Synthesis of tetrasubstituted and functionalized enol ethers by E-selective olefination of esters with ynolates

Article abstract of DOI:10.1021/ja0561082

We have developed the E-selective olefination of ester carbonyls to afford tetrasubstituted, functionalized olefins and the C-S insertion of thiol esters to give β-keto thiol esters via ynolates. Copyright

Full text of DOI:10.1021/ja0561082

Published on Web 01/04/2006
Synthesis of Tetrasubstituted and Functionalized Enol Ethers by E-Selective
Olefination of Esters with Ynolates
Mitsuru Shindo,*,† Taisuke Kita, Toshihiro Kumagai, Kenji Matsumoto, and Kozo Shishido
Institute of Health Biosciences, The UniVersity of Tokushima Graduate School, Sho-machi 1,
Tokushima 770-8505, Japan
Received September 5, 2005; E-mail: shindo@cm.kyushu-u.ac.jp
Scheme 1
Esters are versatile electrophiles for carbon-carbon bond forma-
tion, which includes Claisen condensation and related acylations.1
Although olefination of ester carbonyls would appear to be useful
for the synthesis of enol ethers, conventional methods such as the
Wittig reaction generally have been unsuccessful in realizing
olefination2 due to the lower electrophilicity of esters. Instead, metal
carbenoids, such as Tebbe reagents, are used to accomplish this
transformation; however, they are limited to the preparation of
simple enol ethers.3 The stereocontrolled synthesis of multisubsti-
tuted and functionalized enol ethers via olefination therefore still
remains a challenge for organic chemists. If a new, reactive
olefination reagent were available, this problem essentially could
be overcome. Over the past few years, we have developed the
Scheme 2
torquoselective olefination of aldehydes, ketones, and acylsilanes
with ynolates4 via ring-opening of â-lactone enolates and have
demonstrated the versatility of ynolates as olefination reagents.5
Herein, we describe the first highly stereoselective synthesis of
tetrasubstituted, functionalized (E)-enol ethers via olefination of
esters with ynolates and also report the homologation of thiol esters
with C-S insertion (Scheme 1).
We first examined the reaction of O-alkyl esters with ynolates
(Scheme 2). At -78 °C, the ynolate, generated by treatment of
Table 1. Olefination of Esters via Reaction with Ynolates
phenyl 2,2-dibromopropanoate6 with tert-butyllithium,7 did not react
with ethyl benzoate; however, at room temperature, the starting
ester disappeared in 1 h. Consequently, the enol ether, â-ethoxy-
R,â-unsaturated carboxylic acid, was obtained in 94% yield with
an E/Z ratio of 89/11 (Table 1, entry 1). Encouraged by this result,
we decided to survey the generality for the olefination of esters, as
shown in Table 1. While the olefination of ethyl p-methoxybenzoate
(1b) gave the desired olefin 3ba in good yield with moderate
selectivity (entry 2), ethyl p-nitrobenzoate (1c) afforded the product
3ca with higher E-selectivity (entry 3). Aliphatic and unsaturated
esters provided olefins with excellent E-selectivities in good yields
(entries 4-13). Sterically hindered and aromatic ynolates can also
be used in this olefination (entries 6 and 7). The fact that allyl and
tert-butyl esters, as well as ethyl esters, could furnish olefins with
excellent E-selectivities would indicate that this olefination can be
used for the preparation of enol ethers bearing intricate O-alkyl
groups. Acetal and siloxy functions were tolerated during the
reaction (entries 10 and 11). It should be noted that excellent yields
and selectivities were achieved using R-amino esters derived from
L-amino acids (entries 12 and 13).8 Compared with the correspond-
a A small amount of â-keto ester was obtained as a side product. b Isolated
ing allyl ester 1f without an amino group, this tendency toward
as the methyl ester.
higher efficiency was outstanding. From these results, we have
demonstrated the versatility and generality of this olefination of
quenched at -30 °C; however, only the carboxylic acid was
esters via their reaction with ynolates.
obtained, suggesting that the â-lactone enolate, the most probable
To trap the intermediate â-lactone, the reaction mixture was
intermediate, immediately ring-opens as the cycloaddition proceeds.
The E/Z selectivity would be controlled in the electrocyclic ring-
opening of the â-lactone enolate, as described in our previous
† Current address: Institute for Materials Chemistry and Engineering, Kyushu
University, 6-1, Kasugako-en, Kasuga, 816-8580, Japan.
9
1062
J. AM. CHEM. SOC. 2006, 128, 1062-1063
10.1021/ja0561082 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
depending especially on the leaving-group ability of the corre-
sponding alkoxide or thioalkoxide on the ester. This methodology
with ynolates could be applied to a wide variety of esters and related
carbonyl compounds. Synthetic applications are now in progress
in our laboratory.
Acknowledgment. We thank Professor S. Kanemasa (Kyushu
University) for valuable discussions and Dr. J. Tanaka for X-ray
crystal structure analysis. This research was partially supported by
a Grant in Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan, and
PRESTO, JST.
Scheme 4
Supporting Information Available: Characterization of new
compounds, general procedures (PDF), and X-ray crystal structures
(CIF). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) For a review, see: Davis, B. R.; Garratt, P. J. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
2, pp 795-863.
(2) Nonclassical Wittig reagents undergo olefination of esters. See: Tsunoda,
T.; Takagi, H.; Takada, D.; Kaku, H.; Ito, S. Tetrahedron Lett. 2000, 41,
235-237.
(3) (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978,
100, 3611. (b) Pine, S. H.; Pettit, R. J.; Geib, G. D.; Cruz, S. G.; Gallego,
C. H.; Tijerina, T.; Pine, R. D. J. Org. Chem. 1985, 50, 1212-1216. (c)
Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. J. Am. Chem. Soc.
1980, 102, 3270-3272. (d) Grubbs, R. H.; Tumas, W. Science 1989, 243,
907-915. (e) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112,
6392-6394. (f) Petasis, N. A.; Bzowej, E. I. J. Org. Chem. 1992, 57,
1327-1330. (g) Petasis, N.; Akritopoulou, I. Synlett 1992, 665-667. (h)
Petasis, N. A.; Bzowej, E. I. Tetrahedron Lett. 1993, 34, 943-946. (i)
Okazoe, T.; Takai, K.; Oshima, K.; Utimoto, K. J. Org. Chem. 1987, 52,
4412-4414. (j) Takai, K.; Kataoka, Y.; Okazoe, T.; Utimoto, K.
Tetrahedron Lett. 1988, 29, 1065-1068. (k) Matsubara, S.; Ukai, K.;
Mizuno, T.; Utimoto, K. Chem. Lett. 1999, 825-826. (l) Horikawa, Y.;
Watanabe, M.; Fujiwara, T.; Takeda, T. J. Am. Chem. Soc. 1997, 119,
1127-1128. (m) Takeda, T.; Sasaki, R.; Fujiwara, T. J. Org. Chem. 1998,
63, 7286-7288. (n) Takeda, T.; Watanabe, M.; Rahim, M. A.; Fujiwara,
T. Tetrahedron Lett. 1998, 39, 3753-3756. (o) Rahim, M. A.; Sasaki,
H.; Saito, J.; Fujiwara, T.; Takeda, T. Chem. Commun. 2001, 625-626.
(p) Takeda, T.; Shimane, K.; Ito, K.; Saeki, N.; Tsubouchi, A. Chem.
Commun. 2002, 1974-1975. (q) Yan, T.-H.; Chien, C.-T.; Tsai, C.-C.;
Lin, K.-W.; Wu, Y.-H. Org. Lett. 2004, 6, 4965-4967.
reports.5 The preferential generation of the E-form indicates outward
rotation of the alkoxy substituent on the oxetene (â-lactone enolate).
These results can be elucidated by Houk’s torquoselectivity, which
shows that electron-donating substituents, such as alkoxy groups,
rotate outward.5e,9
The olefinated products, R,â-substituted (E)-â-alkoxyacrylic
acids, were converted to synthetically useful intermediates. For
example, the carboxylic acid 3da was transformed to the Weinreb
amide 4,10 which was reacted with methyllithium to give the methyl
ketone 5 in good yield (Scheme 3). The Claisen rearrangement of
the â-allyloxyacrylic ester 6, prepared from 3fa, furnished the â-keto
ester 7 bearing a quaternary carbon in good yield. These transfor-
mations demonstrate the high potential of â-alkoxy acrylic acids
in synthetic organic chemistry.
In contrast to esters, thiol esters 8 did not provide the olefins,
but instead gave the homologated â-keto thiol esters 12 in good
yields (Scheme 4). The efficient elimination of the thiolates (R2-
SLi) from the initial adducts 9, formed by the addition of the
ynolates to 8, would be followed by the attack of the thiolate on
the resulting R-keto ketene 10 to afford the â-keto thiol ester
enolates 11. Both esters of dodecanethiol and thiophenol provided
the desired â-keto thiol esters 12 in good yields. This homologation
can be formally regarded as the insertion of the ynolate carbon
framework into the C-S bond of thiol esters, which is a new type
of Claisen condensation. This olefination-insertion switching would
depend on the leaving-group ability of the (thio)alkoxides.11
In conclusion, we have developed the first stereoselective
olefination of esters affording tetrasubstituted, functionalized enol
ethers, which are useful synthetic intermediates for various C-C
bond formations. We also have found a new homologation of thiol
esters giving â-keto thiol esters. The reaction mode changes
(4) For reviews, see: (a) Shindo, M. Synthesis 2003, 2275-2288. (b) Shindo,
M. J. Synth. Org. Chem. Jpn. 2000, 58, 1155-1166. (c) Shindo, M.
Yakugaku Zasshi 2000, 120, 1233-1246. (d) Shindo, M. Chem. Soc. ReV.
1998, 27, 367-374.
(5) (a) Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron Lett. 1998, 39, 4857-
4860. (b) Shindo, M.; Sato, Y.; Shishido, K. J. Org. Chem. 2000, 65,
5443-5445. (c) Shindo, M.; Matsumoto, K.; Mori, S.; Shishido, K. J.
Am. Chem. Soc. 2002, 124, 6840-6841. (d) Shindo, M.; Sato, Y.;
Yoshikawa, T.; Koretsune, R.; Shishido, K. J. Org. Chem. 2004, 69, 3912-
3916. (e) Mori, S.; Shindo, M. Org. Lett. 2004, 6, 3945-3948. (f) Shindo,
M.; Yoshikawa, T.; Itou, Y.; Mori, S.; Nishii, T.; Shishido, K. Chem.-
Eur. J. 2006, 12, 524-536.
(6) Shindo, M.; Sato, Y.; Koretsune, R.; Yoshikawa, T.; Matsumoto, K.; Itoh,
K.; Shishido, K. Chem. Pharm. Bull. 2003, 51, 477-478.
(7) (a) Shindo, M. Tetrahedron Lett. 1997, 38, 4433-4436. (b) Shindo, M.;
Sato, Y.; Shishido, K. Tetrahedron 1998, 54, 2411-2422. (c) Shindo,
M.; Koretsune, R.; Yokota, W.; Itoh, K.; Shishido, K. Tetrahedron Lett.
2001, 42, 8357-8360.
(8) The product was obtained without loss of optical purity.
(9) (a) Kirmse, W.; Rondan, N. G.; Houk, K. N. J. Am. Chem. Soc. 1984,
106, 7989-7991. (b) Rondan, N. G.; Houk, K. N. J. Am. Chem. Soc.
1985, 107, 2099-2111. (c) Dolbier, W. R., Jr.; Koroniak, H.; Houk, K.
N.; Sheu, C. Acc. Chem. Res. 1996, 29, 471-477.
(10) Knorr, R.; Trzeciak, A.; Bannwarth, W.; Gillessen, D. Tetrahedron Lett.
1989, 30, 1927-1930.
(11) The reaction of phenyl benzoate with ynolate 2a gave no olefin but gave
the â-keto phenyl ester in ca. 30% yield. The allyl ester (Table 1, entry
8, footnote a) also produced the homologated product as a side product.
JA0561082
9
J. AM. CHEM. SOC. VOL. 128, NO. 4, 2006 1063