explored the outcome of furan photooxygenation sequences
wherein a substrate is used that bears a ꢀ-,6 γ- or δ-hydroxyl7
appended to the 2-alkyl substituent. In this new study, the
substrate bears two adjacent hydroxyls at both ꢀ- and
γ-positions of the 2-alkyl substituent (3, Scheme 1). An
intramolecular nucleophilic opening of a furan endoperoxide8
(4, Scheme 1) might be expected to afford the corresponding
[5,5] spirocyclic hydroperoxide 5, which should then be
possible to dehydrate yielding the desired γ-spiroketal-γ-
lactone 6 as the final result of the one-pot reaction sequence.
an equimolar mixture of the four possible diastereomeric
spiro-hydroperoxides 14 (Scheme 3). Treatment of the crude
Scheme 3
.
Photooxygenation of Furan 13 to γ-Spiroketal
γ-Lactones 15 and 16
The photooxygenation precursor 3 (Scheme 1) bearing the
requisite adjacent oxygen functionalities at the ꢀ and γ
positions of the alkyl side chain can be easily generated by
alkylation of furan with an allylic bromide and dihydroxy-
lation of the resultant double bond. The required double-
bond geometry for the alkylating agent can be found by
examining the relative stereochemistry at the C6 and C7
positions of the final products (i.e., trans-geometry in the
case of pyrenolide D but cis-geometry for crassalactone D).
Beginning with pyrenolide D (1) as the target, the synthesis
of the requisite photooxygenation precursor furan 13 is
described in Scheme 2. Thus, oxidation of 2-butyn-1-ol (7)
hydroperoxides 14 with acetic anhydride in pyridine11 gave
a chromatographically separable diastereomeric mixture of
γ-spiroketal γ-lactones (15/16 ) 2.7:1) in 56% yield over
the two steps. NOE experiments proved that the stereochem-
istry of the major diastereoisomer 15 is identical to that of
pyrenolide D, while the stereochemistry of the spiro center
(C4) of the minor diastereoisomer 16 is the opposite to that
of the natural product (see NOEs, Scheme 3). The formation
of amounts of the minor stereoisomer 16 did not present an
obstacle to the synthesis since the isomerization of 4-epi-
pyrenolide D to natural pyrenolide D under acidic conditions
(8 N aq HCl) is known.3b
Scheme 2. Synthesis of the Photooxygenation Precursor 13
With γ-spiroketal γ-lactone 15 in hand, we hoped to
complete the synthesis of 1 via epoxidation of the cis C8-C9
double bond followed by a 5-endo epoxide opening. m-
CPBA epoxidation afforded a separable mixture of 17 and
18 in a 3:1 ratio and in 80% total yield (Scheme 4). The
stereochemistry of the two epoxides remained uncertain at
this stage (NOE experiments are not useful because of
rotation of the epoxy side chain). An alternative epoxidation
of 15 using VO(acac)2 and t-BuOOH was also examined.
This resulted in the formation of a 2:1 mixture of the
expected epoxides 17 and 18, accompanied by a substantial
followed by in situ9 Wittig reaction with stabilized ylide 8
affords ester 9 accompanied by its easily separable cis isomer
(trans/cis ) 4:1). Reduction of ester 9 with LiAlH4, followed
by bromination of the resulting allylic alcohol using PBr3,
gave allylic bromide 10. Furyllithium alkylation with allylic
bromide 10 gave rise to the monosubstituted furan 11, which
then became the subject of a Sharpless dihydroxylation10 and
subsequent Lindlar hydrogenation to furnish the desired furan
13.
1
amount of a new product 19, whose H and 13C NMR data
are very similar, but not identical, to that of pyrenolide D.
At this stage, it was thought that the new product 19 might
be a diasteroisomer of pyrenolide D which came from 5-endo
opening of the stereochemically incorrect epoxide 18.
In order to verify this suspicion and before undertaking any
NOE studies on compound 19, the 5-endo opening of epoxides
(6) Tofi, M.; Koltsida, K.; Vassilikogiannakis, G. Org. Lett. 2009, 11,
313–316.
1
Furan 13 was then subjected to a standard set of O2
(7) (a) Feringa, B. L.; Butselaar, R. J. Tetrahedron Lett. 1982, 23, 1941–
1942. (b) Feringa, B. L.; Butselaar, R. J. Tetrahedron Lett. 1983, 24, 1193–
1196. (c) Georgiou, T.; Tofi, M.; Montagnon, T.; Vassilikogiannakis, G.
Org. Lett. 2006, 8, 1945–1948. (d) Tofi, M.; Montagnon, T.; Georgiou, T.;
Vassilikogiannakis, G. Org. Biomol. Chem. 2007, 5, 772–777.
photooxygenation conditions (methylene blue as photosen-
sitizer, oxygen bubbling through the reaction mixture, and
irradiation with visible spectrum light) for 2.5 min to afford
Org. Lett., Vol. 11, No. 20, 2009
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