Scheme 3a
Figure 2.
(OTf)3 (1.0 equiv)6 in CF3CH2OH at -10 to 0 °C afforded
a mixture of 18 and 19 (ratio 1.2:1). Because of less shielding
of the R-protons of â-keto esters 18 and 19 by the aromatic
group,19 the deprotonation occurred smoothly with KHMDS,
and the desired vinyl triflate (+)-9 was obtained in 33% yield
over two steps (61% yield based on the amount of 18 in the
mixture of 18 and 19). After the Pd-catalyzed carbonylation
and the oxidative cleavage reaction, compound (+)-9 was
converted to (-)-wilforonide ([R]D -26.6° (c 0.14, CH2Cl2)),
which showed the same sign of the specific optical rotation
as natural (-)-wilforonide ([R]D -26.8° (c 0.045, CH2Cl2)).20
HPLC analysis of the 2,4-DNP derivative 22 of synthetic
(-)-wilforonide revealed that its ee value was also greater
than 98%.
The assignments of stereochemistry for the cyclization
products 13/14 and 18/19 were made by comparison to
closely related systems in which the absolute stereochemistry
was proved by conversion to compounds of known absolute
configuration.6c As shown in Figure 3, in the cyclization of
a Reagents and conditions: (a) DMAP, toluene, reflux, 30 h,
97%; (b) Mn(OAc)3‚2H2O, Cu(OAc)2, Yb(OTf)3, CF3CH2OH, -10
to 0 °C, 10 h, 50% of 18 and 19 (ratio 1.2:1); (c) (i) KHMDS,
PhNTf2, THF; (ii) DIBAL-H, CH2Cl2, 33% of (+)-9, 20% of 10,
and recovered 82% of 20 in two steps; (d) LiCl, Et3N, Pd(PPh3)4,
CO (1 atm), CH3CN, 60 °C, 14 h, 94%; (e) NaIO4, OsO4, t-BuOH,
H2O, 85%; (f) 2,4-DNP, EtOH/H+, 60%.
14 were shielded by the phenyl group of the auxiliary17 and
the angular methyl group of the cyclic skeleton (Figure 2),
the deprotonation, followed by reduction with DIBAL,
resulted in a low chemical yield of the desired product (-)-9
(12% yield, 27% based on the amount of 13 in the mixture
of 13 and 14) along with a side product, 15. With the chiral
intermediate (-)-9 in hand, we accomplished the first
enantioselective synthesis of (+)-wilforonide ([R]D +25.1°
(c 0.18, CH2Cl2)) by following the same procedure shown
in Scheme 1. While the direct determination of the enan-
tiomeric purity of synthetic (+)-wilforonide failed, the HPLC
analysis of its 2,4-DNP derivative 2118 showed more than
98% ee.
Figure 3.
12, the 8-phenyl group of the chiral auxiliary can effectively
shield the (si)-face of the Mn(III)-enolate21 and restrict the
As shown in Scheme 3, cyclization of 17 with Mn(OAc)3
(2.1 equiv) and Cu(OAc)2 (0.5 equiv) in the presence of Yb-
(9) (a) Axelrod, E. H.; Milne, G. M.; van Tamelen, E. E. J. Am. Chem.
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Org. Lett., Vol. 3, No. 12, 2001
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