Highly enantioselective alkynylation of α-keto ester: An efficient method for constructing a chiral tertiary carbon center

Article abstract of DOI:10.1021/ol026544i

(matrix presented) The asymmetric addition of terminal alkynes to α-keto ester was carried out using a catalytic amount of (1S,2S)-3-(tert-butyldimethylsilyloxyl)-2-N,N-(dimethylamino)-1-(p-nitrophenyl)- propane-1-ol in the presence of Zn(OTf)₂

Full text of DOI:10.1021/ol026544i

ORGANIC
LETTERS
2
002
Vol. 4, No. 20
451-3453
Highly Enantioselective Alkynylation of
r-Keto Ester: An Efficient Method for
Constructing a Chiral Tertiary Carbon
Center
3
Biao Jiang,* Zili Chen, and Xiaoxia Tang
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
jiangb@pub.sioc.ac.cn
Received July 17, 2002
ABSTRACT
The asymmetric addition of terminal alkynes to r-keto ester was carried out using a catalytic amount of (1S,2S)-3-(tert-butyldimethylsilyloxyl)-
-N,N-(dimethylamino)-1-(p-nitrophenyl)-propane-1-ol in the presence of Zn(OTf) to give the corresponding tertiary propargylic alcohols in
2
2
high yields with up to 94% ee. N-Methylephedrine and Zn(OSO
2
CHF
2
)
2
were also examined in this reaction.
Optically active propargylic alcohols are important synthetic
intermediates in asymmetric synthesis. The methods that
co-workers have demonstrated the formation of a zinc
alkynylide intermediate in the course of the reaction. This
observation raised the possibility of additional enantioselec-
tive alkynylation of ketones and imines. In this paper, we
report that (1S,2S)-3-(tert-butyldimethylsilyloxyl)-2-N,N-
dimethyl amino-1-(p-nitrophenyl)-propane-1-ol (1), a new
inexpensive chiral amino alcohol based ligand that was
developed to catalyze the asymmetric alkynylation of alde-
1
have been devised to prepare chiral propargylic alcohols
involve either nucleophilic addition of metalated acetylenes
2
3
to the carbonyl group or ynone reduction. Recently, great
progress has been made in the stereocontrolled nucleophilic
alkynylation of aldehydes to give chiral secondary propar-
4
2 3
gylic alcohols in the presence of Zn(OTf) and Et N.
5
Mechanistic studies of this transformation by Carreira and
hydes, can be used to catalyze the enantioselective addition
of zinc alkynylide to R-ketoester to prepare tertiary R-hy-
droxy-â-ynyl ester. To date, the methods that have been
reported to prepare chiral tertiary propargylic alcohols have
(
1) (a) Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1994, 116, 6457.
b) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492. (c) Frantz,
D. E.; F a¨ ssler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000,
(
6
been very limited.
3
3, 373.
(
2) (a) Bradshaw, C. W.; Hummel, W.; Wong, C. J. Org. Chem. 1992,
In preliminary studies, phenylacetylene (3a) underwent
addition to benzoylformate (2a) at 50 °C for 24 h in the
5
1
7, 1532. (b) Ansari, M. H.; Kusumoto, T.; Hiyama, T. Tetrahedron Lett.
993, 34, 8271.
(3) (a) Ramos T. G. M.; Didier, E.; Loubinoux, B. Synlett 1990, 547.
presence of ligand (1S,2S)-1 (1.2 equiv), Zn(OTf)
2
(1.1
(
b) Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937. (d) Tan,
equiv), and Et N (1.1 equiv) to give a tertiary propargylic
3
L.; Chen, C.; Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Angew. Chem.,
Int. Ed. 1999, 38, 711. (e) Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichele,
L.; Reider, P. J. Synthesis 1999, 1453.
(5) Jiang, B.; Chen, Z.; Xiong, W. Chem. Commun. 2002, 1524.
(
4) (a) Frantz, D. E.; F a¨ ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
22, 1806. (b) Pu, L.; Yu, H. B. Chem. ReV. 2001, 101, 757. (c) Anand, N.
E.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
(6) (a) Chen, M.-Y.; Fang, J.-M. J. Org. Chem. 1992, 57, 2937. (b) Youn,
S. W.; Kim, Y. H.; Hwang, J.-W.; Do, Y. Chem. Commun. 2001, 11, 996.
(c) Solladie-Cavallo, A.; Suffert, J. Tetrahedron Lett. 1984, 25, 1897.
1
1
0.1021/ol026544i CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/05/2002

Table 2. Enantioselective Addition of RCtCH to Keto Estera
Scheme 1. Enantioselective Addition of Phenylacetylene to
Benzoylformate
alcohol (4a) (Scheme 1) in 92% yield and 89% enantiomeric
excess (entry 1, Table 1). Catalytic conditions (0.2 equiv of
Table 1. Enantioselective Addition of PhCtCH to
Benzoylformatea
L*
Zn
Et3N time/temp additive
(equiv)
yield
(%)b
eec
(
equiv) (equiv) (equiv) (d)/(°C)
(%)
1
2
3
4
5
6
7
8
9
1
1.2
1.1
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.5
1.1
0.5
0.5
0.5
0.5
0.5
0.5
0.3
0.15
0.07
1/50
1/70
1/80
1/70
1/70
1/70
2/70d
2/70d
3/70d
3/70d
92
26
Complex
89
82
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.11
0.055
ZnCl2 (1) 67
13
LiCl (1)
<5%
DBU (0.1) complex
43
91
58
22
89
89
87
73
0
a
Reactions were carried out with the addition of (1S,2S)-1, Zn(OTf)2,
b
c
and Et3N; the product was (+)-4a. Isolated yield. Enantiomeric excess
was determined by chiral HPLC. PhCtCH was used as solvent (PhCtCH/
d
keto ester ) 3/1).
Zn(OTf)
toluene at 70 °C for 1 day) gave a low yield of product (enry
, Table 1) in 82% ee. Several conditions of the reaction
the equivalence of some additives, reaction temperature and
2 3
, 0.22 equiv of (1S,2S)-1, and 0.5 equiv of Et N in
2
(
time) were then optimized. The results are summarized in
Table 1. The reaction was not improved by raising the
temperature to 80 °C or by adding 0.1 equiv of DBU (very
complex phenomena were observed by TLC tracing, entries
3
and 6, Table 1). Tests with other additives such as ZnCl
2
and LiCl resulted in no reaction (entries 4 and 5, Table 1).
However, when phenylacetylene was used as solvent (PhCt
CH/keto ester ) 3/1) with a slightly decreased amount of
a
Unless stated otherwise, the reactions were carried out with the addition
of 0.22 equiv of (1S,2S)-1, 0.2 equiv of Zn(OTf)2, and 0.3 equiv of Et3N
2 mL) at 70 °C for 2 d, RCtCH/keto ester ) 3/1. Isolated yield.
Enantiomeric excess was determined by HPLC analysis of the alcohol.
-)-(1R,2S)-N-Methylephedrine 5 was used as ligand. Zn(OSO2CHF2)2
was used as an additive. RCtCH/keto ester ) 5/1.
b
(
Et
3
N (from 0.5 to 0.3 equiv), the reaction proceeded at 70
c
d
e
(
°
C for 2 days to give product 4a in 91% yield and 89% ee
f
(
(
entry 8, Table 1). Further reduction of the amount of ligand
1S,2S)-1 was fruitless (entries 9 and 10, Table 1).
The reactions of various aliphatic or aromatic keto esters
glyoxylate (2b, 2c) underwent an alkynylation reaction to
give the product in high yield and good enantiomeric excess.
For example, the indolyl glyoxylate (2c) reacted with
phenylacetylene (3a) or aliphatic acetylene (3b, 3c) to give
the product in a yield of 67-81% and 81-86% ee (entries
7-9, Table 2). The addition of phenylacetylene (3a) to
with several terminal alkynes under optimal conditions (entry
in Table 1) are summarized in Table 2. As shown, almost
8
all of the tertiary R-hydroxy-â-ynyl esters were obtained with
excellent enantiomeric excess (up to 94%) and high chemical
yield (up to 93%). Interestingly, the heterocyclic alkyl
3452
Org. Lett., Vol. 4, No. 20, 2002

thiophenyl glyoxylate (2b) gave the product in 93% yield
and 73% ee (entry 4, Table 2). When the reaction was
performed with a primary alkyl-substituted glyoxylate, such
as ethyl propionate (2d), a very low chemical yield was
observed (entry 10, Table 2). This can be explained by the
easy formation of the enolate of ketone with the base, which
inhibited the addition reaction. When the substrate was
switched to a tertiary alkyl group, excellent chemical and
optical yields were observed (entries 11 and 12, Table 2).
Similar results were obtained when (-)-N-methylephedrine
Scheme 2. Hydrogenation Reaction of Compound 4h
ester based on the addition of terminal alkynes to R-keto
esters in the presence of a catalytic amount of (1S,2S)-1 as
ligand and Zn(OTf) as an additive. These highly functional
2
R-hydroxyl â-ynyl esters are valuable chiral synthons for
the further preparation of complex chiral compounds. The
fact that a tertiary R-hydroxyl carbon center can be generated
under mild conditions in the presence of inexpensive ligands
may lead to new opportunities in pharmaceutical synthesis.
5
was examined as ligand in this reaction (entry 2, Table 2;
the rotation data were in contrast to those with ligand (1S,2S)-
1). Zn(OSO
2 2 2
CHF ) gave the product in moderate ee (entry
3, Table 2).
Compound 4h was hydrogenated with Pd-C under
hydrogen at 4 atm to provide R-hydroxyl ester 6 (Scheme
7
2
). Comparing the optical rotation of the synthesized 6 (-26,
c 0.26, CHCl ) with that of ethyl (S)-2-hydroxy-2-methyl-
-phenyl-butyrate, which has been reported to be +29.6 (c
Acknowledgment. This work was financially supported
by the State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences.
3
4
2
8
3
.4, CHCl ), the absolute stereochemistry of the tertiary
asymmetric alcohol carbon in 4h was assigned to be R.
In summary, we have described a practical method for
the synthesis of optically active tertiary R-hydroxyl â-ynyl
Supporting Information Available: General catalytic
reaction conditions and the structural data for synthesized
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
7) Jones, S. R.; Selinsky, B. S.; Rao, M. N.; Zhang, X.; Kinney, W. A.
J. Org. Chem. 1998, 63, 3786.
8) Buhler, H.; Bayer, A.; Effenberger, F. Chem. Eur. J. 2000, 14, 6.
(
OL026544I
Org. Lett., Vol. 4, No. 20, 2002
3453