Total Synthesis of Pyrolaside B: Phenol Trimerization through Sequenced Oxidative C?C and C?O Coupling

Article abstract of DOI:10.1002/anie.201915654

A facile method to oxidatively trimerize phenols using a catalytic aerobic copper system is described. The mechanism of this transformation was probed, yielding insight that enabled cross-coupling trimerizations. With this method, the natural product pyro

Full text of DOI:10.1002/anie.201915654

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Angewandte
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Accepted Article
Title: Total Synthesis of Pyrolaside B: PhenolTrimerization via
Sequenced Oxidative C-C and C-O Coupling
Authors: Marisa C Kozlowski and Wlliam C. Neuhaus
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915654
Angew. Chem. 10.1002/ange.201915654
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10.1002/anie.201915654
Angewandte Chemie International Edition
COMMUNICATION
Total Synthesis of Pyrolaside B: Phenol Trimerization via
Sequenced Oxidative C-C and C-O Coupling
William C. Neuhaus and Marisa C. Kozlowski*
Abstract: A facile method to oxidatively trimerize phenols using a low
loading catalytic aerobic copper system is described. The mechanism
of this transformation is probed, an understanding of which enabled
cross coupling trimerizations. With this method, the natural product
pyrolaside B has been synthesized for the first time. The key strategy
used for this novel synthesis is the facile one-step construction of a
spiroketal trimer intermediate which can be selectively reduced to give
the natural product framework without recourse to stepwise Ullmann-
and Suzuki-type couplings. As a result, pyrolaside B can be obtained
expeditiously in five steps and 16% overall yield. Two other analogues
were synthesized highlighting the utility of the method and new
accessibility to this range of chemical space. A novel xanthene was
also synthesized through controlled Lewis acid promoted
rearrangement of a spiroketal trimer.
We envisaged that pyrolaside B could be constructed by
reduction of the corresponding ortho-quinone/bisphenol dimer
spiroketal (5) illustrated in Scheme 1. In particular, utilization of a
version of 5 with each of the phenols already appended a glucose
equivalent would circumvent the considerable challenges entailed
in selectively glucosylating three of the five phenols of the
pyrasolide B aglycone. In turn, 5 can be dissected to monomer 6.
However, oxidative trimerization to
challenging selective formation of one C-C bond as well as two C-
O bonds. Finally, stereoselective glycosylation of phenol
6 would involve the
precursor 7 would be needed to set the stage for the oxidative
trimerization.
OR1
OH
OH
Me
Me
O
HO
O
C
C
B
O
OH
O
O
HO
O
HO
A
Me
Phenol trimers (Figure 1) encompass a diverse range of
compounds found in nature which have been shown to have
unique biological activities. Pyrolaside B (1) was isolated from
Pyrola rotundifoliai in 2005 and from Pyrola calliantha in 2010,
and was found to inhibit Micrococcus luteus and Staphylococcus
aureus.[1] Fucophlorethol C (2)[2] from brown alga Colpomenia
bullosa acts as a lipoxygenase inhibitor. Pyrocallianthaside B (3)[3]
and isotrityrosin (4)[4] have been isolated from Pyrola calliantha
and haemonchus contortus infective larvae, respectively.
Me
A
Deprotection,
Reduction
B
OR1
OH
OH
OR1
Me
O
HO
OH
OH
O
Me
O
HO
5
O
OH
Oxidation
OH
OH
O
1
Me
Beta Selective
Glycosylation
OH
O
H
R1
=
O
H
O
OAc
OAc
OAc
OAc
OH
OH
Me
O
HO
O
AcO
OH
AcO
OAc
OH
7
OH
HO
O
HO
OAc
6
Me
OH HO
O
OH
OH
OH
OH
Scheme 1: Retrosynthetic analysis of pyrolaside B.
Me
O
HO
O
O
HO
O
OH
OH
OH
HO
HO
OH
OH
OH
Beginning in 1965, limited reports of stoichiometric oxidative
trimerizations of phenols to form spiroketals of structure 9 have
appeared (Scheme 2).[ 5 , 6 ] In 2012, the Lei Group gave one
example of cyclic trimer formation via stoichiometric silver
oxidation (Scheme 2a).[7] In the same year, the Beifuss group
generated a similar cyclic trimer from sesamol via laccase
oxidation in 3% yields (Scheme 2b).[8] Likewise, in 2018, it was
found that methylcarbazoles were able to form spiroketal trimers,
albeit in low yield (Scheme 2c).[9] The low yields in such processes
likely arise from the selectivity challenges associated with phenol
C-C dimerization in addition to two C-O bond forming reactions.
1
2
Pyrolaside B
Fucophlorethol C
OH
OH
Me
O
HO
O
O
OH
NH2
OH
HO
O
HO
O
HO
Me
O
Me
OH
OH
NH2
H2N
O
OH
OH
HO
O
HO
OH
O
3
4
Pyrocallianthaside B
Isotrityrosin
Figure 1: Phenol trimer natural products.
[*]
Marisa C. Kozlowski
Department of Chemistry
University of Pennsylvania
Philadelphia, Pennsylvania 19104, United States
E-mail: marisa@sas.upenn.edu
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.201915654
Angewandte Chemie International Edition
COMMUNICATION
Me
OMe
a)
OH
O
O
O
Me
Me
Table 1. Optimization of reaction conditions and control reactions
1.2 equiv Ag2O
OMe
Me
benzene, rt
OH
OMe
x mol % CuCl,
x mol % ligand
OMe
56%
O
OMe
Me
Me
O
O
Me
8
9
O
14 h, solvent, O2
O
b)
OMe
OMe
Me
MeO
O
O
8
laccasse, air
O
9
buffer
O
#
Solvent (M)
Ligand (mol%)
t-BuNH2 (20)
CuCl (mol%)
Yield[a]
O
OH
O
O
3%
10
O
1
toluene (0.05M)
toluene (0.05M)
THF (0.05 M)
2
20
2
2
2
2
2
2
2
2
2
2
0
0
0%
O
11
c)
10 mol %
[CuOH.TMEDA]2Cl2
air
2
pyridine (200)
pyridine (20)
pyridine (20)
pyridine (20)
pyridine (20)
pyridine (20)
pyridine (4)
pyridine (20)
pyridine (20)
pyridine (20)
None
(57%)
0%
Me
NH
Me
OH
3
N
O
CH2Cl2, rt, 1 h
18%
H
N
4
EtOAc (0.05 M)
CH2Cl2 (0.05 M)
toluene (0.5M)
toluene (0.05 M)
toluene (0.05M)
toluene (0.05M)
toluene (0.05M)
toluene (0.05M)
toluene (0.05M)
toluene (0.05M)
toluene (0.05M)
(40%)
(26%)
(63%)
(39%)[b]
(42%)
(26%)[c]
(57%)[d]
64%
0
H
N
H
O
12
Me
O
5
Me
13
6
7
Scheme 2: Precedents for oxidative trimer cyclization.
8
In the course of examining catalytic C-C[10,11,12,13,14,15,16,17] vs
C-O[18] phenol dimerization using our oxidative catalyst library,[14]
copper complexes were identified as potential candidates for C-O
coupling. However, mixed selectivity was observed including
spiroketal trimer 9, which had not been observed previously.
Generally speaking there is wide precedent for C-C oxidative
dimerizations of phenols with copper systems.[19,20] There are,
however few examples of oxidative couplings which give
controlled selectivity for both C-C and C-O coupled
products.[19,20,21,22,23] In polymerization of 1-naphthol, the relative
amount of C-O vs C-C coupling with a Cu (I) pyridine system
heavily depends on the number of pyridine ligand equivalents.[24]
In 2014 and 2016, the Lumb group elegantly showed that the
formation of ortho-quinones from para-substituted phenols
proceeds well with an aerobic copper (I) system with nitrogen
ligands.[18, 25 ] In 2015, the Lumb and Ottenwaelder group
elaborated on this finding by describing the mechanism of Cu (I)
promoted selective oxygenation of 4-tert-butylphenol.[26] In 2014,
this group also presented that copper salt choice, as well as ligand
can alter the ratios of C-C oxidative coupling versus ortho-quinone
oxygenation products.[19a]
9
10
11
12
13
14
pyridine (20)
None
0
0
[a] Yields in parantheses determined by NMR spectroscopy using CH2Br2 as
internal standard. [b] Air used as oxidant. [c] Reaction conducted at 0 oC. [d]
Reaction conducted at 60 oC.
A variety of analogous phenols also afford the cyclic trimer
under these conditions (Figure 2). Substrates 16-19 with the same
ortho-alkyl, para-alkoxy motif all proceeded well. Even, allyl
groups are tolerated under these oxidizing conditions in the case
of 19 with a yield of 76%. A para tert-butyl group likewise appears
sufficient to promote the desired reactivity with 20 giving 22%
yield. A sterically unencumbered ortho-alkyl group was proposed
as necessary for the selectivity, but 21 shows that even a phenyl
group is well-tolerated. Having a para-aryl substituent is also well-
tolerated as in the case of 22 which forms in 84% yield at slightly
elevated temperatures (40 oC). Other bulky para-alkyl groups are
tolerated but give low yields (c.f. 20, 22-25). On the other hand,
2,4-dimethylphenol, 2-methyl-4-isopropylphenol, 2-methyl-4-
chlorophenol, and 2-methyl-4-dimethylaminophenol resulted in
decomposition.
Reasoning that an ortho-quinone might be an intermediate en
route to ortho-quinone/bisphenol dimer spiroketal 9, further
copper catalyst conditions were screened with the goal of
identifying conditions that would allow catalytic oxidative C-C
coupling as well as oxygenation to the ortho-quinone. It was
further postulated that the copper(II) species formed under
oxygen could also act as a Lewis acid catalyst to permit the
spiroketalization. A brief screen (Table 1, entires 1-11) showed
that toluene was the optimum solvent with high pyridine
concentrations relative to copper being necessary (entry 6). A
series of control experiments (entries 12-14) verified that the
copper ligand system was indeed acting catalytically, and both the
ligand and the copper were necessary for any conversion to occur.
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10.1002/anie.201915654
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COMMUNICATION
R2
R1
CCl3
NH
OAc
OH
H
OH
R1
=
O
2 mol % CuCl,
20 mol % pyridine
O
O
O
O
R2
R2
OHC
OAc
OAc
H
OH
OH
O
AcO
OAc
OHC
rt, O2, 14 h,
0.05 M toluene
R1
H
OAc
R1
14
O
R1
O
R2
15
AcO
OAc
OAc
.
BF3 Et2O, CH2Cl2
0 oC, 1 h
OAc
AcO
OMe
OMe
69%
Me
OMe
OAc
26
27
O
O
O
O
O
OR1
O
Me
H2
H2
Pd/C,
EtOH,
2 mol % CuCl,
20 mol% pyridine,
rt, O2, 40 h,
O
O
Me
O
Pd/C,
EtOH,
rt, 14 h
O
C
OH
OMe
OMe
OMe
OMe
Me
OMe
O
rt, 14 h
toluene
MeO
Me
Me
OR1
65%
(72% brsm)
B
O
A
98%
96%
9, 64% (0.5 mmol)
61% (14.5 mmol)
OR1
28
16, 64%
17, 27%
Me
29
OR1
t-Bu
Me
O
OBn
Me
t-Bu
O
OH
OH
O
Me
O
O
HO
O
O
O
O
O
Me
Me
t-Bu
O
Me
OR1
OH
HO
O
HO
NaOMe,
MeOH,
rt, 1 h
O
C
Me
t-Bu
OBn
t-Bu
OH HO
O
BnO
t-Bu
Me
Me
OH
OH
Me
38%
(93% NMR)
Me
O
HO
OH
OH
18, 48%
19, 76% (86% brsm)
20, 22%
A
B
O
HO
OR1
OH
O
Me
Me
Ad
OR1
Ph
OMe
Me
Ph
OH
30
Pyrolaside B (1)
O
O
O
O
O
O
O
Me
Ph
Me
OMe
O
O
Scheme 3: Route to synthetic pyrolaside B.
Ad
Ph
Ad
MeO
Ph
Me
Ph
Me
21, 43% (0.25 mmol)
22, 84% (18 h, 40 °C)
23, 30% (16 h)
Deconvolution of quinone-like intermediate 29 to the acyclic
trimer precursor to pyrolaside B 30 occurred in near quantitative
yield via hydrogenation with Pd/C. Notably, the spiroketal
underwent scission under these conditions while the anomeric
ketal linkage remained intact. Removal of the acetate protecting
groups was performed with NaOMe resulting in an efficient
reaction (93% yield, ~95% purity; see 1H NMR in SI). Preparatory
HPLC was needed to remove trace aromatic impurities, but led to
poor mass recovery (38% isolated yield). All spectra matched the
spectra for the reported natural product (see SI). Thus, pyrolaside
B was synthesized in 16% yield over 5 steps.
Me Me
Me Me
Me
O
Me
O
O
O
Me
Me
O
O
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
25, 17% (15 h)
24, 18% (15 h)
Figure 2: Scope of phenol trimerization (Ad = adamantyl).
In order to afford the a-anomer of a pyrolaside B analogue
monomer, longer glycosylation conditions, a greater amount of
Lewis acid, and a less electrophilic glucose donor were used to
drive the reaction to the thermodynamic product (Scheme 4).
Reduction of the ortho-aldehyde 31 via hydrogenation using Pd/C
gave the alkane in 98% yield without purification. The oxidative
trimerization of the cis-glycosylated substrate 32 similarly formed
33.
To implement this method in a synthesis of pyraloside B,
commercially available phenol 26 was glycosylated in good yield
(Scheme 3). The glycosylated monomer was then hydrogenated
to 28 using Pd/C in 98% yield without the need for purification.
With monomeric phenol 28 in hand, an oxidation using our aerobic
copper (I) pyridine system was explored. To our delight, cyclic
trimer 29 was generated in 65% with some starting material
remaining.
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10.1002/anie.201915654
Angewandte Chemie International Edition
COMMUNICATION
OH
O
OH
H
AcO
O
OAc
Me
OH
OHC
O
O
Dimerization &
Tautomerization
H2
R2
R2
Cu2O2L2
R2
H
Pd/C,
EtOH,
rt, 19 h
AcO
OAc
– H+, – e–
H
H
OAc
O
O
O
OAc
OAc
OAc
OAc
26
R1
37
R1
R1
.
BF3 Et2O, CH2Cl2
rt, 19 h
98%
AcO
AcO
R1 = OMe, R2 = Me
Eox = 0.97 V
R1
O
OAc
OAc
R2
15%
R1
31
32
OAc
OAc
OH
R2
O
O
Me
R1
Cu2O2L2
R2
O
R2
R2
O
O
2 mol % CuCl,
20 mol % pyridine,
rt, O2, 15 h,
– H+, – e–
O
OAc
AcO
Me
OH
OH
R1
R1
O
38
39
toluene
O
R1 = OMe, R2 = Me
Eox = 0.85 V
R2
OAc
OAc
Me
50%
O
R1
AcO
OAc
OAc
O
OAc
AcO
R2
Possible
Catalyst
Structure:
R1
OH
C
C
OAc
Cu2O2L2
O
33
OH
O
R2
R1
R2
B
R1
O
O
– 2 H+ ,– 2 e–
O
B
L Cu Cu L
O
A
A
Scheme 4: Synthesis of tris-α-glucosyl epimer of pyrolaside B.
R2
R2
R1
R1
40
41
With this success, we interrogated the initially proposed
mechanism involving formation of ortho-quinone and C-C coupled
dimer intermediates that subsequently spiroketalize. Monitoring of
reactions revealed that the C-C dimer did form initially and was
then converted to product. To probe the mechanism, the reaction
in eq 1 was attempted. However, no condensation product was
observed and the majority of the ortho-quinone was recovered,
while the C-C homodimer decomposed. Previous work on ortho-
quinones also shows that typically the 4-position is more reactive
to nucleophiles.[18] Altogether, these results point away from an
ortho-quinone intermediate.
Scheme 5: Proposed mechanism for trimerization.
From this mechanism, cross-couplings of dimer intermediate
38 with different phenols should be possible. Reaction pairs were
selected where the corresponding phenol constituents had similar
oxidation potentials such that dimer 35 would remain more
oxidizable than monomer 42 (Scheme 6). In doing so, products
43 and 44 were afforded with similar efficiency as
homotrimerization. In line with the reasoning above, no
homotrimers were observed in the reaction mixture.
6 mol % CuCl,
OMe
Me
60 mol % pyridine,
OH
rt, O2, 14 h,
0.0167 M
toluene
Me
O
OMe
R1
O
Me
OMe
HO
HO
t-Bu
O
+
O
+
t-Bu
(eq 1)
HO
HO
OR2
X
O
Me
OMe
t-Bu
OMe
42
35
Me
OMe
t-Bu
Me
36
Result: 66%
recovered
ortho-quinone 30
6 mol % CuCl, 60 mol % pyridine,
rt, 14 h, O2, 0.0167 M toluene
34
35
R1 = n-Pr
R1 = Me
Me
O
OMe
R2 = Me
R2 = β-Glu
O
O
It was then hypothesized that cross C-O coupling of the
Me
phenol and C-C coupled dimer lead to product (Scheme 5). The
monomeric phenol is first oxidized to C-C dimer 38 via a copper
(II) pyridine complex formed in situ.[19a] Previous work in phenol
oxidation would suggest that this homodimerization most likely
goes through a one electron pathway in which two identical
radicals recombine to allow for maximum SOMO orbital
overlap.[16d] Once the dimer is formed it is more oxidizable giving
rise to 39 which has no open positions for C-C coupling; instead,
coupling occurs from the oxygen of the bisphenol with a carbon
of the phenol monomer. The measured oxidation potentials (vs
ferrocene in MeCN) of the monomer (0.97 V) and dimer (0.85 V)
(see SI for details) support this sequence. A final oxidation then
could occur at the more electron rich A-ring of 40 to form the cyclic
trimer. Support for this last step comes from precedent with the
acyclic trimer of 2,4-diphenylphenol being converted to the
corresponding cyclized trimer with MnO2 in 92% yield.[6]
Me
OMe
O
O
OMe
O
Me
H
O
O
H
OMe
AcO
AcO
44, 59%
OAc
MeO
Me
OAc
43, 34%
Scheme 6: Formation of mixed trimers.
With these new products in hand, formation of the linear
trimers was examined (Figure 3). With the same reductive
conditions, linear trimers 47, 48 and 49 were obtained in good
yields. Importantly, selective installation of a glucose group is
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10.1002/anie.201915654
Angewandte Chemie International Edition
COMMUNICATION
feasible providing an entry to a large number of selectively
substituted trisphenol C-O/C-C linked compounds.
OR2
OR2
Me
Me
O
H2, Pd/C,
EtOH,
rt, 14 h
C
B
C
HO
O
HO
O
Me
Me
O
B
OR2
A
A
OR2
Me
R1O
OR1
Me
46
45
Me
OMe
Figure 4: a) Rearrangement to xanthene. b) X-ray structure of 50.
C
B
HO
O
HO
Me
A
In summary, a process for a catalytic coupling of phenols to
afford trimeric spiroketal adducts has been described using a
base metal catalyst and environmentally benign oxygen as the
terminal oxidant. Mechanism studies reveal that the dioxepine
adducts arise from a controlled sequence of three two electron
oxidations involving C-C, C-O, and C-O coupling. The relative
reactivity of dimerization vs trimerization is controlled by the
slightly higher susceptibility of the intermediate dimer toward
oxidation. Undoubtedly, such oxidation events occur in a number
of other reported dimerizations. [10-17] In most cases, the oxidation
would be readily reversible allowing the dimer to accumulated. In
other cases, such oxidation gives rise to decomposition. A
hallmark of this case is the ability of the oxidized dimer to engage
in selective C-O bond formation with an additional monomer. This
method allowed the expeditious assembly of the natural product
pyrolaside B over 5 steps. This first total synthesis of pyrolaside
Me
OMe
OMe
47, 75%a
OAc
OAc
Me
O
Me
OMe
O
C
B
C
HO
O
HO
HO
O
OAc
HO
AcO
O
Me
Me
A
A
B
Me
Me
OMe
OAc
O
O
O
AcO
OAc
OAc
O
O
AcO
OAc
OAc
OAc
AcO
OAc
OAc
48, 81%
OAc
49, 65%
Figure 3: Scope of phenol trimer reduction. aReaction time was 16 h.
It was postulated that the inherit instability of a 7-membered
ring containing four sp2 carbons facilitated the reductive openings
in Figure 3. In a similar vein, these same driving forces were
harnessed in a redox neutral rearrangement. With a mild Lewis
acid (BF3 Et2O) under mild conditions (–78 C), a bright yellow
compound, tetracyclic xanthene 50,27] was formed in 69% yield
(Figure 4a). With the limited number of hydrogens to probe
structure by 1H NMR spectroscopy, the structure of 50 was
secured by single crystal X-ray analysis (Figure 4b). At higher
temperatures, this process was not nearly as selective leading to
the possibility of a variety of other rearrangements that could be
performed using cyclic phenol trimers.
B
overcomes the challenges associated with conventional
approaches that involve multiple functionalizations to allow
Ullmann- and Suzuki-type couplings and selective O-
glycosylation of some phenols in the presence of others.[28] The
oxidative coupling protocol tolerates incorporation of the glucose
linkage into the monomer allowing construction of the overall
architecture in a single assembly step that unites three monomers.
The resultant spiroketal trimers can be reduced to the linear C-
C/C-O linked timers or rearranged to a xanthene scaffold.
.
o
Acknowledgements
BF3.Et2O,
CH2Cl2
–78 oC, 7 h
a)
Me
O
OMe
OH
Me
Me
O
O
We are grateful to the NSF (CHE1764298) and the NIH (R35
GM131902, RO1 GM112684) for financial support of this
research. Partial instrumentation support was provided by the NIH
and NSF (1S10RR023444, 1S10RR022442, CHE-0840438,
CHE-0848460, 1S10OD011980, CHE-1827457). Dr. Charles W.
Ross III is acknowledged for obtaining accurate mass data. This
work was supported by the Vagelos Institute for Energy Science
Technology at the University of Pennsylvania. We thank Michael
R. Gau for X-ray analysis. We thank Prof. J.P. Lumb (McGill
University) for helpful discussions.
Me
OMe
69%
O
MeO
OMe
O
OMe
MeO
Me
Me
9
50
F3B
H+
O
OH
Me
Me
Me
O
O
Me
OMe
OMe
H
MeO
O
MeO
F3B
O
OMe
OMe
Me
Me
Conflicts of interest
b)
The authors declare no conflicts of interest
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10.1002/anie.201915654
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COMMUNICATION
Keywords: Oxidative coupling • Phenol • Copper • Total
Synthesis • Xanthene
[1]
[2]
J. Chang, T. Inui, Chem. Pharm. Bul. 2005, 53, 1051-1053.
H. Kurihara, R. Konno, K. Takahashi, Biosci. Biotechnol. Biochem. 2015,
79, 1954-1956.
[15] Catalytic Cr in phenol C-C coupling: a) A. E. Solinski, C. Ochoa, Y. E.
Lee, T. Paniak, M. C. Kozlowski, W. M. Wuest, ACS Inf. Dis, 2018, 4,
118-122; b) Y. Nieves-Quinones, T. J. Paniak, Y. E. Lee, S. M. Kim, S.
Tcyrulnikov, M. C. Kozlowski, J. Am. Chem. Soc. 2019, 141, 10016-
10032.
[3]
Y.-L. Chen, C.-H. Tan, J.-J. Tan, S.-J. Qu, H.-B. Wang, Q. Zhang, S.-H.
Jiang, D.-Y. Zhu, Helv. Chim. Acta 2007, 90, 2421-2426.
R. H. Fetterer, M. L. Rhoads, J. Parasitol. 1990, 76, 619-624.
a) F. R. Hewgill, D. G. Hewitt, J. Chem. Soc. 1965, 3660-3666; b) D. F.
Bowman, F. R. Hewgill, B. R. Kennedy, J. Chem. Soc. C 1966, 2274-
2279.
[4]
[5]
[16] Catalytic Fe in phenol C-C coupling: a) A. Libman, H. Shalit, Y. Vainer,
S. Narute, S. Kozuch, D. Pappo, J. Am. Chem. Soc. 2015, 137, 11453-
11460; b) H. Shalit, A. Libman, D. Pappo, J. Am. Chem. Soc. 2017, 139,
13404-13413; c) V. Vershinin, A. Dyadyuk, D. Pappo, Tetrahedron 2017,
73, 3660-3668; d) H. Shalit, A. Dyadyuk, D. Pappo, J. Org. Chem. 2019,
84, 1677-1686.
[6]
[7]
[8]
H. D. Becker, J. Org. Chem. 1969, 34, 2027-2029.
D. Liao, H. Li, X. Lei, Org. Lett. 2012, 14, 18-21.
M.-A. Constantin, J. Conrad, U. Beifuss, Tetrahedron Lett. 2012, 53,
3254-3258.
[17] Catalytic NOBF4 in phenol C-C coupling: L. Bering, M. Vogt, F. M.
Paulussen, A. P. Antonchick, Org. Lett. 2018, 20, 4077-4080.
[18] Catalytic Cu in phenol C-O coupling: a) Z. Huang, J.-P. Lumb, Angew.
Chem. Int. Ed. 2016, 55, 11543-11547; b) K. V. N. Esguerra, J.-P. Lumb
ACS Catal. 2017, 7, 3477−3482; c) W. Xu, Z. Huang, X. Ji, J.-P. Lumb
ACS Catal. 2019, 9, 3800−3810.
[9]
C. Brütting, R. F. Fritsche, S. K. Kutz, C. Börger, A. W. Schmidt, O.
Kataeva, H.-J. Knölker, Chem. Eur. J. 2018, 24, 458-470.
[10] Catalytic V in phenol C-C coupling: a) D.-R. Hwang, C.-P. Chen, B.-J.
Uang, Chem. Commun. 1999, 1207-1208; b) H. Kang, Y. E. Lee, P. Vasu
Govardhana Reddy, S. Dey, S. E. Allen, , K. A. Niederer, P. Sung, C.
Torruellas, M. R. Herling, M. C. Kozlowski, Org. Lett. 2017, 19,
5505−5508; c) H. Kang, C. Torruellas, J. Liu, M. C. Kozlowski, Org. Lett.
2018, 20, 5554-5558; d) H. Kang, M. R. Herling, K. A. Niederer, Y. E.
Lee, P. Vasu Govardhana Reddy, S. Dey, S. E. Allen, P. Sung, K. Hewitt,
C. Torruellas, G. J. Kim, M. C. Kozlowski, J. Org. Chem. 2018, 83,
14362-14384; e) M. Sako, T. Aoki, N. Zumbrägel, L. Schober, H. Gröger,
S. Takizawa, H. Sasai, J. Org. Chem. 2019, 84, 1580-1587.
[19] Catalytic Cu in phenol C-C and C-O coupling: a) K. V. N. Esguerra, Y.
Fall, L. Petitjean, J.-P. Lumb, J. Am. Chem. Soc. 2014, 136, 7662-7668.
b) W. Li, F. Song, J. You, Chem. Eur. J. 2015, 21, 13913-13918.
[20] For reviews of catalytic Cu in phenol C-C and C-O coupling: a) S. E. Allen,
R. R. Walvoord, R. Padilla-Salinas, M. C. Kozlowski, Chem. Rev. 2013,
113, 6234-6458; b) Z. Huang, J.-P. Lumb, ACS Catal. 2019, 9, 521-555.
[21] Gold catalyzed phenol C-C and C-O coupling: a) Y. Cheneviere, V. Caps,
A. Tuel, Appl. Catal. A 2010, 387, 129-134; b) D. V. Jawale, E. Gravel,
V. Geertsen, H. Li, N. Shah, I. N. N. Namboothiri, E. Doris
ChemCatChem 2014, 6, 719 – 723
[11] Electrochemical phenol C-C coupling: a) A. Kirste, G. Schnakenburg, F.
Stecker, A. Fischer, S. R. Waldvogel, Angew. Chem. Int. Ed. 2010, 49,
971-975; b) B. Elsler, D. Schollmeyer, K. M. Dyballa, R. Franke, S. R.
Waldvogel, , Angew. Chem. Int. Ed. 2014, 53, 5210-5213; c) B. Dahms,
P. J. Kohlpaintner, A. Wiebe, R. Breinbauer, D. Schollmeyer, S. R.
Waldvogel, Chem. Eur. J. 2019, 25, 2713-2716; d) S. R. Waldvogel, J.
Röckl, D. Schollmeyer, R. Franke, Angew. Chem. Int. Ed. 2019, 59, 315-
319.
[22] Electrochemical phenol C-C and C-O coupling: B. Elsler, D. Schollmeyer
and S. R. Waldvogel Faraday Discuss. 2014, 172, 413–420
[23] Photocatalytic phenol/arene C-C and C-O coupling: A. Eisenhofer, J.
Hioe, R. M. Gschwind, B. König, Eur. J. Org. Chem. 2017, 2017, 2194-
2204.
[24] R. N. Mukherjea, A. K. Bandyopadhyay, Polymer 1977, 18, 1081-1082.
[25] K. V. N. Esguerra, Y. Fall, J.-P. Lumb, Angew. Chem. Int. Ed. 2014, 53,
5877-5881.
[12] Catalytic Cu in phenol C-C coupling: B. S. Liao, Y. H. Liu, S. M. Peng, S.
T. Liu, J. Chem. Soc. Dalton Trans 2012, 41, 1158-1164.
[13] Catalytic Co in phenol C-C coupling: a) Q. Jiang, W. Sheng, M. Tian, J.
Tang, C. Guo, Eur. J. Org. Chem. 2013, 2013, 1861-1866; b) H. Reiss,
H. Shalit, V. Vershinin, N. Y. More, H. Forckosh, D. Pappo, J. Org. Chem.
2019, 84, 7950-7960.
[26] M. S. Askari, K. V. N. Esguerra, J.-P. Lumb, X. Ottenwaelder, Inorg.
Chem. 2015, 54, 8665-8672.
[27] For formation of tetraphenol derived xanthene of similar structure through
a different oxidative process, see: L. T. Byrne, F. R. Hewgill, F. Legge, B.
W. Skelton, A. H. White, J. Chem. Soc. Perk. Trans.1 1982, 2855-2862.
[28] J.-H. Lin, M. Ishimatsu, T. Tanaka, G.-i. Nonaka, I. Nishioka, Chem.
Pharm. Bull. 1990, 38, 1844-1851.
[14] Catalyic phenol C-C coupling with several metals: Y. E. Lee, T. Cao, C.
Torruellas, M. C. Kozlowski, J. Am. Chem. Soc. 2014, 136, 6782-6785.
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A facile method to oxidatively trimerize phenols using a low loading catalytic aerobic copper system is
described. The natural product pyrolaside B has been synthesized for the first time using this method,
which allows an expeditious entry in five steps and 16% overall yield. Two analogues were also
synthesized.
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