First asymmetric synthesis of orthoquinone monoketal enantiomers via anodic oxidation

Article abstract of DOI:10.1021/ol048030k

(Chemical equation presented) An asymmetric synthesis of orthoquinone monoketals was accomplished using anodic oxidation to convert aryl methyl ethers bearing a chiral ethanol unit into orthoquinone bisketals, followed by monohydrolysis of their dimethyl ketal unit. All four possible stereoisomers were generated in a diastereoselective manner by varying the attachment point of the chiral pro-ketal alcoholic auxiliary to the starting arene. A preliminary screening of subsequent nucleophilic addition reactions confirmed the potential utility of these synthons in asymmetric synthesis.

Full text of DOI:10.1021/ol048030k

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4571-4573
First Asymmetric Synthesis of
Orthoquinone Monoketal Enantiomers
via Anodic Oxidation
Ste´phane Quideau,* Isabelle Fabre, and Denis Deffieux
Institut Europe´en de Chimie et Biologie, 2 rue Robert Escarpit,
33607 Pessac Cedex, France, and Centre de Recherche en Chimie Mole´culaire,
Laboratoire de Chimie des Substances Ve´ge´tales, UniVersite´ Bordeaux 1,
351 cours de la Libe´ration, 33405 Talence Cedex, France
s.quideau@iecb.u-bordeaux.fr
Received September 27, 2004
ABSTRACT
An asymmetric synthesis of orthoquinone monoketals was accomplished using anodic oxidation to convert aryl methyl ethers bearing a chiral
ethanol unit into orthoquinone bisketals, followed by monohydrolysis of their dimethyl ketal unit. All four possible stereoisomers were generated
in a diastereoselective manner by varying the attachment point of the chiral pro-ketal alcoholic auxiliary to the starting arene. A preliminary
screening of subsequent nucleophilic addition reactions confirmed the potential utility of these synthons in asymmetric synthesis.
Orthoquinone monoketals, 6,6-dialkoxycyclohexa-2,4-di-
enone derivatives (e.g., A), are synthetically useful species,
for their dienone unit and adjacent oxygen functions, which
are displayed on a six-membered ring system, render them
ideally suited for a large variety of chemical transformations,
including 1,2- and 1,4-additions, as well as a variety of
cycloadditions (Scheme 1). Several such utilizations have
been elegantly implemented in the total synthesis of complex
natural products.1
stereocontrol over the C-6 ketal center concerning subsequent
diastereoselective transformations. While the first two prob-
lems have found satisfactory solutions in the use of ap-
propriate substitution patterns and reaction conditions,1b,4 no
Scheme 1. Selection of Synthecially Useful Chemical
Transformations of Orthoquinone Monoketals A into
Functionalized Six-Membered Ring Systems I-IV
However, the lack of control over the chemistry of these
systems has hindered the general use of orthoquinone
monoketals as synthons in organic chemistry. Three draw-
backs to their preparation include (1) their overwhelming
tendency toward [4 + 2] dimerization,2 (2) rearomatization
under acidic and reductive conditions,1b,3 and (3) the lack of
(1) For recent reviews on synthetic applications of orthoquinone mono-
ketals, see: (a) Quideau, S. In Modern Arene Chemistry; Astruc, D., Ed.;
Wiley-VCH: Weinheim, 2002; pp 539-573. (b) Magdziak, D.; Meek, S.
J.; Pettus, T. R. R. Chem. ReV. 2004, 104, 1383-1429.
(2) Liao, C.-C.; Chu, C.-S.; Lee, T.-H.; Rao, P. D.; Ko, S.; Song, L.-D.;
Shia, H.-C. J. Org. Chem. 1999, 64, 4102-4110.
10.1021/ol048030k CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/28/2004

Scheme 2. Diastereoselective Anodic spiro-Cyclization of
Chiral Primary and Secondary Alcoholic Phenyl Alkyl
Ethers 3 and 4 into the Four Possible Orthoquinone
Bisketal Enantiomers 5
Scheme 3. Proposed Transition State Models for the
Rationalization of the Diastereoselectivity Observed in the
Anodic spiro-Cyclization of Chiral Primary and Secondary
Alcoholic Phenyl Alkyl Ethers 3 and 4 into Orthoquinone
Bisketal Enantiomers 5
asymmetric preparation of orthoquinone monoketals has been
described in the benzoid series.5 As Pettus recently wrote,1b
the development of such methods is a worthy goal in organic
chemistry considering the potential of these entities for
enantioselective synthesis. Herein we report for the first time
a promising and environmentally benign approach to this
challenge.
Our interest in the oxidative dearomatization of 2-alkoxy-
phenols into such cyclohexa-2,4-dienone derivatives led us
to envisage asymmetric versions of the reactions we are
investigating.6 We found inspiration in the work done on
cyclohexa-2,5-dienones equipped with chiral cyclic ketal
moieties.7,8 These compounds are usually generated via mild
acid-mediated transketalization reactions by heating together
paraquinone dimethyl monoketals and enantiopure diols.7
These conditions are not suitable for the targeted cyclohexa-
2,4-dienones, which are sensitive to both acids and heat. In
this study, we instead relied on anodic oxidation to generate
orthoquinone bisketals from phenyl methyl ethers bearing a
chiral ethanol unit O-tethered to the phenyl ring next to the
methyl ether group (Scheme 2). The two enantiomers of both
phenyl methyl ethers 3 and 4 were generated by a William-
son-type reaction between 5-bromoguaiacol (1) and (S)-2-
chloro-1-phenylethanol (2) or its enantiomer (R)-2 (see
Supporting Information for details on these preparations).
The chirality of their ethanol unit was thus anticipated to
induce asymmetry at the aromatic carbon center undergoing
the sp2 f sp3 geometry change during anodic spiro-
cyclization (Schemes 2 and 3). The 5-bromo substituent on
guaiacol is needed to hinder dimerization of the product
(Scheme 4).4a All four enantiopure alcohols were then
individually electrolyzed, under the conditions developed by
Dolson and Swenton,9 to furnish the desired bisketals 5
(Scheme 2).
This anodic spiro-cyclization afforded the bisketals in only
low yields when starting from the secondary alcohols (R)-
and (S)-4, whereas the less encumbered primary alcohols (R)-
and (S)-3 were both converted into the desired products in
ca. 30% yield. Off course, these isolated yields still deserve
to be further optimized to expand the preparative value of
this methodology, but the fact that, in each of the four cases,
a different stereoisomer was isolated as the sole spiro-ketal
product shows the remarkable potential of this unprecedented
anodic oxidation approach to chiral orthoquinone ketals. The
configuration at the newly generated spiro-centers was
determined via two-dimensional NOE spectroscopy (Scheme
2). Thus, (R)-3 led to the bisketal (RS)-5 as indicated by the
observation of two NOE correlations between each of the
two spiro-ketal protons H1′ and H3′ and the aromatic proton
H5. A similar couple of correlations were observed for (SR)-5
that was generated from the primary alcohol (S)-3. In the
case of the other enantiomeric pair of bisketals (RR)- and
(3) Quideau, S.; Looney, M. A.; Pouyse´gu, L.; Ham, S.; Birney, D. M.
Tetrahedron Lett. 1999, 40, 615-618.
(4) (a) Lai, C.-H.; Shen, Y.-L.; Wang, M.-N.; Rao, K.; Liao, C.-C. J.
Org. Chem. 2002, 67, 6493-6502. (b) Andersson, G. Acta Chem. Scand.
1976, B 30, 403-406.
(5) For an example of chiral naphthoid orthoquinone monoketals, see:
(a) Fujioka, H.; Annoura, H.; Murano, K.; Kita, Y.; Tamura, Y. Chem.
Pharm. Bull. 1989, 37, 2047-2052.
(6) (a) Deffieux, D.; Fabre, I.; Courseille, C.; Quideau, S. J. Org. Chem
2002, 67, 4458-4465. (b) Pouyse´gu, L.; Avellan, A.-V.; Quideau, S. J.
Org. Chem. 2002, 67, 3425-3436.
(7) (a) Corey, E. J.; Wu, L. I. J. Am. Chem. Soc. 1993, 115, 9327-
9328. (b) de March, P. ; Escoda, M.; Figueredo, M.; Font, J.; Alvarez-
Larena, A.; Piniella, J. F. J. Org. Chem. 1995, 60, 3895-3897. (c) Hu, Y.;
Li, C.; Kulkarni, B. A.; Strobel, G.; Lobkovsky, E.; Torczynski, R. M.;
Porco, J. A., Jr. Org. Lett. 2001, 3, 1649-1652. For another approach, see:
(d) Wipf, P.; Jung, J.-K. Angew. Chem., Int. Ed. 1997, 37, 7764-767.
(8) For a related example of an enantioselective access to paraquinols,
see: Mejorado, L. H.; Hoarau, C.; Pettus, T. R. R. Org. Lett. 2004, 6, 1535-
1538.
(9) Dolson, M. G.; Swenton, J. S. J. Org. Chem. 1981, 46, 177-179.
Org. Lett., Vol. 6, No. 24, 2004
4572

alkoxide onto the R-face of the cationic center should be
preferred, as depicted in the pro-(SS) envelope B4-TS derived
from (S)-4. The alternative pro-(SR) B5- and B6-TSs both
suffer from interactions involving the methoxy group of the
benzoid radical cation unit (Scheme 3). Overall, this simple
analysis does provide an adequate model to rationalize the
diastereoselectivity observed in these spiro-cyclizations.
All four bisketals 5 were then individually treated with a
1:3 H2O-TFA mixture in Et2O at 0 °C. Under these
conditions, selective hydrolysis of their dimethylketal unit
furnished the four orthoquinone spiro-monoketals 6 in
reasonable yields (Scheme 4). As expected, the 4-bromine
substituent does retard their dimerization long enough to
conveniently carry out further transformations. The capability
of their chirality to induce asymmetry in subsequent reactions
was then briefly examined using (RS)-6 (Scheme 4). Treat-
ment with LAH/LiBr5 at -78 °C furnished the cyclohexa-
2,4-dienols 7 in only 30% de and the use of the bulkier
hydride reagent L-selectride led to a 1,4-reduction into the
ketone 8 in 33% yield. However, an excellent induction of
asymmetry was obtained using PhMgBr at -78 °C to furnish
the tertiary alcohol 9 in 88% yield and 90% de. Addition of
allylMgCl proceeded in a 1,4-fashion with concomitant
rearomatization and opening of the spiro-ketal unit to furnish
a 1:1 mixture of the two phenols 10a/b. However, the
KHMDS-mediated 1,4-addition of dimethylmalonate at -50
°C in THF gave the ketones 11 in 34% yield and 31% de.
This excess is only moderate but nevertheless remarkable,
since it resulted from a 1,4-asymmetry induction from the
spiro-center. The fact that ketones are here obtained in
contrast to the case of the allyl addition is probably due to
a rapid quench of the initial enolate adduct from the
remaining malonate acidic R-proton.
Scheme 4. Selective Monohydrolysis of Bisketals 5 into
Enantiopure Orthoquinone Monoketals 6 and Evaluation of the
Capability of (RS)-6 to Induce Asymmetry in Subsequent
Reactions
(SS)-5 that were respectively generated from the secondary
alcohols (R)- and (S)-4, only one spiro-ketal proton should
point toward the side of the molecule bearing the aromatic
proton H5. This was indeed verified in their NOESY spectra
(Scheme 2 and Supporting Information). Thus, all four
possible bisketal stereoisomers are independently accessible
thanks to the apparent diastereospecificity of this anodic
spiro-ketalization reaction.
A rationalization of this stereochemical control can be
made on the basis of the transition state models proposed in
Scheme 3. Assuming that the reaction performed in 1%
KOH/MeOH follows a classical ECEC mechanistic se-
quence,10 spiro-ketalization (B f C) is very likely the first
chemical (C) event. Our transition state (TS) models are
hence derived from the radical cation alkoxide intermediate
B. No major torsional or steric impediment appears in the
intramolecular pro-(RS/SR) attack of the primary alkoxide
onto the â-face of the cationic center as depicted in the pro-
(RS) envelope B1-TS derived from (R)-3, whereas the
corresponding pro-(RR) attack suffers from a bad interaction
between the phenyl group and the benzoid radical cation unit
in the B2-TS. This interaction can be released by positioning
the phenyl-bearing out-of-plane carbon of the envelope on
the other side of this plane, but the resulting pseudo-boat
B3-TS would then display a van der Waals interaction
between the benzylic hydrogen atom and the methoxy group.
An analogous examination of the secondary alcohol spiro-
cyclization shows that, this time, a pro-(SS/RR) attack of the
In conclusion, the work described therein constitutes the
first example of an asymmetric preparation of orthoquinone
monoketals in the benzoid series and shows that intramo-
lecular additions to electrochemically generated arene radical
cations have the capacity to undergo in situ diastereoselective
reactions. By simply varying the attachment point of the
chiral pro-ketal auxiliary to the starting arene, all four
possible monoketal diastereomers are accessible. A prelimi-
nary screening of their synthetic applications did confirm
their potential utility in asymmetric nucleophilic 1,2- and
1,4-addition reactions.
Acknowledgment. We thank the French Ministry of
Research for Isabelle Fabre’s research assistantship and Jean-
Marie Schmitter and Katell Bathany for performing APCI
and MALDI-ToF mass spectrometric analyses.
Supporting Information Available: Detailed experi-
1
mental procedures and H and 13C NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(10) Belleau, B.; Weinberg, N. L. J. Am. Chem. Soc. 1963, 85, 2525-
2526.
OL048030K
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4573