Asymmetric alkynylation of aldehydes with propiolates without high reagent loading and any additives

Article abstract of DOI:10.1039/c1ob05489a

The asymmetric alkynylation of aliphatic and aromatic aldehydes with propiolates was mediated by dialkylzinc and a novel prolinol catalyst without high reagent loading and any additives, such as Ti(Oi-Pr)₄, to give the corresponding γ-hydroxy-α,β-acetylenic esters with high enantiomeric excess of up to 95%.

Full text of DOI:10.1039/c1ob05489a

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Asymmetric alkynylation of aldehydes with propiolates without high reagent
loading and any additives†
Naoto Kojima,* Shogo Nishijima, Kaoru Tsuge and Tetsuaki Tanaka*
Received 29th March 2011, Accepted 20th April 2011
DOI: 10.1039/c1ob05489a
The asymmetric alkynylation of aliphatic and aromatic alde-
hydes with propiolates was mediated by dialkylzinc and a
novel prolinol catalyst without high reagent loading and any
additives, such as Ti(Oi-Pr)4, to give the corresponding c-
hydroxy-a,b-acetylenic esters with high enantiomeric excess
of up to 95%.
to aldehydes without any additives. However, their reactions
still required excess amounts of Me2Zn and propiolate. Herein,
we disclose a dialkylzinc-mediated asymmetric alkynylation of
aliphatic and aromatic aldehydes using propiolates, which is
catalysed by a novel prolinol system and does not require any
additives and high reagent loading.
We focused on a prolinol derivative for its potential use as
a chiral ligand in the asymmetric alkynylation with propiolates,
because there are many reports of the asymmetric alkylation and
alkenylation of aldehydes with prolinol as the catalyst.10 However,
to our knowledge, there are few studies of the asymmetric
alkynylation of aldehydes using prolinol as the catalyst.8
First, we attempted to perform the enantioselective addition
of ethyl propiolate to cyclohexanecarbaldehyde using (S)-(+)-
diphenyl(1-methylpyrrolidin-2-yl)methanol (DPMPM, 2c) as the
ligand, and obtained chiral g-hydroxy-a,b-acetylenic ester 1a in
good yield with moderate enantioselectivity (88%, 69% ee) (Table
1, Entry 3).11 At the same time, Zhang and co-workers reported the
enantioselective addition of alkynes to aldehydes using N-benzyl
prolinol as the catalyst.12 As the reaction using propiolates was not
Chiral propargyl alcohols are versatile building blocks for fine
chemicals, pharmaceuticals, and natural products.1 A typical
example is chiral g-hydroxy-a,b-acetylenic esters, considered at-
tractive molecules because they contain three functionalities: a
hydroxyl group, an alkyne, and an ester, in a small structure. Many
efficient syntheses that employed them as useful and versatile inter-
mediates have been reported.2,3 The two most common methods
to prepare optically active g-hydroxy-a,b-acetylenic esters are i)
the asymmetric reduction of g-oxo-a,b-acetylenic esters with a
chiral reagent, and ii) the asymmetric alkynylation of aldehydes
with propiolates. The latter has attracted widespread interest in
recent years because it is able to achieve both new C–C bond
formation and construction of a stereogenic centre. However,
previous studies of the asymmetric alkynylation of aldehydes
have concentrated on the addition of simple terminal alkynes,
for example, phenylacetylene.4 Difficulty arises in the asymmetric
alkynylation using propiolate as the nucleophile because the
reactivity of propiolate is greatly different from that of simple
terminal alkynes.5
Table 1 Ligand screening in the model reaction
Recently, Pu and co-workers reported that BINOL and H8-
BINOL derivatives catalysed the Et2Zn-mediated asymmetric
alkynylation of aldehydes with methyl propiolate.6 Wang’s group
developed the enantioselective addition of methyl propiolate to
aromatic aldehydes with b-sulfonamide alcohol as the ligand.7 Al-
though previous studies, including those methods, gave products
in good yields with high enantioselectivities, most of them required
excess amounts of reagents and additives, such as Ti(Oi-Pr)4. Trost
et al.8 and Wang and co-workers9 independently demonstrated the
Me2Zn-mediated enantioselective addition of methyl propiolate
Entry
Ligand
Yield (%)a
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Ya-
madaoka, Suita, Osaka 565-0879, Japan. E-mail: kojima@phs.osaka-
u.ac.jp, t-tanaka@phs.osaka-u.ac.jp; Fax: +81-6-6879-8214; Tel: +81-6-
6879-8210
† Electronic supplementary information (ESI) available: Synthesis of
ligand 2d, experimental procedures of asymmetric alkynylation, determi-
nation of stereochemistry of products, characterization data, and 1H/13C
NMR spectra of products. See DOI: 10.1039/c1ob05489a
1
2
3
4
2a
2b
2c
2d
75 (50% ee)
80 (51% ee)
88 (69% ee)
87 (75% ee)
a Determined by 1H NMR. Ee was determined by HPLC.
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Table 2 Optimization of reaction conditions
Conditions 1
Conditions 2
Entry
Propiolate (eq.)
Et2Zn (eq.)
Ligand (eq.)
Solvent
T/◦C
Time (h)
T/◦C
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
2.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
1.2
1.1
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.4
0.1
0.3
0.3
0.3
0.3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
n-hexane
Et2O
rt
rt
rt
rt
rt
0
40
rt
rt
rt
rt
rt
rt
12
0
0
0
0
0
0
0
0
0
0
0
0
rt
rt
rt
rt
rt
0
40
rt
rt
rt
rt
rt
rt
3
3
1.5
3
5
5
3
3
3
3
3
3
3
87 (75% ee)
89 (89% ee)
84 (91% ee)
84 (89% ee)
73 (89% ee)
<56 (91% ee)
83 (86% ee)
79 (89% ee)
72 (91% ee)
66 (81% ee)
70 (77% ee)
63 (81% ee)
trace
9
10
11
12
13
THF
a Determined by 1H NMR. Ee was determined by HPLC.
reported in their letter, we examined the asymmetric alkynylation
with their chiral ligands (2a and b).
using 1.0 equiv. of propiolate and 1.2 equiv. of Et2Zn gave almost
the same result as that of Entry 2 (Entry 4). When the reaction
temperature was lowered to 0 ◦C, the yield was decreased (Entry
6). On the other hand, there was no significant change in both
yield and selectivity when the reaction was conducted at 40 ◦C
compared with the case at room temperature (Entry 7). Increasing
the amount of 2d did not improve yield or selectivity (Entry 8), and
the yield in the reaction using 0.1 equiv. of 2d was reduced (Entry
9). The use of CH2Cl2, n-hexane, and Et2O instead of toluene
decreased both yield and enantioselectivity, whereas the reaction
in THF hardly occurred (Entries 10–13).
Under the above optimal conditions (Table 2, Entry 4), we
examined the alkynylation of aliphatic aldehydes with ethyl
propiolate (Table 3). The reaction with propionaldehyde gave
alcohol 1b in moderate yield but with high enantioselectivity
(Entry 1). Isobutylaldehyde gave the corresponding alcohol 1c
in good yield with high enantioselectivity (Entry 3). The use of a
bulky aldehyde, pivalaldehyde, resulted in only a small decrease in
enantioselectivity (Entry 4).
Next, we examined the alkynylation of aromatic aldehydes
(Table 4). The asymmetric alkynylation of benzaldehyde with
ethyl propiolate under the optimal conditions afforded the desired
alkynylated compound 1e with high enantioselectivity, but the
yield was low (32%) because the conditions gave an ethylation
product (44%) as the main product (Entry 1). The use of Me2Zn
in place of Et2Zn dramatically decreased the alkyl adduct (3%)
and increased the yield of 1e to 52% (Entry 2).17 By increasing the
reagent loading (Me2Zn and ethyl propiolate) to 2.0 equiv., the
yield of 1e was improved to 78% with high enantioselectivity (95%
ee) (Entry 3). Having established the optimal reaction conditions
for aromatic aldehydes, we investigated the alkynylation of various
The reactions catalysed by their chiral ligands (2a and b)
gave g-hydroxy-a,b-acetylenic esters in good yields, but the
enantioselectivities were low (~50% ee) (Entries 1 and 2). As a
result of several investigations, we found that a novel N-methyl
prolinol derivative with two 3,5-dimethylphenyl moieties (2d)13
catalysed the asymmetric alkynylation in high yield with good
enantioselectivity (Entry 4).
Table 2 shows the optimization of the reaction conditions. To
a solution of 30 mol% of ligand 2d in toluene, Et2Zn (2.0 equiv.)
and ethyl propiolate (2.0 equiv.) were added at room temperature.
After 12 h, cyclohexanecarbaldehyde (1.0 equiv.) was added and
the reaction mixture was stirred for 3 h, giving chiral propargyl
alcohol 1a in good yield with high enantioselectivity (Entry
1). The previously reported dialkylzinc-mediated alkynylation of
aldehydes required a mixing step prior to the addition of aldehydes
to prepare an alkynylzinc species. Without this step, the alkyl
adduct was obtained as a by-product14 because chiral ligands,
such as BINOL15 and b-sulfonamide alcohol,16 would catalyse the
addition of dialkylzinc to aldehydes. Surprisingly, the reaction that
did not include a mixing step prior to the addition of aldehyde
in the presence of 2d gave propargyl alcohol 1a in high yield,
and no ethyl adduct was detected (Entry 2). Furthermore, this
improvement not only simplified the reaction but also increased
the enantioselectivity. We surmise that ligand 2d can catalyse the
formation of an alkynylzinc species more efficiently than previous
ligands and therefore, the long mixing time afforded dialkynylzinc
species, thereby decreasing the enantioselectivity.14 Fortunately,
the efficiency of our catalyst 2d enabled the reduction of the
amounts of Et2Zn and propiolate (Entries 2–5). The reaction
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Table 3 Asymmetric alkynylation of aliphatic aldehydesa
6). Both p-anisaldehyde and p-formylphenyl acetate, respectively,
were converted into the corresponding alcohols 1i and 1j with high
enantioselectivities, but the yield of the former was moderate (54%)
because of less reactivity due to the electron-donating substituent
(Entries 7 and 8). The desired product was also obtained when
heterocyclic aldehyde was employed as the substrate, although the
yield and the selectivity were decreased (Entry 9). The results
showed that this catalytic system has a broad generality for
aliphatic and aromatic aldehydes.
Asymmetric alkynylation in the presence of chiral prolinol
2d afforded (R)-propargyl alcohol. The absolute configuration
of the newly created chiral centre is predictable based on the
model (Fig. 1). The model is analogous to that proposed by
Noyori and co-workers for the Me2Zn addition to aldehydes.18
The carbonyl oxygen atom of the aldehyde coordinates to the
zinc of the bimetallic complex generated from the chiral ligand,
zinc acetylide, and Et2Zn, and then an alkynyl group attacks the
carbonyl carbon of the aldehyde as shown, giving an (R)-isomer.
Entry
Aldehyde
Time (h)
Yield (%)b
Selectivityc
1
Et
2
3
4
4
63 (1b)
84d (1a)
76 (1c)
69 (1d)
89% ee (R)
89% ee (R)
92% ee (R)
83% ee (R)
2
c-Hex
i-Pr
t-Bu
3e
4
a Aldehyde (1.0 mmol), ethyl propiolate (1.0 mmol), Et2Zn (1 M solution
in n-hexane, 1.2 mmol), and 2d (0.3 mmol) in toluene (6 mL) were stirred
at rt under Ar. b Isolated yield. c Ee was determined by HPLC. The
stereochemistry of the products was confirmed by the modified Mosher
method. d Determined by H NMR. e The reaction was carried out with
1
3.0 mmol of aldehyde.
Table 4 Asymmetric alkynylation of aromatic aldehydesa
Fig. 1 Model predicting the stereochemistry.
In conclusion, we have demonstrated the enantioselective
addition of propiolates to aliphatic and aromatic aldehydes in
the presence of a novel prolinol catalyst without high reagent
loading and any additives. Our chiral ligand systems make it
possible to prepare easily chiral g-hydroxy-a,b-acetylenic esters.
It is interesting to catalyse the asymmetric addition of propiolates
to aldehydes by structurally simple ligand 2d with good enantios-
electivity. The scope, mechanism, and synthetic application are
under investigation.
Entry
Aldehyde
C6H5
Yield (%)b
Selectivityc
Acknowledgements
1d
2e
3
4
5
6
7
8
9
32 (1e)
52 (1e)
78 (1e)
76 (1f)
71 (1g)
75 (1h)
54 (1i)
71 (1j)
66 (1k)
>99% ee
95% ee
This work was partially supported by a Grant-in-Aid for Young
Scientists (B) [No. 21790113] from The Ministry of Education,
Culture, Sports, Science and Technology, Japan (MEXT) and a
Grant-in-Aid for Scientific Research on Innovative Areas [No.
22136006] from Japan Society for the Promotion of Science (JSPS).
95% ee (R)f
93% ee (S)
95% ee
o-Br-C6H4
m-Br-C6H4
p-Br-C6H4
p-MeO-C6H4
p-CO2Me-C6H4
2-Furyl
92% ee
90% ee (R)
91% ee (R)
76% ee
a Aldehyde (1.0 mmol), ethyl propiolate (2.0 mmol), Me2Zn (1 M solution
in n-hexane, 2.0 mmol), and 2d (0.3 mmol) in toluene (6 mL) were
stirred at rt under Ar. b Isolated yield. c Ee was determined by HPLC.
The stereochemistry of the products was confirmed by the modified
Mosher method after transformation to the corresponding allyl alcohols.
For details, see Electronic Supplementary Information. d Ethyl propiolate
(1.0 eq.) and Et2Zn (1.2 eq.) were used. e Ethyl propiolate (1.0 eq.) and
Me2Zn (1.2 eq.) were used. f Absolute configuration was determined by
comparing the optical rotation with the literature value after conversion
into the known methyl ester. For details, see Electronic Supplementary
Information.
Notes and references
1 Acetylene Chemistry, ed. F. Diederich, P. J. Stang and R. R. Tykwinski,
WILEY-VCH, Weinheim, Germany, 2005.
2 Review of synthesis and applications of chiral g-hydroxy- a,b-acetylenic
esters: G. Gao and L. Pu, Sci. China Chem., 2010, 53, 21.
3 Recent reports of applications of g-hydroxy-a,b-acetylenic esters in
organic synthesis: (a) R. Csuk, A. Barthel, S. Schwarz, H. Kommera
and R. Paschke, Bioorg. Med. Chem., 2010, 18, 2549; (b) V. Shekhar,
D. K. Reddy, V. Suresh, D. C. Babu and Y. Venkateswarlu, Tetrahedron
Lett., 2010, 51, 946; (c) Y. Zhang, H.-D. Hao and Y. Wu, Synlett,
2010, 905; (d) B. M. Trost, B. M. O’Boyle and D. Hund, J. Am. Chem.
Soc., 2009, 128, 15061; (e) N. Kojima, S. Nishijima and T. Tanaka,
Synlett, 2009, 3171; (f) Y. Yue, M. Turlington, X.-Q. Yu and L. Pu,
J. Org. Chem., 2009, 74, 8681; (g) L. Lin, Q. Zhao, A.-N. Li, F. Ren,
F. Yang and R. Wang, Org. Biomol. Chem., 2009, 7, 3663; (h) L. Liu,
aromatic aldehydes. The reactions of benzaldehydes containing
a bromine atom at the ortho-, meta-, and para-positions gave
good yields and high enantioselectivities, respectively (Entries 4–
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Y. Gao, Y. C. Che, N. Wu, D. Z. Wang, C.-C. Li and Z. Yang, Chem.
Commun., 2009, 662; (i) L.-H. Zhou, X.-Q. Yu and L. Pu, J. Org.
Chem., 2009, 74, 2013; (j) C. L. Morris, Y. Hu, G. D. Head, L. J.
Brown, W. G. Whittingham and R. C. D. Brown, J. Org. Chem., 2009,
74, 981; (k) H. Lebel and M. Parmentier, Org. Lett., 2007, 9, 3563;
(l) D. Gre´e and R. Gre´e, Tetrahedron Lett., 2007, 48, 5435; (m) M.
C. Clasby, S. Chackalamannil, M. Czarniecki, D. Doller, K. Eagen, W.
Greenlee, G. Kao, Y. Lin, H. Tsai, Y. Xia, H.-S. Ahn, J. Agans-Fantuzzi,
G. Boykow, M. Chintala, C. Foster, A. Smith-Torhan, K. Alton, M.
Bryant, Y. Hsieh, J. Lau and J. Palamanda, J. Med. Chem., 2007, 50,
129.
4 Recent review of enantioselective addition of alkynes to carbonyl
groups: B. M. Trost and A. H. Weiss, Adv. Synth. Catal., 2009, 351,
963.
5 For example: S. P. Shahi and K. Koide, Angew. Chem., Int. Ed., 2004,
43, 2525.
9 J.-C. Zhong, S.-C. Hou, Q.-H. Bian, M.-M. Yin, R.-S. Na, B. Zheng,
Z.-Y. Li, S.-Z. Liu and M. Wang, Chem.–Eur. J., 2009, 15, 3069.
10 L. Pu and H.-B. Yu, Chem. Rev., 2001, 101, 757.
11 Niwa and Soai reported the enantioselective addition of phenylacety-
lene to benzaldehyde in the presence of DPMPM (2c). However, there
was only one example, and the enantioselectivity was only 4% ee. S.
Niwa and K. Soai, J. Chem. Soc., Perkin Trans. 1, 1990, 937.
12 Z. Xu, N. Wu, Z. Ding, T. Wang, J. Mao and Y. Zhang, Tetrahedron
Lett., 2009, 50, 926.
13 Ligand 2d was easily prepared from L-proline in 4 steps. For details, see
Electronic Supplementary Information.
14 S. Dahmen, Org. Lett., 2004, 6, 2113.
15 X.-W. Yang, J.-H. Sheng, C.-S. Da, H.-S. Wang, W. Su, R. Wang and
A. S. C. Chan, J. Org. Chem., 2000, 65, 295.
16 (a) M. Yus, D. J. Ramo´n and O. Preito, Tetrahedron: Asymmetry, 2002,
13, 1573; (b) T. Bauer, J. Tarasiuk and K. Pasniczek, Tetrahedron:
Asymmetry, 2002, 13, 77.
17 Noyori and co-workers reported that Me2Zn was less reactive than
Et2Zn in the asymmetric alkylation of aldehydes in the presence of a
chiral amino alcohol: M. Kitamura, S. Okada, S. Suga and R. Noyori,
J. Am. Chem. Soc., 1989, 111, 4028.
18 (a) T. Rasmussen and P.-O. Norrby, J. Am. Chem. Soc., 2003, 125, 5130;
(b) M. Yamakawa and R. Noyori, Organometallics, 1999, 18, 128; (c) M.
Yamakawa and R. Noyori, J. Am. Chem. Soc., 1995, 117, 6327.
6 (a) G. Gao, Q. Wang, X.-Q. Yu, R.-G. Xie and L. Pu, Angew. Chem.,
Int. Ed., 2006, 45, 122; (b) M. Turlington, A. M. DeBerardinis and L.
Pu, Org. Lett., 2009, 11, 2441; (c) X. Chen, W. Chen, L. Wang, X.-Q.
Yu, D.-S. Huang and L. Pu, Tetrahedron, 2010, 66, 1990.
7 L. Lin, X. Jiang, W. Liu, L. Qiu, Z. Xu, J. Xu, A. S. C. Chan and R.
Wang, Org. Lett., 2007, 9, 2329.
8 B. M. Trost, A. H. Weiss and A. J. von Wangelin, J. Am. Chem. Soc.,
2006, 128, 8.
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