Stereoselective Synthesis of (E)-2-En-4-ynoic acids with Ynolates: Catalytic conversion to tetronic acids and 2-pyrones

Article abstract of DOI:10.1021/ol902086t

"Chemical Equation Presented" A highly torquoselective olefinatlon of alkynoates to provide functionalized tetrasubstltuted olefins, (E)-2-en-4-ynoic acids, Is described. Addition of Bronsted acids dramatically switched the mode of the Ag(l)-catalyzed cyclization of the resulting enyne carboxylic acids to give either tetronic acids or 2-pyrones.

Full text of DOI:10.1021/ol902086t

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5378-5381
Stereoselective Synthesis of
(E)-2-En-4-ynoic Acids with Ynolates:
Catalytic Conversion to Tetronic Acids
and 2-Pyrones
Takashi Yoshikawa† and Mitsuru Shindo‡,*
Interdisciplinary Graduate School of Engineering Sciences and Institute for Materials Chemistry
and Engineering, Kyushu UnViersity, 6-1, Kasugako-en, Kasuga 816-8580, Japan
shindo@cm.kyushu-u.ac.jp
Received September 9, 2009
ABSTRACT
A highly torquoselective olefination of alkynoates to provide functionalized tetrasubstituted olefins, (E)-2-en-4-ynoic acids, is described. Addition
of Brønsted acids dramatically switched the mode of the Ag(I)-catalyzed cyclization of the resulting enyne carboxylic acids to give either
tetronic acids or 2-pyrones.
Since tetronic acid is frequently found in biological natural
products as an active site unit,1,2 it was thought that the 5-exo
cyclization of (E)-2-en-4-ynoic acids 1 could afford the
tetronic acid derivatives 23-6 and that the 6-endo cyclization
of 1 would furnish 2-pyrones 3,7 which could be good
substrates for Diels-Alder reactions (Figure 1).8 A regiose-
† Interdisciplinary Graduate School of Engineering Sciences.
‡ Institute for Materials Chemistry and Engineering.
(1) For reviews, see: (a) Haynes, L. J.; Plimmer, J. R. Q. ReV., Chem.
Soc. 1960, 14, 292–315. (b) Rao, Y. S. Chem. ReV. 1976, 76, 625–694. (c)
Schobert, R.; Schlenk, A. Bioorg. Med. Chem. 2008, 16, 4203–4221
.
Figure 1. Tetronic acid derivatives (5-exo) vs pyrones (6-endo)
cyclization.
(2) Zografos, A. L.; Georgiadis, D. Synthesis 2006, 3157–3188
.
(3) For reviews, see: (a) Negishi, E.; Kotora, M. Tetrahedron 1997, 53,
6707–6738. (b) Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin, T. Chem.
Commun. 2009, 5075–5087
.
(4) (a) Lambert, C.; Utimoto, K.; Nozaki, H. Tetrahedron Lett. 1984,
25, 5323–5326. (b) Chan, D. M. T.; Marder, T. B.; Milstein, D.; Taylor,
N. J. J. Am. Chem. Soc. 1987, 109, 6385–6388. (c) Ogawa, Y.; Maruno,
M.; Wakamatsu, T. Heterocycles 1995, 41, 2587–2599. (d) Kotora, M.;
Negishi, E. Synthesis 1997, 121–128. (e) Anastasia, L.; Xu, C.; Negishi, E.
Tetrahedron Lett. 2002, 43, 5673–5676. (f) Uchiyama, M.; Ozawa, H.;
Takuma, K.; Matsumoto, Y.; Yonehara, M.; Hiroya, K.; Sakamoto, T. Org.
lective cyclization of 1 therefore would be a useful method
for the preparation of 2 and 3. However, as of yet there is
no efficient method available for the stereoselective prepara-
tion of ꢀ-alkoxy enyne carboxylic acids 1.
Lett. 2006, 8, 5517–5520
.
10.1021/ol902086t CCC: $40.75
Published on Web 11/04/2009
 2009 American Chemical Society

We have developed a torquoselective olefination for carbonyl
compounds with ynolates to give multisubstituted alkenes with
high stereoselectivities9 in which the ꢀ-lactone enolate inter-
mediates are ring-opened with high torquoselectivity.10 In this
method, electron donating substituents rotate outward whereas
electron-accepting substituents rotate inward to afford the
stereodefined products (Scheme 1). During the course of this
and their Ag(I)-catalyzed cyclization to give either tetronic
acids or pyrones under appropriate conditions.
The ynolate 4, prepared from the reaction of ethyl 2,2-
dibromopropionate with t-BuLi,14 reacted with isobutyl
3-(tert-butyldimethylsilyl)propiolate (5a) to afford the tet-
rasubstituted olefin 6a in a E/Z ratio of 98.5:1.5 (Table 1,
entry 1). Encouraged by this result, we decided to examine
the olefination of several kinds of alkynoates as substrates,
as shown in Table 1. The esters with a silyl or an
alkoxymethyl substituent on the terminal ethynyl group
afforded olefins with excellent selectivity (entries 2, 3, and
4), while the 2-hexynoate and 5-phenylpent-3-en-2-ynoate
provided E-olefins along with a small amount of the minor
Z-isomers (entries 5 and 6). However the 3-phenyl-2-
propynoate afforded the olefin with high E selectivity (entry
7). In these electrocyclic reactions, the alkoxy group prefers
outward rather than inward rotation compared to the alkynyl
group, and the substituent on the terminal position of the
ethynyl group has only a slight effect on the torquoselectivity.
The Ag2CO3-catalyzed cyclization4c,e of 6g was carried
out in various solvents to examine the selective synthesis of
5-exo or 6-endo products (Table 2, entries 1-4). In DMF,
5-exo cyclization proceeded selectively to give the tetronic
acid derivative 7g (entry 1). The reaction in THF also favored
5-exo cyclization, albeit with lower selectively (entry 2). In
benzene and dichloromethane, the 6-endo cyclized product
8g was generated with poor selectivity (entries 3 and 4).
Scheme 1. Torquoselective Olefination
study, esters11 and alkynyl alkyl ketones12 were found to be
olefinated with excellent E selectivities, where alkoxy and
alkynyl groups act as strong electron donating groups (Scheme
2). Consequently, the torquoselectivity of alkynoic acid esters,
Scheme 2. Olefination of the Alkynyl Ketone and Ester
We next examined the effect of the counterions of the
silver salts in DMF (Table 2, entries 5-8). Ag2O allowed
an efficient 5-exo cyclization (entry 5), and AgOAc and
AgClO4 led to poor selectivity (entries 6 and 7). In contrast,
AgSbF6 catalyzed the reaction to afford the 6-exo cyclized
product 8g preferentially (entry 8).
Since Ag2CO3 and Ag2O are oxidizing agents of oxygen
functional groups,15 they could be used to activate the
carboxyl group to form a metal carboxylate, which would
stereoelectronically favor a 5-exo cyclization, along with
slight activation of the alkyne by the Ag(I) catalysts. On the
other hand, AgSbF6 is known for forming π complexes with
or alkynoates, is of interest to determine their relative outward
rotating abilities.13
Herein, we describe the highly E-selective olefination of
alkynoates with ynolates to provide tetrasubstituted alkenes
Table 1. Olefination of Alkynoates with Ynolates
entry
R1
R2
5
conditions
yield (%)
E:Za
1
2
3
4
5
6
7
i-Bu
i-Bu
i-Bu
Et
Et
Et
TBS
5a
5b
5c
5d
5e
5f
-78 °C to rt, 1.5 h
-78 to -20 °C, 1 h
-40 °C to rt, 4 h
-78 to -20 °C, 2 h
-78 °C to rt, 1 h
-78 °C to rt, 1 h
-40 °C to rt, 2 h
63 (6a)
51 (6b)
71 (6c)
41 (6d)
48 (6e)
62 (6f)
49 (6g)
98.5:1.5
>99:1
>99:1
>99:1
88:12
89:11
97:3
TMSb
MPMOCH2
TES
Bu
trans-PhCHdCH
Ph
Et
5g
a Stereochemistry was determined by NOE experiments of the products or their corresponding derivatives. See Supporting Information. b TMS group
was converted to H by addition of water after olefination.
Org. Lett., Vol. 11, No. 23, 2009
5379

Table 2. Ag(I)-Catalyzed Cyclization of (E)-2-En-4-ynoic Acids
Table 3. Ag(I)-Catalyzed 5-exo Cyclization Leading to Tetronic
Acids
entry
Ag cat.
solvent
time (h)
yield (%)
7g:8ga
entry
R1
R2
6
time (h)
yield (%)
93 (7a)
57 (7b)
79 (7c)
1
2
3
4
5
6
7
8
a
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2O
AgOAc
AgClO4
AgSbF6
DMF
THF
benzene
CH2Cl2
DMF
DMF
DMF
DMF
1
5
12
5
1
1
90
80
84
80
68
71
87
89
>95:5
63:37
42:58
40:60
93:7
86:14
63:37
9:91
1
2
3
4
5
6
7
i-Bu TBS
i-Bu
i-Bu MPMOCH2
Et
Et
Et
Et
6a
6b
6c
6d
6e
1
1
H
1.5
1
1.5
1.5
1
TES
Bu
78 (7d)
86a (7e + 8e)
74 (7f)
trans-PhCHdCH 6f
Ph 6g
1
1
90 (7g)
a The product was a 4:1 mixture of 7e and 8e.
1
Ratios were determined by H NMR.
alkynes.16,17 The polarized alkyne was attacked at the δ-posi-
tion of the carboxylate resulting in 6-endo cyclization. AgOAc
and AgClO4 can exhibit hybrid activation18 for both oxygen
and alkyne which may account for the poor selectivity.19
On the basis of these results, we carried out the cyclization
of enyne carboxylic acids (6a-g) bearing various kinds of
substituents to explore the generality of this method, as
shown in Table 3. Most of the substrates afforded the 5-exo
cyclized products 7 without the 6-endo cyclized products
(entries 1-4, 6, and 7). When the R2 group was Bu, a 4:1
mixture of 7e and 8e was obtained (entry 5).
However, when the Ag(I) catalyzed cyclization of 6 was
performed in the presence of Brønsted acids, the pyrones 8
resulted. Although the conversion of 6e to 8e with a
combination of Ag2CO3 and AcOH in DMF showed no
selectivity (50:50) (Table 4, entry 1), the 6-endo products
were produced exclusively in CH2Cl2 (entries 2 and 4). A
slight excess of AcOH compared to the Ag(I) catalyst was
required to achieve selective 6-endo cyclization. The reaction
with AcOH in the absence of Ag2CO3 did not go to
completion (entries 3 and 5). When the R2 group was
MPMOCH2, a 3:1 mixture of 8c and 7c was obtained (entry
6). There was no difference in the selectivity when
CF3CO2Ag was used in place of Ag2CO3 (entry 7). In
contrast, CF3CO2H (TFA) worked efficiently as an acid to
afford the 6-endo product (entry 8). However, when the
reaction rate was sluggish, the acidity of TFA was so strong
that the ꢀ-alkoxy-R,ꢀ-unsaturated carboxylic acid 3 was
isomerized to (Z)-6c (entry 9). On the other hand, the silyl-
substituted alkynes gave exclusively the 5-exo products,
probably due to a stereoelectronic effect (entries 10 and 11).
These results suggest that Brønsted acids and nonpolar
solvent are effective in promoting 6-endo cyclization and
that Ag(I) catalysts increase the reaction rate by strong
complexation with the alkyne.
(5) Ene-yne cross coupling-lactonization cascade route: (a) Lu, X.;
Huang, X.; Ma, S. Tetrahedron Lett. 1993, 34, 5963–5966. (b) Liu, F.;
Negishi, E. J. Org. Chem. 1997, 62, 8591–8594. (c) Nova´k, P.; Pour, M.;
ˇ
Spula´k, M.; Votruba, I.; Kotora, M. Synthesis 2008, 3465–3472
.
(6) Iodolactonization: (a) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi,
R. Tetrahedron 2001, 57, 2857–2870. (b) Biagetti, M.; Bellina, F.; Carpita,
A.; Stabile, P.; Rossi, R. Tetrahedron 2002, 58, 5023–5038. (c) Wang, Y.;
Burton, D. J. J. Org. Chem. 2006, 71, 3859–3862
.
(7) (a) Marco, J. A.; Carda, M.; Murga, J.; Falomir, E. Tetrahedron
2007, 63, 2929–2958. (b) Goel, A.; Ram, V. J. Tetrahedron 2009, 65, 7865–
7913
.
(8) (a) Effenberger, F.; Ziegler, T. Chem. Ber. 1987, 120, 1339–1346.
(b) Ichihara, A.; Murakami, K.; Sakamura, S. Tetrahedron 1987, 43, 5245–
5250. (c) Tanyeli, C.; Tarhan, O. Synth. Commun. 1989, 19, 2453–2460
(9) (a) Shindo, M.; Mori, S. Synlett 2008, 2231–2243. (b) Shindo, M.;
Mori, S. J. Synth. Org. Chem., Jpn. 2008, 66, 28–38
(10) (a) Dolbier, W. R., Jr.; Koroniak, H.; Houk, K. N.; Sheu, C. Acc.
Chem. Res. 1996, 29, 471–477. (b) Kirmse, W.; Rondan, N. G.; Houk, K. N.
J. Am. Chem. Soc. 1984, 106, 7989–7991. (c) Kallel, E. A.; Wang, Y.;
Spellmeyer, D. C.; Houk, K. N. J. Am. Chem. Soc. 1990, 112, 6759–6763
(11) Shindo, M.; Kita, T.; Kumagai, T.; Matsumoto, K.; Shishido, K.
J. Am. Chem. Soc. 2006, 128, 1062–1063
.
.
We sought to understand the 6-endo selective cyclization
with Brønsted acids through DFT-B3LYP/6-31+G* calcula-
tions20 using Gaussian 03 software. Uchiyama et al. ex-
plained the 5-exo vs 6-endo cyclization based on the
electronic bias of the groups on both carbons of the triple
bond.4f We also observed a similar electronic bias on the
carbons of the triple bond as shown in Figure 2, that is, the
more electrophilic carbon atom at the δ-position induced the
6-endo cyclization.
.
.
(12) Yoshikawa, T.; Mori, S.; Shindo, M. J. Am. Chem. Soc. 2009, 131,
2092–2093
.
(13) Mori, S.; Shindo, M. Org. Lett. 2004, 6, 3945–3948
.
(14) (a) Shindo, M. Tetrahedron Lett. 1997, 38, 4433–4436. (b) Shindo,
M.; Sato, Y.; Shishido, K. Tetrahedron 1998, 54, 2411–2422. (c) Shindo,
M.; Matsumoto, K.; Shishido, K. Org. Synth. 2007, 84, 11–21
(15) Fe´tizon, M.; Parker, K. A.; Su, D.-S. Handbook of Reagents for
Organic Synthesis, Oxidizing and Reducing Agents (Eds.>: Paquette, L. A.;
Burke, S. D.; Danheiser, R. L.), Wiley, New York, 1999, pp. 361-366
and pp.368-370.
.
To demonstrate the synthetic utility of the cyclization, an
elongation of the carbon skeleton of the terminal alkene of the
(16) Nishinaga, T.; Kawamura, T.; Komatsu, K. Chem. Commun. 1998,
2263–2264
.
(17) (a) Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. J. Org. Chem. 2005,
70, 10096–10098. (b) Rhee, J. U.; Krische, M. J. Org. Lett. 2005, 7, 2493–
2495
(18) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817–7831.
(19) Godet, T.; Vaxelaire, C.; Michel, C.; Milet, A.; Belmont, P.
Chem.sEur. J. 2007, 13, 5632–5641.
.
(20) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. Lee, C.;
Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785–789. (b) Hehre, W. J.;
Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital
Theory; John Wiley; New York, 1986, and references cited therein.
5380
Org. Lett., Vol. 11, No. 23, 2009

Table 4. Ag(I)-Catalyzed 6-endo Cyclization for Pyrones
entry
R1
R2
6
Ag cat.
H+
solvent
time (h)
yield (%)
8:7
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Bu
Bu
Bu
Ph
Ph
MPMOCH2
MPMOCH2
MPMOCH2
MPMOCH2
TBS
6e
6e
6e
6g
6g
6c
6c
6c
6c
6a
6d
Ag2CO3
Ag2CO3
none
Ag2CO3
none
Ag2CO3
Ag(OCOCF3)
Ag2CO3
none
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
TFA
DMF
1.5
9
9
9
9
14
9
1.5
1.5
17
17
64 (8e)
73 (8e)
50:50
>99:1
>99:1
>99:1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
49a (8e)
64 (8g)
Et
no reaction
70 (8c)
45 (8c)
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
Et
75:25
78:22
93:7
>99:1
<1:99
<1:99
64 (8c)
9
10
11
TFA
AcOH
AcOH
43b (8c)
97c (7a)
62c (7d)
Ag2CO3
Ag2CO3
TES
a Reaction was not completed. b Product was a 1:2 mixture of 8c and the Z-isomer of 6c. c Product was a diastereomeric mixture of the tetronic acid
derivatives 7.
9 and phenylboronic acid was conducted to provide 7g in 60%
yield.22 The Sonogashira coupling between 9 and the terminal
alkyne 10 also proceeded to afford 11 in 63% yield.23
In conclusion, we have shown that a highly torquoselective
olefination of alkynoates provides functionalized tetrasub-
stituted olefins. The mode of the cyclization of the enyne
carboxylic acids was dramatically altered by addition of
Brønsted acids resulting in the selective synthesis of tetronic
acid derivatives and pyrones. Further studies will be carried
out to apply this methodology to the synthesis of bioactive
natural products.
Figure 2. Natural population analysis (B3LYP/6-31+G*).
tetronic acids was attempted, since this kind of tetronic acid
derivative is often seen in bioactive natural products (Scheme
3). The TES-substituted tetronic acid derivative 7d was
converted to vinyl iodide 9 by treatment with iodine in the
presence of AgOTf.21 The Suzuki-Miyaura coupling between
Acknowledgment. This research was partially supported
by Grant-in-Aid for Scientific Research (B) (19390007) and
the Program for Promotion of Basic and Applied Researches
for Innobations in Bio-oriented Industry (BRAIN). T.K. also
acknowledges the support of the JSPS.
Scheme 3
.
Elongation of the Carbon Skeleton of the Tetronic
Acids
Supporting Information Available: General procedures,
1
characterization data of new compounds, H and 13C NMR
spectra of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL902086T
(21) Se´verine, R.; Je´roˆme, T.; Mohamed, A.; Alain, D.; Jean-Luc, P.
Synlett 2000, 260–262.
(22) For a review see: Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457–2483.
(23) (a) Sonogashira, K.; Tohda, Y.; Hagiwara, N. Tetrahedron Lett.
1975, 16, 4467–4470. (b) Spencer, R. W.; Tam, T. F.; Thomas, E.; Robinson,
V. J.; Krantz, A. J. Am. Chem. Soc. 1986, 108, 5589–5597.
Org. Lett., Vol. 11, No. 23, 2009
5381