Total Synthesis of Aurofusarin: Studies on the Atropisomeric Stability of Bis-Naphthoquinones

Article abstract of DOI:10.1002/anie.201711535

An efficient annulation involving pyrone addition to a quinone and Dieckmann condensation was developed for rapid assembly of a γ-naphthopyrone monomeric precursor to the bis-naphthoquinone natural product aurofusarin. Dimerization was achieved through Pd

Full text of DOI:10.1002/anie.201711535

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Accepted Article
Title: Total Synthesis of Aurofusarin: Studies of the Atropisomeric
Stability of Bis-Naphthoquinones
Authors: John Porco, Chao Qi, Wenyu Wang, Kyle Reichl, and James
McNeely
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201711535
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10.1002/anie.201711535
Angewandte Chemie International Edition
COMMUNICATION
Total Synthesis of Aurofusarin: Studies of the Atropisomeric
Stability of Bis-Naphthoquinones
Chao Qi,+ Wenyu Wang,+ Kyle D. Reichl, James McNeely, and John A. Porco, Jr.*
Abstract: An efficient annulation involving pyrone addition to a
quinone and Dieckmann condensation has been developed for rapid
assembly of a γ-naphthopyrone monomeric precursor to the bis-
naphthoquinone natural product aurofusarin. Dimerization was
achieved through Pd(II)-catalyzed dehydrogenative coupling. Further
studies employing asymmetric nucleophilic epoxidation indicate that
the atropisomers of aurofusarin and derivatives are not
configurationally stable at ambient temperature.
bismurrayaquinone A (5)[7] and seminal work by Shair and
coworkers on dimeric methoxyquinone-containing natural
products,[8d] we wondered whether the atropisomers of bis-
naphthoquinones such as (1)[2] and (2) are configurationally
stable. Accordingly, we have studied the question of axial chirality
of 2 as it is crucial for the enantioselective synthesis of the
congener diaporine (4).
Retrosynthetically, we envisioned that aurofusarin (2) may
be accessed through oxidation of biaryl precursor 6 (Scheme 1).
Construction of biaryl 6 requires highly selective conditions for
oxidative dimerization, considering possible oxidation of 7 to a
naphthoquinone. We proposed that monomer 7 may be obtained
from aryl pyrone 8, a compound derived from tandem Michael
addition/Dieckmann condensation of methoxy benzoquinone 9[8]
and dienol ether 10. Compound 10 may be accessed from the
commercially available dimethyl -pyrone 11.
Naphthopyranone natural products[1] are widely found in
nature and typically possess the 1H-naphtho-[2,3-c]pyran-1-one
core structure as present in the dimer xanthomegnin (1)[2] (Figure
1). Aurofusarin (2)[3] and the bis-epoxyquinol diaporine (4),[4] an
inhibitor of macrophage differentiation which induces conversion
from the M2 ("repair-type") to the M1 (“kill-type”) phenotype, are
likely derived from the monomeric naphtho-γ-pyrone rubrofusarin
(3).[5] Such γ-naphthopyranone scaffolds are difficult to access
and there are few reported syntheses to date. For example,
rubrofusarin (3) was previously synthesized in 14 steps in low
yield[6] and a formal synthesis of 1 was achieved from a
monomeric precursor (semi-vioxanthin).[2]
Scheme 1. Retrosynthetic analysis for aurofusarin.
To prepare substituted pyrone 8, we envisioned that
treatment of 11 with trimethylsilyl triflate (TMSOTf) should afford
a siloxypyrylium intermediate[9] which may be deprotonated under
basic conditions. Accordingly, 11 was consecutively treated with
TMSOTf and 2,6-lutidine, which was followed by addition of
quinone 9.[10] Acidic conditions for workup (aq. HCl) were found to
be crucial for fomation of 8, as a basic workup using tetra-N-
butylammonium fluoride (TBAF) afforded an undesired
benzofuran product[11] (Scheme 2). To overcome difficulties
encountered in the monomethylation of 8, -pyrone 12 was
synthesized via a double-methylation/selective demethylation
sequence and was further converted to MOM ether 13. We next
evaluated Dieckmann cyclization of 13. To our delight, use of
lithium diisopropylamide (LDA) as base produced a 30% yield of
the desired product 14 which was further improved to 77% using
degassed solvent. Methylation of 14 with Cs2CO3/dimethyl sulfate
(Me2SO4) in degassed acetone led to 15 which was treated with
trifluoroacetic acid (TFA) in CH2Cl2 to afford monomer 16 for
dimerization studies.
Figure 1. Aurofusarin (2) and related dimeric natural products.
Herein, we report
a concise synthesis of the γ-
naphthopyranone monomeric unit and its Pd-catalyzed
dehydrogenative dimerization to a biaryl precursor for aurofusarin.
Based on the work of Thomson and coworkers concerning
[*]
[+]
Dr. C. Qi,[+] Dr. W. Wang,[+] Dr. K. D. Reichl, Dr. J. McNeely, Prof.
Dr. J. A. Porco Jr.
Department of Chemistry and Center for Molecular Discovery (BU-
CMD), Boston University, Boston, Massachusetts 02215
E-mail: porco@bu.edu
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201711535
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COMMUNICATION
(±)-17 (Table 1, entry 1). However, to achieve full conversion, a
stoichiometric amount of Pd(OAc)2 was required. Encouraged by
these results, we evaluated a number of ligands to facilitate
catalyst turnover. Yu and coworkers[15] have demonstrated that
monoprotected amino acids can be utilized as chiral ligands in
asymmetric C−H bond activation. Accordingly, we evaluated use
of monoprotected amino acids with Pd(OAc)2. Treatment of 16
with catalytic Pd(OAc)2 and N-acetyl-L-leucine under aerobic
conditions led to dimer (±)-17 after heating at 70 ºC for 4 h (entry
2). The structure of (±)-17 was unambiguously confirmed by X-ray
crystallographic analysis.[16] Evaluation of solvents showed that
anhydrous DMSO provided optimal results while non-coordinating
solvents such as DCE (entry 3) led to lower reactivity. Other
monoprotected amino acid ligands were found to be less effective
for the transformation (entries 5-6). Among chiral amino acid
ligands evaluated, we unfortunately did not observe
atropselectivity for the biaryl product 17.[17]
Scheme 2. Synthesis of a 9-hydroxy rubrofusarin derivative.
Inspired by studies on the biosynthesis of aurofusarin in
which dimerization was shown to be catalyzed by Gip1, a copper-
containing laccase enzyme,[12] we wished to mimic this process
using metal-mediated, oxidative conditions. Accordingly, we
initiated dimerization studies using copper salts with diamine
ligands[13a] which have been widely used in biaryl couplings.
However, in general conditions employing single electron
oxidation metal catalysts such as NH4VO3, FeCl3, SnCl4 and
Attention was next turned to the synthesis of aurofusarin (2)
(Scheme 3). Treatment of (±)-17 with ceric ammonium nitrate
(CAN) led to formation of bis-naphthoquinone 18 (88% yield).
Synthesis of aurofusarin (2) was achieved on a gram scale in 78%
yield by selective demethylation of 18 using BBr3. To study the
atropisomeric stability of the bis-naphthoquinone moiety, a gram-
scale synthesis of (±)-17 (cf. Table 1) was achieved and the
compound subjected to deracemization using Cu(I)/(+)-
sparteine.[18] Optimal conditions involved in situ generation of a
stoichiometric copper(II)/sparteine complex which led to 71%
AgOTFA only led to the production of
naphthoquinone product.[11,13]
a
monomeric
25
mass recovery and (–)-17 in 95% ee ([α]d = –45°, c = 0.1,
Table 1. Dehydrogenative coupling of monomer 16.
CH2Cl2) (Scheme 4). Determination of the absolute configuration
of (–)-17 was attempted using X-ray crystallography, but only a
chiral, racemic crystal of (±)-17 was obtained. Presumably,
photoracemization of (–)-17 (max = 405 nm) may occur during
crystallization via excited state intramolecular proton transfer.[11,19]
entry
ligand
none
Ac-L-Leu-OH DMSO
Ac-L-Leu-OH
Ac-L-Leu-OH
Boc-L-Pro-OH DMSO
Boc-L-Val-OH DMSO
solvent
DMSO
temp.
70 ºC
70 ºC
70 ºC
70 ºC
70 ºC
70 ºC
time
20 h
4 h
24 h
4 h
yield[a] (conv.[b]
)
1
2
3
4
5
6
23% (30%)
77% (100%)
35% (47%)
decomposition
28% (41%)
Scheme 4. Deracemization of biaryl 17.
DCE
DMA
14 h
12 h
To determine whether the atropisomers of bis-
naphthoquinone 18 are configurationally stable, (–)-17 was
oxidized with CAN (Scheme 5a). Analytical chiral HPLC analysis
of the resulting bis-quinone 18 did not reveal enantiomer
separation, and, additionally, no optical rotation was observed.[11]
Accordingly, further derivatization of 18 to epoxide 19 was
performed. Epoxidation by NaOCl afforded bis-epoxide 19 as a
single diastereomer. However, from chiral HPLC analysis,
compound 19 derived from (–)-17 was racemic which further
supports that the atropisomers of 18 are likely rapidly
interconverting. The relative stereochemistry of bis-epoxide 19
was further studied by the model reaction shown in Scheme 5b.
Model bis-quinone 20[20] was treated with NaOCl in CH3CN to
afford epoxide 22 as a single diastereomer in 78% yield and the
relative stereochemistry of 22 was determined by X-ray
crystallographic analysis.[16] From this model reaction, it appears
that the cis-relationship of the epoxides in 22 is derived from
48% (81%)
[a] Isolated yield of purified (±)-17. [b] Conversion as determined by 1H NMR
integration.
Scheme 3. Synthesis of aurofusarin from the protected dimer (±)-18.
We reasoned that the electron-rich substrate 16 may require
milder oxidative coupling conditions which prompted our
investigation
of
palladium-mediated,
dehydrogenative
coupling.[14] After considerable experimentation, we found that
treatment of 16 with Pd(OAc)2 (10 mol%) in DMSO afforded dimer
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10.1002/anie.201711535
Angewandte Chemie International Edition
COMMUNICATION
epoxidations anti to the methoxy groups in the bisected bis-
quinone conformer 21.
related contributing zwitterionic structures and deviation of the
quinone carbonyl group from planarity may be relevant for
xanthomegnin 1 and aurofusarin 2,[11] a comparison of the X-ray
structures of 1 and 5 along with a DFT model of 2 (Figure 2) also
shows shortening of the C-OCH3 bond of 1 and 2 (1.342 Å and
1.337 Å) in comparison to the C-CH3 bond length of 5 (1.479 Å).
This bond shortening appears to be a factor in lowering the barrier
for atropisomerization of 2. The calculated barrier for 18 (24.6
24]
kcal/mol, B3LYP/6-31G(d))[11,
is also similar to the energy
barrier for interconversion of atropisomers (22.2 kcal/mol)
suggested by Ōki.[25]
Scheme 5. Synthesis of bis-epoxide 22 and a model study for epoxidation.
Figure 2. Bond length analysis of the X-ray structures of 1 and 5 along with a
DFT model of 2.
Based on the reactivity observed, we envisioned that
asymmetric epoxidation of 18 derived from (±)-17 could be utilized
to further validate our hypothesis for atropisomeric instability of
18.[20] Asymmetric nucleophilic epoxidations of enones have been
extensively studied,[21] but are generally conducted on simple
monomeric quinones.[22] Accordingly, a series of phase transfer
catalysts (PTC’s) were examined which showed that cinchonine-
derived catalysts 23 and the corresponding dimeric cinchonine
catalyst 24 provided up to 75% ee. We ultimately identified the
Maruoka phase transfer catalyst 25[23] (Scheme 7) as a suitable
catalyst for asymmetric epoxidation which afforded bis-epoxide
()-19 in 62% yield and 97% ee as a single diastereomer. The
absolute configuration of ()-19 was determined by comparison of
the experimental electronic circular dichroism (ECD) spectrum
with calculated spectra.[11] In this reaction, four stereocenters are
formed in high selectivity.
In summary, we have developed an efficient annulation
involving pyrone addition to a quinone for rapid assembly of a γ-
naphthopyrone monomer enroute to the natural product
aurofusarin. Dimerization of the γ-naphthopyrone was achieved
through Pd(II)-mediated dehydrogenative coupling wherein a
simple mono-protected amino acid was found to be a suitable
ligand for a catalytic process. In addition asymmetric nucleophilic
epoxidation of aurofusarin derivative 18 supports the hypothesis
that the atropisomers of bis-methoxy naphthoquinones such as
aurofusarin are not configurationally stable. Extension of the
methodology to access an enantioenriched bis-epoxide
intermediate for the synthesis of diaporine is currently in progress
and will be reported in due course.
Acknowledgements
We thank the National Institutes of Health (R35 GM118173) for
research support and Dr. Jeffrey Bacon (Boston University) for X-
ray crystal structures. K.D.R. is supported by a postdoctoral
fellowship (PF-16-235-01-CDD) from the American Cancer
Society. Work at the BU-CMD was supported by NIH
R24GM111625. We thank Profs. Regan Thomson (Northwestern),
Jin-Quan Yu (Scripps Research Institute) and Mr. Marcus Farmer
(Scripps Research Institute) for helpful discussions. We thank
Prof. Rasmus Frandsen (Technical University of Denmark) for
providing crude fungal extracts of Fusarium graminearum.
Scheme 6. Dynamic kinetic resolution in asymmetric nucleophilic epoxidation.
Keywords: naphthoquinone • dehydrogenative coupling • bis-
quinone • axial chirality • enantioselective epoxidation
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of the methoxyquinone-containing natural product hibarimicinone
which involves cross-conjugated resonance structures.[8d] While
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COMMUNICATION
Layout 2:
COMMUNICATION
Chao Qi+, Wenyu Wang+, Kyle D. Reichl,
James McNeely, and John A. Porco, Jr.*
Page No. – Page No.
Total Synthesis of Aurofusarin:
Studies of the Atropisomeric Stability
of Bis-Naphthoquinones
A rapid synthesis of a γ-naphthopyrone precursor to the natural product aurofusarin
has been achieved using a Michael addition/Dieckmann sequence. Pd(II)-catalyzed
dehydrogenative coupling followed by selective demethylation afforded the bis-
naphthoquinone aurofusarin. Further studies showed that the atropisomers of bis-
methoxynaphthoquinones such as aurofusarin and derivatives are not
configurationally stable.
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