Typically, these products have been obtained by addition
of 3-furanyllithium to a suitably functionalized terpenoidic
molecule followed by photooxidation of the furan to the
hydroxybutenolide.5
(1 mmol) as well as on the gram scale (6.8 mmol). The
availability of 3 and 4, in fact, further enhanced the chemical
diversity potentially attainable, by allowing access to two
regioisomeric series of products.
The simple one-pot, singlet-oxygen photooxidation of
furans to γ-hydroxybutenolides, in the presence of rose-
bengale as the photosensitizer, is known to suffer from
relatively low yields and is limited by the sole access to
4-substituted butenolides. Faulkner and co-workers reported
good yields and regioselectivities submitting naturally oc-
curring 3-alkylfuran models to an improved process based
on exposing the endoperoxide intermediate to a base.7
However, when this oxidation protocol was applied in the
course of several total syntheses, the results were not so
satisfactory.8 Moreover, all these synthetic schemes invari-
ably required the use of experimental conditions, such as
the handling of 3-furanyllithium, which is hardly suitable
for combichem.
The serendipitous observation that by using DBU as base
only the 3-substituted vinyl bromide 4 was formed prompted
us to probe the matter of base-promoted regiocontrol, as this
result was in striking contrast to the literature reports in which
DIPEA was employed instead. In the beginning, a regiose-
lective photooxidation of 3-bromofuran appeared to us as a
quite challenging task, as the bromine atom is the only
element of regiodifferentiation.
In practice, however, it was shown that, in fact, a wise
selection of the base allowed effective regiocontrol, as
indicated by the entries of Table 1, even if a convincing
Table 1. Yields and Regioisomeric Ratios Observed in the
We envisaged that an alternative route to chemical
diversity around the butenolide scaffold might employ an
appropriate 3-bromofuran derivative for Pd-catalyzed cou-
pling reactions. Two alternative paths emerge from this
concept, differing for the sequence of the coupling and
oxidation maneuvers. The route in which the bromofuran 1
was first coupled to one building block and then photooxi-
dized was soon discarded due to the incompatibility of 1,
which is very prone to polymerization, to the coupling
conditions. Once ascertained that the oxidation of 1 followed
by Pd coupling was feasible, we worked on the optimization
of the photooxidation step, so as to be able to access both
3-bromo- (3) and 4-bromobutenolides (4) (Scheme 1). This
Base-Promoted Photooxidation of 3-Bromofuran
entry
base
yielda
time (h)
ratio (3/4)
1
2
3
4
5
6
(TMS)3N
ndb
ndb
64
82
70
6.0
5.3
5.0
4.5
5.3
4.3
-
-
67:33
50:50
80:20
0:100
2,6-di-tert-Bu-pyr
pempidine
DIPEA
phosphazene
DBU
78
a Calculated after C-18 reverse-phase HPLC purification. b A complex
mixture of oxidized products was observed.
explanation of how the observed regioisomeric ratios are
related to the nature of the base employed is not easy to
grasp.
However, two remarks can be made: (a) a complex
mixture of byproducts is observed in the absence of relatively
strong bases (entries 1 and 2); (b) strong and particularly
bulky bases, such as the phosphazene of Figure 2, lead to
Scheme 1. Base-Promoted Photooxidation of 3-Bromofuran
reaction gave satisfactory results on small substrate amounts
(5) (a) Katsumura, S.; Fujiwara, S.; Isoe, S. Tetrahedron Lett. 1985, 26,
5827. (b) Coombs, J.; Lattmann, E.; Hoffmann, H. M. R. Synthesis 1998,
1367. (c) Soriente, A.; De Rosa, M.; Apicella, A.; Scettri, A.; Sodano, G.
Tetrahedron: Asymmetry 1999, 10, 4481. (d) Cheung, A. K.; Murelli, R.;
Snapper, M. L. J. Org. Chem. 2004, 69, 5712.
(6) (a) Brohm, D.; Philippe, N.; Metzger, S.; Bhargava, A.; Mu¨ller, O.;
Lieb, F.; Waldmann, H. J. Am. Chem. Soc. 2002, 124, 13171. (b) Brohm,
D.; Metzger, S.; Bhargava, A.; Mu¨ller, O.; Lieb, F.; Waldmann, H. Angew.
Chem. 2002, 114, 319. (c) Brohm, D.; Metzger, S.; Bhargava, A.; Mu¨ller,
O.; Lieb, F.; Waldmann, H. Angew. Chem., Int. Ed. 2002, 41, 307.
(7) Kernan, M. R.; Faulkner, D. J. J. Org. Chem. 1988, 53, 2773.
Figure 2. Different bases tested in the photooxidation of 1.
the preferential formation of precursor 3. In fact, we observe
(8) (a) Sodano, G.; Paya`, M. et al. J. Med. Chem. 1998, 41, 3232. (b)
Koch, M. A.; Wittenberg, L.-O.; Basu, S.; Jeyaraj, D. A.; Gourzoulidou,
E.; Reinecke, K.; Odermatt, A.; Waldmann, H. PNAS 2004, 101, 16721.
(c) Cheung, A. K.; Snapper, L. M. J. Am. Chem. Soc. 2002, 124, 11584.
4832
Org. Lett., Vol. 8, No. 21, 2006