Coumarins by Direct Annulation: β-Borylacrylates as Ambiphilic C3-Synthons

Article abstract of DOI:10.1002/anie.202012099

Modular β-borylacrylates have been validated as programmable, ambiphilic C₃-synthons in the cascade annulation of 2-halo-phenol derivatives to generate structurally and electronically diverse coumarins. Key to this [3+3] disconnection is the BPin unit which serves a dual purpose as both a traceless linker for C(sp²)–C(sp²) coupling, and as a chromophore extension to enable inversion of the alkene geometry via selective energy transfer catalysis. Mild isomerisation is a pre-condition to access 3-substituted coumarins and provides a handle for divergence. The method is showcased in the synthesis of representative natural products that contain this venerable chemotype. Facile entry into π-expanded estrone derivatives modified at the A-ring is disclosed to demonstrate the potential of the method in bioassay development or in drug repurposing.

Full text of DOI:10.1002/anie.202012099

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Accepted Article
Title: Coumarins by Direct Annulation: β-Borylacrylates as Ambiphilic
C3-Synthons
Authors: Max Wienhold, John J. Molloy, Constantin G. Daniliuc, and
Ryan Gilmour
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10.1002/anie.202012099
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COMMUNICATION
Coumarins by Direct Annulation: β-Borylacrylates as Ambiphilic
C3-Synthons
Max Wienhold, John J. Molloy, Constantin G. Daniliuc, and Ryan Gilmour*
Dedicated to Prof. Dr. Albert Eschenmoser on the occasion of his 95th birthday.
M.Sc. M. Wienhold, Dr. J. J. Molloy, Dr. C. G. Daniliuc, Prof. Dr. R. Gilmour
Organisch Chemisches Intitut
Westfälische Wilhelms-Universität Münster
Corrensstraße 36, 48149 Münster (Germany)
E-mail: ryan.gilmour@uni-muenster.de
https://www.uni-muenster.de/Chemie.oc/gilmour/
Supporting information for this article is given via a link at the end of the document.
Abstract: Modular β-borylacrylates have been validated as
programmable, ambiphilic C3-synthons in the cascade annulation of
2-halo-phenol derivatives to generate structurally and electronically
diverse coumarins. Key to this [3+3] disconnection is the BPin unit
which serves a dual purpose as both a traceless linker for C(sp2)-
C(sp2) coupling, and as a chromophore extension to enable inversion
of the alkene geometry via selective energy transfer catalysis. Mild
isomerisation is a pre-condition to access 3-substituted coumarins
and provides a handle for divergence. The method is showcased in
the synthesis of representative natural products that contain this
venerable chemotype. Facile entry into π-expanded estrone
derivatives modified at the A-ring is disclosed to demonstrate the
potential of the method in bioassay development or in drug
repurposing.
linker for C(sp2)-C(sp2) coupling, and as a chromophore antennae
to enable inversion of the alkene geometry[14] via selective energy
transfer catalysis.[15] In the absence of base-mediated
isomerisation,[16] regulating alkene geometry is necessary to
facilitate lactonisation to access 3-substituted coumarins.
This disconnection capitalises upon abundance of 2-halophenols
in biology (Figure 1, bottom),[17] their regioselective halogenation
chemistries[17,18] and the importance of the coumarin scaffold (III)
in both drug discovery and molecular imaging.[19] Given the
notable methodological advances in selective halogenation,[20] it
was envisaged that this [3+3] annulation may facilitate natural
product/drug re-purposing.[21]
Innovative advances in annulation chemistry have been a defining
feature in the evolution of organic synthesis: This reflects the
importance of heterocycles in target synthesis, and in the design
of functional small molecules in a broader sense.[1] As exemplified
by the venerable Huisgen cycloaddition,[2,3] operationally simple
“click” processes to construct unnatural heterocyclic scaffolds
have been intensively pursued and enjoy widespread application
in chemical biology.[4] Predicated on high efficiency, tolerance and
atom economy,[5] these enduring processes serve as valuable
guidelines for the conception of annulation routes to naturally-
occurring heterocyclic scaffolds. In particular, the revered history
of the coumarin nucleus as a drug module and natural product
core, together with its importance in functional materials,
constitute persuasive arguments to devise more effective
synthesis routes based on direct annulation.[6] The long-standing
importance of this bicyclic framework is evident from the early
works of Perkin[7] and Pechmann,[8] which have since been
complemented by an array of transition metal,[9] photochemical[10]
and modified Knoevenagel condensation approaches.[11] To
further strengthen this diverse synthesis arsenal with a direct
coupling, a [3+3] approach was envisaged that would unify
halogenated phenols (I) with a simple ambiphilic C3 fragment (II)
via two successive bond forming events (Figure 1). β-
borylacrylates (II)[12] were conceived as attractive coupling
partners for a Suzuki-Miyaura/substitution cascade due to their
ease of preparation and structural tenacity.[13] Moreover, the BPin
unit in this modular acrylate platform serves as both a traceless
Figure 1: Upper: Conceptual framework for a direct 2-halo-phenol to coumarin
annulation using β-borylacrylates. Bottom: Halogenated natural products.[17]
1
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To validate the conceptual framework outlined in Figure 1, the
coupling of 2-bromophenol and β-borylacrylate Z-2 (1.0 eq.) was
explored (Table 1). Gratifyingly, exposing the coupling partners to
Pd(OAc)2 and SPhos in 1,4-dioxane at 80 °C generated the
desired coumarin 3 in 30% yield after 16 h (entry 1). Switching
solvent to N,N,-dimethylformamide led to a modest improvement
in yield (41%, entry 2), whereas DMSO was detrimental (32%,
entry 3). Utilising 2.0 eq. of β-borylacrylate Z-2 in DMF led to an
increased yield of 53% (entry 4) and so these parameters were
fixed for the reminder of the optimisation. Variation in the Pd
source (entries 5 and 6) and base (entries 7 and 8) was then
with the general conditions (10, 71%), as were anisole derivatives
enabling formation of 11 (63%). Expected chemoselective C(sp2)-
C(sp2) coupling was confirmed by formation of the chlorinated
derivative 12 (63%). To demonstrate the utility of the method in
accessing more sterically congested, 2-bromo-3-methylphenol
and 1-bromo-2-naphtol were exposed to the standard annulation
conditions enabling formation of 13 (85%) and 14 (80%),
respectively. The latter system demonstrates the suitability of this
approach in accessing the naphthopyran-2-one class of
photochromic dyes.[24] Furthermore, the transformation enables
formation of -expanded systems such as the biaryl derivative 15
explored, but these alterations did not confer a notable advantage. in 68%.[6b]
Altering the temperature had a negative impact on yield (entries 9
and 10), but exclusion of water proved to be beneficial (82%, entry
11). This observation, together with the yield enhancement when
using 2.0 eq., suggests that Z-2 displays limited stability under
basic aqueous conditions. Given the involvement of an
oxopalladium-complex in the Suzuki-Miyaura mechanism,[22] it is
pertinent to note that the DMF used is not fully anhydrous and
thus water is likely present in the reaction mixture.
Table 1: Reaction optimisation in the formation of coumarin 3.
En
try
H2O
(eq.)
T
°C
Catalyst
Ligand
SPhos
Base
Solvent
Yield
30
1,4-
dioxane
DMF
1b
Pd(OAc)2
K3PO4
5.0
80
2b
3b
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(dppf)
SPhos
SPhos
SPhos
-
K3PO4
K3PO4
K3PO4
K3PO4
5.0
5.0
5.0
5.0
80
80
80
80
41
32
53
37
DMSO
DMF
5
DMF
45
6
-
K3PO4
DMF
5.0
80
c
Cl2
50
31
41
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
SPhos
SPhos
SPhos
K2CO3
CsCO3
K3PO4
DMF
DMF
DMF
5.0
5.0
5.0
80
80
50
10
0
39
10
11
Pd(OAc)2
Pd(OAc)2
SPhos
SPhos
K3PO4
K3PO4
DMF
DMF
5.0
/
82
80
(76)d
a
Yields determined by NMR using 1,3,5-trimethoxybenzene as internal
standard; b 1.0 eq. of Z-2 was used; c DCM complex; d Numbers in parenthesis
are isolated yields.
Having identified optimised reaction conditions for the catalytic
annulation, the scope and limitations were investigated using a
range of electronically and structurally modified 2-bromophenols
(Figure 2). Systematically increasing the steric demand of the β-
substituent of the β-borylacrylate from n-propyl (4) to cyclopropyl
(5) and methylcyclohexyl (6) was well tolerated (69%, 67% and
75% yield, respectively). Incorporation of an aryl group furnished
7 in 73% yield. The addition of an -substituent was also well
tolerated enabling the formation of 3,4-dimethylcoumarin (8) in
83%. Given the importance of fluorinated aryl systems in drug
discovery,[23] the influence of bioisosteric H to F substitution on the
phenol coupling partner was examined. This led to smooth
formation of 9 in 76% yield. Free amines were also compatible
Figure 2: Scope of the annulation and application in natural product synthesis
and derivatisation.
To demonstrate the synthetic utility of β-borylacrylates in
derivatising biological frameworks, commercially available 3-
bromotyrosine was processed to 16 in 81%. Moreover, the
terpene derivatives 2- and 4-bromoestrone could be smoothly
transformed into 17 and 18 (50% and 55%, respectively), enabling
entry into novel π-extended analogs of this the parent hormone.
2
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A brominated derivative of the anti-tumour agent combretastatin
A-4 underwent smooth annulation, enabling formation of the
coumarin derivative 19 in 59% yield. It is pertinent to note that
combretastatin A-4-phosphate is currently in clinical development
for ovarian cancer.[25]
natural product synthesis as indicated in Figure 3 (lower). Since
the 3- and 4-positions of angelicin (26) are unsubstituted, the Z-
configured C3-synthon Z-20 was employed. Under the general
conditions developed, this direct [3+3] annulation proceeded
smoothly to deliver the target natural products Angelicin 26. By
employing the geometric isomer E-20, it was possible to access
compound 27 which is the core of Pongamol and Lanceolatin B.[26]
The structure of compound 18 was unequivocally established by
single crystal X-ray analysis (CCDC number 2022960, Figure 3,
top). This compound crystallised in the chiral space group P212121
(Flack parameter was refined to 0.00(6)). In the packing diagram
the formation of linear chains along the a-axis involving …
interactions (Cg1…Cg1 3.286 Å) supported by additional C-H…O
interactions (C8-H8B…O2 3.418(2) Å; 157.9° and C22-H22B…O2
3.434(2) Å; 159.6°) were observed (Figure 3, lower). The
prominence of … interactions between the aromatic units of
estrone derivative 18 is presented in the supporting information
file (see figure 3d). The 3D network of estrone derivative 18 is
compact, Moreover, the influence of the coumarin in generating
linear chains due to additional C-H…O interactions is evident from
the extended packing analysis (Figure 3, lower).
Figure 3: Merging energy transfer catalysis with the Suzuki-
Miyaura/substitution cascade to enable divergence to 3-substuted coumarins.
Figure 3. Top: The X-ray crystal structure of estrone derivative 18 (CCDC
2022960). Thermal ellipsoids are shown at 30% probability. Bottom: Excerpt of
the packing diagram of compound 18 presenting the formation of a linear chain
along a-axis involving … and C-H…O interactions.
Finally, preliminary validation of the strategy in modulating the
photophysical properties of selected systems was conducted
(Figure 5). As illustrated, clear peaks that correspond to the
coumarin scaffold are clearly visible in 14, 16, 17 and 18 which
supports the notion that this simply annulation strategy based on
β-borylacrylates may find application in the development of tools
for molecular imaging.
In the course of this scope investigation, it was noted that β-
borylacrylates that were unsubstituted in the β-position were
problematic (Figure 3). Indeed, exposing compound E-20 (R=H)
to the general reaction conditions yielded the cross-coupled
product 22 exclusively, indicating that in situ isomerisation does
not occur. This selectivity was also noted for E-21 (R=Me),
generating product 23 in 58%. Although attractive from the
perspective of divergence, a solution was required to expand the
substrate scope. To that end, a photocatalytic isomerisation of the
β-borylacrylate was performed under the auspices of selective
energy transfer catalysis to generate substrates Z-20 and Z-21.[15]
Exposure to the general condition reported above enabled
formation of the desired coumarins 24 and 25 (55% and 90%,
respectively). The direct annulation was employed in a short
In conclusion, a direct annulation of 2-halophenols has been
devised utilising simple, modular β-borylacrylates as ambiphilic
C3 synthons. This study contributes to venerable role of
organoborons in creating well defined synthons for organic
synthesis.[27,28] In this modular platform, the boron substituent
serves a dual purpose as both a traceless linker for C(sp2)-C(sp2)
coupling, and as a chromophore extension to enable inversion of
the alkene geometry via selective energy transfer catalysis. This
latter attribute enables access to C-3 and C-4 unsubstituted
coumarins and provides
a
basis for divergence. The
transformation is operationally simple, displays high functional
3
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We acknowledge generous financial support from the
Westälische Wilhelms-Universität Münster, the DFG (SFB 858
and Excellence Cluster EXC 1003 “Cells in Motion”) and the
Alexander von Humboldt Foundation (post-doctoral research
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Keywords: annulation • boron • catalysis • heterocycle •
isomerisation
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4
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Entry for the Table of Contents
Modular β-borylacrylates are validated as programmable, ambiphilic C3-synthons for the annulation of 2-halo-phenol derivatives to
generate diverse coumarins. Key to this [3+3] disconnection is the BPin unit which serves a dual purpose as both a traceless linker
for C(sp2)-C(sp2) coupling, and as a chromophore extension to enable E → Z alkene isomerisation. Inverting alkene geometry is a
pre-condition to access 3-susbtituted derivatives. This approach capitalises upon the abundance of 2-halophenols in biology and may
facilitate natural product/drug re-purposing and the development of imaging tools.
5
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