Perylenequinone natural products: Total synthesis of hypocrellin A

Article abstract of DOI:10.1021/jo901386d

(Chemical Equation Presented) An efficient and stereoselective total synthesis of the perylenequinone natural product hypocrellin A (1) is described. The key features include a potentially biomimetic 1,8-diketone aldol cyclization to set the centrochiral C7,C7′-stereochemistry, bis(trifluoroacetoxy)iodobenzene mediated oxygenation, a palladium-catalyzed decarboxylation, and an enantioselective catalytic oxidative 2-naphthol coupling to establish the biaryl axial chirality. The helical stereochemistry is formed from an axial chiral intermediate and is then utilized in a dynamic stereochemical transfer to dictate the stereochemistry of the C7,C7′-seven membered ring formed during the aldol cyclization.

Full text of DOI:10.1021/jo901386d

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Perylenequinone Natural Products: Total Synthesis of Hypocrellin A
Erin M. O’Brien, Barbara J. Morgan, Carol A. Mulrooney, Patrick J. Carroll, 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 efficient and stereoselective total synthesis of the perylenequinone natural product hypocrellin A
(1) is described. The key features include a potentially biomimetic 1,8-diketone aldol cyclization to set
the centrochiral C7,C70-stereochemistry, bis(trifluoroacetoxy)iodobenzene mediated oxygenation,
a palladium-catalyzed decarboxylation, and an enantioselective catalytic oxidative 2-naphthol
coupling to establish the biaryl axial chirality. The helical stereochemistry is formed from an axial
chiral intermediate and is then utilized in a dynamic stereochemical transfer to dictate the stereo-
chemistry of the C7,C70-seven membered ring formed during the aldol cyclization.
Introduction
The hypocrellin family 1-3 (Figure 1) are members of the
naturally occurring mold perylenequinones.1 Similar to
many other natural perylenequinones, the hypocrellins are
characterized by a helical chiral pentacyclic conjugated core
combined with C7,C70-substitution containing centrochiral
stereochemistry. However, pigments 1-3 are distinct from
other perylenequinones due to the unsymmetrical seven-
membered carbocyclic ring, which except for 2, contains
two stereogenic centers, one of which is quaternary. As a
result, these natural products lack the characteristic C2
symmetry which is present in most of the other members of
this class.2
The parent members of this family are the enantiomers
hypocrellin A (1) and hypocrellin (ent-1). Interestingly, 1 and
ent-1 arise from different fungal species (Figure 1). The first
member to be isolated and characterized was hypocrellin
FIGURE 1. Hypocrellin natural product family.
(ent-1) from Hypocrella bambusae.3 In subsequent seminal
publications from Wu4 and Kishi,5 1, 2, and 3, but not ent-1,
were isolated from Shiraia bambusicola. There has been
(1) For reviews, see: (a) Weiss, U.; Merlini, L.; Nasini, G. Prog. Chem.
€
Org. Nat. Prod. 1987, 52, 1–71. (b) Bringmann, G.; Gunther, C.; Ochse, M.;
Schupp, O.; Tasler, S. Prog. Chem. Org. Nat. Prod. 2001, 82, 1–249.
(2) For example, the perylenequinones (þ)-phleichrome, (þ)-calphostin
D, and cercosporin detailed in the previous papers in this series (DOIs:
10.1021/jo9012832, 10.1021/jo901384h, and 10.1021/jo9013854) are C2-sym-
metric due to the same identity of the C7,C70-positions.
(4) Wu, H; Lao, X. F.; Wang, Q. W.; Lu, R. R. J. Nat. Prod. 1989, 52,
948–951. (hypocrellin A is called shiraiachrome B here).
(3) Chen, W. S.; Chen, Y. T.; Wang, X. Y.; Friedrichs, E.; Puff, H.;
Breitmaier, E. Liebigs Ann. Chem. 1981, 1880–1885.
(5) Kishi, T.; Tahara, S.; Tsuda, M.; Tanaka, C.; Takahashi, S. Planta
Med. 1991, 57, 376–379. (shiraiachrome A is called hypocrellin B here).
DOI: 10.1021/jo901386d
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O’Brien et al.
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considerable variation and confusion in the naming of these
perylenequinones. For example, hypocrellin A (1) has been
referred to as shiraiachrome B.4 Furthermore, hypocrellin
(ent-1) has been referred to as hypocrellin A in several
reported studies on the biological and photodynamic proper-
ties of this family.6 Although attempts have been made to
systematize the nomenclature, irregularities still exist and for
1 and ent-1 the best way to determine the enantiomer utilized
is by its fungal species, Shiraia bambusicola and Hypocrella
bambusae, respectively. Here, we employ the names and
structural assignments suggested by Mondelli et al.7
Although misunderstandings did originate from the varied
nomenclature of 1-3, further confusion is present due to the
unusual architectural aspects of the hypocrellins, namely
keto-enol tautomerism and rapid atropisomerization of the
helical perylene core (Figure 2). In particular, hypocrellin A
exists as an equilibrium mixture of four forms (Figure 2) and
no single structure is uniformly utilized in the literature. The
NMR spectrum for the resultant diastereomers.8 Thus,
hypocrellin A (Figure 2) exists as an equilibrium mixture of
atropisomers (1, 1 atrop) favoring the more stable atrop-
3
diastereomer 1. In support of this assertion, 1, ent-1, and 3
exhibit CD spectra characteristic of helical stereochemistry.
Notably, the CD spectra of ent-1 and 3 are quite similar
indicating that the main contributor to the CD is the helical
stereochemistry vs the centrochiral stereochemistry. On the
other hand, hypocrellin B (2), which would form by elimina-
tion of water from hypocrellin A, exhibits no peaks in the CD
spectrum.5 The presence of a double bond in the seven-
membered ring of hypocrellin B could lead to a planar
structure accounting for this phenomenon. However, wehave
performed calculations which indicate that the ground state of
2 contains a similar stereogenic helix as the related congeners 1,
ent-1, and 3. Apparently, for 2, the CD signals from the
atropisomeric enantiomers (Figure 3) cancel each other.
keto-enol tautomeric process (1 to 1 taut) is fast with
3
respect to the NMR time scale resulting in a single set of
sharp peaks at ambient temperature.8 The important factors
governing the position of the tautomerization equilibria are
substituent effects, strength of the intramolecular phenol-
quinone hydrogen bonds, and distortion of the planarity of
the naphthalene core. For the hypocrellins, including 1, ent-1
and 3, the two tautomers represented by 1 and 1 taut in
3
Figure 2 are present in almost equal amounts.7,8
FIGURE 3. Atropisomers of hypocrellin B.
Prior to our efforts, the syntheses of the calphostins and
phleichrome had been reported.9 However, the more architec-
turally complex perylenequinones, including 1, ent-1, and 3, had
not succumbed to total synthesis. Given the exciting biological
activity, one of the parent members of the hypocrellins, hypo-
crellin A (1), was selected as a synthetic target. Here, we disclose
a full description of the development of this synthesis.10
Given the facile atropisomerization of 1, it is unclear which
stereochemical elements are established first in the biosynthe-
sis, the helical axis or the 7-membered ring stereocenters.
Establishing the centrochiral stereochemistry first would
require a regio-, diastereo-, and enantioselective intermole-
cular aldol reaction between two ketones to provide 4a
(path a, Scheme 1), a conceptually simple but practically
difficult transformation. Furthermore, the centrochiral ele-
ments of 4a would then need to direct the diastereoselection
in the coupling to form the binaphthalene/perylenequinone.
Alternately, the helical stereochemistry could be formed first
(path b, Scheme 1), which would in turn be used to the direct
the centrochiral stereochemistry via a diastereoselective
aldol reaction. The observation that certain enzymes can
catalyze enantioselective coupling of 2-naphthol provides
considerable confidence that the enantioselective coupling of
an intermediate similar to 5 is accessible biosynthetically.
Furthermore, intermediate 4b is a plausible biosynthetic
intermediate in the genesis of all the mold perylenequinone
FIGURE 2. Tautomeric and atropisomeric forms of hypocrellin A.
The barrier to atropisomerization of the helical con-
figuration varies substantially for the perylenequinones.
Whereas most are atropisomerically stable at ambient
temperature, the additional seven-membered ring in the
hypocrellins lowers the barrier, making them particularly
challenging synthetic targets. Spectroscopic studies showed
that both 1 and ent-1 atropisomerize rapidly at ambient
temperature presenting two sets of sharp peaks in the
(9) (a) Broka, C. A. Tetrahedron Lett. 1991, 32, 859–862. (b) Hauser,
F. M.; Sengupta, D.; Corlett, S. A. J. Org. Chem. 1994, 59, 1967–1969.
(c) Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1994, 116, 8795–8796. (d)
Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1995, 117, 10889–10904. (e)
Merlic, C. A.; Aldrich, C. C.; Albaneze-Walker, J.; Saghatelian, A. J. Am.
Chem. Soc. 2000, 122, 3224–3225. (f ) Merlic, C. A.; Aldrich, C. C.; Albaneze-
Walker, J.; Saghatelian, A.; Mammen, J. J. Org. Chem. 2001, 66, 1297–1309.
(10) For an initial communication of this work, see: O’Brien, E. M.;
Morgan, B. J.; Kozlowski, M. C. Angew. Chem., Int. Ed. 2008, 47, 6877–
6880.
(6) SciFinder indexes hypocrellin and hypocrellin A as the identical
compound.
(7) For the correct structural assignment of shiraiachrome A, see: (a)
Mazzini, S.; Merlini, L.; Mondelli, R.; Scagloni, L. J. Chem. Soc., Perkin
Trans. 2 2001, 409–416. Which corrects: (b) Smirnov, A.; Fulton, D. B.;
Andreotti, A.; Petrich, J. W. J. Am. Chem. Soc. 1999, 121, 7979–7988.
(8) Arnone, A.; Merlini, L.; Mondelli, R.; Nasini, G.; Ragg, E.; Scaglioni,
L.; Weiss, U. J. Chem. Soc., Perkin Trans. 2 1993, 1447–1454.
58 J. Org. Chem. Vol. 75, No. 1, 2010

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natural products with ketone reduction giving rise to the
calphostins/phleichromes/cercosporin, aldol cyclization giv-
ing rise to the hypocrellins/shiraiachromes, and oxidative
enol coupling giving rise to the elsinochromes as outlined in
the first paper of this series. For these reasons, we believe that
path b reflects the biosynthesis and were inspired to use it as
the basis of our synthetic approach.
SCHEME 2. Retrosynthesis of Hypocrellin A via Path b
SCHEME 1. Retrosynthetic Analysis of Hypocrellin A
preceding papers of this series, we described the total synthe-
ses of the perylenequinones (þ)-calphostin D (ent-10d), (þ)-
phleichrome (ent-11) and cercosporin (12) utilizing an ep-
oxide opening to introduce the C7,C70-stereochemistry.
Each of the syntheses evolved from a common late-stage
intermediate, enantiopure 14 (Scheme 3). In the synthesis of
1, this intermediate is again employed, but in this case, as
the P-antipode. Notably, access to both enantiomers of
the common intermediate 14 permits the synthesis of all
the perylenequinones, including the unnatural epimers of the
natural products. In addition, bisiodide 14 is readily coupled
to different fragments providing considerable versatility
(Scheme 3).
In implementing such a biomimetic approach, the viability
of the aldol cyclization needed to be reconciled with the rapid
atropisomeric interconversion of the product 1. In the retro-
synthetic analysis of this biomimetic approach (Scheme 2),
the helical stereochemistry of 6 is proposed to control the C7,
C70-stereochemistry prior to any atropisomerization of the
product 1. Such a dynamic stereochemistry transfer (DST)
reaction fulfilling the following criteria is rare:11 1) a directing
stereocenter that is not involved in any bond-forming or
bond-breaking processes, 2) diastereocontrol from this di-
recting stereocenter in the formation of a new stereocenter,
and 3) loss of the integrity of the original directing stereo-
center subsequent to the transformation. To implement this
strategy, the helical axis as found in enantiomerically pure
perylenequinone 6 would be synthesized first. This helical
chiral perylenenquinone 6 would, in turn, be generated with
complete stereocontrol from axial chiral 7. The intermediate
7 would be generated from 8 via a Wacker oxidation and
C5,C50-oxidation. A Suzuki coupling of the enantiopure
intermediate 9 would provide the C7,C70-allyl substituents
seen in 8.
SCHEME 3. Enantiopure Common Intermediate to the Pery-
lenequinone Natural Products
This strategy permits a flexible approach to all of the
perylenequinone natural products. Either the helical stereo-
chemistry of 6 (Scheme 2), arising from axial diketone 16
(Scheme 3) can be used to control formation of C7,C70-
stereochemistry or it can be introduced from an external
source in conjunction with bisiodide 14 (Scheme 3). In
contrast, other reported perylenequinone syntheses involved
the diastereoselective coupling of chiral napthalenes.9 To
adapt such syntheses to the hypocrellins would involve
an oxidation of the C7,C70-substitutents (i.e., 13 to 16,
Scheme 3) thereby negating the centrochiral stereochemistry
which had required much effort to generate. In two of the
Results and Discussion
Model System for a 1,8-Diketone Aldol Reaction. The
investigation of hypocrellin A (1) commenced with an
(11) Ohmori, K.; Kitamura, M.; Suzuki, K. Angew. Chem., Int. Ed. 1999,
38, 1226–1229.
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assessment of the key transannular 1,8-diketone aldol reac-
tion. Lown had reported the use of a 1,8-diketone aldol
condensation in a synthesis of hypocrellin B (2, Scheme 4),
which lacks optical activity (see Figure 3 and accompanying
discussion above).12 Notably, a stereoselective synthesis of
hypocrellin A relying on the route in Scheme 4 would require
oxidation of the initially formed alcohol stereocenters (i.e.,
those in 17) resulting in loss of this stereochemical informa-
tion. With the racemic diketone 6, the aldol addition and the
elimination reaction proceeded very readily raising concerns
that suppressing elimination to doubly conjugated alkene 2
would be difficult. Furthermore, this system does not
address whether the necessary stereochemical array can be
established in such a process.
Presumably, the conformational restriction afforded by the
biaryl bond and the four sp2 centers in the forming ring
permits an efficient aldol reaction between ketone centers in
a 1,8-relationship. These results were highly encouraging
with respect to the desired aldol reaction of hypocrellin A
(Scheme 2). However, it remained unclear how well these
results would translate to the natural product substrate 6
(Scheme 2), which possesses a 20° dihedral angle between the
upper and lower rings of the perylenequinone vs the 70°
dihedral angle in model 18. Presumably, the closer proximity
between the reacting centers caused by the smaller dihedral
angle would facilitate the aldol reaction. However, the lower
dihedral angle might also facilitate elimination to hypocrel-
lin B (2, Scheme 4) since there would be less strain in the
seven-membered ring. A further complication is the peryle-
nequinone itself, which is highly electron-withdrawing
and would be expected to acidify the enolic positions in 6
(Scheme 2) similar to a 1,3-dicarbonyl. This effect would
facilitate enolate formation but also render the enolate less
reactive.
SCHEME 4. Hypocrellin B Synthesis
Helical Chiral Perylenequinone Formation. With the
knowledge that the required stereochemical array is acces-
sible in the intramolecular 1,8-diketone aldol reaction of a
model system, investigations began to generate of helical axis
of 6 (Scheme 2). To this end, we examined the applicable
routes to axial chiral 8 (Scheme 5).
SCHEME 5. Synthesis of C7,C70-Allyl Intermediate 8
To shed light on these concerns, racemic model system 18
was selected to evaluate the regio- and diastereoselectivity of
the process, including the effect of the biaryl axis, as well as
the propensity for elimination. In principle, four diastereo-
mers are possible in the aldol reaction, provided that no
elimination products form. As described in the preceding
paper in this series,13 silazide bases were found to provide the
syn aldol diastereomer (19) corresponding to that required
for the synthesis of hypocrellin A (1) in high yields by means
of a (Z) enolate (eq 1).
As previously seen in this series, a cationic cyclization
readily provided the desired halo-naphthalenes 20a and 20b
(Scheme 5), though iodonaphthalene 20b was somewhat
more difficult to purify than bromo analog 20a. This parti-
cular substitution pattern was selected in order to achieve
high selectivity in the subsequent asymmetric oxidative
coupling.16 While some refunctionalization of the naphtha-
lene portion will be required to complete hypocrellin A, the
The high yield observed in the 1,8-diketone aldol reac-
tion of 18 was remarkable in light of past precedent.13-15
(12) Lown, J. W. Can. J. Chem. 1997, 75, 99–119.
(13) O’Brien, E. M.; Li, J.; Carroll, P. J.; Kozlowski, M. C. J. Org. Chem.
2010, 75, DOI: 10.1021/jo9018914.
(14) For selected examples, see: (a) Miyahara, Y. J. Org. Chem. 2006, 71,
6516–6521. (b) Davies, S.; Sheppard, R. L.; Smith, A. D.; Thomson, J. E.
Chem. Commun. 2005, 3802–3804. (c) Piers, E.; Skupinska, K. A.; Wallace,
D. J. Synlett 1999, 12, 1867–1870. (d) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.;
Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418–4420. (e) Shizuri, Y.;
Ohtsuka, J.; Kosemura, S.; Terada, Y.; Yamamura, S. Tetrahedron Lett.
1984, 25, 5547–5550.
(16) (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) Mulrooney, C. A.; Li, X.; DiVirgilio, E. S.;
Kozlowski, M. C. J. Am. Chem. Soc. 2003, 125, 6856–6857. (e) Li, X.;
Hewgley, J. B.; Mulrooney, C.; Yang, J.; Kozlowski, M. C. J. Org. Chem.
2003, 68, 5500–5511. (f ) Hewgley, J. B.; Stahl, S. S.; Kozlowski, M. C. J. Am.
Chem. Soc. 2008, 130, 12232–12233.
(15) Baik, T. G.; Luis, A. L.; Wang, L. C.; Krische, M. J. J. Am. Chem.
Soc. 2001, 123, 5112–5113.
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scalability of these intermediates and the functionality
needed to access novel analogs outweighed these concerns.
As outlined in Scheme 5 the C7,C70-allyl substitution could
be installed either before or after the enantioselective cou-
pling. Addition of the allyl group prior to oxidative dimeriza-
tion was best accomplished with a Stille reaction. With trifuryl
phosphine as the palladium ligand, a significant amount of
butyl transfer (20%) was observed. As the allyl and butyl
products have the same Rf value, purification was proble-
matic. Fortunately, no butyl transfer was observed with
triphenyl arsine as the ligand,17 ameliorating this problem.
While the dimerization of the allyl substrate was superior, the
Stille coupling and removal of the tin byproducts to provide
the requisite precursor proved problematic on preparative
scale (>10.0 mmol, ∼35% yield). Furthermore, generation of
enantiopure 8 (g99% ee) from 22 required multiple tritura-
tions (5-10) contributing to a poor mass recovery. Unfortu-
nately, the Stille reaction was the only coupling procedure
compatible with the acetate protecting groups in 20a.
reported examples with a C7,C70-keto-derivative. Thus, the
transformation was examined with 25 (Scheme 6), which
varies from the required substrate 16 (Scheme 3) by addition
of the C3,C30-esters.
We commenced these efforts with the C5,C50-oxygenation
of 8 (Scheme 6) via a nucleophilic substitution reaction
induced by a hypervalent iodine reagent as has been dis-
cussed in the earlier papers of this series. Accordingly,
treatment of bisallyl 8 with bis(trifluoroacetoxy)iodoben-
zene (PIFA) in (CF3)2CHOH afforded the desired com-
pound in yields ranging from 50% to 73%. Protection of
the bisphenol with a benzyl group proceeded smoothly with
benzyl bromide and NaH in 78% yield. Finally, the Wacker
oxidation afforded the desired diketone 25 without the
formation of any regioisomeric aldehyde.
Following C5,C50-debenzylation of 25 to generate the
required bisphenol, perylenequinone formation was exam-
ined (Scheme 6). Unfortunately, treatment with MnO29c,d or
9a
alternatively, K3Fe(CN)6 did not provide the desired 26
For these reasons, a different sequence to 8 was in-
vestigated culminating in allylation after biaryl coupling
(Scheme 5). This route utilized 14, an antipode of the
intermediate utilized in our investigation of (þ)-phleichrome
(see Scheme 3) as detailed in the second paper in this series.
This route permitted allylation after removal of the labile
acetate protecting groups of 14. In the absence of acetates,
the less toxic, more efficient Suzuki reaction could now be
employed, supplying enantiopure 8 in high yield on a pre-
parative scale (90%, 2 steps).18
and resulted in only decomposed starting material. The same
result was observed with diallyl biaryl 24. Since the use of
MnO2 with the corresponding C7,C70-propyl16d or C7,C70-2-
hydroxypropyl9c,d derivatives proceeded smoothly to pery-
lenequinone, it appears that substitution of the benzylic
centers in 24 and 25 can dramatically change the outcome
of this reaction. Apparently, the addition of acidifying
groups to this position (ketones or alkenes) allows alternate
reaction pathways.
Since the secondary alcohols at the C7,C70-positions are
stable to the MnO2 oxidation protocol9c,d and oxidation of
bisalcohol 17 to diketone 6 has been reported (Scheme 4),12 a
route using reduction to “protect” the ketone was examined
(Scheme 7). Distinct from prior efforts involving the diaster-
eoselective dimerizations of chiral naphthalenes,9 this route
would not rely on the C7,C70-alcohol stereochemistry to
form the axial stereochemistry. As such, the diketone could
be reduced with no regard to selectivity. As was seen in
similar reductions examined in the second paper in this
series, treatment of diketone 29 with NaBH4 and subsequent
hydrogenation provided 28 as a statistical mixture of three
diastereomers (Scheme 7). Oxidation of 28 with MnO2 to the
perylenequinone supplied 29 as the sole product. To our
dismay, applying Lown’s conditions (Scheme 4)12 to 29
provided none of the oxidized product 26 (Scheme 7) with
SCHEME 6. Attempted Formation of Perylenequinones 26 and 27
SCHEME 7. Attempted Formation of Diketone Intermediate 26
The reported calphostin syntheses demonstrated that for-
mation of the perylenequinone core was possible with a
variety of functionalized C7,C70-substituents.9 Additionally,
we previously reported that C7,C70-propyls are also compa-
tible with these conditions.16d However, we could find no
(17) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585–9587.
(18) For a simple synthetic approach to allylated aromatics via the
Suzuki-Miyaura cross-coupling reaction, see: Kotha, S.; Behera, M.; Shah,
V. Synlett 2005, 1877–1880.
J. Org. Chem. Vol. 75, No. 1, 2010 61

O’Brien et al.
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only rapid decomposition being observed even when a rapid
quench was employed. Presumably, the electron-withdraw-
ing C3,C30-esters acidify the benzylic protons of 29 resulting
in a more rapid decomposition pathway. All attempts to
oxidize the secondary alcohols with mild oxidation proto-
cols, such as Dess-Martin periodinane or the Swern oxida-
tion, resulted in unreacted starting material. It was reasoned
that the congested steric environment of the hydroxyl groups
accounted these results. As seen with CrO3, stronger oxi-
dants resulted in decomposition.
palladium dichloride acetonitrile complex was found to re-
move the ketal20 as well as tautomerize the dihydroperylene-
quinone to the perylene 32 (Scheme 9). The desired diketone
perylenequinone 26 was obtained after oxidation of perylene
32 with air in the presence of silica. With a viable route to
synthesizing the key diketone perylenequinone structure in
hand, efforts turned to removal of the C3,C30-methyl esters.
SCHEME 9. Synthesis of Model Diketone Perylenequinone 26
The results of Scheme 6 and Scheme 7 led us to use a ketal
protection group that would be stable to the oxidative
cyclization and would be readily removed following peryle-
nequinone formation. To this end, bisketone 25 was treated
with acidic ethylene glycol to yield bisketal 30 (Scheme 8).
Hydrogenolysis of 30, followed by reaction with MnO2
resulted in clean conversion to the unexpected dihydro-
perylenequinone 31, which was confirmed with a crystal
structure. Remarkably, the enantiopurity was conserved
during this process as judged by chiral HPLC (95% ee).
Apparently, the increased steric congestion caused by ketal
substitution, compared to the propyl side chains, distorts the
molecule such that formation of the more planar perylene-
quinone (20° vs 70° biaryl dihedral) is disfavored.19
First Total Synthesis of Hypocrellin A. Returning to the
synthesis of hypocrellin A, we investigated the removal of the
C3,C30-methyl esters via decarboxylation of the respective
C3,C30-diacid. As outlined in the previous papers in this
series, the ineffectiveness of standard decarboxylation pro-
tocols21 led us to develop a palladium-catalyzed decarbox-
ylation protocol,22 which worked well with biaryl systems.
The standard three-step protocol that we had used pre-
viously to form the required calphostin and cercosporin
diacid intermediates, provided the requisite diacid 33 here
in high yield (entry 1, Table 1). However, in an attempt to
form 33 directly from 30 we evaluated other procedures. Due
to steric hindrance, an efficient saponification of 30 was only
observed at temperatures greater than 130 °C, at which
atropisomerization is also observed (entries 2-4). Anionic
displacement was investigated next, but iodide nucleophiles
proved ineffective (entries 5-6, Table 1). Application of the
Krapcho conditions used to decarboxylate esters via the
corresponding carboxylate (excess NaCN in DMSO and
H2O at 100-110 °C) afforded the diacid 33 quantitatively
after neutralization (entry 7).23 Not unexpectedly, these
conditions did not cause decarboxylation since the resultant
aromatic anion is not stabilized.
SCHEME 8. Formation of an Unexpected Hydroperylenequi-
none (31) (ORTEPs Shown with 30% Probability Thermal
Ellipsoids)
The palladium-catalyzed decarboxylation20 that was ap-
plied in the previous two papers of this series was optimized
originally with 33 because it proved to be the most recalci-
trant of all the substrates. By virtue of the ketal protecting
groups, 33 possesses the largest C7,C70- substituents which
cause steric gearing leading to considerable congestion of the
(20) For the use of PdCl2(CH3CN)2 as a catalyst for deacetalization, see:
Lipshutz, B. H.; Pollart, D.; Monforte, J.; Kotsuki, H. Tetrahedron Lett.
1985, 26, 705–708.
(21) Protic acid protocol: Horper, W.; Marner, F.-J. Phytochemistry
1996, 41, 451. Copper/quinoline protocol: Cohen, T.; Schambach, R. A.
J. Am. Chem. Soc. 1970, 92, 3189.
(22) Dickstein, J. S.; Mulrooney, C. A.; O’Brien, E. M; Morgan, B. J.;
Kozlowski, M. C. Org. Lett. 2007, 9, 2441–2444.
Initial attempts to hydrolyze the ketals of 31 with stan-
dard acidic conditions were unsuccessful. Fortunately, a
(23) For synthetic applications of NaCN in dealkoxycarbonylations, see:
(a) Krapcho, A. P. Synthesis 1982, 805–822. (b) Krapcho, A. P. Synthesis
1982, 893–914.
(19) See ref 9a for another report of a dihydroperylenequinone.
62 J. Org. Chem. Vol. 75, No. 1, 2010

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TABLE 1. Screening Conditions for Formation of Diacid 33
SCHEME 10. Attempted Synthesis of Perylenequinone 6
entry
1
conditions
yield (%)
90
(1) DIBALH, PhCH3; (2) o-iodoxybenzoic acid; (3)
NaC1O2, NaH2PO4, 2-butene, THF, H2O, t-BuOH
LiOH, 10%H2O-dioxane, 100 °C
Ba(OH)2 10% H2O-DMSO, 100 °C
KOH, ethylene glycol, 130 °C
2
3
4
5
6
7
0a
<50
100b
0a
NaI, 10% H2O-DMSO, 100 °C
LiI, DMF, 100 °C
0a
NaCN,10% H2O-DMSO, 105 °C
100
aStarting material recovered. bAtropisomerization observed.
The generation of unsymmetrical ortho-quinone 36
(Scheme 10) was perplexing considering no such product
was observed for the C3,C30-ester model system (26,
Scheme 9). The proposed mechanism for the formation of
36 is shown in Scheme 11. Coordination of either palladium
or trace HCl (formed from PdCl2(CH3CN)2 by exposure to
trace water) sets the stage for ring cleavage which, presum-
ably, is driven by the release of ring strain. The absence of the
ester provides a more electron rich ring which facilitates this
cleavage by providing a superior coordinating agent for the
acid and by better stabilizing the positive charge build up in
the upper ring. The subsequent cascade would result in
cleavage of the hydroperylenequinone bond. Ketal removal
before or after ortho-quinone formation would supply the
observed product 36.
C3,C30-positions and thereby slowing the decarboxylative
palladation22 necessary for decarboxylation. Utilizing the
previously successful conditions for the corresponding C7,
C70-propyl derivative seen in the first paper in this series
provided decarboxylated 34 in a disappointing 30% yield
(Table 2, entry 1). A screen of reductants (entries 2-5)
provided only a modest improvement. Performing the dec-
arboxylation under basic conditions with Ag2CO3 proved
beneficial providing 34 in 60% yield (entry 6).
TABLE 2. Optimization of the Palladium-Catalyzed Decarboxylation
of 33
SCHEME 11. Possible Mechanism for Formation of Unsym-
metrical o-Quinone 36
Pd(O2CCF3)2
(mol %)
yield
(%)
entry
(a) conditions
(b) reductant
1
2
3
300
220
220
90 °C, 1.5 h
70 °C, 1.5 h
70 °C, 1 h
H2, THF
HSi(Oi-Pr)3
KF, H2O
PHMS
30
37
25
4
5
6
220
220
220
70 °C, 1.5 h
70 °C, 3 h
NaBH4
NaBH4
Ag2CO3, 70 °C, 1 h NaBH4
44
28
60
A mechanism such as the one shown in Scheme 11 would
not be possible for the fully oxidized perylenequinone; hence,
we reexamined the oxidation of 39 (Scheme 12). Addition of
base during the oxidation step was proposed to facilitate
tautomerization of dihydroperylenequinone 35 to perylene
37 which should, in turn, readily oxidize to perylenequinone
6 (Scheme 10). Pleasingly, reaction of 39 with MnO2 and
NaOH in a mixture of EtOH and THF afforded the desired
perylenequinone 40 (Scheme 12). Unfortunately, ketal re-
moval from 40 was again problematic. In contrast to 31
(Scheme 9), the PdCl2(CH3CN)2 reaction was sluggish with
40 providing less than 20% product after 4 d. Stoichiometric
palladium did not to facilitate the reaction and conventional
acidic ketal hydrolysis resulted in decomposition.
With a viable route to 34 established, investigations
centered on forming diketone perylenequinone 6 to com-
plete the synthesis. Thus, 34 was subjected to hydrogeno-
lysis conditions (Scheme 10) and oxidized to dihydro-
perylenequinone 35 (86% yield over two steps). Akin to
the C3,C30-ester model system 31 (Scheme 8), the fully
oxidized perylenequinone was not observed under these
conditions (Scheme 10). Ketal deprotection of 35 with
catalytic PdCl2(CH3CN)2 in acetone provided a mixture
of perylene 37 and desired perylenequinone 6; however,
the yield was inconsistent due to a significant amount of
ortho-quinone (36) formation.
From the above results, it appears that neither the dihy-
droperylenequinone (35) or the perylenequinone (40) can
J. Org. Chem. Vol. 75, No. 1, 2010 63

O’Brien et al.
JOCArticle
withstand conditions need for deketalization. Reasoning
that the acidic species (PdII or Hþ) were activating the
carbonyls of these compounds and promoting undesired
reactions, the use of a reduced perylene such as 41
(Scheme 13) that should bypass such a manifold was con-
sidered. Pleasingly, perylene, 41 was readily formed by
reduction of 40 with Na2S2O4 in benzene. Frustratingly, all
attempts to alkylate or acylate perylene 41 to provide 42
resulted in reversion to the fully oxidized perylenequinone
40, even though 41 was sufficiently stable to be observed
quantitatively by 1H NMR. To our delight, perylene 41 itself
was sufficient to alleviate the undesirable properties of
perylenequinone 40 and treatment of in situ generated
perylene 41 with PdCl2(CH3CN)2 provided a facile hydro-
lysis of the ketal protecting group. Exposure to air during
isolation resulted in reoxidation to the desired perylenequi-
none 6 in very good yield.
SCHEME 12. Attempted Formation of Diketone Aldol Sub-
strate 6
With a practical route to the diketone 6 in hand, the stage
was set to investigate the key intramolecular diketone aldol
cyclization. Although we proposed such an aldol reaction for
the biosynthesis of the hypocrellins, precedent for this type of
1,8-diketone aldol reaction, with the exception of our model
system 18, is uncommon. To predict if the stereochemical
outcome would be the same as in the model system13 we
again turned to molecular modeling (Scheme 14). With 6, a
Z-enolate geometry would give rise to the syn aldol product
corresponding to hypocrellin A via closed chairlike transi-
tion states, while the E-enolate would produce the anti
product corresponding to shiraiachrome A.24 An analysis
of the relevant transition states revealed that the helical
stereochemistry of 6 would expose one diastereoface of
the ketone, resulting in the required (S) tertiary alcohol
stereochemistry of both hypocrellin A (1) and shiraiachrome
A (3). MM2 calculations found that of the two possible
Z-enolate transition states, transition state A, correspond-
ing to the configuration of the target hypocrellin A, was
lower in energy (Scheme 14). Interestingly, if the reaction
were to progress via transition state B, the cyclization of 6
with P-helical stereochemistry would lead to the enantio-
mer hypocrellin (ent-1), which would equilibrate after
cyclization to predominantly the opposite M-atropisomer.
Significantly, this approach requires that the helical stereo-
chemistry be sufficiently stable during the aldol reaction,
even though it atropisomerizes freely thereafter. To under-
take this proposal, the previously evaluated silazide bases
SCHEME 13. Formation of Diketone Aldol Substrate 6
SCHEME 14. Z-Enolate Transition States and Correlation to Natural Products
64 J. Org. Chem. Vol. 75, No. 1, 2010

O’Brien et al.
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TABLE 3. Transannular 1,8-Diketone Aldol Cyclization in the Synthe-
sis of Hypocrellin A, 1
diastereoselectivity of the desired syn aldol product (dr 4:1,
entry 3). However, it was surprising that even at very low
temperatures (-105 °C) the less favored transition state B of
the Z-enolate was accessible, leading to lower enantioselec-
tivities than expected (79% ee, entry 3). Use of the bulkier
LiN(SiPhMe2)2 enhanced the diastereoselective formation
of 1 (dr 10:1) though it did not effect the enantioselectivity
(entries 4-5). Fortunately, a single trituration afforded 1
with 92% ee (entry 5). Spectroscopic data from our synthetic
1:1 atrop was identical to the data from hypocrellin (ent-1)
3
from natural sources, with the exception of the absolute
stereochemistry, as determined by direct comparison. As
expected, the minor diastereomer, 3, resulting from the
anti-aldol product was confirmed by 1H NMR spectroscopy
to be shiraiachrome A. Significantly, in the case of shiraia-
chrome A (3), the atropisomeric equilibrium after the aldol
reaction favors the opposite (M) helical configuration even
though both hypocrellin A (1) and 3 originally arose from the
same (P) configuration of 6 (Scheme 14).
entry
base
T (°C) dr (1:3)
ee (%)
Conclusions
1
2
3
4
5
LiHMDS
LiHMDS
LiHMDS
-15
-78
55
70
4:1 79
As seen in Scheme 15 we have completed the first total
synthesis of the hypocrellin A in 19 steps (1.6% overall yield;
average 82% per step). Key points of our enantioselective
synthesis include: 1) an enantioselective oxidative coupling
to provide the P-antipode of the common enantiopure
intermediate; 2) a mild aromatic decarboxylation; and 3) a
biomimetic 1,8-diketone aldol reaction to establish the
7-membered ring of hypocrellin A. In the aldol reaction,
the two newly formed centrochiral stereocenters in the
7-membered ring are dictated by the stable perylenequinone
helical stereochemistry16d and the enolate geometry. After
the aldol reaction, however, the helical stereochemistry is
labile as observed in the natural product (4:1 mixture of
atropisomers). As such, we have shown that a dynamic
stereochemical transfer is viable for the construction of
hypocrellin. Significantly, our approach to hypocrellin A
also provides an avenue to shiraiachrome A by formation of
the anti aldol product.
-105
LiN(SiPhMe2)2 -78 10:1 70
LiN(SiPhMe2)2 -105 10:1 (92 after trituration) 74% yield
were chosen to effect deprotonation as their use with model
system 18 (eq 1) gave predominantly Z-enolates.
In an examination of the crucial aldol reaction, the
diastereomeric ratios reflect the formation of the syn vs anti
aldol product, which presumably reflects the ratio of the
Z-enolate to the E-enolate, while the enantioselectivity is a
measure of the predilection for transition state A over B as
seen in Scheme 14. Since the diastereomeric mixture from the
cyclization was difficult to analyze, a selective removal of the
C4,C40-methyl ethers with MgI2 was undertaken to yield
hypocrellin A (1) and shiraiachrome A (3) (both isolated
from Shiraia bambusicola) as a distinguishable mixture. To
examine the effect of temperature on the aldol transforma-
tion (entry 1-3, Table 3), LiHMDS was chosen to achieve
deprotonation. As expected, the cyclization was much more
facile than the model system, accompanied with lower
As seen in the first paper of this series, we established that
helical chiral perylenequinones can be configurationally
stable even if no other stereocenters are present. This key
SCHEME 15. Total Synthesis of Hypocrellin A (1)
J. Org. Chem. Vol. 75, No. 1, 2010 65

O’Brien et al.
JOCArticle
discovery enabled the biomimetic synthesis of hypocrellin
A (1) via a dynamic stereochemistry transfer, as described in
this paper, via intermediate 6. The additional discovery of
an efficient double epoxide alkylation with the complex
biaryl biscuprate derived from 14, enabled the synthesis
of the diastereomeric (þ)-calphostin D and (þ)-phlei-
chrome as well as the atropisomerically labile cercosporin
as detailed in the second and third papers of this series,
respectively. Thus, all of the stereoisomeric mold perylene-
quinone natural products, as well as a number of ana-
logs,25 can be generated in stereosiomerically pure form
from common intermediates M-14 and P-14 which are
readily generated via a catalytic, enantioselective naphthol
coupling.
(1.96 g, 3.10 mmol) and [bis(trifluoroacetoxy)-iodo]benzene
(3.3 g, 7.67 mmol) were dissolved in 2,2,2-trifluoroethanol
(50 mL) and stirred at 25 °C under argon. After 2.5 h, the purple
reaction mixture was quenched with NaOAc (1.40 g). After
stirring for 5 min, the resulting red solution was diluted with
EtOAc, and the organic phase was washed with H2O and brine,
dried (Na2SO4), and the solvent evaporated. The red residue was
diluted with H2O/THF/EtOH (1:3:3, 35 mL) and 10% aq. NaOH
(10 mL) was added. After stirring for 5 h at room temperature
under argon, the mixture was quenched with 1 N HCl. The
aqueous phase was extracted with EtOAc, the organics were
washed with brine, dried (Na2SO4), and the solvent was evapo-
rated. The concentrate was purified by column chromatography
(30% EtOAc/hexanes) to afford 24 as a red resin (1.5 g, 73%):
[R]2D0þ53.3 (c 0.75, CH2Cl2, >99% ee (S)); IR (thin film) 3365,
2948, 2360, 1734, 1595, 1568 cm-1; 1H NMR (500 MHz, CDCl3)
δ 3.24-3.36 (m, 4H), 3.31 (s, 6H), 3.89 (s, 6H), 3.98 (s, 6H), 4.15
(s, 6H), 4.78 (d, J = 1.6, 17.1 Hz, 2H), 4.84 (dd, J = 1.3, 10.1 Hz,
2H), 5.71-5.78 (m, 2H), 6.44 (s, 2H), 9.26 (s, 2H); 13C NMR (125
MHz, CDCl3) δ 34.9, 53.1, 60.7, 62.2, 64.5, 114.3, 115.8, 117.7,
119.3, 120.6, 132.7, 136.9, 137.1, 142.2, 146.0, 152.5, 154.3, 166.8;
HRMS (ESI) calcd for C36H38O12Na (MNaþ) 685.2261, found
685.2242.
(P)-Dimethyl 5,50-bis(benzyloxy)-2,20,4,40,6,60-hexamethoxy-
7,70-bis(2-oxopropyl)-1,10-binaphthyl-3,30-dicarboxylate (25). A
solution of 24 (215 mg, 0.32 mmol) in DMF (8 mL) was cooled
to 0 °C. NaH (60% in oil, 31 mg, 0.77 mmol) was added and
stirred for 15 min. Benzyl bromide (0.91 mL, 0.77 mmol) and
Bu4NI (19 mg, 0.051 mmol) were added at 25 °C. After
completion as judged by TLC, the mixture was acidified with
1 M HCl, diluted with EtOAc, washed with H2O (6X) and brine,
and dried (Na2SO4). The concentrate was purified by column
chromatography (20% EtOAc/hexanes) to afford the bisbenzyl
ether as a yellow resin (212 mg, 78%): [R]2D0þ40.0 (c 0.45,
CH2Cl2, >99% ee (S)); IR (thin film) 2942, 1736, 1587, 1562
cm-1; 1H NMR (500 MHz, CDCl3) δ 3.22-3.34 (m, 4H), 2.97
(s, 6H), 3.90 (s, 6H), 3.93 (s, 6H), 3.95 (s, 6H), 4.74-4.77
(m, 2H), 4.82-4.84 (m, 2H), 5.02 (d, J = 9.8 Hz, 2H), 5.05 (d,
J = 9.8 Hz, 2H), 5.69-5.77 (m, 2H), 6.75 (s, 2H), 7.31 (t, J = 7.3
Hz, 2H), 7.38 (t, J = 7.2 Hz, 4H), 7.59 (d, J = 7.1, 4H); 13C
NMR (500 MHz, CDCl3) δ 35.1, 52.1, 61.9, 64.4, 64.9, 76.9,
115.7, 120.4, 120.5, 123.1, 123.2, 128.1, 128.6, 129.1, 133.6,
136.2, 136.9, 138.1, 146.8, 150.2, 152.5, 154.3, 167.5; HRMS
(ESI) calcd for C50H50O12Na (MNaþ) 865.3199, found
865.3182.
Experimental Section
(P)-Dimethyl 4,40-diacetoxy-2,20-dihydroxy-7,70-diiodo-6,60-
dimethoxy-1,10-binaphthyl-3,30-dicarboxylate (14). Bisacetate
(P)-14 was synthesized as a white foam (1.3 g, 80%) follow-
ing our previously reported procedure for the enantiomer.26
Spectral data agreed with those reported previously for the
enantiomer with the exception of the optical rotation: [R]D20
-26.5 (c 0.5, CH2Cl2, >99% ee).
(P)-Dimethyl 7,70-diallyl-2,20,4,40,6,60-hexamethoxy-1,10-bina-
phthyl-3,30-dicarboxylate (8). To a solution of 14 (725 mg, 0.87
mmol) in DMF (25 mL) was added NaH (60% in oil, 1 g, 26.2
mmol), and MeI (1.6 mL, 26.2 mmol). After stirring for 4 h at
room temperature under argon, the mixture was quenched with
1 N HCl. The aqueous phase was extracted with EtOAc and the
combined organics were washed with 1 N HCl (3 ꢀ 20 mL) and
brine (2 ꢀ 20 mL). The organics were dried (Na2SO4), and after
the solvent was evaporated, the residue was chromatographed
(25% EtOAc/hexanes)toyieldthe bismethyletherasa white solid
(660 mg, 94%): [R]2D0þ57.4 (c 0.5, CH2Cl2, >99%ee (S)); IR(thin
1
film) 2945, 1733, 1579, 1463, 1436 cm-1; H NMR (360 MHz,
CDCl3) δ 3.36 (s, 6H), 4.00 (s, 6H), 4.02 (s, 6H), 4.14 (s, 6H), 7.42
(s, 2H), 7.63 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 52.7, 56.5,
61.9, 62.6, 91.9, 100.7, 118.3, 120.9, 125.9, 131.4, 136.9, 152.0,
153.3, 155.2, 166.9; HRMS (ESI) calcd for C30H28I2O10Na
(MNaþ) 824.9669, found 824.9638.
To a solution of the bismethyl ether (1.41 g, 1.75 mmol) in
anhydrous THF (20 mL) was added Pd(PPh3)4 (303 mg, 0.26
mmol) and CsF (2.13 g, 0.014 mol). The mixture was stirred at
25 °C for 0.5 h. Allylpinacol borane (1.4 mL, 7.1 mmol) was
added neat and the reaction mixture heated to reflux. After
removing from the oil bath, the reaction was quenched with
H2O. The mixture was diluted with EtOAc, and the organic
phase was washed with H2O and brine, dried (Na2SO4), and the
solvent evaporated. Purification was accomplished via chroma-
tography (20-30% EtOAc/hexanes) to yield 8 (1.1 g, 96%) as a
resin: [R]2D0þ102.2 (c 0.85, CH2Cl2, >99% ee); IR (thin film)
2945, 2845, 1733, 1590, 1494 cm-1; 1H NMR (500 MHz, CDCl3)
δ 3.22-3.33 (m, 4H), 3.33 (s, 6H), 3.96 (s, 6H), 3.98 (s, 6H), 4.13
(s, 6H), 4.78-4.85 (m, 4H), 5.74-5.82 (m, 2H), 6.95 (s, 2H), 7.43
(s, 2H); 13C NMR (125 MHz, CDCl3) δ 34.9, 52.7, 55.7, 62.1,
62.9, 100.3, 115.7, 120.1, 120.4, 125.1, 127.2, 130.6, 132.9, 136.5,
151.7, 153.5, 156.3, 167.6; HRMS (ESI) calcd for C36H38O10Na
(MNaþ) 653.2363, found 653.2377.
PdCl2 (76 mg, 0.43 mmol) and CuCl (212 mg, 2.14 mmol)
were stirred in a DMF/H2O mixture (7:1, 1 mL) at room
temperature for 30 min. The bisbenzyl ether (87 mg, 0.10
mmol) was added and the mixture stirred under oxygen for
18 h. The mixture was acidified with 1 M HCl, diluted with
EtOAc, washed with H2O (6X), brine, and dried (Na2SO4). The
concentrate was purified by column chromatography (40%
EtOAc/hexanes) to afford 25 as a yellow resin (68 mg, 75%):
[R]2D0þ2.0 (c 0.5, CH2Cl2, >99% ee (S)); IR (thin film) 2944,
1732, 1588, 1563 cm-1; 1H NMR (500 MHz, CDCl3) δ 2.10 (s,
6H), 3.41 (s, 6H), 3.61-3.67 (m, 4H), 3.96 (s, 6H), 3.97 (s, 6H),
4.01 (s, 6H), 5.08 (s, 4H), 6.82 (s, 2H), 7.37 (t, J = 7.1 Hz, 2H),
7.43 (t, J = 7.6 Hz, 4H), 7.62 (d, J = 7.5 Hz, 4H); 13C NMR
(125 MHz, CDCl3) δ 29.7, 46.6, 52.8, 61.3, 62.0, 64.6,
76.9, 120.6, 121.1, 123.6, 124.2, 128.2, 128.6, 129.1, 131.7,
133.4, 137.8, 146.6, 150.0, 152.6, 154.3, 167.4, 205.7;
HRMS (ESI) calcd for C50H50O14Na (MNaþ) 897.3098, found
897.3088.
(P)-Dimethyl 7,70-diallyl-5,50-dihydroxy-2,20,4,40,6,60-hexa-
methoxy-1,10-binaphthyl-3,30-dicarboxylate (24). Biaryl
8
(24) Still, W. C. MacroModel, V4.0, V5.0, V6.0, V6.5; Columbia Uni-
versity.
(25) Morgan, B. J.; Dey, S.; Johnson, S. W.; Kozlowski, M. C. J. Am.
Chem. Soc. 2009, 131, 9413–9425.
(26) See theexperimental description in the second paper of this series
(DOI: 10.1021/jo901384h).
(P)-Dimethyl 5,50-bis(benzyloxy)-2,20,4,40,6,60-hexamethoxy-
7,70-bis((2-methyl-1,3-dioxolan-2-yl)methyl)-1,10-binaphthyl-
3,30-dicarboxylate (30). Ketone 25 (145 mg, 0.219 mmol),
triethyl orthoformate (972 mg, 6.57 mmol), ethylene glycol
(394 mg, 6.57 mmol), and p-toluenesulfonic acid (4.0 mg,
66 J. Org. Chem. Vol. 75, No. 1, 2010

O’Brien et al.
JOCArticle
0.0219 mmol) were refluxed in CH2Cl2 (5 mL) under Ar for
24 h. The mixture was diluted with CH2Cl2, washed with
aqueous NaHCO3 (5%) and brine, and dried (Na2SO4). The
concentrate was purified by column chromatography (30%
EtOAc/hexanes) to afford 30 as a white solid (148 mg, 90%):
[R]2D0þ10.1 (c 0.82, CH2Cl2, >99% ee (S)); mp 158-162 °C; IR
3.63-3.74 (m, 4H), 3.71 (s, 6H), 3.91 (s, 6H), 4.16 (s, 6H), 6.53 (s,
2H), 6.72 (s, 2H), 9.28 (s, 2H); 13C NMR (125 MHz, CDCl3) δ
25.1, 38.3, 56.4, 57.5, 60.4, 64.7, 64.9, 94.8, 110.2, 111.6, 113.4,
118.9, 132.1, 132.5, 141.5, 145.9, 154.3, 156.8; HRMS (ESI)
calcd for C36H42O12Na (MNaþ) 689.2574, found 689.2571; CSP
HPLC (Chiralpak AD, 1.0 mL/min, 80:20 hexanes:i-PrOH):
tR(R) = 15.7 min, tR(S) = 17.6 min.
1
(thin film) 2942, 2880, 1735, 1588, 1560 cm-1; H NMR (500
MHz, CDCl3) δ 1.16 (s, 6H), 2.85 (d, J = 13.8, 2H), 2.98 (d, J =
13.8 Hz, 2H), 3.39-3.50 (m, 4H), 3.45 (s, 6H), 3.67-3.71
(m, 4H) 3.95 (s, 6H), 3.99 (s, 6H), 2.40 (s, 6H), 5.06 (d, J =
9.8 Hz, 2H), 5.10 (d, J = 9.8 Hz, 2H), 6.94 (s, 2H), 7.36 (t, J =
7.3 Hz, 2H), 7.44 (t, J = 7.6 Hz, 4H), 7.65 (d, J = 8.2 Hz, 4H);
13C NMR (125 MHz, CDCl3) δ 26.4, 40.0, 54.5, 63.3, 63.7,
66.2, 66.5, 66.6, 78.8, 111.6, 122.3, 122.9, 125.1, 127.4, 130.0,
130.5, 130.9, 135.0, 135.2, 140.1, 148.4, 152.9, 154.0, 169.2;
HRMS (ESI) calcd for C54H58O16Na (MNaþ) 985.3622, found
985.3646. The structure was further confirmed by crystallo-
graphy, the data for the X-ray structure is supplied in the
Supporting Information.
(P)-2,4,6,7,9,11-hexamethoxy-1,12-bis((2-methyl-1,3-dioxo-
lan-2-yl)methyl)perylene-3,10-dione (40). Substrate 39 (40 mg,
0.060 mmol) was dissolved in THF (4 mL) under argon. MnO2
(157 mg, 1.80 mmol) was added and the mixture stirred for 1 h.
NaOH (116 mg, 2.89 mmol) in EtOH/H2O (1:1 v:v, 5 mL) was
added and the reaction stirred for an additional 1 h. The mixture
was filtered through Celite (EtOAc). The organic phase was
washed with 1 N HCl, dried (Na2SO4), and the solvent evapo-
rated. Purification was accomplished via chromatography (10%
MeOH/CH2Cl2) to yield 40 as a red oil (35 mg, 88%):
[R]2D0-780.0 (c 0.05, CH2Cl2, >99% ee (S)); IR (thin film)
1
2941, 1617, 1575, 1544 cm-1; H NMR (500 MHz, CDCl3) δ
(P)-5,50-bis(benzyloxy)-2,20,4,40,6,60-hexamethoxy-7,70-bis-
((2-methyl-1,3-dioxolan-2-yl)methyl)-1,10-binaphthyl-3,30-di-
carboxylic acid (33). To a solution of 30 (25 mg, 0.026 mmol)
in 5% H2O-DMSO (1 mL) was added NaCN (10 mg, 0.21
mmol). The mixture was heated in an oil bath (100-110 °C)
oil bath for 24 h. The mixture was diluted with EtOAc, and
the organic phase washed with 1N HCl and brine, dried
(Na2SO4), and the solvent was evaporated to yield diacid 33
as a white resin (24 mg, 100%): [R]2D0þ34.0 (c 0.85, CH2Cl2,
>99% ee); 1H NMR (500 MHz, CDCl3) δ 1.14 (s, 6H), 2.85
(d, J = 13.8 Hz, 2H); 3.03 (d, J = 13.8 Hz, 2H), 3.42 (m, 2H),
3.52 (m, 2H), 3.52 (s, 6H), 3.71 (m, 4H), 4.02 (s, 6H), 4.05 (s,
6H), 5.08 (d, J = 9.8 Hz, 2H), 5.12 (d, J = 9.7 Hz, 2H), 6.99
(s, 2H), 7.37 (m, 2H), 7.44 (t, J = 7.2 Hz, 4H), 7.65 (d, J = 7.8
Hz, 4H); HRMS (ESI) calcd for C52H54O16Na (MNaþ)
957.3310, found 957.3277.
0.85 (s, 6H), 2.86 (d, J = 13.3 Hz, 2H); 3.31-3.33 (m, 4H),
3.46-3.53 (m, 4H), 3.55 (d, J = 13.4 Hz, 2H), 4.08 (s, 6H), 4.11
(s, 6H), 4.16 (s, 6H), 6.78 (s, 2H); 13C NMR (125 MHz, CDCl3) δ
24.5, 39.1, 56.3, 56.7, 60.5, 64.5, 65.1, 94.9, 109.1, 109.9, 110.8,
128.9, 131.7, 132.9, 155.1, 163.1, 163.8, 178.9; HRMS (ESI)
calcd for C36H39O12 (MHþ) 663.2441, found 663.2421.
(P)-2,4,6,7,9,11-hexamethoxy-1,12-bis(2-oxopropyl)perylene-
3,10-dione (6). Substrate 40 (26 mg, 0.039 mmol) was dissolved
in benzene (2 mL) and a saturated solution of Na2S2O4 was
added (2 mL). After stirring vigorously for 30 min, the orange
organic layer was separated and concentrated using standard
rotary evaporation without special measures to exclude air. The
perylene (41) was dissolved in acetone (2 mL) under argon.
PdCl2(CH3CN)2 (2.0 mg, 0.0080 mmol) was added and the
mixture stirred for 12 h under argon. The reaction mixture
was filtered through silica (5% MeOH/CH2Cl2) to afford 6 as a
red oil (20 mg, 89%): [R]2D0 þ 908.0 (c 0.025, CH2Cl2, >99% ee
(S)); IR (thin film) 2926, 2853, 1722, 1617, 1579 cm-1; 1H NMR
(500 MHz, CDCl3) δ 2.07 (s, 6H), 3.52 (d, J = 16.7 Hz, 2H), 3.99
(s, 6H), 4.09 (s, 6H), 4.11 (d, J = 14.5 Hz, 2H), 4.18 (s, 6H), 6.77
(s, 2H); 13C NMR (125 MHz, CDCl3) δ 30.2, 45.7, 56.4, 56.8,
60.1, 95.2, 111.8, 125.6, 129.1, 131.3, 131.5, 154.4, 163.5,
164.3, 178.1, 204.1; HRMS (ESI) calcd for C32H31O10 (MHþ)
575.1917, found 575.1924.
(P)-2,20-(5,50-Bis(benzyloxy)-2,20,4,40,6,60-hexamethoxy-1,10-
binaphthyl-7,70-diyl)bis-(methylene)bis(2-methyl-1,3-dioxolane)
(34). To a solution of the diacid 33 (100 mg, 0.11 mmol) in 5%
DMSO-DMF (4 mL) was added Pd(OC(O)CF3)2 (89 mg, 0.27
mmol) and Ag2CO3 (177 mg, 0.64 mmol). After heating in a
75 °C oil bath for 1 h, the mixture was removed from the oil bath
and quenched with NaBH4 (28 mg, 0.428 mmol). The resultant
black mixture was diluted with EtOAc, and the organic phase
washed with 1N HCl and brine, dried (Na2SO4), and the solvent
was evaporated. Purification was accomplished via chromatog-
raphy (50% EtOAc/hexanes) to yield 34 (50 mg, 60%) as an oil:
[R]2D0-27.7 (c 1.0, CH2Cl2, >99% ee (S)); IR (thin film) 2937,
Hypocrellin A (1). A solution of 6 (5.0 mg, 0.0087 mmol) in
anhydrous THF (3 mL) was cooled to -105 °C under argon.
LiN(SiMe2Ph)2 (57 μL, 0.0218 mmol, 0.38 M in THF) was
added. After the solution stirred for 15 min, it was quenched
with saturated NH4Cl (aq), making sure the solution tempera-
ture was still at -105 °C when quenched. The frozen mixture
was diluted with EtOAc, and the organics were separated upon
melting, washed with brine, and dried (Na2SO4). The concen-
trate was purified by column chromatography (2.5% MeOH/
CH2Cl2) to afford the cyclized product as a mixture of two
diastereomers red oil (3.7 mg, 74%): [R]2D0-825 (c 0.025,
CH2Cl2, >99% ee); IR (thin film) 3416, 2922, 2853, 1702,
1
1590, 1575, 1463 cm-1; H NMR (500 MHz, CDCl3) δ 1.20
(s, 6H), 2.79 (d, J = 13.7 Hz, 2H); 2.94 (d, J = 13.7 Hz, 2H), 3.32
(dd, J = 5.1, 11.5 Hz, 2H), 3.43 (dd, J = 7.2, 13.1 Hz, 2H),
3.61-3.69 (m, 4H), 3.75 (s, 6H), 3.95 (s, 6H), 4.01 (s, 6H), 5.08
(d, J = 10.1 Hz, 2H), 5.13 (d, J = 10.1 Hz, 2H), 6.79 (s, 2H), 6.83
(s, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.46 (t, J = 7.2 Hz, 4H), 7.64 (d,
J = 7.0 Hz, 4H); 13C NMR (500 MHz, CDCl3) δ 25.1, 38.5, 56.1,
57.4, 61.4, 64.7, 64.9, 76.3, 96.1, 110.1, 112.6, 116.9, 124.6, 127.9,
128.5, 128.6, 131.3, 133.4, 138.8, 147.1, 149.3, 154.8, 157.1;
HRMS (ESI) calcd for C50H54O12Na (MNaþ) 869.3513, found
869.3505.
(P)-2,20,4,40,6,60-hexamethoxy-7,70-bis((2-methyl-1,3-dioxo-
lan-2-yl)methyl)-1,10-binaphthyl-5,50-diol (39). Biaryl 34 (19 mg,
0.021 mmol) was dissolved in MeOH/THF mixture (1:1 v:v,
4 mL) with 10% Pd/C (22 mg, 0.021 mmol). A hydrogen balloon
was added. After stirring for 1 h, the mixture was filtered
through silica (2.5% MeOH/CH2Cl2) to afford 39 as a colorless
oil (14 mg, 100%): [R]2D0-35.8 (c 0.60, CH2Cl2, >99% ee (S)); IR
(thin film) 3401, 2841,1606 cm-1; 1H NMR (500 MHz, CDCl3) δ
1.21 (s, 6H), 2.76 (d, J = 13.6 Hz, 2H), 2.94 (d, J = 13.6 Hz, 2H),
3.39 (dd, J = 5.3, 11.9 Hz, 2H), 3.48 (dd, J = 7.2, 13.2 Hz, 2H),
1
1613, 1579, 1540, 1463 cm-1; H NMR (500 MHz, CDCl3) δ
1.63 (s, 3H), 1.95 (s, 3H), 2.54 (d, J = 12.2 Hz, 1H), 3.28 (s, 1H),
3.38 (d, J = 12.0 Hz, 1H), 4.06 (s, 3H), 4.08 (s, 3H), 4.14 (s, 3H),
4.15 (s, 3H), 4.20 (s, 3H), 4.21 (s, 3H), 4.63 (s, 1H), 6.84 (s, 1H),
6.86 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 27.2, 29.9, 41.6,
56.4, 56.5, 56.8, 56.9, 60.6, 61.6, 61.7, 76.8, 95.3, 95.4, 109.0,
109.5, 111.5, 111.6, 129.1, 130.1, 130.2, 130.3, 132.7, 133.1,
153.1, 154.1, 163.5, 163.6, 164.5, 164.6, 178.3, 178.9, 207.7;
HRMS (ESI) calcd for C32H31O10 (MHþ) 575.1917, found
575.1939.
A 0.076 M solution of MgI2 was prepared by stirring Mg
turnings (10.2 mg, 0.42 mmol) and I2 (55 mg, 0.21 mmol) in
anhydrous Et2O (2.75 mL) for 3 h, during which the solution
J. Org. Chem. Vol. 75, No. 1, 2010 67

O’Brien et al.
JOCArticle
turns from red/brown to clear. To a solution of perylenequinone
(3.5 mg, 0.0061 mmol) in dry THF (1 mL) under an argon
atmosphere was added a solution of MgI2 in Et2O (0.16 mL,
0.076 M, 0.0122 mmol). The dark green solution was stirred for
15 min, diluted with EtOAc, washed with saturated NH4Cl (aq)
and brine, dried (Na2SO4), and the solvent evaporated to yield a
10:1 mixture of diastereomers (hypocrellin A and shiraichrome
A, respectively), which was determined by crude 1H NMR. The
diastereomers were separated by preparatory thin layer chro-
matography. The plate was treated with a 3% oxalic acid
solution in EtOH and dried before elution (1% EtOH/CHCl3).
The top fraction was concentrated and triturated (hexanes:
n-pentane:i-PrOH) to yield hypocrellin A (1) as a red resin
(57%, 92% ee): See CD spectra in spectral section of Supporting
Information; IR (thin film) 3505, 2941, 1702, 1610, 1540, 1455
cm-1; 1H NMR (500 MHz, CDCl3) δ 1.70 (s, 3H), 1.89 (s, 3H),
4.07 (s, 6H), 4.12 (s, 6H), 6.56 (s, 1H), 6.57 (s, 1H), 15.91 (s, 1H),
15.95 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 26.9, 30.1, 41.9,
56.5, 56.6, 60.8, 61.7, 62.1, 78.8, 102.0, 102.1, 106.7, 106.9, 117.7,
118.2, 125.0, 125.0, 127.6, 128.5, 133.2, 134.0, 150.6, 150.9,
167.5, 167.5, 170.9, 171.8, 179.9, 180.4, 207.4; MALDI-TOF:
m/z 546.46 (calculated for C30H26O10 (M)þ 546.15).
Acknowledgment. We are grateful to the NIH (CA-
109164) for financial support. Partial instrumentation sup-
port was provided by the NIH for MS (1S10RR023444) and
NMR (1S10RR022442). We thank 3D Pharmaceuticals (C.
A.M.), Novartis (B.J.M.), Eli Lilly (E.O.B.), and the Divi-
sion of Organic Chemistry of the American Chemical Society
(C.A.M., B.J.M.) for graduate fellowships. We acknowledge
the work of Kusha Tavakoli, Miriam Bowring, Andre
Isaacs, and Christine Skibinski in the synthesis of starting
materials. We thank Bill DeGrado and Virgil Percec for
assistance with CD measurements.
Supporting Information Available: Additional experimental
descriptions and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
68 J. Org. Chem. Vol. 75, No. 1, 2010