Diastereoselective dearomatization of resorcinols directed by a lactic acid tether: Unprecedented enantioselective access to p-quinols

Article abstract of DOI:10.1021/ol0498592

An operationally simple oxidative dearomatization of resorcinol derivatives is reported that employs an inexpensive chiral directing group. The method provides access to a variety of p-quinol derivatives in good yield and diastereoselectivity. A short red

Full text of DOI:10.1021/ol0498592

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1535-1538
Diastereoselective Dearomatization of
Resorcinols Directed by a Lactic Acid
Tether: Unprecedented Enantioselective
Access to p-Quinols
Lupe H. Mejorado, Christophe Hoarau, and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106-9150
pettus@chem.ucsb.edu
Received January 24, 2004
ABSTRACT
An operationally simple oxidative dearomatization of resorcinol derivatives is reported that employs an inexpensive chiral directing group.
The method provides access to a variety of p-quinol derivatives in good yield and diastereoselectivity. A short reductive process affords
4-hydroxy-4-alkylcyclohexenone derivatives in excellent yields and enantiomeric excesses.
Four types of chiral cyclohexadienones have proven ex-
tremely useful in natural product synthesis (see Figure 1,
A-D).1 Despite their usefulness, there are relatively few
ways to prepare or use A-D in an enantioselective format.
Fujioka and co-workers prepared and examined the reactivity
of a chiral ketal derived from the masked o-benzoquinone
A and observed it to undergo diastereoselective reductions.2
o-Quinol building blocks of the general structure B have been
examined by a number of groups. Methods for their
preparation include the oxidatively triggered ipso cyclization
of an oxime reported by Hoshino3 and the bacterial oxidations
of phenols described separately by Myers4 and Breitmaier.5
With regard to masked p-benzoquinones C, Corey,6 Wipf,7
(1) Magdziak, D.; Meek, S.; Pettus, T. R. R. Chem. ReV. 2004, 104,
Figure 1. Some useful chiral cyclohexadienones.
1383-1429.
(2) Fujioka, H.; Annoura, H.; Murano, K.; Kita, Y.; Tamura, Y. Chem
Pharm Bull. 1989, 37, 2047-2052.
and Porco8 have independently investigated epoxidations of
chiral ketal derivatives. Taylor, on the other hand, has
(3) Murakata, M.; Yamada, K.; Hoshino, O. J. Chem. Soc., Chem.
Commun. 1994, 443-444.
(4) Myers, A. G.; Siegel, D. R.; Buzzard, D. J.; Charest, M. G. Org.
Lett. 2001, 3, 2923-2926.
(5) Kneifel, H.; Poszich-Buscher, C.; Rittich, S.; Breitmaier, E. Angew.
Chem., Int. Ed. Engl. 1991, 30, 202-203.
(7) Wipf, P.; Kim, Y.; Jahn, H. Synthesis 1995, 1549-1561.
(8) Hu, Y.; Li, C.; Kulkarni, B. A.; Strobel, G.; Lobkovsky, E.;
Torczynski, R. M.; Porco, J. A., Jr. Org. Lett. 2001, 3, 1649-1652.
(6) Corey, E. J.; Wu, L. I. J. Am. Chem. Soc. 1993, 115, 9327-9328.
10.1021/ol0498592 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/16/2004

championed the asymmetric Julia-Colonna epoxidation of
these systems,9 while Feringa has studied asymmetric 1,4-
additions of diethylzinc.10 Other asymmetric strategies
developed by de March,11 Winterfeldt,12 Carreno,13 Wipf,14
and Corey15 utilize enantioselective desymmetrization of
various prochiral MPB ketals with an asymmetric Diels-
Alder cycloaddition followed by subsequent diastereoselec-
tive reactions and a retro-cycloaddition. With regard to
p-quinol systems such as D, a similar masking strategy has
been employed. Winterfeldt demonstrated that these systems
engage in diastereoselective [4 + 2] cycloadditions with an
unusual chiral diene,16 while Feringa has reported that
symmetric derivatives of D undergo asymmetric 1,4-additions
with diethylzinc in the presence of a chiral ligand.17 Despite
these many successes, a careful examination of the literature
suggests that improvements could be made particularly with
regard to the range of derivatives that are prepared by current
enantioselective technologies.
Following a methodical investigation, we are now able to
report that the cyclohexadienone scaffolds of type 14-18
can be obtained with excellent enantioselectivity and in
respectable yield (Table 1). To the best of our knowledge,
Table 1. Diastereoselective Dearomatization of Resorcinol
Derivatives
Recently, we described a novel oxidative dearomatization
for the conversion of 4-alkylated resorcinol derivatives into
a lactone intertwined with a p-quinol. We also showed that
this p-quinol scaffold is capable of undergoing a variety of
diastereoselective reactions, which include 1,2-additions, 1,4-
conjugate additions, and [4 + 2] cycloadditions (Scheme 1).18
Scheme 1. Diastereoselective Reactions of p-Quinols
(R ) -Et)a
a Key: (a) PhMgBr; (b) KHMDS/H2C(CO2Me)2; (c) Danishef-
sky’s diene; (d) MeOH/NBS then Zn; (e) Rh(PPh3)3Cl/H2 for 10
h; (f) Rh(PPh3)3Cl/H2 for 2 h.
Furthermore, we demonstrated the usefulness of this inter-
mediate in efficient albeit racemic syntheses of epoxy-
sorbicillinol and bisorbicillinol.18b
(9) Genski, T.; Macdonald, G.; Wei, X.; Lewis, N.; Taylor, R. J. K.
Synlett 1999, 795-797.
(10) Imbos, R.; Minnaard, A. J.; Feringa, B. L. Tetrahedron 2001, 57,
2485-2489.
(11) de March, P.; Escoda, M.; Figueredo, M.; Font, J.; Garcia-Garcia,
E.; Rodriguez, S. Tetrahedron: Asymmetry 2000, 11, 4473-4483.
(12) Wolter, M.; Borm, C.; Merten, E.; Wartchow, R.; Winterfeldt, E.
Eur. J. Org. Chem. 2001, 4051-4060.
this diastereoselective dearomatization of resorcinol deriva-
tives is unique. However, it requires access to 4-alkyl
(13) Carreno, M. C.; Gonzalez, M. P.; Fisher, J. Tetrahedron Lett. 1995,
36, 4893-4896.
(14) Wipf, P.; Jung, J.-K. J. Org. Chem. 2000, 65, 6319-6337.
(15) Breuning, M.; Corey, E. J. Org. Lett. 2001, 3, 1559-1562.
(16) Gerstenberger, I.; Hansen, M.; Mauvais, A.; Wartchow, R.; Win-
terfeldt, E. Eur. J. Org. Chem. 1998, 643, 3-650.
1536
Org. Lett., Vol. 6, No. 10, 2004

monoprotected resorcinols, which we prepare using o-
quinone methide chemistry developed in our group.19
Our synthesis of these substrates begins with bromination20
of the aldehyde 1 and subsequent bis-BOC protection, which
affords the bromo aldehyde 2 in greater than 70% yield
(Scheme 2). Reduction of the aldehyde 2 with NaBH4
Hydrogenation of p-quinol (+)-14 over rhodium (Rh/Al,
150 psi H2, THF) chemoselectively reduces the enone
functionality and affords the vinylogous ester (+)-20 in 70%
yield (Scheme 3). Subsequent hydrogenolysis of the bromine
Scheme 3. Cleavage of Directing Group
Scheme 2. Preparation of Resorcinol Precursors
atom and hydrogenation of the vinylogous ester in (+)-20
is accomplished with Pd/C (1 atm, 1.0 equiv of Hu¨nig’s base,
0.1 M EtOAc) and affords the lactone (+)-19 in quantitative
yield. The relative stereochemistry of the protons (Ha-Hd)
in (+)-19 was established by 2D-NOESY experiment. In our
experience, a two-step reduction protocol is preferred to a
single-pot reduction of (+)-13 with PtO2 (4 h, 1 atm H2)
because the yields of the latter procedure prove quite variable
(40-80%) and afford significant quantities of rearomatized
materials. Addition of solid KOTMS to (+)-19 (1.1 equiv,
0.1 M Et2O, rt) affords the enantiomerically enriched ketone
(+)-21 in >95% yield. Comparison with a racemic standard
by chiral GC analysis demonstrated that (+)-20 is obtained
in >99% ee by this eight-pot process. It should be noted
that â-elimination, which is necessary for formation of the
enone (+)-21, most likely does not occur until the lactone
undergoes ring opening and a subsequent ring-flip.
With regard to the diastereoselectivity of this process, it
appears that the major isomer arises from the boat transition
state B, while the chair transition state A leads to the minor
diastereomer (Figure 2). The boat transition state is not
objectionable because most sites in the forming and neigh-
boring six-membered ring are sp2 hybridized. The Weinreb
amide affords much higher diastereoselectivity than other
amides. Presumably, there is less steric interaction between
the -OMe and -Br in the Weinreb amide than the
corresponding interaction between an alkyl and -Br sub-
stituent in other amides in the transition state. The >25%
improvement in yields and reproducibility in this dearoma-
tization process as compared with earlier des-bromo des-
methyl examples18a can be attributed to a favorable steric
interaction that facilitates lactonization, as well as prevention
of undesired aryl couplings with the oxidant.18a,22 It appears
that a C2 substituent, such as bromine, limits the degrees of
provides the corresponding benzyl alcohol, which upon
treatment with an excess of a nucleophile generates an
o-quinone methide. A conjugate addition ensues and provides
the monoprotected 4-alkylated resorcinol derivatives 3-7 in
good yields (59-89%). These phenols undergo Mitsunobu
coupling with 2S-hydroxy-N-methoxy-N-methylpropiona-
mide (-)-821 and thereby afford phenols (9-13) upon
deprotection with ZnBr2 (4 equiv, 0.1 M in CH3NO2) in
>75% yield over the three steps.
As shown in Table 1, exposure of these readily prepared
chiral resorcinols (9-13) to 1.1 equiv of PhI(OCOCF3)2 (0.3
h, 0.1 M CH2Cl2:CH3NO2/1:2.5, 0 °C) followed by an
aqueous workup affords a series of chiral lactone scaffolds
(14-18) in good yields with excellent diastereoselectivity.
Because the protocol proves diastereoselective with a variety
of differently sized C4-substituents, the magnitude of asym-
metric induction afforded by the chiral amide appears
independent of the steric bulk of the C-4 substituent.
(17) Imbos, R.; Brilman, M. H. G.; Pineschi, M.; Feringa, B. L. Org.
Lett. 1999, 1, 623-625.
(18) (a) Van De Water, R. W.; Hoarau, C.; Pettus, T. R. R. Tetrahedron
Lett. 2003, 44, 5109-5113. (b) Pettus, L. H.; Van De Water, R. W.; Pettus,
T. R. R. Org. Lett. 2001, 3, 905-908.
(19) (a) Van De Water, R. W.; Magdziak, D. J.; Chau, J. N.; Pettus, T.
R. R. J. Am. Chem. Soc. 2000, 122, 6502-6503. (b) Jones, R.; Van De
Water, R. W.; Lindsey, C.; Hoarau, C.; Ung; T.; Pettus, T. R. R. J. Org.
Chem. 2001, 66, 3435-3441. (c) Hoarau, C.; Pettus, T. R. R. Synlett 2003,
127. (d) Tuttle, K.; Pettus, T. R. R. Synlett 2003, 2234-2236. (e) Lindsey,
C.; Gomez-Diaz, C.; Villalba, J. M.; Pettus, T. R. R. Tetrahedron 2002,
58, 4559-4565.
(20) Bui, E.; Bayle, J. P.; Perez, F.; Liebert, L.; Courtieu, J. Liquid
Crystals 1990, 8, 513-526.
(21) (a) Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639-
652. (b) Less, S. L.; Leadlay, P. F.; Dutton, C. J.; Staunton, J. Tetrahedron
Lett. 1996, 37, 3519-3520.
(22) Murakata, M.; Yamada, K.; Hoshino, O. J. Chem. Soc., Chem.
Commun. 1994, 443-445.
Org. Lett., Vol. 6, No. 10, 2004
1537

This method provides a flexible chiral scaffold, which
subsequently allows access to a variety of p-quinols and their
derivatives in good yield and enantioselectivity. On the basis
of our previous observations with related systems,18 easy
access to a great many types of chiral ensembles can be
imagined. We expect this enantioselective dearomatization
process may prove useful in syntheses of nonracemic
molecules.
Acknowledgment. Research Grants from the National
Science Foundation (Career-0135031) and National Institutes
of Health (GM-64831) are greatly appreciated. L.H.M.
gratefully acknowledges additional financial support provided
by J. H. Tokuyama and a minority supplement (GM-64831)
for furthering his research. We also thank the patient editors
of the American Chemical Society, who strive to do an
outstanding job.
Figure 2. Boatlike transition state is preferred.18b
Supporting Information Available: Experimental pro-
cedures and full spectral data for compounds 2-21. This
material is provided free of charge via the Internet at
http://pubs.acs.org
freedom and assists in placing the amide carbonyl in closer
proximity to the intended site of reaction.
OL0498592
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