A facile solid-phase synthesis of substituted 2(5H)-furanones with sulfone traceless linker

Article abstract of DOI:10.1055/s-2004-834804

A novel solid-phase synthetic method for substituted 2(5H)-furanones with traceless sulfone linker strategy has been developed. The products were obtained in good yields and excellent purities.

Full text of DOI:10.1055/s-2004-834804

LETTER
2603
A Facile Solid-Phase Synthesis of Substituted 2(5H)-Furanones with Sulfone
Traceless Linker
Solid-Phase
S
y
h
nthesis of
S
o
u
5
H
)-Furanon
-
es Ri Sheng,* Pei-Gang Huang, Wei Zhou, Hai-Rong Luo, Shu-Ying Lin, Xiao-Ling Liu
Institutes of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, 330027, P. R. China
Fax +86(791)8517500; E-mail: shengsr@163.com
Received 28 August 2004
ation, (b) the sulfonyl anion alkylation with an epoxide,
c) the acylation of the resulting g-hydroxyl sulfone, (d)
the intramolecular acylation–cyclization of the a-sulfo-
nylcarbanion, and (e) traceless product release by b-elim-
ination reaction (Scheme 1).
Abstract: A novel solid-phase synthetic method for substituted
(5H)-furanones with traceless sulfone linker strategy has been de-
veloped. The products were obtained in good yields and excellent
purities.
(
2
Key words: solid-phase organic synthesis, traceless sulfone linker,
substituted 2(5H)-furanone
5
The phenylmethylsulfone resin 2, which was amenable to
FT-IR monitoring for the appearance of the sulfone
–1
stretch at 1313 and 1150 cm , was prepared in 95% yield
Solid-phase organic synthesis (SPOS) has attracted in- by treating a THF-swollen suspension of resin 1 (contain-
4
h
creasing interest in the last few years because of its appli- ing a loading of 1.0 mmol/g as determined by titration )
cation in the generation of combinatorial libraries of small with methyl iodide at 80 °C for 15 hours. This procedure
1
6
organic molecules. SPOS enjoys several advantages over is similar to that used for solution-phase synthesis. Sub-
solution-phase synthesis such as easy manipulation and sequent alkylation of resin 2 with epoxides according to a
purification of the organic products greatly simplified procedure from Kurth and co-workers4 provided g-hy-
through the use of polymer-bound reagents. Butenolides droxyl sulfone derivatives 3 in good yields (92–94%). The
are a class of compounds of current interest because of the g-phenylsulfonylalkyl methyl carbonates 4 were easily
potential broad range of biological activities of natural derived from resin 3 and methyl chloroformate in the
e
2
and unnatural butenolide-containing products. Several presence of pyridine at 0 °C in nearly quantitative yield,
solid-phase butenolide syntheses have been reported by as monitored by FT-IR for the appearance of new carbon-
3
–1
different groups. However, it is still desirable to develop yl stretches at 1748–1750 cm .
additional efficient solid-phase methodologies for the
The intramolecular acylation–cyclization of the a-sulfo-
nylcarbanion of resin 4 would be the key for the success
of this protocol. Here, the lactonization was investigated
starting with 4a (R = H, R = C H ). n-BuLi was the first
base employed in our trial at various temperatures to per-
form the cyclization.
synthesis of butenolides. To our knowledge, they have not
been prepared via SPOS using sulfone linker strategy. The
sulfone linker was shown to be a robust and versatile
1
2
6
5
4
traceless linker. In this paper we wish to report the exten-
sion of this sulfone-based chemistry to a convenient,
traceless solid-phase synthesis of substituted 2(5H)-fura-
none. The procedure for the synthesis of target
compounds from polystyrene/1% divinylbenzene
lithiophenylsulfinate (1) include (a) sulfinate S-alkyl-
When the lactonization on solid-phase was not complete
at –78 °C, 0 °C, and r.t. or even for longer time), as
monitored by FT-IR study, the spectrum is showing a
(
OH
a
b
c
SO2Li
PhSO2Me
PhSO2
R2
R1
1
2
3
O
CH3
R1
O
O
PhSO2
R1
d
e
R2
PhSO2
R1
O
O
R2
O
O
R2
4
5
6
Scheme 1 Reagents and conditions: (a) MeI, THF–DMF (2:1), 80 °C, 15 h; (b) (i) CH S(O)CH Li, THF, r.t., 0.5 h; (ii) epoxide, THF, r.t.,
3
2
2
h; (c) ClCO CH , pyridine, 0 °C, 1 h; (d) LDA, THF, –78 °C, 1 h, 0 °C, 2 h, then to r.t., 1 h; (e) Et N, CH Cl , r.t., 10 h.
2
3
3
2
2
SYNLETT 2004, No. 14, pp 2603–2605
2
2
.1
1
.2
0
0
4
Advanced online publication: 20.10.2004
DOI: 10.1055/s-2004-834804; Art ID: U24004ST
©
Georg Thieme Verlag Stuttgart · New York

2
604
S.-R. Sheng et al.
LETTER
–
1
relatively intense band at 1770 cm , which corresponds Table 1 Yields and Purities of Substituted 2(5H)-Furanones
to the lactonic carbonyl group and a weak carbonyl ab-
sorption at 1750 cm . However, the best result was ob-
1
2
Producta
–
1
Entry
(Epoxide) R , R
Yield
Purity
(%)c
b
(
%)
tained with LDA at –78 °C. FT-IR spectrum of resin 5a
–
1
showed a single strong carbonyl peak at 1770 cm and the
complete disappearance of the carbonyl absorption at
1
2
3
4
5
6
7
8
9
H, Ph
6a
6b
6c
6d
6e
6f
80
82
80
81
84
85
83
75
82
77
93
95
94
95
92
95
94
90
93
91
–
1
H, C
H, m-CH C H OCH
2
6 5 2
H OCH
1
750 cm .
Finally, a number of elimination conditions were evaluat-
ed, and optimal results were obtained by treating resin 5
in CH Cl with an excess of triethylamine at 25 °C for 10
3
6
4
H, C H CH OCH
2
6
5
2
2
2
hours. Conventional workup procedure provided 3-substi-
H, n-BuOCH
2
7
tuted 2(5H)-furanones (6a–i) in good yields (75–85%)
H, CH3
and high purities (90–95%) of the crude as shown in
Table 1.
H, EtOCH2
H, PhSCH2
6g
6h
6i
In order to further investigate the generality of this meth-
odology, the phenylsulfonylmethyllithium resin 2 was
treated with (R)-styrene oxide using the same procedure
as that for the racemic epoxides. The reaction proceeded
smoothly to give the expected products (5R)-5-phenyl-2
H, Pyrrolidylmethyl
-(CH ) -
1
0
6j
2
4
a
1
All final products were characterized by H NMR, IR, MS
(
5H)-furanones with retention of configuration (>99.0%
spectroscopy.
ee) in 81% yield and with purity of 94%. In a similar way,
the use of cyclohexene oxide or methylenecyclohexane
oxide gave 4,5-disubstituted 2(5H)-furanone (6j, Table 1,
entry 10) in 77% yield and 91% purity, 5,5-disubstituted
b
Overall yield based on the loading of the resin 1.
Purity determined by HPLC of crude cleavage product.
c
2
(5H)-furanone in 76% yield and with 90% purity, re-
References
spectively.
(
1) Recent reviews on SPOS: (a) Guillier, F.; Orain, D.;
An attempt to the application of a-alkylation to the poly-
styrene-supported a-phenylsulfonylbutyrolactones 5 fol-
lowed by elimination as above led to the 3,5-disubstituted
Bradley, M. Chem. Rev. 2000, 100, 2091. (b) Sammelson,
R. E.; Kurth, M. J. Chem. Rev. 2001, 101, 137. (c) Czarnik,
A. W. Solid-Phase Organic Synthesis, Vol. 1; Wiley: New
York, 2001. (d) Nicolaou, K. C.; Hanko, R.; Hartwig, H.
Handbook of Combinatorial Chemistry; Wiley-VCH:
Weinheim: Germany, 2002. (e) Dolle, R. E. J. Comb. Chem.
2002, 4, 369.
2
(5H)-furanone derivatives. 3-Methyl-5-phenyl-2(5H)-
furanone (7a) as a typical example obtained in 76% yield
based on the loading of the resin 1 and with 90% purity is
shown in Scheme 2.
(
2) (a) Brima, T. S. U.S. Patent 4,968,817, 1990; Chem. Abstr.
In summary, we have developed a novel method for the
solid-phase synthesis of substituted 2(5H)-furanones
using sulfone linker strategy. It is noteworthy that the
eliminative release feature of this approach results in a
significant enhancement of the purity of the compounds.
This methodology is applicable for the construction of
combinatorial libraries of substituted 2(5H)-furanones.
1
991, 114, 185246y. (b) Tanabe, A. Jpn. Kokai Tokyo
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3) (a) Fujita, K.; Watanabe, K.; Oishi, A.; Ikeda, Y.; Taguchi,
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Acknowledgment
We gratefully acknowledge financial support from the Natural
Science Foundation of Jiangxi Province (No.0420017).
2000, 2, 1419. (d) Ma, S.; Duan, D.; Wang, Y. J. Comb.
Chem. 2002, 4, 239. (e) Fujita, K.; Hashimoto, S.; Oishi, A.;
Taguchi, Y. Tetrahedron Lett. 2003, 44, 3793. (f) Huang,
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Me
O
CH3
1
) LDA/THF
SO2
SO2
O
0
°C, 30 min
Et3N, CH2Cl2
r.t. , 10 h
6 5
C H
O
O
2) CH3I, 1 h
O
C6H5
C6H5
O
5a
7a
Scheme 2
Synlett 2004, No. 14, 2603–2605 © Thieme Stuttgart · New York

LETTER
Solid-Phase Synthesis of Substituted 2(5H)-Furanones
2605
(4) (a) Chen, Y.; Lam, Y. L.; Lai, Y. H. Org. Lett. 2003, 5,
(7) General Procedure for the Solid-Phase Synthesis of
1
4
6
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Target Molecules (6): Under nitrogen n-BuLi (2.0 mmol,
1.65 M, 1.2 mL) was added to DMSO (4.0 mmol) in THF
(10 mL) at 0 °C and stirred for 5 min. The resulting dimsyl
anion solution was transferred to a suspension of polymer 2
(1.0 g, 1.0 mmol) in THF (8 mL) at r.t. After stirring for 30
min, epoxide (3.0 mmol) was added to this mixture and
stirred for 2 h, the color of the breads turned light orange.
The reaction was quenched with 10% HCl (aq) after 1 h and
the resin was filtered, washed and dried to afford resin 3 as
pale yellow beads. A solution of methyl chloroformate (2.0
mmol) in THF (2 mL) was added to a suspension of the
obtained resin 3 in THF (8 mL) at 0 °C, and followed with
pyridine (1.5 mmol, 0.2 mL). The mixture was stirred 0 °C
for 1 h and the g-phenylsulfonylalkyl methyl carbonate resin
4 was collected by filtration and washed successively with
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3% HCl (3 × 10 mL), H O (3 × 10 mL), THF (3 × 5 mL),
2
and dried in a vacuum. Subsequently, the resin 4 was
swollen in THF (10 mL) and treated with LDA (2.0 mmol)
at –78 °C for 1 h under dry nitrogen, at 0 °C for 2 h, and then
at r.t. for 1 h. The resin 5 was collected by filtration and
washed successively with THF–H O (1:1, 30 mL), H O
(
5) Preparation ofPolymer-SupportedPhenylmethylsulfone
2: Polystyrene/1% divinylbenzene lithium sulfinate (1, 1.0 g,
4
h
1.0 mmol), prepared according to literature, was swollen
2
2
under nitrogen in THF–DMF (2:1, 10 mL). MeI (5.0 mmol)
was added and the reaction mixture was shaken at 80 °C for
(3 × 10 mL), and THF (3 × 5 mL). After drying in a vacuum,
the resin 5 was swollen in CH Cl (10 mL) and treated with
2
2
15 h. After which, the reaction mixture was cooled to r.t.,
Et N (5.0 mmol) at r.t. for 10 h. The residual resin was
3
quenched with H O, and filtered. The resin was washed
collected by filtration and washed with CH Cl (2 × 3 mL).
2
2
2
successively with THF–H O (2:1, 3 × 10 mL), THF (2 × 5
The organic extracts were washed with H O, dried over
2
2
mL), CH Cl (2 × 5 mL) and Et O (2 × 5 mL), and then dried
anhyd MgSO and concentrated to afford crude product 6
2
2
2
4
under vacuum overnight to afford the pale yellow resin 2.
with 90–95% purity (determined by HPLC), which was
further purified by silica gel chromatographic column
(petroleum ether–EtOAc = 20:1) affording the pure products
FT-IR (single bead reflection): 1600, 1495, 1452, 1380,
–
1
1
313, 1150 cm .
1
(
6) Oxley, P.; Partridge, M. W.; Robson, T. D.; Short, W. F. J.
for H NMR and MS analysis.
Chem. Soc. 1946, 763.
Synlett 2004, No. 14, 2603–2605 © Thieme Stuttgart · New York