Highly enantioselective synthesis of γ-hydroxy-α,β- acetylenic esters catalyzed by a β-sulfonamide alcohol

Article abstract of DOI:10.1021/ol070692x

This work concerns the asymmetric addition of methyl propiolate to aldehydes with 1,2-dimethoxyethane (DME) as additive and β-sulfonamide alcohol titanium complex as a catalyst. The reactions proceeded under mild conditions and gave the highly functionali

Full text of DOI:10.1021/ol070692x

ORGANIC
LETTERS
2
007
Vol. 9, No. 12
329-2332
Highly Enantioselective Synthesis of
-Hydroxy- -acetylenic Esters
Catalyzed by a -Sulfonamide Alcohol
2
γ
r,â
â
†
†
†
†
†
†
Li Lin, Xianxing Jiang, Weixia Liu, Li Qiu, Zhaoqing Xu, Jiangke Xu,
‡
,†,‡
Albert S. C. Chan, and Rui Wang*
State Key Laboratory of Applied Organic Chemistry, Institute of Biochemistry and
Molecular Biology, Lanzhou UniVersity, Lanzhou 730000, China, and State Key
Laboratory of Chinese Medicine and Molecular Pharmacology, Department of Applied
Biology and Chemical Technology, The Hong Kong Polytechnic UniVersity, Kowloon,
Hong Kong, China
wangrui@lzu.edu.cn
Received March 21, 2007
ABSTRACT
This work concerns the asymmetric addition of methyl propiolate to aldehydes with 1,2-dimethoxyethane (DME) as additive and â-sulfonamide
alcohol titanium complex as a catalyst. The reactions proceeded under mild conditions and gave the highly functionalized chiral propargylic
alcohols with high ee values and good yields. Differences between three types of ligands have also been discussed.
The asymmetric alkynylation of aldehydes is one of the most
powerful procedures for organic synthetic chemistry, where
the formation of one carbon-carbon bond and one chiral
precursors for many bioactive and natural organic compounds
3
in organic synthesis. Few studies on the enantioselective
reactions of alkynoates to aldehydes have been reported.4
Trost reported the proline-derived dinuclear zinc catalyst
system catalyzed the addition of alkynes to unsaturated
1
center of propargylic alcohol can be achieved in one step.
Recently, several studies have been reported in this area.
2
4
a
However, most studies were focused on the addition of
phenylacetylene to carbonyl compounds. Highly function-
alized γ-hydroxy-R,â-acetylenic esters are very important
aldehydes with high ee values and yields. While using
HMPA as an additive, Pu reported that the BINOL-Ti
(3) (a) Midland, M. M.; Tramontano, A.; Cable, J. R. J. Org. Chem.
1
980, 45, 28-29. (b) Midland, M. M.; McDowell, D. C.; Hatch, R. L.;
*
To whom correspondence should be addressed.
Lanzhou University.
The Hong Kong Polytechnic University.
Tramontano, A. J. Am. Chem. Soc. 1980, 102, 867-869. (c) Trost, B. M.;
Crawley, M. L. J. Am. Chem. Soc. 2002, 124, 9328-9329. (d) Trost, B.
M.; Ball, Z. T. J. Am. Chem. Soc. 2004, 126, 13942-13944. (e) Molander,
G. A.; St. Jean, D. J., Jr. J. Org. Chem. 2002, 67, 3861-3865. (f) Shahi,
S. P.; Koide, K. Angew. Chem., Int. Ed. 2004, 43, 2525-2527. (g) Meta,
C. T.; Koide, K. Org. Lett. 2004, 6, 1785-1787. (h) Albert, B. J.;
Sivaramakrishnan, A.; Naka, T.; Koide, K. J. Am. Chem. Soc. 2006, 128,
2792-2793. (i) Guillarme, S.; Ple, K.; Banchet, A.; Liard, A.; Haudrechy,
A. Chem. ReV. 2006, 106, 2355-2403 and references cited therein.
(4) (a) Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am. Chem.
Soc. 2006, 128, 8-9. (b) Trost, B. M.; Weiss, A. H. Org. Lett. 2006, 8,
4461-4464. (c) Gao, G.; Wang, Q.; Yu, X.-Q.; Xie, R.-G.; Pu, L. Angew.
Chem., Int. Ed. 2005, 45, 122-125. (d) Rajaram, A. R.; Pu, L. Org. Lett.
2006, 8, 2019-2021.
†
‡
(
1) Recent reviews: (a) Pu, L. Tetrahedron 2003, 59, 9873-9886. (b)
Pu, L.; Yu, H. B. Chem. ReV. 2001, 101, 757-824.
2) (a) Fassler, D. E.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
(
1
1
806-1807. (b) Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001,
23, 9687-9688. (c) Gao, G.; Xie, R. G.; Pu, L. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5417-5420. (d) Lu, G.; Li, X.-S.; Jia, X.; Chan, W. L.;
Chan, A. S. C. Angew. Chem., Int. Ed. 2003, 42, 5057-5058. (e) Jiang,
B.; Chen, Z.-L.; Xiong, W.-N. Chem. Commun. 2002, 1524-1525. (f) Cozzi,
P. G. Angew. Chem., Int. Ed. 2003, 42, 2895-2898. (g) Cozzi, P. G.;
Rudolph, J.; Bolm, C.; Norrby, P.-O.; Tomasini, C. J. Org. Chem. 2005,
7
0, 5733-5736.
1
0.1021/ol070692x CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/11/2007

complex can catalyze the addition of methyl propiolate to
both aromatic and aliphatic aldehydes with high ee values
and moderate to good yields.4c,d They found that HMPA can
2
greatly accelerate the reaction rate of ZnEt with terminal
alkynes. However, HMPA is a strong Lewis base and a very
dangerous carcinogen.
5
Recently, we have developed a new system for the
catalytic alkynylation of carbonyl compounds without a
separate step to prepare alkynylzinc. With use of â-sulfon-
amide alcohols as ligands, synthesized from inexpensive
Figure 1. Structural comparison of different ligands.
natural amino acids5
a,c,d
and camphor, the asymmetric
5b
addition of phenylacetylene to aldehydes proceeds under mild
three ligands. There are two ether oxygen atoms (blue) in
TADDOL which may chelate metal via coordination bonds
and act as Lewis bases. Previous reports indicated the
sulfonyl oxygen atoms of the sulfonamide group of the
conditions with high ee values and yields. In our previous
studies,5 while combining ZnEt
c
2
, alkyne, and aldehyde in
one pot (Scheme 1, method A, see the Supporting Informa-
6
â-sulfonamide alcohol can also chelate metal. These are
much stronger Lewis bases compared with the ether oxygen
atoms in TADDOL. However, there is no such similar frame
in BINOL. Then these three ligands can be arranged in the
following sequence by the Lewis base of the groups:
â-sulfonamide alcohol > TADDOL > BINOL.
Scheme 1. Two Possible Products in the One-Pot Procedure
In fact, this catalytic reaction was a two-step but one-pot
procedure: (1) the formation of alkynylzinc and (2) the
transfer of alkynyl to aldyhyde. Reports showed that
7
a
7c,d
BINOL and â-sulfonamide alcohol
can be used as
ligands for the addition of diethylzinc to aldehyde. Then we
proposed that the first step of the one-pot procedure plays
an important role in the ratio of the products of ethylation
and alkynylation. Reports also suggested that the Lewis base
tion), we obtained very different ratios of the products of
ethylation and alkynylation (Table 1) using different Ti
2
c,4c,8
can enhance the reactivity of ZnEt
2
.
So, the structure
Table 1. Addition of Phenylacetylene to Benzaldehyde by the
One-Pot Methoda
of the Lewis base present in the ligands may play an
important role. This presumption encouraged us to prove it
and investigate the possibility of using methyl propiolate as
a nucleophile.
i
ligand/Ti(O Pr)4
(mol %)
1/2
(mol %)
entry
ligand
1
2
3
BINOL
TADDOL
L*
1:3
1:3
1:3
3:97
62:38
93:7
According to our hypothesis, we supposed that the addition
of methyl propiolate to benzaldehyde might proceed favor-
ably when using L* (Figure 1) as the ligand under our initial
method (Method B, see the Supporting Information).5a On
the primary investigation, only a low yield (38%) was
obtained. Then we chose 1,2-dimethoxyethane (DME) as an
additive to optimize the reaction condition. The best condi-
tions for our system are shown in Scheme 2.
a
Data have been published in ref 5c.
complexes of BINOL, TADDOL, and â-sulfonamide alcohol
L*) (Figure 1) as catalysts. The studies suggested that
(
different ligands affect the Lewis acidity of Ti complexs
markedly. A great ratio of alkynylation products was obtained
under our catalytic condition (entry 3, Table 1), since the
â-sulfonamide alcohol-Ti complex acted as a much weaker
Lewis acid.
Scheme 2. Asymmetric Addition of Methyl Propiolate to
Aldehydes Catalyzed by L*
Looking into the structures of the ligands shown in Figure
1, we find that there are similar frames (red) which can be
directly chelated with metal via two organometallic bonds.
However, we also find the obvious differences among these
We found that the enantioselectivity of the reaction is
(
5) Selected reports: (a) Xu, Z. Q.; Wang, R.; Xu, J. K.; Da, C.-S.; Yan,
i
W. J.; Chen, C. Angew. Chem., Int. Ed. 2003, 42, 5747-5749. (b) Xu, Z.
Q.; Chen, C.; Xu, J.; Miao, M.; Yan, W.; Wang, R. Org. Lett. 2004, 6,
greatly affected by the amount of Ti(O Pr)
. When the ratio of L*/Ti(O Pr) was 1:1, the highest ee
4
as shown in Table
4
i
2
1
193-1195. (c) Xu, Z. Q.; Lin, L.; Xu, J. K.; Yan, W. J.; Wang, R. AdV.
Synth. Catal. 2006, 348, 506-514. (d) Ni, M.; Wang, R.; Han, Z. J.; Mao,
B.; Da, C.-S.; Liu, L.; Chen, C. AdV. Synth. Catal. 2005, 347, 1659-1665.
(6) (a) Kanai, M.; Kuramochi, A.; Shibasaki, M. Synthesis 2002, 1956-
(
e) Zhou, Y.; Wang, R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.; Han, Z. Org.
1958. (b) Pritchett, S.; Woodmansee, D. H.; Gantzel, P.; Walsh, P. J. J.
Am. Chem. Soc. 1998, 120, 6423-6424. (c) Walsh, P. J. Acc. Chem. Res.
2003, 36, 739-749.
Lett. 2004, 6, 4147-4149. (f) Chen, C.; Hong, L.; Xu, Z.-Q.; Liu, L.; Wang,
R. Org. Lett. 2006, 8, 2277-2280.
2330
Org. Lett., Vol. 9, No. 12, 2007

drawing-substituents under the optimized condition (entries
2-7, Table 3). Exploring 1-naphthaldehyde, 2-naphthalde-
hyde, and 2-furaldehyde as substrates, high enantioselectivity
was also obtained (entries 8-10, Table 3). The ee values
were 85% and 82% for two R,â-unsaturated aldehydes
Table 2. Results for Optimizing the Reaction Conditionsa
i
L*
(mol %)
Ti(O Pr)4
(mol %)b
DME
(equiv)
ZnEt2
(equiv)
ee
(%)
b
c
entry
1
2
3
4
5
6
7
8
40
40
40
40
40
40
30
20
120
80
50
40
30
20
30
20
2
2
2
2
2
2
1
1
4
4
4
4
4
4
3
3
78
84
91
92
90
34
91
81
(
entries 11 and 12, Table 3). A good result was also observed
when aliphatic aldehyde was employed as a substrate (entry
3, Table 3). Notably, high enantioselecticity and morderate
1
yields were also obtained when substrates had technical
purity (entries 2, 5, and 8, Table 3).
Comparing with the catalytic system which uses BINOL
as a ligand, a much weaker Lewis base (DME) was
introduced into our system. However, the formation of
alkynylzinc was much faster. The significant difference
between these two catalytic systems indicates well that the
Lewis base of the ligand was favorable in the catalytic
procedure. The proposed mechanism is shown in Figure 2.
a
b
All reaction proceed in toluene as the main solvent. Freshly distilled
c
before use. Alkyne:ZnEt2 ) 1:1.
value was obtained. Different loadings of ligand, DME,
ZnEt2, and alkyne were also investigated. Under the optimal
condition (entry 7, Table 2), the asymmetric addition of
methyl propiolate to benzaldehyde led to γ-hydroxy-R,â-
acetylenic product with high enantioselecticity (ee 91%).
Under the optimized condition, high enantioselectivity and
moderate to good yields were obtained in the reaction of
methyl propiolate to a number of aldehydes. The results are
summarized in Table 3.
The high ee values were obtained when the aromatic
aldehydes have either electron-donating or electron with-
Table 3. Asymmetric Addition of Methyl Propiolate to
Aldehydes Catalyzed by L* a,b
Figure 2. Proposed catalytic cycle.
2
In Step 1, ligand, ZnEt , and alkyne were mixed together.
The catalytic center was formed when the sulfonamide and
(
7) Selected examples: (a)Yang, X.-W.; Sheng, J.-H.; Da, C.-S.; Wang,
a
In all of the entries: Et2Zn:alkyne:DME:aldehyde:Ti(OiPr)4:L* ) 3:3:
H.-S.; Su, W.; Wang, R.; Chan, A. S. C. J. Org. Chem. 2000, 65, 295-296
and references cited therein. (c) Yus, M.; Ram’on, D. J.; Preito, O.
Tetrahedron: Asymmetry 2002, 13, 1573-1579. (d) Bauer, T.; Tarasiuk,
J.; Pasniczek, K. Tetrahedron: Asymmetry 2002, 13, 77-82.
b
1
:1:0.3:0.3. 9-15 h were required after the addition of aldehydes
determined by TLC. The ee values were determined by chiral HPLC.
Technical purity. Absolute configuration is based on the comparison of
of the optical rotation with the literature values (refs 4c and 4d).
c
d
e
(8) Kitamura, M.; Okada, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111,
4028-4036.
Org. Lett., Vol. 9, No. 12, 2007
2331

hydroxy group reacted with diethylzinc. This species might
In Step 2, zinc, which chelated N and O atoms of the
ligand, was replaced by the newly added Ti(O Pr) , and
4
6
c,9
i
coordinate with diethylzinc and alkyne to form A. Then
ethyl-transfer occurred under the intramolecular cooperation
of Lewis base (blue frame, Figure 2) and Lewis acid (red
formed a new Lewis acid center (C) for the alkynyl addition
to aldehyde. Under the same intramolecular cooperation of
Lewis base (blue frame, C, B, and D, Figure 2) and the new
Lewis acid center (red frame, C,B,D, Figure 2), alkynyl
transfer proceeds successfully via a proposed catalytic cycle
in Step 2, Figure 2.
2
f,4a,10
frame, Figure 2).
system, this process might take place via the intermolecular
cooperation of HMPA and BINOL-(ZnEt) complexes. This
However, in the BINOL-Ti catalytic
2
difference indicated that a shorter time was needed by our
catalytic system in Step 1.11 When the R group was ester
In summary, we have extended the applicability of our
catalytic system for the alkynylation of aldehydes. Exploring
DME as an additive, the addition of methyl propiolate to
both aromatic and aliphatic aldehydes proceeds under very
mild conditions. Our results indicated that â-sulfonamide
alcohol (L*) can accelerate the formation of alkynylzinc
much more effectively than BINOL. In addition, a highly
toxic reagent was avoided under our conditions.
(methyl propiolate), it could also be chelated to metal (Lewis
acid). But this may not be favorable for the formation of
alkynylzinc. So a strong Lewis acid should be avoided in
Step 1, and extra Lewis base was introduced to promote the
formation of alkynylzinc. Step 1 took a longer reaction time
if a larger dosage of DME was added. We suspected that
1
2
2
DME might chelate ZnEt to avoid other side reactions.
So different efforts were required for the extra Lewis bases
used in the BINOL-Ti catalytic system (HMPA) and the
â-sulfonamide alcohol-Ti catalytic system (DME).
Acknowledgment. We are grateful for the grants from
the National Natural Science Foundation of China (Nos.
2
0525206, 20472026, and 20021001) and the Chang Jiang
(
9) Frantz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem.
Res. 2000, 33, 373-381.
10) Similar reports about the intramolecular cooperation of the ligand:
a) Hatano, M.; Miyamoto, T.; Ishihara, K. J. Org. Chem. 2006, 71, 6474-
484. (b) Qin, Y.-C.; Pu, L. Angew. Chem., Int. Ed. 2005, 45, 273-277.
c) Qin, Y.-C.; Liu, L.; Sabat, M.; Pu, L. Tetrahedron 2006, 62, 9335-
348.
11) In Step 1, which needed 16 h for the BINOL-Ti catalytic system,
and 7 h for our catalytic system.
12) We are grateful for the reviewers who gave us some good advice.
The side reaction is under investigation.
Program of the Ministry of Education of China for financial
support.
(
(
6
(
9
Supporting Information Available: Experimental details
and characterization data for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(
(
OL070692X
2332
Org. Lett., Vol. 9, No. 12, 2007