Vanadium-Catalyzed Oxidative Intramolecular Coupling of Tethered Phenols: Formation of Phenol-Dienone Products

Article abstract of DOI:10.1021/acs.orglett.0c00577

A mild and efficient method for the vanadium-catalyzed intramolecular coupling of tethered free phenols is described. The corresponding phenol-dienone products are prepared directly in good yields with low catalyst loadings. Electronically diverse tethered phenol precursors are well tolerated, and the catalytic method was effectively applied as the key step in syntheses of three natural products and a synthetically useful morphinan alkaloid precursor.

Full text of DOI:10.1021/acs.orglett.0c00577

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Letter
Vanadium-Catalyzed Oxidative Intramolecular Coupling of Tethered
Phenols: Formation of Phenol-Dienone Products
Philip H. Gilmartin and Marisa C. Kozlowski*
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ABSTRACT: A mild and efficient method for the vanadium-catalyzed intramolecular coupling of tethered free phenols is described.
The corresponding phenol-dienone products are prepared directly in good yields with low catalyst loadings. Electronically diverse
tethered phenol precursors are well tolerated, and the catalytic method was effectively applied as the key step in syntheses of three
natural products and a synthetically useful morphinan alkaloid precursor.
isphenols constitute an important class of molecules with
utility as both complex molecule precursors and bio-
Scheme 1. Intramolecular Phenol-Type Couplings
B
logically active natural products.1,2 Such biologically active
compounds often incorporate the bisphenol biaryl motif as
part of a polycyclic system (Figure 1A).3 Other phenol-
Figure 1. Compounds derived from linked phenols.
containing natural products arise from the direct oxidative
coupling of tethered free phenols to afford a phenol-dienone
motif (Figure 1B,C).4,5 Since the discovery that direct phenol
oxidation plays a critical role in the biosynthesis of such
compounds,6−8 analogous reagent-based approaches have been
of considerable interest for their potential application in the
synthesis of plant metabolites.
There are several reports on intermolecular oxidative phenol
coupling, including transition metal-mediated9−13 and electro-
chemical14,15 phenol homocoupling and cross-coupling reac-
tions. Despite this, the intramolecular coupling of tethered free
phenols for the formation of phenol-dienone products is not
well studied. Schwartz et al. disclosed one of the first examples
of this transformation, coupling propyl-tethered phenols with
stoichiometric VOCl3 in good yield (Scheme 1a).16 This work
Received: February 13, 2020
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© XXXX American Chemical Society
A

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a
with stoichiometric VOCl3 was also utilized in the formation of
N-(ethoxycarbonyl)-2-hydroxynorsalutaridine,17 an analogue
of salutaridine (B, Figure 1), a key intermediate in the
biosynthesis of morphine. In addition to V(V), phenol-dienone
products have been prepared directly from tethered free
phenols using stoichiometric Fe(III)18,19 or Tl(III)20,21 as the
oxidant. Despite success with these stoichiometric reagents,
limitations include the air sensitivity of VOCl3, the toxicity of
Tl(III), the need for a significant excess of oxidant, and
reduced yields in converting electron-neutral and electron-
deficient substrates. A catalytic variant of this direct trans-
formation using stable, easily accessible reagents would
therefore be of great utility from the perspective of atom
economy and accessing structurally diverse phenol-dienone
substrates.
An alternative approach for the formation of phenol-dienone
products proceeds via oxidation of the corresponding tethered
aryl ethers or mixed phenol/ether species, followed by
subsequent deprotection. Considerable work in this area has
shown that stoichiometric Mo(V)22 and I(III)23 are competent
in the intramolecular oxidative coupling of tethered aryl ethers.
The stoichiometric nature of the I(III)-mediated trans-
formation was addressed by Kita et al. in 2008, as they
coupled mixed tethered phenol/ethers with catalytic amounts
of aryl iodide, which is activated to I(III) by H2O2 in the
presence of trifluoroacetic acid (Scheme 1b).24 A comple-
mentary approach was also disclosed by Wang et al., wherein
they oxidized similar substrates using a catalytic system of
sodium nitrite in the presence of air and Brønsted acid
(Scheme 1c).25 While both of these reports reflect catalytic
variants of the intramolecular coupling of tethered arenes, both
require the use of electron-rich substrates. Additionally, both
approaches utilize mixed tethered phenol/ether substrates,
which precludes the direct formation of the phenol-dienone
motif. Deprotection of aryl ethers to generate the phenol-
dienones can be challenging in the presence of the newly
formed dienone motif, which is sensitive to acidic and reducing
conditions. The orthogonality of protecting groups also
becomes a challenge when multiple ether moieties are present
in the ether-dienone product.
Table 1. Optimization of Reaction Conditions
b
entry
X
loading (mol %)
time (h)
2a (%)
c
1
OEt
OEt
OEt
OEt
Ot-Bu
F
OCH(CF3)2
OCH(CF3)2
OCH(CF3)2
20
20
20
10
10
10
10
10
5
24
24
48
18
18
18
18
24
24
<5
56
(89)
2
3
4
5
6
7
8
9
d
24
12
<5
70
d
(80)
31
a
Reaction conditions: 1a (0.10 mmol), V (10−20 mol %), HFIP (0.1
b
M), O2 (1 atm) for 18−48 h. Determined by 1H NMR spectroscopy
c
with an internal standard (4,4′-di-tert-butylbiphenyl). DCE as the
d
solvent. Isolated yield.
1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) was identified as a
suitable solvent for this reaction because of its unique ability to
stabilize electron-deficient reaction intermediates.27 The
reaction in HFIP showed good conversion to 2a over 24 h
(Table 1, entry 2), with full conversion observed in 48 h
affording an isolated yield of 89% (Table 1, entry 3).
Interestingly, only para−para coupled products were observed
in this reaction, despite the fact that prior work with this
catalyst uncovered a preference for ortho coupling.12 We
hypothesize that the ortho−para coupled product is not formed
because of unfavorable steric interactions between phenoxy-
bound vanadium and the other aryl partner during the C−C
bond-forming step.
Efforts to reduce reaction time and catalyst loading focused
on the catalyst counterion. Vanadium Schiff base catalysts
bearing the tert-butoxy and fluoride counterions were shown to
form product more slowly over 18 h than the corresponding
ethoxy catalyst over the same time period (Table 1, entries 5
and 6 vs entry 4). The observation that catalyst activity tracks
with the lability of the counterion led to the preparation of a
catalyst bearing HFIP as the counterion. Gratifyingly, V2
proved to be more effective in the transformation, forming 2a
in 70% yield over the same reaction time (Table 1, entry 7).
Reaction for a full 24 h with 10 mol % V2 led to full conversion
of 1a and an 80% isolated yield of 2a (Table 1, entry 8). A
reaction profile for the conversion of 1a to 2a with V2 (see the
Supporting Information, control A) is consistent with first-
order decomposition through 90% conversion with neither a
significant burst nor a significant induction period. Independ-
ent experiments in which 2a was added in variable amounts
prior to reaction of 1a indicate that no product inhibition is
occurring, because 1a is converted to the same extent with
various excesses of 2a. Even so, further reduction of the
catalyst loading led to poor conversion over the 24 h reaction
period (Table 1, entry 9). A screen of solvents (Table S2) and
standard oxidants (Table S3) revealed that HFIP was the
optimal solvent for the transformation and that O2 is the most
An important distinction should be made among bis-ether,
mixed ether/phenol, and bisphenol intramolecular coupling
reactions. These transformations are fundamentally different
and are proposed to proceed via different mechanisms. In the
case of ether systems, a polar, two-electron mechanism
invoking a cationic intermediate is often proposed. In the
case of tethered bisphenol cyclizations to form phenol-dienone
products, the reaction is more likely to proceed through
sequential single-electron oxidation of both coupling partners,
akin to the mechanisms proposed in the biosynthesis of
phenol-derived polycyclic natural products. To the best of our
knowledge, there have been no reports detailing the catalytic
oxidation of tethered free phenols for the formation of phenol-
dienone products.
Inspired by the work of Schwartz16,17 and our prior work
with vanadium Schiff base catalysts,12,26 we envisioned the
development of a catalytic system for the oxidation of tethered
free phenols to form phenol-dienone products directly
(Scheme 1d). Initial reaction studies were conducted with
substrate 1a, 20 mol % vanadium catalyst V1, and O2 as the co-
oxidant (Table 1). When 1,2-dichloroethane (DCE) was
utilized as the solvent, there was little consumption of 1a and
the catalyst system failed to form 2a (Table 1, entry 1).
B
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effective oxidant, outperforming an atmosphere of air,
inorganic persulfates, and organic peroxides.
With the optimized conditions for the formation of phenol-
dienone products in hand, the substrate scope of this
transformation was examined (Scheme 2). In the simplest,
obtained after 85% consumption and several other byproducts
were observed. (3) With the method reported here, a 76%
yield was obtained with 85% consumption. Overall, our
catalytic method was easier to undertake [Tl(III) and VOCl3
need special handling], gave a higher yield, provided a much
cleaner reaction profile, and resulted in more facile purification.
In the case of substitution on the ring where the tether is
attached at C4′ (blue ring in Scheme 2), similar results were
obtained (2i−2p). Electron-releasing and electron-withdraw-
ing groups were well tolerated. Notably, dimethoxy-substituted
1p was converted to its corresponding highly substituted
phenol-dienone product in good yield. Fluoro-substituted 2n
was also obtained in fair yield, revealing that deactivated
substrates are capable of undergoing oxidation by V2 to form
product. Additionally, substitution is tolerated at other
positions of this ring (2m and 2o) with no loss of efficiency.
Even though V2 is a chiral catalyst, no enantioenduction was
observed for 2j−2m, likely due to the catalyst binding phenols
that are distal to the site of C−C bond formation. The overall
substrate scope establishes that this catalyst system is capable
of oxidizing a wide variety of tethered phenol compounds and
that the transformation is not limited by a need for electron-
rich, nucleophilic arenes as is the case for other methods.24,25
Efforts to increase the reaction scale were successful, with a
gram-scale reaction of 2a giving a nearly identical outcome.
To further outline the utility of this method, several natural
products were identified as synthetic targets due to the
presence of the phenol-dienone moiety in their core
structure.17,21,28,29 The natural product pulchelstyrene D
(3)28 differs from the simple substrates prepared above
(Scheme 2) only in the unsaturation of the propyl tether.
Attempts to prepare a version of the substrate with an alkenyl
tether were unsuccessful, so an alternative route through the
saturated precursor was envisioned. As a result, dimethoxy-
substituted substrate 1q was coupled in good yield to generate
saturated phenol-dienone product 2q (Scheme 3a). Efforts to
Scheme 2. Scope of V-Catalyzed Intramolecular Coupling of
a
Tethered Free Phenols
Scheme 3. Formation of Spiro-dienone Natural Products,
Pulchelstyrene D and Spirolouveline, via Intramolecular
Oxidative Coupling
a
Reaction conditions: 1 (0.10−0.20 mmol), V2 (10 mol %), HFIP
b
(0.1 M), O2 (1 atm) for 24−44 h; yields of the isolated material. On
a larger scale (5.00 mmol, 1.14 g). With 20 mol % catalyst. HFIP/
DCE (0.1 M, 1:1) as the solvent. Yield in parentheses based on
c
d
e
recovery of the starting material.
unactivated case, the unsubstituted precursor was oxidized in
good yield to its corresponding cyclized product (2a). In the
case of substitution on the ring where the tether is attached at
C3 (red ring in Scheme 2), electron-releasing and electron-
withdrawing groups were well-tolerated (2b−2h). Bromo-
containing (1d) and chloro-containing (1e) substrates were
oxidized to phenol-dienone products in fair yields requiring an
increased catalyst loading. Additionally, substitution is
tolerated at all positions of this ring with no loss of coupling
efficiency (2c, 2g, and 2h). A direct assessment against prior
art was undertaken to further validate the method. (1) With
Tl(O2CCF3),21 a 30% yield of 2c was obtained with 79%
consumption of 1c. (2) With VOCl3,16 a 39% yield was
directly convert 2q into the natural product 3 were
unsuccessful. To overcome this issue, 2q was subjected to a
three-step sequence of acetylation, radical-mediated bromina-
tion/elimination, and deacetylation to form natural product 3
in 34% yield over three steps (see the Supporting
Information). This synthetic effort represents the first
preparation of this naturally occurring compound.
C
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A further natural product, spirolouveline (4),29 is also
closely related to the simple substrates prepared in Scheme 2.
In addition to a single methoxy group, the compound contains
a free hydroxyl group on the dienone moiety. To directly
access 4, a catechol-containing precursor was prepared and
subjected to the vanadium-catalyzed oxidation conditions.
Unfortunately, a poor reaction profile was observed, likely due
to the presence of multiple oxidizable phenolic hydroxyl
groups. An alternative approach utilizing a protected form of
the catechol was envisioned, and 1r was coupled successfully in
good yield to generate bis-alkoxy phenol-dienone 2r (Scheme
3b). Selective removal of the more labile iso-propoxy group of
2r with Lewis acid furnished racemic 4. This synthetic effort
also represents the first reported preparation of this naturally
occurring compound.
The dracaenone natural products represent a tetracyclic
variant of the tethered phenol-dienone motif. The natural
product 10-hydroxy-11-methoxydracaenone (6) has been
prepared previously via direct coupling of the bisphenol in
37% yield20,21 or by coupling of the protected aryl ether
followed by deprotection with 62% yield over the two steps.21
In each case, a stoichiometric oxidant is required for the key
intramolecular coupling step. Using the optimized conditions
with V2, natural product 6 was obtained in a single step from
its corresponding free phenol precursor in 78% yield (Scheme
4a). This preparation represents a protecting group-free
synthesis of 6 with improved efficiency in the key intra-
molecular phenol coupling step.
dienone products to downstream morphinan alkaloids.17,31,32
The efficiency of the coupling reaction to form 8 compares
well to that of the stoichiometric variant reported by Schwartz
et al.17 and offers a complementary approach to state-of-the-art
electrochemical couplings of the related aryl ethers.31,32
A series of control experiments were conducted to aid in
understanding the mechanism of the vanadium-catalyzed
coupling reaction (see the Supporting Information). Reactions
run without V2 in the presence of dioxygen showed limited
conversion of the substrate and no product formation,
indicating that the catalyst is key in oxidizing the substrate
(Supporting Information, control C). Additionally, a study
concerning catalyst ligand identity (Supporting Information,
control E) showed that electron-rich ligands (V1, with t-Bu in
place of NO2) led to slower reaction rates. This result points
away from catalyst reoxidation [V(IV) to V(V)] being rate-
limiting and suggests substrate−catalyst binding or oxidation
by the catalyst [V(V) to V(IV)] as the turnover-limiting step.
Attempts to couple mixed phenol/ether substrates (Supporting
Information, control F) showed decomposition of the starting
material with no detectable phenol-dienone product formation,
indicating that oxidation likely occurs through covalent
activation by V2, as opposed to outer-sphere electron transfer
from V(V). Furthermore, no homocoupled dimeric products
were observed during a standard reaction with tethered
phenols, supporting a mechanism that proceeds through
vanadium species (see structure II in Scheme 5), as opposed
to free radical forms of oxidized 1a.
Scheme 4. Formation of Bicyclic Systems, a Dracaenone
Natural Product and a Salutaridine Analogue, via
Intramolecular Oxidative Coupling
Scheme 5. Proposed Mechanism
Lastly, a synthetically useful salutaridine derivative was
prepared using the newly developed catalytic method (Scheme
4b). Reticuline derivative 7 was coupled directly to form
salutaridine phenol-dienone product 8 in good yield.
Remarkably, only small quantities of the ortho−ortho coupled
aporphine-type product were observed. It has been hypothe-
sized that products of this type are not observed due to an
unfavorable peri-interaction between the approaching hydroxyl
groups in the C−C bond-forming step.17 Compound 8 is of
significant interest in the context of alkaloid synthesis,30
because the coupling reaction establishes the B ring of the
classic morphine scaffold with limited prefunctionalization.
Considerable precedent exists for conversion of these phenol-
These control results, combined with prior findings,12,33
support a proposed mechanism (Scheme 5) in which a
phenoxide-bound substrate (I) is oxidized by 2 equiv of V2.
Prior work indicated the formation of a V(IV)−V(V)
intermediate (II), which undergoes intersystem crossing to
react via a triplet.33 We propose that the radical on the blue
ring forms first first, as the presence of the tether at the para-
position better stabilizes the electron-deficient species formed
D
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upon oxidation. The subsequent intramolecular coupling
followed by substrate displacement affords bis-dienone
intermediate IV and reduced catalyst species III. Bis-dienone
intermediate IV undergoes a tautomerization to form the
phenol portion of the final phenol-dienone product. Catalyst
intermediate III is then reoxidized in the presence of dioxygen
to re-form active catalyst V2. Additional mechanistic studies
are ongoing, with an emphasis on identifying the nature of the
species involved in the key C−C bond-forming step.
In summary, a new vanadium Schiff base catalyst was
developed for use in the catalytic intramolecular coupling of
tethered phenols to form phenol-dienone products. Modifica-
tions to the catalyst counterion revealed that an HFIP-
coordinated V(V)−oxo catalyst was superior in mediating the
coupling reaction. In total, 20 oxidatively coupled adducts were
prepared in yields up to 94%, including three natural products
and a morphinan alkaloid analogue. This newly developed
catalytic method for intramolecular phenol-dienone coupling
serves as a valuable addition to the rich field of oxidative
phenol C−H functionalization34 and represents an effective
small molecule catalytic approach to the biomimetic coupling
of tethered phenols. Further studies of the mechanism and
enantioselective variants of these processes are underway.
REFERENCES
■
(1) Whiting, D. A. Natural Phenolic Compounds 1900−2000: A
Bird’s Eye View of a Century’s Chemistry. Nat. Prod. Rep. 2001, 18,
583−606.
(2) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M.
Atroposelective Total Synthesis of Axially Chiral Biaryl Natural
Products. Chem. Rev. 2011, 111, 563−639.
́
(3) Joncour, A.; Liu, J.-M.; Decor, A.; Thoret, S.; Wdzieczak-Bakala,
J.; Bignon, J.; Baudoin, O. Synthesis of Anti-Microtubule Biaryls and
Preliminary Evaluation as Vascular-Disrupting Agents. ChemMedChem
2008, 3, 1731−1739.
(4) Barton, D. H. R.; Kirby, G. W.; Steglich, W.; Thomas, G. M.;
Battersby, A. R.; Dobson, T. A.; Ramuz, H. 444. Investigations on the
Biosynthesis of Morphine Alkaloids. J. Chem. Soc. 1965, No. 0, 2423−
2438.
(5) Zong, Y.; Zhong, M.; Li, D.-M.; Zhang, B.-J.; Mai, Z.-P.; Huo,
X.-K.; Huang, S.-S.; Zhang, H.-L.; Wang, C.; Ma, X.-C.; et al.etal
Phenolic Constituents from the Roots of Phyllodium Pulchellum. J.
Asian Nat. Prod. Res. 2014, 16, 741−746.
(6) Barton, D. H. R.; Cohen, T. In Festschrift Prof. Dr. Arthur Stoll
Zum Siebzigsten Geburstag, 8; Birkhauser: Basel, Switzerland, 1957.
(7) Aldemir, H.; Richarz, R.; Gulder, T. A. M. The Biocatalytic
Repertoire of Natural Biaryl Formation. Angew. Chem., Int. Ed. 2014,
53, 8286−8293.
(8) Tang, M.-C.; Zou, Y.; Watanabe, K.; Walsh, C. T.; Tang, Y.
Oxidative Cyclization in Natural Product Biosynthesis. Chem. Rev.
2017, 117, 5226−5333.
(9) Reiss, H.; Shalit, H.; Vershinin, V.; More, N. Y.; Forckosh, H.;
Pappo, D. Cobalt(II)[Salen]-Catalyzed Selective Aerobic Oxidative
Cross-Coupling between Electron-Rich Phenols and 2-Naphthols. J.
Org. Chem. 2019, 84, 7950−7960.
(10) Shalit, H.; Dyadyuk, A.; Pappo, D. Selective Oxidative Phenol
Coupling by Iron Catalysis. J. Org. Chem. 2019, 84, 1677−1686.
(11) Esguerra, K. V. N.; Fall, Y.; Petitjean, L.; Lumb, J.-P.
Controlling the Catalytic Aerobic Oxidation of Phenols. J. Am.
Chem. Soc. 2014, 136, 7662−7668.
̈
ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00577.
Experimental procedures, reaction optimization, reaction
controls, characterization data, and spectral data (PDF)
AUTHOR INFORMATION
(12) Kang, H.; Lee, Y.-E.; Reddy, P. V. G.; Dey, S.; Allen, S. E.;
Niederer, K. A.; Sung, P.; Hewitt, K.; Torruellas, C.; Herling, M. R.;
Kozlowski, M. C. Asymmetric Oxidative Coupling of Phenols and
Hydroxycarbazoles. Org. Lett. 2017, 19, 5505−5508.
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Corresponding Author
Marisa C. Kozlowski − Roy and Diana Vagelos Laboratories,
Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104, United States; orcid.org/
0000-0002-4225-7125; Email: marisa@sas.upenn.edu
(13) Nieves-Quinones, Y.; Paniak, T. J.; Lee, Y. E.; Kim, S. M.;
Tcyrulnikov, S.; Kozlowski, M. C. Chromium-Salen Catalyzed Cross-
Coupling of Phenols: Mechanism and Origin of the Selectivity. J. Am.
Chem. Soc. 2019, 141, 10016−10032.
(14) Kirste, A.; Schnakenburg, G.; Waldvogel, S. R. Anodic Coupling
of Guaiacol Derivatives on Boron-Doped Diamond Electrodes. Org.
Lett. 2011, 13, 3126−3129.
Author
Philip H. Gilmartin − Roy and Diana Vagelos Laboratories,
Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104, United States
̈
(15) Rockl, J. L.; Schollmeyer, D.; Franke, R.; Waldvogel, S. R.
Dehydrogenative Anodic C−C Coupling of Phenols Bearing Electron-
Withdrawing Groups. Angew. Chem., Int. Ed. 2020, 59, 315−319.
(16) Schwartz, M. A.; Rose, B. F.; Holton, R. A.; Scott, S. W.;
Vishnuvajjala, B. Intramolecular Oxidative Coupling of Diphenolic,
Monophenolic, and Nonphenolic Substrates. J. Am. Chem. Soc. 1977,
99, 2571−2578.
Complete contact information is available at:
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Notes
(17) Schwartz, M. A.; Zoda, M. F. Biomimetic Approaches to
Morphine Alkaloids. Total Synthesis of (.+-.)-2-Hydroxycodeine and
(.+-.)-Noroxycodone. J. Org. Chem. 1981, 46, 4623−4625.
(18) Tobinaga, S.; Kotani, E. Intramolecular and Intermolecular
Oxidative Coupling Reactions by a New Iron Complex [Fe(DMF)-
3Cl2][FeCl4]. J. Am. Chem. Soc. 1972, 94, 309−310.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the National Science Foundation
(NSF) (CHE1764298) and the National Institutes of Health
(NIH) (R35 GM131902) for financial support of this research.
Partial instrumentation support was provided by the NIH and
NSF (1S10RR023444, 1S10RR022442, CHE-0840438, CHE-
0848460, 1S10OD011980, and CHE-1827457) as well as the
Vagelos Institute for Energy Science and Technology. P.H.G.
thanks the NSF for fellowship support (DGE-1845298). Dr.
Charles W. Ross III (University of Pennsylvania) is acknowl-
edged for obtaining accurate mass data.
(19) Takasugi, M.; Niino, N.; Anetai, M.; Masamune, T.; Shirata, A.;
Takahashi, K. Structure of Two Stress Metabolites, Spirobroussonin a
and b, from Diseased Paper Mulberry. Chem. Lett. 1984, 13, 693−694.
́
(20) Cordell, G. A.; Blasko, G. Biomimetic Total Synthesis of
Dracaenone Derivatives. Heterocycles 1988, 27, 445−452.
(21) Li, M.-M.; Wu, Y.; Liu, B. Synthesis and Configuration of
Natural Dracaenones. Org. Lett. 2019, 21, 575−578.
(22) Schubert, M.; Wehming, K.; Kehl, A.; Nieger, M.;
̈
Schnakenburg, G.; Frohlich, R.; Schollmeyer, D.; Waldvogel, S. R.
E
https://dx.doi.org/10.1021/acs.orglett.0c00577
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pubs.acs.org/OrgLett
Letter
Molybdenum Pentachloride Mediated Synthesis of Spirocyclic
Compounds by Intramolecular Oxidative Coupling. Eur. J. Org.
Chem. 2016, 2016, 60−63.
(23) Hamamoto, H.; Anilkumar, G.; Tohma, H.; Kita, Y. A Novel
and Useful Oxidative Intramolecular Coupling Reaction of Phenol
Ether Derivatives on Treatment with a Combination of Hypervalent
Iodine(III) Reagent and Heteropoly Acid. Chem. - Eur. J. 2002, 8,
5377−5383.
(24) Dohi, T.; Minamitsuji, Y.; Maruyama, A.; Hirose, S.; Kita, Y. A
New H2O2/Acid Anhydride System for the Iodoarene-Catalyzed C−
C Bond-Forming Reactions of Phenols. Org. Lett. 2008, 10, 3559−
3562.
(25) Su, B.; Deng, M.; Wang, Q. Bioinspired Construction of a
Spirocyclohexadienone Moiety via Sodium Nitrite Catalyzed Aerobic
Intramolecular Oxidative Phenol Coupling. Org. Lett. 2013, 15,
1606−1609.
(26) Neuhaus, W. C.; Jemison, A. L.; Kozlowski, M. C. Vanadium-
Catalyzed Selective Oxidative Homocoupling of Alkenyl Phenols To
Synthesize Lignan Analogs. ACS Catal. 2019, 9, 11067−11073.
(27) Colomer, I.; Chamberlain, A. E. R.; Haughey, M. B.; Donohoe,
T. J. Hexafluoroisopropanol as a Highly Versatile Solvent. Nat. Rev.
Chem. 2017, 1, 0088.
(28) Shen, C.-C.; Wang, S.-T.; Tsai, S.-Y.; Yang, H.-C.; Shieh, B.-J.;
Chen, C.-C. Cinnamylphenols from Phyllodium Pulchellum. J. Nat.
Prod. 2005, 68, 791−793.
(29) Beldjoudi, N.; Mambu, L.; Labaïed, M.; Grellier, P.;
Ramanitrahasimbola, D.; Rasoanaivo, P.; Martin, M. T.; Frappier, F.
Flavonoids from Dalbergia Louvelii and Their Antiplasmodial
Activity. J. Nat. Prod. 2003, 66, 1447−1450.
(30) Blakemore, P. R.; White, J. D. Morphine, the Proteus of
Organic Molecules. Chem. Commun. 2002, 0, 1159−1168.
(31) Lipp, A.; Ferenc, D.; Gutz, C.; Geffe, M.; Vierengel, N.;
̈
̈
Schollmeyer, D.; Schafer, H. J.; Waldvogel, S. R.; Opatz, T. A Regio-
and Diastereoselective Anodic Aryl−Aryl Coupling in the Biomimetic
Total Synthesis of (−)-Thebaine. Angew. Chem., Int. Ed. 2018, 57,
11055−11059.
(32) Lipp, A.; Selt, M.; Ferenc, D.; Schollmeyer, D.; Waldvogel, S.
R.; Opatz, T. Total Synthesis of (−)-Oxycodone via Anodic Aryl−
Aryl Coupling. Org. Lett. 2019, 21, 1828−1831.
(33) Kang, H.; Herling, M. R.; Niederer, K. A.; Lee, Y. E.; Vasu
Govardhana Reddy, P.; Dey, S.; Allen, S. E.; Sung, P.; Hewitt, K.;
Torruellas, C.; Kim, G. J.; Kozlowski, M. C. Enantioselective
Vanadium-Catalyzed Oxidative Coupling: Development and Mecha-
nistic Insights. J. Org. Chem. 2018, 83, 14362−14384.
(34) Huang, Z.; Lumb, J.-P. Phenol-Directed C−H Functionaliza-
tion. ACS Catal. 2019, 9, 521−555.
F
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