Total Synthesis of Benzofuran-Based Aspergillusene B via Halogenative Aromatization of Enones

Article abstract of DOI:10.1021/acs.orglett.0c01259

A novel "non-aromatic pool" synthetic strategy for the synthesis of benzofuran-based natural products via oxidative haloaromatization of enones is reported. This approach is successfully applied in the first total synthesis of the natural product aspergil

Full text of DOI:10.1021/acs.orglett.0c01259

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Letter
Total Synthesis of Benzofuran-Based Aspergillusene B via
Halogenative Aromatization of Enones
Gennadii A. Grabovyi, Aisha Bhatti, and Justin T. Mohr*
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ABSTRACT: A novel “non-aromatic pool” synthetic strategy for
the synthesis of benzofuran-based natural products via oxidative
haloaromatization of enones is reported. This approach is
successfully applied in the first total synthesis of the natural
product aspergillusene B. In comparison with a separately executed
“aromatic pool” synthesis, the “non-aromatic pool” protocol
demonstrates equivalent efficiency but offers a much higher degree
of modularity.
olysubstituted benzofurans represent a common structural
was developed by Herndon in 2003 using a modified Wulff−
P
motif in naturally occurring medicines.1a Members of this
̈
Dotz reaction between a chromium carbenoid and a protected
dienylalkyne (Scheme 1b).3d
family express a diverse range of biological activities, including
antioxidant (1, 2),1b,c anti-inflammatory (3, 4),1d anticancer
(5),1e−i antidiabetic (6),1j antifungal,1k antimalarial,1l and
antibacterial1m,n profiles (Figure 1). As a result, many synthetic
Recently, Tang reported a highly convergent approach to a
series of benzofuran-containing natural products via Rh-
catalyzed carbonylative benzannulation (Scheme 1c).3e In a
creative alternative strategy combining oxidative and acid-
mediated transformations en route to propolisbenzofuran B,
Thomson employed an oxiditave enol coupling to generate a
1,4-diketone poised for a Paal−Knorr-type furan synthesis
(Scheme 1d).3f Collectively, these “non-aromatic” approaches
toward benzofurans add great value as complementary
alternatives to “aromatic pool” methods and offer a greater
degree of strategic freedom.
Because of the scarcity of general examples for constructing
benzofuran moieties from non-aromatic precursors, we sought
to develop an aromatization/annulation sequence as an
efficient entry into the benzofuran class. This strategy was
based on enone aromatization methodology developed in our
group using readily available non-aromatic vinylogous esters.4
Reasoning that the structural homology within the array of
benzofuran-containing targets would facilitate a unified
strategic approach, we selected aspergillusene B (1)1b as a
model case for our synthetic development. The deceptively
simple structural appearance of this target belies the embedded
synthetic challenges of regiocontrol necessary to construct the
core and the difficulty of introducing two different aliphatic
groups at the 2- and 3-positions of the parent heterocycle.
Figure 1. Benzofuran-based natural products.
strategies have been developed to access the substituted
benzofuran rings in such natural products. The majority of
these reported solutions are based on modification of existing
aromatic cores toward fully elaborated benzofurans.2 Only a
few alternative approaches have been realized in which the
arene is obtained efficiently from a non-aromatic precursor.3
However, this synthetic approach provides additional synthetic
flexibility since it allows a greater array of functionalization
techniques than classical methods of arene decoration, such
SEAr and SNAr, which have well-established limitations.
Received: April 9, 2020
Among the aromatization methods for non-aromatic pool-
based synthesis, the most common is oxidation of electron-rich
systems with quinones (e.g., DDQ), as exemplified in total
syntheses of furoventalene,3a lanceolatin B,3b pongamol,3b and
corsifuran C3c (Scheme 1a). An elegant synthesis of egonol
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derivative 7 as a suitable substrate for the endgame metal
catalysis. We expected the specifically functionalized arene to
be readily prepared via our oxidative aromatization method-
ology4,5 applied to vinylogous ester 8. This non-aromatic
monocycle could be constructed from commercially available
cyclohexane-1,3-dione (9) and known 2° allylic alcohol 10.6
We note that this approach is highly modular since analogues
of alcohol 10 could readily vary the 2- and 3-substituents in the
target and the established reactivity of vinylogous esters,7 such
as intermediate 8, could be leveraged to introduce functionality
around the benzene ring system embedded in the target
molecule.
Scheme 1. “Non-aromatic” Approaches to Benzofurans
We commenced our synthesis by attempting esterification of
cyclohexane-1,3-dione (9) with allylic alcohol 10,6 which
proved surprisingly challenging (Scheme 3). At first, diketone
Scheme 3. Preparation of Key Aromatic Intermediates
With these potential pitfalls in mind, we sought a modular
strategy that would confront these problems directly.
Our synthetic approach toward aspergillusene B (Scheme 2)
is founded on our recently developed regioselective enone
9 was converted into the corresponding known vinylogous
mesylate8 and tosylate9 (compounds 11 and 12) under basic
conditions on a multigram scale in excellent yield. Unfortu-
nately, treatment of either of these materials with 2° allylic
alcohol 10 under various basic conditions did not afford the
substitution product. An attempt to overcome this challenge by
forming the vinylogous mesylate in situ10 followed by
nucleophilic displacement with alcohol 10 did not result in
any detectable ester 8. Direct acid-catalyzed condensation
between cyclohexadione 9 and 2° allylic alcohol 10 yielded the
desired intermediate 8, albeit in only 23% yield on a 1 mmol
scale. This yield was reduced to 14% on a larger scale (5
mmol). Seeking further improvements, we examined a
Mitsunobu displacement process to reverse the polarity of
the coupling. Thus, treatment of a DIAD/Ph3P mixture with a
solution of diketone 9 and alcohol 10 in THF furnished the
desired vinylogous ester 8 in a much improved 58% yield. The
efficiency of this reaction was not affected by changes in the
alcohol/diketone ratio, temperature, or choice of solvent; all of
the performed trials afforded 8 in yields of ∼60%. Most
importantly, the yield was maintained at this level on a larger
scale, allowing reasonable throughput of material to further the
synthesis.
Scheme 2. Retrosynthetic Analysis of the “Non-aromatic
Pool” Synthesis of Aspergillusene B via Oxidative
Aromatization
aromatization/halogenation methodology4 that has already
proven to be a powerful synthetic tool in the total synthesis of
a family of phenolic natural products.5 In particular, we
envisioned the benzoic acid moiety to be available via a metal-
catalyzed carboxylation protocol from the corresponding aryl
triflate, while the furan ring was predicted to be available via an
intramolecular 5-exo-trig Heck-type cyclization (with concom-
itant alkene isomerization) between an aryl halide and a
tethered allylic ether. Thus, we targeted the resorcinol
With good quantities of vinylogous ester 8 in hand, we
continued the synthesis of 1 with exploration of the key
oxidative aromatization/bromination reaction (Scheme 3). To
our delight, the established reaction protocol (LiHMDS,
HMPA, p-TsBr) secured a 61% yield of the desired γ-
B
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brominated arene product 13 via putative γ,γ-dibromoenone
14. We also obtained a 23% yield of the desbromo congener
15, presumably as a result of premature elimination from γ-
monobromoenone 16. Screening of various Br+ sources
(including NBS, DBDMH, Me3PhNBr3, Br2, and DABCO·
2Br2) and other reaction parameters did not improve efficiency
or selectivity in this case. Predicting that the free phenol
functionality might be problematic, two derivatives were
prepared: aryl triflate 7 and silyl ether 17.
Bu)3)2 catalyst reported for related aromatic systems.4
Unfortunately, we were not able to improve this set of
conditions and therefore continued testing of other parame-
ters. We were pleased to find that Larock’s intramolecular
cyclization protocol14 employing Jeffrey’s Pd catalyst system
and sodium formate as a reducing agent resulted in very clean
conversion of aryl bromide 13 into the desired benzofuran 22.
Triflation of phenol 22 supplied benzofuran 20 in high yield.
Unfortunately, subsequent cyanation attempts with Zn(CN)2
and Pd catalyst11 again failed, with complete recovery of
unchanged starting material. Fortunately, aryl triflate 20
proved to be reactive under recently developed carboxylation
conditions reported by Peng and Wu.15 Interestingly, in the
initial disclosure only the parent aryl triflate (PhOTf) was
reported, and our success in a more complex case suggests that
the scope of this transformation may be significantly broader.
However, we were surprised to discover that the desired
carboxylation of aryl triflate 20 is highly sensitive to
temperature. Moderate heating is required since at higher
temperature competing hydrodetriflation prevails, delivering
benzofuran 23 exclusively. This optimization led to an efficient
end to the first total synthesis of aspergillusene B (1) via a
“non-aromatic pool” approach.
With both resorcylic intermediates 7 and 17 in hand, we
began exploring the intramolecular Heck-type cyclization
(Scheme 4). We first attempted cyanation of the aryl triflate,
Scheme 4. Intramolecular Heck Cyclization with
Resorcinols
To benchmark the success of our aromatization strategy, we
proposed an alternative “aromatic pool” route to assemble this
molecule. To this end, 3-hydroxybenzoic acid (24) was
converted to known bromoarene 2516 in moderate yield,
which was then esterified to furnish known benzoate derivative
2617 (Scheme 6). The aryl bromide was then coupled with 2°
a fragment that would later be converted into the requisite
carboxylic acid in the target molecule. Unfortunately, Pd-
catalyzed conditions11 with Zn(CN)2 did not deliver the
desired benzonitrile 18 or the benzofuran 19 that might result
from cascade cyclization with or without cyanation of aryl
triflate 7. Disappointingly, neither aryl silyl ether 17 nor aryl
triflate 7 participated in Heck cyclization under several metal-
catalyzed reaction conditions,12,13 and no benzofuran products
(20 or 21) were isolated in any explored case. Attempts
involving triflate 7 returned unchanged starting material, and
those utilizing silyl ether 17 led to a complex mixture with no
detectable cyclization.
Scheme 6. “Aromatic Pool” Total Synthesis of
Aspergillusene B
Confronted with the difficulty of benzofuran construction,
we took one step back and started exploring the feasibility of
Pd-catalyzed reactions with free phenol 13 (Scheme 5).
Although we anticipated that this electron-rich arene would
resist oxidative addition, we were delighted to discover that
benzofuran 22 was observed under conditions with a Pd(P(t-
allylic alcohol 10 under the Mitsunobu protocol that we
developed for vinylogous ester formation (see Scheme 3),
efficiently yielding aryl ether 27. With full knowledge of
suitable Heck cyclization conditions from our already
completed synthesis, brominated arene 27 was readily
transformed to benzofuran 28 with the Jeffrey-type Pd-based
system14 in good yield. The “aromatic pool” total synthesis of 1
was then completed through saponification with aqueous
LiOH in THF.
Scheme 5. Completion of the “Non-aromatic Pool”
Synthesis of Aspergillusene B
Having developed two different approaches to the
benzofuran-based natural product aspergillusene B (1), we
conclude that the syntheses offer comparable efficiency in
terms of yield and step count (Scheme 7). The non-aromatic
strategy has significant potential for diversification since
standard transformations of intermediate vinylogous ester 8
are readily incorporated, whereas the alternative “aromatic”
route relies on aromatic substitution reactions with well-
established limitations. Notably, the “non-aromatic” route does
not require protective groups. We therefore anticipate that the
C
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Scheme 7. Comparison of Aspergillusene B Total Syntheses
non-aromatic route will be better suited to analogue syn-
thesis.18
In conclusion, we have developed the first two total
syntheses of the natural product aspergillusene B (1). The
“non-aromatic” route utilizes a novel oxidative haloaromatiza-
tion of enones, is efficient and free from protecting groups, and
offers equivalent efficiency as the conventional “aromatic pool”
synthesis. The non-aromatic pool approach is poised for
analogue synthesis, which is a current pursuit in our laboratory.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01259.
Experimental procedures, characterization data, and
copies of NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
W. A. Phytochemistry 2004, 65, 3113−3118. (d) Zhang, J.; Zhang, Y.;
Zhang, Y.; Herndon, J. W. Tetrahedron 2003, 59, 5609−5616. (e) Liu,
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Thomson, R. J. Chem. Sci. 2014, 5, 1794−1798.
■
Justin T. Mohr − Department of Chemistry, University of Illinois
at Chicago, Chicago, Illinois 60607, United States;
orcid.org/0000-0002-7005-3322; Email: jtmohr@uic.edu
(4) (a) Chen, X.; Liu, X.; Martinez, J. S.; Mohr, J. T. Tetrahedron
2016, 72, 3653−3665. (b) Chen, X.; Martinez, J. S.; Mohr, J. T. Org.
Lett. 2015, 17, 378−381.
Authors
Gennadii A. Grabovyi − Department of Chemistry, University
of Illinois at Chicago, Chicago, Illinois 60607, United States
Aisha Bhatti − Department of Chemistry, University of Illinois at
Chicago, Chicago, Illinois 60607, United States
(5) Grabovyi, G. A.; Mohr, J. T. Org. Lett. 2016, 18, 5010−5013.
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(9) Blons, C.; Morin, M. S. T.; Schmid, T. E.; Vives, T.; Colombel-
Complete contact information is available at:
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Rouen, S.; Basle, O.; Reynaldo, T.; Covington, C. L.; Halbert, S.;
Cuskelly, S. N.; Bernhardt, P. V.; Williams, C. M.; Crassous, J.;
́
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Polavarapu, P. L.; Crevisy, C.; Gerard, H.; Mauduit, M. Chem. - Eur. J.
2017, 23, 7515−7525.
Notes
The authors declare no competing financial interest.
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293−295.
(11) Nguyen, S. T.; Williams, J. D.; Majgier-Baranowska, H.; Li, B.;
Neelagiri, V. R.; Kim, H.-O.; Peet, N. P. Synth. Commun. 2014, 44,
1307−1313.
ACKNOWLEDGMENTS
■
Funding was provided through startup funds from the UIC
Department of Chemistry, the National Science Foundation
(CAREER Award 1654490), and the UIC Chancellors
Undergraduate Research Award (to A.B.). We thank Dr.
Xiaohong Chen (UIC) for experimental insights and
assistance, Prof. Duncan Wardrop (UIC) for helpful
discussions, and Prof. Stephanie Cologna (UIC) and Thu
Nguyen (UIC) for experimental mass spectrometry assistance.
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