Enantiocontrolled synthesis of tertiary a-hydroxy-a-ynyl esters by dimethylzinc-mediated addition of alkynes to a-keto esters

Article abstract of DOI:10.1002/adsc.201200185

A perhydro-1,3-benzoxazine behaves as an excellent chiral ligand in the nucleophilic addition of alkynylzinc derivatives, prepared from terminal alkynes and dimethylzinc, to a-keto esters without using other Lewis acids. The enantioselectivity is excellent and homogeneous for a wide variety of aromatic and heteroaromatic a-keto esters. Aliphatic enolizable a-keto esters were alkynylated with moderate enantioselection.

Full text of DOI:10.1002/adsc.201200185

FULL PAPERS
DOI: 10.1002/adsc.201200185
Enantiocontrolled Synthesis of Tertiary a-Hydroxy-a-ynyl Esters
by Dimethylzinc-Mediated Addition of Alkynes to a-Keto Esters
Rebeca Infante,a Alfonso Gago,a Javier Nieto,a,* and Celia Andrꢀsa,*
a
Instituto CINQUIMA and Departamento de Quꢁmica Orgꢂnica, Facultad de Ciencias, Universidad de Valladolid, 47011
Valladolid, Spain
Fax : (+34)-983-423-013; e-mail: javiernr@qo.uva.es or celian@qo.uva.es
Received: March 5, 2012; Revised: May 17, 2012; Published online: September 28, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200185.
Abstract: A perhydro-1,3-benzoxazine behaves as an matic and heteroaromatic a-keto esters. Aliphatic
excellent chiral ligand in the nucleophilic addition of enolizable a-keto esters were alkynylated with mod-
alkynylzinc derivatives, prepared from terminal al- erate enantioselection.
kynes and dimethylzinc, to a-keto esters without
using other Lewis acids. The enantioselectivity is ex- Keywords: alkynylation; asymmetric catalysis; enan-
cellent and homogeneous for a wide variety of aro- tioselectivity; ketones; propargylic alcohols; zinc
Introduction
er, this excess of reactivity might be a problem due to
the competing non-catalyzed reaction pathway. In
Among the enantioselective catalytic transformations fact, although some reports of catalytic enantioselec-
that involve the generation of a carbon-carbon bond, tive addition of dialkylzinc to a-keto esters have been
the addition of organometallic reagents to carbonyl disclosed,[8] as far as we know only one study has
compounds has attracted special interest and consti- been reported concerning the preparation of chiral
tutes a valuable method for the obtention of chiral propargylic alcohols through nucleophilic addition of
secondary and tertiary alcohols.[1] Particularly inter- alkynylzinc to a-keto esters.[9] In this report the alkyn-
esting are the optically active propargylic alcohols,
ACHTUNGTRENyNGNU lzinc derivative was prepared in situ by the protocol
which are versatile building blocks in asymmetric syn- described by Carreira,[10] using catalytic amounts of
thesis[2] and whose structure is present in numerous zinc triflate in the presence of triethylamine and an
drugs and natural products.[3]
amino alcohol. The alkynylation reaction was per-
The most common methods for the preparation of formed neat at 708C, and a relatively large amount of
optically active propargylic alcohols involve (i) the chiral ligand (22 mol%) was required. Under these
asymmetric reduction of the corresponding propargyl- conditions, high yields and good enantioselectivities
ic ketone[4] or (ii) the asymmetric alkynylation of car- are obtained for the alkynylation of aromatic and
bonyl compounds catalyzed by metal complexes.[5–7] cyclic keto esters, while enolizable a-keto esters pro-
Although numerous examples of the first method vide poor results. In this context, we decided to
have been reported, two major limitations are pres- embark on the synthesis of chiral tertiary propargylic
ent: the starting alkynyl ketones are usually prone to alcohols through addition of organometallic species to
decompose and isomerize and tertiary alcohols are in- a-keto esters.
accessible by this method. Conversely, both problems
are solved by the addition of a terminal acetylide to ally
Recently, it has been found that the conformation-
restricted perhydro-1,3-benzoxazines 1a–f
simple aldehydes or ketones. Nevertheless, although (Figure 1) behave as excellent ligands for the enantio-
the asymmetric alkynylation of aldehydes has been selective alkylation and arylation of carbonyl com-
well developed, few studies concerning the alkynyla- pounds,[11] and in this way we envisioned their utiliza-
tion of ketones have been disclosed, probably due to tion as ligands for the enantioselective alkynylation of
their low reactivity toward alkynylides and the diffi- a-keto esters with alkynylzinc derivatives.
culties for high enantiocontrol. An interesting class of
carbonyl compounds which might overcome this
weakness are the more reactive a-keto esters. Howev-
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To our delight, although the chemical yield after
20 h was poor under these conditions, the enantiose-
lectivity of the process was significantly attractive
(75% ee). Encouraged by this result, we carried out
a set of experiments for the optimization of the reac-
tion conditions using the protocol described above, by
considering parameters such as (i) nature of ligand,
(ii) nature of alkynylzinc derivative, (iii) temperature
of the addition of keto ester, (iv) ligand and reactive
loadings and (v) the use of additives. The results ob-
tained are summarized in Table 1 and Table 2.
Figure 1. Structures of perhydro-1,3-benzoxazine-based li-
gands 1a–f.
Results and Discussion
Although longer reaction times (45 h) did not im-
The alkynylation of ethyl 2-oxo-2-phenylacetate 2a prove considerably the chemical yield (entry 2,
with phenylacetylene 3a was chosen as a model reac- Table 1), the use of 4 equiv, of phenylacetylene and
tion. We initially proposed a different procedure for dimethylzinc under the same conditions led to an ac-
the preparation of the alkynylzinc species, which in- ceptable chemical yield, and more interestingly, to an
volved the pre-formation of zinc phenylacetylide by improvement of enantioselectivity (80% ee, entry 3,
treatment of the alkyne (2 equiv.) with dimethylzinc Table 1). The chemical yield was further improved
(2 equiv.) in toluene at room temperature.[12] The alk- when diethylzinc was used instead of dimethylzinc, al-
ACHTUNGTRENNUNGynylzinc derivative was treated with 20 mol% of though the enantioselectivity was eroded (64% ee,
ligand 1a and, after cooling at 08C, it was reacted entry 4, Table 1), probably due to the higher reactivity
with ethyl 2-oxo-2-phenylacetate 2a (see entry 1, of the alkynylzinc derivative (competition between
Table 1).
non-catalyzed and catalyzed reaction pathway). When
the effect of the temperature was later explored (en-
Table 1. Enantioselective addition of alkynylzinc derivatives to 2a: optimization of reaction conditions and screening of li-
gands 1a–f.
Entry
Ligand (mol%)
ZnR2 (equiv.)[a]
Temp. T [8C]
Yield [%][b]
ee [%][c]
1[d]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1a (20)
1b (20)
1c (20)
1d (20)
1e (20)
1f (20)
1b (10)
1b (5)
ZnMe2 (2)
ZnMe2 (2)
ZnMe2 (4)
ZnEt2 (4)
ZnMe2 (4)
ZnMe2 (4)
ZnMe2 (4)
ZnMe2 (4)
ZnMe2 (4)
ZnMe2 (4)
ZnMe2 (4)
ZnMe2 (4)
ZnMe2 (4)
ZnMe2 (4)
ZnMe2 (4)
ZnMe2 (4)
0
0
0
0
20
38
68
92
78
75
80
58
62
89
58
75
81
60
89
56
75
76
80
64
73
81
83
66
70
93
35
71
85
48
92
90
23
À10
À20
À35
À50
À20
À20
À20
À20
À20
À20
À20
[a]
Same equiv. of phenylacetylene.
[b]
[c]
[d]
Yield of product after chromatographic purification.
Determined by HPLC (OD column).
Reaction time was 20 h.
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Enantiocontrolled Synthesis of Tertiary a-Hydroxy-a-ynyl Esters by Dimethylzinc-Mediated Addition
Table 2. Enantioselective addition of alkynylzinc derivatives to 2a in the presence of 1b. Screening of additives.
Entry[a]
1b (mol%)
Additive (mol%)
Temp. T [8C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
20
20
20
20
20
10
DiMPEG (20)
i-PrOH (10)
TiACHTUGNTRENNNUG
À20
À20
À20
À20
À20
À20
78
84
54
79
74
56
86
87
93
93
93
91
B
B
B
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[a]
ZnMe2/phenylacetylene/keto ester 4:4:1.
Yield of product after chromatographic purification.
Determined by HPLC (OD column).
[b]
[c]
tries 3, 5–9, Table 1) it was found that the reaction with the exception of the ortho-substituted derivative
proceeded with good enantiocontrol in the range of 0 2g (entry 7), which led to the corresponding alcohol
to À208C. At room temperature or below À208C, the with good yield and moderate enantioselectivity. Keto
enantioselectivity decreased significantly. The optimal esters 2a–c bearing alkoxy groups (OR1) of different
temperature was determined to be À208C, and steric volumes afforded the corresponding products
a good level of enantiocontrol was obtained (83% ee, with high enantioselectivities (91–93% ee, entries 1–3)
entry 7, Table 1).
The enantiocontrol seemed not to be influenced by
Under the best reaction conditions found so far electronic effects, as both electron-donating (entries 4
(4 equiv. of phenylacetylene and dimethylzinc, and 5) and electron-withdrawing substituents
20 mol% ligand, À208C, 45 h) a screening of ligands (entry 6) were tolerated in the aromatic ring without
(1a–f) was carried out (entries 7, 10–14, Table 1). The significant changes of the selectivity. Also a more
presence of a tertiary stereocenter on the carbon that bulky keto ester such as the 2-naphthyl derivative 2i
bears the hydroxy group in the ligand is crucial to and the heteroaromatic derivative 2j were alkynylated
obtain good enantioselectivity, since the secondary al- with excellent enantioselectivity (94% ee).
cohols 1c and 1f led to a considerable decrease of
When enolizable aliphatic keto esters were em-
enantiocontrol (entries 11 and 14, Table 1). The best ployed instead of aromatic derivatives (entries 11–13),
result was achieved with ligand 1b (entry 10, 89% the enantiomeric excesses diminished slightly. Al-
yield and 93% ee), which bears a sterically bulky iso- though the chemical yields were moderate for these
propyl group on the mentioned tertiary stereocenter. substrates, they were clearly superior to the only pre-
In addition, the ligand loading could be reduced viously reported result.[9a] When keto esters 2l and
from 20 to 10 mol%, without any substantial changes 2m, bearing an isopropyl and a phenethyl substituent,
in either chemical yield or enantioselectivity (en- respectively, the corresponding alcohols were ob-
tries 10 vs. 15, Table 1), and even with 5 mol% of tained with moderate enantioselectivities (77% and
ligand the enantioselectivity was maintained at good 75% ee, respectively, entries 12 and 13). However,
levels (90% ee, entry 16, Table 1).
with ethyl pyruvate 2k the enantioselection was main-
Finally, the influence of different additives on the tained at a good level (86% ee, entry 11).
enantiocontrol of the process was also studied
A screening of ligands 1a–f showed again that
(Table 2).[13] The addition of DiMPEG (MW 2000) or ligand 1b provides the highest enantioselectivity
2-propanol led to a reduction of the selectivity (en- among the six ligands in the alkynylation of alkyl de-
tries 1 and 2, Table 2), whereas the addition of rivatives (entries 13–18, Table 3).
a Lewis acid, such as Ti
G
G
On the other hand, the alkynylation of keto ester
ent proportions afforded the product in essentially 2a with an aliphatic terminal alkyne was also per-
the same enantiomeric excess, although the chemical formed (Scheme 1). The less reactive 3-(tert-butyldi-
yields were reduced (entries 3–6, Table 2).
methylsilyloxy)-1-propyne 3b was used and the corre-
After determining the optimal reaction conditions sponding product 4n was isolated in a moderate yield
(4 equiv. of phenylacetylene and dimethylzinc, (45%) with excellent enantioselectivity (93% ee).
10 mol% of 1b as ligand, at À208C), the substrate
Although a detailed mechanistic discussion is diffi-
scope was explored in the alkynylation of a series of cult at present, we propose the model shown in
a-keto esters with different electronic and steric Figure 2, in agreement with the anti-transition state
nature, and the results are collected in Table 3.
structure proposed by Noyori,[14] to account for the
It is noteworthy that the efficiency of our catalytic stereoselectivity observed with chiral ligand 1b. In
system was maintained at high levels for all aromatic this model, the transfer of the alkynyl group occurs to
a-keto esters in terms of enantiocontrol (91–96% ee,), the Si face of the ketone carbonyl.
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Table 3. Enantioselective addition of phenylacetylene to a-keto esters in the presence of 1b.
Entry
Ligand
2
R1
R2
4
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1a
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2m
2m
2m
2m
2m
Et
Me
i-Pr
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4m
4m
4m
4m
4m
89
96
65
50
89
71
87
92
84
60
66
50
73
68
62
60
65
49
92
91
93
96
96
93
81
91
94
94
86
77
75
66
46
50
65
42
p-Me-C6H4
p-MeO-C6H4
p-Cl-C6H4
o-Me-C6H4
o-MeO-C6H4
2-naphthyl
2-furyl
9
10
11
12
13
14
15
16
17
18
Me
i-Pr
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
[a]
Yield of product after chromatographic purification.
[b]
Determined by HPLC (OD, AD-H, AS-H columns). The absolute configurations of 4b and 4k were assigned by compari-
son of the sign of specific rotation with literature data, whereas the absolute configurations of 4a, 4c–j and 4l–m were as-
signed by assuming an analogous mechanism for the phenylacetylene transfer
Scheme 1. Asymmetric addition of aliphatic alkynes to ethyl
2-oxo-2-phenylacetate.
Figure 2. Proposed model for the addition of alkynylzinc de-
rivatives to a-keto esters catalyzed by ligand 1b.
In summary, chiral tertiary propargylic alcohols
were afforded through a mild enantioselective zinc-
mediated alkynylation of a-keto esters, which was ef-
ficiently promoted by perhydro-1,3-benzoxazines de- Experimental Section
rived from 8-aminomenthol, without using other
Lewis acids. Under optimal conditions, the enantiose- General Remarks
lectivity was excellent and homogeneous for a wide
All reactions were carried out in anhydrous solvents under
variety of aromatic and heteroaromatic a-keto esters,
with independence of the electronic effects or steric
hindrance on the aromatic ring. Aliphatic alkynes
were also tolerated and no detrimental effect on
enantioselectivity was observed, and even the chal-
lenging aliphatic enolizable a-keto esters were alkyn-
an argon atmosphere in dried glassware by means of
Schlenk techniques. 1H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded in CDCl3. Chemical shifts
for protons are reported in ppm from tetramethylsilane with
the residual CHCl3 resonance as internal reference. Chemi-
cal shifts for carbons are reported in ppm from tetramethyl-
silane and are referenced to the carbon resonance of the sol-
ACHTUNGTRENNUNGylated with moderate enantioselection.
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Enantiocontrolled Synthesis of Tertiary a-Hydroxy-a-ynyl Esters by Dimethylzinc-Mediated Addition
vent. Data are reported as follows: chemical shift, multiplici-
ty (s=singlet, d=doublet, t=triplet, q=quartet, quint=
quintet, sext=sextet sp=septet, m=multiplet, br=broad),
coupling constants in Hertz, and integration. Specific rota-
tions were measured using a 5-mL cell with a 1-dm path
length, and a sodium lamp, and concentration is given in g
per 100 mL. Flash chromatography was carried out using
silica gel (230–240 mesh). Chemical yields refer to pure iso-
lated substances. TLC analysis was performed on glass-
backed plates coated with silica gel 60 and an F254 indicator,
and visualized by either UV irradiation or by staining with
I2 or phosphomolybdic acid solution. Chiral HPLC analysis
was performed using a Daicel Chiralcel OD Column, Chiral-
pak AD-H or Chiralpak AS-H. UV detection was moni-
tored at 220 nm or at 254 nm. High resolution mass spec-
trometry analysis (HR-MS) were performed on a quadrupole
spectrometer with TOF analyzer.
Keto esters 2a, 2b, 2k, 2l, 2m were purchased from com-
mercial sources and used as received. Phenylacetylene 3a
and tert-butyldimethyl(2-propynyloxy)silane 3b were pur-
chased and distilled prior to use. Keto esters 2c–j were pre-
pared according to described procedures.[8d,15] Racemic hy-
droxy esters were synthesized by addition of the correspond-
ing freshly prepared lithium acetylide solution in THF
(1 equiv.) to the corresponding keto esters (1 equiv.) in THF
at low temperature (À788C). Ligands 1a–f were prepared
according to the literature.[11,16]
220 nm): tR =37.5 min for enantiomer R, tR =40.5 min for
enantiomer S.
(S)-Methyl 2-hydroxy-2,4-diphenylbut-3-ynoate (4b): This
compound was obtained from 2b (37 mL, 0.25 mmol) and 3a
(117 mL, 1.05 mmol), and purified by flash chromatography
(ethyl acetate/hexane=1/45); colorless oil; yield: 96%; [a]2D0:
À15.4 (c 1.2, CHCl3), (lit.[9] [a]D20: +19.56, c 4.04, CHCl3, R).
1H NMR (400 MHz, CDCl3): d=3.82 (s, 3H), 4.38 (s, 1H,
OH), 7.32–7.46 (m, 6H), 7.53–7.58 (m, 2H), 7.76–7.81 (m,
2H); 13C NMR (100 MHz, CDCl3): d=54.2, 73.2, 86.2, 86.9,
121.8, 126.2 (2), 128.2 (2), 128.3 (2), 128.7, 128.9, 131.9 (2),
139.2, 172.3; IR (neat): n=3492, 2951, 2228, 1737, 1255,
1096, 1071, 766, 753, 694, 650 cmÀ1; HR-MS: m/z=289.0831,
calcd. for C17H14O3 +Na+: 289.0835; HPLC (Chiralpak AS-
H, hexane:2-propanol=99:01, 1 mLminÀ1, l=220 nm): tR =
32.6 min for enantiomer R, tR =41.7 min for enantiomer S.
(S)-Isopropyl 2-hydroxy-2,4-diphenylbut-3-ynoate (4c):
This compound was obtained from 2c (48.0 mg, 0.25 mmol)
and 3a (117 mL, 1.05 mmol), and purified by flash chroma-
tography (ethyl acetate/hexane=1/45); colorless oil; yield:
65%; [a]2D0: À27.9 (c 0.5, CHCl3). 1H NMR (400 MHz,
CDCl3): d=1.14 (d, J=6.3 Hz, 3H), 1.33 (d, J=6.3 Hz, 3H),
4.40 (s, 1H, OH), 5.11 (hept, J=6.3 Hz, 1H), 7.31–7.44 (m,
6H), 7.50–7.56 (m, 2H), 7.74–7.79. (m, 2H); 13C NMR
(100 MHz, CDCl3): d=13.8, 21.1, 63.4, 73.1, 85.9, 87.3,
122.0, 126.1 (2), 128.3 (2), 128.8, 129.0 (2), 131.9 (2), 136.5,
138.5, 172.0; IR (neat): n=3475, 2987, 2923, 2858, 2238,
1845, 1713, 1276, 1254, 1098, 1070, 762, 758, 726, 693,
653 cmÀ1; HR-MS: m/z=317.1153, calcd. for C19H18O3 +
Na+: 317.1148; HPLC (Chiralpak AD-H, hexane:2-propa-
nol=99:01, 1 mLminÀ1, l=220 nm): tR =21.8 min for enan-
tiomer R, tR =26.7 min for enantiomer S.
Typical Procedure for Enantioselective Acetylene
Addition to a-Keto Esters
To a solution of acetylene 3 (1.05 mmol) in anhydrous tolu-
ene (1.0 mL) under an argon atmosphere was added drop-
wise a 1.2M solution of Me2Zn in toluene (0.83 mL,
1.0 mmol) at room temperature. After stirring the mixture
for 1 h at that temperature, a solution of ligand 1b (8.0 mg,
0.025 mmol) in anhydrous toluene (1 mL) was added. The
resulting mixture was stirred for another 30 min at the same
temperature and was then cooled to À208C. Once this solu-
tion was cooled, the corresponding keto ester (0.25 mmol)
was added and the reaction mixture was stirred at this tem-
perature for 45 h. Afterwards, the mixture was quenched
with an aqueous HCl solution (5%), extracted with Et2O
(4ꢄ15 mL), washed with brine, dried over MgSO4, filtered
off, and the solvents were evaporated. Purification by silica
gel column chromatography with different mixtures of ethyl
acetate/hexane gave the pure hydroxy esters. Enantiomeric
excess was determined by chiral HPLC.
(S)-Ethyl 2-hydroxy-4-phenyl-2-p-tolylbut-3-ynoate (4d):
This compound was obtained from 2d (48.0 mg, 0.25 mmol)
and 3a (117 mL, 1.05 mmol), and purified by flash chroma-
tography (ethyl acetate/hexane=1/45); colorless oil; yield:
50%; [a]2D0: À22.9 (c 1.1, CHCl3). 1H NMR (400 MHz,
CDCl3): d=1.26 (t, J=7.1 Hz, 3H), 2.38 (s, 3H), 4.21 (dq,
J1 =10.7 Hz, J2 =7.1 Hz, 1H), 4.29 (br s, 1H, OH), 4.32 (dq,
J1 =10.7 Hz, J2 =7.1 Hz, 1H), 7.21 (d, J=8.2 Hz, 2H), 7.30–
7.39 (m, 3H), 7.50–7.56 (m, 2H), 7.64 (d, J=8.2 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=13.8, 21.1, 63.4, 73.1, 85.9,
87.3, 122.1, 126.1 (2), 128.3 (2), 128.8, 129.0 (2), 131.9 (2),
136.6, 138.5, 172.0; IR (neat): n=3478, 2923, 2853, 2233,
1736, 1238, 1172, 1080, 1040, 826, 762, 694 cmÀ1; HR-MS:
m/z=317.1157, calcd. for C19H18O3 +Na+: 317.1148; HPLC
(Chiralpak AD-H, hexane:2-propanol=80:20, 1 mLminÀ1,
l=220 nm): tR =9.5 min for enantiomer R, tR =14.4 min for
enantiomer S.
(S)-Ethyl 2-hydroxy-2-(p-methoxyphenyl)-4-phenylbut-3-
ynoate (4e): This compound was obtained from 2e (52.0 mg,
0.25 mmol) and 3a (117 mL, 1.05 mmol), and purified by
flash chromatography (ethyl acetate/hexane=1/45); color-
less oil; yield: 89%; [a]2D0: À30.8 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): d=1.25 (t, J=7.1 Hz, 3H), 3.82 (s, 3H),
4.23 (dq, J1 =10.7 Hz, J2 =7.1 Hz, 1H), 4.29 (s, 1H, OH),
4.34 (dq, J1 =10.7 Hz, J2 =7.1 Hz, 1H), 6.92 (d, J=9.0 Hz,
2H), 7.29–7.40 (m, 3H), 7.47–7.56 (m, 2H), 7.66 (d, J=
9.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=13.9, 55.3,
63.4, 72.8, 85.9, 87.3, 113.6 (2), 122.0, 127.5 (2), 128.3 (2),
128.8, 131.6, 131.9 (2), 159.8, 172.0; IR (neat): n=3473,
2981, 2837, 2228, 1731, 1608, 1509, 1245, 1170, 1086, 1031,
(S)-Ethyl 2-hydroxy-2,4-diphenylbut-3-ynoate (4a): This
compound was obtained from 2a (42 mL, 0.25 mmol) and 3a
(117 mL, 1.05 mmol), and purified by flash chromatography
(ethyl acetate/hexane=1/45); colorless oil; yield: 89%; [a]2D0:
1
À23.9 (c 0.8, CHCl3). H NMR (400 MHz, CDCl3): d=1.25
(t, J=7.1 Hz, 3H), 4.22 (dq, J1 =10.7 Hz, J2 =7.1 Hz, 1H),
4.32 (dq, J1 =10.7 Hz, J2 =7.1 Hz, 1H), 4.34 (br s, 1H, OH),
7.31–7.44 (m, 6H), 7.51–7.56 (m, 2H), 7.74–7.80 (m, 2H);[17]
13C NMR (100 MHz, CDCl3): d=13.8, 63.5, 73.2, 86.1, 87.1,
121.9, 126.2 (2), 128.3 (2), 128.3 (2), 128.6, 128.9, 131.9 (2),
139.4, 171.9; IR (neat): n=3416, 2997, 2923, 2853, 2233,
1741, 1235, 1068, 765, 743, 698, 654, 600 cmÀ1; HR-MS:
m/z=303.0993, calcd. for C18H16O3 +Na+: 303.0992; HPLC
(Chiralcel OD, hexane:2-propanol=99:01, 0.6 mLminÀ1, l=
Adv. Synth. Catal. 2012, 354, 2797 – 2804
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2801

Rebeca Infante et al.
FULL PAPERS
835, 757, 691, 621 cmÀ1: HR-MS: m/z=333.1101, calcd. for
C19H18O4 +Na+: 333.1097; HPLC (Chiralpak AD-H,
hexane:2-propanol=90:10, 1 mLminÀ1, l=220 nm): tR =
23.5 min for enantiomer R, tR =33.0 min for enantiomer S.
2H), 7.56–7.61 (m, 2H), 7.79–7.94 (m, 4H), 8.29 (s, 1H);
13C NMR (100 MHz, CDCl3): d=13.8, 63.6, 73.3, 86.3, 87.1,
122.0, 123.9, 125.6, 126.3, 126.5, 127.6, 128.2, 128.3 (2), 128.5,
128.9, 132.0 (2), 132.9, 133.3, 136.7, 171.8; IR (neat): n=
3474, 3059, 2981, 2231, 1731, 1235, 1092, 1038, 858, 820, 756,
690 cmÀ1; HR-MS: m/z=353.1145, calcd. for C22H18O3 +
Na+: 353.1148; HPLC (Chiralpak AD-H, hexane:2-propa-
nol=99:01, 1 mLminÀ1, l=220 nm): tR =89.9 min for enan-
tiomer R, tR =97.4 min for enantiomer S.
(S)-Ethyl
2-(p-chlorophenyl)-2-hydroxy-4-phenylbut-3-
ynoate (4f): This compound was obtained from 2f (53.0 mg,
0.25 mmol) and 3a (117 mL, 1.05 mmol), and purified by
flash chromatography (ethyl acetate/hexane=1/45); color-
less oil; yield: 71%; [a]20: À26.0 (c 0.8, CHCl3). 1H NMR
(400 MHz, CDCl3): d=1.D25 (t, J=7.1 Hz, 3H), 4.23 (dq, J1 =
10.7 Hz, J2 =7.1 Hz, 1H), 4.32 (dq, J1 =10.7 Hz, J2 =7.1 Hz,
1H), 4.35 (br s, 1H, OH), 7.31–7.40 (m, 5H), 7.50–7.54 (m,
2H), 7.70 (d, J=8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d=13.8, 63.7, 72.7, 86.3, 86.8, 121.7, 127.8 (2), 128.3 (2),
128.4 (2), 129.0, 131.9 (2), 134.7, 138.0, 171.5; IR (neat): n=
3474, 2982, 2231, 1733, 1489, 1240, 1089, 108, 1015, 835, 756,
(R)-Ethyl
2-(2-furyl)-2-hydroxy-4-phenylbut-3-ynoate
(4j): This compound was obtained from 2j (42.0 mg,
0.25 mmol) and 3a (117 mL, 1.05 mmol), and purified by
flash chromatography (dichloromethane/hexane=1/2); col-
1
orless oil; yield: 60%; [a]20: +7.2 (c 0.6, CHCl3). H NMR
(400 MHz, CDCl3): d=1.3D0 (t, J=7.1 Hz, 3H), 4.29 (s, 1H,
OH), 4.30–4.43 (m, 2H), 6.39 (dd, J1 =3.3 Hz, J2 =1.8 Hz,
1H), 6.70 (dd, J1 =3.3 Hz, J2 =0.9 Hz, 1H), 7.31–7.38 (m,
3H), 7.42 (dd, J1 =1.8 Hz, J2 =0.9 Hz, 1H), 7.50–7.54 (m,
2H); 13C NMR (100 MHz, CDCl3): d=13.9, 63.9, 68.5, 84.7,
85.3, 109.4, 110.5, 121.6, 128.3 (2), 129.1, 132.0 (2), 143.4,
151.2, 169.8; IR (neat): n=3476, 2923, 2853, 2233, 1732,
1489, 1446, 1244, 1206, 1070, 1065, 1039, 1007, 760, 748,
694 cmÀ1; HR-MS: m/z=293.0783, calcd. for C16H14O4 +
Na+: 293.0784; HPLC (Chiralpak AD-H, hexane:2-propa-
nol=99:01, 1 mLminÀ1, l=220 nm): tR =57.0 min for enan-
tiomer S, tR =84.0 min for enantiomer R.
690, 611 cmÀ1
;
HR-MS: m/z=337.0615, calcd. for
C18H15ClO3 +Na+; 337.0602; HPLC (Chiralcel OD,
hexane:2-propanol=99:01, 0.6 mLminÀ1, l=220 nm): tR =
33.4 min for enantiomer R, tR =37.9 min for enantiomer S.
(R)-Ethyl 2-hydroxy-4-phenyl-2-o-tolylbut-3-ynoate (4g):
This compound was obtained from 2g (43.0 mg, 0.25 mmol)
and 3a (117 mL, 1.05 mmol), and purified by flash chroma-
tography (ethyl acetate/hexane=1/45); colorless oil; yield:
87%; [a]2D0: À2.4 (c 1.7, CHCl3); 1H NMR (400 MHz,
CDCl3): d=1.27 (t, J=7.1 Hz, 3H), 2.39 (s, 3H), 4.10 (s,
1H, OH), 4.28 (dq, J1 =10.7 Hz, J2 =7.1 Hz, 1H), 4.39 (dq,
J1 =10.7 Hz, J2 =7.1 Hz, 1H), 7.16–7.20 (m, 1H), 7.22–7.30
(m, 2H), 7.31–7.39 (m, 3H), 7.49–7.56 (m, 2H), 7.97–8.02
(m, 1H); 13C NMR (100 MHz, CDCl3): d=13.8, 19.9, 63.3,
74.5, 87.3, 87.8, 121.9, 125.7, 128.3 (2), 128.7, 128.9, 128.9,
131.8 (3), 136.1, 136.6, 172.3; IR (neat): n=3475, 2981, 2226,
1729, 1239, 1072, 1054, 1033, 754, 725, 690, 650 cmÀ1; HR-
MS: m/z=317.1151, calcd. for C19H18O3 +Na+: 317.1148;
HPLC (Chiralpak AD-H, hexane:2-propanol=80:20,
1 mLminÀ1, l=220 nm): tR =8.9 min for enantiomer S, tR =
10.1 min for enantiomer R.
(S)-Ethyl 2-hydroxy-2-methyl-4-phenylbut-3-ynoate (4k):
This compound was obtained from 2k (29 mL, 0.25 mmol)
and 3a (117 mL, 1.05 mmol), and purified by flash chroma-
tography (ethyl acetate/hexane=1/45); colorless oil; yield:
66%; [a]20: +28.6 (c 0.9, CHCl3), (lit.[9] [a]2D0: À15.3, c 0.38,
CHCl3, 9D2% ee for R). H NMR (400 MHz, CDCl3): d=1.35
(t, J=7.1 Hz, 3H), 1.78 (s, 3H), 3.64 (s, 1H, OH), 4.33 (q,
J=7.1 Hz, 2H), 7.27–7.35 (m, 3H), 7.40–7.46 (m, 2H);
13C NMR (100 MHz, CDCl3): d=14.0, 27.1, 62.9, 68.3, 83.8,
88.4, 122.0, 128.2 (2), 128.7, 131.8 (2), 172.7; IR (neat): n=
3476, 2987, 2238, 1840, 1733, 1246, 1146, 1123, 1015, 756,
(R)-Ethyl 2-hydroxy-2-(o-methoxyphenyl)-4-phenylbut-3-
ynoate (4h): This compound was obtained from 2h (52.0 mg,
0.25 mmol) and 3a (117 mL, 1.05 mmol), and purified by
flash chromatography (ethyl acetate/hexane=1/45); color-
691, 615 cmÀ1
;
HR-MS: m/z=241.0829, calcd. for
C13H14O3 +Na+: 241.0835; HPLC (Chiralcel OD, hexane:2-
propanol=99:01, 0.6 mLminÀ1, l=220 nm): tR =33.0 min
for enantiomer S, tR =41.6 min for enantiomer R.
1
less oil; yield: 92%; [a]2D0: +19.0 (c 2.2, CHCl3). H NMR
(S)-Ethyl
2-hydroxy-2-isopropyl-4-phenylbut-3-ynoate
(400 MHz, CDCl3): d=1.25 (t, J=7.1 Hz, 3H), 3.81 (s, 3H),
4.31 (q, J=7.1 Hz, 2H), 4.44 (br s, 1H, OH), 6.91 (dd, J1 =
8.2 Hz, J2 =0.9 Hz, 1H), 7.04 (td, J1 =7.5 Hz, J2 =1.1 Hz,
1H), 7.31–7.39 (m, 4H), 7.52–7.58 (m, 2H), 8.00 (dd, J1 =
7.6 Hz, J2 =1.7 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
13.9, 55.4, 62.7, 72.6, 86.1, 87.4, 111.1, 120.7, 121.9, 127.8,
128.2 (2), 128.8, 129.3, 130.3, 131.8 (2), 156.3, 171.9; IR
(neat): n=3463, 2956, 2923, 2853, 2233, 1732, 1257, 1235,
1076, 1035, 759, 745, 693, 647 cmÀ1; HR-MS: m/z=333.1100,
calcd. for C19H18O4 +Na+: 333.1097; HPLC (Chiralpak AD-
H, hexane:2-propanol=90:10, 1 mLminÀ1, l=220 nm): tR =
25.0 min for enantiomer S, tR =48.7 min for enantiomer R.
(4l): This compound was obtained from 2l (38 mL,
0.25 mmol) and 3a (117 mL, 1.05 mmol), and purified by
flash chromatography (ethyl acetate/hexane=1/30); color-
1
less oil; yield: 50%; [a]20: +28.8 (c 0.8, CHCl3). H NMR
(400 MHz, CDCl3): d=0D.95 (d, J=6.8 Hz, 3H), 1.19 (d, J=
6.8 Hz, 3H), 1.36 (t, J=7.1 Hz, 3H), 2.32 (hept, J=6.8 Hz,
1H), 3.51 (s, 1H, OH), 4.29–4.41 (m, 2H), 7.27–7.35 (m,
3H), 7.42–7.48 (m, 2H); 13C NMR (100 MHz, CDCl3): d=
14.1, 16.3, 16.9, 37.0, 62.9, 74.7, 84.7, 87.6, 122.3, 128.2 (2),
128.5, 131.8 (2), 172.8; IR (neat): n=3501, 2971, 2935, 2873,
2228, 1840, 1731, 1244, 1146, 1027, 1013, 756, 723, 691 cmÀ1
;
HR-MS: m/z=269.1140, calcd. for C15H18O3 +Na+:
269.1148; HPLC (Chiralpak AD-H, hexane:2-propanol=
99:01, 1 mLminÀ1, l=220 nm): tR =13.6 min for enantiomer
R, tR =16.2 min for enantiomer S.
(S)-Ethyl
2-hydroxy-2-(naphthalen-2-yl)-4-phenylbut-3-
ynoate (4i): This compound was obtained from 2i (57.0 mg,
0.25 mmol) and 3a (117 mL, 1.05 mmol), and purified by
flash chromatography (ethyl acetate/hexane=1/45); color-
less oil; yield: 84%; [a]20: À44.8 (c 0.9, CHCl3). 1H NMR
(400 MHz, CDCl3): d=1.D25 (t, J=7.1 Hz, 3H), 4.24 (dq, J1 =
10.7 Hz, J2 =7.1 Hz, 1H), 4.36 (dq, J1 =10.7 Hz, J2 =7.1 Hz,
1H), 4.47 (s, 1H, OH), 7.33–7.43 (m, 3H), 7.49–7.55 (m,
(S)-Ethyl
2-hydroxy-2-phenethyl-4-phenylbut-3-ynoate
(4m): This compound was obtained from 2m (48 mL,
0.25 mmol) and 3a (117 mL, 1.05 mmol), and purified by
flash chromatography (ethyl acetate/hexane=1/45); color-
1
less oil; yield: 73%; [a]2D0: +36.9 (c 0.6, CHCl3). H NMR
2802
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ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 2797 – 2804

Enantiocontrolled Synthesis of Tertiary a-Hydroxy-a-ynyl Esters by Dimethylzinc-Mediated Addition
(400 MHz, CDCl3): d=1.37 (t, J=7.1 Hz, 3H), 2.25–2.50
(m, 2H), 2.71–2.85 (m, 1H), 2.94–3.07 (m, 1H), 3.72 (br s,
1H, OH), 4.27–4.39 (m, 2H), 7.18–7.28 (m, 3H), 7.28–7.37
(m, 5H), 7.43–7.50 (m, 2H); 13C NMR (100 MHz, CDCl3):
d=14.1, 30.1, 41.7, 63.0, 71.0, 84.7, 87.4, 122.0, 126.0, 128.2
(2), 128.4 (2), 128.5 (2), 128.7, 131.8 (2), 141.1, 172.4; IR
(neat): n=3489, 3028, 2977, 2932, 2873, 2228, 1840, 1733,
1239, 1186, 1097, 1016, 755, 690 cmÀ1; HR-MS: m/z=
331.1294, calcd. for C20H20O3 +Na+: 331.1305; HPLC (Chir-
alcel OD, hexane:2-propanol=99:01, 0.6 mLminÀ1, l=
220 nm): tR =36.5 min for enantiomer S, tR =42.8 min for
enantiomer R.
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Adv. Synth. Catal. 2009, 351, 963–983; e) E. M. Car-
reira, D. E. Frantz, in: Science of Synthesis, Stereoselec-
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P. A. Evans), Georg Thieme Verlag, Stuttgart, 2011,
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[6] For selected recent examples of alkynylation of alde-
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4425-4428.
(S)-Ethyl 5-(tert-butyldimethylsilyloxy)-2-hydroxy-2-phe-
nylpent-3-ynoate (4n): This compound was obtained from 2a
(42 mL, 0.25 mmol) and 3b (219 mL, 1.05 mmol), and purified
by flash chromatography (ethyl acetate/hexane=1/45); col-
1
orless oil; yield: 45%. H NMR (400 MHz, CDCl3): d=0.14
(s, 6H), 0.92 (s, 9H), 1.22 (t, J=7.1 Hz, 3H), 4.15–4.31 (m,
3H), 4.45 (s, 2H), 7.30–7.40 (m, 3H), 7.64–7.71 (m, 2H);
13C NMR (100 MHz, CDCl3): d=À5.1 (2), 13.8, 18.2, 25.7
(3), 51.7, 63.5, 72.7, 82.8, 85.0, 126.2 (2), 128.2 (2), 128.6,
139.2, 171.7: IR (neat): n=3453, 2956, 2930, 2858, 1734,
1251, 1145, 1063, 1008, 834, 778, 729, 696, 668 cmÀ1; HR-
MS: m/z=371.1639, calcd. for C19H28O4Si+Na+: 371.1649;
[7] For recent examples of alkynylation of ketones, see:
a) R. Motoki, M. Kanai, M. Shibasaki, Org. Lett. 2007,
9, 2997–3000; b) P. K. Dhondi, P. Carberry, L. B. Choi,
J. D. Chisholm, J. Org. Chem. 2007, 72, 9590–9596; c) T.
Ueda, K. Tanaka, T. Ichibakase, Y. Orito, M. Nakajima,
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47, 5614–5616.
[8] a) E. F. DiMauro, M. C. Kozlowski, Org. Lett. 2002, 4,
3781–3784; b) K. Funabashi, M. Jachmann, M. Kanai,
M. Shibasaki, Angew. Chem. 2003, 115, 5647–5650;
Angew. Chem. Int. Ed. 2003, 42, 5489–5492; c) L. C.
Wieland, H. Deng, M. L. Snapper, A. H. Hoveyda, J.
Am. Chem. Soc. 2005, 127, 15453–15456; d) G. Blay, I.
Fernandez, A. Marco-Aleixandre, J. R. Pedro, Org.
Lett. 2006, 8, 1287–1290; e) H.-L. Wu, P.-Y. Wu, Y.-Y.
Shen, B.-J. Uang, J. Org. Chem. 2008, 73, 6445–6447;
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Tetrahedron: Asymmetry 2009, 20, 2125–2129.
[9] a) B. Jiang, Z. Chen, X. Tang, Org. Lett. 2002, 4, 3451-
3453. For two recent examples of enantioselective alky-
nylation of trifluoropyruvate, see: b) K. Aikawa, Y.
Hioki, K. Mikami, Org. Lett. 2010, 12, 5716–5719; c) T.
Ohshima, T. Kawabata, Y. Takeuchi, T. Kakinuma, T.
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[10] For a review, see: D. E. Frantz, R. Fꢅssler, C. S. Tomoo-
ka, E. M. Carreira, Acc. Chem. Res. 2000, 33, 373–381.
[11] a) C. Andrꢀs, R. Infante, J. Nieto, Tetrahedron: Asym-
metry Tetrahedron:Asymmetry 2010, 21, 2230–2237;
b) R. Infante, J. Nieto, C. Andrꢀs, Org. Biomol. Chem.
2011, 9, 6691-6699; c) R. Infante, J. Nieto, C. Andrꢀs,
Chem. Eur. J. 2012, 18, 4375–4379; d) R. Infante, J.
Nieto, C. Andrꢀs, Synthesis 2012, 44, 1343-1348.
HPLC
(Chiralcel
OD,
hexane:2-propanol=99:01,
0.6 mLminÀ1, l=254 nm): tR =21.9 min for enantiomer R,
tR =26.3 min for enantiomer S.
Acknowledgements
We acknowledge the financial support from the Spanish Min-
isterio de Ciencia
CTQ2011-28487/BQU) and Junta de Castilla
(GR168). R. I. also thanks Junta de Castilla y Leꢀn for a pre-
doctoral fellowship.
e
Innovaciꢀn (MICINN) (Project
Leꢀn
y
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Adv. Synth. Catal. 2012, 354, 2797 – 2804