Perylenequinone natural products: Evolution of the total synthesis of cercosporin

Article abstract of DOI:10.1021/jo9013854

(Chemical Equation Presented) The evolution of the first total synthesis of perylenequinone cercosporin is described. The key features developed during these efforts include a biscuprate epoxide alkylation, installation of the methylidene acetal, palladium-catalyzed O-arylation, and C3,C3′- decarbonylation. Due to the rapid atropisomerization of the helical axis of cercosporin (at 37°C), the sequencing of these transformations was critical. To this end, the developed protocol enabled the formation of a key advanced intermediate on preparative scale absent any atropisomerization. Furthermore, the O-arylation proved to be general, and the strategy was used in an improved synthesis of a helical chiral perylenequinone structure.

Full text of DOI:10.1021/jo9013854

pubs.acs.org/joc
Perylenequinone Natural Products: Evolution of the Total Synthesis of
Cercosporin
Barbara J. Morgan, Carol A. Mulrooney, 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
The evolution of the first total synthesis of perylenequinone cercosporin is described. The key
features developed during these efforts include a biscuprate epoxide alkylation, installation of the
methylidene acetal, palladium-catalyzed O-arylation, and C3,C30-decarbonylation. Due to the rapid
atropisomerization of the helical axis of cercosporin (at 37 °C), the sequencing of these transforma-
tions was critical. To this end, the developed protocol enabled the formation of a key advanced
intermediate on preparative scale absent any atropisomerization. Furthermore, the O-arylation
proved to be general, and the strategy was used in an improved synthesis of a helical chiral
perylenequinone structure.
Introduction
the pathogenic nature of the Cercospora species, cercosporin
has become one of the most widely studied perylenequi-
nones.5
The perylenequinone cercosporin (1, Figure 1) was first
isolated by Kuyama and Tamura from the pathogenic
soybean fungus Cercospora kikuchii.1 Following this discov-
ery, it was found to be prevalent in nature and was isolated
from multiple members of the genus Cercospora. The de-
structive Cercospora species is responsible for causing dis-
ease worldwide on a variety of crop plants, including corn,
sugar, beet, bananas, tobacco, coffee, and soybean.2 Prior to
an understanding of the pathogen toxicity, it was observed
that intense light was required for symptom development of
infected plants.3 Though 1 was isolated in 1957 and con-
jectured to be photodynamic, it was not until the 1970s that
the structure was elucidated and it was confirmed to be the
phototoxin produced by the respective fungi.4 Largely due to
FIGURE 1. Cercosporin atropisomerization.
As represented by cercosporin (1) in Figure 1, the peryl-
enequinone natural products are characterized by a chiral
helical oxidized core and stereogenic C7,C70-substitution.6
Interestingly, the helicity of cercosporin, which is M, differs
(1) Kuyama, S.; Tamura, T. J. Am. Chem. Soc. 1957, 79, 5725–5726.
(2) For a review, see: Daub, M. E.; Ehrenshaft, M. Annu. Rev. Phytopath.
2000, 38, 461–490.
(3) Calpouzos, L.; Stalknecht, G. F. Phytopathology 1967, 57, 799–800.
(4) (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. (c) Yamazaki, S.; Okube, A.;
Akiyama, Y.; Fuwa, K. Agric. Biol. Chem. 1975, 39, 287–288.
(5) Daub, M. E.; Herrero, S.; Chung, K.-R. FEMS Microbiol. Lett. 2005,
252, 197–206. and references cited therein.
(6) The entire mold perylenequinone family can be seen in Figure 2 of the
first paper in this series: Mulrooney, C. A.; Morgan, B. J.; Li, X.; Kozlowski,
M. C. J. Org. Chem. 2010, 75 (DOI 10.1021/jo9013832).
44 J. Org. Chem. 2010, 75, 44–56
Published on Web 11/09/2009
DOI: 10.1021/jo9013854
r
2009 American Chemical Society

Morgan et al.
JOCArticle
from that of the calphostins (2) and phleichrome (3), which
are P (Figure 2). Furthermore, cercosporin is distinguished
from the structurally similar perylenequinones, calphostins,
and phleichrome by a seven-membered ring spanning the C2,
C20-positions. This seven-membered ring lowers the atrop-
isomerization barrier, allowing 1 to readily atropisomerize at
37 °C (Figure 1).7 The formation of a ∼1:1 mixture of 1/epi-1
under thermodynamic conditions7,8 contraindicates a simple
thermodynamic equilibration following biosynthesis of the
dioxepane ring as the source of the M-stereochemistry;
rather, it appears that the formation of the helical stereo-
chemistry itself occurs differently in the Cercospora species
vs the Cladosporium fungi. This facile atropisomerization of
cercosporin presents significant synthetic challenges; while
atropisomerically stable 2 and 3 had been synthesized
(Figure 2),9 the labile cercosporin remained a challenging
synthetic target.8
In examining these measurements, it was clear that the
combination of the perylenequinone and the methylidene
acetal must be reserved to occur as late as possible. Further-
more, it became clear that the perylenequinone was a greater
contributor to the atropisomerization barrier than the methy-
lidene acetal (Scheme 1). In addition, the methods for form-
ing the methylidene acetal require higher temperatures than
those for forming the perylenequinone. For these reasons, we
determined that path a in Scheme 1 was far more viable than
path b.
SCHEME 1. Atropisomerization in the Retrosynthetic Routes
to Cercosporin
FIGURE 2. Perylenequinones, (-)-calphostins (2), and (-)-phlei-
chrome (3).
The common theme of the previously reported syntheses of
2 and 3 centered on a diastereoselective coupling of a chiral
naphthalene, affording the biaryl with modest diastereoselec-
tivity.9 Distinct from these approaches, our synthetic strategy
involved the use of an enantioselective coupling to set the biaryl
axis followed by installation of the C7,C70-stereochemistry. In
the preceding papers of this series (DOIs 10.1021/jo9013832
and 10.1021/jo901384h), we detailed these aspects in the
context of total syntheses of (þ)-calphostin D (ent-2d) and
(þ)-phleichrome (ent-3). In this paper, we provide a complete
account of our strategy to accomplish the total synthesis of
atropisomerically sensitive cercosporin (1), with a focus on the
sequence of transformations needed to form a key advanced
intermediate (4) containing the methylidene acetal.
As such, our synthetic efforts rapidly focused on 4(Scheme2)
with the 7-membered methylidene acetal as a late-stage inter-
mediate, which would be less prone to atropisomerization than
early intermediates with the perylenequinone core. From this
key intermediate, paths a-c(Scheme 2) were identified, varying
in the sequence of three transformations: C5,C50-oxygenation,
biscuprate epoxide opening, and methylidene acetal formation.
All of these paths converge on common enantiopure intermedi-
ate 9, congruent with our goal of synthesizing all the perylene-
quinone natural products from this compound.
Thus, helical chiral 1 would arise from axial chiral 4
(Scheme 2). At this branchpoint, retrosynthetic installation
of the C3,C30-methyl esters and C5,C50-deoxygenation leads
to intermediate 7. The C3,C30-esters are necessary to achieve
a highly selective biaryl coupling and also serve to protect the
C3,C30-positions during the C5,C50-oxygenation. In path a,
the epoxide opening disconnection is applied to 7 and is
followed by removal of the methylidene acetal to generate the
common enantiopure intermediate 9. By installing the methy-
lidene acetal prior to epoxide opening, path a offers the most
direct route by avoiding unnecessary C2,C20-protecting
groups. Intercepting the intermediate 7 from path a, path
b diverges with the cleavage of the methylidene acetal to
afford 11 (Scheme 2). Following the epoxide opening dis-
connection to provide 12, removal of protecting groups yields
common intermediate 9. Path b would be necessary if the
methylidene acetal is not stable to the epoxide opening
conditions needed to add the C7,C70-substitution (i.e., 8 to
7 in path a). However, by reserving the oxygenation until
after methylidene acetal installation in path b, the three sets of
orthogonal protecting groups in intermediate 10 of path c
Results and Discussion
Retrosynthetic Analysis. In our strategy toward cercos-
porin (1), the central concern was the installation of the
methylidene acetal, which lowers the atropisomerization
barrier relative to the calphostins (2a-d) and phleichrome
(3). In a previous publication, we explored the combined
effects of the perylenequinone, the methylidene acetal, and
the C7,C70-2-hydroxypropyl groups on atropisomerization.8
(7) Nasini, G.; Merlini, L.; Andreetti, G. D.; Bocelli, G.; Sgarabotto, P.
Tetrahedron 1982, 38, 2787–2796.
(8) For a preliminary account of this work, see: Morgan, B. J.; Dey, S.;
Johnson, S. W.; Kozlowski, M. C. J. Am. Chem. Soc. 2009, 131, 9413–9425.
(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.
J. Org. Chem. Vol. 75, No. 1, 2010 45

Morgan et al.
JOCArticle
SCHEME 2. Retrosynthetic Sequencing for Cercosporin from Key Advanced Intermediate 4
SCHEME 3. Formation of Iodonaphthalene 8
afford a pure sample of 8, a longer alternate route was
employed. Specifically, the C2,C20-phenols were masked as
benzyl ethers via a Mitsunobu reaction (Scheme 3). Follow-
ing a one-pot deacylation/methylation of the C4,C40-phe-
nols, the orthogonally protected 14 was generated in high
yield. Selective deprotection of the C2,C20-benzyl ethers was
achieved with BCl3. Treatment of the resulting bisphenol
with BrCH2Cl and Cs2CO3 provided the desired 8 as the only
product. With pure 8 in hand, the biscuprate epoxide open-
ing was investigated.
In the preceding paper of this series (DOI 10.1021/
jo901384h), we investigated the dianionic cuprate formation
of a biaryl system similar to 8 in a double-epoxide alkylation.
Pleasingly, the resulting complex biscuprate was well-behaved
with no evidence of deleterious interactions between the two
reacting centers. However, use of these optimized conditions
with 8 provided the desired product 15 (eq 1) in only moderate
acetal may be avoided. Path c moves methylidene acetal
formation to after C5,C50-oxygenation and epoxide opening
and intercepts intermediate 11 from path b. Even though
path c involves the greatest number of protecting group
manipulations, it is the most conservative route since the
sensitive methylidene acetal is installed after the most demand-
ing transformations. Due to its efficiency, we began with the
most speculative route, path a, even though the methylidene
acetal may not be orthogonal to all the reaction conditions.
Path a: Biscuprate Containing a Methylidene Acetal. As
outlined in path a (Scheme 2), a direct installation of the
methylidene acetal was to be attempted using enantiopure 9.
The synthesis of the common enantiopure intermediate 9,
involving an enantioselective naphthol dimerization, is de-
tailed in the preceding paper of this series. In the initial
formation of 8 (Scheme 3), the base i-PrMgBr was used in
conjunction with BrCH2Cl to install the methylidene acetal.
As described below, these conditions were optimal (see
Table 2). Even so, cleavage of the labile C4,C40-acetates
was competitive and conditions that drove the C2,C20-
alkylation with BrCH2Cl to completion resulted in undesired
alkylation of the C4,C40-positions. Milder reaction condi-
tions led to incomplete reaction resulting in an inseparable
mixture of 8 and 13 after one-pot deacylation/methylation
with NaH and MeI in wet DMF.
yield (40%). One of the challenges of these structures is that
every step involves reaction at two separate sites on the same
molecule. In this case, yet another reaction was competitive.
In particular, the less hindered C2,C20-methylidene acetal
permitted reaction at the C3,C30-esters resulting in a halo-
decarboxylation product that was inseparable from 15.
Due to the difficulties encountered in this route (Scheme 3,
eq 1), our efforts shifted to path b (Scheme 2) where the
Before optimizing this difficult transformation further, the
viability of the epoxide alkylation with 8 was tested. To
46 J. Org. Chem. Vol. 75, No. 1, 2010

Morgan et al.
JOCArticle
methylidene acetal would be generated after the epoxide
alkylation.
SCHEME 4. Attempted Selective Demethylation on Model
Substrate 18
Path b: C5,C50-Oxygenation with the Methylidene Acetal.
As seen in the previous paper of this series, the epoxide
alkylation proceeded smoothly with bisiodonaphthalene 13
containing C2,C20,C4,C40-methyl ethers (eq 2). Thus, we
desired to intercept the calphostin intermediate 16 in the
synthesis of 1. In order to utilize this path b strategy
(Scheme 2), a selective cleavage of the C2,C20-methyl ethers
vs the C4,C40,C6,C60-methyl ethers was required to permit
formation of the methylidene acetal. Encouragingly, aryl
methyl ethers ortho to carbonyls (such as, the C2,C20,C4,C40-
methyl ethers of 16) can be selectively demethylated with
relatively mild Lewis acids in the presence of unactivated aryl
methyl ethers (such as the C6,C60-methyl ethers of 16).10
SCHEME 5. Selective Cleavage of C2,C20-Isopropyl Ethers
In order to distinguish between the C2,C20- and C4,C40-
methyl ethers, model system 18 was examined which was
available from our hypocrellin A synthesis (Scheme 4).11 Due
to substitution at the C5,C50-peri positions, it was expected
that the C4,C40-methyl ethers would be more hindered than
the C2,C20-methyl ethers resulting in selective cleavage of the
latter. Screening of reagents to demethylate phenols revealed
that BCl3 in combination with n-Bu4NI10b was the most
selective. Unfortunately, a complex mixture of C2,C20,C4,
C40-demethylated products was produced, and the C2,C20-
bisphenol 19 was obtained in only a modest 35% yield. With
such a nonselective process, the C2,C20-demethylation of a
calphostin intermediate was eliminated as a route to cercos-
porin (1).
Although the selective demethylation was disappointing, the
observation of some intrinsic selectivity provided an impetus to
consider other alkyl groups for protection of the C2,C20-
phenols. Choices include the less hindered, more stable isopro-
pyl ether and the bulkier, more labile tert-butyl ether. Precedent
for the selective removal of isopropyl aryl ethers in the presence
of methyl aryl ethers,12 in conjunction with the stability and
more facile installation, led to selection of the isopropyl group.
To examine the selectivity for cleavage of C2,C20-isopro-
pyl ethers, model 23 was generated (Scheme 5). Bis-isopro-
poxy compound 33 was synthesized from the allyl biaryl
coupling product 21.13 Mitsunobu reaction of 21 with 2-
propanol followed by the deacylation/methylation afforded
22 in high yield. As will become apparent in subsequent
discussion, the PhI(OCOCF3)2-induced14 C5,C50-oxygena-
tion was sensitive to most ether functionality. Pleasingly, the
isopropyl ethers departed from this trend and PhI(OCOC-
F3)2 treatment followed by bisacetylation furnished bisace-
tate 23 in 80% yield, with no erosion of the enantiopurity.
Selective removal of the C2,C20-isopropyl ethers proceeded
smoothly upon treatment of 23 with BCl3 at low tempera-
tures to yield the desired C2,C20-bisphenol 24. While these
results were encouraging, the ultimate test would be if the
isopropoxy groups could withstand the biscuprate epoxide
opening.
To this end, the biscuprate epoxide opening was examined
with the bis-isopropyl ether 25 (Scheme 6). Using the same
method as before (Scheme 5), Mitsunobu reaction of 9
followed by deacylation/methylation provided the required
bisiodide 25. This route was readily scalable allowing the
generation of over 15 g of enantiopure 25. Furthermore,
using the developed conditions,13 the epoxide openings of
(R)-propylene oxide with the biscuprate of 25 afforded 26 in
high yield supplying two new stereocenters (two couplings,
(10) (a) Dean, F. M.; Goodchild, J.; Houghton, L. E.; Martin, J. A.;
Morton, R. B.; Parton, B.; Price, A. W.; Somvichien, N. Tetrahedron Lett.
1966, 4153–4159. (b) Brooks, P. R.; Wirtz, M. C.; Vetelino, M. G.; Rescek, D.
M.; Woodworth, G. F.; Morgan, B. P.; Coe, J. W. J. Org. Chem. 1999, 64,
9719–9721.
(11) O’Brien, E. M.; Morgan, B. J.; Kozlowski, M. C. Angew. Chem., Int.
Ed. 2008, 47, 6877–6880.
(12) Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1979, 2593–
2598.
(13) See the preceding 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).
(14) (a) Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.;
Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684–3691.
(b) Arisawa, M.; Ramesh, N. G.; Nakajima, M.; Tohma, H.; Kita, Y. J. Org.
Chem. 2001, 66, 59–65.
J. Org. Chem. Vol. 75, No. 1, 2010 47

Morgan et al.
JOCArticle
81% yield each). With establishment of the C7,C70-stereo-
chemistry, the next transformation to address in path
b (Scheme 2) is installation of the methylidene acetal.
Table 1), but tolerated a small subset of other functionalities
including halogens.15 Thus, oxygenation of 25 successfully
yielded 30. Unfortunately, the attempted epoxide alkylation
on 30 was unsuccessful; the additional C5,C50-substituents
cause steric gearing with the C6,C60-methoxy groups which
in turn hindered the C7,C70-metalated species. As a conse-
quence, only the arene from protodemetalation was obtained
with the C5,C50-acetates intact.8
SCHEME 6. Dianion Epoxide Opening with 25
SCHEME 8. PIFA Oxygenation of Iodonaphthalene 25
As outlined in the preceding paper in this series (DOI
10.1021/jo901384h), the benzoyl group was the only sub-
stitution compatible with the PIFA conditions. Thus, the
newly formed alcohol stereocenters of 26 were protected as
benzoates providing 27 in 96% yield (Scheme 7). As seen
with 23 (Scheme 5), the C2,C20-isopropyls of 27 (Scheme 7)
were selectively cleaved using BCl3 to afford the desired
bisphenol. Methylidene ketal 28 was generated upon expo-
sure to BrCH2Cl and NaH. Unfortunately, the PIFA oxyge-
nation conditions with the C2,C20-methylidene acetal
resulted in decomposition and provided none of the desired
product 29. Apparently, PIFA is sufficiently oxidizing to
react with the activated methylidene. The low functional
group tolerance of the PIFA reagent compelled us to turn
from path b to path c (Scheme 2) to generate intermediate 4.
TABLE 1. Screening Substrates and Conditions for PIFA Oxygenation
entry
R1
R2
solventa
product
yield (%)
1
2
3
4
5
Bz
Bz
Piv
Bz
Bz
Me
i-Pr
i-Pr
Bn
TFE/HFIP(1:1)
TFE/HFIP(1:1)
TFE/HFIP(1:1)
TFE/HFIP(1:1)
HFIP
32
33
34
35
33
59
25
<20
0
55
SCHEME 7. Attempted PIFA Oxygenation on Methylidene
Acetal 28
i-Pr
aTFE = CF3CH2OH; HFIP = (CF3)2CHOH.
Path c: Late-Stage Methylidene Acetal Installation. With
the elimination of path a and path b, attention turned to
path c (Scheme 2). Path c diverges from path b by reserving
formation of the methylidene acetal to after C5,C50-oxyge-
nation. As seen in Scheme 8, the C2,C20-isopropyl ethers are
compatible with the PIFA oxygenation condition providing
promise that 27 would be successful as well. Unfortunately,
the same conditions that had been successfully employed to
provide the calphostin intermediate 32 (entry 1, Table 1),
generated 33 in only 25% yield (entry 2). With the more
robust pivaloyl esters of the C7,C70-hydroxypropyl groups
(34) or with the orthogonal C2,C20-benzyl ethers (35) even
more unsatisfactory results were obtained (entries 3 and 4).
The use of neat 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)
compared to a 1:1 mixture of HFIP/2,2,2-trifluoroethanol
proved essential and afforded the desired product 33 in
Though not following one of the paths outlined in
Scheme 2, the above success with the C2,C20-isopropoxy
protecting groups stimulated us to evaluate PIFA oxygena-
tion and subsequent epoxide opening of the readily available
25 (Scheme 8). Advantages of this plan include avoidance of
the three sets of orthogonal protecting groups necessary in
path c and late stage introduction of the C7,C70-subsitution
which would facilitate synthesis of analogs. The PIFA
oxygenation was sensitive to most ethers (see Scheme 7,
(15) The other functionalities include C2,C20-isopropoxy and C7,C70-
propyls and -allyls, as can be seen in the other papers of this series (DOIs
10.1021/jo9013832 and 10.1021/jo901384h) and in Scheme 5 and Table1.
48 J. Org. Chem. Vol. 75, No. 1, 2010

Morgan et al.
JOCArticle
55% yield (entry 5). The more polar HFIP provided faster
reaction times, which allowed less time for concurrent pro-
duct decomposition as was seen with entry 2. Even with these
harsher reaction conditions, no atropisomerization was ob-
served in contrast to the case when C7,C70-propyl groups
were employed as described in the first paper of this series
(DOI 10.1021/jo9013832)”. With the C5,C50-oxygenation in
place, selective removal of the C2,C20-isopropyl ethers was
assessed to set the stage for methylidene acetal installation.
As seen in the discussions above, the installation and
presence of the methylidene acetal has provided many chal-
lenges. Thus, it has been the central focus of our work toward
cercosporin. To optimize the success in methylidene acetal
installation, a variety of orthogonal C5,C50-protecting
groups were assessed during the selective removal of the
C2,C20-isopropyl ethers and the subsequent formation of the
methylidene acetal. Happily, C5,C50-acetates and silyl ethers
(TBS and TIPS) were compatible with the BCl3-mediated
deprotection of the C2,C20-isopropyl ethers supplying bis-
phenols 37a-c (eq 3). Unfortunately, these transformations
proved to be sensitive to scale and attempts to perform them
on more than 0.06 mmol were unsuccessful, providing
mixtures of C2,C20,C4,C40-dealkylation. Prior to further
optimization of these reactions, the installation of the methy-
lidene acetal was examined.
present during the reaction. To circumvent this problem, the
self-desiccating base i-PrMgBr was employed, which would
form polymeric MgO/Mg(OH)2. Under these conditions,
methylidene acetal 38c formed smoothly with no loss of the
C5,C50-silyl groups (entries 6 and 7). Furthermore, no
atropisomerization was observed. With the methylidene
acetal achieved, our efforts focused on removal of the C3,
C30-methyl esters.
TABLE 2. Screening Substrates and Conditions for Methylidene Acetal
Installation
entry
R
base
NaH
NaH
temp (°C)
product
yield (%)
1
2
3
4
5
6
7
Ac
65
65
rt
rt
rt
a
b
b
b
c
c
c
<5a,b
TBS
TBS
TBS
TIPS
TIPS
TIPS
<5a,b
LiH
<5a,b
LHMDS
LHMDS
i-PrMgBr
i-PrMgBr
<10a,b
<10a,b
40 (85% brsm)
73
rt
45
aConversion by NMR. bC5,C50-protecting groups cleaved.
Decarboxylation vs Decarbonylation (Path c). Upon re-
moval of the C3,C30-esters, the key advanced intermediate 4
(Scheme 2) would be obtained. Based upon the success with a
similar calphostin intermediate described in the previous
paper of this series, a palladium-catalyzed decarboxylation16
was employed here. To apply this transformation, the incom-
patible benozyl and silyl of 38c need to be converted to more
robust protecting groups (Scheme 9). Removal of the silyl
ethers with TBAF and quenching with benzyl bromide af-
forded the C5,C50-bisbenzyl ether. Following hydrolysis of
the benzoates with NaOMe, benzylation yielded tetrabenzyl
ether 39. Due to the steric hindrance of the C3,C3-esters, a
three-step sequence was used to furnish diacid 40 in a higher
overall yield and no atropisomerization compared to a base
mediated hydrolysis. Surprisingly, application of the decar-
boxylation procedure to 40 furnished less than 20% of the key
intermediate 41. Molecular models indicated that the protons
of the 7-membered ring in 42a are in close proximity to the
palladium of the intermediate palladium carboxylate causing
a competing C-H insertion into the methylidene ring as seen
in 42b.
Although formation of the methylidene acetal is presented
above (Schemes 3 and 7), this transformation was not trivial
and required considerable optimization. Presumably, the
disfavorable entropy in forming the seven-membered ring
combined with ring strain slows this process. Use of for-
maldehyde equivalents under acidic conditions failed. Of all
the potential methylidene equivalents, ring formation was
most facile via SN2 displacements with BrCH2Cl vs
BrCH2Br, BrCH2I, ICH2Cl, and ClCH2Cl. Clearly, there is
a necessary balance between leaving group ability and halide
size. For example, BrCH2Br or ICH2Cl with superior leaving
groups would be expected to supersede BrCH2Cl; however,
the larger bromo/iodo group appears to hinder the first
alkylation event. On the other hand, ClCH2Cl performed
poorly since the chloride is an inferior leaving group in the
crucial first alkylation. Furthermore, DMF provides sub-
stantial acceleration of the SN2 displacements and was the
only acceptable solvent.
With substrates 37a-c, the lability of the C5,C50-phenolic
protecting groups presented a serious challenge (Table 2).
For example, the use a hydride base (NaH or LiH) and
BrCH2Cl failed to provide significant amounts of 38a,b due
to cleavage of C5,C50-acetates or -silyls (entries 1-3). After a
survey of both the more robust TIPS group and other non-
nucleophilic bases (entries 3-5), we attributed the C5,C50-
cleavage to hydroxide formed from small amounts of water
In the hope of avoiding this unproductive pathway, the
C3,C30-decarboxylation was evaluated with the bis-isopro-
poxy 44. After hydroxylation, the C5,C50-phenols of 33 were
benzylated (Scheme 10). Hydrolysis of the benzoate groups
and replacement with the benzyl ethers afforded the desired
product 43 in high yield. The three-step reduction/oxidation/
oxidation sequence was used to provide the bisacid 44. The
yield of this sequence was slightly lower due to greater steric
(16) Dickstein, J. S.; Mulrooney, C. A.; O’Brien, E. M; Morgan, B. J.;
Kozlowski, M. C. Org. Lett. 2007, 9, 2441–2444.
J. Org. Chem. Vol. 75, No. 1, 2010 49

Morgan et al.
JOCArticle
SCHEME 9. Attempted Palladium-Mediated Decarboxylation
of Methylidene Substrate 40
the corresponding thiohydroxamate ester could be gener-
ated.17 It has been reported that Barton ester formation can
be stalled by hindered reaction sites.18 As such, an alternate
method was sought.
The decarbonylation of aldehydes by rhodium complexes
represents an important method for total synthesis in that
it permits the removal of a sensitive functional group under mild
and neutral conditions.19 Though there have been some descrip-
tions of catalytic processes,20 most applications require stoichio-
metric rhodium. Utilizing the epoxide alkylation product 48
formed during optimization of the cuprate procedure described
in the preceding paper of this series, model aldehyde 49b was
generated to investigate the potential of the rhodium-mediated
decarbonylation in a hindered system (eq 5).
Studies began with the simple aldehyde 49a using RhCl3 H2O
3
with 1,3-bis(diphenylphosphino)propane (dppp)21 (entry 1,
Table 3) as an alternative to the more air-sensitive system of
[RhCl(COD)2]2 and dppp. Due to the atropisomerically labile
cercosporin system (cf. 39, Scheme 9), a lower temperature (105
vs 162 °C) was employed, but none of the desired product 50a
was observed. Apparently, the higher temperatures are vital to
the in situ formation of Rh(dppp)2Cl from this rhodium(III)
source. On the other hand, the active catalyst readily forms
from [RhCl(COD)2]2, and the decarbonylated 50a was gener-
ated in good yields (entries 2 and 3). Using Wilkinson’s catalyst
[RhCl(PPh3)3] was superior (entries 4 and 5) with the best results
observed using diglyme as the solvent (90%). Notably, the
reactions involving [RhCl(COD)2]2 and RhCl(PPh3)3 were ex-
tremely sensitive to air, and rigorously air-free conditions were
required to obtain satisfactory results. With these optimized
conditions, more complex naphthalene 49b supplied the desired
arene 50b in excellent yield (80-96%, entries 6 and 7).
hindrance at the C3,C30-esters due to the larger C2,C20-
isopropoxy groups. Unfortunately, the sterically large
C2,C20-isopropoxys also effected the decarboxylation, and
less than a 10% yield of the desired 45 was isolated. The
sluggish reaction primarily afforded monodecarboxylated
product along with unreacted starting material.
SCHEME 10. Attempted Palladium-Mediated Decarboxyla-
tion on Bis-isopropoxy 44
To obtain the dialdehyde (51) needed for the double de-
carbonylation, bisester 39 was reduced with DIBALH and then
oxidized with o-iodoxybenzoic acid (IBX) (Scheme 11). To our
(17) For a review, see: Chimiak, A.; Przychodzen, W.; Rachon, J.
Heteroatom Chem. 2002, 13, 169–194.
(18) Garner, P.; Anderson, J. T.; Dey, S.; Youngs, W. J.; Galat, K. J. Org.
Chem. 1998, 63, 5732–5733.
(19) For a review, see: Necas, D.; Kotora, M. Curr. Org. Chem. 2007, 11,
1566–1591.
(20) Catalytic decarbonylations: (a) Doughty, D. H.; Pignolet, L. H.
J. Am. Chem. Soc. 1978, 100, 7083–7085. (b) Meier, M. D.; Kruse, L. I. J.
Org. Chem. 1984, 49, 3195–3199. (c) Beck, C. M.; Rathmill, S. E.; Park, Y. J.;
Chen, J.; Crabtree, R. H.; Liable-Sands, L. M.; Rheingold, A. L. Organo-
metallics 1999, 18, 5311–5317.
At this point, a Barton decarboxylation protocol was
assessed on the naphthalene model system 46 (eq 4). The
required acid chloride of 46 was readily formed, but none of
(21) Kreis, M.; Palmelund, A.; Bunch, L.; Madsena, R. Adv. Synth. Catal.
2006, 348, 2148–2154.
50 J. Org. Chem. Vol. 75, No. 1, 2010

Morgan et al.
JOCArticle
TABLE 3. Rhodium-Mediated Decarbonylation
To summarize, the complete route to cercosporin is out-
lined in Scheme 12 (problematic steps shown in boxes). This
synthesis established methods for several key steps including
biscuprate epoxide alkylation, methylidene acetal forma-
tion, and C3,C30-decarbonylation. Due to functional group
incompatibilities, the synthesis required the most conserva-
tive of the proposed routes (path c) from Scheme 2. Though
alternative, more direct routes were examined, the installa-
tion of the methylidene acetal (path a) and the sensitive
nature of the PIFA-induced C5,C50-oxygenation (path b)
proved to be impediments. The primary culprit contributing
to the length of path c was the PIFA oxygenation
(Scheme 12). Since the C7,C70-benzoate substitution and
C2,C20-isopropoxys were the only protecting groups toler-
ated in the reaction, deprotection/reprotection sequences
resulted. In addition, the selective removal of the C2,C20-
isopropyl ethers with BCl3 was scale-sensitive, inhibiting
generation of scalable amounts of the bisphenol needed for
methylidene acetal installation. Due to these limiting factors,
we revised our synthetic strategy by pursuing a different
C5,C50-oxygenation protocol to streamline the synthesis.
Second-Generation Strategy: Palladium-Catalyzed O-Ar-
ylation. As seen in the preceding paper of this series (DOI
10.1021/jo901384h), the palladium-catalyzed O-arylation
was investigated in order to avoid the cumbersome PIFA
reaction. In addition to providing a more efficient synthesis
of 1, a less sensitive transformation was sought to provide
strategic flexibility, permitting derivatization to different
analogs at many points in the pathway.8 Here, we provide
a complete account of the palladium-catalyzed O-arylation,
which was investigated as a result of the limitations encoun-
tered in the first total synthesis of 1.
While arylations of alcohols have been reported for a host
of systems,22 we could locate no O-arylations of highly
functionalized, hindered, electron-rich systems. Further-
more, the arylation of aliphatic alcohols, such as benzyl
alcohol, is particularly challenging due to a competitive β-
hydride elimination of the coordinated alcohol. While early
reports centered on couplings with 2-methyl-2-propanol,
which contains no hydrogens that can undergo β-hydride
elimination,23 Buchwald later described the arylation of
primary and secondary alcohols containing R-hydrogens.24
A further report of phenol formation by palladium-catalyzed
coupling of KOH with aryl chlorides and bromides (eq 6),
including several hindered aryl halides,25 provided the im-
petus for us to examine this method.
adppp = diphenylphosphinopropane. bStarting material recovered.
delight, decarbonylation of the dialdehyde with RhCl(PPh3)3
proceeded well. Furthermore, the moderate temperatures
(90 °C in diglyme) required for this process were well tolerated,
and no atropisomerization of the biaryl was observed. With
this result, a reliable route (via path c, Scheme 2) to the key
advanced intermediate 41 (cf. 4, Scheme 2) was secured.
SCHEME 11. Formation of Key Advanced Intermediate 41 via
Decarbonylation
First Total Synthesis of Cercosporin. To complete the
synthesis of 1, we employed the same steps used in the
conclusion of the calphostin synthesis as described in the
previous paper of this series (DOI 10.1021/jo901384h). After
a global debenzylation of 41, the bisphenol was oxidized by
MnO2 to afford perylenequinone (Scheme 12).9c,d This final
cyclization step was held until this stage because formation
of the perylenequinone reduces the dihedral angle from 50° in
axial chiral 41 to 20° in helical chiral 1, further facilitating
atropisomerization. The selective removal of the C4,C40-methyl
ethers was accomplished under mild conditions with MgI2,9b,e,f
completing the first total synthesis of cercosporin (1) in 23 steps
and 0.4% overall yield (82% average yield per step).
(22) Reviews: (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 131–209. (b) Hartwig, J. F. Nature 2008, 455, 314–322. (c) Carril, M.;
SanMartin, R.; Dominguez, E. Chem. Soc. Rev. 2008, 37, 639–647.
J. Org. Chem. Vol. 75, No. 1, 2010 51

Morgan et al.
JOCArticle
SCHEME 12. Summary of the First Total Synthesis of Cercosporin (1)
Studies commenced with the C7,C70-propyl substrate 56
TABLE 4. Screening Buchwald Cross-Coupling Conditions for
Formation of 57
(Table 4), an intermediate utilized in the synthesis of per-
ylenequinone analogues.8 Due to the steric crowding of the
C5,C50-positions, we elected to use the smaller chlorides. An
evaluation of chloride electrophiles (NCS, SOCl2, SO2Cl2)
revealed that sulfuryl chloride (SO2Cl2) effected chlorination
with the highest yield (92%). Since the X-phos(t-Bu) (L1)
ligand was reported as the most effective for phenyl halides
bearing two ortho-substituents, it was employed with our
sterically demanding aryl chloride. Using the reported con-
ditions, involving the catalyst system derived from Pd2dba3
and L1,25 provided the monophenol and arene products but
none of the desired bisphenol 57 (entry 1, Table 4). Distinct
from other systems, the biaryls here require two couplings
per reacting structure to obtain the desired product. En-
couragingly, this preliminary result indicated that the oxida-
tive addition and reductive elimination are feasible. Though
the more hindered L2 ligand was reported be more stable
(Pd-black was observed with L1), none of the desired product
was observed with our sterically demanding system (entry 2).
Since the starting material was recovered, the bulky L2
appeared to prevent oxidative addition. Utilizing a higher
catalyst loading and rigorously air-free conditions with the
less stable L1 were paramount to an effective C-O coupling,
supplying 57 in 90% yield (entry 3).
The success of the C5,C50-O-arylation in the model system
led us to evaluate the C-O coupling with cercosporin
intermediate 59 (Scheme 13). Starting from the same com-
mon intermediate 9 employed in the first-generation synth-
esis (Scheme 12), Mitsunobu reaction with benzyl alcohol
and one-step deacetylation/methylation provided 14. The
C2,C20-bisbenzyl ether 14 was employed since the methyli-
dene acetal led to the formation of undesired halodecarbox-
ylation products in the epoxide alkylation (eq 1).
Furthermore, it would not be possible to remove C2,C20-
bis-isopropoxy ethers (cf. 27, Scheme 12) in the presence of
aliphatic benzyl ethers on the C7,C70-hydroxypropyl groups
entry liganda
conditionsb
yield (%)
0c
1
2
3
L1 Pd2dba3, KOH, H2O/1,4-dioxane, 80 °C, 2 h
L2 Pd2dba3, KOH, H2O/1,4-dioxane, 80 °C, 17 h
L1 Pd2dba3, KOH, H2O/1,4-dioxane, 95 °C, 5 h
0d
90e
aFor L1 and L2, see eq 6. b4 mol % of Pd2dba3, 8 mol % of ligand, 6
c
equiv of KOH, H2O/1,4-dioxane (1:1). Isolated 48% arene and 47%
mono-oxidation product. dStarting material recovered. 20 mol % of
Pd2dba3, 40 mol % of ligand, 8 equiv of KOH.
e
(see below). Pleasingly, the double alkylation of the biscup-
rate of 14 with (R)-propylene oxide furnished the desired
alkylated product in 65% yield as a single diastereomer
(Scheme 13). The newly installed aliphatic alcohol stereo-
centers were directly benzylated, and subsequent debenzyla-
tion of the C2,C20-phenolic benzyl ethers to provide 58 was
accomplished using pyridine to attenuate the activity of the
Pd/C.26 As previously detailed (see Table 2 and correspond-
ing discussion), generation of the methylidene acetal was not
trivial. In this system, however, the use of a self-desiccating
base was unnecessary since no other labile functional groups
were present. Thus, treatment of the bisphenol 58 with
BrCH2Cl and Cs2CO3 supplied the desired methylidene
acetal. Finally, the necessary aryl chloride 59 was synthesized
efficiently using sulfuryl chloride.
Disappointingly, direct O-arylation of bischloride 59 with
benzyl alcohol (entries 1 and 2, Table 5) to generate a
protected bisphenol directly was unsuccessful. In these reac-
tions, the oxidative addition of aryl chloride 59 proceeded
smoothly, but as previously discussed, β-hydride elimination
was favored over reductive elimination resulting in arene
(23) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109–13110.
(24) (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 3395–3396. (b) Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S.
L. J. Am. Chem. Soc. 2001, 123, 10770–10771. (c) Vorogushi, A. V.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 8146–8149.
(25) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am.
Chem. Soc. 2006, 128, 10694–10695.
(26) (a) Sajiki, H. Tetrahedron Lett. 1995, 36, 3465–3468. (b) Sajiki, H.;
Kuno, H.; Hirota, K. Tetrahedron Lett. 1997, 38, 399–402.
52 J. Org. Chem. Vol. 75, No. 1, 2010

Morgan et al.
JOCArticle
TABLE 5. Screening Coupling Conditions for Formation of 39
entry
Pd catalyst
liganda
coupling conditions
benzylation conditions
yield (%)
0b
1
2
3
4
5
6
Pd2dba3
Pd2OAc2
Pd2dba3
L1
L3c
L1
L1c
L1c
L1
BnOH, Cs2CO3, toluene, 80 °C
BnOH, Cs2CO3, toluene, 80 °C
KOH, 1,4-dioxane/H2O (5:3), 80 °C
KOH, 1,4-dioxane: H2O (5:3), 80 °C
KOH, 1,4-dioxane/H2O (5:3), 80 °C
KOH, 1,4-dioxane/H2O (5:3), 80 °C
0b
40d
0e
c
Pd2dba3c
Pd2dba3c
Pd2dba3
Me3NC16H33Br, BnBr, KOH, 90 °C
Me3NC16H33Br, BnBr, KOH, rt
BnBr, NaH, DMF
0e
70f
aL1 = X-phos(t-Bu); see eq 6. bArene recovered. cLigand and Pd2dba3 stored and dispensed in an inert atmosphere box. dIsolated yield of diphenol;
diphenol decomposes on SiO2 column. eDiphenol formed, but benzylation conditions afforded decomposition. fReaction mixture was quenched at 0 °C
with 0.5 M HCl after phenol formation and immediately subjected to benzylation conditions.
SCHEME 13. Formation of Aryl Chloride Substrate
approach. After decarbonylation and perylenequinone for-
mation, the second-generation synthesis of 1 (Scheme 14)
was completed in 20 steps and a 2.8% overall yield (86%
average yield per step).
Use of the mild O-arylation protocol (61 f 39, Scheme 14)
allowed C5,C50-oxygenation in the presence of the methyli-
dene acetal, thereby permitting a shift to the more efficient
path b (Scheme 2) which was not possible with the PIFA
method due to reaction at the methylidene acetal (Scheme 7).
In addition, the milder C5,C50-oxygenation allowed the use
of benzyl ether protection at the C7,C70-substitution and the
C5,C50-centers which eliminated two protecting group ex-
changes needed in the first-generation approach (Scheme 12)
via path c (Scheme 2). The second-generation approach
required three fewer steps and improved the efficiency
dramatically providing a 7-fold increase in the overall yield
(2.8%, Scheme 14 vs 0.4%, Scheme 12). The greater func-
tional group tolerance and generality of the palladium-
catalyzed O-arylation also provided synthetic flexibility
permitting the synthesis of analogs.8 For example, the O-
arylation protocol was viable with a variety of C2,C20-
substitution (-CH2-, Me, i-Pr, n-Pr, and Bn) affording high
yields of the desired products.
formation. Thus, attempts were made to use Buchwald’s
two-step, one-pot protocol for formation of benzyl ether 39.
The catalyst identified above (Table 4) derived from Pd2dba3
and Buchwald’s X-phos(t-Bu) ligand (L1) again proved
effective in the coupling with KOH to provide the desired
bisphenol (entry 3, Table 5). Due to the lower atropisome-
rization barrier of 59 containing a seven-membered ring (see
Scheme 1), lower temperatures (80 vs 95 °C) were employed
here compared to the reaction of the system lacking the
methylidene bridge (Table 4). Pleasingly, no atropisomeriza-
tion was observed under these conditions. However, the
resulting bisphenol was highly unstable (40% isolated yield)
and could not withstand the typical one-pot benzylation
protocols (entries 4-5). To solve this problem, the C-O
coupling reaction was quenched at low temperature (0 °C)
with dilute HCl to supply the bisphenol. After immediate
concentration and exposure to standard benzylation proce-
dures (BnBr, NaH, and DMF), the advanced intermediate 39
was isolated in 70% yield (entry 6).
Conclusions
The first total synthesis of cercosporin has been completed
comprising 20 steps from commercially available 52 and
proceeding with 2.8% overall yield (86% average yield per
step). The synthetic work encompassed two generations. In
the first synthesis, the methylidene acetal installation and C3,
C30-decarbonylation problems were solved resulting in the
completion of the atropisomerically sensitive cercosporin
without any accompanying atropisomerization. However,
the PIFA C5,C50-oxygenation was identified as a major
limitation of the synthesis due to high cross reactivity with
other functional groups and low generality. In the second
generation synthesis, an alternate C5,C50-oxygenation was
identified relying on a palladium-catalyzed O-arylation. This
protocol enabled the formation of the key advanced inter-
mediate 41 on preparative scale with enhanced yields and no
Notably, the first- and second-generation approaches
diverged at the common enantiopure intermediate 9 and
then intersected in the formation of 39 (Scheme 12). The
synthesis of 39, therefore, concludes the second-generation
J. Org. Chem. Vol. 75, No. 1, 2010 53

Morgan et al.
JOCArticle
SCHEME 14. Second-Generation Synthesis of Cercosporin (1)
SCHEME 15. Second-Generation Synthesis of Enantiopure Perylenequinone 67
loss of enantioenrichment. Furthermore, the O-arylation
proved to be general, and the strategy was used in an
improved synthesis of helical chiral perylenequinone 67
(Scheme 15). In the first paper of this series, we focused on
the generation of the perylenequinone helical chirality, cul-
minating in the synthesis of 67. In the synthesis seen in
Scheme 15 employing the palladium-catalyzed O-arylation
for C5,C50-oxygenation, 67 is provided in fewer steps, higher
overall yield, and increased optical purity: 16 steps, 5.6%
overall yield (average of 86% per step), 98% ee. Though the
new C5,C50-oxygenation protocol enabled higher yields of
64, the shortened synthesis and increased enantioenrichment
of 67 also arose from the use of the common enantiopure
intermediate 9. As seen here and in the syntheses of 2 and 3,
detailed in the previous paper of this series (DOI 10.1021/
jo901384h), we desired to utilize this common intermediate
in the syntheses of all the perylenequinone natural products.
To this end, its use in the total synthesis of hypocrellin A is
detailed in the fifth paper in this series (DOI 10.1021/
jo901386d).
an argon atmosphere. The resulting solution was cooled to
0 °C, at which time a diisopropyl azodicarboxylate (0.63 mL,
3.2 mmol) solution in THF (5 mL) was added dropwise. After
the mixture was stirred for 1.5 h, the reaction was quenched with
1 M HCl. The aqueous phase was extracted with EtOAc, and the
organic portions were washed with brine and dried (Na2SO4).
After concentration, the residue was chromatographed (30%
EtOAc/hexanes) to yield the bisacetate as a yellow solid (860 mg,
94%): [R] -91.3 (c 0.7, CH2Cl2, >99% ee); 1H NMR (300 MHz,
CDCl3) δ 2.52 (s, 6H), 3.88 (s, 6H), 3.99 (s, 6H), 4.40 (d, J = 10.0
Hz, 2H), 4.82 (d, J = 10.0 Hz, 2H), 6.77 (m, 4H), 7.06 (s, 2H),
7.12 (m, 6H), 7.66 (s, 2H); 13C NMR (75 MHz, (CD3)2CO) δ
20.2, 52.7, 56.6, 76.9, 93.1, 101.0, 122.1, 122.7, 126.4, 128.2,
128.5, 128.6, 131.3, 136.8, 137.2, 145.9, 151.3, 156.4, 165.4,
168.6; IR (film) 2950, 1730, 1583, 1468, 1236 cm-1; HRMS
(ESI) calcd for C44H36I2O12Na (MNaþ) 1033.0194, found
1033.0234.
To a solution of the bisacetate (585 mg, 0.58 mmol) in DMF
(7 mL) were added NaH (60% in oil, 350 mg, 8.8 mmol) and MeI
(0.7 mL, 11 mmol). After being stirred for 1 h at room tempera-
ture under argon, the mixture was quenched with 1 M HCl. The
aqueous phase was extracted with EtOAc (2ꢀ), and the com-
bined organics were washed with aq NH4Cl (2ꢀ). The organic
portions were dried (Na2SO4) and concentrated. Chromatogra-
phy (15% EtOAc/hexanes) yielded 14 as a white foam (530 mg,
Experimental Section
1
(M)-Dimethyl 2,20-bis(benzyloxy)-7,70-diiodo-4,40,6,60-tetra-
methoxy-1,10-binaphthyl-3,30-dicarboxylate (14). To a solution
of 9 (750 mg, 0.90 mmol) in THF (20 mL) were added benzyl
alcohol (0.94 mL, 9.0 mmol) and PPh3 (830 mg, 3.2 mmol) under
96%): [R] -94.0 (c 0.35, CH2Cl2, >99% ee); H NMR (360
MHz, (CD3)2CO) δ 3.94 (s, 6H), 4.04 (s, 6H), 4.15 (s, 6H), 4.45
(d, J = 10.5 Hz, 2H), 4.84 (d, J = 10.5 Hz, 2H), 6.80 (m, 4H),
7.12 (m, 6H), 7.54 (s, 2H), 7.80 (s, 2H); 13C NMR (75 MHz,
54 J. Org. Chem. Vol. 75, No. 1, 2010

Morgan et al.
JOCArticle
(CD3)2CO) δ 52.5, 56.5, 62.9, 76.7, 92.1, 101.3, 119.5, 122.7,
126.7, 128.1, 128.1, 128.4, 131.7, 137.2, 137.3, 151.6, 154.2,
(M)-Dimethyl
7,70-Bis((R)-2-(benzyloxy)propyl)-2,20-dihy-
droxy-4,40,6,60-tetramethoxy-1,10-binaphthyl-3,30-dicarboxylate
(58). Upon dissolution of 60 (135 mg, 0.14 mmol) in a pyridine
solution (0.037 M in 1,4-dioxane, 2.25 mL; too much pyridine
significantly hinders the reaction), MeOH (2.25 mL) was added
and argon was bubbled through the solution for 5 min. Pd/C
(120 mg) was added to the solution, and argon was bubbled
through for 5 min. Hydrogen (balloon) was bubbled through the
solution until the reaction was complete, as judged by TLC. The
mixture was purged with argon and then filtered through Celite,
washing with EtOAc. After concentration, the residue was
chromatographed (25% EtOAc/hexanes) to yield 58 as a yellow
solid (110 mg, 100%): [R]-54.2 (c 0.2, CH2Cl2, >99% ee); 1H
NMR (500 MHz, CDCl3) δ 1.05 (d, J = 6.1 Hz, 6H), 2.53 (dd,
J = 6.9, 13.3 Hz, 2H), 3.02 (dd, J = 6.0, 13.3 Hz, 2H), 3.68
(m, 2H), 3.89 (s, 6H), 4.07 (s, 6H), 4.10 (s, 6H), 4.30 (d, J = 11.9
Hz, 2H), 4.35 (d, J = 11.9 Hz, 2H), 7.04 (s, 2H), 7.10 (m, 4H),
7.19 (m, 6H), 7.42 (s, 2H), 10.6 (s, 2H); 13C NMR (125 MHz,
(CD3)2CO) δ 19.9, 38.7, 52.9, 55.7, 63.3, 70.5, 74.5, 101.3, 112.1,
112.4, 123.6, 127.7, 127.8, 128.0, 128.7, 132.7, 133.4, 140.3,
152.3, 156.0, 157.4, 170.1; IR (film) 3429, 2935, 1730, 1668,
1498, 1444 cm-1; HRMS (ES) calcd for C48H51O12 (MHþ)
819.3381, found 819.3408.
(M)-Dimethyl 10,13-Bis((R)-2-(benzyloxy)propyl)-1,7,9,14-te-
tramethoxydinaphtho[2,1-d:10,20-f][1,3]dioxepine-2,6-dicarboxy-
late (61). To a solution of 58 (107 mg, 0.13 mmol) and
anhydrous ClCH2Br (40 μL, 0.39 mmol) in anhydrous
DMF (3 mL) under argon was added Cs2CO3 (383 mg,
1.2 mmol). The yellow mixture was heated to 60 °C. After
the mixture was stirred for 1 h, additional ClCH2Br (40 μL,
0.392 mmol) was added; a further aliquot was added after 2 h.
After being stirred for a total of 3 h under argon, the mixture
was cooled, quenched with NH4Cl (aq), and washed with
EtOAc (2ꢀ). The organic phase was washed with aq NH4Cl
(2ꢀ), dried (Na2SO4), and concentrated to yield an orange
oil. Purification was accomplished by chromatography
(10-25% EtOAc/hexanes) to yield 61 as a yellow resin (82
mg, 76%, 86% based on recovered starting material): [R]
-202.0 (c 0.25, CH2Cl2, >99% ee); 1H NMR (500 MHz,
CDCl3) δ 0.99 (d, J = 6.1 Hz, 6H), 2.52 (dd, J = 7.6, 13.8 Hz,
2H), 3.08 (dd, J = 5.5, 13.8 Hz, 2H), 3.65 (m, 2H), 3.94 (s,
6H), 4.02 (s, 6H), 4.07 (s, 6H), 4.21 (d, J = 11.7 Hz, 2H), 4.39
(d, J = 11.7 Hz, 2H), 5.73 (s, 2H), 7.12 (m, 4H), 7.24 (m, 6H),
7.29 (s, 2H), 7.43 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 19.7,
37.6, 52.8, 55.6, 62.8, 70.5, 74.8, 100.3, 104.4, 118.8, 121.9,
126.2, 127.5, 127.7, 128.4, 128.5, 129.0, 131.5, 139.0,
146.2, 153.6, 156.7, 166.8; IR (film) 2927, 1730, 1583, 1498,
1460 cm-1; HRMS (ES) calcd for C49H50O12Na (MNaþ)
853.3200, found 853.3237.
155.9, 166.7; IR (film) 2943, 1730, 1576, 1468, 1236 cm-1
;
HRMS (ES) calcd for C42H36I2O10Na (MNaþ) 977.0296, found
977.0283.
General Procedure for the Copper-Mediated Epoxide-Open-
ing. A flame-dried Schlenk flask was charged with the aryl
iodide, and the system was vacuum purged with argon (3ꢀ).
After dissolution in anhydrous THF, the solution was cooled
to -40 °C, and i-PrMgBr (1 M in THF, 1.25 equiv) was added
dropwise along the sides of the flask. The reaction mixture
was stirred at -40 °C for 40 min under argon. CuI (recrystallized
from aqueous NaI and stored in an inert atmosphere box,
0.5 equiv) was introduced to a separate flame-dried Schlenk
flask, and the system was vacuum purged with argon (3ꢀ). After
addition of anhydrous THF, the mixture was cooled to -40 °C.
The contents of the first flask (Grignard solution) were added
dropwise to the second flask (CuI mixture) via cannula. After
the mixture was stirred for 30 min at -40 °C under argon, a
solution of (R)-propylene oxide (2.5 equiv) was added dropwise
over 5 min. The mixture was stirred at -40 °C for 30 min and
was then allowed to slowly warm to 0 °C over 1 h. The reaction
was quenched with 1 N HCl and then extracted with EtOAc. The
combined organic fractions were washed with 1 N HCl and
brine, dried (Na2SO4), and concentrated in vacuo. Purification
was then accomplished by SiO2 chromatography.
(M)-Dimethyl 2,20-Bis(benzyloxy)-7,70-bis((R)-2-hydroxypro-
pyl)-4,40,6,60-tetramethoxy-1,10-binaphthyl-3,30-dicarboxylate (14a).
The epoxide-opening was carried out according to the general
procedure with iodo substrate 14 (260 mg, 0.27 mmol) and
i-PrMgBr (1 M in THF, 820 μL, 0.82 mmol) in THF (3.5 mL)
at -78 °C and CuI (52 mg, 0.27 mmol) in THF (2 mL) and (R)-
propylene oxide (76 μL, 1.1 mmol). The crude material was
chromatographed (SiO2, 50% EtOAc/hexanes). Product 14a
was obtained diastereomerically pure as a white foam (145 mg,
65%): [R] -62.0 (c 0.2, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ
1.09 (d, J = 6.2 Hz, 6H), 1.99 (br s, 2H), 2.38 (dd, J = 8.7, 13.3
Hz, 2H), 2.89 (dd, J = 3.2, 13.3 Hz, 2H), 3.89 (s, 6H), 3.91
(m, 2H), 3.96 (s, 6H), 4.14 (s, 6H), 4.36 (d, J = 10.4 Hz, 2H), 4.72
(d, J = 10.4 Hz, 2H), 6.79 (m, 4H), 7.06 (s, 2H), 7.12 (m, 6H),
7.43 (s, 2H); 13C NMR (125 MHz, (CD3)2CO) δ 23.6, 41.2, 52.7,
55.8, 63.2, 67.2, 77.0, 100.8, 121.6, 122.1, 125.9, 128.4, 128.7,
128.8, 129.4, 131.0, 132.9, 138.0, 151.3, 154.2, 157.4, 167.7; IR
(film) 3321, 2958, 1730, 1591, 1498, 1444 cm-1; HRMS (ES)
calcd for C48H51O12 (MHþ) 819.3381, found 819.3408.
(M)-Dimethyl 2,20-Bis(benzyloxy)-7,70-bis((R)-2-(benzyloxy)-
propyl)-4,40,6,60-tetramethoxy-1,10-binaphthyl-3,30-dicarboxyla-
te (60). To a solution of 14a (277 mg, 0.338 mmol) in DMF
(8.9 mL) were added benzyl bromide (0.810 mL, 6.63 mmol) and
n-Bu4NI (25 mg, 0.119 mmol). NaH (60% in oil, 202 mg, 5.09
mmol) was added and the reaction stirred under argon. After
completion as judged by TLC, the mixture was acidified with
1 M HCl, diluted, and washed with EtOAc (2ꢀ). The combined
organic portions were washed with NH4Cl (aq, 2ꢀ), dried
(Na2SO4), and concentrated. Purification by column chroma-
tography (10-50% EtOAc/hexanes) afforded tetrabenzyl ether
60 as a white resin (309 mg, 91%): [R] -84.5 (c 0.2, CH2Cl2,
>99% ee); 1H NMR (500 MHz, (CD3)2CO) δ 0.93 (d, J = 6.1
Hz, 6H), 2.51 (dd, J = 6.3, 13.6 Hz, 2H), 2.93 (dd, J = 6.1, 13.6
Hz, 2H), 3.63 (m, 2H), 3.89 (s, 6H), 3.92 (s, 6H), 4.11 (s, 6H), 4.24
(d, J = 12.3 Hz, 2H), 4.31 (d, J = 12.3 Hz, 2H), 4.43 (d, J = 10.3
Hz, 2H), 4.78 (d, J = 10.3 Hz, 2H), 6.79 (m, 4H), 7.07 (m, 4H),
7.13 (m, 6H), 7.20 (m, 6H), 7.29 (s, 2H), 7.52 (s, 2H); 13C
NMR (125 MHz, (CD3)2CO) δ 19.9, 38.3, 52.6, 55.8, 63.2, 70.5,
74.5, 77.0, 100.9, 121.5, 122.2, 126.0, 127.8, 128.0, 128.4, 128.6,
128.8, 128.8, 128.9, 131.0, 132.6, 138.0, 140.3, 151.4, 154.3, 157.4,
167.6; IR (film) 2943, 1730, 1591, 1498, 1452 cm-1; HRMS (ES)
calcd for C62H63O12 (MHþ) 999.4320, found 999.4315.
(M)-Dimethyl 10,13-Bis((R)-2-(benzyloxy)propyl)-8,15-dichl-
oro-1,7,9,14-tetramethoxydinaphtho[2,1-d:10,20-f][1,3]dioxepine-
2,6-dicarboxylate (59). Methylidene acetal 61 (30 mg,
0.036 mmol) in anhydrous CH2Cl2 (0.4 mL) was treated with
SO2Cl2 (8.0 μL, 0.090 mmol) and was allowed to stir at room
temperature under argon until the reaction was complete, as
determined by TLC. The mixture was quenched with H2O,
extracted with CH2Cl2, washed with brine, dried (Na2SO4),
and concentrated. Purification was accomplished by chroma-
tography (35% EtOAc/hexanes) to yield bischloride 59 as a
yellow resin (33 mg, 100%): [R] -46.2 (c 0.25, CH2Cl2, >99%
ee); 1H NMR (500 MHz, CDCl3) δ 1.02 (d, J = 6.1 Hz, 6H), 2.56
(dd, J = 6.7, 14.4 Hz, 2H), 3.00 (dd, J = 6.4, 14.4 Hz, 2H), 3.50
(m, 2H), 3.89 (s, 6H), 3.95 (s, 6H), 4.03 (s, 6H), 4.05 (d, J = 11.6
Hz, 2H), 4.34 (d, J = 11.6 Hz, 2H), 5.71 (s, 2H), 7.02 (m, 4H),
7.16 (s, 2H), 7.22 (m, 6H); 13C NMR (90 MHz, CDCl3) δ 19.5,
37.5, 52.8, 60.6, 64.5, 70.4, 74.6, 103.8, 122.1, 122.5, 122.7, 123.4,
127.1, 127.4, 127.5, 128.3, 131.7, 134.8, 138.1, 147.5, 154.4,
154.7, 165.8; IR (film) 2927, 1738, 1591, 1552, 1452 cm-1
;
J. Org. Chem. Vol. 75, No. 1, 2010 55

Morgan et al.
JOCArticle
HRMS (ES) calcd for C49H49O12Cl2 (MHþ) 899.2601, found
899.2637.
cannula to the argon-purged microwave tube containing ClRh-
(PPh3)3. The mixture was vigorously purged with argon for 20
min and then was heated at 90 °C for 17 h. The mixture was
cooled, diluted with EtOAc, and washed with saturated aq
NH4Cl. The organic phases were dried (Na2SO4), and the
solvent was evaporated to yield a yellow resin. Purification
was accomplished by chromatography (10-25% EtOAc/
hexanes) to yield 41 as a yellow resin (11 mg, 71%): [R] -221.7
(c 0.3, CH2Cl2, >99% ee); IR (thin film) 2927, 1738, 1583, 1460
cm-1; 1H NMR (500 MHz, CDCl3) δ 1.04 (d, J = 6.1 Hz, 6H),
2.59 (dd, J = 7.1, 14.2 Hz, 2H), 3.02 (dd, J = 5.8, 14.2 Hz, 2H),
3.55 (m, 2H), 3.93 (s, 6H), 3.93 (s, 6H), 4.09 (d, J = 11.4 Hz, 2H),
4.35 (d, J = 11.4 Hz, 2H), 5.01 (m, 4H), 5.70 (s, 2H), 6.79 (s, 2H),
7.08 (m, 4H), 7.13 (s, 2H), 7.22 (m, 6H), 7.38 (m, 2H), 7.44 (m,
4H), 7.59 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 19.8, 37.3,
56.1, 61.4, 70.7, 75.7, 76.5, 101.0, 102.9, 118.1, 119.2, 124.3,
127.5, 127.8, 128.0, 128.4, 128.6, 128.6, 131.4, 133.6, 138.4,
138.8, 147.6, 149.8, 151.0, 157.3; HRMS (ESI) calcd for
C59H59O10 (MHþ) 927.4108, found 927.4069.
Cercosporin (1). To a solution of 41 (5 mg, 0.0054 mmol)
in THF (0.5 mL) and MeOH (0.5 mL) was added 10% Pd/C
(6 mg). The mixture was stirred while purging with H2 (H2
balloon). After completion as judged by TLC, the mixture was
filtered through Celite, rinsing with EtOAc and CH2Cl2. Con-
centration yielded an unstable bisnaphthol as a brown oil which
was used directly in the next reaction.
To a solution of the bisnaphthol in anhydrous THF (1 mL)
was added MnO2 (10 mg, 0.13 mmol). After completion as
judged by TLC, the mixture was diluted with EtOAc, filtered
through Celite, and concentrated to yield the perylenequinone.
Purification was accomplished by chromatography (2.5%
MeOH/CH2Cl2) to yield the perylenequinone as a red resin
(3 mg, 100%).
To a solution of the above perylenequinone product (3 mg,
0.00534 mmol) in anhydrous THF (0.5 mL) under an argon
atmosphere was added a solution of MgI2 in Et2O (0.07 M,
130 μL, 0.0112 mmol). The dark purple mixture was stirred
10 min (until the mixture turned from purple to black), diluted
with EtOAc, washed with saturated aq NH4Cl, and dried
(Na2SO4). Concentration yielded a red residue, which was
chromatographed (1% MeOH/CH2Cl2) to yield product 1
as a red resin (1.5 mg, 50%): see the Supporting Informa-
tion for the CD spectrum; 1H NMR (500 MHz, CDCl3) δ 0.66
(d, J = 6.1 Hz, 6H), 2.91 (dd, J = 6.1, 13.0 Hz, 2H), 3.39 (m,
2H), 3.54 (dd, J = 6.9, 13.0 Hz, 2H), 4.22 (s, 6H), 5.75 (s, 2H),
7.09 (s, 2H), 14.8 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 23.6,
42.4, 61.4, 68.3, 92.9, 108.5, 109.6, 113.1, 128.2, 130.8, 135.4,
153.1, 163.6, 167.7, 182.0; IR (film) 3398, 2966, 1622, 1583, 1460,
1267 cm-1; HRMS (ES) calcd for C29H27O10 (MHþ) 535.1604,
found 535.1596.
(M)-Dimethyl 8,15-Bis(benzyloxy)-10,13-bis((R)-2-(benzyloxy)-
propyl)-1,7,9,14-tetramethoxydinaphtho[2,1-d:10,20-f][1,3]dioxe-
pine-2,6-dicarboxylate (39). An oven-dried microwave tube
with a crimp top and Teflon septa containing a stirbar was
charged with aryl halide 59 (28 mg, 0.031 mmol) and KOH
(14 mg, 0.25 mmol). In an inert atmosphere box, the substrate-
containing microwave tube was charged with Pd2dba3 (5.7 mg,
0.0062 mmol) and X-phos(t-Bu) ligand (11 mg, 0.025 mmol),
and the reaction tube was crimped in the inert atmosphere box
to avoid exposure to oxygen. The tube was further evacuated
and backfilled with argon (2ꢀ). A solution of 1,4-dioxane
(0.70 mL) and deionized water (0.40 mL) was vigorously
purged with argon for 1 h prior to use. At this time, the solvent
mixture was added to the reaction tube, and the mixture was
stirred in a preheated oil bath (80 °C) until the aryl halide was
consumed as judged by TLC. The reaction mixture was cooled
to 0 °C and carefully acidified with aqueous HCl (0.5 N), and
the resulting mixture was extracted with EtOAc (2ꢀ). The
organic layer was dried (Na2SO4) and concentrated to yield an
orange oil. This unstable oil was immediately dissolved in
anhydrous DMF (2.0 mL) and treated with BnBr (60 μL,
0.52 mmol) and NaH (95%, 15 mg, 0.56 mmol) under argon
and allowed to stir at room temperature for 1 h. The reaction
was quenched with NH4Cl (aq) and washed with EtOAc (2ꢀ).
The organic phase was washed with NH4Cl (aq, 2ꢀ) and dried
(Na2SO4), and the solvent was evaporated. Purification was
accomplished by chromatography (25% EtOAc/hexanes) to
yield tetrabenzyl ether 39 as a yellow resin (23 mg, 70%): [R]
-68.0 (c 0.2, CH2Cl2, >99% ee); 1H NMR (300 MHz, CDCl3)
δ 1.03 (d, J = 6.1 Hz, 6H), 2.56 (dd, J = 7.0, 13.9 Hz, 2H),
3.06 (dd, J = 6.0, 13.9 Hz, 2H), 3.59 (m, 2H), 3.88 (s, 6H),
3.96 (s, 6H), 4.03 (s, 6H), 4.15 (d, J = 11.2 Hz, 2H), 4.37 (d, J =
11.2 Hz, 2H), 4.89 (m, 4H), 5.72 (s, 2H), 7.07 (m, 4H), 7.13 (s,
2H), 7.22 (m, 6H), 7.42 (m, 6H), 7.60 (m, 4H); 13C NMR (125
MHz, (CD3)2CO) δ 19.9, 37.5, 52.7, 61.6, 64.6, 70.8, 75.5, 77.4,
104.8, 122.0, 122.8, 123.1, 125.0, 128.0, 128.3, 128.7, 129.0,
129.2, 129.4, 132.0, 136.2, 138.6, 139.7, 147.5, 147.9, 151.6,
154.9, 166.5; IR (film) 2927, 1738, 1568, 1452 cm-1; HRMS
(ES) calcd for C63H62O14Na (MNaþ) 1065.4037, found
1065.4017.
(M)-8,15-Bis(benzyloxy)-10,13-bis((R)-2-(benzyloxy)propyl)-
1,7,9,14-tetramethoxydinaphtho[2,1-d:10,20-f][1,3]dioxepine (41).
To a chilled (0 °C) solution of 39 (38 mg, 0.0364 mmol) in
toluene (2.5 mL) under argon was added DIBALH (1 M in
hexanes, 250 μL). The solution was stirred for 30 min and then
was quenched with deionized H2O and extracted with EtOAc.
The organic phases were washed with aq NH4Cl, dried (Na2SO4),
and the solvent was evaporated to yield a yellow resin, which was
carried on to the next step without further purification.
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.), and the Division of Organic
Chemistry of the American Chemical Society (C.A.M., B.J.
M.) for graduate fellowships. We thank Feng Gai and Virgil
Percec for assistance with CD measurements.
To a solution of the bisbenzyl alcohol in EtOAc (2 mL) was
added 2-iodoxybenzoic acid (72 mg, 0.255 mmol). The
mixture was heated at reflux under argon until the alcohol
was consumed as judged by TLC. The mixture was diluted
with EtOAc and filtered through Celite. The solvent was
evaporated in vacuo to yield the bisaldehyde as a yellow oil,
which was carried on to the next step without further pur-
ification.
The bisaldehyde (15 mg, 0.0152 mmol) in diglyme (1.2 mL)
was vigorously purged with argon for 30 min. In an inert
atmosphere box, an oven-dried microwave tube with a crimp
top and Teflon septa was charged with ClRh(PPh3)3 (30 mg,
0.0320 mmol). The aldehyde solution was added dropwise via
Supporting Information Available: Additional experimental
descriptions and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
56 J. Org. Chem. Vol. 75, No. 1, 2010