be more amendable to analogue synthesis by introducing a
vinyl halide (9) as a functional handle, and second, a 3-
halogenated 2(2H)-pyranone would be more reactive in a
Diels-Alder reaction. The successful use of 3- (and 5)-
halogenated 2(2H)-pyranones has previously been demon-
strated12 and is a key feature in the Stolz synthesis toward
this compound class.10a
The 3-vinyl carboxyl moiety of intermediate 10 is the
obvious product of an Ireland-Claisen rearrangement. The
involvement of an Ireland-Claisen rearrangement would also
nicely explain the observed stereochemical relationships in
the transtaganolides (i.e., between 2 and 3).
Synthetic asymmetric Ireland-Claisen rearrangements of
geranyl esters have been shown to proceed with high
enantioselectivity but with only modest diastereoselectivity.13
Also, the carboxyl group would be prone to enolization due
to the additional electron-withdrawing properties of the
2-pyranone ring, hopefully excluding the need for the use a
strong base to generate the required enolate for the rear-
rangement. Mild conditions for this type of reaction would
also be in line with a possible biosynthetic route, even though
the involvement of naturally occurring Ireland-Claisen
rearrangements have not been described.
The required Ireland-Claisen precursor, the geranylated
pyranone 11, could be obtained from the corresponding acid
12 which in turn is the possible oxidation product of a
primary alcohol. 6-Substituted 5-iodo-pyran-2-ones are readily
available through iodine catalyzed electrophilic cyclizations
from alkenynes such as 13.14
Figure 1. Structures of thapsigargin, transtaganolides C and D,
basiliolides B and C, and proposed biosynthetic precursors of the
transtaganolides and basiliolides.
2-one 7 from T. transtagana, which is proposed to be a
precursor of the transtaganolides.9
The unique structures of the transtaganolides, as well as
their biological activities, has attracted strong interest from
synthetic chemists, and several groups have recently and
independently reported progress toward the synthesis of
members of this class of natural products via intramolecular
Diels-Alder reactions.10 These reports prompt us to present
our own progress toward the synthesis of transtaganolides
C and D. Our previous interest in the area of naturally
occurring pericyclic reactions11 made us focus on a biomi-
metic route toward the target compound that could also
explain the observed stereochemistry of the basiliolides (i.e.,
the diastereomeric relationship between optically pure tran-
staganolides C and D, 2 and 3, that differ only in the
stereochemistry on C-8).
The likely instability of the oxepine ring prompted us to
design a route that allowed the construction of this ring at
the final stages of the proposed synthesis (Scheme 1).
Selective O-acylation of the methyl ester 8 would yield this
unique structural feature. Disconnecting the C-C bond of
the methyl ester group in 8 at this stage was deemed
favorable for two reasons; first, a successful synthesis would
The synthesis (Scheme 2) starts with a Sonogashira
coupling of (Z)-methyl iodoacrylate 1415 with but-3-yn-1-
ol to provide the cyclization precursor 13. Treatment of 13
with ICl in CH2Cl2 gave a smooth cyclization to the desired
2-pyranone 15 as a solid.13 The furanone product arising from
a competing 5-exo cyclization was not detected. Treatment
of alcohol 15 with H5IO6 in the presence of a catalytic
amount of PCC provided the acid 12 in good yield.16 The
crude acid was directly coupled with geraniol to give the
key geranylated intermediate 11. With iodo compound 11
in hand, we turned our attention to the key Ireland-Claisen/
Diels-Alder sequence.
Reasoning that the electron-poor 2-pyranone ring would
further increase the acidity of the protons on the methylene
position circumventing the need for the use of a strong
base such as LDA to form the enolate, we looked for al-
ternative procedures. Inspired by a report on the decarboxy-
lative Ireland-Claisen reaction of sulfone esters,17 we tried
heating 11 in toluene in a microwave reactor in the presence
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