A novel synthesis of γ-lactones by tandem epoxide opening-cyclization reaction mediated by samarium(II) diiodide

Article abstract of DOI:10.1016/j.tetlet.2008.01.027

Various epoxy esters readily reacted with SmI₂ (2 equiv) in the presence of ethyl bromoacetate (1 equiv) and HMPA (6 equiv) under mild conditions (THF, -78 °C, 2 h, Ar) providing the corresponding γ-lactones via tandem epoxide opening-cyclizati

Full text of DOI:10.1016/j.tetlet.2008.01.027

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1616–1618
A novel synthesis of c-lactones by tandem epoxide
opening-cyclization reaction mediated by samarium(II) diiodide
Heui Sul Park a, Doo Won Kwon a, Kieseung Lee b, Yong Hae Kim a,*
a Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea
b Department of Chemistry, Woosuk University, Chonbuk 565-701, Republic of Korea
Received 17 December 2007; revised 7 January 2008; accepted 8 January 2008
Available online 11 January 2008
Abstract
Various epoxy esters readily reacted with SmI2 (2 equiv) in the presence of ethyl bromoacetate (1 equiv) and HMPA (6 equiv) under
mild conditions (THF, À78 °C, 2 h, Ar) providing the corresponding c-lactones via tandem epoxide opening-cyclization reaction in good
to excellent yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Samarium diiodide; c-Lactone; c-Butyrolactone; Tandem reaction
c-Lactones have attracted much attention in organic and
medicinal chemistry due to the extensive occurrence in
numerous biologically active natural products,1 and also
versatile utility as synthetic intermediates in the synthesis
of a wide range of bioactive compounds.2 Therefore, a num-
ber of new synthetic route for c-lactones have been reported
in recent years,3 for example, Ni-catalyzed reductive cyana-
tion of alkynols,3a selective reaction of aldehydes/ketones
with carbene-catalyzed conjugate umpolung of a,b-unsatu-
rated aldehydes,3b reaction of alkyl phenyl selenides with
p-toluenesulfonic acid,3c Pd-catalyzed cyclization of unsat-
urated malonates,3d Pd-catalyzed carbonylative cyclization
of b-bromovinyl aldehydes,3e and diastereoselective osmyl-
ation of unsaturated syn-aldol adduct with OsO4/NMO.3f
We have recently reported an efficient synthesis of 1,3-
dioxolane derivatives from acrylic acid esters bearing an
oxiranylmethoxy substituent at b-position utilizing samar-
ium(II) diiodide4 under mild reaction conditions.5a This
initial result together with the great importance of c-lact-
ones in organic and medicinal chemistry prompted us to
devise a new synthetic route to c-lactones based on our
samarium diiodide chemistry.5 We herein wish to report
an efficient synthesis of c-lactone derivatives from epoxy
esters (ethyl/methyl a-oxiranylmethylacetate derivatives)
via tandem epoxide opening-iodocyclization reaction using
SmI2 as a key reagent under mild conditions (Table 1).
Initial tandem reaction was studied by using appropriate
epoxy malonates 2a–e,6 and optimum reaction conditions
involved the addition of SmI2 (2 equiv) in THF to a solu-
tion of substrate 2, ethyl bromoacetate (1 equiv) and
HMPA (6 equiv) in dry THF at À78 °C and stirring the
resulting solution at À78 °C for ca. 2 h under Ar. After
usual work-up, c-lactones 3a–e were obtained in 80–85%
yields as a mixture (1:1) of diastereomers (runs 1–5).7 These
optimized reaction conditions were successfully extended
to a simple epoxy ester 2f affording c-lactone 3f in 90%
yield (run 6).
To determine the scope of this new tandem reaction, a
diverse set of functionalized epoxy esters (2h–l) were also
tested with SmI2 under the same reaction conditions (Table
2).
This attempted tandem reaction of 2h–j is important
from the synthetic point of view since it enables rapid
access to the cis-fused bicyclic c-lactones (3h–j), which
*
Corresponding author. Tel.: +82 42 869 2818; fax: +82 42 869 2810.
E-mail address: kimyh@kaist.ac.kr (Y. H. Kim).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.027

H. S. Park et al. / Tetrahedron Letters 49 (2008) 1616–1618
1617
Table 1
Table 2
Tandem epoxide opening-cyclization of epoxy esters 2 to various c-
lactones 3 mediated by SmI2
Tandem epoxide opening-cyclization of epoxy esters 2 to cis-fused bicyclic
and spiro c-lactones 3 mediated by SmI2
a
a
Run
Substrate
Product
Yieldb,c
(%)
Run Substrate
Product
Yieldb,c (%)
O
O
O
O
H
H
O
O
O
O
O
O
EtO
OEt
O
3h
1
2
3
4
5
2hd
85e,f
EtO
H
O
2a
2b
H
1
85d
EtO
OEt
O
3a
3b
H
EtO
O
O
I
I
I
O
O
O
O
H
H
Et
H
Et
OEt
O
2i
3i
81f,g
84f,g
91
EtO
OEt
O
EtO
2
3
82d
H
H
I
O
Me
Me
O
O
O
O
O
O
EtO
2c
OEt
OEt
3c
2j
O
EtO
O
3j
80d
H
O
H
H
I
I
O
Me
O
Me
O
Me
Me
O
O
O
O
4
5
82d
83d
90
OMe
3k
2d
2e
EtO
Et
OEt
O
2k
2l
3d
3e
EtO
Et
O
O
O
O
O
O
I
I
I
I
O
O
EtO
O
O
O
MeO
MeO
O
OEt
O
3l
EtO
91
Ph
MeO
Ph
O
O
a
O
O
Reagents and conditions: 2, BrCH2CO2Et (1 equiv), SmI2 (2 equiv),
HMPA (6 equiv), À78 °C, 2 h, Ar.
OEt
O
b
O
6
2f
Isolated yields after flash column chromatography.
3f
c
Structures were determined by NMR and mass spectra.
I
d
Used as a mixture (10:1) of diastereomers by 1H NMR.
Me
Me
e
Isolated as a mixture (10:1) of diastereomers by 1H NMR.
a
Reagents and conditions: 2, BrCH2CO2Et (1 equiv), SmI2 (2 equiv),
HMPA (6 equiv), À78 °C, 2 h, Ar.
f
Stereochemistry was confirmed by NOE experiment.
13C NMR indicated that a single diastereomer was formed.
g
b
Isolated yields after flash column chromatography.
Structures were determined by NMR and mass spectra.
Isolated as a mixture (1:1) of diastereomers by 1H NMR.
c
d
The synthesis of a-methylene-c-lactone derivatives has
been of great interest due to their biological activities and
occurrence in numerous natural products.10 Scheme 1
demonstrates an additional benefit of our protocol in the
synthesis of a-methylene-c-lactone derivatives. The SmI2-
mediated tandem reaction of a-phosphoryl epoxy ester
2m gave a-phosphoryl-c-lactone 3m in good yield, which
in turn reacted readily with benzaldehyde providing
a-methylene-c-lactone 4 in a concise manner.
The plausible reaction mechanism including stereochem-
ical outcome could be rationalized as shown in Figure 1
using 2j as a starting material.
The reaction appears to be initiated by the formation
of samariumiodide complex A. Nucleophilic addition of
are known to be valuable intermediates for natural product
synthesis.8 Substrate 2h (a mixture (10:1) of diastereomers
1
by H NMR) afforded a mixture (10:1) of 3h as a major
diastereomer (run 1), while substrates 2i,j gave the corres-
ponding c-lactones 3i,j as a single diastereomer (runs
2 and 3). The assigned structure and stereochemistry of
3h–j were fully supported by NMR, mass spectra together
with NOE experiments. The spiro c-lactone fragment has
proven to be an important subunit in several classes of bio-
active compounds.9 As indicated by runs 4 and 5 in Table
2, substrates 2k,l were transformed cleanly into spiro c-lact-
ones 3k,l in excellent yields.

1618
H. S. Park et al. / Tetrahedron Letters 49 (2008) 1616–1618
O
O
O
O
same cond.
as before
O
NaH/PhCHO
86%
(EtO)2P
(EtO)2P
OEt
O
Ph
O
O
72%
I
I
4
2m
3m
Scheme 1. Attempted synthesis of a-methylene-c-lactone 4.
2. (a) Harchen, C.; Bruckner, R. Angew. Chem., Int. Ed. 1997, 36, 2750;
(b) Drioli, S.; Felluga, F.; Forzato, C.; Nitti, P.; Pitacco, G.; Valentin,
E. J. Org. Chem. 1998, 63, 2385; (c) de March, P.; Figueredo, M.;
Font, J.; Raya, J. Org. Lett. 2000, 2, 163; (d) He, M.; Lei, A.; Zhang,
X. Tetrahedron Lett. 2005, 46, 1823; (e) Delhaye, L.; Merschaert, A.;
Diker, K.; Houpis, I. N. Synthesis 2006, 1437.
3. (a) Gutierrez, J. L. G.; Jimenez-Cruz, F.; Espinosa, N. R. Tetrahedron
Lett. 2005, 46, 803; (b) Burstein, C.; Tschan, S.; Xie, X.; Glorius, F.
Synthesis 2006, 2418; (c) Tiecco, M.; Testaferri, L.; Temperini, A.;
Terlizzi, R.; Bagnoli, L.; Marini, F.; Santi, C. Synlett 2006, 587; (d)
Vitale, M.; Prestat, G.; Lopes, D.; Madec, D.; Poli, G. Synlett 2006,
2231; (e) Cho, C. S.; Shim, H. S. Tetrahedron Lett. 2006, 47, 3835; (f)
Dias, L. C.; de Castro, I. B. D.; Steil, L. J.; Augusto, T. Tetrahedron
Lett. 2006, 47, 213. Other important references cited therein.
4. (a) Namy, J.-L.; Girard, P.; Kagan, H. B. Nouv. J. Chim. 1977, 1, 5;
(b) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980,
102, 2693.
EtO
I
O
O
OSmI2
O
SmI2 (2eq)
2j
Sm
L
L
H
Br
EtO
EtO
O
I
A (SmI2L)
H
H
I
I
O
O
Sm
L
Sm
H
O
H
NH4Cl (aq)
H
O
O
H
H
H
H
H
H
I
I
I
3j
C
B
Fig. 1. Plausible reaction mechanism for c-lactone 3j.
5. (a) Kwon, D. W.; Cho, M. S.; Kim, Y. H. Synlett 2003, 959; (b)
Chung, S. H.; Cho, M. S.; Choi, J. Y.; Kwon, D. W.; Kim, Y. H.
Synlett 2001, 1266; (c) Jung, D. Y.; Kim, Y. H. Synlett 2005, 3019.
6. Epoxy esters 2a–e were prepared in two steps via allylation of
malonates followed by epoxidation with m-CPBA.
IÀ derived from iodosamarium complex A to epoxide 2j,
would deliver an iodohydrin intermediate B which, upon
hydrolysis, afford 3j in complete regio- and diastereoselec-
tive way.
In conclusion, a novel method for generating c-lactones
from epoxy esters using SmI2 as a key reagent has been
developed. Considering several advantages, for example,
easy preparation of starting materials, mild reaction condi-
tions together with good to excellent yields, and further-
more flexibility of this new tandem reaction providing
diverse sets of c-lactones from simple c-lactones to cis-
fused bycyclic/spiro and a-methylene-c-lactones, this new
synthetic route should be a method of choice in the synthe-
sis of various c-lactone derivatives.
7. Typical synthetic procedure for c-lactones: To a precooled (À78 °C)
solution of 2a (0.50 mmol), ethyl bromoacetate (1 equiv) and HMPA
(6 equiv) in dry THF (2 mL) was added SmI2 (2 equiv, 0.1 M solution
in THF), and the resulting mixture was stirred at À78 °C for 2 h under
Ar. The reaction was quenched by aqueous NH4Cl solution, and the
organic layer was separated. The aqueous layer was extracted with
Et2O (10 mL Â 3), and the combined organic layers were washed with
brine, dried over MgSO4, filtered and concentrated. The residue was
purified by flash column chromatography on SiO2 using (EtOAc/
hexane, 1/3) as an eluent affording pure 3a. 1H NMR (CDCl3,
400 MHz) d 1.22–1.32 (m, 3H), 2.19–2.46 (m, 1H), 2.67–2.80 (m, 1H),
3.26–3.71 (m, 3H), 4.19–4.28 (m, 2H), 4.54–4.69 (m, 1H); 13C NMR
(CDCl3, 100 MHz) d 5.7, 7.6, 14.5, 32.7, 47.5, 47.9, 62.8, 62.9, 77.9,
78.1, 167.8, 171.3; HRMS(EI) calcd for C8H11IO4: 297.9702; found:
297.9713.
Acknowledgment
8. (a) Shiu, L.-H.; Li, Y.-L.; Lao, C.-Y.; Chen, W.-C.; Yu, C.-H.; Liu,
R.-S. J. Org. Chem. 1999, 64, 7552; (b) Velazquez, F.; Olivo, H. F.
Org. Lett. 2000, 2, 1931; (c) Bergner, E. J.; Helmchen, G. J. Org.
Chem. 2000, 65, 5072; (d) Zanoni, G.; Porta, A.; Meriggi, A.;
Franzini, M.; Vidari, G. J. Org. Chem. 2002, 67, 6064; (e) Ginn, J.;
Padwa, A. Org. Lett. 2002, 4, 1515.
This work was supported by Center for Molecular
Design and Synthesis of Korea Science and Engineering
foundation.
9. (a) Trost, B. M.; Balkove, J. M.; Mao, M. K.-T. J. Am. Chem. Soc.
1983, 105, 6755; (b) Peterson, E. M.; Xu, K.; Holland, K. D.; Mckeon,
A. C.; Rothman, S. M.; Ferrendelli, J. A.; Covey, D. F. J. Med. Chem.
1994, 37, 275; (c) Silva, L. F. J. Synthesis 2001, 671; (d) Vyvyan, J. R.;
Rubens, C. A.; Halfen, J. A. Tetrahedron Lett. 2002, 43, 221.
10. (a) Kupchan, S. M.; Fessler, D. C.; Eakin, M. A.; Giacobbe, T. J.
Science 1970, 168, 376; (b) Iio, H.; Isobe, M.; Kawai, T.; Goto, T. J.
Am. Chem. Soc. 1979, 101, 6067; (c) Bartel, S.; Bohlmann, F.
Tetrahedron Lett. 1989, 30, 685; (d) Gonzalez, A. G.; Hernandez, S.;
Margarita, P.; Juan, I.; Leon, F.; Reyes, E.; Alvarez-Mon, M.; Pivel, J.
P.; Quintana, J.; Estevez, F.; Bermejo, J. J. Med. Chem. 2002, 45, 2358.
References and notes
1. (a) Koch, S. S. C.; Chamberlin, A. R. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1995; Vol.
16, pp 687–725; (b) Rao, Y. S. Chem. Rev. 1976, 76, 625; (c)
Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24,
94; (d) Mulzer, J.; Salimi, N.; Hartl, H. Tetrahedron: Asymmetry
1993, 4, 457; (e) Schmitz, W. D.; Messerschmidt, N. B.; Romo, D. J.
Org. Chem. 1998, 63, 2058; (f) Maier, M. S.; Marimon, D. I. G.;
Stortz, C. A.; Adler, M. J. J. Nat. Prod. 1999, 62, 1565.