Perylenequinone natural products: Enantioselective synthesis of the oxidized pentacyclic core

Article abstract of DOI:10.1021/jo9013832

(Chemical Equation Presented) An enantioselective approach to the perylenequinone core found in the mold perylenequinone natural products is outlined. Specifically, the first asymmetric syntheses of helical chiral perylenequinones absent any additional st

Full text of DOI:10.1021/jo9013832

pubs.acs.org/joc
Perylenequinone Natural Products: Enantioselective Synthesis of the
Oxidized Pentacyclic Core†
Carol A. Mulrooney, Barbara J. Morgan, Xiaolin Li, and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia,
Pennsylvania 19104-6323
marisa@sas.upenn.edu
Received June 30, 2009
An enantioselective approach to the perylenequinone core found in the mold perylenequinone natural
products is outlined. Specifically, the first asymmetric syntheses of helical chiral perylenequinones absent
any additional stereogenic centers are described. Key elements of the synthetic venture include a catalytic
enantioselective biaryl coupling, a PIFA-induced naphthalene hydroxylation, and a palladium-mediated
aromatic decarboxylation. Transfer of the binaphthalene axial stereochemistry to the perylenequinone
helical stereochemistry proceeded with good fidelity. Furthermore, the resultant perylenequinones were
shown to possess sufficient atropisomeric stability to be viable intermediates in the biogenesis of the
perylenequinone natural products. This stability supports the use of the helical axis as a stereochemical
relay in synthesis of the natural products containing additional stereochemical centers.
Introduction
The parent perylenequinone 1 was first prepared by Zinke
in 1929,1 but it was not until 1954 that the correct structure
was elucidated (Figure 1).2 This compound was subsequently
isolated from the fungus Daldinia concentrica as blue-black
crystals and is the simplest of the naturally occurring peryle-
nequinones.3 Mostmembersofthis family of natural products
fall into three classes (examples of each in Figure 1): (a) C20
compounds without carbon substituents,4 (b) mold perylene-
quinones containing carbon substituents, and (c) perylene-
quinones from aphids. Of the three, class B is the most
prevalent. Due to their diversity, interesting stereochemistries,
and anticancer activities we have undertaken the syntheses of
these compounds via dimerization of achiral naphthols.
† Dedicated to the memory of Ralph Hirschmann.
(1) Zinke, A.; Hirsch, W.; Brozek, E. Monatsch. Chem. 1929, 51, 205–220.
(2) Calderbank, A.; Johnson, A. W.; Todd, A. R. J. Chem. Soc. 1954,
1285–1289.
FIGURE 1. Representative structures of the perylenequinone
classes.
(3) Anderson, J. M.; Murray, J. Chem. Ind. 1956, 376–376.
(4) This class also includes some partially reduced compounds from the
molds of Alternaria and Stemphylium.
The archetypical cercosporin 6 (Figure 2) was among the
first of the mold perylenequinones to be isolated in 1957.5 The
(5) Kuyama, S.; Tamura, T. J. Am. Chem. Soc. 1957, 79, 5725–5726.
16 J. Org. Chem. 2010, 75, 16–29
Published on Web 11/09/2009
DOI: 10.1021/jo9013832
r
2009 American Chemical Society

Mulrooney et al.
JOCArticle
FIGURE 2. Mold perylenequinones 2-17.
unusual features of this molecule hindered a complete structu-
ral determination until the 1970s.6 The majority of the structural
details were determined by classical redox quinone chemistry,
but the most significant finding was the transformation invol-
ving the thermal atropisomerization of (M)-cercosporin into
(P)-epi-cercosporin. The opposite helical configuration of the
perylenequinone epimers was confirmed by circular dichroism
(CD) analysis,6b and the helical nature along with the absolute
and relative configuration of 6 was established crystallographi-
cally.7 Since the discovery of 6, more than 20 perylenequinones
have been isolated as dark red pigments from a variety of fungi
within the Ascomycota phylum (Figure 2).8 Correlation with
the CD and NMR spectra of 6has allowed determination of the
helical configurations and relative stereochemistries of most of
the remaining natural products.
Notably, all of the mold perylenequinones (Figure 2) are
derivatives of 1 (Figure 1). With the exception of hypomycin
B (15), the C4,C40- or C5,C50-phenols are not alkylated.
These acidic phenols (pKa ∼7.3-8.3)9 are characteristic of
the structures and form strong internal hydrogen bonds with
the quinone carbonyls.10 Many of the mold perylenequi-
nones are C2-symmetric, having C7,C70-substitution with
centrochiral stereocenters of the same absolute configura-
tion. The remainder (hypocrellin, hypocrellin A-B, shiraia-
chrome A, elsinochrome B1-B2, and hypomycin B11) likely
originated from C2-symmetric intermediates.
the perylenequinone natural products has been examined by
several groups.12-19 Prior to these achievements, there had
been relatively few synthetic efforts devoted to this family of
natural products. As mentioned above, 1 (class A, Figure 1)
was first unknowingly prepared by Zinke and co-workers
(ca. 1929) from tetranitroperylene 18 upon exposure to
sulfuric acid at 140 °C under air.1 Due to the atypical stability
of the proposed product 19, Calderbank and co-workers
repeated the procedure (Scheme 1),2 and the structure of
4,40,5,50-tetraquinone 19 reported by Zinke was correctly
reassigned as the parent perylenequinone 1.
Surprisingly, it was not until 1972 that there was further
progress when Weisgraber and Weiss attempted to synthe-
size the oxygenation pattern present in the mold perylene-
quinones (Figure 2). The initial assignments of both the
coupling product 21 and the subsequent perylenequinone
22 were discovered to be incorrect,20,21 and the final cyclized
product was reassigned as dinaphthofuranedione 24 (Scheme 2).
In work by Dallacker and Leidig, a different approach was
used in the synthesis of 2,20,4,40-tetramethoxyperylenequi-
none, commencing with formation of bisphenyl substrate 25
(12) Chao, C.; Zhang, P. Tetrahedron Lett. 1988, 29, 225–226.
(13) Diwu, Z.; Lown, J. W. Tetrahedron 1992, 48, 45–54. (b) Liu, J.; Diwu,
Z.; Lown, J. W. Tetrahedron 1993, 49, 10785–10792.
(14) Broka, C. A. Tetrahedron Lett. 1991, 32, 859–862.
(15) Hauser, F. M.; Sengupta, D.; Corlett, S. A. J. Org. Chem. 1994, 59,
1967–1969.
(16) (a) Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1994, 116, 8795–
8796. (b) Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1995, 117, 10889–
10904.
(17) (a) Merlic, C. A.; Aldrich, C. C.; Albaneze-Walker, J.; Saghatelian,
A. J. Am. Chem. Soc. 2000, 122, 3224–3225. (b) Merlic, C. A.; Aldrich, C. C.;
Albaneze-Walker, J.; Saghatelian, A.; Mammen, J. J. Org. Chem. 2001, 66,
1297–1309.
Regardless of the varied C7,C70-substitution, all class B
perylenequinones contain a conjugated pentacyclic core in a
highly oxidized state. Furthermore, the distinct oxygenation
pattern at the C2,C20,C4,C40,C5,C50,C6,C60-centers (Figure 2)
is conserved throughout the series. In the past two decades,
the construction of this highly oxygenated core en route to
(18) O’Brien, E. M.; Morgan, B. J.; Kozlowski, M. C. Angew. Chem., Int.
Ed. 2008, 47, 6877–6880.
(19) Morgan, B. J.; Dey, S.; Johnson, S. W.; Kozlowski, M. C. J. Am.
Chem. Soc. 2009, 131, 9413–9425.
(6) (a) Lousberg, R. J. J.; Weiss, U.; Salemink, C. A.; Arnone, A.; Merlini,
L.; Nasini, G. Chem. Commun. 1971, 1463–1464. (b) Yamazaki, S.; Ogawa,
T. Agric. Biol. Chem. 1972, 36, 1707–1718.
(7) Nasini, G.; Merlini, L.; Andreetti, G. D.; Bocelli, G.; Sgarabotto, P.
Tetrahedron 1982, 38, 2787–2796.
(20) (a) Weisgraber, K. H.; Weiss, U. J. Chem. Soc., Perkin Trans. 1 1972,
83–88. (b) Weiss, U.; Fales, H. M.; Weisgraber, K. H. Liebigs Ann. Chem.
1979, 914–919. (c) Fales, H. M.; Weiss, U.; Jaouni, T. Liebigs Ann. Chem.
1983, 367–371.
(21) The proposed structure of 22 is the keto-enol tautomer of the mold
perylenequinones seen in Figure 2, with the exception of hypomycin B, 15.
The perylenequinones actually exist as a mixture of the two tautomers,
though the predominance of each tautomeric form is different for each
natural product: Arnone, A.; Merlini, L.; Mondelli, R.; Nasini, G.; Ragg, E.;
Scaglioni, L.; Weiss, U. J. Chem. Soc., Perkin Trans. 2 1993, 1447–1454.
(8) For a review, see: Daub, M. E.; Herrero, S.; Chung, K.-R. FEMS
Microbiol. Lett. 2005, 252, 197–206. and references cited therein.
(9) Hongyu, Z.; Zhiyi, Z. Chin. Sci. Bull. 1997, 42, 2005–2009.
(10) The chelation allows for keto-enol tautomerization; see ref 21.
(11) (a) Liu, W. Z. Fermentation and Structure Determination of Hypomycin
B. M.D. thesis, Yunnan University, 2000. (b) Liu, W. Z.; Chen, Y. T.; Xie, J. L.
J. Yunnan Univ., Nat. Sci. Ed. 2000, 22, 389–391. (c) Liu, W. Z.; Ma, L. Y.; Li,
C.; Chen, Y. T.; Xie, J. L. Acta Pharmacol. Sin. 2001, 36, 313–314.
J. Org. Chem. Vol. 75, No. 1, 2010 17

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SCHEME 1. Previous Synthesis of Parent Perylenequinone 1
lower the atropisomerization barrier such that the two
helical forms rapidly interconvert.23,24
The helicity of the perylenequinone natural products is not
uniform. Rather, compounds exhibiting both (M)- and (P)-
helicity have been isolated, leaving the origin of the helical
stereochemistry an interesting and unsolved issue. Since
different helical stereochemistries arise from different organ-
isms (hypocrellin from Hypocrella bambusae25 and hypocrel-
lin A from Shiraia bambusicola23), it seems likely that an
enzyme-mediated enantioselective dimerization occurs in the
biosynthetic routes. The fact that horseradish peroxidase, a
metalloporphyrin enzyme, has been found to elicit asym-
metric naphthol couplings with good yields and modest
enantioselectivities indicates that enzymes are capable of
catalyzing this transformation (eq 1).26 Presumably, the
peroxidase catalyzes the production of a stabilized radical
to enable the homocoupling.27 It is entirely probable, there-
fore, that helical chiral perylenequinones, such as 30, absent
any centrochiral elements (i.e., R2 not containing further
stereocenters) can be produced enzymatically. Such produc-
tion likely occurs via an axial chiral binaphthalene with
transfer of axial stereochemistry to helical stereochemistry
in the perylenequinone-forming step (Scheme 5).
SCHEME 2. Weiss Attempted Synthesis of Perylenequinone 22
(PPA = Polyphosphoric Acid)
SCHEME 3. Dallacker Synthesis of Perylenequinone 27
In an examination of prior approaches, the installation of
the helical chirality has been the most difficult aspect and
thus the focal point of the syntheses.14-17 Poor diastereo-
control in the couplings of chiral C7,C70-substituted naph-
thalenes also points away from such a pathway in the bio-
synthesis (i.e., 38 to 8a-d, Scheme6).14-17 Thus, we formulated
a plan revolving around diketone perylenequinone 33. Nota-
bly, perylenequinone 33 is a retrosynthetic intermediate to four
different natural product classes: the calphostins (8a-d) and
cercosporins (6) via reduction, the hypocrellins (2) via aldol
cyclization, and the elsinochromes (10) via oxidative enol
coupling. In contrast, there is no direct route from monomer
38 to the hypocrellins (2) and elsinochromes (10); oxidation and
loss of the two alcohol stereocenters would be required first. We
proposed that helical perylenequinone 33 could be produced
from cyclization of axial chiral binaphthalene 34 which would
in turn be produced by facile enantioselective oxidative coup-
ling of the corresponding monomer 35. The illustrated mono-
mer 35 is generated in a few simple steps from phenylacetic acid
37, in contrast to the laborious preparations of enantiopure
monomers 38.
(Scheme 3). Unfortunately, the synthesis was lengthy and
lacked the necessary C6,C60-oxygenation.22
Prior to the report by Broka on the calphostins,14 synthe-
ses of the highly oxidized perylenequinone core were either
racemic or yielded optically inactive products. Thus, these
early efforts did not address a key architectural element
of the perylenequinones; the chiral helical pentacyclic core.
Due to steric interactions of the C7,C70- and C2,C20-sub-
stitution, the pentacyclic core is forced to adopt a chiral
helical structure (dihedral angle of 20°). With larger C7,C70-
and C2,C20-groups, the rate of interconversion of the two
possible enantiomeric conformational isomers is slow lead-
ing to stable atropisomers. As discussed above, the helicity of
most perylenequinones was determined by correlation to
cercosporin. In the cases of hypocrellin B (4) and scutiaqui-
none B (17), there is an absence of helicity in the CD spectra.
However, calculations indicate that the lowest energy
ground-state structures are in fact helical (Scheme 4). Pre-
sumably, the double bond of hypocrellin B (4) and the lack of
substituents at C2,C70-positions of scutiaquinone B (17)
A central element of this synthetic plan is the atropiso-
meric stability of the key intermediate 33. The calphostins
(8a-d) exhibit good atropisomeric stability, but the simple
change of introducing a bridging methylidene as in cercosporin
(24) Ayers, S.; Zink, D. L.; Mohn, K.; Powell, J. S.; Brown, C. M.;
Murphy, T.; Brand, R.; Pretorius, S.; Stevenson, D.; Thompson, D.; Singh,
S. B. J. Nat. Prod. 2007, 70, 425–427.
(25) Chen, W. S.; Chen, Y. T.; Wang, X. Y.; Friedrichs, E.; Puff, H.;
Breitmaier, E. Liebigs Ann. Chem. 1981, 1880–1885.
(22) Dallacker, F.; Leidig, H. Chem. Ber. 1979, 112, 2672–2679.
(23) Kishi, T.; Tahara, S.; Tsuda, M.; Tanaka, C.; Takahashi, S. Planta
Med. 1991, 57, 376–379.
(26) Sridhar, M.; Vadivel, S. K.; Bhalerao, U. T. Tetrahedron Lett. 1997,
38, 5695–5696.
(27) Feringa, B.; Wynberg, H. Bioorg. Chem. 1978, 7, 397–408.
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SCHEME 4. Conformational Isomers of Hypocrellin B and
Scutiaquinone B
intermediate 41 (Scheme 7). Merlic has reported diastereose-
lective oxidative couplings to either provide the calphos-
tin perylenequinone directly or via a bis-o-quinone intermedi-
ate,17,29 such as 40 (path a). Similarly, Broka14 and Coleman16
utilized a diastereoselective biaryl coupling to yield an axial
chiral biaryl as an intermediate in their calphostin syntheses.
The perylenequinone arose from the cyclization of the cor-
responding 5,50-bisnaphthol, similar to debenzylated 42
(path b). For both paths a and b, effective stereochemistry
transfer of the axial stereochemistry to the ultimate helical
stereochemistry was observed.14-17 However, the role of the
bulky protected C7,C70-hydoxypropyl groups in stabilizing
this stereochemistry transfer was unknown.
Due to both the reported success of Merlic29 and also the
precedent for the oxidation of naphthalenes to bis-o-qui-
nones,30 we initially chose to pursue path a. We commenced
this effort by exploring the ability of our catalyst system in
the enantioselective coupling of a series of highly substituted
naphthols to provide the required axial chiral precursor 41.28
Monomer Synthesis and Asymmetric Oxidative Coupling.
Based on prior methods for the formation of highly sub-
stituted naphthols,20a we developed a protocol to generate
naphthols 45a-d with high efficiency (Schemes 8 and 9).28
Commencing with simple commercially available phenyl-
acetic acids (43a-c), the requisite naphthols were generated
rapidly via acid chloride formation, malonate acylation, and
cationic cyclization. After diacetylation, the less hindered
C2-acetate was hydrolyzed with NaOMe to provide the
desired coupling substrates 45a-c (Scheme 8). The flexibility
of this route to quickly generate substrates with a variety of
substitution patterns has proven invaluable in identifying
optimal substrates for the enantioselective oxidative biaryl
coupling and for the perylenequinone syntheses.
SCHEME 5. Proposed Enzymatic Perylenequinone Formation
In the formation of biaryl intermediate 41 (Scheme 7), the
first naphthol proposed was C7-allyl 48 (Scheme 9). The allyl
group would provide a platform both to intermediate 41
(Scheme 7) and also to introduce functional groups present
in the natural products. The synthesis began with an allyla-
tion of the hydroxyl and carboxyl groups of commercially
available 46 followed by a Claisen rearrangement and
methylation of the revealed phenol (Scheme 9). Unfortu-
nately, all attempts to form the desired 48 from 47 were
unsuccessful, most likely due to incompatibility of the allyl
group with the strongly acidic cyclization conditions. In light
of this result, the hydrogenation of 47 was performed to yield
the inert propyl derivative. After saponification to supply 49,
the naphthol 45d was successfully prepared using the opti-
mized conditions for 45a-c.
(6) abrogates much of this stability with atropisomerization
occurring at 37 °C.7 Due to the sterically larger C7,C70-
hydroxypropyl groups in the calphostins (8a-d) compared
to the 2-oxopropyl groups of 33, we anticipated that 33
would exhibit lower atropisomeric stability. Since no enan-
tiopure perylenequinones with only the helical stereochem-
istry as a chiral element had been reported previously, we set
out to establish the degree of configurational stability of such
species. In this paper, we detail the synthesis of the enantio-
pure perylenequinone core, addressing installation of the
necessary oxygenation pattern as well as the formation and
stability of the helical stereochemistry in the absence of other
stereochemical substitution.28
Results and Discussion
In previous efforts, we have assessed the versatility of our
diaza-cis-decalin catalyst 51 in catalytic asymmetric oxi-
dative naphthol couplings.18,19,28,31 Table 1 outlines the
Retrosynthetic Analysis. With an initial goal of producing
an enantiopure perylenequinone possessing only the helical
stereochemical component, we elected to undertake the synth-
esis of analogue 39 possessing simple n-propyl groups at the
C7, C70-positions. Based on prior reports, we identified two
intermediates (40 and 42) that could lead to the desired
perylenequinone 39, both devolving to common chiral biaryl
(30) Broadhurst, M. J.; Hassal, C. H.; Thomas, G. J. J. Chem. Soc.,
Perkin Trans. 1 1982, 2239–2248.
(31) (a) Li, X.; Yang, J.; Kozlowski, M. C. Org. Lett. 2001, 3, 1137–1140.
(b) Kozlowski, M. C.; Li, X.; Carroll, P. J.; Xu, Z. Organometallics 2002, 21,
4513–4522. (c) Xie, X.; Phuan, P.-W.; Kozlowski, M. C. Angew. Chem., Int.
Ed. 2003, 42, 2168–2170. (d) Li, X.; Hewgley, J. B.; Mulrooney, C.; Yang, J.;
Kozlowski, M. C. J. Org. Chem. 2003, 68, 5500–5511. (e) Morgan, B. J.; Xie,
X.; Phuan, P.-W.; Kozlowski, M. C. J. Org. Chem. 2007, 72, 6171–6182.
(f) DiVirgilio, E. S.; Dugan, E. C.; Mulrooney, C. A.; Kozlowski, M. C. Org.
Lett. 2007, 9, 385–388. (g) Kozlowski, M. C.; Dugan, E. C.; DiVirgilio, E. S.;
Maksimenka, K.; Bringmann, G. Adv. Synth. Catal. 2007, 349, 583–594.
(h) Hewgley, J. B.; Stahl, S. S.; Kozlowski, M. C. J. Am. Chem. Soc. 2008,
130, 12232–12233.
(28) For a preliminary communication of this work, see: Mulrooney,
C. A.; Li, X.; DiVirgilio, E. S.; Kozlowski, M. C. J. Am. Chem. Soc. 2003,
125, 6856–6857.
(29) In prior work, Zhang (ref 12) and Lown (ref 13) have shown similar
transformations in the racemic syntheses of perylenequinones. Hauser (ref
15) also utilized dimerization of an o-quinone but found the pathway from
the bis-o-quinone to the perylenequinone to be unproductive.
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SCHEME 6. Retrosynthesis of the Perylenequinone Natural Products
SCHEME 7. Perylenequinone Retrosynthetic Analysis
SCHEME 9. Synthesis of C7-Propyl Substrate
counteracted the effect of the C4-acetoxy group and facili-
tated enantiomerization of 52c (entry 4).28 Additionally, the
steric gearing effects prevented the substrate from adopting
the conformation needed for catalyst coordination, explain-
ing the slow conversion as well as the low enantioselectivity.
With these results in hand, it was straightforward to design
substrates with a suitable oxidation potential (sufficiently
electron rich for the substrate to oxidize but not too electron
rich to allow product oxidation) to obtain high reactivity and
selectivity. For example, 52a,b,d (entries 1, 3, 5) furnish
functionalized binaphthols in high yield and enantioselec-
tivity. The M-helicity of these products was assigned on the
basis of trends observed with related substrates; in the over
30 cases where the stereochemistry has been assigned via
correlation, crystallization, or calculation, the S,S-catalyst
provides the M-helicity and the R,R-catalyst the P-helicity.31
Significantly, the enantioenriched naphthol 52d for this
investigation is generated with the necessary functionaliza-
tion at the C2,C3,C4,C7-centers.
Perylenequinone via a Bis-o-quinone. Following the success
of the enantioselective biaryl couplings, investigations began
into transforming biaryl 52d, arising from 45d, to perylene-
quinone 39 via bis-o-quinone 40 (Scheme 7). As previously
mentioned, there is precedent for oxidation of naphthalenes
with a phenol at the position peri to the reaction center using
various oxidants.30 Our efforts commenced with the synth-
esis of model biaryl 53, containing the necessary C4,C40-
phenols, but possessing C7,C70-methoxy groups instead of
propyl groups. Direct benzylation of the C2,C20-phenols to
SCHEME 8. Synthesis of Naphthol Substrates
significant results pertinent to this study.32 Notably, an
electron-withdrawing, coordinating group at C3 enhances
selectivity,31 presumably by via coordination to the copper
complex together with the C2-phenol. The effects of the
substrate oxidation potential are illustrated in entries 1-3
(Table 1),28 where the electron-rich nature of the trimethoxy
substrate (entry 2) led to lower optical purities due to rapid
atropisomerization of the product 52e via further oxidation.
Replacement of the donating C4-methoxy group with an
electron-withdrawing acetoxy group (entry 3) reduced the
oxidation potential and furnished the pentasubstituted
naphthalene 52b in high enantioselectivity. The introduction
of an additional electron-donating group (C5-methoxy)
(32) Further investigations of the biaryl coupling reaction are examined
in the subsequent paper in this series. Morgan, B. J.; Mulrooney, C.A.;
O’Brien, E. M.; Kozlowski, M. C. J. Org. Chem. 2010, 75, (DOI 10.1021/
jo901384h).
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TABLE 1. Enantioselective Biaryl Coupling with Diaza-cis-decalin
(S,S)-51
SCHEME 10. Synthesis of Bis-o-quinone 54 (ORTEP Drawing
with 30% Probability Thermal Ellipsoids)
entry
R1
R2
R3
product
yield (%), ee (%)
1
2
3
4
5
H
OMe
OMe
OMe
n-propyl
H
H
H
OMe
H
Ac
Me
Ac
Ac
Ac
a
e
b
c
d
71, 86
81, 35 (P)a
72, 90 (P)b
41, 27
85, 87
a(M)-Enantiomer formed initially. b(R,R)-51 catalyst complex was
used.
more closely approximate Merlic’s system (eq 2) in forma-
tion of the pentacyclic core. Coupling of 45d with CuCl(OH)-
TMEDA under O2 provided large quantities of the racemic
biaryl 52d, which we employed to develop a viable route to
39. Biaryl 52d was treated with NaH and MeI to methylate
the C2,C20-phenols. As has been seen throughout the series,
alkylation of the hindered C2,C20-phenols is difficult, and
this transformation required the use of anhydrous DMF33 to
succeed. Subsequent hydrolysis of C4,C40-acetates effi-
ciently afforded 59 (Scheme 11). Oxidation utilizing PIFA
yielded the desired bis-o-quinone 60 in quantitative yield, but
this compound was unstable to chromatography or pro-
longed exposure to air. Immediate methylation of the C4,
C40-phenols with n-Bu4NF and MeI provided the stable 61,
which could be purified. Surprisingly, 61 could not be
isomerized to the perylenequinone 62 and only decomposi-
tion occurred following the procedure developed by Merlic.
Presumably, the isomerization requires one of the o-quinone
moieties to reduce so that a nucleophilic phenol can undergo
a transannular addition to the remaining electrophilic
o-quinone. Subsequent tautomerization and air oxida-
tion would then furnish the perylenequinone. In an
attempt to reproduce this manifold, bis-o-quinone 61 was
treated under conditions to induce reduction (NaBH4 and O2
or DBU and O2); however, only decomposition was ob-
served.
generate 53 was unsuccessful, a trend that was observed
throughout the series. Apparently, the C2,C20-positions
are relatively hindered, which slows alkylation significantly.
On the other hand, Mitsunobu reaction generally proceeded
well on these centers and was used here to install the
C2,C20-benzyl ethers. Subsequent hydrolysis of the
C4,C40-acetates afforded 53 (Scheme 10). After screening
a number of oxidants, the hypervalent iodine reagent
bis(trifluoroacetoxy)iodobenzene [PIFA = PhI(O2CCF3)2]
following McKillop’s protocol was found to generate
the desired bis-o-quinone 54 as confirmed by the crystal
structure.
With the model bis-o-quinone 54 in hand, we next exami-
ned formation of the perylenequinone core. Merlic has
reported the transformation of a similar bis-o-quinone 55
to perylenequinone 56 using trifluoroacetic acid (TFA)
under O2 (eq 2).17 When applied to methylated 57, this
procedure yielded only decomposition products (eq 3). We
attributed this result to the differences between the
two o-quinones (55 vs 57), specifically the presence of C2,
C20-benzyl ether, C3,C30-ester, and C7,C70-methyl ether
groups in 57.
The presence of the C3,C30-methyl ester groups accounts
for the last major difference between the previously isomer-
ized bis-o-quinone 55 (eq 2) and the structures 57 (eq 3) and
61 (Scheme 11). The electron-withdrawing nature of the
methyl esters may destabilize the perylenequinone 62 and/
or interfere with the isomerization. To test the hypothesis,
decarboxylation of the biaryl was examined. To generate a
biaryl that would be stable to saponification and decarbox-
ylation, the previously formed bis-o-quinone 61 (Scheme 11)
was reduced with sodium dithionite (Na2S2O4) and methy-
lated (Scheme 12). Unfortunately, mixtures of the desired
octamethyl ether 63, partially reduced hexamethyl ether 63a
Reasoning that the C7,C70-methoxy groups of 57 (eq 3)
changed the electronic characteristics of the o-quinone re-
lative to 55 (eq 2), we moved to biaryl 59 (Scheme 11) with
C7,C7-n-propyl groups as well as C2,C20-methoxy groups to
(33) In a later synthesis involving substrate 52d, wet DMF is used as the
solvent. These conditions cleave the acetates (presumably due to NaOH
formed from trace H2O combined with the NaH) revealing a tetraphenol,
which is exhaustively alkylated with the MeI to form a tetramethyl ether (82,
Scheme 18).
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SCHEME 11. Attempted Synthesis of C7,C70-Bispropyl Pery-
lenequinone
SCHEME 12. Decarboxylation and Attempted Synthesis of a
Perylenequinone
and starting material 61 were obtained with the highest yield
of 46% for 63. Saponification of 63 proceeded smoothly with
aqueous LiOH in refluxing dioxane, to afford the bisacid.
Subsequent decarboxylation with Cu-quinoline at 180 °C
furnished 64 in a modest 30% yield over two steps
(Scheme 12). Thereafter, treatment of 64 with BCl3 in an
attempt to selectively cleave the C5,C50-methyl ethers re-
sulted in a mixture of demethylated compounds, which upon
treatment with K3Fe(CN)6 yielded only a complex mixture
from which none of the desired 65 was isolated. Fortunately,
removal of the C5,C50-methyl ethers was not necessary for
oxidation and direct exposure of 64 to ceric ammonium
nitrate (CAN) afforded the oxidized bis-o-quinone 40
(Scheme 12). Longer reaction times in the CAN oxidation
did not afford the desired perylenequinone 65, and all
attempts to isomerize 40 to 65 led only to decomposition.
This result was surprising due to the close structural simila-
rity of 40 (Scheme 12) to 55 (eq 2).
With confidence that the synthesis of perylenequinone
62 via this route could be optimized the reactions were
examined with enantioenriched 52d to verify the optical
purity of the synthetic intermediates. Formation of enan-
tioenriched 59 (70% ee) following the racemic synthesis
seen in Scheme 11, permitted the PIFA-mediated oxida-
tion of the optically active intermediate to bis-o-quinone
61 in 70% yield (eq 4). Disappointingly, when evaluated by
both optical rotation and HPLC, compound 61 was found
to be racemic.
Since an examination of the transformation proposed
by Hauser and Merlic15,17 indicated that a direct isomer-
ization of 40 to 65 (Scheme 12) is not viable without a
reducing agent, protocols involving a reduction were
examined. Strong precedent for such an approach is seen
in the work of Lown13 and Zhang12 on the syntheses of a
perylenequinones from bis-o-quinones via a two-step
reduction-oxidation sequence (FeCl2, then FeCl3; SO2-
H2O, then FeCl3). Due to the length of the synthetic route
needed to obtain large quantities of bis-o-quinone 40,
61 was used to examine these new isomerization proce-
dures. Treatment of 61 with the reducing agent Na2S2O4
followed by FeCl3 afforded a complex mixture that
was determined to contain the undesired isomer 61 as
the major product as well as the desired product 62
(Scheme 13).34
The mechanism of the oxidation reaction was studied to
provide an explanation of the atropisomerization. The use of
PIFA and phenyliodonium diacetate [PIDA = PhI(OAc)2]
for phenolic oxidation has been well reviewed,35 and notably,
biphenol 67, upon oxidation leads to the extended quinone
68 (eq 5).36 When only 2 equiv of PIFA (7.5 equiv used in
eq 4) were used in the oxidation of 59, a binaphthone
(69, Figure 3) was isolated as a dark green material from
(35) (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123–1178.
(b) Moriarty, R. M.; Prakash, O. Acc. Chem. Res. 1986, 19, 244–250.
(c) Pohnert, G. J. Prakt. Chem. 2000, 342, 731–734.
(34) Compound 62 proved unstable to SiO2 chromatography, but a small
portion was purified by semipreparative reversed-phase HPLC to confirm
the structure via 1H NMR spectroscopy.
(36) Pelter, A.; Ward, R. S. Tetrahedron 2001, 57, 273–282.
22 J. Org. Chem. Vol. 75, No. 1, 2010

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FIGURE 3. Strained extended quinone structures.
FIGURE 4. Proposed racemization pathway of 69.
SCHEME 13. Two-Step Synthesis of Perylenequinone from
Bis-o-quinone
SCHEME 14. Isolated Intermediate in the Oxidation to Bis-o-
Quinone 60
the reaction mixture. In our assignment of 69, the propyl
1
groups are placed anti to each other because the H NMR
intermediacy of 69 during the PIFA-oxidation of 59 to bis-o-
quinone 61 (eq 4).
spectrum does not indicate any restricted rotation about the
propyl groups (i.e., diastereotopic protons), which is seen in
the 1H NMR spectra of perylenequinones where the
propyl groups are in close proximity. Similar to 69, the
highly strained bianthrone 70 has been reported in the
literature.37,38 Interestingly, bianthrone 70 was found to
equilibrate between twisted and stack conformations
(Figure 3). Analogously, it is clear that 69 is a chiral
compound, but the facile interconversion of the twisted
and stacked conformations provides a ready racemization
pathway (Figure 4).
Based upon the above evidence, an oxidative mechanism
for conversion of binaphthol 59 to o-quinone 60 is proposed
in Scheme 15. One equivalent of PIFA oxidizes 59 to the
binaphthone 69 via adduct 71. The trifluoroacetic acid
liberated from the PIFA protonates the C4-carbonyl, pro-
moting conjugate addition of H2O to the C5-center. After
tautomerization, another oxidation forms the binaphthone
74. A second conjugate addition of H2O at the C50-position is
followed by tautomerization to intermediate 75 that can then
be oxidized twice further. Final hydrolysis of the alkylated
carbonyls of 76 with the excess H2O present furnishes bis-o-
quinone 60. This mechanism requires 4 equiv of an oxidant
to form 60 from 59, which is consistent with the amount
employed in eq 4.
Perylenequinone via an Oxidized Binaphthalene. Due to the
racemization of biaryl 59 during the formation of bis-o-
quinone 60, path a (Scheme 7) was not a viable route to
enantiopure 39. Shifting to path b, we examined the forma-
tion of 39 via an advanced biaryl intermediate 42, containing
C5,C50-benzyl ethers (Scheme 7). The first undertaking was
the hydroxylation of the C5,C50-centers to provide 42 from
available precursor 41. Based upon the above results
(Scheme 15), the C4,C40-phenols needed to be masked as
ethers during this oxidation to prevent formation of bina-
phthone 69. Thus, an oxidation was required that did not rely
on hydroxyl activation in oxidizing the C5,C50-centers. One
such method is the oxygenation of aryl lithiums with electro-
philic oxygen sources. Since the requisite binaphthalene (see
82 below) is very electron rich and the C5,C50-centers are
hindered, a naphthalene model system 78 was utilized to
The use of the less reactive PIDA allowed a full evaluation
of the oxidation pathway of 59 (Scheme 14). While all efforts
to optimize formation of binaphthone 69 with PIFA as the
oxidant proved to be unsuccessful, PIDA allows 69 to be
isolated in a 91% yield (Scheme 14) with minimal amounts of
decomposition during the reaction. The treatment of 69 with
2 equiv of PIFA yielded racemic 60, strongly supporting the
(37) The dinaphthofuranedione 24 in Scheme 2 (ref 20) is also similar to
the strained extended quinone structure of 69.
(38) (a) Kral, A.; Laatsch, H. Z. Naturforsch. 1993, 48b, 1401–1407.
(b) Tapuhi, Y.; Kalisky, O.; Agranat, I. J. Org. Chem. 1979, 44, 1949–1952.
(c) Evans, D. H.; Fitch, A. J. Am. Chem. Soc. 1984, 106, 3039–3041.
J. Org. Chem. Vol. 75, No. 1, 2010 23

Mulrooney et al.
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SCHEME 15. Proposed Mechanism for Bis-o-quinone Formation
explore the stability and reactivity of the corresponding
C5-lithium species. Model 78 was prepared by C5-bromina-
tion of 77 followed by hydrolysis of the C2,C4-acetates and
methylation to provide trimethyl ether 78 (Scheme 16). With
tert-butyllithium, lithium-halogen exchange provided inter-
mediate 79 as confirmed by quenching with D2O which gene-
rated the corresponding C5-deuterated arene and minimal
amounts of C3-tert-butyl ketone. Unfortunately, reaction
with a series of oxidants and electrophiles (oxygen gas, Davis
oxaziridine, lithium salt of tert-butyl hydroperoxide, and
B(OMe)3)39 was unsuccessful, which was attributed to the
hindered nature of the C5 center. Given this challenge, an
alternate aryl hydroxylation reaction was sought.
SCHEME 16. Attempted C5-Oxidation of a Naphthalene
Model System
Notably, Kita has utilized PIFA to induce the nucleophilic
substitution of phenyl ethers to afford functionalized arenes.40,41
His studies indicate that the reaction proceeds by a single-
electron transfer (SET) resulting in the formation of
a radical cation [ArH•þ] as the reactive intermediate (81,
eq 6).40 This mechanism contrasts with PIFA-oxidations
SCHEME 17. Regioselection in the PIFA-Mediated Hydroxy-
lation
described above (Scheme 10, 11, 14, and 15; eq 4), which
proceeded via phenolic C4,C40-hydroxyl activation
(Scheme 15). Based on the reported success of the acetoxy
group as a nucleophile in the PIFA-induced SET pathway,
we set out to synthesize an intermediate containing the
necessary perylenequinone oxygenation in this manner.
The greatest concern in this transformation was the re-
gioselection in the addition to the radical cation. In con-
sidering the radical cation, many resonance structures
are possible, but the two that are pertinent (cations at
(39) (a) Parker, K. A.; Koziski, K. A. J. Org. Chem. 1987, 52, 674–676.
(b) Davis, F. A.; Wei, J.; Sheppard, A. C.; Gubernick, S. Tetrahedron Lett.
1987, 28, 5115–5118. (c) Green, K. J. Org. Chem. 1991, 56, 4325–4326.
(40) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.; Mitoh,
S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684–3691.
(41) Arisawa, M.; Ramesh, N. G.; Nakajima, M.; Tohma, H.; Kita, Y.
J. Org. Chem. 2001, 66, 59–65.
unsubstituted positions where reaction will allow regene-
ration of aromaticity via deprotonation) are illustrated in
Scheme 17. The stabilization of the cations is expected to
24 J. Org. Chem. Vol. 75, No. 1, 2010

Mulrooney et al.
JOCArticle
be similar at C5 and C8. However, the radical would need
to reside at C6 or C7 to maintain the greatest amount of
conjugation in the system. The C6-methoxy would be
expected to stabilize radical character at the C6-position
to a greater degree. Thus, resonance structure 82b is
expected to predominate leading to reaction at the C5-
center. In addition, the C5-position is less hindered by
the neighboring C4,C6-methoxys than the C8-position
with larger flanking groups (C1-aryl group and C7-propyl
group). The requisite substrate to test this hypothesis was
prepared from 52d using reagent-grade DMF during methyla-
tion to conveniently prepare hexamethyl ether 82 in one step.33
After initial C2,C20-methylation, the small amount of water in
the DMF was converted to NaOH, cleaving the C4,C40-
acetates; subsequent methylation afforded 82 (Scheme 18).
Treatment of 82 with PIFA and TMSOAc in (CF3)2CHOH
afforded a mixture of compounds, from which bisphenol 87
and the C5,C50-bistrifluoroacetate 86 were isolated. The reac-
tion also proceeded well without TMSOAc; presumably, tri-
fluoroacetate from the PIFA is sufficiently nucleophilic to trap
the radical cation. When the reaction mixture (without
TMSOAc) was treated with aqueous NaOH, the bistrifluor-
oacetate intermediate 86 was efficiently cleaved furnishing 87
in 89% yield (Scheme 18). However, there was erosion in the
optical purity, from 86% ee in 82 to 68-70% ee in bisnaphthol
87. We propose that this attrition arises from racemization of
radical cation or cation intermediates where the atropisome-
rization barrier is lower.28 To mitigate this effect, hexafluoro-
2-propanol was replaced with the less polar trifluoroethanol,
which should be sufficiently polar to permit the initial SET to
the radical cation but will reduce its lifetime. Pleasingly,
bisnaphthol 87 was obtained with improved enantiopurity
(82% ee) but in a diminished 51% yield.42
The oxidative cyclization of 87 with MnO2 proceeded
smoothly to yield perylenequinone 88,16 representing the
first enantioselective synthesis of a perylenequinone with
the helical chirality as the only stereochemical element. Since
the optical purity of 88 could not be measured directly, the
C4,C40-methyl ethers were selectively removed using MgI2 to
provide 89.15,17 An HPLC assay verified the stereochemical
integrity of the axial to helical chirality transfer (Scheme 19).
Decarboxylation and Atropisomeric Stability. This initial
result on the atropisomeric stability of a perylenequinone
with no stereogenic elements aside from the helical axis was
encouraging. However, it was unclear that the corresponding
compounds lacking the C3,C30-ester groups, which were
needed as outlined in the retrosynthesis (see 33 in Scheme 6),
would possess the same degree of atropisomeric stability.
Removal of the C3,C30-ester groups alleviates steric gearing
interactions, thereby decreasing the effective size of the C2,
C20-groups so that they might more easily slide by one
another and thereby lower the atropisomerization barrier.
Thus, the synthesis of 39, which contains the necessary
substitution pattern of the natural products perylenequinone
core, was our next goal (Scheme 20). To accomplish this goal,
SCHEME 18. PIFA-Mediated Hydroxylation
SCHEME 19. Synthesis of Optically Active Perylenequinone 89
87 was treated with benzyl bromide and NaH to mask the
reactive C5,C50-phenols. Hydrolysis was affected by LiOH
to supply the diacid 90. Disappointingly, the high tempera-
tures of conventional aromatic decarboxylation protocols,
such as Cu-quinoline, caused not only atropisomerization
of the biaryl but also significant decomposition resulting
in modest yields of 42 (31% after optimization). As a
consequence, we developed a palladium decarboxylation
protocol involving stoichiometric palladium(II) trifluoro-
acetate and silver carbonate followed by the reduction of the
resultant aryl palladium species. The described procedure
worked well on these systems and supplied the key intermedi-
ate 42 in 87% yield without racemization.19,43 Further exam-
ination of this strategy lead to the development of a single-step
decarboxylation using catalytic palladium and excess of tri-
fluoroacetic acid as the proton source to provide a variety
arenes in good yield.43 After hydrogenolysis of bisbenzyl ether
42, the axial chiral bisphenol was oxidized by MnO2 to afford
the helical chiral perylenequinone as a bright red resin
(Scheme 20). The directed, selective cleavage of the C4,C40-
methyl ethers was accomplished by MgI2 to complete the
first synthesis of optically active perylenequinone 39.44,45
(43) Dickstein, J. S.; Mulrooney, C. A.; O’Brien, E. M; Morgan, B. J.;
Kozlowski, M. C. Org. Lett. 2007, 9, 2441–2444.
(44) Merlic, in ref 17, synthesized perylenequinone 39 as the racemate via
the dimerization of an o-quinone, but no logical entry to the enantioenriched
variant is available with such a route.
(45) Following this work, the synthesis of 39 evolved further, culminating
in a 16-step protocol with 4.2% overall yield of 98% ee material. The
evolution is described briefly in ref 19 and in detail in the third paper in this
series. Morgan, B. J.; Mulrooney, C.; Kozlowski, M. C. J. Org. Chem. 2010,
75 (DOI 10.1021/jo9013854).
(42) Improvements to the hydroxylation reaction were later developed,
mitigating the loss of yield and enantioenrichment. As seen in the subsequent
papers in this series on more complex intermediates, no erosion of enan-
tioenrichment was observed when NaOAc was used to quench the reagents
after oxidation. The NaOAc was added prior to solvent evaporation and
subsequent NaOH treatment removes excess oxidant and TFA that can
cause degradation.
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SCHEME 20. Palladium-Mediated Decarboxylation and
Synthesis of Optically Active 39
1.57-1.67 (m, 4H), 2.57 (t, J = 7.5 Hz, 2H), 3.54 (s, 2H), 3.80
(s, 3H), 4.05 (t, J = 6.5 Hz, 2H), 6.78 (d, J = 8.1 Hz, 1H), 7.06
(m, 2H).
A mixture of propyl ester (329 mg, 1.31 mmol) and 1 N NaOH
(5 mL, 5 mmol) in THF (5 mL) was stirred for 16 h. The reaction
was diluted with 1 N NaOH and hexanes, and the aqueous phase
was extracted with hexanes. The aqueous phase was then
acidified with 1 N HCl and extracted with EtOAc. The organic
phase was washed with H2O and brine and dried (Na2SO4), and
the solvent was evaporated to yield 49 as a white solid (250 mg,
92%): mp 58-60 °C; IR (thin film) 3076 (br), 3003, 2961, 1710,
1251 cm-1; 1H NMR (500 MHz, CDCl3) δ 0.94 (t, J = 7.4 Hz,
3H), 1.56-1.62 (m, 2H), 2.56 (t, J = 7.6 Hz, 2H), 3.57 (s, 2H),
3.80 (s, 3H), 6.79 (d, J =8.2 Hz, 1H), 7.03 (s, 1H), 7.07 (d, J=
8.3 Hz, 1H), 11.0 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ
178.5, 157.0, 131.8, 131.3, 128.0, 125.3, 110.8, 55.8, 40.7, 32.6,
23.3, 14.5; HRMS (CI) [Mþ] calcd for C12H16O3 208.1099,
found 208.1104.
Methyl 1,3-Dihydroxy-7-methoxy-6-propyl-2-naphthoate (50).
To a solution of acid 49 (6.4 g, 30.7 mmol) in PhH (30 mL) was
added SOCl2 (9.0 mL, 123 mmol). The reaction was heated to
reflux under Ar for 2 h. The solvent was evaporated in vacuo to
yield a brown oil. To a suspension of NaH (60% in mineral oil,
3.7 g, 92.1 mmol) in THF (200 mL) under Ar was added dimethyl
malonate (10.5mL, 92.1 mmol). After being stirred for 30 min, the
mixture was chilled in an ice-H2O bath, and a solution of the
above acid chloride in THF (50 mL) was added. The reaction was
stirred for 3 h with warming to room temperature. The mixture
was poured into a mixture of ice and 1 N HCl and extracted into
EtOAc. The organic phase was washed with H2O and brine and
dried (Na2SO4), and the solvent was evaporated. The oil was
filtered through SiO2, rinsing with 0-20% EtOAc/hexanes. The
solvent was evaporated, the oil was dissolved in MeSO3H (55mL),
and P2O5 (5.0 g) was added. After being stirred under Ar for 3 h,
the mixture was poured over ice-H2O and filtered. The yellow
solid was dissolved in CH2Cl2, was washed with H2O and brine,
and dried (Na2SO4), and the solvent was evaporated to yield 50
(6.9 g, 77%), which was carried on to the next step without further
purification: IR (thin film) 3443, 2957, 1670, 1644, 1252, 1217,
1158 cm-1; 1H NMR (500 MHz, CDCl3) δ 0.99 (t, J = 7.3 Hz,
3H), 1.64-1.71 (m, 2H), 2.69 (t, J=7.4 Hz, 2H), 3.92 (s, 3H), 4.10
(s, 3H), 6.71 (s, 1H), 7.29 (s, 1H), 7.43 (s, 1H), 8.63 (br s,1H), 11.32
(br s, 1H); 13C NMR (125 MHz, CDCl3) δ 171.0, 160.4, 155.2,
152.4, 138.5, 133.7, 126.7, 118.9, 102.4, 101.2, 97.2, 55.7, 53.3, 33.3,
23.0, 14.5; HRMS (CI) [Mþ] calcd for C16H18O5 290.1154, found
290.1156.
Pleasingly, perylenequinone 39 was also found to exhibit
considerable atropisomeric stability with an atropisomeriza-
tion half-life of 4 d at 60 °C in benzene.19
Summary. As summarized in Scheme 21, the final route to
39 proceeded in 18 steps and a 5.4% overall yield (92%
average yield per step). The key steps in this synthesis were an
enantioselective biaryl coupling, a PIFA-induced phenol
formation, and a palladium-mediated aromatic decarboxy-
lation. The development and optimization of these transfor-
mations was crucial not only to this investigation but also for
the syntheses of the perylenequinone natural products de-
tailed in the subsequent papers in this series.
Conclusions. The synthesis of 39 provided the first helical
chiral perylenequinone containing the natural product sub-
stitution pattern but absent the conventional stereogenic C7,
C70-substitution. The central issues addressed here including
generation of the necessary oxygenation pattern in a complex
binaphthol and formation of the helical stereochemistry.
Importantly, such perylenequinones were shown to possess
sufficient atropisomeric stability to be viable intermediates
in the biogenesis of the perylenequinone natural products.
Furthermore, this stability supports their use as key inter-
mediates in biomimetic total synthesis ventures (see 33 in the
retrosynthesis in Scheme 6). Thus, these discoveries laid the
groundwork for the total syntheses of (þ)-calphostin D (8d)
and (þ)-phleichrome (9)19 and the first total syntheses of
cercosporin (6)19 and hypocrellin A (ent-2),18 which are des-
cribed in the following papers in this series (DOIs 10.1021/
jo901384h, 10.1021/jo9013854, and 10.1021/jo901386d). Im-
portantly, the versatility of this strategy enabled selective and
convergent synthesis of all stereoisomeric combinations per-
mitting comparison of their biological effects for the first
time.19
Methyl 1-Acetoxy-3-hydroxy-7-methoxy-6-propyl-2-naphtho-
ate (45d). A solution of naphthol 50 (6.0 g, 20.7 mmol), Ac2O
(60 mL), and pyridine (60 mL) was stirred for 3 h. The reaction
mixture was poured over ice-1 N HCl and stirred for 30 min.
The solid was filtered, rinsed with H2O, and dried by pulling air
through the filter cake to yield the diacetate (6.9 g, 89%): IR
(thin film) 2955, 1776, 1724, 1316, 1195 cm-1 1H NMR
;
(500 MHz, CDCl3) δ 0.97 (t, J = 7.3 Hz, 3H), 1.64-1.69 (m,
2H), 2.32 (s, 3H), 2.44 (s, 3H), 2.72 (t, J =7.4 Hz, 2H), 3.90 (s,
3H), 3.91 (s, 3H), 7.01 (s, 1H), 7.37 (s, 1H), 7.52 (s, 1H); 13C
NMR (125 MHz, CDCl3) δ 170.0, 169.2, 164.6, 158.0, 146.4,
143.8, 137.1, 130.6, 128.2, 125.6, 118.4, 116.5, 99.5, 55.7, 52.8,
33.1, 22.9, 21.3, 21.2, 14.4; HRMS (ESI) calcd for C20H22O7
(Mþ) 374.1366, found 374.1364.
Experimental Section
To a solution of this acetate (2.5 g, 6.7 mmol) in MeOH
(150 mL) and CH2Cl2 (15 mL) under Ar was added K2CO3
(913 mg, 6.6 mmol). After being stirred for 15 min, the green
reaction mixture was poured over ice-1 N HCl. The aqueous
phase was extracted with CH2Cl2 and the organic extracts were
washed with brine, dried (Na2SO4), and the solvent was evapo-
rated. Purification was accomplished with chromatography
(10-20% EtOAc/hexanes) to yield product 45d as a yellow
2-(4-Methoxy-3-propylphenyl)acetic Acid (49). To a solution
of 47 (1.0 g, 4.0 mmol) in MeOH (50 mL) was added 10% Pd/C
(106 mg), and the mixture was stirred under H2 (1 atm). After
2 d, the reaction was filtered through Celite, rinsing with
CH2Cl2. This solution was filtered through SiO2, and the solvent
was evaporated to yield the dipropyl product as an oil (1.0 g,
100%): 1H NMR (360 MHz, CDCl3) δ 0.90-0.97 (m, 6H),
26 J. Org. Chem. Vol. 75, No. 1, 2010

Mulrooney et al.
JOCArticle
SCHEME 21. Enantioselective Total Synthesis of (M)-39
solid (1.7 g, 76%): mp 121.5-125.5 °C; IR (thin film) 3155, 2957,
1773,46 1675, 1223, 1197 cm-1; 1H NMR (500 MHz, CDCl3) δ
0.98 (t. J=7.4 Hz, 3H), 1.65-1.69 (m, 2H), 2.48 (s, 3H), 2.69 (t,
J=7.5 Hz, 2H), 3.89 (s, 3H), 4.00 (s, 3H), 6.91 (s, 1H), 7.17 (s,
1H), 7.39 (s, 1H), 10.48 (s, 1H); 13C NMR (125 MHz, CDCl3) δ
169.9, 169.6, 156.3, 155.2, 147.6, 138.5, 133.8, 127.0, 121.6,
110.1, 107.2, 99.1, 55.5, 53.4, 33.2, 22.9, 21.3, 14.4; HRMS
(CI) calcd for C18H20O6 (Mþ) 332.1260, found 332.1250.
General Procedure for the Oxidative Biaryl Coupling. To a
solution of the 2-naphthol substrate dissolved in the appropriate
solvent was added the copper catalyst (10 mol %). The mixture
was sonicated to yield a clear green, blue, purple, or red solution,
which was stirred under O2 (1 atm) at the indicated temperature
and time. After cooling, the reaction mixture was diluted with
CH2Cl2 and washed with 1 N HCl. The aqueous phase was back
extracted with CH2Cl2 and the combined organic solutions were
dried over Na2SO4. Filtration and concentration afforded the
crude product. Purification was accomplished by SiO2 chroma-
tography.
washed with H2O. Concentration afforded an oil which was
purified by SiO2 chromatography (2-3.5% MeOH/CH2Cl2) to
provide 54 as a red solid (45 mg, 88%): IR (thin film) 3683, 2954,
1733, 1693, 1636, 1608, 1274, 1261, 1227, 1115 cm-1; 1H NMR
(500 MHz, CD2Cl2/DMSO-d6) δ 3.60 (s, 6H), 3.99 (s, 6H), 4.84
(d, J=9.0 Hz, 2H), 5.08 (d, J=9.0 Hz, 2H), 5.84 (s, 2OH), 7.09
(m, 4H), 7.24 (m, 6H), 12.9 (s, 2OH); 13C NMR (125 MHz,
CD2Cl2/DMSO-d6) δ 179.8, 175.3, 165.4, 163.6, 152.8, 137.1,
135.6, 128.5, 128.4, 128.1, 127.7, 126.7, 119.7, 115.3, 109.2,
109.1, 76.2, 56.0, 53.0; HRMS (ESI) cald for C40H30O14Na
(MNaþ) 757.1558, found 757.1533.
Dimethyl 2,20,4,40-Tetramethoxy-5,50,6,60-tetraoxo-7,70-di-
propyl-5,50,6,60-tetrahydro-1,10-binaphthyl-3,30-dicarboxylate (61).
To a solution of binaphthol 59 (230 mg, 0.379 mmol) in MeCN
(50 mL), CH2Cl2 (20 mL), and H2O (10 mL) was added PhI(OC-
(O)CF3)2 (1.2 g, 2.8 mmol). The dark blue reaction mixture was
stirred for 45 min and then diluted with H2O and EtOAc. The
phases were separated, and the aqueous phase was washed with
EtOAc. The organic phase was extracted with H2O and brine and
dried (Na2SO4), and the solvent was evaporated to yield 60 as an
orange solid that was carried on to the next step without further
purification: 1H NMR (500 MHz, CDCl3) δ 0.87 (t, J = 7.3 Hz,
6H), 1.39-1.44 (m, 4H), 2.32 (t, J=6.7 Hz, 4H), 3.80 (s, 6H), 3.99
(s, 6H), 6.60 (s, 2H), 12.8 (br s, 2H); CSP HPLC (Chiralpak AD,
1.0 mL/min, 70:30 hexanes/i-PrOH) tR(S) = 12.3 min, tR(R) =
22.2 min.
(M)-Dimethyl 4,40-Diacetoxy-2,20-dihydroxy-6,60-dimethoxy-
7,70-dipropyl-1,10-binaphthyl-3,30-dicarboxylate (52d). A mix-
˚
ture of naphthol 45d (103 mg, 0.309 mmol), 4 A molecular
sieves (86 mg), and CuI-(S,S)-51 (11.4 mg, 0.0329 mmol) in
MeCN (1.5 mL) was stirred at room temperature under an O2
atmosphere for 24 h. The reaction was quenched with 1 N HCl,
and the aqueous phase was extracted with EtOAc. The organic
extracts were washed with H2O and brine, dried (Na2SO4), and
filtered through SiO2 with 10% MeOH/CH2Cl2. Purification
was accomplished via chromatography to yield the product as a
resin (86.7 mg, 85%) in 87% ee: [R]2D0 þ20.9 (c 0.23, MeOH, 87%
ee); IR (thin film) 3130, 2958, 1770, 1672, 1234, 1195 cm-1; 1H
NMR (300 MHz, CDCl3) δ 0.79 (t, J=7.4 Hz, 6H), 1.39-1.44
(m, 4H), 2.44-2.55 (m, 10H), 3.90 (s, 6H), 4.01 (s, 6H), 6.91 (s,
2H), 7.05 (s, 2H), 10.64 (s, 2H); 13C NMR (125 MHz, CDCl3) δ
170.1, 169.7, 156.3, 152.9, 147.8, 138.7, 133.2, 125.8, 121.8,
115.4, 107.3, 99.7, 55.5, 53.4, 33.5, 23.2, 21.9, 14.3; HRMS
(ESI) calcd for C36H38O12Na (MNaþ) 685.2261, found
685.2276; CSP HPLC (Chiralpak AD, 1.0 mL/min, 70:30
hexanes/i-PrOH) tR(S)= 10.5 min, tR(R)= 13.3 min.
To a solution of o-quinone (0.379 mmol) and MeI (0.20 mL,
3.2 mmol) in THF (30 mL) was added TBAF (1 M in THF,
1.5 mL, 1.5 mmol). The black reaction mixture was stirred for
16 h and then diluted with EtOAc and H2O. The phases were
separated, and the aqueous phase was washed with EtOAc. The
organic phase was washed with H2O and brine and dried
(Na2SO4), and the solvent was evaporated to yield an orange
solid. Purification by chromatography (30% EtOAc/hexanes)
yielded product 61 as an orange solid (168 mg, 70%): mp 95-
1
97 °C; IR (thin film) 2955, 1737, 1667, 1224 cm-1; H NMR
(500 MHz, CDCl3) δ 0.87 (t, J=7.3 Hz, 6H), 1.41 (m, 4H), 2.31
(m, 4H), 3.71 (s, 6H), 3.94 (s, 6H), 3.97 (s, 6H), 6.71 (s, 2H); 13C
NMR (125 MHz, CDCl3) δ 180.8, 177.3, 165.7, 163.6, 161.1,
143.0, 138.0, 137.0, 122.9, 122.7, 118.9, 63.8, 60.8, 53.5, 32.0,
21.9, 14.0; HRMS (ESI) calcd for C34H34O12Na (MNaþ)
657.1948, found 657.1936; CSP HPLC (Chiralpak AD, 1.0 mL/
min, 70:30 hexanes/i-PrOH) tR(S)=14.7 min, tR(R)=36.3 min.
2,20,4,40-Tetramethoxy-7,70-dipropyl-1,10-binaphthyl-5,50,6,60-
tetraone (40). To a solution of 64 (3.0 mg, 0.0052 mmol) in MeCN
(0.5 mL) were addedH2O(1drop) andCAN(31mg, 0.057 mmol).
The red reaction mixture was stirred for 10 min, diluted with H2O,
and extracted with EtOAc. The organic phase was washed
with H2O and brine and dried (Na2SO4), and the solvent was
Dimethyl 2,20-Bis(benzyloxy)-4,40-dihydroxy-7,70-dimethoxy-
5,50,6,60-tetraoxo-5,50,6,60-tetrahydro-1,10-binaphthyl-3,30-dicar-
boxylate (54). Bisphenol 53 (51 mg, 0.07 mmol, 74% ee) was
dissolved in MeCN/CH2Cl2/H2O (6:1:1, 8 mL), and PhI-
(OCOCF3)2 (300 mg, 0.7 mmol) was added. After 2 h at room
temperature, the deep red solution was diluted with CH2Cl2 and
(46) The high wavenumber of the CdO in the acetate groups has been
observed in simple acetate protected phenols: The Aldrich Library of 13C and
1H FTNMR Spectra, 1st ed.; Pouchert, C. J., Behnke, J., Eds.; Aldrich
Chemical Co.: Milwaukee, WI, 1993.
J. Org. Chem. Vol. 75, No. 1, 2010 27

Mulrooney et al.
JOCArticle
evaporated to yield 40 as an orange oil that was not stable
to further purification: H NMR (500 MHz, CDCl3) δ 0.83 (t,
J=7.4 Hz, 6H), 1.35-1.40 (m, 4H), 2.26 (t, J=6.4 Hz, 4H), 3.83
(s, 6H), 4.08 (s, 6H), 6.52 (s, 2H), 6.69 (s, 2H).
added 60% NaH (12.5 mg, 0.312 mmol). The dark green mixture
was stirred for 15 h, quenched with H2O, and washed with EtOAc.
The organic phase was washed with H2O and brine and dried
(Na2SO4), and the solvent was evaporated to yield an orange oil.
Purification was accomplished by chromatography (15% EtOAc/
hexanes) to yield the bisbenzyl ether (36 mg, 78%) as a yellow
resin: [R]2D0 -24.7 (c 1.0, CHCl3, 68% ee); IR (thin film) 2939,
1735, 1330, 1094 cm-1; 1H NMR (500 MHz, CDCl3) δ 0.75 (t, J=
7.4 Hz, 6H), 1.39-1.43 (m, 4H), 2.49-2.54 (m, 4H), 3.39 (s, 6H),
3.95 (s, 6H), 3.98 (s, 6H), 4.00 (s, 6H), 5.09 (m, 4H), 6.76 (s, 2H),
7.38 (t, J = 7.3 Hz, 2H), 7.44 (t, J = 7.3 Hz, 4H), 7.63 (d, J =
7.0 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 167.8, 154.4, 152.6,
146.8, 138.9, 138.4, 133.8, 129.2, 128.8, 128.3, 127.4, 123.1, 120.7,
120.3, 114.2, 77.1, 64.6, 62.3, 60.9, 53.2, 33.2, 23.9, 14.2; HRMS
(ESI) calcd for C50H54O12Na (MNaþ) 869.3513, found 869.3541.
To a suspension of the bisbenzyl ether (163 mg, 0.192 mmol)
1
2,20,6,60-Tetramethoxy-4,40-dioxo-7,70-dipropyl-4H,40H-[1,10]-
binaphthalenylidene-3,30-dicarboxylic Acid Dimethyl Ester (69).
A mixture of MeCN (7 mL), CH2Cl2 (3 mL), and H2O (1 mL)
was degassed with Ar for 15 min. Naphthol 59 (32.3 mg, 0.0532
mmol) was added followed by PIDA (44.2 mg, 0.118 mmol). The
reaction mixture turned a dark blue color and was stirred for 1 h.
The reactionmixture wasdilutedwithEtOAc andH2O, the phases
were partitioned, and the organic layer was washed with H2O and
brine. After drying (Na2SO4), the solvent was evaporated. Puri-
fication was accomplished with chromatography to yield 29 mg
(91%) of a dark green resin that was not stable in solution over
extended periods of time: IR (thin film) 2957, 1737, 1586, 1227 cm-1
;
1H NMR (500 MHz, CD2Cl2) δ 0.86 (t, J = 7.4 Hz, 6H),
1.47-1.50 (m, 2H), 2.52 (m, 4H), 3.58 (s, 6H), 3.90 (s, 6H), 3.97
(s, 6H), 7.34, (s, 2H), 7.50 (s, 2H); HRMS (ES) calcd for
C34H37O10 (MHþ) 605.2387, found 605.2412. Bianthrone 69
was unstable in solution over time precluding 13C NMR char-
acterization.
in dioxane (8 mL) and H2O (9 mL) was added LiOH H2O
3
(402 mg, 9.57 mmol), and the mixture was heated to reflux for
24 h. The brown mixture was cooled to room temperature and
diluted with H2O. The aqueous phase was washed with EtOAc,
the organic phase was washed with H2O and brine and dried
(Na2SO4), and the solvent was evaporated to recover 73 mg
(0.086 mmol, 45%) of starting material. The aqueous phase was
acidified with 1 N HCl and extracted with EtOAc, the organic
phase was washed with H2O and brine and dried (Na2SO4), and
the solvent was evaporated to yield the diacid 90 (81 mg, 93%
based on recovered starting material) as an orange resin that was
used for the next step without further purification: [R]2D0 -29.1 (c
1.0, CHCl3, 82% ee); IR (thin film) 2937, 1736, 1707, 1327, 1107
cm-1; 1H NMR (500 MHz, CDCl3) δ 0.76 (t, J = 7.3 Hz, 6H),
1.40-1.44 (m, 4H), 2.50-2.54 (m, 4H), 3.44 (s, 6H), 3.72 (s, 6H),
3.98 (s, 6H), 3.99 (s, 6H), 5.11 (dd, J=9.8, 14.9 Hz, 4H), 6.80 (s,
2H), 7.36 (t, J=7.3 Hz, 2H), 7.43 (t, J=7.3 Hz, 4H), 7.64 (d, J=
7.0 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 172.5, 155.2, 152.4,
150.7, 146.9, 139.3, 138.2, 134.5, 129.3, 128.8, 128.3, 122.9,
122.1, 120.6, 120.1, 67.5, 65.2, 62.4, 61.7, 33.2, 23.9, 14.2; HRMS
(ESI) calcd for C48H50O12Na (MNaþ) 841.3200, found
841.3240.
(M)-Dimethyl 2,20,4,40,6,60-Hexamethoxy-7,70-dipropyl-1,10-
binaphthyl-3,30-dicarboxylate (82). To a solution of binaphthol
(M)-52d (70 mg, 0.11 mmol) in DMF (2 mL) under an Ar
atmosphere was added NaH (60%, 82 mg, 2.1 mmol). The
mixture was stirred for 10 min, and then CH3I (0.2 mL,
3.2 mmol) was added. The reaction was stirred at room tem-
perature for 18 h. The yellow mixture was quenched with H2O,
and the aqueous phase was extracted with EtOAc. The organics
were washed with brine and dried (MgSO4), and the solvent was
evaporated in vacuo to yield a yellow oil. Purification was
accomplished via chromatography (25% EtOAc/hexanes) to
yield 82 as a resin (52 mg, 75%): [R]2D0 -26.4 (c 0.22, MeOH, 86%
ee); IR (thin film) 2956, 1731, 1592, 1493, 1454, 1224, 1085, 1015,
1
733 cm-1; H NMR (500 MHz, CDCl3) δ 0.74 (t, J = 7.3 Hz,
6H), 1.37-1.41 (m, 4H), 2.44-2.49 (m, 4H), 3.31 (s, 6H), 3.95 (s,
6H), 3.97 (s, 6H), 4.13 (s, 6H), 6.90 (s, 2H), 7.40 (s, 2H); 13C
NMR (125 MHz, CDCl3) δ 167.9, 156.7, 153.6, 151.8, 135.5,
130.8, 127.1, 124.9, 120.4, 120.2, 100.2, 63.1, 62.3, 55.8, 52.9,
33.2, 23.2, 14.2; HRMS (ESI) calcd for C36H42O10Na (MNaþ)
657.2676, found 657.2666.
(M)-5,50-Bis(benzyloxy)-2,20,4,40,6,60-hexamethoxy-7,70-dipro-
pyl-1,10-binaphthyl (42). To a solution of diacid 90 (26.7 mg,
0.0326 mmol) in DMSO-DMF (0.3 mL) was added Pd(OC(O)-
CF3)2 (22.8 mg, 0.0739 mmol). The mixture was heated in a 90 °C
oil bath for 1 h. After the brown reaction mixture was cooled to
room temperature, 1 N HCl was added, and the mixture was
extracted with EtOAc. The organic phase was washed with H2O
and brine and dried (Na2SO4), and the solvent was evaporated to
yield a brown oil. This material was dissolved in THF (1.0 mL)
and stirred under a H2 atmosphere for 5 min. After filtration
through Celite, purification was accomplished via chromatogra-
phy (20% EtOAc/heanes) to yield 42 (20.7 mg, 87%) as a resin:
[R]2D0 0 (c 1.0, CHCl3, 70% ee) (this compound was resynthesized
but the optical rotation was still 0; the compound was carried on to
the next step and enantioselectivity confirmed by CSP HPLC (69%
ee)); IR (thin film) 2933, 1338 cm-1; 1H NMR (500 MHz, CDCl3)
δ 0.75 (t, J=7.2 Hz, 6H), 1.35-1.42 (m, 4H), 2.46-2.53 (m, 4H),
3.74 (s, 6H), 3.92 (s, 6H), 3.99 (s, 6H), 5.10 (m, 4H), 6.64 (s, 2H),
6.76 (s, 2H), 7.37 (t, J=7.3 Hz, 2H), 7.43 (t, J=7.3 Hz, 4H), 7.62
(d, J=7.0 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 157.1, 154.9,
148.8, 147.2, 138.9, 137.0, 133.7, 129.0, 128.5, 127.8, 122.1, 116.5,
112.5, 95.9, 76.2, 61.4, 57.5, 56.1, 32.8, 23.6, 14.0; HRMS (ESI)
calcd for C46H50O8Na (MNaþ) 753.3403, found 753.3427.
4,9-Dihydroxy-2,6,7,11-tetramethoxy-1,12-dipropylperylene-
3,10-dione (39). To a solution of binaphthalene 42 (6.4 mg, 0.0088
mmol) in MeOH (0.3 mL) and THF (0.3 mL) was added 10% Pd/
C (2 mg). The mixture was stirred under an atmosphere of H2
for 3 h. The reaction was filtered through Celite, rinsing with
MeOH and CH2Cl2. The solvents were evaporated to yield an
unstable yellow oil (69% ee): 1H NMR (500 MHz, CDCl3) δ 0.76
(M)-Dimethyl 5,50-Dihydroxy-2,20,4,40,6,60-hexamethoxy-7,70-
dipropyl-1,10-binaphthyl-3,30-dicarboxylate (87). To a solution of
binaphthalene 82 (131 mg, 0.269 mmol) in CF3CH2OH (10 mL)
under an Ar atmosphere was added PhI(OC(O)CF3)2 (199 mg,
0.463 mmol). After the purple mixture was stirred for 30 min, the
solvent was evaporated in vacuo. The resultant mixture was
treated with a mixture of 1 N NaOH (0.1 mL, 0.1 mmol) in
H2O/THF/EtOH (1:1:1, v/v/v) for 30 min, followed by acidifica-
tion with 1 N HCl. The aqueous phase was extracted with EtOAc,
the organics were washed with brine and dried (Na2SO4), and the
solvent was evaporated. Purification was accomplished by chro-
matography (25% EtOAc/hexanes) to yieldproduct 87 as a yellow
resin (70 mg, 51%, 82% ee): [R]2D0 -12.1 (c 0.22, MeOH, 76% ee);
1
IR (film) 3369, 2957, 1732, 1311 cm-1; H NMR (500 MHz,
CDCl3) δ 0.74 (t, J=7.2 Hz, 6H), 1.35-1.42 (m, 4H), 2.42-2.51
(m, 4H), 3.32 (s, 6H), 3.93 (s, 6H), 3.98 (s, 6H), 4.16 (s, 6H), 6.42 (s,
2H), 9.24 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 167.1, 154.4,
152.6, 146.0, 142.6, 139.8, 132.9, 120.8, 119.2, 117.6, 114.2, 64.6,
62.3, 60.9, 53.2, 33.2, 23.9, 14.2; HRMS (ESI) calcd for
C36H42O12Na (MNaþ) 689.2574, found 689.2599; CSP HPLC
(Chiralpak AD, 1.0 mL/min, 98:2 hexanes/i-PrOH) tR(S) =12.3
min, tR(R) =15.6 min.
(M)-5,50-Bis(benzyloxy)-2,20,4,40,6,60-hexamethoxy-7,70-dipro-
pyl-1,10-binaphthyl-3,30-dicarboxylic Acid (90). To a solution of
68% ee binaphthol 87 (37 mg, 0.055 mmol) and benzyl bromide
(46μL, 0.38 mmol) in DMF (1.0mL) under an Ar atmosphere was
28 J. Org. Chem. Vol. 75, No. 1, 2010

Mulrooney et al.
JOCArticle
(t, J=7.3 Hz, 6H), 1.38-1.43 (m, 4H), 2.43-2.47 (m, 4H), 3.69
(s, 6H), 3.89 (s, 6H), 4.16 (s, 6H), 6.37 (s, 2H), 6.70 (s, 2H), 9.28
(s, 2H); CSP HPLC (Chiralpak AD, 1.0 mL/min, 98:2 hexanes/
i-PrOH) tR(S) =37.9 min, tR(R) =45.2 min.
To a solution of bisnaphthol (11 mg, 0.020 mmol) in Et2O
(1 mL) was added MnO2 (60 mg, 0.69 mmol). The mixture was
stirred for 30 min and filtered through Celite, and the solvent
was evaporated to yield a red resin, which was chromatographed
(2.5% MeOH/CH2Cl2) to yield the perylenequinone as a red
resin: [R]2D0 -410 (c 0.021, MeOH, 69% ee); 1H NMR (500 MHz,
CDCl3) δ 0.54 (t, J=7.3 Hz, 6H), 0.96-0.99 (m, 2H), 1.18-1.22
(m, 2H), 2.48-2.51 (m, 2H), 3.08-3.11 (m, 2H), 4.05 (s, 6H),
4.11 (s, 6H), 4.17 (s, 6H), 6.78 (s, 2H).
To a solution of the above perylenequinone product (12 mg,
0.0221 mmol) in THF (2 mL) under an argon atmosphere was
added a solution of MgI2 in Et2O (0.07 M, 665 μL, 0.0464
mmol). The dark purple mixture was stirred for 10 min (until the
mixture turns from purple to black), diluted with EtOAc,
washed with saturated aq NH4Cl, and dried (Na2SO4). Con-
centration yielded a red residue, which was chromatographed
(2.5% MeOH/CH2Cl2) to yield product 39 as a red resin (10 mg,
87% (69% for the three steps)): 1H NMR (500 MHz, CDCl3) δ
0.52 (t, J=7.2 Hz, 6H), 0.88 (m, 2H), 1.25 (m, 2H), 2.76 (m, 2H),
3.33 (m, 2H), 4.09 (s, 6H), 4.21 (s, 6H), 6.59 (s, 2H), 15.82 (s, 2H);
13C NMR (125 MHz, CDCl3) δ 14.1, 24.3, 35.0, 56.3, 61.1,
101.1, 105.7, 116.5, 126.2, 127.5, 140.5, 151.0, 166.5, 174.1,
176.8; IR (film) 3383, 2927, 2858, 1607, 1460, 1274, 1213
cm-1; HRMS (ES) calcd for C30H31O8 (MHþ) 519.2019, found
519.2036; see the Supporting Information for the CD spectrum;
CSP HPLC (Chiralpak AD-H, 0.5 mL/min, 95:5 hexanes/
i-PrOH) tR (P)=15.9 min, tR (M)=17.1 min.
Acknowledgment. We are grateful to the NIH (CA-
109164) and NSF (CHE-0911713) for financial support.
Partial instrumentation support was provided by the NIH
for MS (1S10RR023444) and NMR (1S10RR022442). We
thank 3D Pharmaceuticals (C.A.M.), Novartis (B.J.M.), and
the Division of Organic Chemistry of the American Chemi-
cal Society (C.A.M., B.J.M.) for graduate fellowships. We
thank Feng Gai for assistance with CD measurements.
Thank you to Genette McGrew for the cover art prepara-
tion. The background to the cover art is being used with
permission of Wiley-Blackwell: Daub, M. E.; Herrero, S.;
Chung, K.-R. FEMS Microbiol. Lett. 2005, 252, 197-206.
Supporting Information Available: Additional experimental
descriptions, NMR spectra, and crystallographic data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 1, 2010 29