The furan approach to oxacycles. Part 5: Synthesis of a chiral butenolide, building block towards biologically interesting natural products

Article abstract of DOI:10.1016/j.tetlet.2005.06.124

We describe an efficient new approach for the synthesis of a chiral butenolide that is based on the oxidation of a chiral furan ring with singlet oxygen in the presence of Hünig's base, followed by Luche reduction and in situ lactonization.

Full text of DOI:10.1016/j.tetlet.2005.06.124

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5889–5892
The furan approach to oxacycles. Part 5: Synthesis of a chiral
butenolide, building block towards biologically interesting
natural products
*
´ ´ ´
Marta Teijeira, Pedro Lois Suarez, Generosa Gomez, Carmen Teran and Yagamare Fall
´ ´ ´
Departamento de Quımica Organica, Facultad de Quımica, Universidad de Vigo, 36200 Vigo, Spain
Received 24May 2005; revised 17 June 2005; accepted 22 June 2005
Available online 11 July 2005
Abstract—We describe an efficient new approach for the synthesis of a chiral butenolide that is based on the oxidation of a chiral
furan ring with singlet oxygen in the presence of Hunigꢀs base, followed by Luche reduction and in situ lactonization.
¨
ꢀ 2005 Elsevier Ltd. All rights reserved.
Butenolides and their corresponding saturated c-lac-
tones are found as structural subunits in a wide range
of natural products with biological activities.1 They
are often used as intermediates for the synthesis of bio-
logically and chemically significant natural products,2
some of them are depicted in Figure 1.
(Scheme 1). The reason for the non-formation of 8 could
be explained by the steric hindrance of the two bulky
protecting groups.
This setback steered us to look for an alternative to
compound 8. It was anticipated that the effect of the ste-
ric hindrance of the TBDPS groups would not prevent
the formation of 4-hydroxybutenolide 9. Indeed oxida-
tion of 7 with singlet oxygen in methanol in the presence
We recently described a new methodology for the syn-
thesis of oxacyclic compounds using either methoxyal-
lene3a,e or furan.3b–d In order to further enlarge the
scope of our methodology, we decided to use chiral fur-
an 7 as starting material. Much to our surprise, we could
not synthesize 4-methoxy butenolide 8 using the experi-
mental conditions previously developed by us3b–d
of diisopropylethylamine (Hunigꢀs base)4 cleanly affor-
¨
ded 4-hydroxybutenolide 9 (Scheme 1). Our initial aim
was to synthesize butenolide 8 and transform it into
the titled building block compound 14. As shown in
Scheme 2, 4-hydroxy butenolide 9 is even better than
O
O
O
O
OH
OH
OH
(-)-muricatacin
2
1
iso-cladospolide B
HO
OH
O
R
O
O
O
O
OH
O
4
5
(+) trans whisky lactone (R = Pr)
(+) trans cognac lactone ( R = Bu)
OH
6
vitamin C
3
eldanolide
Figure 1. Some natural products containing the butenolide and the c-lactone moiety.
Keywords: Butenolide; Singlet oxygen; Michael addition; Oxacycles; Natural products.
*
Corresponding author. Fax: +34986 81 22 62; e-mail: yagamare@uvigo.es
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.124

5890
M. Teijeira et al. / Tetrahedron Letters 46 (2005) 5889–5892
1) O2, hν, Rose Bengal, MeOH
OTBDPS
OTBDPS
O
X
O
OMe
2) Ac2O, pyr, rt
8
OTBDPS
OTBDPS
O
OTBDPS
OTBDPS
7
O2, hν, Rose Bengal
O
O
OH
MeOH, Hünig's base
9
H
OTBDPS
OTBDPS
O
N
O
O
10
Scheme 1.
OH
OAc
OH
OH
In.Cl3.3H2O, CH3CN
70%
K2CO3, MeOH
100%
OAc
OAc
O
O
12
11
O2, MeOH, hν, Rose Bengal
Hünig's base
ClTBDPS, DMF,Imid
93%
OTBDPS
OTBDPS
O
OH
O
88%
7
OH
13
O
4
1) NaBH4, CeCl3.7H2O, MeOH
O
OTBDPS
OTBDPS
OTBDPS
OTBDPS
O
14
O
OH
2) HCl, MeOH
98%
9
Lactonization
OTBDPS
OTBDPS
OTBDPS
O
Luche's reduction
O
HO
O
OTBDPS
15
HO
HO
16
Scheme 2.
4-methoxybutenolide 8 as synthon for compound 14.
Accordingly, 9 being in equilibrium with its open form
15 could be reduced with sodium borohydride under
Lucheꢀs conditions to give hydroxy acid 16 which under-
went acid catalyzed in situ lactonization, affording
butenolide 14 in excellent yield (98%).5 4-Hydroxy-
butenolide 9 can be synthesized as follows: commercially
available tri-O-acetyl-D-glucal (11)6 was deacetylated
with methanolic K2CO3, in quantitative yield, giving
D-glucal (12),7 which on reaction with indium chloride

M. Teijeira et al. / Tetrahedron Letters 46 (2005) 5889–5892
5891
H
O
O
NaHCO3
47%
HF.Pyr, CH3CN
40%
O
O
O
OH
O
O
OTBDPS
OTBDPS
H
18
OTBDPS
OTBDPS
17
14
1.2%
98%
Me2CuLi / TMSCl, Et2O
H
O
-20º C
O
OTBDPS
1.8%
O
H
H
1.9%
2.6%
2.4%
O
1.3%
18
NOE correlations for 18
O
OTBDPS
OTBDPS
H
H
3.5%
H
1.1%
19
O
O
OTBDPS
OTBDPS
H
1.5%
19
NOE correlations for 19
Scheme 3.
in acetonitrile afforded chiral furan diol 138 in 70% yield.
The hydroxy groups of the latter were protected as tert-
butyldiphenylsilylethers affording 7 in 93% yield. Furan
7 was oxidized with singlet oxygen in the presence of
NMR service of the CACTI, University of Vigo, for
NMR studies. M.T. thanks the Xunta de Galicia for a
Parga Pondal contract.
Hunigꢀs base giving the desired 4-hydroxybutenolide 9
¨
in 88% yield.
References and notes
1. (a) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod
1999, 62, 504–540; (b) Zafra-polo, M. C.; Figadere, B.;
Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochemistry
1998, 48, 1087–1117; (c) Koch, S. S. C.; Chamberlin, A. R.
Butenolide 14 was obtained enantiomerically pure but at
this stage the stereochemistry of C-4was unknown, so
we decided to establish the stereochemistry by carrying
out the following reaction sequence: the primary hydrox-
yl group of 14 was selectively deprotected and the
resulting alcohol 17 on reaction with NaHCO3 afforded
bicyclic lactone 189 through an intramolecular Michael
addition (Scheme 3). From the NOE correlations of 18
it could be deduced that the stereochemistry of C-4of
butenolide 14 was the one depicted in Scheme 2. Buteno-
lide 14 is a valuable building block for the synthesis of
biologically and chemically significant natural prod-
ucts.2,10 Reaction of 14 with dimethylcuprate11 afforded
1912 in excellent yield (Scheme 3). The stereochemistry
of 19 was established by NOE correlations. 19 is an ad-
vanced intermediate towards the synthesis of eldanolide
(3), whisky lactone (4) and cognac lactone (5) (Fig. 1).
In EnantiomericallyPure c-Butyrolactones in Natural
Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier
Science: Amsterdam, 1995, pp 687–725.
2. (a) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org.
Chem. 2004, 69, 1993–1998; (b) Ma, S. Acc. Chem. Res.
2003, 36, 701–712; (c) de March, P.; Figueredo, M.; Font,
J.; Raya, J.; Alvarez-Larena, A.; Piniella, J. F. J. Org.
Chem. 2003, 68, 2437–2447; (d) Kang, K. H.; Cha, M. Y.;
Pae, A. N.; Choi, K. I.; Cho, Y. S.; Koh, H. Y.; Chung, B.
Y. Tetrahedron Lett. 2000, 41, 8137–8140; (e) Ha, J. D.;
Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012–10020; (f)
Sinha, S. C.; Keinan, E. J. Org. Chem. 1999, 64, 7067–
7073; (g) Kabeya, M.; Hamada, Y.; Shioiri, T. Tetra-
hedron 1997, 53, 9769–9776; (h) Pearson, W. H.; Hembre,
E. J. J. Org. Chem. 1996, 61, 7217–7221.
´
´
3. (a) Fall, Y.; Gomez, G.; Fernandez, C. Tetrahedron Lett.
1999, 40, 8307–8308; (b) Fall, Y.; Vidal, B.; Alonso, D.;
In conclusion, we demonstrated that from tri-O-acetyl-
D-glucal (11) a commercially available chiral synthon,
we could efficiently synthesize chiral butenolide 14 in
excellent yield. The use of butenolide 14 as building
block for the synthesis of various natural products is
now under way in our laboratories.
´
Gomez, G. Tetrahedron Lett. 2003, 44, 4467–4469; (c)
´
Perez, M.; Canoa, P.; Gomez, G.; Teran, C.; Fall, Y.
Tetrahedron Lett. 2004, 45, 5207–5209; (d) Alonso, D.;
´
´
´
´
Perez, M.; Gomez, G.; Covelo, B.; Fall, Y. Tetrahedron
2005, 61, 2021–2026; (e) Perez, M.; Canoa, P.; Gomez, G.;
´
´
Teijeira, M.; Fall, Y. Synthesis 2005, 411–414.
4. Kernan, M. R.; Faulkner, D. J. J. Org. Chem. 1988, 53,
2773–2776.
5. Obtention of 14 from 9: To a solution of 4-hydroxy-
butenolide 9 (200 mg, 0.31 mmol) in MeOH (6 mL) were
added CeCl3Æ7H2O (6 mg) and NaBH4 (48 mg, 1.27 mmol)
at 0 ꢁC. After being stirred for 1 h, the reaction mixture
Acknowledgements
This work was supported by a grant from the Xunta de
Galicia (PGIDIT04BTF301031PR). We also thank the

5892
M. Teijeira et al. / Tetrahedron Letters 46 (2005) 5889–5892
was acidified by adding concd HCl (pH = 3) and extracted
3.78 (2H, m, 2 · H7), 2.65 (2H, m, 2 · H4), 1.07 (1H, s,
tBu); 13C NMR (CDCl3): d 175.00 (CO), 135.58 (CH–Ph),
132.68 (C–Ph), 130.22 (CH–Ph), 130.17 (CH–Ph), 128.01
(CH–Ph), 127.94(CH–Ph), 88.42 (C1), 77.17 (C5), 76.25
(C8), 74.13 (C7), 35.93 (C4), 26.81 (3CH3–tBu), 19.11
(C–tBu); HRMS (FAB+) calcd for C22H24O4Si [M+1]
383.1600. Found 583.1676.
with CH2Cl2. The organic phase was washed with H2O,
dried with Na2SO4 and concentrated under reduced
pressure giving a residue which was chromatographed on
silica gel using 20% EtOAc/hexane as eluent affording
0.19 g of butenolide 14 [98%; solid mp: 83–85 ꢁC;
25
½aŠ À2.18 (c 0.55, MeOH); Rf: 0.33 (20% EtOAc/hex-
D
1
ane)]. H NMR (CDCl3): d 7.28–7.55 (20H, m, –Ph), 6.97
(1H, dd, J = 5.72, 1.58 Hz, H4), 5.99 (1H, dd, J = 5.72,
2.08 Hz, H3), 5.26 (1H, m, H5), 3.89 (1H, m, H10), 3.80
10. For some chemistry related to the preparation of com-
pounds of type 14 using ADH or vinylogous aldol
reaction, see: (a) Wang, Z.-M.; Kolb, H. C.; Sharpless,
K. B. J. Org. Chem. 1994, 59, 5104–5105; (b) Casiraghi,
G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev.
2000, 100, 1929–1972; Evans, P.; Leffray, M. Tetrahedron
2003, 59, 7973–7981.
t
(1H, m, CH2), 3.63 (1H, m, CH2), 0.98 (9H, s, Bu) 0.95
t
(9H, s, Bu); 13C NMR (CDCl3): d 173.14(CO), 154.17
(C4), 135.93 (CH–Ph), 135.76 (CH–Ph), 135.49 (CH–Ph),
135.36 (CH–Ph), 133.10 (C–Ph), 133.06 (C–Ph), 132.78
(C–Ph), 132.67 (C–Ph), 130.02 (CH–Ph), 129.85 (CH–Ph),
129.78 (CH–Ph), 129.74(CH–Ph), 127.75 (CH–Ph),
127.72 (CH–Ph), 127.57 (CH–Ph), 122.37 (C3), 83.05
(C5), 72.62 (C10), 64.04 (C20), 26.82 (6CH3–tBu), 19.26
(C–tBu), 19.15 (C–tBu); HRMS (FAB+) calcd for
11. Mandville, G.; Ahmar, M.; Bloch, R. J. Org. Chem. 1996,
61, 1122–1124.
25
D
12. Compound 19: ½aŠ À30.71 (c 0.28, MeOH); 1H NMR
(CDCl3): d 7.24–7.54 (20H, m, –Ph), 4.31 (1H, m, H5),
3.78 (1H, m, H20), 3.72 (1H, m, H10), 3.60 (1H, m, H20),
2.65 (1H, dd, J = 17.33, 8.88 Hz, H3), 2.44 (1H, m, H4),
2.10 (1H, dd, J = 17.33, 8.10 Hz H3), 0.94(9H, s, tBu),
0.84(3H, d, J = 6.78, Hz, CH3); 13C NMR (CDCl3): d
176.79 (CO), 135.74(CH–Ph), 135.4(CH–Ph), 135.35
(CH–Ph), 133.27 (C–Ph), 133.11 (C–Ph), 132.86 (C–Ph),
129.88 (CH–Ph), 129.81 (CH–Ph), 129.67 (CH–Ph),
129.63 (CH–Ph), 127.80 (CH–Ph), 127.67 (CH–Ph),
127.64(CH–Ph), 127.58 (CH–Ph), 85.53 (C5), 72.54
(C10), 63.79 (C20), 37.03 (C3), 30.65 (C4), 26.88
(3CH3–tBu), 26.80 (3CH3–tBu), 19.38 (C–tBu), 19.13
(C–tBu), 18.07 (CH3).
t
C38H44O4Si2 [MÀ Bu] 564.2200. Found 563.2065.
6. Mori, Y.; Hayashi, H. J. Org. Chem. 2001, 66, 8666–
8668.
7. Although D-glucal is commercially available, tri-O-acetyl-
D-glucal is much cheaper and should be used for large
scale synthesis.
8. Sobhana Babu, B.; Balasubramanian, K. K. J. Org. Chem.
2000, 65, 4198–4199.
25
D
9. Compound 18: ½aŠ À40.65 (c 0.46, MeOH); 1H NMR
(CDCl3): d 7.62 (4H, m, Ho–Ph), 7.47–7.38 (6H, m, Hm,p
Ph), 4.90 (1H, m, H5), 4.76 (1H, m, H1), 4.49 (1H, m, H8),
–