A Direct Synthesis of 2-(ω-Carboxyalkyl)isoflavones from ortho-Hydroxylated Deoxybenzoins

Article abstract of DOI:10.1002/ejoc.201801171

As part of a program focused on the development of new antineoplastic agents based on scaffolds found in natural products, we explored the isoflavone family as potential enzyme inhibitors. We required biotin-modified isoflavones to identify potential biological targets, and we selected the C-2 position in isoflavones as an attachment site for an alkyl group bearing a terminal carboxylic acid to which we could attach a biotin derivative. The base-catalyzed condensation of 2,4-dihydroxy-substituted deoxybenzoins with cyclic anhydrides mediated by a combination of triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene led to an efficient synthesis of the desired 2-(ω-carboxyalkyl)isoflavones with functional groups at C-5, 6 and 7 and with various substituents in the C-3 phenyl group.

Full text of DOI:10.1002/ejoc.201801171

A Journal of
Accepted Article
Title: A Direct Synthesis of 2-(ω-Carboxyalkyl)isoflavones from ortho-
Hydroxylated Deoxybenzoins
Authors: Galyna P. Mrug, Bogdan A. Demydchyk, Svitlana P.
Bondarenko, Vitaliy M. Sviripa, Przemyslaw Wyrebek, James
L. Mohler, Michael V. Fiandalo, Chunming Liu, Mykhaylo
Frasinyuk, and David S. Watt
This manuscript has been accepted after peer review and appears as an
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the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801171
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801171
Supported by

10.1002/ejoc.201801171
European Journal of Organic Chemistry
COMMUNICATION
A Direct Synthesis of 2-(ω-Carboxyalkyl)isoflavones from ortho-
Hydroxylated Deoxybenzoins
Galyna P. Mrug,[a] Bogdan A. Demydchyk,[a] Svitlana P. Bondarenko,[b] Vitaliy M. Sviripa,[c],[d]
Przemyslaw Wyrebek,[c], [f] James L. Mohler,[e] Michael V. Fiandalo,[e] Chunming Liu,[f], [g] Mykhaylo S.
Frasinyuk,[a],[c],[f]* and David S. Watt [c], [f], [g]
*
Abstract: As part of a program focused on the development of new
antineoplastic agents based on scaffolds found in natural products,
we explored the isoflavone family as potential enzyme inhibitors.
We required biotin-modified isoflavones to identify potential
biological targets, and we selected the C-2 position in isoflavones as
an attachment site for an alkyl group bearing a terminal carboxylic
acid to which we could attach a biotin derivative. The base-
catalyzed condensation of 2,4-dihydroxy-substituted deoxybenzoins
with cyclic anhydrides mediated by a combination of triethylamine
and 1,8-diazabicyclo[5.4.0]undec-7-ene led to an efficient synthesis
of the desired 2-(ω-carboxyalkyl)isoflavones with functional groups
target specific enzymes, we required methodology to synthesize
isoflavones 1 related to naturally occurring chromones[1] 2 (n=2
or 3) bearing ω-(carboxy)alkyl groups at the C-2 position (Fig. 1).
We planned to modify these ω-(carboxy)alkyl derivatives with an
appropriate biotinylated linker to facilitate enzyme target
identification in pull-down assays. In screening studies, we
identified the C-2 position as a potential site for modification
based on modest changes in cancer cell proliferation seen in
chromones bearing either a hydrogen or a methyl group at C-2.
In summary, we required a convenient synthetic procedure that
would furnish isoflavones 1 with ω-(carboxy)alkyl groups at the
at C-5, 6 and 7 and with various substituents in the C-3 phenyl group. C-2 position.
R1
O
2
2H
MeO
2H
nCO
2
O
nCO
O
O
(CH2)
(CH2)
A
C
Introduction
B
R2
O
OMe
OR3
Isoflavones and chromones possess a dazzling spectrum of
biological activities in which they alter the catalytic function of
numerous enzymatic reactions. As part of our interest in
2
1
Figure 1. Isoflavone 1 and chromone 2 structures with C-2 ω-(carboxy)alkyl
developing natural product-based, antineoplastic agents that
groups.
[a]
G. P. Mrug, B. A. Demydchyk, M.S. Frasinyuk*
Institute of Bioorganic Chemistry and Petrochemistry, National
Academy of Science of Ukraine
Kyiv 02094, Ukraine
E-mail: mylhaylo.frasinyuk@ukr.net
S. P. Bondarenko
Isoflavones and chromones with similar modifications at the
C-2 position previously found application as haptens for the
attachment to carrier proteins and the subsequent development
of immunoassay techniques for the epidemiological screening of
plant phytoestrogens. [2] In addition to their utility in screening
programs, several ω-(carboxy)alkyl chromones occur in nature.
Oxalicumone C[3] appears in the marine-derived fungus
Penicillium oxalicum and bears a C-2 ω-(carbomethoxy)ethyl
group in a chromone skeleton. Related chromones 2 also
appear in Penicillium citreonigrum. [1] Other recent reports also
identified isoflavones bearing ω-(carboxy)alkyl groups that
[b]
[c]
National University of Food Technologies
Kyiv 01601, Ukraine
V. M. Sviripa, P. Wyrebek, M.S. Frasinyuk, D. S. Watt*
Center for Pharmaceutical Research and Innovation
College of Pharmacy, University of Kentucky
Lexington, KY 40536-0509, USA
E-mail: dwatt@uky.edu
[d]
[e]
[f]
V. M. Sviripa
Department of Pharmaceutical Sciences
College of Pharmacy, University of Kentucky
Lexington, KY 40536-0509, USA
J.L. Mohler, M. V. Fiandalo
Department of Urology
Roswell Park Cancer Institute
possessed promising antiproliferative[4] and anticoccidian
[5]
activities.
These findings, in addition to our own needs,
warranted the development of an efficient protocol for the
synthesis of isoflavone 1 possessing an ω-(carboxy)alkyl group
at the C-2 position in which the number of methylene subunits in
the alkyl linker (i.e., the value of n) could be varied over a
substantial range.
Buffalo, NY 14263
P. Wyrebek, M.S. Frasinyuk, C. Liu, D. S. Watt
Department of Molecular and Cellular Biochemistry
College of Medicine, University of Kentucky
Lexington, KY 40536-0509, USA
C. Liu, D. S. Watt
Lucille Parker Markey Cancer Center,
University of Kentucky
Lexington, KY 40536-0509, USA
Previously reported methods for the synthesis of isoflavones 1
with C-2 ω-(carboxy)alkyl groups typically required multistep
[g]
procedures.
For example, these procedures involved the
acylation of ortho-hydroxybenzoins with oxalyl chloride and
related bis(acyl) chlorides. The acylation, for example, of ortho-
hydroxy group of O-protected deoxybenzoins followed by a
Baker-Venkataraman rearrangement[6] led to formation of
Supporting information for this article is given via a link at the end of
the document.
isoflavones.
Subsequent deprotection afforded the target
genistein-related acids 1 (R1= R3 = H, R2 = OH).[6] Further
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801171
European Journal of Organic Chemistry
COMMUNICATION
improvements in this procedure included ring-closure reactions
using acylation of 2-hydroxydeoxybenzoins with aliphatic ω-
alkoxycarbonyl acid chlorides (i.e., RO2C(CH2)nCOCl) in the
presence of tetra-n-butylammonium bromide[7] or lithium
bis(trimethylsilyl)amide[2a] followed by saponification. Finally, the
alkylation of an isoflavone bearing a C-2 bromomethyl group
with ethyl cyanoacetate led to a dimeric bis-isoflavonoid bearing
a carboxylic acid in the bridging propyl group between the two
isoflavone subunits. [8]
promoted the desired acylation and condensation and led, after
acidification, to the efficient synthesis of isoflavone 4.
Applying these conditions to condensations using glutaric
anhydride, diglycolic anhydride, or 1,2-cis-cyclopropane
dicarboxylic anhydride and using 2,4-dihydroxyacetophenones
5a-5f[14] or 2,4,6-trihydroxyacetophenones 5g-5m[6, 15] led to the
desired isoflavones 6, 7, 8 and 9, respectively, in 22-96% yields
(Scheme 2). The use of succinic anhydride under similar
conditions gave dark-colored mixtures and was limited to
condensations with 2,4,6-trihydroxyacetophenones 5g–5m.
Results and Discussion
HO
H
CO2
O
(CH2)2
e
a,
R3
R4
Many naturally occurring isoflavones with alleged health benefits
contain hydroxy, methoxy or methylenedioxy groups. Unlike
prior efforts that required the selective protection/deprotection of
phenolic groups other than the participating ortho-hydroxyl group,
we describe an efficient synthesis of isoflavones containing C-2
ω-(carboxy)alkyl groups from hydroxylated deoxybenzoins 3 and
other readily available materials and without resorting to the use
of any protection or activation steps.
OH
O
6g-6m
HO
R2
H
CO2
O
(CH2)3
e
b,
R3
R4
HO
R2
OH
In the 1920’s, the first reports appeared involving the cyclization
of 2’-hydroxydeoxybenzoins with carboxylic acid anhydrides in
presence of base,[9] now known as Kostanetski-Robinson
reaction and the related Baker-Venkataraman rearrangement. In
recent years, this method found wide application in the
preparation of 2-alkyl, [10] 2-fluoroalkyl, [10b, 11] 2-arylisoflavones,
R1
O
R3
R4
7a-7o
R1
O
5a-5o
HO
R2
O
H
O
CO2
R3
e
c,
[12]
and their C-2 unsubstituted counterparts when using mixed
[13]
carboxylic acid-formic anhydrides.
However, there is no
R1
O
R4
precedent for using this pathway for the synthesis of isoflavones
bearing functional groups at position C-2 of the chromone
8a-8o
subunit.
H
H
Z
HO
Z
O
O
e
H
R3
CO2
CO2
d,
O
O
O
Z
HO
OH
O
O
O
R2
CO2
Ar
R1
O
O
base
R4
Ar
C(=O)CH2
R
9a-9o
R
3
R4 F;
=
1
2
3
1
3
a
=
=
=
=
=
=
=
=
=
=
=
=
=
i
R
R
R
R4
R4
R
R2
R2
R
R
OH;
OH,
H,
H,
H,
H,
H,
H
3O
Z
O
=
=
CO2
b R1
R
R
R1
R4
R4
2
3
3
=
=
=
=
=
=
=
OMe;
OH,
OH,
Cl;
j
k
HO
Z
H
CO2
O
O
R
R
R
R4 F;
R
R2
1
2
2
3
3
1
3
c
=
=
= =
R
=
OCF3
H,
=
Z
O
O
O
R4 OCF3
R
R3
R
1
1
2
4
CO2
=
=
=
=
=
;
l
d
e
OH, R
OMe;
R
R
R
H,
=
H,
R3R4
4
1
m
=
OCH2O;
R
R
R
R
=
=
=
R
R2
1
2
=
=
=
R2
OMe;
OH,
H,
H,
R2
R2
H,
Ar
3
R
Ar
1
2
1
3
4
R3R4
R
R
R
R
n
=
=
=
=
=
=
=
R
f
R
R
OCH2O;
R4
OMe,
H,
=
4
g R1
R
R
R2
R
3
1
3
4
o
=
=
=
=
=
=
R
OMe
OH,
OH,
=OH;
H,
H,
H,
R
R4
1
3
h
=OMe;
Scheme 1. Synthesis of ω-(carboxy)alkyl isoflavones
hydroxylated deoxybenzoins 3.
4
from ortho-
Scheme 2. Synthesis of isoflavones bearing ω-(carboxy)alkyl group.
Reagents and conditions: a, succinic anhydride, Et3N, DBU, dioxane, 100OC,
6-8 h; b, glutaric anhydride, Et3N, DBU, dioxane, 100OC, 6-8 h; c, diglicolic
anhydride, Et3N, DBU, dioxane, 100OC, 6-8 h; d, 1,2-cyclpropanedicarboxylic
acid anhydride, Et3N, DBU, dioxane, 100OC, 6-8 h; e, H2SO4, H2O, 80OC, 10-
20 min.
Acylation of polyhydroxylated deoxybenzoins
dicarboxylic anhydrides in presence of an organic base (e.g.,
3
with cyclic
triethylamine; pKb 10.7) led to polyacylation of the free phenolic
groups and cyclization (Scheme 1).
After quenching the
reaction with aqueous acid, we obtained principally unreacted 3
and only traces of the desired isoflavone 4.
However, the addition of a more basic reagent than triethylamine,
namely 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (pKa 12),
The efficient formation of isoflavones 6-9 under these conditions
was dependent on the presence of electron-donating
substituents in the deoxybenzoin substrates 5. Despite this
limitation, the procedure reported here provided access to not
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10.1002/ejoc.201801171
European Journal of Organic Chemistry
COMMUNICATION
General procedures for the synthesis of deoxybenzoins 5a-5e and
5n-5o. A solution of 0.11 mol resorcinol or 4-methoxyresorcinol, 0.1 mol
of the appropriate arylacetonitrile in 50 mL of boron trifluoride etherate
was saturated with anhydrous HCl gas over a 6h period at room
temperature. The mixture was carefully poured into 500 mL of water at
80oC. The resulting mixture was heated to reflux for 2h, and cooled to
room temperature. The resulting solid was collected by fitltration and
recrystallized from MeOH/H2O.
only C-2 ω-(carboxy)alkyl analogs of unnatural isoflavones but
also analogs of natural products. For example, the use of 2,4-
dihydroxy-5,5’-dimethoxydeoxybenzoin 5n[16] and 2,4-dihydroxy-
4’,5,5’-trmethoxydeoxybenzoin 5o[17] furnished derivatives of
naturally occurring isoflavones afromosin (7-hydroxy-4’,6-
dimethoxyisoflavone)
and
cladrastin
(7-hydroxy-3’,4’,6-
trimethoxyisoflavone). We also extended this approach to the
synthesis of analogs of irilone (i.e., 7-(4-hydroxyphenyl)-8H-
[1,3]dioxolo[4,5-g]chromen-8-one). To acquire these analogs,
we first synthesized the appropriate deoxybenzoins 5p-5r with
benzo[d][1,3]dioxole rings using a standard Hoesch procedure
catalyzed by zinc chloride.
General procedures for the synthesis of deoxybenzoines 5f-5m and
5p-5r. A vigorously stirred solution of 0.11 mol of resorcinol, either
phloroglucinol, or sesamol, and 0.1 mol of the appropriate arylacetonitrile
in 100 mL of anhydrous ether was saturated with HCl gas for 1h at 0 0C.
A suspension of 0.1 mol (in case of compounds 5f, 5p-5r) or 0.001 mol
(in case compounds 5g-5m) of freshly fused zinc chloride in 100 mL of
anhydrous ether was added, and the mixture was saturated with
anhydrous HCl gas for an additional 6-8h at room temperature. The
ethereal layer was decanted, and the residue washed with 100 mL of
ether. To the residue was added 300 mL of 0.1M H2SO4 solution, and
the mixture was heated at reflux for 2h. The mixture was cooled, and the
resulting solid was collected by filtration and recrystallized from methanol
or water-methanol mixtures.
O
O
O
COOH
R2
n
O
O
O
O
OR1
O
n
COOH
R2
11
O
OR1
10
H
H
O
O
1-(7-Hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-
methoxyphenyl)ethanone (5s). A mixture of 3.80 g (25 mmol) of 2,3-
O
n
COOH
R2
2
R1
H;
2
a n
=
=
=
=
=
=
R
1,
1,
1,
2,
dihydrobenzo[b][1,4]dioxin-6-ol,
4.15
g
(25
mmol)
of
4-
O
R1 Me, R H;
R1 Me, R
R1 Me, R
n
=
=
b
methoxyphenylacetic acid in 50 mL of BF3⋅Et2O under an argon
atmosphere was heated at 900C for 6 h. The mixture was cooled and
poured into 200 mL of a ice-cooled 10% NaOAc solution. The resulting
solid was collected by filtration, and after drying, the solid was purified by
column chromatography on silica gel using 100:1 CH2Cl2-MeOH as
eluent.
2
c n
=
=
=
OMe;
H
OR1
2
n
12
=
d
Figure 2. Structure of synthesized irilone analogs 10-12 with C-2 ω-
(carboxy)alkyl groups.
General procedure for the synthesis of isoflavones with C-2 ω-
(carboxy)alkyl groups. To a solution of 2 mmol of deoxybenzoin 5 in 5
mL of 1,4-dioxane was added 6 mmol (or 8 mmol in case of 2,4,6-
trihydroxydeoxybenzoins) of a dicarboxylic acid anhydride and 1.12 mL
(8 mmol) (or 1.4 mL, 10 mmol in case of 2,4,6-trihydroxydeoxybenzoins)
of Et3N. The mixture was heated to reflux for 0.5 h, and 0.3 mL of DBU
(2 mmol) in 1,4-dioxane was added. The mixture was refluxed for an
additional 6-16h. After cooling, the mixture was diluted with 30 mL of
aqueous 1N H2SO4 solution, heated at 80oC for 2h, cooled and diluted
with 50 mL of water. The resulting solid was collected by filtration and
recrystallized from acetonitrile. Some isoflavones required additional
purification by column chromatography on silica gel using a mixture of
100:1 CH2Cl2-MeOH as eluent.
We also synthesized the corresponding ring-expanded 2,3-
dihydrobenzo[b][1,4]dioxins using
a
condensation of 2,3-
dihydrobenzo[b][1,4]dioxin-6-ol with 4-methoxyphenylacetic acid
in boron trifluoride etherate[18] to afford the appropriate
deoxybenzoin 5s. Condensation of these deoxybenzoins 5p-5s
with cyclic anhydrides led to the formation of the desired irilone
analogs 10, 11 and 12 bearing C-2 ω-(carboxy)alkyl groups (Fig.
2).
Conclusions
In
summary,
using
a
1:(n+1):(n+2):0.1
ratio
of
Acknowledgements
deoxybenzoin:cyclic anhydride:tertiary amine:DBU where n is
the number of phenolic hydroxyl group in starting deoxybenzoin
furnished a procedure that did not require activation, protection
and deprotection steps and led to an array of ω-(carboxy)alkyl-
substituted isoflavones. Application of this technology to the
construction of D-(+)-biotin derivatives of these ω-(carboxy)alkyl-
substituted isoflavones for studies focused on biological targets
will be reported in due course.
CL and DSW were supported by CA172379 from the NIH. DSW
was also supported by the Office of the Dean of the College of
Medicine, by the Center for Pharmaceutical Research and
Innovation in the College of Pharmacy, and by NIH Grant
Number P30 GM110787 from the National Institute of General
Medical Sciences to L. Hersh, PI. Its contents are solely the
responsibility of the authors and do not necessarily represent the
official views of the NIH or the NIGMS. DSW was also
supported by a subcontract under CA205108 to J. Mohler, PI and
by the Office of the Assistant Secretary of Defense for Health
Affairs, through the Prostate Cancer Research Program under
Experimental Section
Supplementary data for compounds and copies of NMR spectra are
given in supporting information.
Award No. W81XWH-16-1-0635.
Opinions, interpretations,
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10.1002/ejoc.201801171
European Journal of Organic Chemistry
COMMUNICATION
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Disclosure
CL and DSW have partial ownership of a new-start company,
Epionc, Inc., that seeks to develop these compounds as
commercial agents. CL and DSW disclosed this information and
complied with requirements to mitigate any potential conflicts of
interest in accord with University of Kentucky policy.
Keywords: Baker-Venkataraman rearrangement • cyclic
anhydride • isoflavone • natural compound • ring-closure
reaction
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10.1002/ejoc.201801171
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
R1
O
O
COOH
(CH2)n
Ar
Biological Scaffolds
The base-catalyzed chromone ring-
closure reaction was developed for
one-step synthesis of various 2-(ω-
R2
O
O
Z
O
Galyna P. Mrug, Bogdan A. Demydchyk,
Svitlana P. Bondarenko, Vitaliy M.
Sviripa, Przemyslaw Wyrebek, James L.
Mohler, Michael V. Fiandalo, Chunming
Liu, Mykhaylo S. Frasinyuk*, and David
S. Watt*
R1
O
CH2OCH2COOH
Ar
R1
O
OH
O
O
O
carboxyalkyl)isoflavones
bearing
R2
1-step
O
O
Ar
R2
electron-donating
and
electron-
64
exapmles
withdrawing groups.
R1
O
COOH
Ar
R2
O
Page No. – Page No.
A Direct Synthesis of 2-(ω-
Carboxyalkyl)isoflavones from ortho-
Hydroxylated Deoxybenzoins
This article is protected by copyright. All rights reserved.