Highly enantioselective synthesis of γ-hydroxy-α,β- acetylenic esters by asymmetric alkyne addition to aldehydes

Article abstract of DOI:10.1002/anie.200500469

(Chemical Equation Presented) Alkynoates are added to aromatic and α,β-unsaturated aldehydes in the synthesis of the title compounds in optically active form. This highly enantioselective and useful method is carried out under mild reaction conditions and

Full text of DOI:10.1002/anie.200500469

Communications
Asymmetric Synthesis
DOI: 10.1002/anie.200500469
Highly Enantioselective Synthesis of g-Hydroxy-
a,b-acetylenic Esters by Asymmetric Alkyne
Addition to Aldehydes**
Ge Gao, Qin Wang, Xiao-Qi Yu,* Ru-Gang Xie, and
Lin Pu*
g-Hydroxy-a,b-acetylenic esters containing three adjacent
and structurally very different functional groups are very
useful in the synthesis of highly functionalized organic
molecules.[1,2] This class of compound is normally prepared
by treatment of an alkyl propiolate with nBuLi at ꢀ À788C
[*] Dr. G. Gao, Q. Wang, Prof. X.-Q. Yu, Prof. R.-G. Xie
Department of Chemistry
Key Laboratory of Green Chemistry and Technology (Ministry of
Education)
Sichuan University, Chengdu 610064 (P.R. China)
Fax: (+86)288-541-5886
E-mail: xqyu@tfol.com
Prof. L. Pu
Department of Chemistry
University of Virginia
Charlottesville, VA 22904-4319 (USA)
Fax: (+1)434-924-3170
E-mail: lp6n@virginia.edu
[**] This work is supported by the National Natural Science Foundation
of China (No. 20328203 and 20132020). L.P. thanks the US National
Institute of Health for partial support of this work (R01M58454/
R01EB002037-05).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angew. Chem. Int. Ed. 2006, 45, 122 –125

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Chemie
followed by the addition of aldehydes,[1] as originally reported
by Midland et al.[1a] Recently, Shahi and Koide reported a
ꢁ
milder method in which AgC CCO2Me was reacted with
aldehydes in the presence of [Cp2ZrCl2] (Cp = cyclopenta-
dienyl) and AgOTf (Tf = trifluoromethanesulfonyl) at room
temperature.[3] Asymmetric reductions of g-oxo-a,b-acety-
lenic esters have been used to synthesize optically active g-
hydroxy-a,b-acetylenic esters (Scheme 1).[2] This process first
Scheme 2. Asymmetric addition of methyl propiolate to benzaldehyde.
optical rotation was found to be
[a]2D8 = À3.56 (c = 0.73, CHCl3),
and the absolute configuration
was determined to be S by
studying the 19F NMR spectra
of its Mosher ester.[10] This
configuration assignment is
consistent with other studies
on the binol-catalyzed alkyne
addition to aldehydes.[6a]
Scheme 1. Synthesis of optically active g-hydroxy-a,b-acetylenic esters by asymmetric reduction of g-oxo-
a,b-acetylenic esters.
We applied this procedure
requires the synthesis of racemic g-hydroxy-a,b-acetylenic
esters, which are then oxidized to g-oxo-a,b-acetylenic esters
before asymmetric reduction. However, the most efficient
way to prepare optically active g-hydroxy-a,b-acetylenic
esters should be the direct asymmetric addition of an alkyl
propiolate to aldehydes, as this one-step reaction simulta-
neously produces both a carbon–carbon bond and a stereo-
genic propargylic alcohol center. Although major progress
has been made in recent years in the area of asymmetric
addition of alkynes to aldehydes,[4–7] no enantioselective
reaction of alkynoates with aldehydes has been reported.[8,9]
Herein, we report a highly enantioselective, as well as
practical, method for the addition of methyl propiolate to
aromatic aldehydes to generate optically
to the reaction of methyl propiolate with a variety of aromatic
and a,b-unsaturated aldehydes. The results summarized in
Table 1 show that high enantioselectivities (85–95% ee) were
achieved for the reaction of benzaldehyde derivatives with
either electron-donating or -withdrawing substituents at the
ortho, meta, or para positions in the presence of a substoi-
chiometric amount of the chiral ligand (R)-binol (Table 1,
entries 1–12). Other types of aromatic aldehydes, such as 1-
naphthaldehyde, 2-naphthaldehyde, and 2-furaldehyde, also
showed high enantioselectivity (87–95% ee; Table 1,
entries 13–15). An excellent result was obtained as well
when the a,b-unsaturated aldehyde cinnamaldehyde was used
(91% ee; Table 1, entry 16).
In summary, we have discovered the first highly enantio-
selective reaction of an alkynoate with aromatic and a,b-
unsaturated aldehydes for the synthesis of optically active g-
hydroxy-a,b-acetylenic esters. This reaction can be carried
out at room temperature by using a substoichiometric amount
of the chiral binol ligand. The easy availability of the chiral
ligand as well as the metal reagents and the mild reaction
conditions make this process practically very useful. Cur-
rently, we are further expanding the scope of this reaction to
include substrates such as aliphatic and other functionalized
aldehydes.
active g-hydroxy-a,b-acetylenic esters.
Earlier, we discovered that 1,1’-bi-2-
naphthol (binol) in combination with [Ti-
(OiPr)4] can catalyze the highly enantiose-
lective addition of alkynes to both aliphatic
and aromatic aldehydes with high enantio-
selectivity.[6a,b] However, this method cannot
be used for the reaction of methyl propiolate
with aldehydes because the solution of the
alkyne in toluene needs to be heated with
Et2Zn at reflux, which leads to the decomposition of methyl
propiolate. Later, we found that addition of hexamethylphos-
phoramide (HMPA) greatly accelerates the reaction of Et2Zn
with terminal alkynes at room temperature while maintaining
the high enantioselectivity for the addition to aldehydes.[6c]
When we initially tested the use of this method for the
addition of methyl propiolate to benzaldehyde, the product
was obtained only in low yield.
Further investigation revealed that prolonging the treat-
ment of methyl propiolate with Et2Zn in the presence of (R)-
binol and HMPA at room temperature before the addition of
[Ti(OiPr)4] and benzaldehyde led to the desired g-hydroxy-
a,b-acetylenic product both in good yield and with high
enantioselectivity (Scheme 2): methyl 4-hydroxy-4-phenyl-
but-2-ynoate was obtained in 69% yield and with 91% ee (see
the Experimental Section for further details). The specific
Experimental Section
HMPA (88 mL, 0.50 mmol), methyl propiolate (85 mL, 1.0 mmol), and
Et2Zn (0.91 mL (1.1m in toluene), 1.0 mmol) were added sequentially
to (R)-binol (28.6 mg, 0.10 mmol, 40 mol%) in dry CH2Cl2 (3 mL) in
a 10-mL round-bottomed flask under argon. The reaction mixture was
allowed to stir at room temperature for 16 h. After the addition of
[Ti(OiPr)4] (74 mL, 0.25 mmol), the solution was stirred for another
hour. Benzaldehyde (25.5 mL, 0.25 mmol) was then added and the
reaction was allowed to proceed for 4 h. Saturated ammonium
chloride was added to quench the reaction, and CH2Cl2 was used for
extraction. After removal of the organic solvent under reduced
pressure, the residue was purified by using a short column of silica gel
with petroleum ether/ethyl acetate (9:1) as the eluant to afford methyl
4-hydroxy-4-phenylbut-2-ynoate in 69% yield with 91% ee, as
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Communications
determined with a HPLC-Diacel Chiralcel OD
Table 1: Enantioselective addition of methyl propiolate to aldehydes.
column; [a]2D8 = À3.56 (c = 0.73, CHCl3).
Entry
Aldehyde
Product
Yield of isolated
product [%]
ee [%]
Received: February 7, 2005
Revised: September 12, 2005
Published online: November 21, 2005
1
2
3
69
96
91
91
91
93
Keywords: aldehydes · alkynes · asymmetric
.
synthesis · binol ligands · esters
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