F. Doi et al. / Tetrahedron Letters 44 (2003) 4877–4880
4879
ing hydroxyl or alkyloxycarbonylamino groups.9 If
epimerization occurred, the optical purity of synthetic
1 would be decreased. However, over 92% ee was
observed by HPLC examination using the chiral
column.10 The absolute configuration of heliannuols
A and D carrying methyl substituents at the benzylic
position have been determined to have S-configura-
tion (Scheme 3).11,12 However, according to the
biosynthetic hypothesis of heliannuol C possessing a
similar vinyl group to 1,2 there might be no need to
have the same stereochemistry of its precursors
expected to control the oxidation potential to provide
the desired 8 in good yield.3 Anodic oxidation under
the conditions as described in Scheme 2, produced the
desired spiro compound 8 in 68% yield. A six-mem-
bered spiro derivative, cyclized with the tert-hydroxyl
group, was not observed. The Lewis acid-promoted
ring-expansion reaction of 8 afforded an inseparable
mixture of the chroman-type product 9. After
removal of the bromine substituent, the tert-hydroxyl
group and the phenol were protected as MOM ethers,
followed by solvolysis to give alcohols 10 and 11 as a
3:1 chromatographically separable mixture. Com-
pound 10 carrying the desired aromatic substitution,
was manipulated in three steps to produce a vinyl
group, which on acid-hydrolysis gave 1 and its epimer
12. Although the former product showed the same
spectroscopic data as those of the reported one, the
optical rotation of the synthetic sample ([h]D +79.7 (c
0.1, CHCl3)) exhibited an opposite sign to the natural
one ([h]D −68.6 (c 0.1, CHCl3)), although Shishido
mentioned that (−)-1 had the absolute structure as
depicted in Scheme 2.5 We carefully inspected the
synthetic process, and confirmed that the following
points would support our results. First of all, the
stereochemistry of the benzylic position, which was
enzymatically separated, was unambiguously confirm-
ed by X-ray single crystallographic analysis of the
phenylethylamide derivative 4. From our extensive
studies on phenolic oxidation, there was no serious
epimerization at the benzylic positions even if carry-
carrying methyl groups: heliannuol
C was pro-
duced by the ring contraction reaction with loss of
the stereochemistry of the benzylic carbon of the pre-
cursor. Therefore, we undertook synthesis of (−)-1
carrying R-configuration at the benzylic position, as
follows.
The lactone 5 was converted into the corresponding
thioacetal 13 (Scheme 4). Compound 13 was con-
verted into TBS ether 14, which on six-step manipula-
tion gave 15, an antipode of 6. After asymmetric
dihydroxylation and hydrogenolysis, the resultant
phenol was selectively brominated to give the sub-
strate 16 for electrolysis. Anodic oxidation under the
same conditions as in the case of 7 provided the spiro
derivative 17, which was treated with BF3·OEt2 to
give a mixture of the expected chromans 18 in good
yields. The conventional procedure enabled conver-
sion of 18 into the chromatographically separable
diols 19, 20 (9:2). Finally, 19 was subjected to intro-
duction of a vinyl group and deprotection to give
(−)-1 ([h]D −77.1 (c 0.1, CHCl3)) and 21. The spectro-
scopic data were superimposable with those of the
reported one.1
In conclusion, we have accomplished total synthesis
of heliannuol E 1 in both optically active forms, by
employing our novel ring-expansion reaction of the
spiro derivatives 8 and 17, produced by anodic oxida-
tion of the corresponding phenols. Comparison of
their optical rotations revealed that the natural (−)-
heliannuol E should have the absolute structure as
shown in Scheme 4.
Acknowledgements
This work was supported by Grant-in-Aid for the
21st Century COE program ‘KEIO Life Conjugate
Chemistry’ from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan, as well as
Keio Gijyuku Fund for the Advancement of Educa-
tion and Research. The authors are indebted to Dr.
M. Tsuchimoto and Mr. N. Kutsumura for the X-ray
crystallographic analysis.
Scheme 3. Natural heliannuols and biosynthetic hypothesis
of heliannuol C.