Perylenequinone natural products: Total syntheses of the diastereomers (+)-phleichrome and (+)-calphostin D by assembly of centrochiral and axial chiral fragments

Article abstract of DOI:10.1021/jo901384h

(Chemical Equation Presented) The first total synthesis of (+)-calphostin D and the total synthesis of (+)-phleichrome are outlined. The convergent syntheses utilize an enantiopure biaryl common intermediate, which is formed via an enantioselective cataly

Full text of DOI:10.1021/jo901384h

pubs.acs.org/joc
Perylenequinone Natural Products: Total Syntheses of the Diastereomers
(þ)-Phleichrome and (þ)-Calphostin D by Assembly of Centrochiral and
Axial Chiral Fragments
Barbara J. Morgan, Carol A. Mulrooney, Erin M. O’Brien, 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 first total synthesis of (þ)-calphostin D and the total synthesis of (þ)-phleichrome are outlined.
The convergent syntheses utilize an enantiopure biaryl common intermediate, which is formed via an
enantioselective catalytic biaryl coupling. The established axial chirality is transferred to the
perylenequinone helical stereochemistry with good fidelity. Additionally, efforts focused on the
installation of the stereogenic C7,C70-2-hydroxypropyl groups. Three routes were evaluated to
establish the C7,C70-stereochemistry, in which the successful route involved a double epoxide
alkylation with a complex axial chiral biscuprate. This strategy not only allowed the synthesis of
the unnatural isomers of calphostin D and phleichrome for assessment in biological systems but also
provided valuable information for the syntheses of the more complex cercosporin and hypocrellin A.
Introduction
cladosporioides (1a-d) and Cladosporium phlei (2).2,3 The more
architecturally complex perylenequinones cercosporin (3)4 and
hypocrellin A (4)5 have also been isolated from different fungi.
From a synthetic viewpoint, 1-3 contain the same stere-
ochemical elements - helical chirality and stereogenic C7,
C70-2-hydroxypropyl groups. Prior to our investigations, the
total syntheses of the calphostins and phleichrome were
reported involving diastereoselective biaryl couplings.6 Un-
fortunately, the chiral naphthalenes provided only modest
The natural products 1-4 (Figure 1) are representative
members of the mold perylenequinones, one of the three major
classes of naturally occurring perylenequinones.1 They are
characterized by a helical chiral oxidized pentacyclic core in
conjunction with C7,C70-substitution containing centrochiral
stereocenters. Calphostin D (R1=R2=H, 1d) and phleichrome
(2) are the simplest of this growing class of natural products.
Calphostin D (1d) is accompanied in nature by its substituted
counterparts: calphostin A (R1=R2=COPh, 1a), calphostin
B (R1=H, R2=COPh; 1b), and calphostin C (R1=COPh,
R2=CO2(p-OH-Ph); 1c). The pigments 1a-d and 2 are iso-
lates of the Cladosporium fungi, specifically Cladosporium
(3) Yoshihara, T.; Shimanuki, T.; Araki, T.; Saramura, S. Agric. Biol.
Chem. 1975, 39, 1683–1684.
(4) (a) Kuyama, S.; Tamura, T. J. Am. Chem. Soc. 1957, 79, 5725–5726.
(b) Kuyama, S.; Tamura, T. J. Am. Chem. Soc. 1957, 79, 5726–5729.
(5) Chen, W. S.; Chen, Y. T.; Wang, X. Y.; Friedrichs, E.; Puff, H.;
Breitmaier, E. Liebigs Ann. Chem. 1981, 1880–1885.
(1) Perylenequinone reviews: (a) Weiss, U.; Merlini, L.; Nasini, G. Prog.
€
(6) (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.
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) (a) Kobayashi, E.; Ando, K.; Nakano, H.; Iida, T.; Ohno, H.;
Morimoto, M.; Tamaoki, T. J. Antibiot. 1989, 42, 1470–1474. (b) Iida, T.;
Kobayashi, E.; Yoshida, M.; Sano, H. J. Antibiot. 1989, 42, 1475–1481.
30 J. Org. Chem. 2010, 75, 30–43
Published on Web 11/09/2009
DOI: 10.1021/jo901384h
r
2009 American Chemical Society

Morgan et al.
JOCArticle
Results and Discussion
Retrosynthetic Analysis. We sought a synthetic strategy to
permit a flexible approach to all the perylenequinone natural
products 1-4 (Figure 1). In the previous installment of this
series (DOI 10.1021/jo9013832), we described the synthesis
of helical chiral perylenequinones absent any centrochiral
stereocenters. The synthesis employed an enantioselective
biaryl coupling to establish the axial chirality from which the
corresponding helical stereochemistry was generated with
complete stereocontrol. Having shown with this work that
compounds such as helical chiral 9 are configurationally
stable, we proposed that such an intermediate could be
employed in a biomimetic synthesis of ent-1, ent-2, 3, and
4. Specifically, reduction of intermediate 9 directed by the
helical axis would furnish ent-2 and 3 (path a) while chelate-
controlled reduction would provide ent-1d (path a0).
Furthermore, a transannular aldol reaction would access
hypocrellin ent-4 (path b). This proposal would circumvent
the moderate selectivities encountered in the establishing the
axial/helical stereochemistry in prior approaches (Scheme 1,
Scheme 2, path c).9 Furthermore, there is no direct means to
generate hypocrellin (ent-4) via the strategy in path c; oxida-
tion of the alcohols would be required resulting in loss of
their stereochemical information.
FIGURE 1. Representatives of the naturally occurring mold per-
ylenequinones.
stereocontrol during the dimerizations (Scheme 1).7 Further-
more, 3 with the opposite helical chirality and an additional
seven-membered ring remained a target that would be
difficult to access via the reported approaches. The synthetic
challenge of 3 centers on the bridging seven-membered ring,
which lowers the atropisomerization barrier such that sig-
nificant atropisomerization occurs at 37 °C.8
SCHEME 2. Retrosynthetic Analysis of Calphostins
SCHEME 1. Diastereoselective Dimerization to the Calphostins
Catalytic Enantioselective Oxidative Binaphthol Coupling.
Thus, we began our efforts toward (þ)-calphostin D (ent-1d)
and (þ)-phleichrome (ent-2) by devising a synthesis of chiral
binaphthalene 10 in order to prepare 9 (Scheme 2). Pre-
viously, we had discovered that diaza-cis-decalin catalyst 28
(Table 1) was effective in the coupling of functionalized 2-
naphthols and determined the optimal substitution patterns
to generate products with high yield and selectivity.10 With
these constraints in mind, 15-17 illustrated in Scheme 3 were
anticipated to be suitable substrates. Binaphthol coupling as
As such, we pursued a flexible strategy that would
permit stereoselective synthesis of any stereoisomer of
the calphostin/phleichrome framework for biological
evaluation and provide an entry into the more complex
3. In this paper, we describe the evolution of the total
synthesis of ent-2 and ent-1, with the main focus being the
stereoselective installation of the C7,C70-2-hydroxypro-
pyl groups.
(9) Morgan, B. J.; Dey, S.; Johnson, S. W.; Kozlowski, M. C. J. Am.
Chem. Soc. 2009, 131, 9413–9425.
(10) (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.
(7) In all of the prior approaches the C7-stereochemistry was generated
first and was followed by a diastereoselective coupling (moderate selectivity)
of the chiral naphthalene. Additionally, the predominant diastereomer does
not generally correspond to the expected calphostin array, although it does
match that needed for phleichrome.
(8) Nasini, G.; Merlini, L.; Andreetti, G. D.; Bocelli, G.; Sgarabotto, P.
Tetrahedron 1982, 38, 2787–2796.
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SCHEME 3. Potential Binaphthol Coupling Substrates
late as possible (i.e., 15) was desirable as the monomers were
simpler to manipulate than the corresponding dimers. To
determine the optimal pathway in Scheme 3, a series of
substrates was synthesized and examined in the asymmetric
catalytic naphthol coupling.
SCHEME 4. Synthesis of Naphthol Coupling Substrates
TABLE 1. Biaryl Coupling with Diaza-cis-decalin Catalyst Complex 28
under O2
group to the Friedel-Crafts cyclization conditions. How-
ever, installation of the allyl group after formation of the
naphthalene proceeded readily. While the bromo-substrates
20a,b performed poorly in Suzuki couplings, Stille coupling
with allyl trin-butyltin provided the desired C7-allyl
naphthalenes 22a and 22b in suitable yields (Scheme 4). An
efficient selective deprotection of the C2-acetate yielded the
allyl coupling monomer 24. A Wacker oxidation of 22b
afforded the ketone in 63% yield, and after removal of the
C2-pivalate, the crucial ketone naphthol 23 was provided.
Because substrates with C7,C70-halogens provide a readily
convertible scaffold, the C7-iodonaphthol12 was examined in
addition to the C7-bromo variant. Beginning with the use of
iodine monochloride as the halogen source (Scheme 5), the
route mirrors that of bromonaphthol 20a (Scheme 4).
Though the syntheses are comparable, significant differences
were noted in the Friedel-Crafts cyclization step. The use
of sulfuric acid with the iodo analogue 25 provided none
of the desired product, whereas these conditions efficiently
afforded bromo analogue 19. For the more sensitive iodo
analogue, P2O5 in methanesulfonic acid proved essential
in the cyclization, although small amounts of byproduct
were still observed. The overall yields to the diacetates
are slightly less for the iodo (40%) vs the bromo (53%)
series; however, the iodo substrate provided advantages
at later stages (see below).
Commercially available p-methoxyphenylacetic acid (18)
was subjected to regioselective bromination, acid chloride
formation, condensation with dimethyl malonate, and Frie-
del-Crafts cyclization to afford 19 (Scheme 4).11 The bro-
monaphthalenediol 19 was protected as the bisacetate 20a,
using acetic anhydride and pyridine, and as the bispivalate
20b, using pivaloyl chloride and triethylamine. In the first
branch point of the naphthol syntheses, selective removal of
the less sterically encumbered C2-acyl groups supplied the
coupling substrates 21a and 21b.
In the previous paper of this series (DOI 10.1021/
jo9013832), the failed synthesis of 22a via cyclization of
C3-allylated-18 was attributed to the instability of the allyl
(11) Morgan, B. J.; Xie, X.; Phuan, P.-W.; Kozlowski, M. C. J. Org.
Chem. 2007, 72, 6171–6182.
(12) O0Brien, E. M.; Morgan, B. J.; Kozlowski, M. C. Angew. Chem., Int.
Ed. 2008, 47, 6877–6880.
32 J. Org. Chem. Vol. 75, No. 1, 2010

Morgan et al.
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this stereochemical array after coupling, maximum diver-
sity is possible permitting the synthesis of multiple natural
products.
SCHEME 5. Synthesis of Iodonaphthol Biaryl Coupling Monomer
Two distinct paths were envisioned (Scheme 6). In path a,
the axial stereochemistry could be utilized as a relay to control
the C7,C70-stereochemistry. We demonstrated the fidelity of
this approach in our synthesis of hypocrellin A,12 which is
detailed in the fifth paper in this series (DOI 10.1021/
jo901386d). In applying the strategy to phleichrome, the
alcohol stereocenters could be generated in a diastereoselec-
tive fashion by either the reduction of diketone 31 (path a,
R = Me) or the methyladdition todialdehyde32(patha, R =
H). Alternatively, the stereogenic C7,C70-substitution could
be introduced from an external source, as seen in the epoxide
opening of path b. The latter approach is attractive in that
independent introduction of the C7,C70-stereochemistry
would permit a more facile synthesis of the complete diaster-
eomeric series of 1, 2, and 3. Though the flexibility of path b
was attractive, we initially investigated the likely biomimetic
path a (R = Me). Specifically, the breadth of precedent for
stereoselective ketone reduction and the interception of a late-
stage intermediate (9) from the hypocrellin A synthesis led us
to investigate the diastereoselective reduction of 31.
Employing the optimized conditions (40 °C under oxy-
gen for 48 h), the biaryl coupling screening results for the
above substrates are collected in Table 1. As expected,
substrates with the electron-withdrawing bromo substitu-
ent reacted more slowly compared to reported substrate
29a (entry 1).10d Rates improved with acetonitrile as a
solvent in place of dichloroethane such that bromo analo-
gue 29b was obtained with good yield (67%) and selectivity
(81% ee) (entry 2). Replacement of the C4-acetoxy group
with the more stable pivaloyl group was promising but
would require further optimization due to lower yield and
selectivity (entry 3). With iodo substrate 27, the standard
coupling conditions again provided low conversion (entry
4). Use of a mixed solvent system (1:1 dichloroethane/
acetonitrile) resulted in some improvement in yield and
good enantioselection (entry 5). Due to substrate solubi-
lity, acetonitrile alone was initially not considered, but
reaction at lower concentrations for a longer period of
time (2 days) afforded 29d in 81% yield and 80% enantios-
electivity (entry 6). Further attempts to increase selectivity
were halted when it was discovered that the high crystal-
linity of 29d could provide >99% ee material in one
trituration with excellent mass recovery. In a final com-
parison of the bromo and iodo derivatives, this property
rendered the synthesis of highly enantioenriched material
with iodobiaryl 29d more efficient even though the yields
in the synthesis of iodonaphthol substrate 27 were some-
what lower than that of the corresponding bromona-
phthol 21a.
SCHEME 6. Retrosynthetic Paths for Stereogenic C7,C70-2-
Hydroxypropyl Groups
The best results for the asymmetric biaryl coupling were
obtained with the allylated naphthol 24 to provide 29e in
good yield (94%) and enantioselectivity (85%) (entry 7,
Table 1). Enantiopure material could be obtained, but unlike
the iodo analogue 29d, multiple triturations had to be
employed. The survival of the oxidatively sensitive allyl
group speaks to the compatibility of the coupling conditions
with most functionality. Unfortunately, this generaliza-
tion did not hold true with the corresponding ketone
(2-oxopropyl) substrate (entry 8), where formation of 29f
was slow and accompanied by significant decomposition.
Both enol formation and oxidative enol coupling could
compete with the coupling reaction, accounting for these
observations.
Stereoselective Generation of the C7,C70 2-Hydroxypropyl
Groups (Parts I-III). To install the C7,C70-stereochemistry
we desired a synthetic strategy that was both direct and
flexible, utilizing intermediates that could lead to all of the
natural products 1-4. In the prior syntheses of the cal-
phostins and phleichrome, formation of the stereogenic
C7,C70 2-hydroxypropyl groups preceded dimerization
(see Scheme 1). Since our strategy (Scheme 2) introduces
I. Stereoselective Ketone Reductions. The asymmetric re-
duction of ketones to form chiral secondary alcohols13 is a
common transformation in synthesis that is widely regarded
as a “solved problem”. However, consideration of the re-
duction of a diketone 31 to form 30a reveals problematic
aspects still encountered in this methodology. First, the
groups flanking the ketone, methyl, and benzyl are sterically
similar such that facial bias in asymmetric reductions is
difficult. Second, the enolization of benzylic ketones results
in low yields. The challenges of the motif can be seen in the
approaches to these centers in the prior calphostins synth-
eses.6
To test the viability of the ketone reduction approach,
bisketone 31 was employed initially. The allyl biaryl 29e
(13) For reviews, see: (a) Singh, V. K. Synthesis 1991, 605–617. (b) Corey,
E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–2012. (c) Daverio, P.;
Zanda, M. Tetrahedron: Asymm. 2001, 12, 2225–2259.
J. Org. Chem. Vol. 75, No. 1, 2010 33

Morgan et al.
SCHEME 9. Synthesis of Ketone Model System 34
JOCArticle
offered the most direct means to the desired bisketone 31.
Following a one-pot deacetylation/methylation, a Wacker
reaction provided substrate 31 (Scheme 7).
SCHEME 7. Formation of Diketone Intermediate 31
steric demands of the methyl and benzyl ketone substituents,
the development of asymmetric reductions of arylacetones
has been limited. Although 3714 and 3815 were well prece-
dented for this transformation (eq 1), they were ineffectual
with naphthalene 34 (17% and 36% ee), respectively (entries
1 and 2; Table 2). Even the reliable CBS catalyst16 only
provided a modest 50% ee (entry 3). Commercially available
amino alcohol 41 was also evaluated but with no improve-
ment to selectivity (entry 4).
Molecular models (Scheme 8) suggested that the axial
biaryl stereochemistry would block one prochiral face of
the ketone to allow for a stereoselective approach of an
achiral reducing agent. The reductions could provide three
diastereomers: (M,R,R)-diastereomer 30a, (M,S,S)-diaster-
eomer 30b, and meso-(M,R,S)-diastereomer 30c. Unfortu-
nately, statistical mixtures of the isomers (dr = 1:1:2, 30a/b/
c; Scheme 8) were obtained using NaBH4 or the larger L-
Selectride. Apparently, the biaryl axis is too distant to
provide any stereocontrol over approach to the C7,C70-
ketone functionality. This outcome is reminiscent of the
prior perylenequinone syntheses,6 where poor diastereos-
electivity was observed due to the distance of the C7,C70-
stereochemistry from the forming biaryl bond (Scheme 1).
Furthermore, the free rotation about the aryl-methylene
bond would result in conformers where the opposite faces are
blocked by the axial chiral biaryl.
Other reduction methods including R-pinene borane re-
agent 42,17 (þ)-TADDOL/Ti(Oi-Pr)4/catecholborane,18
pyrrolidinylproline 43/DIBAL/SnCl2,19 BINAL 44,20 and
21
RuCl2(BINAP)/diphenylethylenediamine/1000 psi H2
provided little or no enantioselectivity with 34 (entries
5-9, Table 2) in spite of strong precedents with related
systems. Most surprising was the complete absence of hydro-
silylation of ketone 34 with a rhodium-pybox catalyst (entry
10), even though the same catalyst performed well in our
hands with the closely related 2-methoxyphenylacetone
(82% ee).22 Both immobilized Geotrichum candidum
and baker’s yeast have been known to reduce phenylace-
tone in >99% ee.23,24 Unfortunately, baker’s yeast had
no effect on our model ketone 34 (entry 11, Table 2),
although we successfully reduced acetophenone under the
SCHEME 8. Attempted Diastereoselective Reductions of 31
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At this point, external asymmetric reducing agents were
examined since internal diastereocontrol was absent. In a
parallel synthesis to the biaryl counterpart, a deacetylation/
methylation followed by a Wacker reaction yielded model
naphthalene 34 (Scheme 9) for this study. Due to the similar
(23) Enzymatic reduction review: Moore, J. C.; Pollard, D. J.; Kosjek, B.;
Devine, P. N. Acc. Chem. Res. 2007, 40, 1412–1419.
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34 J. Org. Chem. Vol. 75, No. 1, 2010

Morgan et al.
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TABLE 2. Attempted Enantioselective Formation of 39
alkyl ketones or even many dialkyl ketones.13,16,23 At this
point, attention was turned to the second strategy in path a:
stereoselective methyl addition to bisaldehyde 32 (Scheme 6).
II. Asymmetric Aldehyde Alkylation. We initially proposed
to use the biaryl axis to direct a diastereoselective methyl
addition to 32 (path a R = H, Scheme 6), but the lack of
stereocontrol observed in the reduction of 31 would likely be
problematic in this route as well. Thus, chiral catalysts were
surveyed in the enantioselective addition of Me2Zn to model
phenylacetaldehyde 45. Although the asymmetric addition
of dialkylzinc reagents to aldehydes is quite common,25 few
examples have been reported with R-arylacetaldehydes and
Me2Zn,26 likely due to the challenges surrounding the reac-
tion: (1) the acidity of the aldehyde 45, making aldol by-
product likely, and (2) the use of the less reactive, more basic
ZnMe2 relative to the more common ZnEt2. A survey of
several promising catalyst systems from the literature includ-
ing MIB,27 more reactive amino alcohol 47,28 BINOL tita-
nium complexes,29 and titanium salen complexes30,31 (entries
1-4, Table 3) was not promising as aldol byproducts pre-
dominated.32
Since substrate activation seemed to be crucial, the highly
reactive bis(sulfonamide) catalysts,25,33 which catalyze addi-
tions even to less reactive ketones,34 were assessed. Encoura-
gingly, the bis(sulfonamides) 49a and 49b were capable of
catalyzing the methyl addition to generate the desired alco-
hol 46 (41-65% yield, 10-24% ee; entry 5, Table 3). Redu-
cing the amount of Ti(O-i-Pr)4 and ZnMe2 did increase the
selectivity up to 70% ee but also increased the aldol by-
adducts. Prior to further optimization, the bis(sulfonamide)
catalysts were applied to model naphthalene 52.
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N.; Katsuki, T. Bull. Chem. Soc. Jpn. 1999, 72, 603–619. (e) Canali, L.;
Sherrington, D. C. Chem. Soc. Rev. 1999, 28, 85–93.
(31) Fennie, M. W.; DiMauro, E. F.; O’Brien, E. M.; Annamalai, V.;
Kozlowski, M. C. Tetrahedron 2005, 61, 6249–6265.
same conditions. Apparently, the additional steric hindrance
from the o-methoxy group has a profound effect on reactiv-
ity with enzymatic catalysts.
Since the best result was obtained with the CBS catalyst 40
(entry 3, Table 2), these conditions were applied to the chiral
biaryl 31 (Scheme 8). Unfortunately, only moderate selec-
tivity (dr = 1.3:1.0:2.0, 30a/b/c) was observed regardless
of which axial antipode (M or P) was used. These results
highlight that benzyl methyl ketone substrates remain a
problematic asymmetric reduction class compared to aryl
(32) For comparison, the reaction was also run with (()-MIB and ZnEt2
as the alkylating agent, which provided complete conversion to the alkylated
product, pointing to the less reactive, more basic ZnMe2 as the problem.
(33) (a) Takahashi, H; Kawakita, T.; Yoshioka, M.; Kobayashi, S.;
Ohno, M. Tetrahedron Lett. 1989, 30, 7095–7098. (b) Takahashi, H;
Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S. Tetrahedron 1992,
48, 5691–5700. For reviews, see: (c) Knochel, P. Synlett 1995, 393–403.
(d) Knochel, P.; Perea, J.; Almena, J.; Jones, P. Tetrahedron 1998, 54, 8275–
8319. (e) Walsh, P. J. Acc. Chem. Res. 2003, 36, 739–749.
(34) (a) Garcia, C.; LaRochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc.
2002, 124, 10970–10971. (b) Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003,
125, 9544–9545.
J. Org. Chem. Vol. 75, No. 1, 2010 35

Morgan et al.
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TABLE 3. Screening of Catalysts for Me2Zn Addition to Model
Substrate 45
SCHEME 10. Synthesis of Naphthalene Aldehyde 52 and At-
tempted Asymmetric Alkylation
III. Organocopper Epoxide-Opening. Although we had
initially examined biomimetic diastereoselective ap-
proaches, the introduction of an independent chiral frag-
ment (path b, Scheme 6) presents distinct advantages with
respect to convergency. As discussed previously, the use of
separate fragments allows facile entry to all diastereomeric
combinations of the natural products 1-3 including the
unnatural isomers. We elected to investigate copper-medi-
ated epoxide openings to achieve this goal. Since the biaryl
axis seems to exert minimal stereocontrol over reactions at
the C7,C70-position, the epoxide opening should not be
limited to a matched case (double diastereocontrol), mean-
ing both the (R)- and (S)-epoxide can be utilized with equal
facility. Prior to this series of papers, we published an
overview of this work;9 Table 4 and the discussion below
provide a full report of this chemistry in the calphostin/
phleichrome system.35
While Grignard-derived cuprates enjoy considerable
precedent in epoxide openings,36 there are few examples
of biscuprates being employed in this alkylation. While
complex cuprates have been used successfully (eq 2)37 and
simple biscuprates have been employed in epoxide alkyla-
tion (eq 3),38 we could locate no reports of a highly
functionalized dianion effecting two ring-openings. Our
primary concerns were (1) the metal-halogen exchange on
an electron-rich system and in the presence of the C3-
methyl esters, (2) the stability of the electron-rich bisaryl-
cuprate, and (3) the use of stoichiometric biscuprate rather
than the excess that is typical for cuprate additions. These
concerns were assessed by means of several naphthalene
aComplex mixture resulting from aldol byproducts.
Synthesis of naphthalene aldehyde 52 commenced from
intermediate 20a, which was subjected to a Sonagashira
coupling to install generate alkyne 50 (Scheme 10). Subse-
quent tetra-n-butylammonium fluoride treatment furnished
the terminal alkyne. A one-pot deacetylation/methylation of
the C2,C4 phenols was achieved using NaH (60%) and MeI
in wet DMF to supply 51 with in high yield. Upon screening a
range of hydroboration reagents [bis-sec-isoamylborane
(35) The next paper in this series describes the further evolution
of the biscuprates for the cercosporin synthesis. Morgan, B. J.;
Mulrooney, C.; Kozlowski, M. C. J. Org. Chem. 2010, 75 (DOI: 10.1021/
jo9013854).
(Sia2BH), BH3 THF, catecholborane, and Cy2BH], Cy2BH
3
was found to be the most successful providing 52 after
hydrogen peroxide oxidation in low yield (30%). Before
further optimization, the alkylation conditions were exam-
ined on this substrate. Unfortunately, when the methyl
addition with 49b was attempted only a mixture of aldol
adducts were produced. Steric interactions from the C6-
methyl ether that is not present in model 45 could account
for the inability of the catalyst to activate the substrate,
allowing deprotonation of the R-center as the only viable
pathway. At this juncture, the difficulties encountered in
both routes of path a from Scheme 6 stimulated us to
investigate the alternate path b utilizing an external chiral
reagent as a source for the C7,C70-stereochemical array.
(36) (a) Lipshutz, B. H.; Kozlowski, J.; Wilhelm, R. S. J. Am. Chem. Soc.
1982, 104, 2305–2307. (b) Smith, J. G. Synthesis 1984, 629–656. (c) Sheperd,
T.; Aikins, J.; Bleakman, D.; Cantrell, B.; Rearick, J.; Simon, R.; Smith, E.;
Stephenson, G.; Zimmerman, D. J. Med. Chem. 2002, 45, 2101–2111. (d)
Taber, D. F.; He, Y. J. Org. Chem. 2005, 70, 7711–7714. (e) Nakamura, E.;
Mori, S. Angew. Chem., Int. Ed. 2000, 39, 3751–3771. (f) Review of
organocopper reagents: Lipshutz, B. H.; Sengupta, S. Org. React. 1992,
41, 135.
(37) (a) Ireland, R. E.; Gleason, J. L.; Gegnas, L. D.; Highsmith, T. K. J.
Org. Chem. 1996, 61, 6856–6872. (b) Ireland, R. E.; Liu, L.; Roper, T. D.
Tetrahedron 1997, 53, 13221–13256.
(38) (a) Cahill, S.; Evans, L. A.; O’Brien, M. Tetrahedron Lett. 2007, 48,
5683–5686. For simple bis-Grignard and bis-lithium reagents in epoxide
opening, see: (b) Bianchetti, G. Farm. Ed. Sci. 1957, 12, 441–448. (c) Ghorai,
P.; Dussault, P. H.; Hu, C. Org. Lett. 2008, 10, 2401–2404. (d) Gordon, B. III;
Blumenthal, M.; Mera, A. E.; Kumpf, R. J. J. Org. Chem. 1985, 50, 1540–
1542.
36 J. Org. Chem. Vol. 75, No. 1, 2010

Morgan et al.
JOCArticle
systems, including bismethyl ether 61 and isopropyl
ether 60.39
desired product (40%). Fortunately, the use of rigorously
oxygen- and water-free conditions drastically decreased the
amount of arene formed, improving the yield of 64 to 77%
(entry 5a, Table 4). The use of Et2O as a solvent (entry 5b)
had no effect on the reaction. The use of other copper
reagents (CuCN, entry 5c; CuBr, entry 5d) and additives
such as TMSCl or HMPA (entries 5e and f) provided lower
yields of the desired 64 due to more protodemetalation of the
organocopper reagent. Ultimately, careful purification of
the CuI by recrystallization proved to be the most important
finding, providing 64 in 87% yield (entry 5g). Interestingly,
the use of lower temperatures (-78 °C) did not improve the
outcome (entry 5h), indicating that the cuprate and product
are fairly robust. With isolated yields in the 85% range (entry
5g), acceptable yields (85% ꢀ 85% = 72%) were anticipated
in the dimeric systems.
The fact that acetate protecting groups were unacceptable
in the epoxide opening (entry 3, Table 4) indicated that this
key transformation must be conducted after biaryl forma-
tion (a C4-acetate is necessary for high selectivity in the
biaryl coupling)10d in order to reduce the number of protect-
ing group steps. Conveniently, this sequence permits more
flexibility in the strategy, allowing the syntheses of 1-3 to
diverge at a late biaryl intermediate (33, Scheme 6). In spite
of these advantages, the formation of a functionalized
dianionic organocuprate and two epoxide alkylations re-
mained speculative. The success of the transformation relies
on the derived biscuprate behaving as two independent
cuprates (Scheme 12). If the two entities interact signifi-
cantly, side products resulting from an intramolecular reac-
tion of intermediate 66 would occur. In spite of these
reservations, enantiopure M-29d was deacetylated and
methylated in a one-pot protocol using the previously de-
scribed conditions (Schemes 7,9) to yield 33 in 94% yield
(Scheme 12). With the optimized epoxide-opening condi-
tions, we discovered that (R)-propylene oxide reacted
smoothly with the biscuprate of 33 providing the target
structure 30a with two new stereocenters in 75% yield as a
single diastereomer (two couplings, 81% yield each). Inter-
estingly, the cuprates formed from 65 do appear to act
independently since the only byproduct isolated arose from
protodemetalation.
First-Generation Approach: Radical Cation C5,C50-Oxida-
tion and Palladium-Mediated C3,C30-Decarboxylation. With
the stereochemical issue resolved, synthesis of one of the
simplest mold perylenequinone natural products, (þ)-phlei-
chrome (ent-2), was undertaken. Our studies commenced
with application of the PhI(OCOCF3)2-induced oxidation41
of the C5,C50-positions described in the previous paper of
this series (DOI 10.1021/jo9013832) to epoxide-opening
product 30a (Scheme 12). A survey of protecting groups
(Me, TBS, Ac, and Bz) on the newly installed C7,C70-
hydroxyl stereocenters revealed that only the benzoate group
was able to withstand the reaction conditions to provide 68d
without substantial decomposition (Scheme 13).
Starting from iodo intermediates, the two naphthalene
substrates were synthesized as shown in Scheme 11. Mitsu-
nobu reaction with 27 was used to install the C2-isopropyl
ether and was followed by a one-pot deacetylation/methyla-
tion to generate 60 in high yield. Methylation of the bis-
naphthol 59 with dimethyl sulfate and potassium hydroxide
provided the bismethyl ether 61 directly. The low yield (33%)
was attributed to a byproduct resulting from the electrophilic
methylation of the C1-position.
SCHEME 11. Synthesis of Iodo Substrates
To examine the functional group compatibility of the
epoxide-opening reaction, a variety of substrates were eval-
uated. Bromonaphthalene 20a formed the Grignard reagent,
but only at elevated temperatures, which caused removal of
the C2,C4-acetate groups (entry 1, Table 4). While organo-
lithium formation from the iodonaphthalene 26 with t-BuLi
was unsuccessful due to addition to the C3-ester, the corre-
sponding Grignard reagent was formed readily at low
temperatures (-40 °C) using i-PrMgBr40 (entry 2). The
attempted cuprate formation and epoxide-opening from this
Grignard only resulted in cleavage of the C2,C4-acetates
(entry 3). Pleasingly, when the C2,C4-hydroxyl groups
were masked as methyl ethers in 61, the epoxide-opening
could be completed in 65% yield with complete regioselec-
tion (entry 4).
Since we plan to undertake this same transformation twice
on one substrate (65% yield with the monomer would
correspond to 43% yield with the dimer), the conditions
were optimized further with iodonaphthalene 60. The initial
epoxide-opening with 60 yielded modest amounts of the
With the necessary oxygenation pattern established, our
next task was removal of the C3,C30-ester groups via dec-
arboxylation of the respective C3,C30-diacid. Significantly,
(39) A C2,C20-bis-isopropyl ether was utilized in the epoxide opening in
the first-generation synthesis of cercosporin 3, which is detailed in the next
paper of this series (DOI: 10.1021/jo9013854).
(40) For a review, see: Knochel, P.; Wolfgang, D.; Gommermann, N.;
Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Anh Vu, V. Angew. Chem.,
Int. Ed. 2003, 42, 4302–4320.
(41) (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 37

Morgan et al.
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TABLE 4. Screening of Epoxide-Opening Conditions on Naphthalene Substrates
a1.25 equiv of i-PrMgBr; 0.5 equiv of CuX. bConversion. cRemaining yield attributed to dehalogenated arene. dIsolated yield in parentheses.
SCHEME 12. Biscuprate Epoxide Opening
SCHEME 13. Screening of Protecting Groups for PIFA Oxi-
dation
led us to develop a palladium-catalyzed decarboxyla-
tion protocol.12,43 Following benzylation of the bisphenol
68d, a deprotection/reprotection sequence of the C7,C70-
hydroxypropyl groups was needed to withstand the decar-
boxylation protocol. Thus, the bisbenzoate was cleaved
with K2CO3 and MeOH to afford 69, which was subjected
to TBSOTf and 2,6-lutidine to provide the bissilyl ether
(Scheme 14). The high temperatures that were needed
to saponify the sterically encumbered C3,C30-ester groups
resulted in atropisomerization of the biaryl axis. Con-
sequently, a three-step (reduction/oxidation/oxidation)
protocol was used to synthesize diacid 70 in high yield
(85% over three steps). The novel palladium-mediated
decarboxylation of 70 proceeded smoothly to provide the
key intermediate 71 in moderate yield and with no loss of
enantioenrichment.43
the C3,C30-ester groups served four distinct purposes: (1)
coordination to the catalyst during biaryl coupling (Table 1)
to enable a highly enantioselective process, (2) stabilization
of the highly electron-rich biaryl in the biscuprate epoxide
alkylations (Scheme 12), (3) blocking the C3,C30-position
during the C5,C50-oxidation (Scheme 13), and (4) providing
an avenue for C3,C30-derivatization.9 As outlined in the
previous paper of this series (DOI 10.1021/jo9013832), the
lack of success of conventional decarboxylation protocols42
(42) Protic acid protocol: (a) Horper, W.; Marner, F.-J. Phytochemistry
1996, 41, 451. Copper/quinoline protocol: (b) Cohen, T.; Schambach, R. A.
J. Am. Chem. Soc. 1970, 92, 3189.
(43) Dickstein, J. S.; Mulrooney, C. A.; O’Brien, E. M; Morgan, B. J.;
Kozlowski, M. C. Org. Lett. 2007, 9, 2441–2444.
38 J. Org. Chem. Vol. 75, No. 1, 2010

Morgan et al.
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SCHEME 14. Decarboxylation of Functionalized Intermediate 70
stereocenters. While different rates might be expected due to
double diastereodifferentiation (matched and mismatched
cases), no difference in the reaction rate was seen here. The
benzyl protection was chosen to minimize protecting group
manipulations, since a global debenzylation would be under-
taken prior to perylenequinone formation. While such ben-
zyl ethers are compatible with the latter stages of chemistry
described above (Scheme 14-Scheme 15), they are not com-
patible with the key PIFA oxidation (Scheme 13).46 The only
suitable protecting group of the C7,C70-hydroxypropyl
groups for the PIFA oxidation was benzoate which was
not viable in the remainder of the synthesis, requiring
protecting group exchanges. For these reasons, a new C5,
C50-oxidation route was investigated with benzyl ethers (M,
R,R)-73 and (M,S,S)-73 (Scheme 16).
In initial work, we had shown that halogenation and
lithiation of the C5-position was facile; however, oxygena-
tion did not proceed.47 In the intervening time, important
advances were made in the palladium-catalyzed couplings of
aryl halides with oxygen nucleophiles.48,49 Even though these
methods had not been utilized in highly hindered systems as
encountered here, we aimed to test their feasibility with our
challenging highly functionalized, electron-rich system. To
this end, chlorination using sulfuryl chloride readily afforded
the aryl chloride substrate (Scheme 16).45 Optimization of
Buchwald’s protocol,48c involving the catalyst system de-
rived from Pd2dba3 and the X-phos(t-Bu) ligand, enabled the
coupling of the bisaryl chloride with KOH to provide the
desired bisphenols. Unfortunately, the same reactions with
alkoxides such as benzyl alkoxide were poor. Presumably,
the steric hindrance of the reacting position combined with
that of the alkoxide disfavors O-arylation. However, im-
mediate protection of the unstable bisphenols with benzyl
bromide supplied the tetrabenzyl ethers (M,R,R)-74 and (M,
S,S)-74 in high yield. In comparison to the first generation
approach, the new oxidation procedure allowed a more
direct and higher yielding route to 74 (Scheme 16). Whereas
the electronics of the naphthalenes played a large role in the
PIFA oxidation chemistry such that each substrate required
optimization, the palladium-catalyzed coupling was surpris-
ing general.
SCHEME 15. Attempted Formation of (þ)-Phleichrome
After cleavage of the benzyl ethers, the bisphenol was oxi-
dized by MnO2 to afford perylenequinone (Scheme 15).6c,d
The use of MgI2 allowed for the selective removal of the C4,
C40-methyl ethers yielding 72.6b,e,f However, all attempts to
remove the C7,C70-silyl groups resulted in no reaction or
significant decomposition, providing none of the desired
ent-2.44 Analysis of our initial foray revealed many protec-
tion/deprotection steps in addition to the final protecting
group problem. Central to these problems was the PhI-
(OCOCF3)2 (PIFA) oxidation. While the method enabled
phenol formation, its incompatibility with most protecting
groups (Scheme 13) ultimately restricted and lengthened the
synthesis.
Second Generation Approach: Palladium-Catalyzed C5,
C50-O-Arylation and C3,C30-Decarbonylation in the Total
Syntheses of (þ)-Phleichrome and (þ)-Calphostin D. Though
our initial goal was the synthesis of (þ)-phleichrome (ent-2),
the use of an external chiral source in the epoxide alkylations
(Scheme 12) made a convergent synthesis of the epimers, ent-
1 and ent-2,9 straightforward (Scheme 16). For the purposes
of this discussion, the total syntheses illustrated in Scheme 16
represent the culmination of our synthetic studies and will be
used to draw a comparison between the first and second
approaches.45
The final improvement in the second-generation strategy
was the rhodium-mediated decarbonylation protocol uti-
lized in the removal of the C3,C30-ester groups of (M,R,R)-
74 and (M,S,S)-74 (Scheme 16). Though the palladium-
mediated decarboxylation43 of diacid 70 (Scheme 14) was
an important contribution employed in the synthesis of
perylenequinone analogues,9 an unexpected reaction oc-
curred in this transformation during the cercosporin synth-
esis.45 As such, a rhodium-mediated decarbonylation
The first- and second-generation strategies diverge
after the epoxide alkylation of intermediate 33 (Scheme 16).
Notably, both (R)- and (S)-propylene oxide were used to
provide the diastereomers (M,R,R)-73 and (M,S,S)-73,
respectively, after benzylation of the newly formed alcohol
(46) For further details on the sensitivity of different functional groups to
PIFA, see the next paper in this series (DOI: 10.1021/jo9013854).
(47) See Scheme 16 in the preceding paper of this series: Mulrooney, C.;
Morgan, B. J.; Li, X.; Kozlowski, M. C. J. Org. Chem. 2010, 75 (DOI:
10.1021/jo9013832).
(48) 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.
(49) (a) Mann, G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109–
13110. (b) Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 10770–10771. (c) Kataoka, N.; Shelby, Q.; Stambuli, J.
P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553–5566. (d) Vorogushi, A. V.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 8146–8149. (e)
Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am. Chem.
Soc. 2006, 128, 10694–10695.
(44) Broka in ref 6a reported long reaction times (3 d) in cleaving TBDPS
ethers (present in the C7,C70-substitution) of a biaryl similar to 71. In
addition, the oxidative cyclization to the perylenequinone stalled at the
hydroperylenequinone when the TBDPS groups were present.
(45) For further details on the optimization of the palladium-catalyzed O-
arylation and the rhodium-mediated decarbonylation, see the next paper in
this series (DOI: 10.1021/jo9013854).
J. Org. Chem. Vol. 75, No. 1, 2010 39

Morgan et al.
JOCArticle
SCHEME 16. Total Syntheses of (þ)-Phleichrome and (þ)-Calphostin D
approach was examined. After optimization on several
model systems,45 the (þ)-calphostin D (ent-1d) and (þ)-
phleichrome (ent-2) syntheses were used as the penultimate
test of the decarbonylation protocol.
substitution pattern. This investigation not only provided
the unnatural isomers of calphostin D (1) and phleichrome
(2) for assessment in biological systems, but also provided
valuable information for the syntheses of the more complex
cercosporin (3)9 and hypocrellin (ent-4)12 which are detailed
in the subsequent papers in this series.
The requisite bisaldehydes were generated by reduction to
the alcohol using DIBALH and then oxidation with o-
iodoxybenzoic acid (IBX) (Scheme 16). Pleasingly, treatment
with RhCl(PPh3)3 in diglyme at 95 °C supplied a smooth
decarbonylation provided that rigorously oxygen-free con-
ditions were employed. The desired (M,R,R)-75 and (M,S,
S)-75 were provided with no loss in enantioenrichment and
with increased yields of 75% and 90% (cf. 71, Scheme 14).
After global removal of all four benzyl ethers of 75, the total
syntheses of ent-2 and ent-1 culminated with perylenequi-
none formation and a selective cleavage of the C4,C40-
methyl ethers.
Experimental Section
Methyl 1-Acetoxy-3-hydroxy-6-iodo-7-methoxy-2-naphthoate
(27). A MeOH (275 mL ꢀ 2) and K2CO3 (1.4 g ꢀ 2, 10.5 mmol)
mixture is heated and sonicated to promote salt dissolution and
then cooled to 0 °C. To a chilled (0 °C/ice bath) solution of
diacetate 26 (6.0 g ꢀ 2, 13.1 mmol) in CH2Cl2 (110 mL ꢀ 2) was
added the MeOH/K2CO3 mixture. The mixture was stirred at
0 °C for 0.5 h under argon. After being quenched with 1 N HCl,
the aqueous phase was extracted with CH2Cl2. The organics
were washed with brine and dried (Na2SO4). After the solvent
was evaporated, the residue was recrystallized from hexanes/
CH2Cl2 to yield 27. Subsequent reacylation of the filtrate
(containing C4-naphthol and C2,C4-diol) and application of
the above procedure afforded 9.5 g of 27 in an 84% overall yield:
1H NMR (360 MHz, CDCl3) δ 2.49 (s, 6H), 3.96 (s, 6H), 4.04 (s,
6H), 7.03 (s, 2H), 7.15 (s, 2H), 8.22 (s, 2H), 10.50 (s, 2H); 13C
NMR (125 MHz, CDCl3) δ 20.8, 53.1, 56.2, 94.8, 99.5, 108.2,
109.1, 122.3, 134.1, 137.9, 154.4, 155.3, 168.9; IR (thin film)
2926, 1772, 1729, 1440 cm-1; HRMS (ESI) calcd for C15H13IO6-
Na (MNaþ) 438.9654, found 438.9643.
Conclusions
The first total synthesis of (þ)-calphostin D and the total
synthesis of (þ)-phleichrome from commercially available
18 have been developed. The products were generated in 17
steps with overall yields of 5.3% (average of 87% per step)
for ent-2 and 5.2% (average of 87% per step) for ent-1. The
syntheses diverge after the first seven steps from enantiopure
biaryl (M)-29d, which is formed via an enantioselective
catalytic biaryl coupling. While our initial biomimetic route
to the stereogenic C7,C70-2-hydroxypropyl groups was un-
successful, invaluable information was gained concerning
the challenges surrounding this substitution pattern. Fur-
thermore, weaknesses in current asymmetric ketone reduc-
tion and aldehyde alkylation methods have been highlighted
providing impetus for further study. Ultimately, a three-
component coupling reaction was developed involving the
union of a complex axial chiral biscuprate with two equiva-
lents of a centrochiral epoxide. This strategy permitted
stereoselective access to both ent-2 and ent-1. With the cen-
trochiral centers established, the C5,C50-oxidation evolved
from a capricious PIFA reaction to a remarkably robust
palladium-catalyzed O-arylation. Two strategies, a palla-
dium-catalyzed decarboxylation and rhodium-mediated
decarbonylation, were found viable for removal of the C3,
C30-ester functionality to establish the perylenequinone
(M)-Dimethyl-4,40-diacetoxy-2,20-dihydroxy-7,70diiodo-6,60-
dimethoxy[1,10]binaphthalenyl-3,30-dicarboxylate (29d). To a so-
lution of 27 (1.7 g, 4.1 mmol) in MeCN (550 mL) was added
20 mol % of CuI (S,S)-1,5-diaza-cis-decalin catalyst 28 (292
3
mg, 0.84 mmol). After being stirred for 3 d under oxygen, the
solution was quenched with 1 N HCl. The aqueous phase was
extracted with EtOAc, and the organics were washed with brine,
dried (Na2SO4), and concentrated. The resultant resin was
chromatographed (50% EtOAc/hexanes) to give 29d in 81%
ee. Trituration from CH2Cl2 and hexane (1:5) afforded 29d in
>99% ee as a yellow solid (1.3 g, 80%): [R]2D0 þ26.5 (c 0.5,
CH2Cl2, >99% ee (M)); 1H NMR (360 MHz, CDCl3) δ 2.54 (s,
6H), 3.98 (s, 6H), 4.04 (s, 6H), 7.07 (s, 2H), 7.65 (s, 2H), 10.72 (s,
2H); 13C NMR (125 MHz, CDCl3) δ 21.2, 53.6, 56.6, 96.2, 100.5,
108.7, 113.9, 122.9, 133.8, 136.3, 148.2, 153.3, 154.8, 169.1,
169.6; IR (film) 3096, 2957, 1768, 1671, 1613, 1563, 1478, 1440
cm-1; HRMS (ES) calcd for C30H24I2O12Na (MNaþ) 852.9300,
found 852.9250; CSP HPLC (Chiralpak AD, 1.0 mL/min, 80:20
hexanes/i-PrOH) tR (M) = 22.0 min, tR (P) = 30.2 min.
40 J. Org. Chem. Vol. 75, No. 1, 2010

Morgan et al.
JOCArticle
(M)-Dimethyl 7,70-Diiodo-2,20,4,40,6,60-hexamethoxy-1,10-bi-
naphthyl-3,30-dicarboxylate (33). To a solution of 29d (725 mg,
0.87 mmol) in DMF (25 mL) were added NaH (60% in oil, 1.0 g,
26 mmol) and MeI (1.6 mL, 26 mmol). After being stirred 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 organic fractions were washed with 1 N HCl
(3ꢀ) and brine (2ꢀ). After drying (Na2SO4) and concentration,
the residue was chromatographed (25% EtOAc/hexanes) to
yield 33 as a white foam (660 mg, 94%): [R]2D0 -57.4 (c 0.5,
CH2Cl2, >99% ee (M)); 1H 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; IR (film) 2945, 1733, 1579, 1463, 1436 cm-1; HRMS
(ESI) calcd for C30H28I2O10Na (MNaþ) 824.9669, found
824.9638.
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
being 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 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.
(s, 6H), 3.98 (s, 6H), 4.13 (s, 6H), 6.97 (s, 2H), 7.45 (s, 2H); 13
C
NMR (125 MHz, CDCl3) δ 23.1, 40.4, 52.8, 55.7, 62.1, 62.9,
67.8, 100.6, 119.8, 120.6, 125.2, 128.4, 130.4, 131.3, 151.9, 153.5,
156.3, 167.5; IR (film) 3414, 2950, 1730, 1591, 1498, 1444 cm-1
;
HRMS (ESI) calcd for C36H42O12Na (MNaþ) 689.2572, found
689.2565.
(M)-Dimethyl 7,70-Bis((R)-2-(benzyloxy)propyl)-2,20,4,40,6,
60-hexamethoxy-1,10-binaphthyl-3,30-dicarboxylate ((M,R,R)-
73). To a solution of 30a (300 mg, 0.45 mmol) in DMF
(12 mL) were added benzyl bromide (1.1 mL, 9.0 mmol) and
n-Bu4NI (33 mg, 0.090 mmol). NaH (60% in oil, 270 mg,
6.8 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
chromatography (10-50% EtOAc/hexanes) afforded (M,R,
R)-73 as a yellow resin (337 mg, 88%): [R]2D0 -103.3 (c 0.3,
CH2Cl2, >99% ee); 1H NMR (300 MHz, CDCl3) δ 0.97 (d, J =
6.1 Hz, 6H), 2.48 (dd, J = 7.1, 13.2 Hz, 2H), 3.00 (dd, J = 5.7,
13.2 Hz, 2H), 3.33 (s, 6H), 3.64 (m, 2H), 3.91 (s, 6H), 3.97 (s, 6H),
4.13 (s, 6H), 4.34 (br m, 4H), 7.03 (s, 2H), 7.11 (m, 4H), 7.22 (m,
6H), 7.40 (s, 2H); 13C NMR (125 MHz, (CD3)2CO) δ 19.9, 38.4,
52.6, 55.8, 61.9, 63.0, 70.5, 74.5, 100.8, 120.7, 121.5, 125.7, 127.7,
128.0, 128.8, 128.9, 130.9, 132.3, 140.3, 152.2, 154.1, 157.3,
167.5; IR (film) 2943, 1738, 1591, 1498, 1452 cm-1; HRMS
(ES) calcd for C50H54O12Na (MNaþ) 869.3513, found 869.3480.
(M)-Dimethyl 7,70-Bis((S)-2-(benzyloxy)propyl)-2,20,4,40,6,60-
hexamethoxy-1,10-binaphthyl-3,30-dicarboxylate ((M,S,S)-73).
Bisbenzyl ether (M,S,S)-73 was prepared in the same manner
as (M,R,R)-73 and was obtained as a yellow resin (285 mg,
1
79%): [R]2D0 -68.1 (c 0.3, CH2Cl2, >99% ee); H NMR (500
MHz, (CD3)2CO) δ 0.96 (d, J = 6.1 Hz, 6H), 2.61 (dd, J = 5.6,
13.6 Hz, 2H), 2.76 (dd, J = 7.0, 13.6 Hz, 2H), 3.30 (s, 6H), 3.71
(m, 2H), 3.93 (s, 6H), 3.94 (s, 6H), 4.09 (s, 6H), 4.19 (d, J = 12.2
Hz, 2H), 4.32 (d, J = 12.2 Hz, 2H), 7.00 (m, 4H), 7.06 (s, 2H),
7.16 (m, 6H), 7.46 (s, 2H); 13C NMR (125 MHz, (CD3)2CO) δ
20.0, 39.0, 52.6, 55.8, 61.9, 63.0, 70.6, 74.3, 100.8, 120.7, 121.5,
125.7, 127.7, 127.9, 128.7, 128.9, 130.9, 132.4, 140.2, 152.3,
154.0, 157.2, 167.5; IR (film) 2943, 1738, 1591, 1498, 1452
cm-1; HRMS (ES) calcd for C50H54O12Na (MNaþ) 869.3513,
found 869.3517.
(M)-Dimethyl
7,70-Bis((R)-2-hydroxypropyl)-2,20,4,40,6,60-
hexamethoxy-1,10-binaphthyl-3,30-dicarboxylate (30a). The ep-
oxide-opening was carried out according to the general proce-
dure with 33 (500 mg, 0.623 mmol) and i-PrMgBr (1 M in THF,
1.87 mL, 1.87 mmol) in THF (7.0 mL) and CuI (119 mg, 0.623
mmol) in THF (4 mL) and (R)-propylene oxide (175 μL, 2.49
mmol). The material was chromatographed (SiO2, 50% EtOAc/
hexanes), and the product 30a was obtained diastereomerically
pure as a white foam (312 mg, 75%): [R]2D0 -120.2 (c 0.45,
(M)-Dimethyl 5,50-Bis(benzyloxy)-7,70-bis((R)-2-(benzyloxy)
propyl)-2,20,4,40,6,60-hexamethoxy-1,10-binaphthyl-3,30-dicarb-
oxylate ((M,R,R)-74). Bisbenzyl ether (M,R,R)-73 (30 mg, 0.036
mmol) in anhydrous CH2Cl2 (0.7 mL) was treated with SO2Cl2
(7.0 μL, 0.089 mmol) and was allowed to stir at room tempera-
ture 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 chromatography (25%
EtOAc/hexanes) to yield (M,R,R)-bischloride as a yellow resin
(30 mg, 94%): [R]2D0 -49.0 (c 0.15, CH2Cl2, >99% ee); 1H NMR
(500 MHz, CDCl3) δ 1.00 (d, J = 6.1 Hz, 6H), 2.50 (dd, J = 6.6,
13.6 Hz, 2H), 2.97 (dd, J = 6.4, 13.6 Hz, 2H), 3.35 (s, 6H), 3.59
(m, 2H), 3.84 (s, 6H), 3.97 (s, 6H), 4.01 (s, 6H), 4.25 (d, J = 12.1
Hz, 2H), 4.34 (d, J = 12.1 Hz, 2H), 7.02 (s, 2H), 7.06 (m, 4H),
7.20 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 19.7, 38.3, 52.9,
60.9, 61.9, 64.8, 70.7, 75.0, 120.7, 122.5, 122.7, 124.4, 127.2,
127.5, 127.6, 128.4, 133.7, 135.2, 138.9, 152.9, 154.6, 154.8,
167.0; IR (film) 2935, 1738, 1591, 1552, 1452 cm-1; HRMS
(ESI) calcd for C50H52Cl2O12Na (MNaþ) 937.2734, found
937.2750.
1
CH2Cl2); H NMR (300 MHz, CDCl3) δ 1.10 (d, J = 6.2 Hz,
6H), 1.99 (br s, 2H), 2.37 (dd, J = 8.7, 13.2 Hz, 2H), 2.89 (dd,
J = 3.1, 13.2 Hz, 2H), 3.32 (s, 6H), 3.95 (m, 2H), 3.96 (s, 6H),
3.98 (s, 6H), 4.14 (s, 6H), 6.95 (s, 2H), 7.44 (s, 2H); 13C NMR
(125 MHz, CDCl3) δ 23.6, 41.2, 52.8, 55.7, 62.1, 62.9, 67.4,
100.6, 119.9, 120.5, 125.2, 128.5, 130.4, 131.6, 151.7, 153.5,
156.3, 167.6; IR (film) 3313, 2950, 1730, 1591, 1498, 1444
cm-1; HRMS (ES) calcd for C36H42O12Na (MNaþ) 689.2572,
found 689.2563.
(M)-Dimethyl
7,70-Bis((S)-2-hydroxypropyl)-2,20,4,40,6,60-
hexamethoxy-1,10-binaphthyl-3,30-dicarboxylate (30b). The ep-
oxide-opening was carried out according to the general proce-
dure with iodo substrate 33 (475 mg, 0.592 mmol) and i-PrMgBr
(1 M in THF, 1.8 mL, 1.8 mmol) in THF (7.0 mL) at -78 °C and
CuI (113 mg, 0.592 mmol) in THF (4.0 mL) and (S)-propylene
oxide (166 μL, 2.37 mmol). The material was chromatographed
(SiO2, 50% EtOAc/hexanes). Product 30b was obtained diaster-
eomerically pure as a white foam (292 mg, 74%): [R]2D0 -61.4 (c
0.35, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 1.04 (d, J = 6.2
Hz, 6H), 2.04 (br s, 2H), 2.66 (dd, J = 7.5, 13.5 Hz, 2H), 2.71
(dd, J = 4.6, 13.5 Hz, 2H), 3.32 (s, 6H), 3.88 (m, 2H), 3.97
An oven-dried microwave tube with a crimp top and Teflon sep-
tum containing a stirbar was charged with aryl halide (M,R,R)-
bischloride (120 mg, 0.13 mmol) and KOH (44 mg, 0.79 mmol).
In an inert atmosphere box, the substrate-containing microwave
tube was charged with Pd2dba3 (18 mg, 0.020 mmol) and
J. Org. Chem. Vol. 75, No. 1, 2010 41

Morgan et al.
JOCArticle
Xphos(t-Bu) ligand (33 mg, 0.79 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 (1.7 mL) and deionized
water (1.2 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 (90 °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 (2.5 mL) and treated
with BnBr (300 μL, 2.6 mmol) and NaH (95%, 70 mg, 2.6 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 (M,R,R)-74 as a yellow resin (120
mg, 86% yield): [R]D20 -29.5 (c 0.3, CH2Cl2, >99% ee); 1H
NMR (300 MHz, CDCl3) δ 1.02 (d, J = 6.1 Hz, 6H), 2.50 (dd,
J = 6.6, 13.3 Hz, 2H), 2.99 (dd, J = 6.4, 13.2 Hz, 2H), 3.37 (s,
6H), 3.60 (m, 2H), 3.85 (s, 6H), 3.96 (s, 6H), 3.99 (s, 6H), 4.27 (d,
J = 12.1 Hz, 2H), 4.36 (d, J = 12.1 Hz, 2H), 5.02 (d, J = 10.0
Hz, 2H), 5.06 (d, J = 10.0 Hz, 2H), 6.93 (s, 2H), 7.07 (m, 4H),
7.18 (m, 6H), 7.40 (m, 6H), 7.61 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 19.9, 38.2, 52.7, 61.4, 61.9, 64.5, 70.7, 75.4, 76.9, 120.5,
120.6, 123.1, 124.0, 127.5, 127.6, 128.1, 128.4, 128.6, 129.0,
133.4, 135.4, 138.0, 139.1, 146.6, 150.5, 152.3, 154.3, 167.5; IR
(film) 2935, 1738, 1591, 1452 cm-1; HRMS (ESI) calcd for
C64H66O14Na (MNaþ) 1081.4350, found 1081.4380.
(M)-Dimethyl 5,50-Bis(benzyloxy)-7,70-bis((S)-2-(benzyloxy)-
propyl)-2,20,4,40,6,60-hexamethoxy-1,10-binaphthyl-3,30-dicarb-
oxylate ((M,S,S)-74). (M,S,S)-Bischloride was prepared in the
same manner as diastereomer (M,R,R)-bischloride and was
obtained as a yellow resin (215 mg, 99%): [R]2D0 -20.0 (c 0.15,
CH2Cl2, >99% ee); 1H NMR (500 MHz, CDCl3) δ 0.94 (d, J =
6.1 Hz, 6H), 2.57 (dd, J = 6.3, 13.6 Hz, 2H), 2.81 (dd, J = 6.8,
13.6 Hz, 2H), 3.31 (s, 6H), 3.68 (m, 2H), 3.84 (s, 6H), 3.98 (s, 6H),
4.02 (s, 6H), 4.22 (d, J = 12.0 Hz, 2H), 4.35 (d, J = 12.0 Hz, 2H),
6.95 (s, 2H), 7.03 (m, 4H), 7.19 (m, 6H); 13C NMR (125 MHz,
CDCl3) δ 19.8, 38.9, 52.9, 60.9, 61.9, 64.7, 70.7, 74.7, 120.6,
122.5, 122.7, 124.5, 127.4, 127.5, 127.6, 128.4, 133.8, 135.1,
138.8, 153.1, 154.4, 154.8, 166.9; IR (film) 2935, 1738, 1591,
1552, 1452 cm-1; HRMS (ESI) calcd for C50H52Cl2O12Na
(MNaþ) 937.2734, found 937.2726.
Bisbenzyl ether (M,S,S)-74 was prepared in the same manner
as diastereomer (M,R,R)-74 and was obtained as a yellow resin
(182 mg, 77%): [R]D20 -22.0 (c 0.25, CH2Cl2, >99% ee); 1H
NMR (360 MHz, CDCl3 δ 0.96 (d, J = 6.1 Hz, 6H), 2.56 (dd,
J = 6.3, 13.3 Hz, 2H), 2.85 (dd, J = 6.7, 13.3 Hz, 2H), 3.35 (s,
6H), 3.67 (m, 2H), 3.89 (s, 6H), 3.99 (s, 6H), 4.03 (s, 6H), 4.28 (d,
J = 12.1 Hz, 2H), 4.38 (d, J = 12.1 Hz, 2H), 5.01 (d, J = 9.9 Hz,
2H), 5.05 (d, J = 9.9 Hz, 2H), 6.86 (s, 2H), 7.05 (m, 4H), 7.19 (m,
6H), 7.37 (m, 2H), 7.44 (m, 4H), 7.61 (m, 4H); 13C NMR (125
MHz, (CD3)2CO) δ 20.0, 39.1, 52.6, 61.5, 61.8, 64.5, 70.7, 75.0,
77.3, 120.8, 121.4, 124.1, 124.8, 127.8, 128.1, 128.7, 128.8, 129.2,
129.4, 134.0, 136.1, 138.7, 140.2, 147.0, 151.2, 153.1, 154.6,
167.3; IR (film) 2943, 1738, 1591, 1452 cm-1; HRMS (ESI)
calcd for C64H67O14 (MHþ) 1059.4531, found 1059.4524.
(M)-5,50-Bis(benzyloxy)-7,70-bis((R)-2-(benzyloxy)propyl)-2,
20,4,40,6,60-hexamethoxy-1,10-binaphthyl ((M,R,R)-75). To a
chilled (0 °C) solution of (M,R,R)-74 (50 mg, 0.047 mmol) in
toluene (4 mL) under argon was added DIBALH (1 M in
hexanes, 0.4 mL, 0.40 mmol). 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
and dried (Na2SO4), and the solvent was evaporated to yield a
yellow resin, which was carried on to the next step without
further purification.
To a solution of the bisbenzyl alcohol in EtOAc (2.5 mL) was
added 2-iodoxybenzoic acid (112 mg, 0.40 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 a yellow oil, which was carried on to the next step without
further purification.
The bisaldehyde in diglyme (3 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 (92 mg, 0.0992 mmol). The aldehyde
solution was added dropwise via 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 (M,R,R)-75 as a yellow resin
(33 mg, 75%): [R]D20 -10 (c 0.25, CH2Cl2, >99% ee); 1H NMR
(500 MHz, CDCl3) δ 1.03 (d, J = 6.1 Hz, 6H), 2.41 (dd, J = 7.3,
13.4 Hz, 2H), 3.06 (dd, J = 5.8, 13.3 Hz, 2H), 3.64 (m, 2H), 3.67
(s, 6H), 3.89 (s, 6H), 3.99 (s, 6H), 4.33 (d, J = 12.0 Hz, 2H), 4.39
(d, J = 12.0 Hz, 2H), 5.06 (d, J = 10.1 Hz, 2H), 5.09 (d, J = 10.1
Hz, 2H), 6.75 (s, 2H), 6.80 (s, 2H), 7.17 (m, 4H), 7.21 (m, 6H),
7.37 (m, 2H), 7.45 (m, 4H), 7.62 (m, 4H); 13C NMR (125 MHz,
(CD3)2CO) δ 20.0, 38.7, 56.3, 56.7, 61.3, 70.8, 75.7, 76.4, 96.5,
112.7, 117.2, 123.7, 127.8, 128.1, 128.2, 128.8, 128.9, 129.0,
134.1, 134.4, 139.8, 140.6, 148.1, 149.2, 155.8, 157.9; IR (film)
2927, 2858, 1645, 1591, 1460, 1336, 1259, 1205 cm-1; HRMS
(ES) calcd for C60H63O10 (MHþ) 943.4421, found 943.4413.
(M)-5,50-Bis(benzyloxy)-7,70-bis((S)-2-(benzyloxy)propyl)-2,
20,4,40,6,60-hexamethoxy-1,10-binaphthyl ((M,S,S)-75). Com-
pound (M,S,S)-75 was prepared in the same manner as diaster-
eomer (M,R,R)-75 and was obtained as a yellow resin (80 mg,
1
90%): [R]2D0 -6.0 (c 0.25, CH2Cl2, >99% ee); H NMR (500
MHz, (CD3)2CO) δ 0.96 (d, J = 6.1 Hz, 6H), 2.56 (dd, J = 6.0,
13.5 Hz, 2H), 2.76 (dd, J = 6.7, 13.5 Hz, 2H), 3.64 (m, 2H), 3.67
(s, 6H), 3.83 (s, 6H), 4.02 (s, 6H), 4.26 (d, J = 12.2 Hz, 2H), 4.35
(d, J = 12.2 Hz, 2H), 4.99 (d, J = 10.1 Hz, 2H), 5.03 (d, J = 10.1
Hz, 2H), 6.82 (s, 2H), 6.97 (s, 2H), 7.09 (m, 4H), 7.18 (m, 6H),
7.36 (m, 2H), 7.45 (m, 4H), 7.64 (m, 4H); 13C NMR (125 MHz,
(CD3)2CO) δ 20.1, 38.9, 56.3, 56.8, 61.2, 70.8, 75.6, 76.4, 96.7,
112.8, 117.2, 123.7, 127.7, 128.2, 128.3, 128.8, 128.9, 129.0,
134.1, 134.4, 139.8, 140.4, 18.1, 149.2, 155.9, 157.8; IR (film)
2927, 2858, 1730, 1591, 1460, 1336, 1259, 1205 cm-1; HRMS
(ES) calcd for C60H63O10 (MHþ) 943.4421, found 943.4431.
(þ)-Phleichrome (ent-2). To a solution of (M,R,R)-75 (10 mg,
0.011 mmol) in THF (0.7 mL) and MeOH (0.7 mL) was added
10% Pd/C (15 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. Concentration yielded an unstable brown oil which was
used directly in the next reaction.
To a solution of the binaphthol in anhydrous THF (1 mL) was
added MnO2 (20 mg, 0.23 mmol). After completion as judged by
TLC, the mixture was diluted with EtOAc, filtered through
Celite, and concentrated to yield the perylenequinone. Purifica-
tion was accomplished by chromatography (5% MeOH/
CH2Cl2) to yield the perylenequinone as red resin (5 mg, 82%).
To a solution of the above perylenequinone product (1.5 mg,
0.0026 mmol) in THF (1 mL) under an argon atmosphere was
added a solution of MgI2 in Et2O (0.07 M, 80 μL, 0.0055 mmol).
The dark purple mixture was stirred for 10 min (until the mixture
turned from purple to black), diluted with EtOAc, washed with
42 J. Org. Chem. Vol. 75, No. 1, 2010

Morgan et al.
JOCArticle
saturatedaq NH4Cl, and dried (Na2SO4). Concentration yielded a
red residue, which was chromatographed (5% MeOH/CH2Cl2) to
yield product ent-2 as a red resin (1 mg, 70%): see the Supporting
Information for the CD spectrum; 1H NMR (500 MHz, CDCl3) δ
0.54 (d, J = 6.1 Hz, 6H), 2.96 (dd, J = 6.3, 12.7 Hz, 2H), 3.42 (m,
2H), 3.61 (dd, J = 6.6, 12.7 Hz, 2H), 4.07 (s, 6H), 4.22 (s, 6H), 6.59
(s, 2H), 15.8 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 23.4, 42.4,
56.7, 61.7, 68.7, 101.7, 106.1, 117.3, 126.4, 127.3, 135.5, 152.0,
167.0, 173.7, 177.8; IR (film) 3298, 2927, 2858, 1730, 1607, 1452,
1413, 1375, 1267, 1220 cm-1; HRMS (ES) calcd for C30H29O10
(MH-) 549.1761, found 549.1776.
(þ)-Calphostin D (ent-1d). The perylenequinone ent-1d was
prepared in the same manner as diastereomer ent-2 and was
obtained as a red resin (1.3 mg, 57%): see the Supporting
Information for the CD spectrum; 1H NMR (300 MHz, CDCl3)
δ 0.94 (d, J = 6.1 Hz, 6H), 2.92 (dd, J = 8.1 Hz, 13.3 Hz, 2H),
3.54 (dd, J = 3.3 Hz, 13.4 Hz, 2H), 3.74 (m, 2H), 4.05 (s, 6H),
4.22 (s, 6H), 6.54 (s, 2H), 15.9 (s, 2H); 13C NMR (125 MHz,
CDCl3) δ 23.8, 42.5, 56.6, 61.5, 69.3, 101.8, 106.5, 117.9, 125.8,
127.9, 136.3, 151.4, 167.2, 172.4, 179.1; IR (film) 3375, 2927,
2858, 1607, 1522, 1452, 1413, 1282, 1244 cm-1; HRMS (ES)
calcd for C30H30O10Na (MNaþ) 573.1737, found 573.1757.
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 thank Dr.
Joseph Kozlowski for helpful discussions regarding the
epoxide alkylation chemistry. We acknowledge the work of
Michelle Clasquin in the synthesis of starting materials. We
thank 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.
J. Org. Chem. Vol. 75, No. 1, 2010 43