Highly enantioselective alkynylation of aldehydes catalyzed by a readily available chiral amino alcohol-based ligand

Article abstract of DOI:10.1039/b203984b

A new inexpensive chiral amino alcohol-based ligand, (1S,2S)-2-N,N-dimethylamino-1-(p-nitrophenyl)-3-(t-butyl-dimethylsilyloxy) propane-1-ol, was developed for the asymmetric alkynylation of aliphatic and aromatic aldehydes, to prepare the corresponding propargylic alcohols in high yields with up to 99% ee.

Full text of DOI:10.1039/b203984b

Highly enantioselective alkynylation of aldehydes catalyzed by a readily
available chiral amino alcohol-based ligand
Biao Jiang,* Zili Chen and Wennan Xiong
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China. E-mail: jiangb@pub.sioc.ac.cn
Received (in Cambridge, UK) 25th April 2002, Accepted 28th May 2002
First published as an Advance Article on the web 14th June 2002
A new inexpensive chiral amino alcohol-based ligand,
(1S,2S)-2-N,N-dimethylamino-1-(p-nitrophenyl)-3-(t-butyl-
dimethylsilyloxy)propane-1-ol, was developed for the asym-
metric alkynylation of aliphatic and aromatic aldehydes, to
prepare the corresponding propargylic alcohols in high
yields with up to 99% ee.
interesting that the ee value significantly increased from 91% to
97% ee in THF instead of toluene since in the well-studied
addition of dialkylzinc reagents to aldehydes the product
enantioselectivity is adversely affected in THF5a (Table 1).
When alkyne was added to the mixture of Zn(OTf)2, Et3N
and (1S,2S)-2 in toluene, an oily product was formed on the
glass wall. The oily product was unstable in air and sensitive to
moisture. It has been proposed that a zinc alkynylide-ligand
complex was formed in the catalytic enantioselective alkynyla-
tion reaction.1c,6b The yield of this reaction may be affected by
the solubility of the zinc alkynylide-ligand intermediate. We
thought that improvement of the lipid-solubility of the ligand
might increase the chemical yield of the reaction. Therefore,
(1S,2S)-2 was transformed into the more lipid-soluble silyl ether
(1S,2S)-3 in 95% yield by selectively masking the terminal
hydroxy group in (1S,2S)-2 with tert-butyldimethylsilyl chlo-
ride in the presence of the imidazole and a catalytic amount of
DMAP at 0 °C.9 Interesting results were obtained with (1S,2S)-
3 as a chiral ligand in the enantioselective alkynylation reaction.
The reaction was completed within 2 h and a secondary
propargylic alcohol was obtained with 98% ee and in almost
quantitative yield (Table 2, entry 1). Further optimization of the
amount of zinc triflate was studied. The best results were
obtained in toluene with 1.1 equiv. of Zn(OTf)2, 1.1 equiv. of
Et3N and 1.2 equiv. of (1S,2S)-3. The results using various
aliphatic or aromatic aldehydes with alkynes under similar
conditions are summarized in Table 2. As shown, all of the
propargylic alcohols were obtained with excellent enantiomeric
excess (up to 99%) and in high chemical yield (up to 99%). The
reactions of aliphatic aldehydes were finished in 2 h while those
of aromatic aldehydes were completed in 12 h.
The catalytic asymmetric nucleophilic alkynylation of carbonyl
compounds has considerable synthetic and industrial im-
portance.1 Great progress has been made in the enantioselective
alkylation of aldehydes using chiral amino alcohols as ligands.2
In contrast, there has been very limited success with the
enantioselective nucleophilic alkynylation of aldehydes. Up to
now, ligands (such as ephedrine derivatives) which have been
successfully applied to catalyze the alkynylation of aldehydes
with highly ee are relatively rare.3–6 We report here the
preparation of secondary chiral propargylic alcohols involving
the highly enantioselective addition of alkynes to aldehydes in
the presence of a new economical chiral ligand, (1S,2S)-
2-amino-3-(p-nitrophenyl)propane-1,3-diol derivative.† Inex-
pensive
(1S,2S)-2-amino-3-(p-nitrophenyl)propane-1,3-diol
(1), which is obtained from chloramphenicol synthesis (its
(1R,2R)-enantiomer can be obtained from the same source), is
commercially available, and has been used in the resolution of
racemic chrysanthemic acid on an industrial scale.7 However, it
has never been used in a catalytic asymmetric reaction.
To study the enantioselective alkynylation of the aldehyde
with zinc alkynylide using (1S,2S)-2-amino-3-(p-nitrophenyl)
propane-1,3-diol (1) as a ligand, the amino group in (1S, 2S)-1
was converted to N,N-dimethyl derivative (1S,2S)-2 in quantita-
tive yield by reacting (1S,2S)-1 with formaldehyde and formic
acid.8 A preliminary study was performed to determine the
feasibility of enantioselective alkynylation using (1S, 2S)-2 as a
chiral auxiliary. We found that the nucleophilic addition of
phenylacetylene with isobutyraldehyde proceeded in toluene
with 1.1 equiv. of Zn(OTf)2, 1.1 equiv. of triethylamine and 1.2
equiv. of ligand (1S, 2S)-2. An enantiomeric excess of 88% was
obtained, but with poor chemical yield (21%). Attempts to
improve the chemical yield by using different solvents such as
THF, CH2Cl2 or toluene/CH2Cl2 (1+1) and by the addition of
TMSCl or 4 Å sieves were fruitless, whereas the optical purity
was increased to 97% ee in THF. When 2.0 equiv. Zn(OTf)2
was added, the yield was slightly increased. It is rather
(1S, 2S)-2-N,N-Dimethylamino-1-phenyl-3-(tert-butyldime-
thyl silyloxy)propane-1-ol (4)10 as ligand also was tested in the
Table 1 The effect of reaction conditions on the enantioselectivity of the
alkynylation of cyclohexane carboxaldehydesa
Yield
(%)b
Entry Solvent
Zn(OTf)2 Additive
Ee %c Config.d
1
2
3
Toluene
DCM
THF
1 equiv.
1 equiv.
1 equiv.
21
8
28
91
91
97
(+)-(R)
(+)-(R)
(+)-(R)
Toluene/
4
5
6
7
DCM(1+1) 1 equiv.
16
33
No react.
93
93
(+)-(R)
(+)-(R)
Toluene
Toluene
Toluene
2 equiv.
1 equiv.
1 equiv.
TMSCl
4 Å sieves 25
91
(+)-(R)
a Reactions carried out with addition of 1.1 equiv. of (1S, 2S)-2 and 1.1
equiv. of Et3N (2 mL) at 25 °C for 24 h; R = cyclohexyl, RA = Ph. b Isolated
yield. c Enantiomeric excess was determined by HPLC analysis of the
alcohol or its derivatives. d Absolute configuration is based on the
comparison with the literature.6
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CHEM. COMMUN., 2002, 1524–1525
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a
Table 2 Asymmetric alkynylation of aldehydes with terminal alkynes catalyzed by (1S, 2S)-3 and Zn(OTf)2
Entry
Alkyne (RACMCH)
Aldehyde (RCHO)
Yield of 7 (%)b
Ee (%)c
Rotat. Sign/Config.d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
PhC·CH
(CH3)2CHCHO
(CH3)2CHCHO
n-C6H13CHO
n-C6H13CHO
n-C6H13CHO
c-C6H11CHO
c-C6H11CHO
(Et)2CHCHO
(Et)2CHCHO
c-C3H5CHO
PhCHOf
99
99
94
92
94
99
97
99
99
93
85
73
82
83
93
98
94
98
91
85
89
95
98
> 99
96.5
96e
99
96.5
99
97
(+)-(R)d
(+)-(R)d
(2)
PhCH2CH2C·CH
PhC·CH
PhC·CH
(2)
PhCH2CH2C·CH
PhC·CH
(+)
(2)-(R)d
(2)-(R)d
(2)
PhCH2CH2C·CH
PhC·CH
PhCH2CH2C·CH
PhC·CH
98
93.5
97
(2)
(2)
PhC·CH
(+)-(R)d
(+)-(R)d
(2)
PhCH2CH2C·CH
n-C4H9C·CH
TMSC·CH
(CH3)3CC·CH
c-C3H5C·CH
TBDMSOCH2C·CH
PhC·CH
PhCHOf
94
c-C6H11CHO
c-C6H11CHO
c-C6H11CHO
c-C6H11CHO
c-C6H11CHO
(CH3)2CHCHO
n-C6H13CHO
c-C6H11CHO
c-C3H5CHO
(Et)2CHCHO
95g
96g
96g
97g
99g
92h
93h
93h
85h
93h
(2)-(R)d
(2)
(2)
(2)-(R)d
(+)-(R)d
(2)
PhC·CH
PhC·CH
(2)-(R)d
(2)
PhC·CH
PhC·CH
(2)
a Unless otherwise stated the reactions were carried out with addition of 1.1 equiv. of (1S, 2S)-3 and 1.05 equiv. of Zn(OTf)2 and 1.1 equiv. of Et3N in toluene
(2 mL) at 25 °C for 2 h. b Isolated yield. c Enantiomeric excess was determined by HPLC analysis of the alcohol or its derivatives. d Absolute configuration
is based on the comparison with the literature.6c,7 e 1.2 equiv. of (1S,2S)-4 as ligand. f Reaction time was 12 h. g Enantiomeric excess was determined by 19
NMR of the corresponding (R)-MTPA ester, h 0.22 equiv. of (1S, 2S)-3 and 0.2 equiv. of Zn(OTf)2 and 0.5 equiv of Et3N.
F
The catalytic condition is as follows: To a solution of Zn(OTf)2 (0.2
equiv.) and chiral ligand (0.22 equiv.) in toluene was added triethylamine
(0.5 equiv.) under a nitrogen atmosphere at ambient temperature. Alkyne
(1.2 equiv.) was then added to the mixture. After 15 min, the aldehyde (1
equiv.) was introduced by syringe. The reaction mixture was then stirred for
4–6 h at 50 °C. then work up as usual to give the corresponding propargylic
alcohols and recycle the ligand.
reaction, and gave a result similar to (1S,2S)-3 (Table 2, entry
4).
Further study found that another catalytic condition, 0.22
equiv. ligand (1S,2S)-3 and 0.2 equiv. Zn(OTf)2 as additive,6c
was effective for this reaction too, although the enantiomeric
excess was slightly decreased (Entries 18–22, Table 2).
In conclusion, (1S,2S)-2-N,N-dimethylamino-1-(p-nitrophe-
nyl)-3-(tert-butyldimethylsilyloxy)propane-1-ol (3) was con-
veniently prepared in two steps and in high yields from
inexpensive commercially available (1S,2S)-2-amino-3-(p-ni-
trophenyl)propane-1,3-diol. This is the first time that this chiral
compound has been used as ligand in the asymmetric reaction
for the preparation of optically active propargylic alcohols in
high yields with up to 99% ee. The reaction was carried out in
a homogenous phase using various aldehydes and alkynes in the
presence of ligand 3 and zinc triflate. We found that a different
catalytic condition (0.22 equiv. ligand (1S,2S)-3 and 0.2 equiv.
Zn(OTf)2 as additive) was also effective for this reaction, but
with slightly decreased ee. A more detailed study using this new
ligand to catalyze asymmetric alkynylation of carbonyl com-
pounds is underway.
1 (a) W. R. Roush and R. J. Sciotti, J. Am. Chem. Soc., 1994, 116, 6457;
(b) A. G. Myers and B. Zheng, J.Am.Chem.Soc., 1996, 118, 4492; (c) D.
E. Frantz, R. Fässler, C. S. Tomooka and E. M. Carreira, Acc. Chem.
Res., 2000, 33, 373.
2 (a) R. Noyori and M. Kitamura, Angew. Chem., 1991, 103, 34; Angew.
Chem., Int. Ed. Engl., 1991, 30, 49; (b) D. R. Williams and M. G.
Fromhold, Synlett, 1997, 523.
3 (a) K. Soai and S. Niwa, Chem. Lett., 1989, 481; (b) K. Soai and S.
Niwa, J. Chem. Soc., Perkin Trans. 1, 1990, 937; (c) A. S. Thompson,
E. G. Corley, M. F. Huntington, E. J. J. Grabowski, J. F. Remenar and
D. B. Collum, J. Am. Chem. Soc., 1998, 120, 2028; (d) L. Tan, C. Chen,
R. D. Tillyer, E. J. J. Grabowski and P. J. Reider, Angew. Chem., Int. Ed.
Engl., 1999, 38, 711.
4 M. Ishizaki and O. Hoshino, Tetrahedron: Asymmetry, 1994, 5, 1901.
5 (a) G. Lu, X. Li, W. L. Chan and S. C. Chan, Chem. Commun., 2002,
172; (b) Z. Li, Upadhyay, A. E. Decamp, L. Dimichele and P. J. Reider,
Synthesis-Stuttgart, 1999, 1453.
6 (a) D. E. Frantz, R. Fässler and E. M. Carreira, J. Am. Chem. Soc., 2000,
122, 1806; (b) L. Pu and H. B. Yu, Chem. Rev., 2001, 101, 757; (c) N.
E. Anand and E. M. Carreira, J. Am. Chem. Soc., 2001, 123, 9687.
7 E. J. Corey and K. A. Cimprich, J. Am. Chem. Soc., 1994, 116, 3151.
8 (a) J. Tessier, Chem. Ind., 1984, 199; (b) G. Nominé, G. Amiard and V.
Torelli, Bull. Soc. Chim. Fr., 1968, 3664; (c) V. M. Potapov, V. M.
DemAyanovich, V. P. Zaitsev and S. K. Sharipova, J. Org. Chem. USSR
(Engl. Transl.), 1987, 23, 460; V. M. Potapov, V. M. DemAyanovich, V.
P. Zaitsev and S. K. Sharipova, Zh. Org. Khim., 1987, 23, 510.
9 (a) D. Pini, A. Mastantuono and P. Salvadori, Tetrahedron: Asymmetry,
1994, 5, 1875; (b) A. Mastantuono, D. Pini, C. Rolfini and P. Salvadori,
Chirality, 1995, 7, 499.
Notes and references
†
A typical procedure for the asymmetric alkynylation reaction is as
follows: To a solution of Zn(OTf)2 and chiral ligand (1.2 equiv.) in toluene
was added triethylamine (1.1 equiv.) under a nitrogen atmosphere at
ambient temperature. Alkyne (1.2 equiv.) was then added to the mixture.
After 15 min, the aldehyde (1.0 equiv.) was introduced by syringe. The
reaction mixture was then stirred for 2–12 h at 25 °C. After the reaction was
completed, the propargylic alcohol was separated from the ligand by
washing with acid. The ligand was recovered in 98% yield by extracting the
oily substance obtained by neutralizing the acidified aqueous solution. The
crude product was purified through a short flash chromatography column to
give the corresponding propargylic alcohols.
10 G. A. Olah, P. S. Iyer and G. K. S. Prakash, Synthesis, 1986, 513.
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