A Common C2-Symmetric 2,2’-Biphenol Building Block and
its Application in the Synthesis of (+)-di-epi-Gonytolide A
Julian Greb,[a] Till Drennhaus,[b] Moritz K. T. Klischan,[a] Zachary W. Schroeder,[a]

Wolfgang Frey,[c] and Jörg Pietruszka*[a, b]

Abstract: A variety of biaryl polyketides exhibit remarkable
bioactivities. However, their synthetic accessibility is often
challenging. Herein, the enantioselective preparation and
synthetic application of an axially chiral 2,2’-biphenol building
block is outlined that represents a common motif of these
intriguing natural products. Based on the highly regioselec-
tive and scalable bromination of a phenol precursor, a
coupling process by Lipshutz cuprate oxidation was devel-
oped. A copper-mediated deracemization strategy proved to

be superior to derivatization or kinetic resolution approaches.
Key steps in the overall building block synthesis were
rationalized through DFT studies. Utilizing the 2,2’-biphenol, a
highly diastereoselective five step synthesis of formerly
unknown (+)-di-epi-gonytolide A was developed, thus show-
casing the building block’s general potential for the synthesis
of natural products and their derivatives. En route, the first
enantioselective construction of a chromone dimer intermedi-
ate was established.

Introduction

Aromatic polyketides represent a structurally highly diverse
class of natural products produced by fungi, bacteria, and
plants.[1] Among the variety of late-stage tailoring transforma-
tions that nature uses to expand their chemical space,
dimerization reactions have received increasing attention over
the last two decades.[2] Along with non-biaryl representatives,
these oxidative coupling processes form structurally intriguing
biaryl compounds that exhibit a remarkable range of clinically
relevant bioactivities and are often more potent than their
monomeric counterparts.[3] The binaphtho-α-pyranone[4] viridi-
toxin for instance shows antibacterial activity against drug-
resistant bacterial pathogens[5] as well as potent antitumor
activities, which were also found for a variety of binaphtho-γ-
pyranones[6] such as ustilaginoidin A (Figure 1A).[7] Further

examples include the antifeedant bicoumarin isokotanin A[8] or
the more complex tetrahydroxanthone dimer[9] rugulotrosin
A[10] and chromanone lactone dimer[11] gonytolide A[3b] that

[a] J. Greb, M. K. T. Klischan, Z. W. Schroeder, Prof. Dr. J. Pietruszka
Institute for Bioorganic Chemistry & Bioeconomy Science Center (BioSC)
Heinrich Heine University Düsseldorf in Forschungszentrum Jülich
52426 Jülich (Germany)
E-mail: j.pietruszka@fz-juelich.de

[b] T. Drennhaus, Prof. Dr. J. Pietruszka
Institute of Bio- and Geosciences (IBG-1: Biotechnology)
Forschungszentrum Jülich
52426 Jülich (Germany)

[c] Dr. W. Frey
Institute of Organic Chemistry
University of Stuttgart
70569 Stuttgart (Germany)

Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202300941

© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH
GmbH. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which permits use
and distribution in any medium, provided the original work is properly cited,
the use is non-commercial and no modifications or adaptations are made.

Figure 1. A 2,2’-biphenol as common motif building block for the synthesis
of aromatic polyketide dimer natural products and their derivatives.

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http://orcid.org/0000-0003-2614-9308
http://orcid.org/0000-0003-0368-2898
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https://doi.org/10.1002/chem.202300941


feature antibacterial and immuno-stimulating activities, respec-
tively. In many of these dimeric polyketides, rotation around
the biaryl axis is hindered, which causes the corresponding
molecules to be axially chiral. This phenomenon of
atropisomerism[12] has found growing interest among medicinal
chemists in recent times[13] highlighting the impact of natural
product structures on drug development.[14] However, from a
synthetic point of view,[15] the construction of the stereogenic
axis is a major challenge due to its inherently crowded nature,
which is exemplified by the lack of well-established atropselec-
tive coupling[16] or resolution[17] methods that are broadly
applicable. Hence, there is no general solution for the
construction of bioactive molecules featuring a stereogenic axis.
Still, for certain targets tailor-made and remarkable solutions
have been developed. Often, the stereogenic axis is introduced
by a late-stage biaryl coupling.[18] The atropselectivity of these
methods, however, commonly relies on specific carbon scaf-
folds, substitution patterns or coordinating groups. In other
cases, the atropselectivity of the coupling step depends on a
stereoinduction by chiral monomeric precursors, which is
difficult to anticipate. To avoid these uncertainties, alternative
strategies seek to establish the axial configuration early on by
using hindered biaryl intermediates in the initial stages of the
synthesis.[19] While these strategies eliminate atropselectivity
concerns, the intermediates used are often highly specialized
and require lengthy auxiliary chemistry or tedious chromato-
graphic separations and functional group interconversions. This
can limit their scalable preparation and general applicability.
Therefore, a readily accessible axially chiral biaryl with a
common substitution pattern would be a valuable building
block. It would not only provide control over the axial
configuration, but also enable more modular synthetic ap-
proaches. This, in turn, should allow for an efficient synthesis of
biaryl polyketides and their analogues.

The specific biaryl suggested is 2,2’-biphenol 1 (Figure 1B),
which represents a common 1,1’,5,5’-tetraoxy-3,3’-dicarbo-2,2’-
biaryl motif that can be found in a variety of aromatic
polyketide dimers (Figure 1A). Indeed, biphenol 1 is known by
seminal work of Musso since the late 1960 s[20] and later
syntheses by Solladie.[21] However, considering our intended
use, the reported synthetic routes suffer from insufficient overall
yield, scalability or enantiomeric excess. In consequence, no
application of 2,2’-biphenol 1 in the field of natural product
synthesis is known to date.

Results and Discussion

Three structural features of 2,2’-biphenol 1 have been identified
as key challenges for an efficient synthesis: (a) the 1,3,5-
substitution pattern, (b) the tetra-ortho-substituted biaryl bond,
and (c) the axial configuration. The substitution pattern was
established early in the synthesis. This should avoid lengthy,
and potentially harsh functional group interconversions that
could potentially deteriorate the overall yield or enantiomeric
excess of biphenol 1 at a late stage. The atropselective
construction of the stereogenic axis was divided into a coupling

and resolution step. This division aimed to overcome challenges
related to steric crowding and enantioselectivity in an inde-
pendent manner. Herein, our optimized route to 2,2’-biphenol 1
is outlined and its first application as dimeric polyketide
building block is showcased in the selective and efficient
preparation of (+)-2’,11-di-epi-gonytolide A (2).

Bromophenol synthesis

The monomeric unit of 2,2’-biphenol 1, 3-methyl-5-methoxy
phenol (3) was synthesized starting from low-cost orcinol (4) in
two steps (Scheme 1A). First, dimethyl orcinol 5 was obtained in

Scheme 1. Synthesis and bromination of unprotected phenol 3 (A); robust
and scalable preparation of 2-bromophenol 6 enabled by a transient acetyl
protection likely leading to a change in mechanism (B). [a] Ratios determined
by 1H-NMR analysis; used to derive regioisomeric ratios (r.r.). [b] Most
prominently 2,4-dibromophenol.

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98% yield through permethylation using dimethyl sulfate.
Subsequently, the arene was efficiently desymmetrized by
selective monodemethylation with sodium n-propyl thiolate,
possibly facilitated by the intermediate sodium phenolate’s
reduced electrophilicity. Distillation afforded phenol 3 in 89%
yield on a 50 g-scale.[22]

To enable a regioselective coupling of the monomeric unit
3, typical bromination conditions were investigated. When
treated with elemental bromine or N-bromosuccinimide (NBS)
on small scales of 0.5 mmol, phenol 3 was predominately
brominated in the 2-position and 2-bromophenol 6 could be
isolated in up to 61% yield.[23] In addition, 4-bromophenol 7
and other brominated arenes 8 were formed as side products.
However, upon scaling (up to 29 mmol phenol 3), the observed
regioisomeric ratios (r.r.) generally varied and a marked increase
in the formation of side products 8 was observed (most
prominently 2,4-dibromination, up to 42%, see Table SI-2).
Separation of these side products was challenging, thereby
impeding the reproducible isolation of desired 2-bromophenol
6 in larger amounts.

The bromination of free phenols proceeds via cyclohexadie-
none intermediates 9.[24] These intermediates are thought to be
formed in a concerted and exothermic manner after electro-
phile coordination by the phenolic alcohol (Scheme 1B, upper
gray box). This results in a kinetically controlled ortho-selectivity,
which is in accordance with the predominant 2-bromination of
phenol 3. Hence, the lack of robustness and selectivity observed
during scaling may be attributed to the concentration depend-
ency of the initial coordination, along with the exothermic
nature of the selectivity-determining bromination step. Con-
sequently, the protection of the hydroxy group was reasoned to
enhance the overall robustness, chemo- and regioselectivity.
After simple ester formation using acetic anhydride, phenol
acetate 10 was selectively monobrominated to 2-bromo- (11)
and 4-bromoacetate 12 with a highly reproducible and
improved r.r. of 85 :15 (Scheme 1B). Methanolysis yielded a
mixture of regioisomers 6 and 7 which were easily separated
and purified due to the absence of any side products 8.
Repetitive recrystallization and distillation of the concentrated
mother liquor provided desired 2-bromophenol 6 on a 60 g-
scale in an useful overall yield of 82%.

The improved control in regioselectivity was attributed to a
change in mechanism towards a canonical SEAr pathway. This
likely involved the initial endothermic formation of the 2-bromo
and 4-bromo σ-complex intermediates 13 a and 14 a (Sche-
me 1B, lower gray box).[25] To validate this hypothesis and
explain the protecting group’s influence on the selectivity, DFT
studies[26] on the theoretical regioisomeric σ-complexes 13, 14
and 15 were conducted that carry different protecting groups
(Scheme 2 and Figures S7–S11).[25,27] Following the Hammond
postulate, these should resemble the late transition states of a
canonical bromination process. As a result, their energetic
difference should match the observed regioselectivities. Indeed,
it was found that there is a good correlation between the
relative free energies of O-acetyl- (a), O-methoxymethyl (MOM)-
(b) or O-methyl- (c) protected σ-complexes and experimental
r.r. data. As the protecting group’s acceptor ability increases

(from methyl to MOM to acetyl), a more pronounced energetic
differentiation of the 2- and 4-position was predicted which
was in perfect agreement with the observed regioselectivities.
The corresponding 6-bromo intermediates 15 a–c were signifi-
cantly disfavored and generally not observed experimentally. In
contrast, for the free phenol intermediates 13 d, 14 d and 15 d
the theoretical ratios deviate qualitatively from the experimen-
tal results, which is in line with the suggested change in
mechanism.

Homocoupling

With 2-bromophenol 6 in hand, we turned towards the
development of an efficient protocol for the challenging
formation of the tetra-ortho-substituted biaryl axis. After
protection, O-MOM-bromophenol 16 was subjected to various
homocoupling conditions. While simple Ullmann coupling as
well as halogen-metal exchange of the electron-rich arene using
Grignard reagents[28] failed, treatment with n-butyllithium
followed by oxidation with iron(III) chloride[19i] led to an initial
formation of O-MOM-diprotected 2,2’-biphenol 17 in 9% yield
(Table S4, Figure S22 for X-ray structure, CCDC 2240361).
However, predominant formation of protodehalogenated side
product 18 and minor amounts of butylated side product 19 a
were observed. Ultimately, oxidation of a higher order biaryl
Lipshutz cuprate[29] turned out to be particularly suited for the
construction of the crowded biaryl bond (Scheme 3).

Scheme 2. DFT studies on theoretical regioisomeric σ-complexes validated
the hypothesized change in mechanism. [a] Experimental data for the
bromination of (protected) phenols at the indicated conditions; calculations
were performed at the M06-2X/def2-TZVPP/C-PCM(CH2Cl2)//r

2SCAN-3c/C-
PCM(CH2Cl2) level of theory.

[26] [b] Regioisomeric ratios (r.r.) varied and the
formation of over-brominated products was observed.

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The di-lithium cyano cuprate Ar2Cu(CN)Li2 was formed by a
halogen-metal exchange of bromide 16 with tert-butyllithium
followed by the addition of 0.5 equivalents of a copper(I)
cyanide di-lithium chloride solution. While the literature-
described direct treatment of this cuprate with molecular
oxygen[29] produced phenol 20 as major side product, the use
of readily available tetra-tert-butyldiphenoquinone (DPQ) as
alternative oxidant yielded biaryl 17 in 83% yield. Though
quinones are known oxidants for such copper-mediated
homocouplings,[30] the particular combination of a Lipshutz
cuprate with DPQ[28] is, to the best of our knowledge, a new
reagent combination and might be generally useful for the
construction of sterically demanding biaryl bonds. Scaled
reaction conditions employing up to 125 mmol starting material
used n-butyl- instead of tert-butyllithium due to safety consid-
erations and showed only slightly diminished yields of 74%.
Additional modifications of the scaled conditions included the
use of crude starting material, solid copper cyanide as well as
reduced amounts of organolithium reagent and diquinone
oxidant. Furthermore, the biaryl product was isolated by
recrystallization and reoxidation of the hydrodiquinone by-
product DPQH2 under alkaline conditions could be used to
regenerate DPQ in 86% yield. Subsequent deprotection of 17
with trifluoracetic acid in methanol yielded the desired tetra-
ortho-substituted 2,2’-biphenol 1 on a decagram scale. In total,

starting from monophenol 3,[22] yields of up to 66% over six
steps were obtained without the need for column chromato-
graphic purification or precious transition metals.

Resolution and deracemization

For the resolution of racemic 1, we strategically utilized its 2,2’-
diol motif. In search for an efficient process, various methods
have been evaluated.

Initially, a classic derivatization approach was investigated
using (+)-camphorsulfonyl chloride as chiral auxiliary
(Scheme 4A).[31] After clean diester formation, the resulting pair
of diastereomeric sulfonates (Sa)-21 and (Ra)-22 was subjected
to a single column chromatographic isolation, resulting in an
incomplete separation and yields of 9% and 8%, respectively.
While the subsequent hydrolysis of 21 proceeded cleanly and
enantiomerically pure (Sa)-biphenol 1 was obtained successfully,
the overall practicality was limited by the inefficient and
laborious chromatographic separation. Subsequently, a recently
established kinetic resolution method for biaryl-2,2’-diols was
examined.[32] Birman’s (S)-benzotetramisole (BTM) catalyst was
used in an enantioselective monoacylation of racemic 1 using
diphenylacetic anhydride as acyl donor (Scheme 4B). The
reaction yielded (Sa)-biphenol 1 and (Ra)-monoester 23 in 32%
and 64% with 98%ee and 50%ee, respectively. The moderate
selectivity factor[33] s of 11–13 for biphenyl 1 may not be
unexpected, as the applied as well as other known resolution
methods for atropisomers are optimized for arguably less
challenging binaphthyl systems.[17b,32,34] While the overall scale
and efficacy could be increased relative to the derivatization
approach, the methodology still lacked sufficient practicality for
a building block synthesis.

Scheme 3. Optimized homocoupling for the column-free synthesis of tetra-
ortho-substituted 2,2’-biphenol 1 on a decagram scale. The use of recovered
DPQ resulted in an identical reaction outcome; the X-ray structure (CCDC
2240360) is shown as ORTEP at 50% probability.

Scheme 4. Atropenantiomer resolution by ‘chiral derivatization’-chromato-
graphic separation (A) or kinetic resolution (B); the methods yielded highly
enantioenriched (� )-(Sa)-2,2’-biphenol 1 but showed limited efficacy.

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Consequently, we turned towards a copper-mediated
deracemization approach that should have the advantage of
inherently higher yields and was originally developed for the
enantioselective synthesis of BINOL-type ligand scaffolds[35] as
well as more recently applied in total synthesis.[36] The method
involves formation of diastereomeric sparteine copper(II) com-
plexes with chiral biaryl-2,2’-diols. These complexes enable an
epimerization of the biaryl axis and result in an accumulation of
one atropenantiomer by favoring the thermodynamically more
stable complex with a matching axial configuration relative to
the rigid chiral diamine ligand. The deracemization method was
successfully transferred to 2,2’-biphenol 1 (Scheme 5A).

Reproducibility and stable yields were ensured by formation
of the diastereomeric (� )-sparteine copper(II) biphenol com-
plexes (Sa)-24 and (Ra)-25 from copper(II) chloride[35a] rather than
in-situ oxidized copper(I) chloride.[35c] Addition of sodium
carbonate as auxiliary base was needed to keep enantiomeric
excesses stable and is thought to prevent protonation of the
chiral amine ligand by the additionally released equivalent of
hydrogen chloride.[35d] Complex hydrolysis after 48 h at 23 °C
yielded (Sa)-1 in up to 76% yield and 90%ee. As electron-rich
and bidentate 2,2’-biphenol 1 was found to be sensitive to
oxidation in the presence of residual copper during the
quenching process, a workup using hexadentate ethylenediami-
netetraacetic acid (EDTA) was developed, that prevented post-
reaction product degradation. Additionally, it allowed an

effortless acid-base extraction of sparteine that could be
reisolated in 93% yield after column chromatography. Alter-
natively, crude sparteine could be used directly in another
deracemization reaction with only slight effects on the final
enantiomeric excess of biphenol 1 (84%ee after second reuse).
Recycling (� )-sparteine in this batch-wise manner resulted in
the preparation of (� )-(Sa)-2,2’-biphenol 1 on a gram scale and
with >99%ee after additional recrystallization (78% mass
recovery). Besides HPLC analyses, the excellent enantiomeric
excess of 1 was highlighted by its high specific rotation and an
elevated melting point of 175–176 °C relative to the racemate
(145–146 °C).[20]

To understand the thermodynamic factors, which led to the
observed stereochemical outcome, corresponding DFT
studies[26] were performed (Scheme 5B). Geometries and relative
free energies of the theoretical diastereomeric complexes (Sa)-
24 and (Ra)-25 were calculated. The resulting energetic differ-
ence of 2.0 kcal mol� 1 in favor of the (Sa)-complex with the
matched configuration correlated well with the observed
equilibrium ratio of 95 :5 e.r. after complex hydrolysis. While a
more detailed analysis is provided in the Supporting Informa-
tion, it can be briefly summarized that the cause of the
energetic enantio-discrimination likely originates from an
increased distortion of the copper(II) ligand sphere from a
preferred square planar geometry and a strained biphenol
ligand scaffold within mismatched complex (Ra)-24 relative to
(Sa)-25 (chelate plane angle Ψ indicated in Scheme 5B and
Figure S15–S17).[35b,c,36d] Kinetically, the deracemization reaction
is believed to be enabled by a single electron transfer from one
of the phenol moieties to copper(II), resulting in a copper(I)
phenoxyl radical with increased sp3-character in the 1-position
and a thereby reduced rotational barrier of the biphenol
ligand.[12b,35d,37] By contrast, the isolated (Sa)-2,2’-biphenol 1 is
configurationally stable. Additional DFT studies[26,38] indicated a
high thermal rotational barrier of ΔG�

rot=49.1 kcalmol� 1 (Fig-
ure S4) ensuring stereochemical integrity in subsequent trans-
formations. In combination with the straightforward prepara-
tion of racemic material, the single-step resolution process
allowed for efficient access to large quantities of enantiopure
2,2’-biphenol 1 in sufficient yields to be of use as a building
block.

Application

To exemplify its applicability in the preparation of complex
polyketide dimer structures and their derivatives, a synthetic
showcase is presented. Starting from biphenol 1, a concise
approach towards a diastereomer of natural chromanone
lactone dimer gonytolide A[3b,18e,f,39] via an axially chiral chro-
mone-8,8’-dimer 26 was developed (Scheme 6). It was envi-
sioned that the presence of a stereogenic axis within
intermediate 26 could be utilized for a diastereoselective
construction of the stereochemical dyads within the chroma-
none lactone moieties.

Synthesis of chromone dimer 26 commenced with a bidirec-
tional Friedel–Crafts acylation of biphenol 1. A regioselective

Scheme 5. Single-step preparation of (� )-(Sa)-2,2’-biphenol 1 by a (� )-
sparteine/copper(II) mediated deracemization featuring ligand recycling and
EDTA workup (A); DFT studies on the theoretical diastereomeric complexes
(Sa)-24 and (Ra)-25 (B); Ψ refers to the angle between the two chelate planes
(N� Cu� N and O� Cu� O, indicated as blue and red disks); calculations were
performed at the M06/def2-QZVP//r2SCAN-3c level of theory.[26]

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functionalization in 6,6’-position was enabled by the 2,2’-diol
motif. After kinetic O-acylation with acetyl chloride, a titanium
chloride-mediated ortho-selective Fries rearrangement yielded
acetophenone dimer 27 in up to 82% yield.[19f]

Enantiomeric excesses were observed to be unaffected,
which agreed with the predicted high rotational barrier of 1
and 27 (ΔG�

rot=39.2 kcalmol� 1, Figure S5).[38] Reaction of
acetophenone dimer 27 with diethyl oxalate and sodium
ethoxide in ethanol, followed by acidic condensation and
transesterification in methanol were found to be ideal con-
ditions and resulted in the clean formation of 5,5’-methoxy
chromone dimer 28 (Schemes S9, S10).[40] Notably, a distinct
increase in solubility for enantiopure (Sa)-28 relative to racemic
material was observed (Figure S31) that was also reflected in
the corresponding melting points [212–214 °C ((Sa)-28), de-
comps. >300 °C (rac-28)].[41] Demethylation of 28 was per-
formed using boron trichloride in dichloromethane. With an
excess of Lewis acid, the double demethylation proceeded
quickly, likely promoted by boron trichloride coordination
through the ketones in direct proximity to the 5,5’-methoxy
substituents. The resulting 5,5’-dihydroxy chromone dimer 26
could be isolated in 89–99% yield (Figure S33 for X-ray
structure, CCDC 2240362). Again, the enantiomeric excess of
(Sa)-26 was found to be unaffected by the employed reaction
conditions in line with a calculated ΔG�

rot of 42.3 kcal mol� 1

(Figure S6).[12b,38] Chromanone lactones can be synthesized from
5-hydroxy chromones through a vinylogous Michael addition of
siloxyfuran to a silyl triflate-generated benzopyrylium followed
by deprotection and hydrogenation of the formed chromanone
butenolides.[42] The method was successfully reproduced in the
synthesis of monomeric (�)-epi- and (�)-gonytolide C and
showed literature consistent yields as well as kinetic syn- and

thermodynamic anti-selectivity (20 :1 d.r., reaction at � 78 °C vs
1 :3 d.r. after epimerization at 0 °C, Figure S11). Subsequently,
the reaction conditions were transferred to dimeric hydrox-
ychromone 26. After presumed formation of a benzopyrylium
triflate dimer with di-iso-propylsilyl bistriflate, addition of
trimethylsiloxyfuran followed by global silyl deprotection after
3–4 h at � 95–(� 78) °C yielded a major non-C2-symmetrical
chromanone butenolide dimer 29 (~85% by crude NMR) as one
out of ten possible diastereomers. Note that, due to the
symmetrical constitution, there are less than the theoretical
maximum of sixteen diastereomers (Scheme S18). After catalytic
hydrogenation in flow, the corresponding chromanone lactone
dimer 2 could be isolated in up to 64% yield and �98%ee on
scales of 30–200 mg. An X-ray crystallographic analysis of the
final product 2 revealed the highly diastereoselective formation
of (syn,syn’)-configured (+)-2’,11-di-epi-gonytolide A (for details
see Figures S18–S21, Scheme S13, S14; CCDC 2240363).

In summary, an effective and highly enantio- as well as
diastereoselective five step synthesis of the complex chroma-
none lactone dimer 2 in up to 46% yield has been developed.
This synthesis started from an axially chiral 2,2’-biphenol
building block 1 that has been designed based on biphenol
motifs found ubiquitously in nature and has been made
accessible on a gram scale.

Conclusion

A scalable and efficient synthesis was developed for the 2,2’-
biphenol building block 1 that represents a common substitu-
tion pattern of dimeric aromatic polyketides. After establishing
the 3-methyl-5-methoxy substitution pattern on the monomeric

Scheme 6. Application of racemic and enantiopure 2,2’-biphenol building block 1 in the selective synthesis of complex chromanone lactone dimer (+)-2’,11-
di-epi-goytolide A (2). Racemic (�)-29 could be isolated by recrystallization and reprecipitation; crude (Sa)-29 was submitted to hydrogenation directly; the X-
ray structure (CCDC 2240363) is shown as ORTEP at 50% probability.

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subunit, a robust and selective 2-bromination of monomeric
phenol 3 on a 60 g scale was enabled by a temporary O-
acetylation. DFT studies confirmed that a modulation of the
phenol’s electronics by the protection likely results in a change
in mechanism alongside a significantly improved regioselectiv-
ity. High-yielding construction of the challenging tetra-ortho-
substituted biaryl bond was achieved via oxidation of a
homomeric biaryl Lipshutz cuprate using the diquinone DPQ as
oxidant that could be recycled using molecular oxygen. Starting
from phenol 3,[22] racemic 2,2’-biphenol 1 was obtained in up to
66% overall yield on a decagram scale and in only six steps
without the need for column chromatography. Different
resolution strategies were established and evaluated. While
derivatization-chromatographic separation and organocatalytic
kinetic resolution approaches proved to be viable routes, a
copper(II)/sparteine-mediated deracemization was found to be
the superior and more efficient strategy. Enantiopure (Sa)-
biphenol 1 was prepared in useful quantities of more than one
gram and copper scavenging using EDTA enabled recycling of
the chiral diamine ligand. Note that even though the availability
and price of sparteine varied in recent years,[43] both natural
alkaloid enantiomers are readily available by O’Brien’s concise
gram scale synthesis[44] granting access to either biaryl anti-
podes. Complementary DFT studies on the molecular basis of
the central-to-axial chirality transfer during deracemization
identified an increased distortion of the ligand-sphere and a
strained biphenol scaffold within the mismatched theoretical
sparteine copper biphenol complex (Ra)-25. The scalable access
to biphenol (Sa)-1 enables application towards complex natural
product synthesis. In a bidirectional manner, the biphenol
building block was advanced to 5,5’-dimethoxy- and 5,5’-
dihydroxy-chromonecarboxylate-8,8’-dimers 28 and 26. While
these axially chiral natural product fragments and simplified
derivatives thereof have been known since the 1960 s[45] and
gained interest more recently,[46] the outlined work represents
their first enantioselective synthesis. Starting from 26, the so far
unknown unsymmetrical chromanone lactone dimer (+)-2’,11-
di-epi-gonytolide A 2 was synthesized. In a highly diastereose-
lective double siloxyfuran addition followed by in-flow hydro-
genation, 2 was obtained as the major product being one out
of ten possible diastereomers and implying a marked stereo-
induction by the biaryl axis. Overall, yields of up to 46% in only
five steps starting from biphenol 1 were obtained, underlining
the strength of the presented building block strategy for the
construction of highly complex natural products, their frag-
ments, or derivatives. While remarkable progress has been seen
in the direct construction of axially chiral biphenyls over the
recent years,[18g,47] the presented synthetic route will serve as a
blueprint for the construction of other homodimeric biphenols
as building blocks or axially chiral ligands. Additionally, and due
to its common polyketide substitution pattern, 2,2’-biphenol 1
should provide a privileged platform for the chemical space
exploration around chromanone lactones and related aromatic
polyketide dimers, supporting the evaluation of their rich
bioactivity profiles in future diversity-oriented or targeted
endeavors.

Supporting Information

Deposition Numbers 2240360 (for 1), 2240361 (for 17), 2240362
(for 26), 2240363 (for 2) contain the supplementary crystallo-
graphic data for this paper. These data are provided free of
charge by the joint Cambridge Crystallographic Data Centre
and Fachinformationszentrum Karlsruhe Access Structures serv-
ice.

Additional references cited within the Supporting
Information.[48]

Acknowledgements

We gratefully acknowledge the DFG (GRK2158), the DAAD RISE
program (Z.W.S.) as well as the Heinrich Heine University
Düsseldorf and the Forschungszentrum Jülich GmbH for their
ongoing support. We thank Fabian Hogenkamp, Marvin R.
Mantel, Sebastian Myllek and Ruth C. Ganardi for scientific
consultation as well as Birgit Henßen, Vera Ophoven and Max
Schlamkow for HPLC analytics and synthesis support. Open
Access funding enabled and organized by Projekt DEAL.

Conflict of Interests

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available
from the corresponding author upon reasonable request.

Keywords: natural products · atropisomerism · total synthesis ·
building block · density functional calculations

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Manuscript received: March 24, 2023
Accepted manuscript online: April 17, 2023
Version of record online: May 2, 2023

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