/IPA = 19:1, 1.0 mL/min, 254 nm, tR = 7.2 min (major), tR =
11.3 min (minor).
literature.8b 79.6 mg (90% yield). [α]19 +6.9 (c 1.2, CHCl3) for 58%
D
1
ee [lit. [α]25 −11.4 (c 3.17, CHCl3) for 97% ee, (R)]. H NMR
D
(S)-(−)-3-(1-Cyclohexenyl)-1-phenylprop-2-yn-1-ol (5ax). The
experimental data are in accordance with those reported in the
(CDCl3, 500 MHz): δ 1.08−1.32 (m, 5H), 1.60−1.99 (m, 7H), 4.38
(t, 1H, J = 5.8 Hz), 7.28−7.32 (m, 3H), 7.41−7.47 (m, 2H). 13C{1H}
4823
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The Journal of Organic Chemistry
Featured Article
NMR (CDCl3, 125 MHz): δ 25.9, 26.4, 28.2, 28.7, 44.3, 67.7, 85.7,
89.2, 122.8, 128.27, 128.32, 131.7. HPLC: Daicel Chiralcel OD-H,
hexane/IPA = 9:1, 1.0 mL/min, 254 nm, tR = 5.9 min (R), tR = 10.8
min (S).
(5) For zinc triflate-catalyzed alkynylations, see: (a) Anand, N. K.;
Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687−9688. (b) Jiang, B.;
Chen, Z.; Tang, X. Org. Lett. 2002, 4, 3451−3453. (c) Fassler, R.;
̈
Tomooka, C. S.; Frantz, D. E.; Carreira, E. M. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5843−5845.
ASSOCIATED CONTENT
(6) For titanium catalysis, see: (a) Lu, G.; Li, X.; Chan, W. L.; Chan,
A. S. C. Chem. Commun. 2002, 172−173. (b) Li, X.; Lu, G.; Kwok, W.
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Jiang, Y.-Z. J. Org. Chem. 2003, 68, 7921−7924. (g) Zhou, Y.; Wang,
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Chan, A. S. C. Angew. Chem., Int. Ed. 2003, 42, 5057−5058. (b) Liu,
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■
S
* Supporting Information
1
Copies of H and 13C NMR spectra and HPLC profiles. This
material is available free of charge via the Internet at http://
pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Author
*E-mail: nakajima@gpo.kumamoto-u.ac.jp.
■
Present Address
§5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Young
Scientists (B) from The Ministry of Education, Culture, Sports,
Science and Technology, Japan.
(8) For other metal catalysis, see: (a) Takita, R.; Fukuta, Y.; Tsuji, R.;
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R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
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J. D. J. Org. Chem. 2007, 72, 9590−9596. (d) Ito, J.-I.; Asai, R.;
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Murakami, H.; Nishiyama, H.; Mashima, K. Angew. Chem., Int. Ed.
2011, 50, 6296−6300.
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