A divergent synthesis of functionalized unsaturated δ-lactones from α-alkenoyl-α-carboxyl ketene dithioacetals

Article abstract of DOI:10.1021/jo0702488

(Chemical Equation Presented) A divergent synthesis of functionalized unsaturated δ-lactones 2, 3, 4, and 5 has been developed starting from the readily available α-alkenoyl-α-carboxyl ketene dithioacetals 1 in high to excellent yields under mild reaction

Full text of DOI:10.1021/jo0702488

A Divergent Synthesis of Functionalized Unsaturated δ-Lactones
from r-Alkenoyl-r-carboxyl Ketene Dithioacetals
Jun Liu, Mang Wang,* Bing Li, Qun Liu,* and Yulong Zhao
Department of Chemistry, Northeast Normal UniVersity, Changchun, 130024, People’s Republic of China
wangm452@nenu.edu.cn
ReceiVed February 6, 2007
A divergent synthesis of functionalized unsaturated δ-lactones 2, 3, 4, and 5 has been developed starting
from the readily available R-alkenoyl-R-carboxyl ketene dithioacetals 1 in high to excellent yields under
mild reaction conditions. Thus, 6-substituted 3-(1,3-dithiolan/dithian-2-ylidene)-3H-pyran-2(6H)-ones 2,
obtained from a consecutive reduction with NaBH4 and acidic workup of 1 via a novel vinylogous
Pummerer cyclization, can be further transformed into R-pyranones 3, 4, and 5 upon a sequential
isomerization catalyzed by triethylamine (to give 3), followed by dethioacetalization (to give 4) or a
formylation with Vilsmeier reagent (to give 5).
Introduction
been reported.3-15 Of these synthetic methods, the divergent
strategy seems to be more efficient due to the diversity of
products.4e,15 Therefore, it is desirable to develop a divergent
methodology toward unsaturated δ-lactones with the advantages
of readily available starting materials, cheap reagents, mild
reaction conditions, high yields, and considerable flexibility.
Unsaturated δ-lactones are found in a variety of biologically
important natural products1 and widely used as intermediates
in organic synthesis.2 To date, a number of inventive approaches
for accessing the unsaturated δ-lactone structural motif have
(1) (a) Davies-Coleman, M. T.; Rivett, D. E. A. In Progress in the
Chemistry of Organic Natural Products; Zechmeister, L., Ed.; Springer-
Verlag: New York, 1989; Vol. 55, p 1. (b) Tsubuki, M.; Kanai, K.; Keino,
K.; Kakinuma, N.; Honda, T. J. Org. Chem. 1992, 57, 2930. (c) Nangia,
A.; Prasuna, G.; Rao, P. B. Tetrahedron 1997, 53, 14507. (d) Go´mez, A.
M.; Lo´pez de Uralde, B.; Valverde, S.; Lo´pez, J. C. Chem. Commun. 1997,
1647. (e) Toshima, H.; Sato, H.; Ichihara, A. Tetrahedron 1999, 55, 2581.
(f) Koch, K.; Podlech, J.; Pfeiffer, E.; Metzler, M. J. Org. Chem. 2005, 70,
3275.
(2) (a) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.
(b) Koskinen, A. M. P.; Otsomaa, L. A. Tetrahedron 1997, 53, 6473. (c)
Nicolaou, K. C.; Rodr´ıguez, R. M.; Mitchell, H. J.; Suzuki, H.; Fylaktakidou,
K. C.; Baudoin, O.; van Delft, F. L. Chem. Eur. J. 2000, 6, 3095. (d)
Solladie´, G.; Gressot, L.; Colobert, F. Eur. J. Org. Chem. 2000, 357. (e)
Wang, L.; Floreancig, P. E. Org. Lett. 2004, 6, 569. (f) Roulland, E.;
Ermolenko, M. S. Org. Lett. 2005, 7, 2225.
(4) Acid-catalyzed lactonization of hydroxy acids: (a) Fabio, F.;
Schneider, M. P. Tetrahedron Lett. 2002, 43, 811. (b) Pa`mies, O.; Ba¨ckvall,
J.-E. J. Org. Chem. 2002, 67, 1261. (c) Aplander, K.; Hidesta´l, O.;
Katebzadeh, K.; Lindstro¨m, U. M. Green Chem. 2006, 8, 22. (d) Singh,
V.; Batra, S. Synthesis 2006, 63. (e) Cateni, F.; Zilic, J.; Zacchigna, M.;
Bonivento, P.; Frausin, F.; Scarcia, V. Eur. J. Med. Chem. 2006, 41, 192.
(5) Electrophile-induced lactonization of unsaturated carboxylic acids and
their derivatives: Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.;
Jayaraman, N. Tetrahedron 2004, 60, 5273.
(6) Ring-closing metathesis: (a) Ghosh, A.; Cappiello, J.; Shin, D.
Tetrahedron Lett. 1998, 39, 4651. (b) Andreana, P. R.; McLellan, J. S.;
Chen, Y.; Wang, P. G. Org. Lett. 2002, 4, 3875. (c) Ramachandran, P. V.;
Prabhudas, B.; Chandra, J. S.; Reddy, M. V. R. J. Org. Chem. 2004, 69,
6294.
(7) Transition metal-catalyzed cyclization: (a) Toyota, M.; Hirota, M.;
Nishikawa, Y.; Fukumoto, K.; Ihara, M. J. Org. Chem. 1998, 63, 5895. (b)
Hsu, J.-L; Chen, C.-T; Fang, J.-M. Org, Lett. 1999, 1, 1989. (c) Hsu, J.-L.;
Fang, J.-M. J. Org. Chem. 2001, 66, 8573.
(8) Transition metal-catalyzed cyclocarbonylation of unsaturated alco-
hols: (a) Knight, J. G.; Ainge, S. W.; Baxter, C. A.; Eastman, T. P.;
Harwood, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3188. (b) Dong, C.;
Alper, H. J. Org. Chem. 2004, 69, 5011.
(3) (a) Ogliarusco, M. A.; Wolfe, J. F. Synthesis of Lactones and Lactams;
Patai, S., Rappoport, Z., Eds.; Wiley: Chichester, UK, 1993. (b) Ley, S.
V.; Cox, L. R.; Meek, G. Chem. ReV. 1996, 96, 423. (c) Collins, I. J. Chem.
Soc., Perkin Trans. 1 1998, 1869. (d) Collins, I. J. Chem. Soc., Perkin Trans.
1 1999, 1377. (e) Boucard, V.; Broustal, G.; Campagne, J. M. Eur. J. Org.
Chem. 2007, 225.
10.1021/jo0702488 CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/12/2007
J. Org. Chem. 2007, 72, 4401-4405
4401

Liu et al.
TABLE 1. Optimization of Conditions for the Reaction of 1a with
SCHEME 1
a
NaBH4
time
(h) product
yieldb
(%)
entry substrate
solvent
1
2
3
4
1a
1a
1a
1a
MeOH
24
3.0
3.5
6.0
c
c
MeOH-CH2Cl2 (v/v, 1:10)
MeOH-DMF (v/v, 1:10)
MeOH-THF (v/v, 1:10)
2a
2a
2a
90
60
82
a NaBH4 (2.5 equiv), rt, then quenched by aq HCl at 0 °C. b Isolated
yields after silica column chromatography. c No reaction.
4-chloro-2,2-bis(methylthio/benzylthio)-2H-pyrans (precursors
of the corresponding R-pyrones) were successfully prepared by
us from 4,4-bis(methylthio/benzylthio)but-3-en-2-one via the
Vilsmeier-Haack reaction (Scheme 1, path C).19c
On the other hand, functionalized ketene dithioacetals are
versatile synthons16 and have found wide applications in the
synthesis of various carbo-17 and heterocyclic compounds.18 In
1988, Dieter and Fishpaugh reported that R-oxo ketene dithio-
acetals could be converted into R-pyrones in good yields by a
strategy involving 1,2-nucleophilic addition of ester, ketone, or
hydrazone enolate anion, followed by acid-promoted rearrange-
ment to a δ-keto ester, thiol ester, or acid and subsequent enol
lactonization (Scheme 1, path A).19a Recently, Rao and Siva-
kumar also reported a facile and efficient synthesis of a
combinatorial library of 3-aroylcoumarins by the condensation
of R-aroylketene dithioacetals and 2-hydroxybenzaldehydes (or
2-hydroxy-1-naphthaldehyde) in the presence of a catalytic
amount of piperidine (Scheme 1, path B).19b A little earlier,
In our research on the functionalized ketene dithioacetal
chemistry,20 we found that the easily available and structurally
flexible R-alkenoyl ketene dithioacetals showed fascinating
structural features as novel synthetic intermediates.21 As a part
of these research efforts, some tetronic acid derivatives were
prepared by performing the acid-mediated intramolecular oxa-
pyridylethylation of the corresponding R-alkenoyl-R-carboxyl
ketene dithioacetals 1.21d Although this cyclization is strongly
dependent on the substituent at the 5-position of 1 (a 2- or
4-pyridinyl is required), the simplicity of the procedure prompted
us to further explore the synthetic utility of the readily available
R-alkenoyl-R-carboxyl ketene dithioacetals 1. In this paper, a
divergent synthesis of functionalized unsaturated δ-lactones 2,
3, 4, and 5 starting from a wide range of ketene dithioacetals 1
is described.
(9) Atom transfer carbonylation: (a) Tsunoi, S.; Ryu, I.; Okuda, T.;
Tanaka, M.; Komatsu, M.; Sonoda, N. J. Am. Chem. Soc. 1998, 120, 8692.
(b) Kreimerman, S.; Ryu, I.; Minakata, S.; Komatsu, M. Org. Lett. 2000,
2, 389.
(10) Modification of the pre-constructed δ-lactone core: (a) Moorthy,
J. N.; Singhal, N.; Mal, P. Tetrahedron Lett. 2004, 45, 309. (b) Casas, J.;
Engqvist, M.; Ibrahem, I.; Kaynak, B.; Co´rdova, A. Angew. Chem., Int.
Ed. 2005, 44, 1343.
Results and Discussion
(11) Cyclic expansion: (a) Harris, J. M.; O’Doherty, G. A. Tetrahedron
Lett. 2002, 43, 8195. (b) Wang, S.; Kayser, M. M.; Jurkauskas, V. J. Org.
Chem. 2003, 68, 6222.
(12) Hetero-Diels-Alder reaction: Lin, L.; Fan, Q.; Qin, B.; Feng, X.
J. Org. Chem. 2006, 71, 4141.
(13) Vinylogous aldol reaction: (a) Schlessinger, R. H.; Li, Y.-J.; Von,
Langen, D. J. J. Org. Chem. 1996, 61, 3226. (b) Bluet, G.; Baza´n-Tejeda,
B.; Campagne, J.-M. Org. Lett. 2001, 3, 3807. (c) Baza´n-Tejeda, B.; Bluet,
G.; Broustal, G.; Campagne, J.-M. Chem. Eur. J. 2006, 12, 8358.
(14) Keto-ester cyclization: Ma, S.; Yu, S.; Yin, S. J. Org. Chem. 2003,
68, 8996.
(15) (a) Dieter, R. K.; Guo, F. Org. Lett. 2006, 8, 4779. (b) Hoye, T. R.;
Ryba, T. D. J. Am. Chem. Soc. 2005, 127, 8256.
(16) (a) Dieter, R. K. Tetrahedron 1986, 42, 3029. (b) Junjappa, H.; Ila,
H.; Asokan, C. V. Tetrahedron 1990, 46, 5423. (c) Kolb, M. Synthesis 1990,
171. (d) Ila, H.; Junjappa, H.; Barun, O. J. Organomet. Chem. 2001, 624,
34.
(17) For selected examples, see: (a) Gill, S.; Kocienski, P.; Kohler, A.;
Pontiroli, A.; Liu, Q. Chem. Commun. 1996, 1743. (b) Kocienski, P. J.;
Alessandro, P.; Liu, Q. J. Chem. Soc., Perkin Trans. 1 2001, 2356. (c)
Barun, O.; Nandi, S.; Panda, K.; Ila, H.; Junjappa, H. J. Org. Chem. 2002,
67, 5398. (d) Nandi, S.; Syam Kumar, U. K.; Ila, H.; Junjappa, H. J. Org.
Chem. 2002, 67, 4916.
(18) For selected examples, see: (a) Ila, H.; Junjappa, H.; Mohanta, P.
K. In Progress in Heterocyclic Chemistry; Gribble, G. H., Gilchrist, L. T.,
Eds.; Pergamon Press: Oxford, UK, 2001; Vol. 13, pp 1ff. (b) Venkatesh,
C.; Singh, B.; Mahata, P. K.; Ila, H.; Junjappa, H. Org. Lett. 2005, 7, 2169.
(c) Peruncheralathan, S.; Khan, T. A.; Ila, H.; Junjappa, H. J. Org. Chem.
2005, 70, 10030.
R-Alkenoyl-R-carboxyl ketene dithioacetals 1 were prepared
by aldol condensation of the corresponding R-acetyl-R-ethoxy-
carbonyl ketene dithioacetals with various aldehydes (including
aliphatic, aromatic, and R,â-unsaturated aldehydes) in high
yields as described in our previous reports.21d,22 As an initial
attempt, the reaction of (E)-2-(1,3-dithiolan-2-ylidene)-3-oxo-
5- phenylpent-4-enoic acid 1a with NaBH4 was carried out at
room temperature in methanol to reduce the carbonyl group at
the 3-position. However, no satisfying results were obtained due
to the poor solubility of 1a in methanol (Table 1, entry 1). To
improve the solubility of 1a, mixed solvent systems, such as
(20) Selective examples: (a) Liu, Q.; Che, G.; Yu, H.; Liu, Y.; Zhang,
J.; Zhang, Q.; Dong, D. J. Org. Chem. 2003, 68, 9148. (b) Sun, S.; Liu, Y.;
Liu, Q.; Zhao, Y.; Dong, D. Synlett 2004, 1731. (c) Zhao, Y.-L.; Liu, Q.;
Zhang, J.-P.; Liu, Z.-Q. J. Org. Chem. 2005, 70, 6913. (d) Ouyang, Y.;
Dong, D.; Yu, H.; Liang, Y.; Liu, Q. AdV. Synth. Catal. 2006, 348, 206.
(21) (a) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B. J. Am.
Chem. Soc. 2005, 127, 4578. (b) Dong, D.; Bi, X.; Liu, Q.; Cong, F. Chem.
Commun. 2005, 3580. (c) Bi, X.; Dong, D.; Li, Y.; Liu, Q. J. Org. Chem.
2005, 70, 10886. (d) Bi, X. H; Liu, Q.; Sun, S. G.; Liu, J.; Pan, W.; Zhao,
L.; Dong, D. W. Synlett 2005, 49. (e) Zhao, L.; Liang, F.; Bi, X.; Sun, S.;
Liu, Q. J. Org. Chem. 2006, 71, 1094. (f) Li, Y.; Liang, F. S.; Bi, X. H.;
Liu, Q. J. Org. Chem. 2006, 71, 8006. (g) Liang, F. S.; Zhang, J. Q.; Tan,
J.; Liu, Q. AdV. Synth. Catal. 2006, 348, 1986.
(19) (a) Dieter, R. K.; Fishpaugh, J. R. J. Org. Chem. 1988, 53, 2031.
(b) Rao, H. S. P.; Sivakumar, S. J. Org. Chem. 2006, 71, 8715. (c) Liu, Y.;
Dong, D.; Liu, Q.; Qi, Y.; Wang, Z. Org. Biomol. Chem. 2004, 2, 28.
(22) (a) Liu, Q.; Li, J. X.; Liu, J. F.; Sun, Z. G.; Xing, Y.; Jia, H. Q.;
Lin, Y. Q. Acta Chim. Sinica 2000, 58, 92. (b) Wang, M.; Xu, X.; Liu, Q.;
Xiong, L.; Yang, B.; Gao, L. Synth. Commun. 2002, 32, 3437.
4402 J. Org. Chem., Vol. 72, No. 12, 2007

Synthesis of Functionalized Unsaturated δ-Lactones
TABLE 2. Tandem Reduction and Acid-Catalyzed Lactonization
of 1a
SCHEME 2
time
(h)
yieldb
(%)
SCHEME 3
entry
substrate
n
R
product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
C6H5
4-FC6H4
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
3.0
3.5
4.5
4.0
4.0
2.5
2.0
3.0
2.0
4.5
4.0
5.0c
3.5
12.0
3.0
3.0
90
87
80
85
82
89
92
90
91
84
82
35d
78
37e
86
89
2-ClC6H4
4-ClC6H4
3-NO2C6H4
4-MeC6H4
4-MeOC6H4
3,4-O2CH2C6H3
4-(Me)2N C6H4
2-furyl
2-thienyl
4-NO2C6H4
t-Bu
cyclohexyl
C6H5CHdCH
C6H5
in excellent yields (Table 2, entries 2-11). In the case of the
strongly electron-withdrawing 4-nitrophenyl group at the 5-posi-
tion, the reaction had to be performed at reflux temperature to
give the desired lactone 2l in fair yield (Table 2, entry 12) with
the recovery of the starting material 1l in 52% yield. In our
research, substrates bearing both aliphatic and styryl groups at
the 5-position of 1 were also tried under the identical conditions.
As expected, the corresponding δ-lactones 2m and 2o were
afforded in high yields (Table 2, entries 13 and 15, respectively),
but 2n was obtained only in moderate yield with recovery of
1n in 51% yield (Table 2, entry 14) even after 12 h of reaction.
Similarly, δ-lactone 2p was also successfully prepared in 89%
yield from 1p bearing a 1,3-dithian-2-ylidene group at the
2-position (Table 2, entry 16).
a NaBH4 (2.5 equiv), MeOH-CH2Cl2 (v/v, 1:10), rt, then quenched by
aq HCl at 0 °C. b Isolated yields after silica column chromatography. c At
reflux temperature. d With recovery of 1l in 52%. e With recovery of 1n in
51%.
TABLE 3. Experimental Results of Isomerization of 2 and
Dethioacetalization of 3
With the consideration that δ-lactones 2 possess the general
structural features of the synthetically versatile R-oxo ketene
dithioacetals16-22 and can be easily prepared by a one-pot
procedure as described above, the transformation from δ-lac-
tones 2 into diverse unsaturated δ-lactones was then probed.
The reaction of 2a in DMSO at 120 °C in the presence of
triethylamine for 1 h gave R-pyranone 3a in 85% yield through
an olefin isomerization process (Scheme 2). Then an aldehyde
4a, the dethioacetalization product of 3a, was successfully
produced in 93% yield by treating 3a in DMSO at 120 °C with
iodine as catalyst.24 Similarly, functionalized R-pyranones 3d,
3f, 4d, and 4f (Table 3) were prepared in high to excellent yields
starting from 2d (with an electron-withdrawing aryl at the
6-position) and 2f (with an electron-donating aryl at the
6-position), respectively.
In our previous research25a,b and also Asokan’s work,25c the
nucleophilicity of the R-carbon atom of R-EWG ketene dithio-
acetals (EWG ) electron-withdrawing group) has been well
developed and a series of heteroatom and carbon electrophiles
are successfully introduced into their R-position. Accordingly,
δ-lactones 2 can be regarded as the R-EWG ketene dithioacetal
analogues with a vinylketene dithioacetal structure. To examine
the nucleophilicity of the C-5 of δ-lactones 2, the reaction of 2
with Vilsmeier reagent was attempted. This was successful and
a formyl group was selectively introduced at the 5-position of
time
(h)
yieldc
(%)
entry
substrate
R
product
1a
2a
3a
4b
5b
6b
2a
2d
2f
3a
3d
3f
C6H5
3a
3d
3f
4a
4d
4f
1
1
1.5
2.5
2
85
84
82
93
92
91
4-ClC6H4
4-MeC6H4
C6H5
4-ClC6H4
4-MeC6H4
3
a NEt3 (1.2 equiv), DMSO, 120 °C. b I2 (1.0 equiv), DMSO, 120 °C.
c Isolated yields.
MeOH-CH2Cl2, MeOH-DMF, and MeOH-THF, were then
examined and the experimental results are listed in Table 1.
Interestingly, all the reactions performed in the mixed solvent
systems proceeded smoothly to directly yield unsaturated
δ-lactone, 3-(1,3-dithiolan-2-ylidene)-6-phenyl-3H-pyran-2(6H)-
one 2a (assigned based on its 1H NMR, 13C NMR, MS spectra,
and single-crystal X-ray diffraction analysis23) as the only
product after acidic workup. By comparison, MeOH-CH2Cl2
(v/v, 1:10) was the best choice for this reaction (Table 1, entry
2).
The above reaction sequence indicates that the transformation
of ketene dithioacetal 1a to δ-lactone 2a may serve as an
efficient route to functionalized unsaturated δ-lactones. To
expand the scope of this reaction, ketene dithioacetals 1b-p
with various substituents at the 5-position, for example, alkyl,
aryl, heteroaryl, and R,â-unsaturated groups (Table 2), were
selected and the lactonization reactions were performed under
the optimized conditions.
(23) Crystal data for 2a: C14H12O2S2, colorless, M ) 276.36, orthor-
hombic, space group P2(1)2(1)2(1), a ) 8.379(5) Å, b ) 17.493(5) Å, c )
17.621(5) Å, V ) 2582.8(19) Å3, R ) 90.000(5)°, â ) 90.000(5)°, γ )
90.000(5)°, Z ) 8, T ) 293 K, F000 ) 1152, R1 ) 0.0624, wR2 ) 0.1030.
(24) Chattopadhyaya, J. B.; Rao, A. V. R. Tetrahedron Lett. 1973, 14,
3735.
(25) (a) Yin, Y.-B.; Wang, M.; Liu, Q.; Hu, J.-L.; Sun, S. -G.; Kang, J.
Tetrahedron Lett. 2005, 46, 4399. (b) Sun, S.; Zhang, Q.; Liu, Q.; Kang,
J.; Yin, Y.; Li, D.; Dong, D. Tetrahedron Lett. 2005, 46, 6271. (c) Anabha,
E. R.; Asokan, C. V. Synthesis 2006, 151.
It is clear that, from the results shown in Table 2, the
cyclization of 1 allows a wide range of substituents at their
5-position. All of the substrates bearing an electron-donating
or electron-withdrawing aryl group can efficiently afford the
corresponding ring-closing products 2b-k at room temperature
J. Org. Chem, Vol. 72, No. 12, 2007 4403

Liu et al.
SCHEME 4
SCHEME 5
the lactone ring of 2 to give the polyfunctionalized unsaturated
δ-lactones 5 in high yields (three examples are included, Scheme
3).
As presented above, we have developed a practical method
to rapidly synthesize diverse unsaturated δ-lactones 2, 3, 4, and
5. These lactones possess powerful and useful functionality and
are expected to be useful building blocks in the library synthesis
and screening of potential bio-/pharmacological compounds. As
the precursors of unsaturated δ-lactones 3, 4, and 5, unsaturated
δ-lactones 2 are believed to be formed via hydroxy acids 6 in
a one-pot, two-step procedure (Scheme 4). However, in all cases,
δ-lactones 2 were directly achieved and hydroxy acids 6 could
not be isolated after acidic workup. These results imply that
acids 6 are very sensitive to acid treatment, which drives the
formation of lactones 2.
SCHEME 6. Proposed Mechanism for Thionium
Ion-Induced Lactonization
Hydroxy acids 6 can be considered as a kind of special
3-hydroxy pent-4-enoic acids with a 1,3-dithiolan/dithian-2-
ylidene unit at the 2-position. It has been proved that simple
3-hydroxy pent-4-enoic acids are generally stable under acidic
conditions. Their lactonizations can be accomplished with
assistance of an electrophile, such as halogen26 and selenenyl
halides,27 to afford the corresponding halolactonization and
selenolactonization products. In 1993, Mestres and Aurell
reported that the lactonization of 3-hydroxy-3,5-dimethylhex-
4-enoic acid had to be carried out under cold concentrated
sulfuric acid to afford 4,6-dimethyl-4,5-unsaturated δ-lactone
via a carbocation intermediate, but this 3-hydroxy acid was
proved to be inert under concentrated hydrochloric acid.28
Compared with simple 3-hydroxy pent-4-enoic acids, function-
alized 3-hydroxy pent-4-enoic acids 6 are apt to lactonize just
upon the aqueous acidic conditions without requiring an
electrophile as mentioned. Apparently, the ketene dithioacetal
functionality of 6 plays a crucial role in this lactonization
reaction.
To discover the important role of the ketene dithioacetal
functionality in the reaction, a simple 3-hydroxy pent-4-enoic
acid, 1-cinnamoylcyclopentanecarboxylic acid 7, was prepared
through the alkylation of ethyl acetoacetate with 1,4-dibro-
mobutane29 followed by the aldol condensation with benzalde-
hyde. Thus, hydroxy acid 8 was obtained in 80% isolated yield
by treating 7 with NaBH4 in MeOH-CH2Cl2 (v/v, 1:10) at room
temperature for 1 h followed by acidic workup (Scheme 5),
while lactone 9 was not observed. Moreover, acid 8 was proved
to be stable and no significant changes were found when it was
heated in aqueous hydrochloric acid for 5 h at reflux temper-
ature.
On the basis of all of the results mentioned above, obviously,
the ketene dithioacetal functionality is crucial for the lacton-
ization reaction. Thus, a possible mechanism, which involves a
novel vinylogous Pummerer cyclization,30 is proposed as
outlined in Scheme 6. Initiated by protonation of the hydroxyl
of intermediate 6 and subsequent dehydration, unsaturated
thionium ion I is generated to result in a highly delocalized
system. Subsequently, δ-lactones 2 are easily formed via the
internal trapping of thionium ion I by the nucleophilic carboxyl
group at the 5-position.
Conclusion
In summary, we have described a rapid and divergent
synthesis of functionalized unsaturated δ-lactones from readily
available R-alkenoyl-R-carboxyl ketene dithioacetals 1 under
mild reaction conditions in high yields. As a key step for the
formation of unsaturated δ-lactones 2, a novel thionium ion-
induced lactonization is proposed. Various unsaturated δ-lac-
tones 3, 4, and 5, which bear powerful and useful functionality,
are obtained via simple modifications of 2. This methodology
provides an efficient and practical route to the functionalized
unsaturated δ-lactones which are expected to be useful building
blocks in library synthesis for the screening of potential bio-/
pharmacological compounds. Further research is in progress.
Experimental Section
Starting Materials. Compounds 1 are prepared by the aldol
condensation of the corresponding R-acetyl-R-ethoxycarbonyl
ketene dithioacetals with various aldehydes according to our
previous reports.21d,22
General Procedure for the Synthesis of 2 (with 2a as an
example). To a well-stirred suspension of 1a (292 mg, 1.0 mmol)
(26) (a) Chamberlin, A. R.; Dezube, M.; Dussault, P.; McMills, M. C.
J. Am. Chem. Soc. 1983, 105, 5819. (b) Ohfune, Y.; Kurokawa, N.
Tetrahedron Lett. 1985, 26, 5307.
(27) (a) Gruttadauria, M.; Aprile, C.; Noto, R. Tetrahedron Lett. 2002,
43, 1669. (b) Aprile, C.; Gruttadauria, M.; Amato, M. E.; D’Anna, F.; Meo,
P. L.; Riela, S.; Noto, R. Tetrahedron 2003, 59, 2241.
(28) Aurell, M. J.; Carne, I.; Clar, J. E.; Gil, S.; Mestres, R.; Parra, M.;
Tortajada, A. Tetrahedron 1993, 49, 6089.
(30) (a) Padwa, A.; Kuethe, J. T. J. Org. Chem. 1998, 63, 4256. (b)
Bur, S. K.; Padwa, A. Chem. ReV. 2004, 104, 2401. (c) Feldman, K. S.
Tetrahedron 2006, 62, 5003.
(29) Muthusamy, S.; Gnanaprakasam, B. Tetrahedron Lett. 2005, 46,
635.
4404 J. Org. Chem., Vol. 72, No. 12, 2007

Synthesis of Functionalized Unsaturated δ-Lactones
in MeOH-CH2Cl2 (v/v, 1:10, 11 mL) was added NaBH4 (90 mg,
2.5 mmol). The reaction mixture was stirred for 4 h at room
temperature and then poured into ice-water (80 mL). The suspen-
sion was acidified by concentrated hydrochloric acid to pH 3 and
extracted by CH2Cl2 (3 × 15 mL). The combined organic phase
was washed with water, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel (eluent, petroleum ether:diethyl ether
) 3:1, v/v) to give 2a (248 mg, 90%) as a white solid.
5-(1,3-Dithiolan-2-ylidene)-6-oxo-2-phenyl-5,6-dihydro-2H-
pyran-3-carbaldehyde (5a): mp 136-138 °C. 1H NMR (500 MHz,
CDCl3) δ 3.52-3.68 (m, 4H), 6.35 (s, 1H), 7.31 (br s, 5H), 7.50
(s, 1H), 9.54 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 188.5, 174.5,
162.6, 140.4, 138.4, 130.1, 128.9, 128.8 (2C), 126.7 (2C), 108.6,
78.7, 40.1, 37.2. IR (KBr, cm-1) 3066, 2361, 2343, 1661, 1613,
1478, 1178, 793. MS calcd m/z 304.0, found 304.9 [(M + 1)]+.
Anal. Calcd for C15H12O3S2: C, 59.19; H, 3.97. Found: C, 59.05;
H, 3.90.
Synthesis of 7. Ethyl 1-acetylcyclopentanecarboxylate was first
synthesized according to the literature.29 Then, to a solution of ethyl
1-acetylcyclopentanecarboxylate (184 mg, 1.0 mmol) in EtOH (10
mL) was added benzaldehyde (0.10 mL, 1.1 mmol) and NaOEt-
EtOH (4.0 mL, M ) 1 mol/L, 4.0 mmol). The reaction was allowed
to proceed at room temperature and complete in 1 h. The reaction
mixture was quenched with water, acidified by concentrated
hydrochloric acid to pH 3, and extracted with CH2Cl2 (3 × 15 mL).
The combined organic phase was washed with water, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography on silica gel (eluent,
petroleum ether:ethyl acetate ) 1:1, v/v) to give 7 (182 mg, 75%)
as a white solid.
1-Cinnamoylcyclopentanecarboxylic acid (7): mp 87-89 °C.
1H NMR (500 MHz, CDCl3) δ 1.67-1.75 (m, 4H), 2.22-2.30 (m,
4H), 6.86 (d, J ) 15.5 Hz, 1H), 7.37-7.41 (m, 3H), 7.55 (d, J )
6.0 Hz, 2H), 7.74 (d, J ) 15.5 Hz, 1H). 13C NMR (125 MHz,
CDCl3) δ 194.7, 179.7, 144.3, 134.3, 130.7, 128.9 (2C), 128.6 (2C),
121.8, 65.6, 33.4 (2C), 25.9 (2C). IR (KBr, cm-1) 3062, 2956, 2360,
2345, 1715, 1608, 1450, 1205. MS calcd m/z 244.1, found 245.0
[(M + 1)]+. Anal. Calcd for C15H16O3: C, 73.75; H, 6.60. Found:
C, 73.70; H, 6.52.
Synthesis of 8. To a well-stirred suspension of 7 (244 mg, 1.0
mmol) in MeOH-CH2Cl2 (v/v, 1:10, 11 mL) was added NaBH4
(90 mg, 2.5 mmol). The reaction mixture was stirred for 1 h at
room temperature and then poured into ice-water (80 mL). The
suspension was acidified by concentrated hydrochloric acid to pH
6, then extracted by CH2Cl2 (3 × 15 mL). The combined organic
phase was washed with water, dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The crude product was purified
by flash chromatography on silica gel (eluent, petroleum ether:
ethyl acetate ) 1:1, v/v) to give 8 (197 mg, 80%) as a colorless
oil.
3-(1,3-Dithiolan-2-ylidene)-6-phenyl-3H-pyran-2(6H)-one (2a):
1
mp 126-128 °C. H NMR (500 MHz, CDCl3) δ 3.42-3.50 (m,
4H), 5.73 (dd, J ) 4.0, 10.0 Hz, 1H), 6.02 (d, J ) 1.5 Hz, 1H),
6.62 (dd, J ) 1.5, 10.0 Hz, 1H), 7.31-7.38 (m, 5H). 13C NMR
(125 MHz, CDCl3) δ 161.8, 160.5, 138.1, 127.8, 127.7 (2C), 125.9
(2C), 123.7, 119.6, 107.6, 80.7, 38.4, 35.8. IR (KBr, cm-1) 3020,
2942, 2362, 1684, 1505, 1280, 1141, 1048, 894. MS calcd m/z
276.0, found 277.0 [(M + 1)]+. Anal. Calcd for C14H12O2S2: C,
60.84; H, 4.38. Found: C, 60.70; H, 4.31.
Representative Procedure for the Preparation of 3 (with 3a
as an example). To a solution of 2a (276 mg, 1.0 mmol) in DMSO
(10 mL) was added Et3N (0.17 mL, 1.2 mmol) at room temperature.
After being stirred at 120 °C for 1 h, the reaction mixture was
quenched with ice-water (80 mL) and extracted with CH2Cl2 (3
× 15 mL). The combined organic extracts were washed with water,
dried over anhydrous MgSO4, filtered, and concentrated. The residue
was purified by flash chromatography on silica gel (eluent,
petroleum ether:ethyl acetate ) 10:1, v/v) to give 3a (235 mg, 85%
yield) as a yellow solid.
3-(1,3-Dithiolan-2-yl)-6-phenyl-2H-pyran-2-one (3a): mp 134-
1
136 °C. H NMR (500 MHz, CDCl3) δ 3.29-3.35 (m, 4H), 5.68
(s, 1H), 6.69 (d, J ) 7.0 Hz, 1H), 7.44-7.46 (m, 3H), 7.78 (d, J
) 7.0 Hz, 1H), 7.81-7.82 (m, 2H). 13C NMR (125 MHz, CDCl3)
δ 160.6, 158.4, 137.7, 130.1, 129.8, 128.0 (2C), 126.4, 124.5 (2C),
100.1, 48.9, 37.9 (2C). IR (KBr, cm-1) 3073, 2360, 2342, 1701,
1558, 1491, 1110, 761. MS calcd m/z 276.0, found 277.1 [(M +
1)]+. Anal. Calcd for C14H12O2S2: C, 60.80; H, 4.38. Found: C,
60.68; H, 4.32.
General Procedure for the Preparation of 4 (with 4a as an
example). To a well-stirred suspension of 3a (138 mg, 0.5 mmol)
in DMSO (5 mL) was added I2 (127 mg, 0.5 mmol) at room
temperature. After being stirred at 120 °C for 2 h, the reaction
mixture was quenched with ice-water (40 mL) and extracted with
CH2Cl2 (3 × 10 mL). The combined organic extracts were washed
with water, dried over anhydrous MgSO4, filtered, and concentrated.
The residue was purified by flash chromatography on silica gel
(eluent, petroleum ether:ethyl acetate ) 9:1, v/v) to give 4a (93
mg, 93% yield) as a yellow solid.
(E)-1-(1-Hydroxy-3-phenylallyl)cyclopentanecarboxylic acid
(8): 1H NMR (500 MHz, CDCl3) δ 1.25 (br s, 1H), 1.65-1.77 (m,
5H), 1.98-2.21 (m, 3H), 4.34 (d, J ) 7.0 Hz, 1H), 6.24 (dd, J )
7.0, 16.0 Hz, 1H), 6.67 (d, J ) 16.0 Hz, 1H), 7.28 (d, J ) 7.5 Hz,
1H), 7.33 (t, J ) 7.5 Hz, 2H), 7.38 (d, J ) 7.5 Hz, 2H). 13C NMR
(125 MHz, CDCl3) δ 206.2, 135.2, 132.4, 127.6 (2C), 127.0, 126.4,
125.6 (2C), 76.5, 56.8, 34.0, 31.3, 25.0, 24.7. IR (KBr, cm-1) 3076,
2924, 2853, 1715, 1653, 1333, 1200. MS calcd m/z 246.1, found
247.0 [(M + 1)]+. Anal. Calcd for C15H18O3: C, 73.15; H, 7.37.
Found: C, 73.01; H, 7.32.
2-Oxo-6-phenyl-2H-pyran-3-carbaldehyde (4a): mp 122-
1
124 °C. H NMR (500 MHz, CDCl3) δ 6.91 (d, J ) 7.0 Hz, 1H),
7.53-7.58 (m, 3H), 7.92 (d, J ) 7.5 Hz, 2H), 8.18 (d, J ) 7.0 Hz,
1H), 10.17 (s, 1H). 13C NMR (125 MHz, CDCl3) δ 186.6, 166.2,
160.0, 145.6, 131.9, 129.4, 128.4 (2C), 125.8 (2C), 118.0, 100.8.
IR (KBr, cm-1) 3041, 2871, 2361, 1717, 1543, 1345, 1186, 827.
MS calcd m/z 200.1, found 201.0 [(M + 1)]+. Anal. Calcd for
C12H8O3: C, 72.00; H, 4.03. Found: C, 71.89; H, 3.96.
Acknowledgment. Financial support from the National
Natural Sciences Foundation of China (20272008 and 20602006)
is gratefully acknowledged.
Typical Procedure for the Synthesis of 5 (with 5a as an
example). To a solution of 2a (276 mg, 1.0 mmol) in DMF
(10 mL) was added POCl3 (0.46 mL, 5 mmol) at room temperature.
After being stirred at 60 °C for 6 h, the reaction mixture was
quenched with ice-water (80 mL) and extracted with CH2Cl2 (3
× 15 mL). The combined organic extracts were washed with water,
dried over anhydrous MgSO4, filtered, and concentrated. The residue
was purified by flash chromatography on silica gel (eluent,
petroleum ether:ethyl acetate ) 3:1, v/v) to give 5a (246 mg, 81%
yield) as a yellow solid.
Supporting Information Available: Experimental details,
spectral and analytical data for compounds 1, 2, 3, 4, 5, 7, and 8,
1
copies of H NMR and 13C NMR spectra of 1n, 2, 3, 4, 5, 7, and
8, and crystallographic data for 2a (CIF file). This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0702488
J. Org. Chem, Vol. 72, No. 12, 2007 4405