Total synthesis of (+)-rishirilide B: Development and application of general processes for enantioselective oxidative dearomatization of resorcinol derivatives

Article abstract of DOI:10.1021/ja062987w

A concise synthesis of (+)-rishirilide B (2) is described. This is the first synthesis to be reported for the (+)-enantiomer of rishirilide B (2) as found in nature. The strategy accentuates the valuable combination of a method for oquinone methide coupli

Full text of DOI:10.1021/ja062987w

Published on Web 11/16/2006
Total Synthesis of (+)-Rishirilide B: Development and
Application of General Processes for Enantioselective
Oxidative Dearomatization of Resorcinol Derivatives
Lupe H. Mejorado and Thomas R. R. Pettus*
Contribution from the Department of Chemistry and Biochemistry, UniVersity of California at
Santa Barbara, Santa Barbara, California 93106
Received April 28, 2006; E-mail: pettus@chem.ucsb.edu
Abstract: A concise synthesis of (+)-rishirilide B (2) is described. This is the first synthesis to be reported
for the (+)-enantiomer of rishirilide B (2) as found in nature. The strategy accentuates the valuable
combination of a method for o-quinone methide coupling with a method for enantioselective resorcinol
dearomatization, which provides a densely functionalized chiral building block. The convergent synthesis
illustrates several improvements and refinements to these methods and their supporting chemistries. Among
these is the in situ generation of PhI[OTMS]OTf. Combination of this oxidant with phenol 31 constitutes
the first example of a diastereoselective oxidative dearomatization of a resorcinol displaying a 2-alkyl
substituent. In addition, the preparation of the cyclic sulfone 34 is reported. As a new dimethide precursor
expressing a readily cleavable O-benzyl residue, sulfone 34 should prove useful in future endeavors. A
protocol using the aluminum amide of dimethylhydrazine for opening and cleavage of a [1,4]-dioxan-2-one
is also described. This procedure unmasks the hydroxy dione 36 by jettisoning the chiral directing group.
Regioselective O-carbamylation of the 1,3-dione 36 enables the transformation of the remaining carbonyl
into the R-hydroxy carboxylic acid found in 2. The total synthesis of (+)-rishirilide B (2) requires 15 pots
from benzaldehyde 17 and 13 pots from benzaldehyde 32. The final product emerges in yields of 12.5%
and 20.3% from compounds 17 and 32, respectively. The longest linear sequence requires eight
chromatographies. Important observations leading to the development of the principle asymmetric method
are described within the context of the total synthesis.
Introduction
(+)-Rishirilide A (1) and (+)-rishirilide B (2) were isolated
from Streptomyces rishiriensis OFR-1056 by Takeuchi and
found to contain structurally related oxygenated anthracene
skeletons (Figure 1). These natural products were found to inhi-
bit R2-macroglobulin with respective IC50’s of 100 µg/mL for
1 and 35 µg/mL for 2.1 R2-Macroglobulin is a tetrameric serum
glycoprotein that provides irreversible protease inhibition
through a unique trapping mechanism. Inhibitors of R2-macro-
globulin are useful in treating thrombosis caused by fibrinolytic
accentuation. (+)-Rishirilide B (2) has also been shown to in-
hibit glutathione S-transferase with an IC50 of 26.9 µM.2
Glutathione S-transferase catalyzes the addition of the tripeptide
glutathione to electrophilic substrates, resulting in their increased
water solubility and excretion. Glutathione S-transferase activity
also causes increased resistance toward anticancer drugs; there-
fore, an inhibitor of it may serve to potentiate certain anticancer
therapies.
Figure 1. The natural products (+)-rishirilides A (1) and B (2), and some
known derivatives (()-3, (()-4, and (()-5.
employed a cycloaddition reaction between a well-known
isobenzofuranone enolate and a novel enone. The remainder of
their efforts was spent in an attempt to remove undesired oxygen
substituents from the resulting naphthazarin intermediate.
In 2001, Danishefsky and Allen completed the first racemic
synthesis of (()-2.3 Their convergent two-pronged strategy
includes a naphthalene disconnection similar to the earlier
Hauser approach. However, there were some crucial distinctions.
The Danishefsky synthesis employs an elaborate o-quinone
In 1999, Hauser and Xu claimed a racemic synthesis of an
analogue of 2, (()-methyl-rishirilide B (3).4 Their strategy
(1) Komagata, D.; Sawa, R.; Kinoshita, N.; Imada, C.; Saw, T.; Naganawa,
H.; Hamada, M; Okami, Y.; Takeuchi, T. J. Antibiot. 1984, 37, 1681.
(2) Iwaki, H.; Nakaya, Y.; Takahashi, M.; Uetsuki, S.; Kido, M.; Fukuyama,
Y. J. Antibiot. 1992, 45, 1091.
(3) Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 351.
(4) Hauser, F. M.; Xu, Y.-J. Org. Lett. 1999, 1, 335.
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J. AM. CHEM. SOC. 2006, 128, 15625-15631
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A R T I C L E S
Mejorado and Pettus
Figure 2. Our strategy for rishirilide B (2).
dimethide intermediate for combination with a simpler cyclic
enedione. Each component displays a reverse regioselective
preference as compared to their Hauser counterparts. A chiral
hydroxyl residue serves as an internal Lewis acid and activates
a portion of the enedione. Because the o-quinone dimethide
exists at a lower oxidation state than Hauser’s isobenzofuranone
enolate, the Danishefsky synthesis is almost completed by the
cycloaddition reaction. The synthesis concludes after just two
additional steps. The chiral hydroxyl residue directs the addition
of an iso-pentyl organometallic reagent to the adjacent carbonyl
affording (()-4, which succumbs to fluoride-mediated depro-
tection of the ester and phenol protecting groups to afford (()-
2. Furthermore, by conversion of rishirilide B (()-2 into its
methyl analogue (()-3 and performing an X-ray analysis,
Danishefsky and co-workers proved that the Hauser-Xu effort
had failed to reach methyl rishirilide (()-3 as earlier claimed.4
The Danishefsky work also illuminates some pitfalls associated
with the rishirilide skeleton. Their choice of fluoride labile
protecting groups arose from appreciation of the instability of
(()-3 and related alkyl esters toward basic saponification
conditions. In 2003, the Danishefsky team reported an enan-
tioselective addendum to the shorter spur of their two-pronged
racemic strategy.5 The crucial chiral enedione dienophile is
prepared in six steps and a 1.9% yield from 3-methylcyclohex-
anone. At that time, only the (R)-antipode of this starting
material was commercially available. It was used to arrive at
ent-(-)-rishirilide B in 0.4% yield, thereby leading to the
assignment of the absolute configuration for the dextrorotatory
natural product.
Scheme 1. Synthesis of Differentially Protected 4-Alkyl
Resorcinols
six-membered rings are needed by the synthetic community.
We, in turn, have investigated general methods leading to the
oxidative dearomatization of resorcinols such as 6 (Figure 2).
Few reactions can be imagined to yield such a densely
functionalized chiral product with such readily distinguished
functionality. Derivatives of 7 would seem to be reasonable
synthetic precursors to many medically relevant natural prod-
ucts.6 Sometime ago, we imagined that a lactonization resulting
in the formation of a [1,4]-dioxan-2-one fused onto the 3,4-
positions of the cyclohexa-2,5-dienone product might overcome
some of the problems surrounding oxidative dearomatizations
and their products.7 Oxidative dearomatization is well known
to be a capricious and fickle transformation.8 Side reactions often
occur, and yields of greater than 50% are an exception rather
than the norm. We postulated that by proper selection of
substituents we could improve the performance of the reaction
and stabilize the product. For example, the orthogonal attach-
The difficult enantioselective synthesis of the Danishefsky
enedione intermediate, which might be viewed as a chiral
o-quinol when enolized, underscores our belief that more
methods for the enantioselective construction of highly oxidized
(6) Magdziak, D.; Meek, S.; Pettus, T. R. R. Chem. ReV. 2004, 104, 1383.
(7) Van De Water, R. W.; Hoarau, C.; Pettus, T. R. R. Tetrahedron Lett. 2003,
44, 5109.
(5) Yamamoto, K.; Hertemann, M. F.; Allen, J. G.; Danishefsky, S. J. Chem.-
Eur. J. 2003, 9, 3242.
(8) Wipf, P.; Kim, Y.; Jahn, H. Synthesis 1995, 1549.
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Total Synthesis of (
+
)-Rishirilide B
A R T I C L E S
Table 1. Auxilliary Approach for Chiral Cyclohexa-2,5-dienones
Table 2. Survey of Substituents and Their Effects on the Ratio of
Ortho versus Ipso Cyclization
ment of the tertiary oxygen substituent relative to the π system
of the product discourages reductive rearomatization, which is
well known to afflict p-quinols. Moreover, the ring fusion
enables the angular alkyl residue to assert diastereocontrol in
subsequent reactions, which normally suffer because of the
inherently flat structure of a p-quinol. In addition, the newly
created alkoxy stereocenter emerges in a protected state. Our
thoughts regarding convenience, stability, and diastereoselec-
tivity were confirmed by a six-pot synthesis of (()-epoxysor-
bicillinol,9 and later by a racemic synthesis of (()-5, a close
relative of (()-2 (Figure 2).10
One pleasing series of reactions in the latter project was the
addition of the carboxylic acid equivalent 11 directed by the
alkoxide of 10 to produce the bis-alkoxide 12, whereupon
cleavage of the enol protecting group (R′) and diastereoselective
protonation affords ketone 13. This cascade establishes two new
stereocenters in a single pot. The transformation also proves
that the conformation of rishirilide B (2) prevents â-elimination
as seen in similar systems.11 However, the remainder of our
strategy was seriously flawed. The saponification of the ethyl
ester in 5 proves impossible. In addition, the naphthol protecting
group (R ) -Me) fails to cleave. Moreover, the yields for the
perruthenate cleavage of enol ether 13 (R′′′ ) -C(OEt)dCH2)
into the ethyl ester 5 are meager at best (less than 35%). These
problems had to be resolved, and our method for the enantio-
selective dearomatization of C2 brominated resorcinol deriva-
tives had to be expanded,12 if we were to complete the synthesis
of the natural product (+)-rishirilide B (2).
report the observations that led to the development of this
enantioselective dearomatization procedure and the solutions that
consequently emerged to these problems that enabled an
enantioselective synthesis of (+)-rishirilide B (2).
Results and Discussion
To develop an enantioselective dearomatization process
applicable to rishirilide B as well as future prospective targets,
we required easy access to the appropriately substituted phenols
that would serve as the platform for dearomatization. Building
upon the observations of McLoughlin,13 we developed a cascade
process for their synthesis beginning with the benzaldehydes
(15-17). This new o-quinone methide generation and consump-
tion technology subsequently enables easy access to many
different prochiral resorcinols, such as 18-23, which display
an assortment of C4-substituents (Scheme 1).14
The oxidative dearomatization involving substrates 18-23
is unusual because it involves an ortho cyclization as opposed
to the usual ipso cyclization most often found among the
intramolecular reactions triggered by oxidative dearomatization.
We thought that this ortho cyclization could be modified to an
enantioselective format by incorporation of a chiral amine.
However, this proved more difficult than we anticipated. The
Early experiments had suggested our chiral technology with
C2 bromo resorcinols would transfer to C2 methyl derivatives
such as 6. However, a new problem surfaced. Whereas the
corresponding R′′ glycolate derivatives of 9 cleaved, the
corresponding lactate derivatives proved too robust. Herein, we
(9) Pettus, L. H.; Van de Water, R. W.; Pettus, T. R. R. Org. Lett. 2001, 3,
905.
(10) (a) Wang, J. H.; Pettus, T. R. R. Tetrahedron Lett. 2004, 45, 5895. (b)
Wang, J. H.; Pettus, T. R. R. Tetrahedron Lett. 2004, 45, 1793.
(11) Stork, G.; Danheiser, R.; Ganem, B. J. Am. Chem. Soc. 1973, 95, 3414.
(12) Mejorado, L.; Hoarau, C.; Pettus, T. R. R. Org. Lett. 2004, 6, 1535-1538.
(13) McLoughlin, B. J. J. Chem. Soc., Chem. Commun. 1969, 540.
(14) (a) Van De Water, R.; Magdziak, D.; Chau, J.; Pettus, T. R. R. J. Am.
Chem. Soc. 2000, 122, 6502. (b) Jones, R. W.; Van De Water, R.; Lindsey,
C. L.; Hoarau, C.; Ung, T.; Pettus, T. R. R. J. Org. Chem. 2001, 122,
3435.
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A R T I C L E S
Mejorado and Pettus
Table 3. Synthesis of a Chiral [1,4]-Dioxan-2-one Fused at the
3,4-Positions with a Cyclohexa-2,5-dienone
achiral glycolate-derived pyrrolidine amide already affords low
yields of the desired lactone 24 (15-36%, Table 1, entry 1).
Chiral amides derived from more encumbered amines proceed
to 24 in even lower yields than their pyrrolidine counterpart.
The poor efficiency of the sequence means that the nonra-
cemic lactone 24 and its analogues are useless from the
standpoint of enantioselective syntheses even though these
adducts easily undergo a variety of chemoselective and dias-
tereoselective reactions.7 We therefore investigated structural
modifications designed to lower the energy barrier for the
desired ortho-lactonization and improve the prospects for these
cyclohexadienone building blocks. The phenoxonium cation
derived from 19 and 20 undergoes two types of cyclization,
the ortho cyclization leading to lactone-A or the more traditional
ipso cyclization leading to the spirocycle-B (Table 2). Modifica-
tions to the R1, R3, and R4 substituents, which improve the A/B
ratio, result in more efficient and higher yielding reactions. The
data shown (Table 2, entries 1-6) testify to the importance of
tether length, amide nucleophilicity, and the steric impact of
the [R1] aryl substituent on the efficiency of the dearomatization
process.
These findings illuminate several key features affecting the
course of the transition into products as well as determining
the ultimate success of the reaction. The results suggested further
electronic and structural amendments to improve yields and
enantioselectivites (Table 3). For example, exchange of the
amine functionality [-NR3R4] for an alkoxyamine [-N(OR3)-
R4] increases amide carbonyl nucleophilicity and improves the
yield of the ortho cyclization. However, the effort required to
build and to survey the new complex chiral amines suggested
by these studies seemed wasteful. Instead, we opted for simpler
modifications that would enable an enantioselective synthesis
of the chiral cyclohexadienone building block. The simplest was
replacement of the achiral glycolate-derived amide with an
amide derived from lactate or leucate, thereby introducing the
chiral center R5 onto a carbon of the [1,4]-dioxan-2-one that
was fused to the cyclohexadienone. This method assumes that
the reaction for coupling the chiral amide occurs with 100%
inversion and that the chiral starting material would be jettisoned
at some later point rather than recycled. However, the avail-
ability and costs associated with the R and S antipodes of methyl
lactate and leucate justified this sacrificial approach, particularly
in view of the scarcity of methods for the enantioselective
synthesis of cyclohexadienones. Furthermore, unlike the steric
interactions of amine auxiliaries, the interaction between the
R5 and R1 substituents appears to improve the likelihood of a
successful cyclization. Our studies further recommended that
the carbonyl moiety, which is involved in the cyclization, carries
sufficient steric encumbrance to reinforce the steric effects of
the R5 stereocenter so that the overall reaction proves diaste-
reoselective. These findings eventually led us to adopt Paterson’s
procedure for preparation of the chiral methoxyamide derived
from methyl lactate.15
than the dipole for the corresponding chair transition state.
Amides with substituents on the sides of the nitrogen atom favor
the chairax transition state, but the yield suffers. Nevertheless,
the six-step protocol that has emerged from these studies enables
an efficient method for preparing enantiomerically enriched
cyclohexa-2,5-dienones carrying an alkyl or bromine C2 sub-
stituent. The process begins with the three-step conversion of
the benzaldehyde 17 into a differentially protected resorcinol
22 (Scheme 1). This material is then coupled with the (R)-
enantiomer of 30 to yield the inverted corresponding product
(Scheme 2). The remaining Boc-residue is cleaved by dissolving
the crude product in nitromethane (0.1 M) and adding zinc
bromide (10 equiv). The phenol 31 emerges in an 84% yield
after chromatography, a 61% yield over the three steps from
22. The stereointegrity of this SN2 inversion process has been
confirmed by chiral HPLC analysis and comparison of 31 with
Given the results (Tables 1-3), some of the important
structural features of this reaction are evident. The amide
substituent R3 forces the R5 substituent into an axial orientation
in the transition states preceding the major and minor products.
Because of the number of contributing sp2 atoms, the boat
experiences few destabilizing effects. Its dipole (µ) is smaller
(15) Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639.
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Total Synthesis of (
+
)-Rishirilide B
A R T I C L E S
Scheme 2
Scheme 3
Figure 3. Lactate and glycolate derivatives behave differently.
cyclohexadienone (-)-29 in both a regioselective and a dias-
tereoselective manner. At this elevated temperature, however,
the cycloadduct suffers immediate â-elimination. Subsequent
oxidation of the cyclohexenone intermediate with DDQ provides
the new anthracene (-)-35 in a 68% overall yield.
In our earlier racemic approach that had used glycolate
derivatives (R5 ) H, Figure 3), the cleavage and removal of
the lactone functionality had proven straightforward.10 The 1,4-
dioxan-2-one opens upon addition of an aqueous solution of
metal hydroxide to give the metalated carboxylate. Subsequent
addition of acid affords the spirocycle. The successive additions
of aqueous lithium hydroxide and hydrochloric acid afford the
â-diketone in good yields. Alternatively, prolonged exposure
of the glycolate-derived lactone to aqueous hydroxide followed
by the addition of acid provides the corresponding â-diketone.
However, the lactate derivative (R5 ) Me) proves much more
robust than its glycolate counterpart. Saponification is very slow.
It can be accompanied by decomposition and even epimerization
of R5. Acidification of the carboxylate leads to a complex
diastereomeric mixture of spirocycles. Upon addition of aqueous
hydroxide, one of these adducts transforms into the 1,3-dione
and the other reverts to the metal carboxylate by â-elimination.
Faced with poor yields of 36 (21-41%), other options for
jettisoning the chiral directing group were investigated. We had
found that treatment of a dimethyl hydrazone expressing an
R-alkoxy substituent with a Lewis acid causes the hydrazone
to expel the alkoxy fragment,18 and therefore we were curious
to see if this protocol could be employed with the corresponding
1,4-dioxan-2-one. Application of Benderly’s conditions for
lactone opening using the aluminum amide derived from
dimethyl hydrazine causes the [1,4]-dioxan-2-one 35 to open
as expected. However, in this case, the hydroxy dione 36 is
also unmasked by cleavage of the chiral directing group that
had fulfilled its role as a stabilizing and protecting group (69%
yield, a mixture of tautomers, Scheme 4).19 We explored the
a racemic standard. Oxidative dearomatization of 31 (0.2 M in
CH2Cl2, -78 °C) with PhIO/TMSOTf (1.1 equiv) affords a 73%
yield of (-)-29. We find this combination of reagents superior
to PhI(OCOCF3)2 or PhI(OCOCH3)2. The carboxylate ligands
of the latter reagents often intercept the phenoxonuim cation
and lead to appreciable amounts of side products. The major
product 29 arises in a readily separable 13:1 mixture with the
minor diastereomer. The relative and absolute stereochemistry
of 29 and its analogs has been established by NOE experiments,
X-ray analysis, and relay synthesis. The optimized six-step
procedure easily provides multigram quantities of (-)-29 for
application toward (+)-rishirilide B.
While Comins’s ortho lithiation process was again em-
ployed,16 an adjustment was made to the precursor of the
dimethide 8 used in our earlier racemic strategy.10 In this
instance, the O-benzylated benzaldehyde 32 is converted into
the C-methylated product 33 (Scheme 3). The subsequent Durst
and Charlton’s procedure (substrate, 0.6 M benzene, 2.5 equiv
of SO2, 450 W Hg lamp, 23 °C, 4 h) provides the new sulfone
34 in 75% yield over the three steps.17 Upon warming 34 to
155 °C as compared to 110 °C used in our earlier racemic
strategy,10 the cycloaddition proceeds with the nonracemic
(16) Comins, D. L.; Brown, J. D. J. Org. Chem. 1989, 54, 3730.
(17) Durst, T.; Kozma, E. C.; Charlton, J. L. J. Org. Chem. 1985, 50, 4829.
(18) Hoarau, C.; Pettus, T. R. R. Org. Lett. 2006, 8, 2843-2846.
(19) Benderly, A.; Stavchansky, S. Tetrahedron Lett. 1988, 29, 739-740.
9
J. AM. CHEM. SOC. VOL. 128, NO. 49, 2006 15629

A R T I C L E S
Scheme 4 a
Mejorado and Pettus
the lithiated vinyl ether to afford the enolate 38. Workup with
aqueous NaCl produces a single diastereomer. This intermediate
enol ether is submitted in crude form to epoxidation with DMDO
(3.0 equiv). Upon workup with 1 N HCl, the robust R-hydroxy
ketone (-)-39 emerges in a very gratifying 87% overall yield
from the â-dione 36.
Much to our surprise given several reports employing
hydroxycortisone,20 the R,R′-dihydroxy ketone 39 fails to cleave
on the least substituted side with sodium periodate to yield the
desired acid. Instead, these conditions afford the dione 36, which
seems to indicate cleavage between the carbonyl and more
hindered tertiary alcohol. However, a comprehensive investiga-
tion performed with a simple tetralone analogue reveals an
unusual sequence of events.21 The primary alcohol first under-
goes oxidation to yield the corresponding aldehyde. However,
in this instance, a cyclization occurs to afford the corresponding
γ-lactol that succumbs to a rapid oxidation to produce lactone
40, whereupon the ketone hydrates and periodate cleavage
occurs between the hydrate and the tertiary alcohol (Scheme
5).
a Other conditions for lactate cleavage: Ba(OH)2/EtOH yields 21% of
36, LiOH/THF yields 41% of 36.
generality of this cleavage reaction and found it limited to the
expulsion of stabilized leaving groups.
Addition of diethylcarbamyl chloride (1.5 equiv) and Hu¨nig’s
base (4.0 equiv) to the dione 36 gives the O-carbamyl product
37 after 4 h (Scheme 5). None of the tautomeric product is
evident. To the best of our knowledge, these are the only
conditions that enable regioselective production of the thermo-
dynamically preferred tautomer. Compound 37 proves very
unstable toward chromatography. Evaporation (0.01 Torr, 1 day)
supplies crude material for the subsequent series of reactions.
Upon addition of an excess of lithiated ethyl vinyl ether (30
equiv, at -78 °C), we suspect that the first equivalent causes
deprotonation of the tertiary alcohol. The resulting metal
alkoxide then directs the addition of a subsequent equivalent to
the vicinal ketone. This chelation manifold affords the corre-
sponding anti dialkoxide. The carbonyl of the vinyl carbamate
then slowly undergoes reaction with additional equivalents of
Once the origins of this unexpected problem were grasped,
a solution became evident. The oxidation state of the R,R′-
dihydroxy ketone in 39 was lowered so that the primary and
secondary alcohols could both interact with the periodate
oxidant. The R,R′-dihydroxy carbonyl reduces with a freshly
prepared solution of sodium triacetoxyborohydride in acetic
acid.22 The tetrol that emerges is a single diastereomer of
unassigned configuration. This crude material (0.08 M in CH2-
Cl2:H2O/5:1, 25 °C) undergoes cleavage with NaIO4 on silica
(2.0 equiv) to cleanly afford the aldehyde (-)-41 in 75% yield
(Scheme 5).23 The aldehyde 41 is then transformed into the
desired carboxylic acid using Kraus’s modification of the
Lindgren oxidation.24 Subsequent hydrogenolysis of the benzyl
residue in 95% EtOH occurs over a catalytic amount of 5%
palladium on carbon under a hydrogen atmosphere and yields
Scheme 5
9
15630 J. AM. CHEM. SOC. VOL. 128, NO. 49, 2006

Total Synthesis of (
+
)-Rishirilide B
A R T I C L E S
(+)-rishirilide B (2) in 90% from aldehyde 41. This synthetic
material proves identical in all respects with natural (+)-
rishirilide B and displays a rotation of (+) 12.6° for c ) 0.5.
accessing highly functionalized chiral building blocks. In
addition, an unusual process for the cleavage of R-alkoxy esters
and [1,4]-dioxan-2-ones is presented. In the near future, we hope
to report syntheses of several other natural products using this
combination of procedures.
Conclusion
In conclusion, the natural product (+)-rishirilide B (2) has
been prepared for the first time. Its synthesis requires 15 steps
from benzaldehyde 7 and 13 steps from aldehyde 32 and
proceeds in overall yields of 12.5% and 20.3%, respectively.
The synthesis requires seven chromatographies. It demonstrates
the powerful combination of a novel method for the enantiose-
lective dearomatization of cyclohexadienones with a process
for the synthesis of differentially protected resorcinols for
Acknowledgment. Research grants from the National Science
Foundation (Career-0135031) for support of the o-quinone
methide chemistry and the National Institutes of Health (GM-
64831) for support of the cyclohexadienone chemistry are
greatly appreciated.
Supporting Information Available: Experimental procedures
and spectral data for compounds 19-36, 39, 41, and 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Kertesz, D. J.; Marx, M. J. J. Org. Chem. 1986, 51, 2315.
(21) Mejorado, L.; Pettus, T. R. R. Synthesis 2006, 3209.
(22) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27, 5939.
(23) (a) Daumas, M.; Vo-Quang, Y.; Vo-Quang, L.; Le Goffic, F. Synthesis
1989, 64-65. (b) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62,
2622.
JA062987W
(24) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
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