DielsÀAlder cycloaddition reaction of 3,5-dibromo-2-pyr-
one with a styrene type dienophile as a key reaction. We
have further envisioned that the same synthetic strategy
could also be effective for pancratistatin, as it differs only
with the C(1)ÀOH function. Reported herein is the suc-
cessful extension of our 2-pyrone strategy for the synthesis
of (()-pancratistatin, which yet required substantial ex-
perimentations in spite of the structural similarity.
Scheme 2. Elimination Reaction of Mesylate 11
Scheme 1. Retrosynthesis of Pancratistatin
Consequently, a new syntheticroute was elaborated, this
time, to go through β-hydroxy silane 10, making use of its
facile elimination process (vide supra, Scheme 1). The
required (E)-β-silyl styrene 5a was prepared from alkyne
6
4 by following the route shown in Scheme 3. Conversion
1
into TMS-alkyne 15 followed by a hydroalumination
reaction provided β-silyl styrene 5 as a mixture of E- and
Z-isomers. As demonstrated in the literature, the stereo-
7
chemical outcome of the hydroalumination is highly sol-
vent-dependent. In toluene, the reaction afforded exclu-
sively Z-isomer 5b in 67% yield. The reaction in pentane
gave the best results, with respect to the E/Z ratio (5:1) and
product yield (78% total yield). Despite the presence of
the Z-isomer (∼17%), the ensuing cycloaddition with 3,
Notable features of our synthetic plan include (1) in-
stallation of the key C(1)ÀOH group via epoxidation and
the hydrolysis reaction of cyclohexene 9 (9 f 8, Scheme 1)
and (2) the use of (E)-β-silyl styrene 5a as a dienophile
partner in the cycloaddition with 3,5-dibromo-2-pyrone 6.
The resultant β-hydroxy silane 10 would be readily elimi-
nated to afford alkene 9.
5
-dibromo-2-pyrone gave 5-endo-6-exo-trans-bicyclolac-
tone 16a only, with no trace of either 5-endo-6-endo-cis-
or 5-exo-6-exo-cis-bicyclolactone. Therefore, the stereo-
chemistry of β-silyl styrene was inconsequential in this
case. Apparently, the cycloaddition reaction proceeded in
8
a stepwise rather than concerted manner. The exclusive
formation of 5-endo-6-exo-trans-bicyclolactone 16a from
the cycloaddition with pure (Z)-β-silyl styrene 5b further
corroborates its stepwise nature. In addition, (Z)-β-silyl
styrene 5b used in excess (1.3 equiv) in the cycloaddition
was found to be isomerized into (E)-isomer 5a. Therefore,
the cycloaddition reaction with (Z)-isomer 5b would go
through zwitterionic intermediate 17a, for example, as a
result of a 1,6-addition type reaction. Rotation about the
CÀC bond gives more stable, less sterically crowded 18a,
resulting in the formation of bicyclolactone 16a. Retro-1,
6-addition of 18a would account for the generation
of (E)-β-silyl styrene 5a in the reaction mixture. The
Initially we planned to make cyclohexene 9 from mesy-
late 11 readily accessed from the corresponding alcohol
intermediate employed in our synthesis of trans-
5
e
dihydronarciclasine. However, all the attempts to bring
about the elimination reaction into 6 were not successful
(
Scheme 2). Epoxide 13 was obtained instead as a major
product in most cases, presumably via the process invol-
ving deprotonation, elimination, and epoxide formation.
(
(
3) Danishefsky, S.; Lee, J. Y. J. Am. Chem. Soc. 1989, 111, 4829.
4) (a) Tian, X.; Hudlicky, T.; Konigsberger, K. J. Am. Chem. Soc.
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(
niently from bromide 19 via the Suzuki coupling reac-
E)-β-silyl styrene 5a was later prepared more conve-
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9
tion with trifluoroborate 20.
(
5) (a) Chang, J. H.; Kang, H.-U.; Jung, I.-H.; Cho, C.-G. Org. Lett.
(6) Direct synthesis of 15 from aryl bromide 19 via the Sonogashira
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(7) (a) Sheshenev, A.; Baird, M. S.; Bolesov, I. G.; Shshkov, A. S.
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2
1
010, 12, 2016. (b) Tam, N. T.; Jung, E.-J.; Cho, C.-G. Org. Lett. 2010,
2, 2012. (c) Tam, N. T.; Cho, C.-G. Org. Lett. 2008, 10, 601. (d) Tam,
N. T.; Chang, J.; Jung, E.-J.; Cho, C.-G. J. Org. Chem. 2008, 73, 6258. (e)
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303. (f) Tam, N. T.; Cho, C.-G. Org. Lett. 2007, 9, 3319. (g) Kim, H.-Y.;
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2
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Org. Lett., Vol. 13, No. 21, 2011
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