a strictly ortho-selective manner.1b,8 For example, we previ-
ously applied the SIBX-mediated HPD reaction to the
synthesis of natural o-quinol-derived [4 + 2] cyclodimers
[e.g., (()-biscarvacrol,1b,8a (()-grandifloracin,8a and (+)-
aquaticol8b] in one step from phenolic precusors. Herein, we
report the first application of this HPD reaction to the
synthesis of the natural nondimerizing o-quinol (+)-wasa-
bidienone B1 (2a), followed by its conversion into (-)-
wasabidienone B0 (14).
Our choice of performing this HPD reaction on a phenolic
substrate to access the title compounds may find some
biomimetic justification in view of investigations on the
biosynthetic origin of the C-6 oxygen atom in other o-quinol-
based natural products such as the humulones9a,b and
dimerizing sorbicillinoids.9c,d The synthesis began with the
multigram-scale preparation of the known symmetric phenol
410a in four steps in 52% overall yield from commercially
available 1,3,5-trimethoxybenzene (3) (Scheme 1, see the
Supporting Information). Installation of the butyryl side chain
was next envisioned through nucleophilic addition of a C-4
lithiated derivative of 4 on 2-methylbutanal (8). Unfortu-
nately, lithiation conditions applied to a O-silylated
derivative10b of 4 failed to generate the desired C-4 carban-
ion. We then relied on a standard halogen-metal exchange
protocol and prepared bromobenzenes 7a,b in high yields
from 4 via either bromination and silylation or benzylation
and bromination (Scheme 1). Coupling of these bromides
with commercially available aldehyde (()-8 or its (S)-
enantiomer, efficiently prepared by oxidation of commercial
(S)-2-methylbutan-1-ol,11 was achieved upon treatment with
tert-butyllithium in pentane at low temperature, which led
to 1.5:1 diastereomeric mixtures (unassigned) of benzylic
alcohols 9. Of particular note is that these coupling conditions
were nonepimerizing when using (S)-8. Debrominated ben-
zene byproducts were successfully recycled in the preparation
of 7a,b (see the Supporting Information).
Figure 1. Examples of natural nondimerizing o-quinols.
another by the nature of their C-5 substituent and the
positioning of their 2-methylbutanoyl side chain. In wasa-
bidienones A (1a),3a-d D (1b),3a and E (1c),3e this chiral
unit acylates the tertiary alcohol function of the o-quinol
moiety, while in wasabidienones B1 (2a)3a,4b and B2 (2b),3a,4a
aspersitin (2c),4c and phomaligin A (2d),4a it is connected
to the C-4 position of the cyclohexa-2,4-dienone core (Figure
1).
Efforts in the total synthesis of these naturally occurring
o-quinols have, to the best of our knowledge, only resulted
in that of wasabidienone A (1a)5a and in that of (+)-aspersitin
(2c).5b In both cases, installation of the 2-methylbutanoyl
moiety was achieved by Friedel-Crafts acylation using
racemic 2-methylbutanoic acid. Sato and co-workers next
developed an acyl rearrangement reaction from carbon to
oxygen for the synthesis of 1a, which was achieved in eight
steps in ca. 4% overall yield from 1,2,3,5-
tetrahydroxybenzene.5a In their six-step synthesis of (+)-2c
obtained in ca. 5% overall yield from dimethylphloroglucinol,
Bu¨chi and co-workers relied on a dearomatizing Wessely
oxidative acetoxylation (i.e., lead tetraacetate in acetic acid)
of a phenolic intermediate to install the required oxygen atom
at C-6.5b
Oxygenating phenol dearomatization methods indeed stand
out among the most straightforward tactics to access o-
quinols, as long as they can efficiently target the desired
o-carbon center. Besides the Wessely oxidation, several other
oxygenative dearomatizing reagents have been examined
over the last 50 years to generate these systems from
2-alkylphenols.1a,6 More recently, the λ5-iodane 2-iodoxy-
benzoic acid (IBX) and its stabilized nonexplosive version
(SIBX)7 were revealed as particularly appropriate reagents
to promote hydroxylative phenol dearomatization (HPD) in
Benzylic alcohols (()-9a and (S)-9a,b were next cleanly
oxidized in excellent yields into their corresponding ketones
(()-10a and (S)-10a,b. This oxidation was performed in a
9:1 (v/v) mixture of THF/DMSO at room temperature for
1.5 h using SIBX, which we previously also unveiled as a
(7) (a) Ozanne, A.; Pouyse´gu, L.; Depernet, D.; Franc¸ois, B.; Quideau,
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A1, U.S. 2002/0107416, PCT/FR02/00189.
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The (R)-8 enantiomer is not commercially available; it can be prepared but
in a yield of 24% over eight steps. Tachihara, T.; Ishizaki, S.; Kurobayashi,
Y.; Tamura, H.; Ikemoto, Y.; Onuma, A.; Yoshikawa, K.; Yanai, T.;
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Org. Lett., Vol. 10, No. 22, 2008