Asymmetric synthesis of γ-hydroxy-α,β-acetylenic esters catalyzed by oxazolidine-titanium complex

Article abstract of DOI:10.1055/s-0029-1217712

An efficient catalytic system has been developed for the enantioselective reaction of alkynoates with aromatic aldehydes for the synthesis of optically active γ-hydroxy-α,β-acetylenic esters (with up to 81% isolated yield and up to 84% enantioselectivity)

Full text of DOI:10.1055/s-0029-1217712

LETTER
2295
Asymmetric Synthesis of g-Hydroxy-a,b-acetylenic Esters Catalyzed by
Oxazolidine–Titanium Complex
A
symme
t
i
n
g
-H
c
ydroxy-
a
,
b
h
-acetylenic
E
e
sters ng Mao,* Jun Guo
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Suzhou University, Suzhou 215123, P. R. of China
Fax +86(512)65880089; E-mail: jcmao@suda.edu.cn
Received 14 April 2009
by the direct asymmetric addition of an alkyl propiolate to
aldehydes. Although great efforts have been made in
asymmetric alkynylations, few attentions on the enantio-
selective reactions of alkynoates to aldehydes have been
paid.9–12 Recently, Pu discovered that 2.0 equivalents of
hexamethylphosphoramide (HMPA) could accelerate the
addition of methyl propiolate to various aldehydes in good
yields and enantioselectivities in the presence of 40 mol%
of BINOL as the chiral ligand.10 In contrast, Wang and co-
workers found that 1.0 equivalent of 1,2-dimethoxyethane
(DME) as an additive could facilitate the asymmetric ad-
dition of methyl propiolate to aldehydes with moderate to
good ee values and yields using 30 mol% of b-sulfon-
amide alcohol.12 Therefore, development of novel effi-
cient chiral catalysts with low loading for this important
asymmetric transition is still desirable.
Abstract: An efficient catalytic system has been developed for the
enantioselective reaction of alkynoates with aromatic aldehydes for
the synthesis of optically active g-hydroxy-a,b-acetylenic esters
(with up to 81% isolated yield and up to 84% enantioselectivity).
Key words: asymmetric synthesis, oxazolidine, aldehyde, addition,
asymmetric alkynylation
In the past decades, it was of great interest to aim at the
catalytic enantioselective addition of terminal alkynes to
aldehydes because of the versatility of the resulting prop-
argylic alcohols.1 Thus, various catalytic methods have
been developed.2 Among them, two typical protocols
proved to be the most practical. One was discovered by
Carreira, who used stoichiometric or catalytic quantities
of Zn(OTf)2, N-methylephedrine, and Et3N to afford the
corresponding products in high yields and enantioselec-
tivities through the alkynylzinc addition to aliphatic alde-
hydes.3 The other was developed independently by Pu4
and Chan.5 They used BINOL/Ti(Oi-Pr)4 to catalyze the
asymmetric addition of terminal alkynes to various alde-
hydes with high ee values. In this way, great progress has
been made in this asymmetric addition reaction.6,7
Recently, we have reported that the readily available and
inexpensive new chiral oxazolidine 1 in combination with
Ti(Oi-Pr)4 could catalyze the asymmetric alkynylation of
various aldehydes to generate chiral propargylic alcohols
with high enantioselectivities (up to 95% ee) and excellent
yields (up to 98%).13 In this paper, we wish to report the
use of chiral oxazolidines (1–4) in the synthesis of g-hy-
droxy-a,b-acetylenic esters (Figure 1).
g-Hydroxy-a,b-acetylenic esters containing three differ-
ent functional groups are very important precursors in the
synthesis of highly functionalized organic molecules. The
traditional way to prepare the optically active product is
shown in Scheme 1.8 Obviously, this route is troublesome
and tedious. Thus, a straightforward way was developed
Chiral oxazolidines (1–4) were easily prepared from
(1R,2S)-cis-1-amino-2-indanol with different aromatic al-
dehydes with high yields. These stable chiral compounds
were then employed in the asymmetric addition of methyl
propiolate to benzaldehyde, and the results are listed in
OH
CHO
Li
CO2Me
≤ –78 °C
CO2Me
asymmetric
addition
[O]
H
CO2Me
O
OH
*
asymmetric reduction
CO2Me
CO2Me
Scheme 1 The traditional way to prepare the optically active g-hydroxy-a,b-acetylenic esters
SYNLETT 2009, No. 14, pp 2295–2300
x
x
.x
x
.2
0
0
9
Advanced online publication: 03.08.2009
DOI: 10.1055/s-0029-1217712; Art ID: W05509ST
© Georg Thieme Verlag Stuttgart · New York

2296
J. Mao, J. Guo
LETTER
Table 1. Using 1 as the model ligand, there is no desired tries 2 and 3). Using toluene as the solvent, we got the
product when THF was employed as solvent (Table 1, en- promising result of 53% yield and 15% ee (entry 4). Ad-
try 1), even using DME and HMPA as the additives (en- dition of DIMPEG (dimethoxy polyethylene glycol,
Table 1 Asymmetric Addition of Methyl Propiolate to Benzaldehyde in the Presence of Chiral Oxazolidine Ligands 1–4a
OH
L* / Ti(Oi-Pr)4
*
+
CHO
H
COOMe
R2Zn, THF, r.t.
COOMe
Entry
1
L* (mol%)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
1 (20)
2 (20)
3 (20)
4 (20)
2 (10)
2 (30)
2 (40)
2 (20)
2 (20)
2 (20)
2 (20)
2 (20)
Base (equiv)
–
DIMPEG (mol%)
R
Yield (%)b
–
ee (%)c
–
–
Et
2
DME (1.0)
HMPA (1.0)
–
–
Et
–
–
3
–
Et
–
–
4d
–
Et
53
15
25
30
27
67
79
10
56
82
75
75
84
80
79
65
79
79
80
73
–
5d
–
1
Et
53
6d
–
10
1
Et
59
7d
HMPA (1.0)
HMPA (1.0)
HMPA (1.0)
DME (1.0)
DME (1.0)
HMPA (2.0)
HMPA (2.0)
HMPA (2.0)
HMPA (2.0)
HMPA (2.0)
HMPA (2.0)
HMPA (2.0)
HMPA (2.0)
HMPA (2.0)
Et3N (3.0)
HMPA (2.0)
HMPA (2.0)
HMPA (2.0)
NMI (0.05)
Et
57
8d
10
10
1
Et
63
9d
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
75
10d
11d
12d
13d,e
14d,f
15d
16d
17d
18d
19d
20d
21d
22d,g
23d,h
24d,i
25d,j
51
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
63
56
52
64
76
65
61
66
56
31
11
26
UD
UD
UD
–
–
a All the reactions were processed under argon at r.t. for 20 h. Ti(Oi-Pr)4 was freshly distilled. Alkynoate/R2Zn/benzaldehyde/ligand/Ti(Oi-
Pr)4 = 3:3:0.5:0.1:0.2.
b Isolated yield.
c The ee was determined by chiral HPLC analysis of the corresponding products on a Chiralcel OD-H column.
d Toluene was used as the solvent.
e Ti(Oi-Pr)4 = 0.1 mmol.
f Ti(Oi-Pr)4 = 0.4 mmol.
g DMAP (10 mol%) as the additive.
h (S)-BINOL (10 mol%) as the additive.
i i-PrOH (1.0 equiv) as the additive.
j NMI (5 mol%) was employed in the absence of HMPA.
Synlett 2009, No. 14, 2295–2300 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of g-Hydroxy-a,b-acetylenic Esters
2297
tioselectivities (entries 18–20). Et3N instead of HMPA
afforded very low yield, though the enantioselectivity was
good (entry 21). In addition, several additives, such as
DMAP, (S)-BINOL, and i-PrOH, did not afford better re-
sults (entries 22–24). Using You’s protocol, NMI did not
favor the catalytic reaction (entry 25).12
OMe
H
H
N
N
O
O
1
2
The influence of various aromatic aldehyde substrates on
the reactivity and enantioselectivity was examined using
the reaction with 2 under the standard conditions. The first
step is about the formation of an active alkynylzinc re-
agent, the second step is the addition of Ti(Oi-Pr)4, while
the final step is the reaction with an aldehyde.15 From
Table 2, it can be seen that para substitution on the aro-
matic ring of aldehydes gave similar yields (57–74%) and
enantioselectivities (80–83% ee, Table 1, entries 2–5), ex-
cept for the electron-donating MeO substituent (entry 6).
Ortho or meta substituents on the aromatic ring did not af-
fect the enantiomeric excess (entries 7 and 8). As expect-
ed, a-naphthaldehyde gave higher ee values than b-
naphthaldehyde (entries 9 and 10). Comparing to methyl
propiolate, the asymmetric addition of ethyl propiolate to
aldehydes gained less attention. Thus, in this paper, sever-
al aromatic aldehydes have also been investigated in the
asymmetric addition of ethyl propiolate. The results
showed that slightly reduced ee values and higher yields
were obtained in comparison with the reaction of methyl
propiolate (entries 11–13).
H
H
N
N
O
Cl
O
3
4
Figure 1 Structures of chiral oxazolidine ligands
Mn = 2000) resulted in clear enhancement of enantio-
selectivities (entries 5 and 6).14 Furthermore, use of 1.0
equivalent of HMPA afforded better ee value (67% ee, en-
try 8). Replacement of Et2Zn with Me2Zn led to good
enantioselectivity (79% ee, entry 9). Under the same con-
ditions, DME instead of HMPA gave decreased enan-
tioselectivities (entries 10 and 11). Subsequently, 2
equivalents of HMPA were investigated in the reaction.
To our delight, 82% ee of the desired product was ob-
tained (entry 12). Varying the amount of Ti(Oi-Pr)4 did
not get better results (entries 13 and 14). Thus, other chiral
oxazolidines (2–4) have also been investigated in the
same asymmetric reaction (entries 15–17). It can be seen
that ligand 2 gave the best result (84% ee, entry 15). Vary-
ing the amount of ligand 2 was not favorable for the enan-
Table 2 Asymmetric Alkyne Addtions to Various Aromatic Aldehydes Catalyzed by 2a
1. 2 (20 mol%), Me2Zn (3.0 equiv)
HMPA (2.0 equiv), DIMPEG (10 mol%)
toluene, r.t., 7 h
OH
*
H
COOR
R = Me, Et
Ar
2. [Ti(Oi-Pr)4] (40 mol%), 0.5 h
3. ArCHO (1 equiv)
COOR
Entry
1
Aldehyde
Product
Yield (%)b
ee (%)c
84
78
OH
*
CHO
CO2Me
2
3
4
5
56
83
82
80
82
OH
*
Br
Cl
CHO
CHO
CO2Me
CO2Me
CO2Me
Br
Cl
F
73
65
61
OH
*
OH
F
CHO
*
OH
*
CHO
CO2Me
Synlett 2009, No. 14, 2295–2300 © Thieme Stuttgart · New York

2298
J. Mao, J. Guo
LETTER
Table 2 Asymmetric Alkyne Addtions to Various Aromatic Aldehydes Catalyzed by 2a (continued)
1. 2 (20 mol%), Me2Zn (3.0 equiv)
HMPA (2.0 equiv), DIMPEG (10 mol%)
toluene, r.t., 7 h
OH
*
H
COOR
R = Me, Et
Ar
2. [Ti(Oi-Pr)4] (40 mol%), 0.5 h
3. ArCHO (1 equiv)
COOR
Entry
6
Aldehyde
Product
Yield (%)b
ee (%)c
63
47
OH
*
MeO
CHO
CO2Me
MeO
Cl
7
8
75
57
81
80
OH
*
CHO
Cl
CO2Me
CO2Me
OH
*
Cl
CHO
Cl
9
73
83
OH
*
CHO
CO2Me
10
11
12
43
81
76
73
81
77
OH
*
CHO
CO2Me
OH
*
CHO
CHO
CO2Et
OH
*
CO2Et
13
70
74
OH
CHO
*
CO2Et
a All the reactions were processed under argon at r.t. for 48 h. Ti(Oi-Pr)4 was freshly distilled. Alkynoate/Me2Zn/aromatic aldehyde/ligand 2/
Ti(Oi-Pr)4 = 3:3:0.5:0.1:0.2.
b Isolated yield.
c The ee was determined by chiral HPLC analysis of the corresponding products on a Chiralcel OD-H column.
A mixture of 20 mol% of 4-methoxybenzaldehyde and ticipate in the coordination, which could avoid other
(1R,2S)-cis-1-amino-2-indanol was stirred in 1 mL of possible side reactions.12
dichloromethane at room temperature for 24 hours. The
In summary, we have developed an efficient catalytic sys-
solvent was evaporated and then directly used to catalyze
tem for the enantioselective reaction of alkynoates with
the asymmetric addition reaction. These two substrates
aromatic aldehydes for the synthesis of optically active g-
were also directly used without being purified. Thus, the
desired product was obtained in 73% ee and 65% yield
(Scheme 2).
hydroxy-a,b-acetylenic esters. Using 20 mol% of easily
prepared oxazolidine 2 as the chiral ligand, the desired
products were obtained in moderate to good yields and
Noteworthy is that in our protocol additional Lewis bases, enantioselectivities. It is noteworthy that our protocol
such as HMPA or DME, played a crucial role for the cat- could be further simplified and still retain its efficiency.
alytic reactions. It is presumed that these bases may par- Thus, the easily available catalyst made this catalytic pro-
cess potentially practical and useful. Further studies on
Synlett 2009, No. 14, 2295–2300 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of g-Hydroxy-a,b-acetylenic Esters
2299
NH2
CH2Cl2, r.t.
OH
+
MeO
CHO
2
24 h
Aldrich,
unpurified
unpurified
2 used directly
OH
*
2 (20 mol%)
Me2Zn (3.0 equiv) (Aldrich)
Ti(Oi-Pr)4 (40 mol%)(Aldrich)
CHO
+
H
COOMe
DIMPEG (10 mol%) (Aldrich)
toluene, r.t., 48 h
COOMe
Aldrich,
unpurified
Aldrich,
unpurified
65% yield, 73% ee
Scheme 2 Asymmetric addition of methyl propiolate to benzaldehyde with commercially available materials
(3) (a) Fassler, D. E.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806. (b) Anand, N. K.; Carreira, E. M. J. Am. Chem.
Soc. 2001, 123, 9687.
highly effective asymmetric addition reactions using nov-
el catalysts are in progress in our laboratory.
(4) (a) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855. (b) Gao, G.;
Moore, D.; Xie, R. G.; Pu, L. Org. Lett. 2002, 4, 4143.
(c) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002,
4, 2605. (d) Liu, Q. Z.; Xie, N. S.; Luo, Z. B.; Cui, X.; Cun,
L. F.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. J. Org. Chem.
2003, 68, 7921. (e) Gao, G.; Xie, R. G.; Pu, L. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5417.
(5) (a) Lu, G.; Li, X.; Chan, W. L.; Chan, A. S. C. Chem.
Commun. 2002, 172. (b) Li, X.; Lu, G.; Kwok, W. H.; Chan,
A. S. C. J. Am. Chem. Soc. 2002, 124, 12636. (c)Lu, G.;Li,
X.-S.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew. Chem. Int.
Ed. 2003, 42, 5057.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are grateful to the grants from the National Natural Science
Foundation of China (No. 20802046) and the Key Laboratory of Or-
ganic Synthesis of Jiangsu Province for financial support.
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All manipulations were carried out under an argon
atmosphere. The ligand 2 (0.1 mmol), base (0.5 mmol), and
DIMPEG (0.05 mmol) were mixed in dry toluene (2.0 mL)
at r.t. Then, a solution of Me2Zn (1.2 M in toluene, 1.5
mmol) and methyl propiolate (1.5 mmol) were added in turn.
Synlett 2009, No. 14, 2295–2300 © Thieme Stuttgart · New York

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J. Mao, J. Guo
LETTER
After the mixture was stirred at r.t. for 7 h, Ti(Oi-Pr)4 (0.2
mmol, 60 mL) was added and the stirring continued for
another 0.5 h. The yellow solution was cooled to 0 °C and
treated with benzaldehyde (0.5 mmol, 50 mL), then the
resultant mixture was allowed to warm up to r.t. naturally
and stirred for 20 h. After the reaction was completed, it was
cooled to 0 °C again and quenched by 5% aq HCl (2 mL).
The mixture was extracted with EtOAc (2 × 10 mL). The
organic layer was dried over Na2SO4 and concentrated under
vacuum. The residue was purified by flash column
chromatography (silica gel H, 10% EtOAc in PE) to give the
pure product.
Methyl 4-Hydroxy-4-phenylbut-2-ynoate
Yield 78%; 84% ee determined by HPLC analysis (Chiralcel
OD-H column, IPA–hexane = 20:80). tR(minor) = 6.60 min,
tR(major) = 7.33 min. 1H NMR (400 MHz, CDCl3): d = 2.67
(d, J = 6.4 Hz, 1 H), 3.80 (s, 3 H), 5.58 (d, J = 6.4 Hz, 1 H),
7.35–7.43 (m, 3 H), 7.52 (d, J = 6.8 Hz, 2 H). 13C NMR (100
MHz, CDCl3): d = 53.4, 64.4, 77.8, 87.4, 127.1, 29.22,
129.3, 138.9, 154.4.
Synlett 2009, No. 14, 2295–2300 © Thieme Stuttgart · New York