Communications
DOI: 10.1002/anie.200705816
Asymmetric Synthesis
Highly Diastereoselective Synthesis of Orthoquinone Monoketals
through l3-Iodane-Mediated Oxidative Dearomatization of Phenols**
Laurent PouysØgu, Stefan Chassaing, Delphine Dejugnac, Anne-Marie Lamidey,
Karinne Miqueu, Jean-Marc Sotiropoulos, and StØphane Quideau*
Orthoquinone monoketals A and orthoquinols B are cyclo-
hexa-2,4-dienone derivatives with valuable reactivity features
for the construction of complex molecular architectures.[1]
Their conjugated dienone unit and the vicinal positioning of
their oxygenated functionalities constitute a unique structural
arrangement that can be transformed rapidly into various
kinds of polyoxygenated (poly)cyclic systems (Scheme 1).[1]
synthesis has by no means been fully exploited. It still remains
to take advantage of their tetrahedral C6 center in asym-
metric synthesis. This development has not yet taken place as
a result of the lack of efficient methods available for
preparing chiral derivatives of A and/or B in nonracemic
form.[1c,3]
Access to these chiral entities would render possible the
enantioselective synthesis of many natural products (e.g.,
calicheamicinone,[2a] trichodimerol,[2b,c] aquaticol,[2d] and
scyphostatin[2e] via transformations I–IV, respectively,
Scheme 1), as stated by Pettus and co-workers,[1c] who
reported an enantioselective route to paraquinols through
diastereoselective phenol dearomatization.[4a] In related con-
current investigations, our initial efforts toward the prepara-
tion of orthoquinonoid derivatives relied on the dearomati-
zation of chiral aryl methyl ethers by anodic oxidation.[4b] This
approach did furnish orthoquinone monoketals of type A as
single enantiomers, but only in poor yields, for it required
monohydrolysis of bisketal intermediates and could not be
applied directly to phenolic substrates. Herein, we report a
convenient, high-yielding, and highly diastereoselective route
to new monoketals of type A through the dearomatization of
phenols mediated by hypervalent iodine.
Scheme 1. Selected synthetically useful transformations of orthoqui-
none monoketals A and orthoquinols B.
The starting phenols 1 contained a chiral ethanol unit
O-tethered to the ortho position of the phenolic ring
(Table 1). These constructs were thus designed to permit
their dearomatization into spiroketals of type A. A substitu-
ent was placed at the para position to prevent or at least
This chemical versatility has often been demonstrated over
the last fifty years, and these benzoquinonoid cyclohexa-
dienones have been used as key intermediates in several
syntheses of natural products.[1,2] However, their potential in
retard the self-dimerization of the dearomatized species
[5]
through [4+2]cycloaddition events.
The substrates were
prepared by a Williamson reaction between 5-substituted
2-benzyloxyphenols and enantiomerically enriched terminal
epoxides generated by using the Jacobsen method (see the
Supporting Information). After extensive screening of the
reaction conditions,[6] we found the use of the l3-iodane
(diacetoxyiodo)benzene (DIB, 1.0 equiv) in 2,2,2-trifluoro-
ethanol (CF3CH2OH, TFE) at ꢀ358C, followed by quenching
of the released acetic acid with powdered NaHCO3 at the
same temperature without addition of water, to be optimal in
furnishing the desired compounds.
All eight phenolic alcohols 1a–h were converted into the
desired spiroketals 2 and 3, which were isolated in a
quantitative combined yield with an excellent level of purity
through a simple filtration–evaporation procedure (Table 1).
Although the further purification of these products was not
necessary before their use in subsequent reactions, they were
separated by column chromatography for the characteriza-
tion of each diastereomer. Their stereochemistry was estab-
lished unambiguously by NOESY experiments (see the
[*] Dr. L. PouysØgu, Dr. S. Chassaing, Dr. D. Dejugnac, A.-M. Lamidey,
Prof. S. Quideau
UniversitØ de Bordeaux
Institut des Sciences MolØculaires (CNRS-UMR 5255) and
Institut EuropØen de Chimie et Biologie
2 rue Robert Escarpit, 33607 Pessac Cedex (France)
Fax: (+33)5-4000-2215
E-mail: s.quideau@iecb.u-bordeaux.fr
Dr. K. Miqueu, Dr. J.-M. Sotiropoulos
IPREM (CNRS-UMR 5254)
UniversitØ de Pau et des Pays de l’Adour
HØlioparc, 2 Avenue Pierre Angot, 64053 Pau Cedex 09 (France)
[**] We thank the Institut Universitaire de France, the CNRS (“Jeunes
Chercheurs” ATIP grant 2005-2007), and the Ministre de la
Recherche for financial support, and IDRIS for the use of
computational facilities.
Supporting information for this article, including experimental and
theoretical details, and characterization data for all new com-
te.org or from the author.
3552
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 3552 –3555