Base-assisted regio- and diastereoselective conversion of functionalized furans to butenolides using singlet oxygen

Article abstract of DOI:10.1021/ol062551l

(Chemical Equation Presented) A facile synthesis of β-functionalized γ-hydroxybutenolides was achieved using a Baylis-Hillman reaction followed by singlet oxygen oxidation. The conversion from 3-furfural was regio- and diastereoselective.

Full text of DOI:10.1021/ol062551l

ORGANIC
LETTERS
2007
Vol. 9, No. 2
195-198
Base-Assisted Regio- and
Diastereoselective Conversion of
Functionalized Furans to Butenolides
Using Singlet Oxygen
Santoshkumar N. Patil and Fei Liu*
Department of Chemistry & Biomolecular Sciences, Macquarie UniVersity,
Sydney, NSW 2109, Australia
fliu@alchemist.chem.mq.edu.au
Received October 17, 2006
ABSTRACT
A facile synthesis of â-functionalized γ-hydroxybutenolides was achieved using a Baylis−Hillman reaction followed by singlet oxygen oxidation.
The conversion from 3-furfural was regio- and diastereoselective.
Butenolides are prevalent structural motifs in bioactive
natural products that have shown a wide range of activities
as antibiotic, antifungal, antifouling, and anticancer agents.1
General and efficient synthetic methods for accessing diverse
structures of this class of compounds as useful synthons
continue to be of interest.2 One attractive approach with
generality is to transform 2-oxyfurans that are already at the
oxidation level of butenolides. Recent examples3 include a
conversion from 2-siloxyfuran using an enantioselective
vinylogous Michael reaction,3a a diastereoselective synthesis
of γ-butenolides via a phosphine-catalyzed allylic alkylation,3b
an enantioselective synthesis of γ-butenolides using a Mu-
kaiyama-Michael reaction,3c a conversion of 2-methoxy-
furans to butenolides catalyzed by iodide anion,3d and a
synthesis of spirocyclic butenolides using 2-(trimethylsilyl-
oxy)furan as a dianion equivalent.3e
Another well-known strategy is to use furans as precursors
in mild photooxidation reactions that mimic the biogenic
process, although stereocontrol in this approach is more
difficult.4 In this paper, we report a base-assisted, regio- and
diastereoselective conversion of 3-hydroxyacrylate furans to
(3) (a) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. J. Am. Chem.
Soc. 2003, 125, 1192-1194. (b) Cho, C. W.; Krische, M. J. Angew. Chem.,
Int. Ed. 2004, 43, 6689-6691. (c) Barluenga, J.; Prado, A. D.; Santamaria,
J.; Tomas, M. Angew. Chem., Int. Ed. 2005, 44, 6583-6585. (d) Ma, S.;
Lu, L.; Lu, P. J. Org. Chem. 2005, 70, 1063-1065. (e) Maulide, N.; Marko,
I. E. Org. Lett. 2006, 8, 3705-3707.
(4) For initial work in photooxidative conversion of furans to γ-hy-
droxybutenolides, see: (a) Grimminger, W.; Kraus, W. Liebigs Ann. Chem.
1979, 10, 1571-1576. (b) Brownbridge, P.; Chan, T. H. Tetrahedron Lett.
1980, 21, 3431-3434. (c) Katsumura, S.; Hori, K.; Fugiwara, S.; Isoe, S.
Tetrahedron Lett. 1985, 26, 4625-4628. (d) Kernan, M. R.; Faulkner, D.
J. J. Org. Chem. 1988, 53, 2773-2776. For a very recent example of
regioselective synthesis of γ-hydroxybutenolides, see: (e) Aqunio, M.;
Riccio, B. R.; Gomez-Paloma, L. Org. Lett. 2006, 8, 4831-4834. For use
of other oxidants, see: (f) Clive, D. L. J.; Minaruzzaman; Ou, L. J. Org.
Chem. 2005, 70, 3318-3320 and refs 4a-h therein.
(1) For recent representative examples of cytotoxic, antibiotic, and
antifungal butenolides, see: (a) Wright, A. D.; Nys, R. D.; Angerhofer, C.
K.; Pezzuto, J. M.; Gurrath, M. J. Nat. Prod. 2006, 69, 1180-1187. (b)
Husain, A.; Khan, M. S. Y.; Hasan, S. M.; Alam, M. M. Eur. J. Med. Chem.
2005, 40, 1394-1404. (c) Mansoor, T. A.; Hong, J.; Lee, C. O.; Sim, C.
J.; Im, K. S.; Lee, D. S.; Jung, J. H. J. Nat. Prod. 2004, 67, 721-724. (d)
Braun, M.; Hohmann, A.; Rahematpura, J.; Buehne, C.; Grimme, S. Chem.
Eur. J. 2004, 10, 4584-4593. (e) Grossmann, G.; Poncioni, M.; Bornand,
M.; Jolivet, B.; Neuburger, M.; Sequin, U. Tetrahedron 2003, 59, 3237-
3251.
(2) For reviews of synthetic routes to butenolides, see: (a) Rao, Y. S.
Chem. ReV. 1976, 76, 625-694. (b) Knight, D. W. Contemp. Org. Synth.
1994, 1, 287-315. (c) Bru¨ckner, R. Curr. Org. Chem. 2001, 5, 679-718.
(d) Carter, N. B.; Nadany, A. E.; Sweeney, J. B. J. Chem. Soc., Perkin
Trans. 1 2002, 2324-2342.
10.1021/ol062551l CCC: $37.00
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â-substituted γ-hydroxybutenolides using singlet oxygen.
Many active natural products containing â-substituted γ-hy-
droxybutenolides, such as manoalide,5 tend to be epimerized
at the γ-carbon, although stereospecificity at this center is
occasionally observed such as in dysidiolide, the first known
natural product inhibitor of protein phosphatase cdc25A
(Figure 1).6 In our approach, the functionalities installed by
specifically access the â-substituted, rather than the R-sub-
stituted, γ-hydroxybutenolides was consistently observed
(Scheme 1). Base-assisted diastereoselective synthesis of
Scheme 1. Base-Assisted Singlet Oxygen Oxidation of
Furans4d
Figure 1. Examples of â-substituted γ-hydroxybutenolides con-
γ-hydroxybutenolides has not been previously reported. In
the case of dysidiolide, one diastereomer (as specified in
Figure 1) could be selectively obtained through crystalli-
zation.6a,b
taining natural products.
the Baylis-Hillman (BH) reaction between 3-furfural and a
range of acrylates are compatible with the singlet oxygen
oxidation conditions,7 which allows for an expedient and mild
synthesis of a variety of functionalized γ-hydroxybutenolides
with stereocontrol at the γ-carbon for the first time.
Although 3-hydroxyacrylate furans have not been used
prior to this study in singlet oxygen oxidation reactions for
synthesizing functionalized butenolides, it is well recognized
that 3-alkyl- or 3-hydroxyalkylfurans are useful synthons for
accessing butenolides with regioselectivity in a base-depend-
ent manner.4d This approach has been applied in a number
of total syntheses of bioactive γ-hydroxybutenolide natural
products such as cacospongionolides and cladocorans.8 The
use of Hu¨nig’s base as the key reagent for controlling the
regioselective opening of the endoperoxide intermediate to
We sought to examine the applicability of this singlet
oxygen oxidation reaction to 3-hydroxyacrylate furan skel-
etons generated from 3-furfural using the BH reaction. The
BH reaction is known as an effective method for preparing
highly functionalized molecules from simple synthons with
expediency.9 Typically, the 3′-hydroxy group, as seen in
manoalide and dysidiolide, can be produced using the
addition reaction between lithiated furans and aldehydes.5,6
The mild BH approach has not been previously used to install
the 3′-hydroxy group frequently observed in butenolide
natural products.
In our approach, 3-furfural (3) was treated with a series
of readily available acrylates (4a-g) to provide the tert-
butyldimethylsilyl (TBS)-protected 3-siloxyacrylate furan
skeletons (5a-g) in 30-40% overall yields in one pot or
over two steps (Scheme 2). It was hypothesized that a bulky
(5) First isolation and structural elucidation of manoalide: (a) De Silva,
D. E.; Scheuer, P. J. Tetrahedron Lett. 1980, 21, 1611-1614. First total
synthesis of manoalide: (b) Katsumura, S.; Fujiwara, S.; Isoe, S. Tetra-
hedron Lett. 1985, 26, 5827-5830.
Scheme 2. Synthesis of 3-Hydroxyacrylate Furans 5a-g
Using the Baylis-Hillman Reaction
(6) First isolation and structural elucidation of dysidiolide: (a) Gunasek-
era, S. P.; McCarthy, P. J.; Kelly-Borges, M.; Lobkovsky, E.; Clardy, J. J.
Am. Chem. Soc. 1996, 118, 8759-8760. First total synthesis of dysid-
iolide: (b) Corey, E. J.; Roberts, B. E. J. Am. Chem. Soc. 1997, 119, 12425-
12431. First enantiospecific total synthesis of dysidiolide: (c) Boukouvalas,
J.; Cheng, Y. X.; Robichaud, J. J. Org. Chem. 1998, 63, 228-229. For
recent efforts in synthesizing dysidiolide analogues, see: (d) Shimazawa,
R.; Suzuki, T.; Dodo, K.; Shirai, R. Bioorg. Med. Chem. Lett. 2004, 14,
3291-3294. (e) Koch, M. A.; Wittenberg, L.; Basu, S.; Jeyaraj, D. A.;
Gourzoulidou, E.; Reinecke, K.; Odermatt, A.; Waldmann, H. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 16721-6. (f) Brohm, D.; Metzger, S.;
Bhargava, A.; Muller, O.; Lieb, F.; Waldmann, H. Angew. Chem., Int. Ed.
2002, 41, 307-311. (g) Takahashi, M.; Dodo, K.; Sugimoto, Y.; Aoyagi,
Y.; Yamada, Y.; Hashimoto, Y.; Shirai, R. Bioorg. Med. Chem. Lett. 2000,
10, 2571-2574.
(7) For a summary of initial applications of singlet oxygen in the synthesis
of bioactive compounds, see (a) Wasserman, H. H.; Lipshutz, B. H. Singlet
Oxygen; Wasserman, H. H., Murray, R. W., Eds.; Academic Press: New
York, 1979; Chapter 9. For a recent summary of the use of singlet oxygen
in biomimetic syntheses, see: (b) Margaros, I.; Montagnon, T.; Tofi, M.;
Pavlakos, E.; Vassilikogiannakis, G. Tetrahedron 2006, 62, 5308-5317.
(8) (a) Cheung, A. K.; Sanpper, M. L. J. Am. Chem. Soc. 2002, 124,
11584-11585. (b) Demeke, D.; Forsyth, C. J. Org. Lett. 2003, 5, 991-
994. (c) Marcos, I. S.; Pedrero, A. B.; Sexmero, M. J.; Diez, D.; Basabe,
P.; Garcia, N.; Moro, R. F.; Broughton, H. B.; Mollinedo, F.; Urones, J. G.
J. Org. Chem. 2003, 68, 7496-7504. (d) Miyaoka, H.; Yamanishi, M.;
Mitome, H. Chem. Pharm. Bull. 2006, 54, 268-270.
substituent, such as a TBS group, could facilitate the
chemoselectivity of this transformation. Mechanistically, the
silyl protection was envisioned to proceed in one pot during
(9) For a recent reveiew of the Baylis-Hillman (BH) reaction, see:
Basavaiah, D.; Rao, A. J.; Satyanarayana T. Chem. ReV. 2003, 103, 811-
891. For a recent example of using BH adducts as butenolide precursors,
see ref 3b.
196
Org. Lett., Vol. 9, No. 2, 2007

the BH reaction after the formation of the alkoxide inter-
mediate from the addition step between the acrylate and the
furfural. In the cases of methyl, ethyl, butyl, and benzyl
acrylates, the silyl protection was successfully introduced
using the one-pot approach. In the other instances, the silyl
protection was required to be installed in a separate step.
The TBS-protected BH adduct of 3-furfural and methyl
acrylate, 5a, was used as the model compound to examine
the following singlet oxygen oxidation step in the presence
of Hu¨nig’s base (Scheme 3). Both nonpolar and polar protic
attributable to the apparent epimerization. When the crude
reaction mixture was purified on neutral silica gel, a single
diastereomer of 7a was obtained in 92% yield. The TBS-
protected BH adducts were then subjected to this Hu¨nig’s
base-assisted singlet oxygen oxidation reaction and returned
excellent yields of the butenolides with regio- and diaste-
reoselectivity under neutral conditions for base removal
(Table 1).
Conformational analysis combined with 2D NOESY
spectroscopy was performed to tentatively assign the relative
configurations of the observed diastereoselectivity (Support-
ing Information), as efforts to crystallize these highly flexible
butenolides were unsuccessful. The NOE results obtained
from the diastereomeric mixture of 7d were compared with
those of the selectively formed single diastereomer of 7d to
confirm that the NOEs are comparable. The distances
between H4-H6 and H2-H6 were calculated using the
observed NOE data as potentially distinguishing factors for
the two diastereomers (Figure 2). Conformational searches
Scheme 3. Regioselective Conversion of 5a to Butenolide 7a
by Singlet Oxygen Oxidation
solvents were investigated as they are known to affect the
efficiency of singlet oxygen oxidation due to their different
abilities in stabilizing singlet oxygen.7 Reactions in general
were complete in 1-3 h in high yields, with methanol
providing the fastest rate of reaction. The conversion was
completely regioselective in the presence of Hu¨nig’s base
as indicated by 1H NMR spectroscopy of the resulting
butenolide, which is consistent with the case reported for
3-alkylfurans.4d The regioselectivity was dependent on the
presence of the TBS group. When trimethylsilyl (TMS)
protection was used instead, the regioselectivity was dimin-
ished to 6:1 with loss of the TMS group during workup,
although the yield remained comparable at 91%.
Figure 2. Distances of H4-H6 and H2-H6 of the diastereomers
of 7d. The distances derived from the NOEs of the selectively
formed diastereomer are shown in bold.
were performed for both the (4S,6S) and (4R,6S) diastere-
omers using MacroModel10 to examine the average distances
of H4-H6 and H2-H6 from conformers within 2 kcal/mol
of the global minimum.
The NOE-based calculation indicated that, while the
distances of H2-H6 in the two diastereomers are similar,
the distance between H4 and H6 would be significantly
smaller in the preferentially formed diastereomer. The
conformational analysis reproduced this relative relationship
where the distance between H4 and H6 in the (4R,6S), or
syn, diastereomer, was found to be smaller than that in the
(4S,6S) diastereomer, while the H2-H6 average distances
in the two diastereomers were found to be similar. A syn, or
(4R,6S), assignment for the preferred diastereomer of 7d
would therefore be consistent with the observed NOE and
modeling results.
The TBS protecting group of 7d was removed using
tetrabutylammonium fluoride (TBAF) in THF in 2 h without
any sign of epimerization, and the deprotected butenolide
10d exhibited a similar NOE pattern for these two sets of
protons, indicating that the diastereoselectivity was main-
tained. This method was able to provide deprotected buteno-
Initially, the oxidation reaction of 5a to 7a would provide
the γ-hydroxybutenolide as a diastereomeric mixture under
standard conditions of workup and purification.) Given the
easily epimerizable γ-hydroxy carbon center, we used neutral
silica gel to examine if mildly acidic silica gel may be
Table 1. Diastereoselective Conversion of 5a-g to
Butenolides 7a-g
entry
furan
ester
product
yielda (%)
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
methyl
ethyl
butyl
benzyl
cinnamyl
allyl
2-chloroethyl
7a
7b
7c
7d
7e
7f
92
90
91
86
86
96
76
5g
7g
(10) Mohamadi, F.; Richard, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton,
M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem.
1990, 11, 440.
a Isolated yields.
Org. Lett., Vol. 9, No. 2, 2007
197

lides 10a-g as a single diastereomer in each case in 24-
60% yields (Supporting Information).
Further investigation confirmed that this diastereoselec-
tivity was base-dependent (Scheme 4). Upon treatment with
selective, depending on the bulkiness of the counterion of
the carboxylate of the butenolide, and this selectivity was
maintained under neutral conditions for base removal. This
is consistent with the observation that the deprotecting step
using TBAF, which also provides a bulky counterion, does
not result in loss of diastereoselectivity. The presence of
Hu¨nig’s base was essential in recovering the diastereoselec-
tivity as triethylamine, a less bulky base, was not able to
return the single diastereomer after acidic epimerization and
base removal under neutral conditions. A proposed transition
state leading to this selectivity is shown in Scheme 4. The
selectivity could be due to the bulkiness of the base in
selecting the less hindered Re face of the intermediate for
stabilizing the carboxylate.
Scheme 4. Base-Dependent Recovery of Diastereoselectivity
in the Formation of 7d and a Proposed Transition State Leading
to the Observed Diastereoselectivity
In conclusion, this work illustrates for the first time the
utility of using the mild Baylis-Hillman reaction to prepare
3-hydroxyacrylate furans as precursors for facile and di-
astereoselective access of â-substituted, γ-hydroxybutenolide
moieties frequently observed in bioactive natural products.
The role of a bulky base in conferring the diastereoselectivity
is revealed, allowing for these densely functionalized buteno-
lides to be considered as useful synthons for further
transformations. Investigations on the scope of this base-
assisted approach with BH adducts from other activated
alkenes are underway and will be reported in due course.
Acknowledgment. This work is supported by an Aus-
tralian Research Council Discovery Project Grant to F.L.
(ARC-DP055068). S.N.P. is supported by a predoctoral
research fellowship from Macquarie University. We thank
Peter Karuso of Macquarie University for helpful discussions
and technical assistance in securing the 2D NOESY spectra.
acidic CDCl3 (stored without molecular sieves), the selec-
tively formed diastereomer of 7d rapidly epimerized to two
diastereomers as expected. Surprisingly, when this diaster-
eomeric mixture of 7d was treated with Hu¨nig’s base
followed by purification using neutral silica gel, the diaster-
eomeric mixture reverted back to the previous single di-
astereomer. NMR spectroscopy indicated that in the presence
of Hu¨nig’s base, the deprotonated γ-hydroxybutenolide
would be in the “ring-open” form (11d). The closing of the
butenolide ring upon removal of this base was diastereo-
Supporting Information Available: Experimental pro-
cedures and spectra of key transformations, characterization
data for compounds 5-11, details of the conformational
analysis, and 2D NOESY spectra of compounds 7d and 10d.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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Org. Lett., Vol. 9, No. 2, 2007