Dimethylzinc-mediated enantioselective addition of terminal alkynes to 1,2-diketones using perhydro-1,3-benzoxazines as ligands

Article abstract of DOI:10.1039/d1ob00249j

A conformationally restricted perhydro-1,3-benzoxazine derived from (-)-8-aminomenthol behaves as a good chiral ligand in the dimethylzinc-mediated enantioselective monoaddition of aromatic and aliphatic terminal alkynes to 1,2-diketones. The correspondin

Full text of DOI:10.1039/d1ob00249j

Organic &
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Dimethylzinc-mediated enantioselective addition
of terminal alkynes to 1,2-diketones using
perhydro-1,3-benzoxazines as ligands†
Cite this: Org. Biomol. Chem., 2021,
19, 3859
Elena Prieto,
Rebeca Infante,
Javier Nieto * and Celia Andrés
*
A conformationally restricted perhydro-1,3-benzoxazine derived from (−)-8-aminomenthol behaves as a
good chiral ligand in the dimethylzinc-mediated enantioselective monoaddition of aromatic and aliphatic
terminal alkynes to 1,2-diketones. The corresponding α-hydroxyketones were obtained in good yields
with high enantioselectivities starting from both aromatic and aliphatic 1,2-diketones. The alkynylation of
unsymmetrical 1,2-diketones with electronically different substituents also proceeds with high regio- and
enantioselectivity. This reaction provides a practical method to synthesize ketones bearing a chiral tertiary
propargylic alcohol.
Received 8th February 2021,
Accepted 31st March 2021
DOI: 10.1039/d1ob00249j
rsc.li/obc
lyzed reaction pathway, which would have a detrimental effect
on the enantioselectivity.
Introduction
The construction of chiral tertiary alcohol functionalities is a
Recently, we have shown that chiral conformationally
continuing challenge in the synthesis of pharmacologically restricted perhydro-1,3-benzoxazines derived from (−)-8-ami-
active compounds, natural products and organic building nomenthol behave as excellent ligands for the enantioselective
blocks.1 The catalytic enantioselective addition of nucleophilic addition of organozinc reagents to carbonyl compounds,10
reagents to carbonyl compounds is an extended method for including α-ketoesters.11
the construction of optically active alcohols and there are
Apart from the previously mentioned substrates, 1,2-dike-
several catalytic enantioselective reactions to access chiral sec- tones have emerged as suitable electrophilic reagents for
ondary alcohols, such as the deeply studied and highly devel- the enantioselective addition of organozinc compounds,
oped addition of organozinc reagents to aldehydes.2 In con- allowing us to obtain chiral tertiary alcohols containing
trast, the formation of optically active tertiary alcohols through α-hydroxyketone moieties, which play an important role in bio-
the addition of nucleophilic organozinc reagents to simple logical processes such as the inhibition of urease12 and the
ketones still remains a challenge. This is due to the lower reac- regulation of the gene expression of Legionella pneumophila.13
tivity of ketones and the difficulties in stereodifferentiation of
Being aware of the relevance of these structures, in a pre-
vious communication we employed our chiral perhydro-1,3-
their two enantiotopic faces.3
The utilization of activated ketones bearing an electron- benzoxazine ligands in the dimethylzinc-mediated addition of
withdrawing-group at the alpha position to the carbonyl group phenylacetylene to benzils to afford the corresponding chiral
helps overcome these problems of a lack of reactivity, as shown tertiary alcohols in high yields with high enantioselectivity.14
in the enantioselective alkylation and alkynylation to Herein we present the complete study of the enantioselective
α-ketoesters,4,5 fluorinated ketones,6,7 and isatines.8,9 dimethylzinc-mediated addition of terminal alkynes to aro-
However, this excess reactivity along with the fact that, many matic, aliphatic and unsymmetrically substituted 1,2-diketones
times, this particular kind of electrophile may act as a chelat- in the presence of perhydro-1,3-benzoxazines as chiral
ing ligand and enhance the reactivity of the nucleophilic ligands.15,16
species might be a problem due to the competing non-cata-
Results and discussion
Instituto CINQUIMA and Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Valladolid, Paseo de Belén, 7, 47011 Valladolid, Spain.
Conformationally restricted perhydro-1,3-benzoxazines have
E-mail: javiernr@qo.uva.es
proved their efficiency as chiral ligands for the enantioselective
alkynylation of α-ketoesters promoted by dimethylzinc.11b
Considering this, we decided to employ 1,2-diketones as sub-
†Electronic supplementary information (ESI) available: NMR spectral data (1H
and 13C) and chiral HPLC chromatograms for newly synthesized compounds.
See DOI: 10.1039/d1ob00249j
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strates for the enantioselective alkynylzinc addition reaction, enough to allow obtaining the α-hydroxyketone in high yield
which represents the first enantioselective organozinc addition with good enantioselectivity.
to ketones activated by another carbonyl group at the alpha
position.
With these conditions in hand, we moved on to explore the
substrate scope of the addition of phenylacetylene to symme-
We first tested our chiral perhydro-1,3-benzoxazines 1a–f in trically substituted 1,2-diketones 2a–k (Table 2).
the model reaction of 1,2-diphenylethane-1,2-dione 2a with
phenylacetylene in toluene at 0 °C (Table 1).
The enantiocontrol did not seem to be influenced by elec-
tronic effects and ortho-, meta-, and para-substituted aromatic
We found that a kinetic resolution takes place on the reac- α-diketones bearing electron-donating and electron-withdraw-
tion product above −20 °C due to a second addition of the ing substituents afforded the corresponding α-hydroxyketones
alkynylzinc derivative to the α-hydroxy ketone. Under the reac- without significant changes in enantiocontrol, with moderate
tion conditions, the minor enantiomer of the hydroxy ketone to good yields (Table 2, entries 3–10); neither steric effects
reacts faster than the major enantiomer and the enantio- caused any variation in the enantioselectivity, even when a
selectivity improves but a large loss of chemical yield occurs.14 bulkier diketone 2i was employed (Table 2, entry 12). We also
Fortunately, under the optimized reaction conditions (4 equiv. tested the heteroaromatic diketone 2h and pleasingly achieved
of phenylacetylene and dimethylzinc, 20 mol% of 1b as the the product in good yield with excellent enantioselectivity
ligand, at −20 °C in toluene for 20 h) this process is slow (Table 2, entry 11).
On the other hand, enantioselectivity can be improved once
the hydroxyl ketones 3 are formed at −20 °C, and the kinetic
resolution is allowed to occur at 0 °C for 4 h (Table 2, entries 2
and 4). However, under these conditions a significant loss of
chemical yield occurs.
Table 1 Screening studies of enantioselective addition of phenyl-
acetylene to 1,2-diphenylethane-1,2-dione 2aa
Then, we studied the influence of the electronic effects of
some phenylacetylene derivatives, as well as the addition of ali-
phatic alkynes (Table 3).
The α-hydroxyketones 3j–l were obtained in good yields
with high enantioselectivity for both phenylacetylene deriva-
tives substituted with electron-donating and electron-with-
drawing groups (Table 3, entries 1–3). The use of aliphatic
terminal alkynes such as octyne and 4-phenyl-1-butyne
Table 2 Substrate scope of the alkynylation of 1,2-diketones 2a–ia
Entry Ligand (mol %) Solvent
T (°C) t (h) Yieldb (%) erc
1
2
3
4
5
6
7
8
1a (20)
1b (20)
1c (20)
1d (20)
1e (20)
1f (20)
1b (20)
1b (20)
1b (20)
1b (20)
1b (20)
1b (20)
1b (20)
1b (20)
1b (20)
1b (20)
1b (20)
1b (15)
1b (10)
1b (20)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene −10
Toluene −20
Toluene −30
Toluene
Toluene
Toluene
Toluene
0
0
0
0
0
0
20
20
20
20
20
20
20
20
30
0.5
44
33
42
36
40
50
76
88
70d
59d
84 : 16
96 : 4
46 : 54
79 : 21
67 : 33
49 : 51
92 : 8
Entry
Diketone, R
Yieldb (%)
erc
1
2a, Ph
2a, Ph
3a (88)
3a (58)
3b (85)
3b (52)
3c (48)
3c (70)
3d (85)
3e (83)
3f (69)
3g (48)
3h (77)
3i (62)
94 : 6
97 : 3
91 : 9
95 : 5
90 : 10
88 : 12
92 : 8
88 : 12
97 : 3
93 : 7
97 : 3
89 : 11
94 : 6
2d
3
9
94 : 6
2b, 4-Me-C6H4
2b, 4-Me-C6H4
2c, 4-OMe-C6H4
2c, 4-OMe-C6H4
2d, 3-OMe-C6H4
2e, 2-Cl-C6H4
2f, 4-Cl-C6H4
2g, 4-Br-C6H4
2h, 2-furyl
10
11
12
13
14
15
16
17
18
19
20e
0
0
0
0
87 : 13 4d
2.25 70
89 : 11
92 : 8
>99 : 1
—
5
6.5
48
20
20
20
20
20
20
30
40
6e
7
18
Hexane −20
CH2Cl2
THF
15d
68d
66
8
−20
−20
−20
92 : 8
9e
77 : 23 10e
65 : 35 11
Et2O
56d
84
Toluene −20
Toluene −20
Toluene −20
93 : 7
89 : 11
92 : 8
12e
2i, 2-naphthyl
80
a Reaction conditions: (1) 1.05 mmol (4.2 equiv.) of phenylacetylene,
1.0 mmol (4.0 equiv.) of dimethylzinc, toluene, rt, 1 h; (2) 0.05 mmol
58d
a Reaction conditions: 0.15 mmol (1.0 equiv.) of 2a, 0.6 mmol (4.0 (20 mol%, 0.2 equiv.) of ligand 1b, toluene, rt, 30 min; and (3)
equiv.) of dimethylzinc and 0.63 mmol (4.2 equiv.) of phenylacetylene. 0.25 mmol (1.0 equiv.) of diketone, toluene, −20 °C, 20 h. b Yield of the
b Yield of the isolated product after purification by flash column isolated product after purification by flash column chromatography.
chromatography. c Enantiomeric ratio determined by HPLC on a chiral c Enantiomeric ratio determined by HPLC on a chiral stationary phase.
stationary phase. d Variable amounts of the starting diketone 2a were d Reaction mixture was stirred for an additional 4 h at 0 °C. e Diketone
recovered. e Only 0.3 mmol of dimethylzinc (2.0 equiv.) and 0.31 mmol was dissolved and added in CH2Cl2 because of their insolubility in
(2.1 equiv.) of phenylacetylene were used.
toluene at −20 °C.
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Table 3 Alkyne scope of the alkynylation of 2aa
ponding alkynylated products 4a–k with good chemical yields
and excellent enantiocontrol, both for aromatic and aliphatic
alkynes. For aliphatic diketones kinetic resolution occurs at
−20 °C (ref. 14) and higher enantioselectivities than those with
aromatic diketones are achieved, although the chemical yield
slightly decreases. We did not find any competitive enolization
process that could decrease the yield of the desired products.
Again, the enantiocontrol did not seem to be influenced by
electron-donating and electron-withdrawing substituents at
different positions in the aromatic ring of the alkyne (Table 4,
entries 3–7). When aliphatic terminal alkynes were employed
the enantioselectivity decreased slightly, although the enantio-
selectivity levels remained higher than the alkynylation of the
aromatic diketone 2a (compare entries 8–11 in Table 4 versus
entries 4–7 in Table 3).
Entry
Alkyne, R
Yieldb (%)
erc
1
2
3
4
5
6
7
4-Me-C6H4
4-Br-C6H4
2-F-C6H4
C6H5-(CH2)2
CH3(CH2)5
TMS
3j (88)
3k (78)
3l (65)
3m (79)
3n (69)
3o (37)
3p (73)
95 : 5
91 : 9
97 : 3
82 : 18
86 : 14
82 : 18
93 : 7
TBDMSO-CH2
a Reaction conditions: (1) 1.05 mmol (4.2 equiv.) of alkyne, 1.0 mmol
(4.0 equiv.) of dimethylzinc, toluene rt, 1 h; (2) 0.05 mmol (20 mol%,
0.2 equiv.) of ligand 1b, toluene, rt, 30 min; and (3) 0.25 mmol (1.0
equiv.) of diketone, toluene, −20 °C, 20 h. b Yield of the isolated
product after purification by flash column chromatography.
c Enantiomeric ratio determined by HPLC on a chiral stationary phase.
Encouraged by these results, we decided to study the regio-
and enantioselectivity of the reaction when unsymmetrically
substituted 1,2-diketones 5a–f were employed. The alkynyla-
tion of diketones with electronically different substituents on
the aromatic rings occurred preferably on the carbonyl
group attached to the ring with the electron-withdrawing
group and proceeded with high regio- and enantioselectivity
afforded the products 3m and 3n with a decrease of enantio- (Table 5).
selectivity with respect to the aromatic substituted alkynes
(Table 3, entries 4 and 5), although the enantioselectivity in
The alkynylation of diketone 5a with an electron-donating
methoxy group on one of the aromatic rings and an electron-
the alkynylation of diketone 2a with 3-((tert-butyldimethylsilyl) withdrawing chlorine on the other occurs preferably on the
oxy)-1-propyne was as good as that observed for aromatic sub-
stituted terminal alkynes (Table 3, entry 7). Only the addition
carbonyl group attached to the ring with the chlorine group.
After 20 h of reaction at −20 °C, a mixture of hydroxy ketones
of trimethylsilylacetylene led to poor yield with moderate 6a and 17a was obtained in a ratio of 93 : 7 with a chemical
enantioselectivity (Table 3, entry 6).
yield of 72%. The enantioselectivity for 6a was 92 : 8 er
The scope of the reaction was further explored and enoliz-
(Table 5, entry 1). A kinetic resolution could be observed again
able aliphatic 1,2-diketones were subjected to the alkynylation when the alkynylation reaction of diketone 5a was allowed to
protocol (Table 4). Diketones 2j and 2k afforded the corres-
proceed with stirring for an additional 4 h at 0 °C, which
resulted in an increase of the regio- and enantioselectivity due
to the consumption of the minor enantiomer (entry 2).
Table 4 Substrate scope of the alkynylation of 1,2-diketones 2a–ia
On the other hand, when 1-(4-methoxyphenyl)-2-(4-(trifluor-
omethyl)phenyl)ethane-1,2-dione 5b acted as the electrophile,
the product 6b was obtained as a single regioisomer, as a
result of the alkynylation of the carbonyl attached to the elec-
tronically deficient aromatic ring (Table 5, entry 3). The alkyny-
lation also proceeds with total regioselectivity if there are two
electron-withdrawing chlorine substituent groups (Table 5,
entries 8–10) or two electron-donating methoxy groups in one
of the aromatic rings (Table 5, entries 4–7). In all cases the
enantioselectivity was good.
The alkynylation of a simple alkyl aryl diketone such as 5e
provided a mixture of hydroxy ketones 6j and 7j without regio-
selectivity although with high enantioselectivity (97 : 3 er for 6j
and 95 : 5 er for 7j). However, the alkynylation of the alkyl aryl
diketone 5f with an electron-withdrawing chlorine substituent
at the aromatic ring and a bulky isopropyl group proceeded
with total regioselectivity, and only the formation of the
hydroxy ketone 6k (93 : 7 er) was observed in the 1H NMR
spectra of the reaction mixture after 20 h of reaction at −20 °C.
The configuration of the newly formed stereogenic center of
6a was established by X-ray diffraction analysis14 and has been
Entry
Diketone, R1
Alkyne, R2
Yieldb (%)
erc
1
2
3
4
5
6
7
8
2j, Me
2k, Et
2k, Et
2k, Et
2k, Et
2k, Et
2k, Et
2k, Et
2k, Et
2k, Et
2k, Et
C6H5
C6H5
4a (68)
4b (72)
4c (71)
4d (63)
4e (79)
4f (80)
4g (84)
4h (56)
4i (60)
4j (50)
4k (58)
99 : 1
>99 : 1
>99 : 1
>99 : 1
95 : 5
96 : 4
95: 5
90 : 10
94 : 6
92 : 8
97 : 3
4-Me-C6H4
4-Br-C6H4
2-F-C6H4
3-OMe-C6H4
3-Cl-C6H4
C6H5-(CH2)2
CH3(CH2)5
TMS
9
10
11
TBDMSO–CH2
a Reaction conditions: (1) 1.05 mmol (4.2 equiv.) of phenylacetylene,
1.0 mmol (4.0 equiv.) of dimethylzinc, toluene, rt, 1 h; (2) 0.05 mmol
(20 mol%, 0.2 equiv.) of ligand 1b, toluene, rt, 30 min; and (3)
0.25 mmol (1.0 equiv.) of diketone, toluene, −20 °C, 20 h. b Yield of the
isolated product after purification by flash column chromatography.
c Enantiomeric ratio determined by HPLC on a chiral stationary phase.
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Table 5 Scope of the alkynylation of asymmetrical 1,2-diketones 5a–fa
Entry
Ketone
R1
R2
Alkyne, R3
Yieldb (%)
Ratio 6 : 7
er 6c
1
5a
5a
5b
5c
5c
5c
5c
5d
5d
5d
5e
5f
4-Cl-C6H4
4-Cl-C6H4
4-CF3-C6H4
2-Cl-C6H4
2-Cl-C6H4
2-Cl-C6H4
2-Cl-C6H4
2,4-Cl2-C6H3
2,4-Cl2-C6H3
2,4-Cl2-C6H3
C6H5
4-OMe-C6H4
4-OMe-C6H4
4-OMe-C6H4
3,4-(OMe)2-C6H3
3,4-(OMe)2-C6H3
3,4-(OMe)2-C6H3
3,4-(OMe)2-C6H3
4-OMe-C6H3
4-OMe-C6H3
4-OMe-C6H3
Me
C6H5
C6H5
C6H5
C6H5
4-Me-C6H4
4-Br-C6H4
CH3(CH2)5
C6H5
4-Me-C6H4
4-Br-C6H4
C6H5
72
48
79
72
91
90
62
95
85
81
85
79
6a (93) : 7a (7)
6a (>98%)e
6b (>98%)e
6c (>98%)e
6d (>98%)e
6e (>98%)e
6f (>98%)e
6g (>98%)e
6h (>98%)e
6i (>98%)e
6j (46) : 7j (54)
6k (>98%)e
92 : 8
96 : 4
96 : 4
95 : 5
95 : 5
94 : 6
97 : 3
93 : 7
2d
3
4
5
6
7
8
9
10
11
12
92 : 8
89 : 11
97 : 3 (95 : 5)f
93 : 7
2-Cl-C6H4
iPr
C6H5
a Reaction conditions: (1) 1.05 mmol (4.2 equiv.) of alkyne, 1.0 mmol (4.0 equiv.) of dimethylzinc, toluene rt, 1 h; (2) 0.05 mmol (20 mol%, 0.2
equiv.) of ligand 1b, toluene, rt, 30 min; and (3) 0.25 mmol (1.0 equiv.) of diketone, toluene, −20 °C, 20 h. b Yield of the isolated product after
purification by flash column chromatography. c Enantiomeric ratio determined by HPLC on a chiral stationary phase. d Reaction mixture was
stirred for an additional 4 h at 0 °C. e Only regioisomer 6 was detected by 1H NMR. f The er value in regioisomer 7j is presented in parentheses.
ring when phenylacetylene derivatives were employed as the
nucleophiles. Aliphatic alkynes and the challenging enolizable
aliphatic diketones were also tolerated and no detrimental
effect on enantiocontrol was observed.
Experimental section
General information
All reactions were carried out in anhydrous solvents under a
nitrogen atmosphere in dried glassware by means of Schlenk
Fig. 1 Proposed model for the addition of alkynylzinc derivatives to
1,2-diketones catalyzed by ligand 1b.
techniques. Flash chromatography was carried out using silica
gel (230–240 mesh). Chemical yields refer to pure isolated sub-
stances. TLC analysis was performed on glass-backed plates
coated with silica gel 60 and an F254 indicator and visualized
extended to all of the other hydroxyketones 3a–p, 4a–k, and
6a–k based on mechanistic analogy.
Although a detailed mechanistic discussion is difficult at
present, we propose the model shown in Fig. 1, in agreement
by either UV irradiation or by staining with I2 or phosphomo-
1
lybdic acid solution. H NMR (400 or 500 MHz) and 13C NMR
with the anti-transition state structure proposed by Noyori,17
(100 or 126 MHz) spectra were recorded in CDCl3. Chemical
shifts for protons are reported in ppm from tetramethylsilane
to account for the stereoselectivity observed with the chiral
ligand 1b. In this model, the transfer of the alkynyl group
occurs to the Si face of the ketone carbonyl.
with the residual CHCl3 resonance as an internal reference.
Chemical shifts for carbons are reported in ppm from tetra-
methylsilane and are referenced to the carbon resonance of
the solvent. Data are reported as follows: chemical shift, multi-
plicity (s = singlet, d = doublet, t = triplet, q = quartet, m = mul-
Conclusions
tiplet, and br = broad), coupling constants, in hertz, and inte-
In conclusion, a wide range of propargylic alcohols have been gration. Specific rotations were measured using a 5 mL cell
prepared through a highly efficient dimethylzinc-mediated with a 1 dm path length, and a sodium lamp, and the concen-
enantioselective addition of terminal alkynes to symmetrical tration is given in g per 100 mL. High resolution mass spec-
and asymmetrical 1,2-diketones in the presence of the chiral trometry analysis (HRMS) was performed on a quadrupole
perhydro-1,3-benzoxazine ligand 1b. Starting from aromatic spectrometer with a TOF analyzer. Chiral HPLC analysis was
1,2-diketones the chiral tertiary alcohols were obtained in performed using Daicel Chiralcel OD, Chiralcel OD-H,
good yields with high enantioselectivity with the independence Chiralcel OJ, Chiralpak AD-H, Chiralpak AS-H, Lux-Amylose-1,
of the electronic effects or steric hindrance on the aromatic Lux-Cellulose-2 or Lux-Cellulose-2 columns. UV detection was
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performed at 254, 220 or 210 nm. Dimethylzinc (1.2 M solu- 88.4, 89.3, 120.8, 123.4, 126.7 (2C), 128.2 (2C), 128.9, 129.0
tion in toluene) was purchased from Acros Organics. (2C), 131.0 (2C), 131.5, 131.7 (2C), 133.1 (2C), 133.9, 140.0,
Diketones 2a–e, 2g, 2h, 2j, 2k, 5c and 5e were purchased from 194.7; IR (neat) v: 3 415 3061, 3028, 2226, 1680, 1596, 1486,
commercial sources and used as received. Diketones 2f,18 2i,19 960, 698, 653 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
and 5a,20 and ligands 1a–f21 were prepared according to the C22H15BrNaO2 413.0148, found 413.0148; HPLC (Chiralcel
methods described in the literature. Compounds 3a–i, 3m, 3o, OD-H, hexane : isopropanol = 90 : 10, 1 mL min−1, λ = 254 nm):
3p, 4a, 4b, 6a, 7a, 6c, 6j and 7j have been described pre- tR = 7.9 min for S enantiomer, tR = 12.7 min for R enantiomer.
viously.14 For the synthesis of diketones 5b, 5d and 5f see the
(S)-4-(2-Fluorophenyl)-2-hydroxy-1,2-diphenylbut-3-yn-1-one
ESI† for this article.
(3l)
General procedure for the enantioselective alkynylation
addition of α-diketones
To a 1.2 M solution of ZnMe2 in anhydrous toluene (0.83 mL, colorless oil; yield: 55 mg, 65%; [α]2D5 = −136.4 (c = 0.8, CH2Cl2,
1.0 mmol) under a nitrogen atmosphere was added the term- 94% ee); H NMR (400 MHz, CDCl3) δ: 5.58 (s, 1H), 7.02–7.14
This compound was obtained from 2a (54 mg, 0.26 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 3);
1
inal alkyne (1.05 mmol) at room temperature. After stirring the (2H), 7.27–7.40 (m, 6H), 7.41–7.49 (m, 2H) 7.66 (d, J = 7.1 Hz,
mixture for 1 h, a solution of ligand 1b (16 mg, 0.05 mmol) in 2H), 8.09 (dd, J1 = 8.5 Hz, J2 = 1.2 Hz, 2H); 13C NMR (100 MHz,
anhydrous toluene (0.5 mL) was added. The resulting mixture CDCl3) δ: 76.4, 83.9, 92.3, 110.6 (d, J = 15.6 Hz), 115.5(d, J =
was stirred for another 30 min at the same temperature and 20.6 Hz), 124.0 (d, J = 3.7 Hz), 126.8 (2), 128.1 (2), 128.8, 129.0
then cooled to −20 °C. Once this solution was cooled, a solu- (2), 130.7 (d, J = 8.0 Hz), 131.2 (2C), 131.3, 133.4, 133.8, 140.0,
tion of the corresponding diketone (0.25 mmol) in anhydrous 163.1 (d, J = 253 Hz), 194.7; IR (neat) v: 3397, 3067, 2227, 1723,
toluene (2 mL) was added and the reaction mixture was stirred 1673, 1597, 1490, 965, 761, 700, 683, 640 cm−1; HRMS
at this temperature for 20 h. Diketones 2c, 2f, 2g and 2i were (ESI-TOF) m/z: [M + Na]+ calcd for C22H15F Na O2 353.0948,
dissolved and added to CH2Cl2 (2 mL) because of their insolu- found 353.0957; HPLC (Chiralcel OD, hexane : isopropanol =
bility in toluene at −20 °C. Afterwards, the mixture was 96 : 4, 1 mL min−1, λ = 254 nm): tR = 10.2 min for R enantio-
quenched under a nitrogen atmosphere with an aqueous satu- mer, tR = 11.5 min for S enantiomer.
rated solution of ammonium chloride, extracted with ethyl
acetate (3 × 15 mL), washed with brine, dried over MgSO4, fil-
(S)-2-Hydroxy-1,2-diphenyldec-3-yn-1-one (3n)
tered and concentrated. Purification by silica gel column This compound was obtained from 2a (53 mg, 0.25 mmol) and
chromatography with different mixtures of ethyl acetate : purified by flash chromatography (CH2Cl2 : hexane = 1 : 3);
hexane or dichloromethane : hexane gave the pure α-hydroxy colorless oil; yield: 56 mg, 69%; [α]2D5 = −143.3 (c = 0.8, CH2Cl2,
1
ketones.
72% ee); H NMR (400 MHz, CDCl3) δ: 0.84 (t, J = 6.8 Hz, 3H),
1.15–1.34 (m, 6H), 1.50 (m, 2H), 2.30 (m, 2H), 5.41 (s, 1H),
7.23–7.36 (m, 5H), 7.43 (m, 1H), 7.57 (dd, J1 = 7.0 Hz, J2 = 1.5
(S)-2-Hydroxy-1,2-diphenyl-4-(p-tolyl)but-3-yn-1-one (3j)
This compound was obtained from 2a (52 mg, 0.25 mmol) and Hz, 2H), 7.99 (d, J1 = 8.4 Hz, J2 = 1.3 Hz 2H); 13C NMR
purified by flash chromatography (ethyl acetate : hexane = (100 MHz, CDCl3) δ: 14.0, 19.0, 22.5, 28.1, 28.5, 31.2, 76.0,
1 : 45); colorless oil; yield: 71 mg, 88%; [α]2D5 = −146.8 (c = 1.5, 78.6, 92.1, 126.8 (2C), 128.0 (2C), 128.6, 128.8 (2C), 131.1 (2C),
CH2Cl2, 90% ee); 1H NMR (400 MHz, CDCl3) δ: 2.34 (s, 3H), 131.6, 133.5, 140.5, 195.5; IR (neat) v: 3428, 3067, 3029, 2232,
5.56 (s, 1H), 7.11 (d, J = 7.9 Hz, 2H), 7.28–7.42 (m, 7H), 7.46 2204, 1679, 1594, 759, 698, 684, 642, 605 cm−1; HRMS
(m, 1H), 7.66 (m, 2H), 8.08 (dd, J1 = 8.5 Hz, J2 = 1.2 Hz, 2H); (ESI-TOF) m/z: [M + Na]+ calcd for C22H24NaO2 343.1669,
13C NMR (100 MHz, CDCl3) δ: 21.5, 76.4, 86.6, 90.7, 118.8, found 343.1667; HPLC (Chiralpak AD-H, hexane : isopropanol
126.8 (2C), 128.1 (2C), 128.8, 129.0 (2C), 129.1 (2C), 131.1 (2C), = 90 : 10, 1 mL min−1, λ = 254 nm): tR = 9.0 min for S enantio-
131.6 (2C), 133.7, 139.3, 140.3, 195.1; IR (neat) v: 3387, 3067, mer, tR = 17.7 min for R enantiomer.
2227, 1671, 1595, 1449, 962, 764, 701, 680 cm−1; HRMS
(S)-4-Ethyl-4-hydroxy-6-(p-tolyl)hex-5-yn-3-one (4c)
(ESI-TOF) m/z: [M + Na]+ calcd for C23H18NaO2 349.1199,
found 349.1206; HPLC (Lux-Amylose-1, hexane : isopropanol = This compound was obtained from 2k (57 mg, 0.50 mmol) and
90 : 10, 1.0 mL min−1, λ = 254 nm): tR = 31.2 min for S enantio- purified by flash chromatography (CH2Cl2 : hexane = 1 : 2);
mer, tR = 34.9 min for R enantiomer.
colorless oil; yield: 82 mg, 71%; [α]2D5 = +246.3 (c = 1.0, CH2Cl2,
99% ee); H NMR (400 MHz, CDCl3) δ: 0.99 (t, J = 7.4 Hz, 3H),
1.17 (t, J = 7.3 Hz, 3H), 1.85 (dq, J1 = 14.7 Hz, J2 = 7.3 Hz, 1H),
2.08 (dq, J1 = 14.7 Hz, J2 = 7.4 Hz, 1H), 2.32 (s, 3H), 2.62 (dq, J1
1
(S)-4-(4-Bromophenyl)-2-hydroxy-1,2-diphenylbut-3-yn-1-one
(3k)
This compound was obtained from 2a (54 mg, 0.26 mmol) and = 18.0 Hz, J2 = 7.3 Hz, 1H), 3.01 (dq, J1 = 18.0 Hz, J2 = 7.3 Hz,
purified by flash chromatography (CH2Cl2 : hexane = 1 : 3); H), 4.16 (s, 1H), 7.10 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz,
colorless oil; yield: 79 mg, 78%; [α]2D5 = −1495 (c = 1.0, CH2Cl2, 2H); 13C NMR (100 MHz, CDCl3) δ: 7.8, 8.2, 21.5, 29.3, 33.3,
1
82% ee); H NMR (400 MHz, CDCl3) δ: 5.56 (s, 1H), 7.25–7.40 76.3, 85.9, 87.0, 119.0, 129.0 (2C), 131.6 (2C), 138.0, 209.1; IR
(m, 7H), 7.41–7.49 (m, 3H), 7.53 (d, J = 8.3 Hz, 2H), 8.05 (dd, J1 (neat) v: 3460, 2975, 2939, 2225, 1717, 1510, 1459, 1173, 1021,
= 8.6 Hz, J2 = 1,2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 76.4, 959, 816, 959, 709 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd
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for C15H18NaO2 253.1199, found 253.1200; HPLC (Chiralcel OJ, (Chiralcel OD, hexane : isopropanol = 99 : 1, 1.0 mL min−1, λ =
hexane : isopropanol = 96 : 4, 0.8 mL min−1, λ = 254 nm): tR
12.2 min for S enantiomer, tR = 13.8 min for R enantiomer.
=
254 nm): tR = 11.7 min for S enantiomer, tR = 15.7 min for R
enantiomer.
(S)-6-(4-Bromophenyl)-4-ethyl-4-hydroxyhex-5-yn-3-one (4d)
(S)-6-(3-Chlorophenyl)-4-ethyl-4-hydroxyhex-5-yn-3-one (4g)
This compound was obtained from 2k (57 mg, 0.50 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 2);
colorless oil; yield: 93 mg, 63%; [α]2D5 = +208.8 (c = 1.0, CH2Cl2,
This compound was obtained from 2k (58 mg, 0.51 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 2);
colorless oil; yield: 107 mg, 84%; [α]2D5 = +160.1 (c = 0.68,
1
99% ee); H NMR (400 MHz, CDCl3) δ: 0.98 (t, J = 7.4 Hz, 3H),
1
CHCl3, 90% ee); H NMR (500 MHz, CDCl3) δ: 1.01 (t, J = 7.4
1.16 (t, J = 7.4 Hz, 3H), 1.85 (dq, J1 = 14.6 Hz, J2 = 7.4 Hz, 1H),
2.07 (dq, J1 = 14.6 Hz, J2 = 7.4 Hz, 1H), 2.62 (dq, J1 = 18.1 Hz, J2
= 7.4 Hz, 1H), 2.97 (dq, J1 = 18.1 Hz, J2 = 7.4 Hz, 1H), 4.17 (s,
1H), 7.26 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ: 7.8, 8.2, 29.4, 33.2, 76.2, 84.7, 88.9, 121.0,
123.1, 129.0, 131.6 (2C), 133.2 (2C), 208.7; IR (neat) v: 3450,
Hz, 3H), 1.20 (t, J = 7.3 Hz, 3H), 1.88 (dq, J1 = 14.9 Hz, J2 = 7.4
Hz, 1H), 2.10 (dq, J1 = 14.9 Hz, J2 = 7.4 Hz, 1H), 2.64 (dq, J1 =
18.1 Hz, J2 = 7.3 Hz, 1H), 3.00 (dq, J1 = 18.1 Hz, J2 = 7.3 Hz,
1H), 4.18 (s, 1H), 7.22–7.27 (m, 2H), 7.30–7.34 (m, 2H), 7.42
(m, 1H); 13C NMR (126 MHz, CDCl3) δ: 7.8, 8.2, 29.4, 33.2,
76.2, 84.3, 89.0, 123.7, 129.1, 129.6, 129.9, 131.6, 134.2, 208.7;
IR (neat) v: 3464, 2972, 2935, 2884, 1722, 1593, 1562, 1474,
1464, 1101, 958, 782, 684 cm−1; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C14H15ClNaO2 273.0653, found 273.0650; HPLC
(Lux-Cellulose-2, hexane : isopropanol = 98 : 2, 1.0 mL min−1, λ
= 254 nm): tR = 5.5 min for R enantiomer, tR = 6.4 min for S
enantiomer.
2982, 2941, 2219, 1721, 1486, 1113, 1011, 960, 821, 778 cm−1
;
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C14H15BrNaO2
317.0148, found 317.0152; HPLC (Chiralcel OJ, hexane :
isopropanol = 96 : 4, 0.8 mL min−1, λ = 254 nm): tR = 13.7 min
for S enantiomer, tR = 14.8 min for R enantiomer.
(S)-4-Ethyl-6-(2-fluorophenyl)-4-hydroxyhex-5-yn-3-one (4e)
This compound was obtained from 2k (58 mg, 0.51 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 3);
colorless oil; yield: 94 mg, 79%; [α]2D5 = +204.9 (c = 0.8, CH2Cl2,
(S)-4-Ethyl-4-hydroxy-8-phenyloct-5-yn-3-one (4h)
This compound was obtained from 2k (57 mg, 0.50 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 2);
colorless oil; yield: 68 mg, 56%; [α]2D5 = +125.8 (c = 1.0, CH2Cl2,
1
90% ee). H NMR (400 MHz, CDCl3) δ: 1.01 (t, J = 7.3 Hz, 3H),
1.18 (t, J = 7.3 Hz, 3H), 1.86 (dq, J1 = 14.7 Hz, J2 = 7.3 Hz, 1H),
2.10 (dq, J1 = 14.7 Hz, J2 = 7.3 Hz, 1H), 2.64 (dq, J1 = 18.1 Hz, J2
= 7.3 Hz, 1H), 3.05 (dq, J1 = 18.1, J2 = 7.3 Hz, 1H), 4.18 (s, 1H),
7.01–7.10 m, (2H), 7.29 (m, 2H), 7.41 (td, J1 = 7.3 Hz, J2 = 1.5
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 7.8, 8.1, 29.3, 33.2,
76.3, 79.2, 92.9, 110.7 (d, J = 15.6 Hz), 115.5 (d, J = 20.8 Hz),
123.9 (d, J = 3.8 Hz), 130.5 (d, J = 8.0 Hz), 133.5, 162.9 (d, J =
252 Hz), 208.8; IR (neat) v: 3455, 2977, 2940, 2231, 1719, 1419,
1492, 1451, 1255, 1102, 961, 839, 755 cm−1; HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C14H15FNaO2 257.0948, found
257.0952; HPLC (Lux-Amylose-1, hexane : isopropanol = 96 : 4,
1
80% ee); H NMR (400 MHz, CDCl3) δ: 0.89 (t, J = 7.3 Hz, 3H),
1.05 (t, J = 7.3 Hz, 3H), 1.68 (dq, J1 = 14.6 Hz, J2 = 7.3 Hz, 1H),
1.90 (dq, J1 = 14.6 Hz, J2 = 7.3 Hz, 1H), 2.40 (dq, J1 = 18.2 Hz, J2
= 7.3 Hz, 1H), 2.52 (t, J = 7.3 Hz, 2H), 2.70 (dq, J1 = 18.2 Hz, J2
= 7.3 Hz, 1H), 2.81 (t, J = 7.3 Hz, 2H), 4.02 (s, 1H), 7.16–7.22
(3H), 7.24–7.30 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 7.7, 8.0,
20.8, 28.9, 33.3, 34.6, 75.8, 79.9, 85.8, 126.3, 128.3 (2C), 128.4
(2C), 140.3, 209.5; IR (neat) v: 3462, 2976, 2938, 2231, 1717,
1496, 1454, 1342, 1185, 1106, 1031, 970, 747, 698 cm−1; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C16H20NaO2 267.1356,
found 267.1356; HPLC (Chiralpak AD-H, hexane : isopropanol
= 95 : 5, 1.0 mL min−1, λ = 220 nm): tR = 7.2 min for S enantio-
mer, tR = 8.4 min for R enantiomer.
1 mL min−1, λ = 254 nm): tR = 6.2 min for R enantiomer, tR
6.8 min for S enantiomer.
=
(S)-4-Ethyl-4-hydroxy-6-(3-methoxyphenyl)hex-5-yn-3-one (4f)
(S)-4-Ethyl-4-hydroxydodec-5-yn-3-one (4i)
This compound was obtained from 2k (58 mg, 0.51 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 2); pale This compound was obtained from 2k (55 mg, 0.48 mmol) and
yellow oil; yield: 100 mg, 80%; [α]2D5 = +112.9 (c = 0.74, CHCl3, purified by flash chromatography (CH2Cl2 : hexane = 1 : 2);
1
92% ee); H NMR (500 MHz, CDCl3) δ: 1.01 (t, J = 7.4 Hz, 3H), colorless oil; yield: 65 mg, 60%; [α]2D5 = +119.6 (c = 0.8, CH2Cl2,
1
1.19 (t, J = 7.4 Hz, 3H), 1.87 (dq, J1 = 14.7 Hz, J2 = 7.4 Hz, 1H), 88% ee); H NMR (400 MHz, CDCl3) δ: 0.86 (t, J = 6.9 Hz, 3H),
2.10 (dq, J1 = 14.7 Hz, J2 = 7.4 Hz, 1H), 2.64 (dq, J1 = 18.1 Hz, J2 0.92 (t, J = 7.3 Hz, 3H), 1.13 (t, J = 7.3 Hz, 3H), 1.22–1.40 (6H),
= 7.4 Hz, 1H), 3.02 (dq, J1 = 18.1 Hz, J2 = 7.4 Hz, 1H), 3.79 (s, 1.48 (m, 2H), 1.73 (dq, J1 = 14.6 Hz, J2 = 7.3 Hz, 1H), 1.94 (dq,
3H), 4.18 (s, 1H), 6.89 (ddd, J1 = 8.3 Hz, J2 = 2.5 Hz, J3 = 1.1 Hz, J1 = 14.6 Hz, J2 = 7.3 Hz, 1H), 2.19 (t, J = 7.3 Hz, 2H), 2.53 (dq,
1H), 6.95 (dd, J1 = 2,5 Hz, J2 = 1.1 Hz, 1H), 7.02 (dt, J1 = 7.8 Hz, J1 = 18.0 Hz, J2 = 7.0 Hz, 1H), 2.93 (dq, J1 = 18.0 Hz, J2 = 7.0 Hz,
J2 = 1.1 Hz, 1H), 7.21 (dd, J1 = 8.3 Hz, J2 = 7.8 Hz, 1H); 13C 1H), 4.01 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 7.7, 8.1, 14.0,
NMR (126 MHz, CDCl3) δ: 7.8, 8.2, 29.4, 33.3, 55.3, 76.3, 85.7, 18.7, 22.5, 28.3, 28.5, 29.1, 31.2, 33.3, 75.9, 79.0, 86.8, 209.6; IR
87.6, 115.3, 116.6, 123.0, 124.3, 129.4, 159.3, 209.0; IR (neat) v: (neat) v: 3465, 2921, 2851, 1739, 1721, 1463, 1373, 1238, 1185,
3454, 2973, 2939, 2878, 2223, 1719, 1593, 1576, 1460, 1289, 1110, 1021, 974, 722, 609 cm−1; HRMS (ESI-TOF) m/z: [M +
1204, 1177, 1042, 958, 784, 686 cm−1; HRMS (ESI-TOF) m/z: [M Na]+ calcd for C14H24NaO2 247.1669, found 247.1667; HPLC
+ Na]+ calcd for C15H18NaO3 269.1148, found 269.1154; HPLC (Chiralpak AD-H, hexane : isopropanol = 99 : 1, 0.5 mL min−1, λ
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= 210 nm): tR = 17.9 min for S enantiomer, tR = 20.9 min for R (R)-2-(2-Chlorophenyl)-1-(3,4-dimethoxyphenyl)-2-hydroxy-4-(p-
enantiomer.
tolyl)but-3-yn-1-one (6d)
This compound was obtained from 5c (75 mg, 0.25 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 2);
colorless oil; yield: 94 mg, 91%; [α]2D5 = −336.4 (c = 1.5, CH2Cl2,
90% ee); 1H NMR (400 MHz, CDCl3) δ: 2.32 (s, 3H), 3.72 (s,
3H), 3.85 (s, 3H), 5.69 (s, 1H), 6.71 (d, J = 8.6 Hz, 1H), 7.10 (d, J
= 7.9 Hz, 2H), 7.24–7.33 (m, 4H), 7.40 (td, J1 = 7.7 Hz, J2 = 2.0
Hz, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.59 (dd, J1 = 8.6 Hz, J2 = 2.0
Hz, 1H), 8.44 (dd, J1 = 7.7 Hz, J2 = 1.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ: 21.5, 55.8 (2C), 76.3, 86.7, 91.7, 109.9,
112.7, 118.6, 124.6, 125.4, 127.0, 129.1 (2C), 130.3, 130.4,
131.4, 131.6 (2), 133.4, 138.2, 139.4, 148.2, 153.6, 192.8; IR
(neat) v: 3396, 2934, 2838, 2218, 1673, 1594, 1510, 1439, 1263,
1170, 1020, 816, 766, 753, 732, 682, 631 cm−1; HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C25H21ClNaO4 443.1021, found
433.1037; HPLC (Chiralcel OD, hexane : isopropanol = 90 : 10,
1.0 mL min−1, λ = 254 nm): tR = 13.3 min for S enantiomer, tR
= 15.6 min for R enantiomer.
(S)-4-Ethyl-4-hydroxy-6-(trimethylsilyl)hex-5-yn-3-one (4j)
This compound was obtained from 2k (57 mg, 0.50 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 2);
colorless oil; yield: 53 mg, 50%; [α]2D5 = +178.5 (c = 0.6, CH2Cl2,
1
84% ee); H NMR (400 MHz, CDCl3) δ: 0.14 (s, 9H), 0.92 (t, J =
7.6 Hz, 3H), 1.14 (t, J = 7.4 Hz, 3H), 1.74 (dq, J1 = 14.6 Hz, J2 =
7.6 Hz, 1H), 1.97 (dq, J1 = 14.6 Hz, J2 = 7.6 Hz, 1H), 2.54 (dq, J1
= 17.9 Hz, J2 = 7.6 Hz, 1H), 2.93 (dq, J1 = 17.9 Hz, J2 = 7.6 Hz,
1H), 4.04 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: −0.3 (3C), 7.7,
8.3, 29.1, 33.2, 76.2, 90.9, 103.8, 208.9; IR (neat) v: 3464, 2966,
2935, 2171, 1719, 1345, 1251, 1103, 1005, 962, 840, 760,
700 cm−1
C11H20NaO2Si 235.1125, found 235.1124; HPLC (Chiralpak
AD-H, hexane : isopropanol , λ =
99 : 1, 0.5 mL min−1
; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for
=
210 nm): tR = 12.4 min for S enantiomer, tR = 13.8 min for R
enantiomer.
(S)-7-((tert-Butyldimethylsilyl)oxy)-4-ethyl-4-hydroxyhept-5-yn-
3-one (4k)
(R)-4-(4-Bromophenyl)-2-(2-chlorophenyl)-1-(3,4-
dimethoxyphenyl)-2-hydroxybut-3-yn-1-one (6e)
This compound was obtained from 2k (55 mg, 0.50 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 2);
colorless oil; yield: 79 mg, 58%; [α]2D5 = +83.6 (c = 0.8, CH2Cl2,
94% ee); 1H NMR (400 MHz, CDCl3) δ: 0.08 (s, 6H), 0.87 (s,
9H), 0.91 (t, J = 7.4 Hz, 3H), 1.12 (t, J = 7.4 Hz, 3H), 1.76 (dq, J
= 14.7, 7.4 Hz, 1H), 1.97 (dq, J1 = 14.7 Hz, J2 = 7.4 Hz, 1H), 2.53
(dq, J1 = 18.1 Hz, J2 = 7.4 Hz, 1H), 2.93 (dq, J1 = 18.1 Hz, J2 =
7.4 Hz, 1H), 4.05 (s, 1H), 4.32 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ: −5.2 (2C), 7.6, 8.0, 18.2, 25.7 (3C), 29.2, 33.0, 51.6,
75.8, 83.4, 84.5, 208.9; IR (neat) v: 3457, 2931, 2858, 1721,
1463, 1363, 1254, 1182, 1092, 966, 833, 777 cm−1; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C15H28NaO3Si 307.1700,
found 307.1703; HPLC (Chiralpak AD-H, hexane : isopropanol
= 95 : 5, 1.0 mL min−1, λ = 210 nm): tR = 11.0 min for S enantio-
mer, tR = 12.5 min for R enantiomer.
This compound was obtained from 5c (76 mg, 0.25 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 2);
colorless oil; yield: 109 mg, 90%; [α]2D5 = −270.7 (c = 2.5,
CH2Cl2, 88% ee); 1H NMR (400 MHz, CDCl3) δ: 3.72 (s, 3H),
3.85 (s, 3H), 5.71 (s, 1H), 6.70 (d, J = 8.6 Hz, 1H), 7.23–7.32 (m,
4H), 7.36–7.45 (m, 3H), 7.50 (d, J = 2.0 Hz, 1H), 7.55 (dd, J1 =
8.6 Hz, J2 = 2.0 Hz, 1H), 7.55 (dd, J1 = 7.8 Hz, J1 = 1.1 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ: 55.8, 56.0, 76.3, 88.5, 90.3,
109.9, 112.6, 120.5, 123.6, 124.4, 125.4, 127.1, 130.2, 130.4,
131.4, 131.7 (2C), 133.1 (2C), 133.3, 137.9, 148.4, 153.8, 192.5;
IR (neat) v: 3395, 2934, 2834, 2221, 1673, 1594, 1583, 1514,
1486, 1134, 1070, 823, 761, 732, 704 cm−1; HRMS (ESI-TOF) m/
z: [M + Na]+ calcd for C24H18BrClNaO4 506.9969, found
506.9973; HPLC (Chiralpak AD-H, hexane : isopropanol
=
80 : 20, 1.5 mL min−1, λ = 254 nm): tR = 37.6 min for S enantio-
mer, tR = 40.3 min for R enantiomer.
(S)-2-Hydroxy-1-(4-methoxyphenyl)-4-phenyl-2-(4-
(trifluoromethyl)phenyl)but-3-yn-1-one (6b)
(R)-2-(2-Chlorophenyl)-1-(3,4-dimethoxyphenyl)-2-hydroxydec-
3-yn-1-one (6f)
This compound was obtained from 5b (77 mg, 0.25 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 2); pale
yellow oil; yield: 81 mg 79%; [α]2D5 = −139.2 (c = 0.4, CHCl3, This compound was obtained from 5c (75 mg, 0.25 mmol) and
92% ee); 1H NMR (500 MHz, CDCl3) δ: 3.82 (s, 3H), 5.76 (s, purified by flash chromatography (CH2Cl2 : hexane = 1 : 2);
1H), 6.83 (ddd, J1 = 9.1 Hz, J2 = 2.8 Hz, J3 = 2.1 Hz, 2H), colorless oil; yield: 63 mg, 62%; [α]2D5 = −248.3 (c = 0.2, CHCl3,
1
7.31–7.38 (3H), 7.47 (m, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.78 (d, J 94% ee); H NMR (500 MHz, CDCl3) δ: 0.84 (t, J = 6.8 Hz, 3H),
= 8.2 Hz, 2H), 8.08 (ddd, J1 = 9.1 Hz, J2 = 2.8 Hz, J3 = 2.1 Hz, 1.16–1.26 (m, 4H), 1.27–1.33 (m, 2H), 1.50 (m, 2H), 2.31 (m,
2H); 13C NMR (126 MHz, CDCl3) δ: 55.5, 75.4, 86.9, 90.6, 113.7 2H), 3.72 (s, 3H), 3.86 (s, 3H), 5.58 (s, 1H), 6.71 (d, J = 8.6 Hz,
(2C), 121.6, 123.6, 125.9 (q, J = 3.7 Hz, 2C), 127.2 (2C), 128.4 1H), 7.22–7.29 (m, 2H), 7.39 (td, J1 = 7.8 Hz, J2 = 1.4 Hz, 1H),
(2C), 129.2, 130.8 (q, J = 32.5 Hz), 131.7 (2C), 133.7 (2C), 144.6, 7.46 (d, J = 2.0 Hz, 1H), 7.53 (dd, J1 = 8.6 Hz, J2 = 2.0 Hz, 1H),
164.3, 192.5; IR (neat) v: 3315, 2974, 2883, 2242, 1642, 1543, 8.39 (dd, J1 = 7.8 Hz, J2 = 1.4 Hz, 1H); 13C NMR (126 MHz,
1383, 1288, 1217, 1087, 1049, 878, 708, 655 cm−1; HRMS CDCl3) δ: 14.0, 19.0, 22.5, 28.2, 28.5, 31.2, 55.8, 55.93, 75.9,
(ESI-TOF) m/z: [M + Na]+ calcd for C24H17F3NaO3 433.1022, 78.9, 93.3, 109.8, 112.7, 124.6, 125.4, 126.9, 130.1, 130.3, 131.2,
found 433.1020; HPLC (Lux-Amylose-1, hexane : isopropanol = 133.4, 138.4, 148.2, 153.5, 193.3; IR (neat) v: 3386, 2970, 2933,
88 : 12, 1.0 mL min−1, λ = 254 nm): tR = 21.8 min for R enantio- 2862, 1677, 1596, 1517, 1465, 1268, 1145, 1135, 951, 816,
mer, tR = 25.1 min for S enantiomer.
764 cm−1 Na]+ calcd for
; HRMS (ESI-TOF) m/z: [M +
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C24H27ClNaO4 437.1490, found 437.1495; HPLC (Lux-Cellulose- Cellulose-2, hexane : isopropanol = 95 : 5, 1.0 mL min−1, λ =
2, hexane : isopropanol = 90 : 10, 1.0 mL min−1, λ = 254 nm): tR 254 nm): tR = 16.1 min for S enantiomer, tR = 36.3 min for R
= 15.7 min for S enantiomer, tR = 30.8 min for R enantiomer.
enantiomer.
(R)-2-(2,4-Dichlorophenyl)-2-hydroxy-1-(4-methoxyphenyl)-4-
(R)-4-(2-Chlorophenyl)-4-hydroxy-2-methyl-6-phenylhex-5-yn-3-
phenylbut-3-yn-1-one (6g)
one (6k)
This compound was obtained from 5d (77 mg, 0.25 mmol) and This compound was obtained from 5f (55 mg, 0.25 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 2); purified by flash chromatography (CH2Cl2 : hexane = 1 : 2);
colorless oil; yield: 98 mg, 95%; [α]2D5 = −168.7 (c = 1.68, CHCl3, white solid; yield: 64 mg, 79%; mp 130–132 °C (from hexane);
86% ee); 1H NMR (400 MHz, CDCl3) δ: 3.81 (s, 3H), 5.71 (s, [α]D25 = +38.6 (c = 1.42, CHCl3, 86%); 1H NMR (500 MHz, CDCl3)
1H), 6.80 (d, J = 9.0 Hz, 2H), 7.25–7.44 (m, 7H), 7.95 (d, J = 9.0 δ: 0.97 (d, J = 6.8 Hz, 3H), 1.32 (d, J = 6.8 Hz, 3H), 2.93 (sp, J =
Hz, 2H), 8.37 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 6.8 Hz, 1H), 5.10 (s, 1H), 7.33–7.41 (m, 6H), 7.53 (m, 2H), 8.26
55.5, 75.7, 86.9, 91.6, 113.6 (2C), 121.5, 124.4, 127.3, 128.4 (ddd, J1 = 8.0 Hz, J2 = 1.9 Hz, J3 = 0.8 Hz, 1H); 13C NMR
(2C), 129.3, 131.1, 131.4, 131.7 (2C), 132.8 (2C), 134.0, 135.5, (126 MHz, CDCl3): δ 19.7, 22.1, 35.8, 78.8, 85.8, 90.3, 121.5,
136.7, 164.0, 192.2; IR (neat) v: 3368, 2975, 2928, 2844, 2221, 127.0, 128.5 (2C), 129.3, 130.5, 131.3, 131.6, 131.8 (2C), 133.2,
1675, 1600, 1510, 1467, 1252, 1170, 965, 946, 785, 757, 690, 135.1, 208.3; IR (neat) v: 3448, 2974, 2935, 2875, 2222, 1725,
604 cm−1
; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for 1590, 1570, 1468, 1443, 1020, 988, 912, 756, 690 cm−1; HRMS
C23H16Cl2NaO3 433.0369, found 433.0361; HPLC (Chiralpak (ESI-TOF) m/z: [M + Na]+ calcd for C19H17ClNaO2 335.0809,
AS-H, hexane : isopropanol = 98 : 2, 1.0 mL min−1, λ = 254 nm): found 335.0814; HPLC (Chiralpak AS-H, hexane : isopropanol =
tR = 26.1 min for S enantiomer, tR = 32.1 min for R 97 : 3, 1.0 mL min−1, λ = 254 nm): tR = 8.8 min for S enantio-
enantiomer.
mer, tR = 11.5 min for R enantiomer.
(R)-2-(2,4-Dichlorophenyl)-2-hydroxy-1-(4-methoxyphenyl)-4-
(p-tolyl)but-3-yn-1-one (6h)
Conflicts of interest
This compound was obtained from 5d (76 mg, 0.25 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 2); pale
yellow oil; yield: 89 mg, 85%; [α]2D5 = −259.3 (c = 1.1, CHCl3,
84% ee); 1H NMR (500 MHz, CDCl3) δ: 2.34 (s, 3H), 3.81 (s,
3H), 5.71 (s, 1H), 6.80 (dt, J1 = 9.0 Hz, J2 = 2.0 Hz, 2H), 7.12 (d,
J = 8.0 Hz, 2H), 7.26 (d, J = 2.1 Hz, 1H), 7.33 (dt, J = 8.0 Hz,
2H), 7.40 (dd, J = 8.5, 2.1 Hz, 1H), 7.95 (dt, J1 = 9.0 Hz, J2 = 2.0
Hz, 2H), 8.38 (dd, J1 = 8.5 Hz, J2 = 2.1 Hz, 1H); 13C NMR
(126 MHz, CDCl3) δ: 21.5, 55.4, 75.7, 86.3, 91.9, 113.6 (2C),
118.4, 124.4, 127.3, 129.1 (2C), 131.0, 131.5, 131.6 (2), 132.8
(2C), 134.0, 135.5, 136.8, 139.6, 164.0, 192.3; IR (neat) v: 3376,
2977, 2926, 2219, 1677, 1600, 1510, 1251, 1171, 1080, 1044,
There are no conflicts to declare.
Acknowledgements
The authors thank Junta de Castilla
FEDER-VA115P17, and VA149G18) for financial support.
y León (Projects
Notes and references
1 For reviews of the construction of chiral tertiary alcohols,
see: (a) E. J. A. Corey and E. Guzman-Perez, Angew. Chem.,
Int. Ed., 1998, 37, 388; (b) M. Shibasaki and M. Kanai,
Chem. Rev., 2008, 108, 2853; (c) O. Riant and
J. Hannedouche, Org. Biomol. Chem., 2007, 5, 873;
(d) P. G. Cozzi, R. Hilgraf and N. Zimmermann, Eur. J. Org.
Chem., 2007, 5969; (e) M. Hatano and K. Ishihara,
Synthesis, 2008, 1647.
965 cm−1
; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for
C24H18Cl2NaO3 447.0525, found 447.0527; HPLC (Chiralcel
OD, hexane : isopropanol = 95 : 5, 1.0 mL min−1, λ = 254 nm):
tR = 9.3 min for S enantiomer, tR = 13.9 min for R enantiomer.
(R)-4-(4-Bromophenyl)-2-(2,4-dichlorophenyl)-2-hydroxy-1-(4-
methoxyphenyl)but-3-yn-1-one (6i)
This compound was obtained from 5d (75 mg, 0.24 mmol) and
purified by flash chromatography (CH2Cl2 : hexane = 1 : 2);
colorless oil, yield: 93 mg, 81%; [α]2D5 = −267.1 (c = 1.14, CHCl3,
78% ee); 1H NMR (500 MHz, CDCl3) δ: 3.81 (s, 3H), 5.73 (s,
1H), 6.81 (d, J = 9.0 Hz, 2H), 7.25–7.30 (m, 3H), 7.40 (dd, J1 =
8.4 Hz, J2 = 2.1 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 9.0
Hz, 2H), 8.32 (d, J = 8.4 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ:
55.5, 75.7, 88.1, 90.5, 113.7 (2C), 120.4, 123.7, 124.2, 127.4,
131.1, 131.3, 131.7 (2C), 132.8 (2C), 133.1 (2C), 134.0, 135.6,
136.5, 164.1, 192.0; IR (neat) v: 3395, 2928, 2871, 2222, 1676,
1600, 1510, 1486, 1250, 1170, 1070, 1012, 964, 824, 753,
2 (a) K. Soai and S. Niwa, Chem. Rev., 1992, 92, 833; (b) L. Pu
and H.-B. Yu, Chem. Rev., 2001, 101, 757.
3 For some examples of enantioselective catalytic addition of
organozinc reagents to simple ketones, see: (a) P. I. Dosa
and G. C. Fu, J. Am. Chem. Soc., 1998, 120, 445;
(b) D. J. Ramon and M. Yus, Tetrahedron, 1998, 54, 5651;
(c) G. Celina, L. K. LaRochelle and P. J. Walsh, J. Am. Chem.
Soc., 2002, 124, 10970; (d) P. G. Cozzi, Angew. Chem., Int.
Ed., 2003, 42, 2895; (e) H. Li and P. J. Walsh, J. Am. Chem.
Soc., 2004, 126, 6538; (f) V. J. Forrat, D. J. Ramon and
M. Yus, Tetrahedron: Asymmetry, 2005, 16, 3341; (g) S.-J. Li,
H. Jeon, C. García, L. K. LaRochelle and P. J. Walsh, J. Org.
Chem., 2005, 70, 448; (h) H. Li and P. J. Walsh, J. Am. Chem.
608 cm−1
; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for
C23H15BrCl2NaO3 510.9474, found: 510.9473; HPLC (Lux-
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Soc., 2005, 127, 8355; (i) L. Liu, R. Wang, Y.-F. Kang, 11 (a) R. Infante, J. Nieto and C. Andrés, Chem. – Eur. J., 2012,
C. Chen, Z.-Q. Xu, Y.-F. Zhou, M. Ni, H.-Q. Cai and
M.-Z. Gong, J. Org. Chem., 2005, 70, 1084; ( j) C. Chen,
18, 4375; (b) R. Infante, A. Gago, J. Nieto and C. Andrés,
Adv. Synth. Catal., 2012, 354, 2797.
L. Hong, Z.-Q. Xu, L. Liu and R. Wang, Org. Lett., 2006, 8, 12 T. Tanaka, M. Kawase and S. Tani, Bioorg. Med. Chem.,
2277; (k) M. Hatano, T. Miyamoto and K. Ishihara, Org. 2004, 12, 501.
Lett., 2007, 9, 4535; (l) H. Hatano, T. Mizuno and 13 U. Schell, S. Simon, T. Sahr, D. Hager, M. F. Albers,
K. Ishihara, Chem. Commun., 2010, 46, 5443.
A. Kessler, F. Fahrnbauer, D. Trauner, C. Hedberg,
4 For some examples of enantioselective alkylation of α-keto
C. Buchrieser and H. Hilbi, Mol. Microbiol., 2016, 94, 778.
esters, see: (a) E. F. DiMauro and M. C. Kozlowski, Org. 14 R. Infante, J. M. Martín-Alvarez, C. Andrés and J. Nieto,
Lett., 2002, 4, 3781; (b) K. Funabashi, M. Jachmann, Org. Lett., 2017, 19, 1516.
M. Kanai and M. Shibasaki, Angew. Chem., Int. Ed., 2003, 15 Recently, while this article was being written, a highly
42, 5489; (c) L. C. Wieland, H. Deng, M. L. Snapper and
A. H. Hoveyda, J. Am. Chem. Soc., 2005, 127, 15453;
(d) G. Blay, I. Fernandez, A. Marco-Aleixandre and
J. R. Pedro, Org. Lett., 2006, 8, 1287; (e) H.-L. Wu, P.-Y. Wu,
Y.-Y. Shen and B.-J. Uang, J. Org. Chem., 2008, 73, 6445;
regio- and enantioselective alkynylation of alkynyl 1,2-dike-
tones mediated by Zn(OTf)2 in the presence of a chiral 1,2-
amino alcohol has been described. R. Liu, S. Yang,
Z. Chen, X. Kong, H. Ding and X. Fang, Org. Lett., 2020, 22,
6948.
(f) M. Yamanaka, M. Inaba, R. Gotoh, Y. Ueki and 16 For recent examples of enantioselective alkynylation of acti-
K. Matsui, Chem. Commun., 2017, 53, 7513.
vated ketones non-mediated by Zn, see: (a) D. Park,
C. I. Jette, J. Kim, W.-O. Jung, Y. Lee, J. Park, S. Kang,
M. S. Han, B. M. Stoltz and S. Hong, Angew. Chem., Int. Ed.,
2020, 59, 775; (b) J.-F. Chen and C. Li, Org. Lett., 2020, 22,
4686; (c) J. Ito, T. Ishihara, T. Fukuoka, S. R. Binti Mat
Napi, H. Kameo and H. Nishiyama, Chem. Commun., 2019,
55, 12765; (d) M. Moskowitz and C. Wolf, Angew. Chem., Int.
Ed., 2019, 58, 3402; (e) S. Paria, H.-J. Lee and K. Maruoka,
ACS Catal., 2019, 9, 2395; (f) T. Cui, J. Qin, K. Harms and
E. Meggers, Eur. J. Inorg. Chem., 2019, 195; (g) J. Lu,
L.-S. Luo, F. Sha, Q. Lia and X.-Y. Wu, Chem. Commun.,
2019, 55, 11603; (h) S. Chen, Y. Zheng, T. Cui, E. Meggers
and K. N. Houk, J. Am. Chem. Soc., 2018, 140, 5146;
(i) Y. Zheng, L. Zhang and E. Meggers, Org. Process Res.
Dev., 2018, 22, 103; ( j) Y. Zheng, Y. Tan, K. Harms,
M. Marsch, R. Riedel, L. Zhang and E. Meggers, J. Am.
Chem. Soc., 2017, 139, 4322; (k) Q. Chen, Y. Tang,
T. Huang, X. Liu, L. Lin and X. Feng, Angew. Chem., Int. Ed.,
2016, 55, 5286; (l) J.-i. Ito, S. Ubukata, S. Muraoka and
5 For examples of enantioselective alkynylation of α-keto
esters, see: (a) B. Jiang, Z. Chen and X. Tang, Org. Lett.,
2002, 4, 3451; (b) H.-B. Chen, W.-H. Lai, Y. Zhao, D.-D. Qin
and Y.-P. Ruan, Synlett, 2014, 25, 809; (c) B. P. Zavesky and
J. S. Johnson, Angew. Chem., Int. Ed., 2017, 56,
8805.
6 For enantioselective alkylation of fluorinated ketones, see:
(a) K. Yearick and C. Wolf, Org. Lett., 2008, 10, 3915;
(b) M. Calvillo-Barahona, J. A. Casares, C. Cordovilla,
M. N. Genov, J. M. Martínez-Ilarduya and P. Espinet, Chem.
– Eur. J., 2014, 20, 14800; (c) S. Sasaki, T. Yamauchi,
M. Kanai, A. Ishii; and K. Higashiyama, Bull. Chem. Soc.
Jpn., 2015, 88, 200; (d) T. Neves-Garcia, A. Vélez,
J. M. Martínez-Ilarduya and P. Espinet, Chem. Commun.,
2018, 54, 11809.
7 (a) G.-W. Zhang, W. Meng, H. Ma, J. Nie, W.-Q. Zhang and
J.-A. Ma, Angew. Chem., Int. Ed., 2011, 50, 3538;
(b) V. Dhayalan, R. Murakami and M. Hayashi, Asian J.
Chem., 2013, 25, 7505; (c) A. M. Cook and C. Wolf, Angew.
Chem., Int. Ed., 2016, 55, 2929; (d) Y. Zheng, H. Ma and
J.-A. Ma, Chin. J. Chem., 2016, 34, 511; (e) L. Tan,
C.-Y. Chen, R. D. Tillyer, E. J. J. Grabowski and P. J. Reider,
H. Nishiyama, Chem.
– Eur. J., 2016, 22, 16801;
(m) Y. Zheng, K. Harms, L. Zhang and E. Meggers, Chem. –
Eur. J., 2016, 22, 11977; (n) N. Xu, D.-W. Gu, J. Zi, X.-Y. Wu
and X.-X. Guo, Org. Lett., 2016, 18, 2439.
Angew. Chem., Int. Ed., 1999, 38, 711; (f) N. Chinkov, 17 (a) M. Yamakawa and R. Noyori, J. Am. Chem. Soc., 1995,
A. Warm and E. M. Carreira, Angew. Chem., Int. Ed., 2011,
50, 2957.
117, 6327; (b) M. Yamakawa and R. Noyori,
Organometallics, 1999, 18, 128.
8 C. Vila, A. del Campo, G. Blay and J. R. Pedro, Catalysts, 18 F. Romanov-Michailidis, C. Besnard and A. Alexakis, Org.
2017, 7, 387. Lett., 2012, 14, 4906.
9 L. Chen, G. Huang, M. Liu, Z. Huang and F. Chen, Adv. 19 L. E. Harrington, J. F. Britten, D. W. Hughes, A. D. Bain,
Synth. Catal., 2018, 360, 3497.
10 (a) C. Andrés, R. Infante and J. Nieto, Tetrahedron:
J.-Y. Thépot and M. J. McGlinchey, J. Organomet. Chem.,
2002, 656, 243.
Asymmetry, 2010, 21, 2230; (b) R. Infante, J. Nieto and 20 S. Cacchi, G. Fabrizi, A. Goggiamani, A. Lazzetti and
C. Andrés, Org. Biomol. Chem., 2011, 9, 6691; (c) R. Infante, R. Verdiglione, Synthesis, 2013, 45, 1701.
J. Nieto and C. Andrés, Synthesis, 2012, 1343; (d) R. Infante, 21 (a) R. Pedrosa, C. Andrés, C. D. Rosón and M. Vicente, J. Org.
J. Nieto and C. Andrés, Org. Biomol. Chem., 2014, 12,
345.
Chem., 2003, 68, 1852; (b) C. Andrés, I. González, J. Nieto and
C. D. Rosón, Tetrahedron, 2009, 65, 9728. See also ref. 11a.
This journal is © The Royal Society of Chemistry 2021
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