Phosphine boranes as less hydrophobic building blocks than alkanes and silanes: Structure-property relationship and estrogen-receptor-modulating potency of 4-phosphinophenol derivatives

Article abstract of DOI:10.1016/j.bmc.2020.115310

Increasing structural options in medicinal chemistry is important for the development of novel and distinctive drug candidates. In this study, we focused on phosphorus-containing functionalities. We designed and synthesized a series of phosphinophenol der

Full text of DOI:10.1016/j.bmc.2020.115310

Bioorganic&MedicinalChemistryxxx(xxxx)xxxx
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Bioorganic & Medicinal Chemistry
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Phosphine boranes as less hydrophobic building blocks than alkanes and
silanes: Structure-property relationship and estrogen-receptor-modulating
potency of 4-phosphinophenol derivatives
⁎
Hiroki Saitoa, Yuichiro Matsumotoa, Yuichi Hashimotoa, Shinya Fujiia,b,
a Institute for Quantitative Biosciences, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
b Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
A R T I C L E I N F O
A B S T R A C T
Keywords:
Increasing structural options in medicinal chemistry is important for the development of novel and distinctive
drug candidates. In this study, we focused on phosphorus-containing functionalities. We designed and synthe-
sized a series of phosphinophenol derivatives and determined their physicochemical properties, including hy-
drophobicity parameter LogP, and their biological activity toward estrogen receptor (ER). Notably, the phos-
phine borane derivatives (9 and 14) exhibited potent ER-antagonistic activity, exceeding the potency of the
corresponding alkane (15) and silane (16) derivatives, despite having a less hydrophobic nature. The determined
physicochemical parameters will be helpful for the rational design of phosphorus-containing biologically active
compounds. Our results indicate that phosphine boranes are a promising new chemical entry in the range of
structural options for drug discovery.
Phosphorus
Phosphine
Phosphine borane
Hydrophobicity
Estrogen receptor
1. Introduction
stable bonds with multiple elements, including sulfur, selenium and
boron, as well as carbon and oxygen, and therefore phosphorus-con-
Phosphorus is ubiquitously present in biological systems, for ex-
ample in the form of phosphates of nucleic acids or phosphorylated
proteins.1 Indeed, several series of phosphonic acid and phosphinic acid
derivatives have been developed as therapeutic agents and drug can-
didates. For example, bisphosphonate agents such as etidronic acid (1)
and zolendronic acid (2), bearing two phosphonic acid groups, are used
clinically for the treatment of osteoporosis and related diseases.2
Phosphonic acids are also used as mimics of phosphoric acids. Teno-
fovir (3), a nucleotide analog bearing a phosphonic acid moiety as a
phosphoric acid isostere, is used in the treatment of human im-
munodeficiency virus (HIV) and hepatitis B virus (HBV) infections.3 In
addition to these nucleotide analogs, several applications of phosphonic
acids as phosphoric acid mimics have been reported.4,5 Furthermore,
phosphinic peptides such as RXP407 (4; an ACE inhibitor)6 are Zn
binder-type or transition state analog (TSA)-type inhibitors of pepti-
dases (Fig. 1).7–9
taining functionalities including phosphines and related chemical spe-
cies might provide a wide variety of chemical options for the structural
development of biologically active compounds. Thus, elucidation of the
physicochemical properties of various phosphorus-containing moieties
as options for structural development of biologically active compounds
is of interest. Here, we describe a systematic investigation of the
structure-property relationship and structure-activity relationship of
phosphine derivatives in order to throw light on their potential utility in
medicinal chemistry.
2. Results and discussion
2.1. Compound design
Because systematic determination of the physicochemical para-
meters of phosphines and related substituents could be helpful in the
rational design of novel biologically active compounds, we set out to
synthesize a series of simple 4-phosphinophenol derivatives 5–14
bearing phosphine, phosphine oxide, phosphine sulfide, phosphine se-
lenide, and phosphine borane functionalities and to examine their
However, in contrast to these oxoacids of phosphorus, applications
of other phosphorus-containing compounds, such as phosphines and
related derivatives, in medicinal chemistry have been little in-
vestigated. Nevertheless, phosphorus is a versatile element which forms
⁎ Corresponding author at: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-
0062, Japan.
E-mail address: fujiis.chem@tmd.ac.jp (S. Fujii).
https://doi.org/10.1016/j.bmc.2020.115310
Received 11 December 2019; Received in revised form 7 January 2020; Accepted 7 January 2020
0968-0896/©2020ElsevierLtd.Allrightsreserved.
Pleasecitethisarticleas:HirokiSaito,etal.,Bioorganic&MedicinalChemistry,https://doi.org/10.1016/j.bmc.2020.115310

H. Saito, et al.
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(Scheme 1).11,12 The preparation of silicon analogue 16 was previously
reported.13
2.3. Hydrophobicity
The hydrophobicity of the synthesized phosphinophenol com-
pounds was determined as the octanol–water partition coefficient (P)
using an HPLC method.14 Table 1 summarizes the LogP values of the
compounds and the Hansch–Fujita hydrophobicity parameter π of the
substituents, deduced by subtraction of the logP value of phenol (1.46)
from the observed logP value. Among derivatives bearing the same core
structure, i.e., methyldiphenylphosphines 5–9 and triphenylphosphines
10–14, larger hydrophobicity parameters were observed in the order of
phosphine, phosphine borane, phosphine selenide, phosphine sulfide,
and phosphine oxide. With regard to phosphine chalcogenides, com-
pounds bearing chalcogen with a larger atomic number on phosphorus
exhibited higher hydrophobicity. Phosphine boranes showed hydro-
phobicity parameters larger than those of phosphine chalcogenides and
smaller than those of phosphines. These results suggest that phosphine-
based substructures would represent a versatile structural option to
produce a series of compounds with a wide range of hydrophobicity.
Phosphine borane 9 is isoelectronic to alkane 15 and silane 16, but
showed a significantly smaller LogP value (Table 1).
Fig. 1. Representative phosphorus-containing therapeutic agents 1–3 and
phosphinic peptide 4.
2.4. Acidity
hydrophobicity, substituent constants, and biological activity. We also
planned to compare their properties and activities with those of the
corresponding alkane and silane analogs (15 and 16) (Fig. 2).
The acid dissociation constant pKa of the phenolic hydroxyl group of
each compound was determined from the pH-dependent change of
absorbance spectra. Table 2 summarizes the pKa values of the com-
pounds and the differences in pKa values between phenol and each
compound. Large pKa values were observed in the order of phosphine,
phosphine borane, and phosphine chalcogenides. Both phosphine
chalcogenides show similar pKa values. Differences between the pKa
values of methyldiphenylphosphine derivatives and the corresponding
triphenylphosphine derivatives are small. All phosphorus substituents
investigated in this study function as strong electron-withdrawing
groups in comparison with related alkyl and silyl groups, and phos-
phine boranes exhibit significant electron-withdrawing character,
comparable to that of corresponding phosphine oxides and other
phosphine chalcogenides (Table 2).
2.2. Synthesis
Synthesis of the designed phosphinophenol derivatives is summar-
ized in Scheme 1. Using methylphenylphosphinic chloride 17 or di-
phenylphosphinic chloride 18 as the starting material, arylation reac-
tion with 4-methoxyphenylmagnesium gave diphenyl phosphine oxide
derivative 19 or 20, respectively. Demethylation with borane tri-
bromide gave the designed phosphine oxides 6 and 11, respectively.
Reduction of 6 and 11 with trichlorosilane gave the designed trivalent
phosphines 5 and 10, respectively.10 Reduction of phosphine oxides 19
and 20 gave phosphines 21 and 22, respectively, and then sulfidation of
21 and 22 with elemental sulfur gave phosphine sulfides 23 and 24,
respectively. The desired phosphine sulfides 7 and 12 were obtained by
demethylation of 23 and 24, respectively. Phosphine selenides 8 and 13
and phosphine boranes 9 and 14 were synthesized from phosphines 1
and 2 by reaction with elemental selenium or borane, respectively
2.5. Activity toward estrogen receptor (ER)
Estrogen receptor (ER) is a member of the nuclear receptor super-
family.15 ER has two subtypes (α and β), and their ligand is the en-
dogenous estrogen estradiol (E2). Estrogens are involved in regulation
Fig. 2. Structures of compounds investigated in this study.
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Scheme 1. Synthesis of the designed phosphinophenol derivatives. Reagents and conditions: (a) 4-methoxyphenylmagnesium bromide, THF, 0 °C to rt, 97% (19),
quant. (20); (b) BBr3, CH2Cl2, rt, quant. (6), 86% (11); (c) trichlorosilane, THF/toluene, rt to reflux, 81% (5), 93% (10); (d) trichlorosilane, THF/toluene, rt to reflux,
95% (21), 93% (22); (e) sulfur, THF, 120 °C microwave, 90% (23), 92% (24); (f) BBr3, CH2Cl2, rt, 90% (7), 91% (12); (g) selenium, CH2Cl2, 100 °C, microwave, 97%
(8), 89% (13); (h) BH3-THF, THF, rt, quant. (9), 95% (14).
Table 1
Table 2
Hydrophobicity parameter of phosphinophenol derivatives.
pKa Values of Phosphinophenol Derivatives.
πa
Compound
R
X
pKa
ΔpKa
(phenol)
Compound
R
X
LogP
Phenol
5
–
10.44
9.49
8.63
8.65
8.64
8.83
9.48
8.51
8.60
8.60
8.81
10.59
10.25
–
Phenol
5
–
1.46
3.67
1.88
2.69
3.27
3.38
5.06
3.22
4.08
4.73
4.96
4.20
4.80
–
Me
–
−0.95
−1.81
−1.79
−1.80
−1.61
−0.96
−1.93
−1.84
−1.84
−1.63
+0.15
−0.19
Me
–
+2.21
+0.42
+1.23
+1.81
+1.92
+3.60
+1.76
+2.62
+3.27
+3.50
+2.74
+3.34
6
]O
]S
]Se
eBH3
–
6
]O
]S
]Se
eBH3
–
7
7
8
8
9
9
10
11
12
13
14
15
16
Ph
10
11
12
13
14
15
16
Ph
]O
]S
]Se
eBH3
]O
]S
]Se
eBH3
–
–
–
–
a
Hansch–Fujita hydrophobicity parameter of each substituent.
or either of ERα and ERβ. Interestingly, phosphine borane 9 exhibited
antagonistic activity toward ERs, and its activity was similar to or
greater than that of silane 16, which is isoelectronic to phosphine
borane 9. None of the triphenylphosphine derivatives 10–14 exhibited
agonistic activity toward ERs. Triphenylphosphinyl structure might be
too bulky to induce ER-agonistic activity. Phosphine sulfide 12 and
phosphine selenide 13 exhibited antagonistic activity toward ERα and
ERβ, while phosphine borane 14 was an even more potent antagonist.
The potency of ER ligands is influenced by the hydrophobicity of the
compounds, and therefore it is reasonable that the relatively highly
hydrophobic phosphine boranes are more potent than the corre-
sponding phosphine chalcogenides. Though the trivalent phosphines 5
and 10 are more hydrophobic, the nucleophilic phosphines may be lost
via reaction with electrophilic substances in the biological environ-
ment. We also examined membrane permeability of the compounds
using immobilized artificial membrane column (IAM column), and the
of the female and male reproductive systems, bone metabolism, and the
cardiovascular system, as well as the central nervous system, and
therefore ER ligands are attractive targets of drug discovery.16,17 We
have previously reported that simple 4-substituted phenols act as ER
ligands,13,18 and here we evaluated the estrogenic activities of our 4-
phosphinophenol derivatives by means of luciferase reporter gene assay
using HEK293 cells. The compounds showed no significant cytotoxicity
toward HEK293 cells in the assay condition (data not shown). The
concentration-dependent transcriptional activity of each compound
was quantified; the agonistic activity was calculated as EC50 and the
antagonistic activity as IC50 (Table 3).
Among the methyldiphenylphosphine derivatives 5–9, phosphine 5
did not exhibit any activity toward ERα or ERβ. Phosphine chalco-
genides 6–8 exhibited only weak partial agonistic activity toward both
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Table 3
conformation as phosphine borane (Fig. 4). Biological evaluation re-
vealed that phosphine borane 9 showed similar ERβ-inhibitory potency
to that of silane 16 (IC50 = 2.5 μM and 5.0 μM, respectively). Though
the hydrophobicity of phosphine borane 9 is smaller than that of silane
16 (there is a difference of 1.42 in the LogP values), the results suggest
that phosphine boranes can function as isosteric building blocks of si-
lanes, albeit with a less hydrophobic nature than silanes. Methods of
decreasing the hydrophobicity of compounds are useful tools for med-
icinal chemists, and therefore phosphine boranes could be useful as less
hydrophobic building blocks than alkanes and silanes.
ER-modulating potency of the synthesized 4-phosphinophenol derivatives.
Compound
R
X
ERα
ERβ
EC50 (μM)a
IC50 (μM)b
EC50 (μM)a
IC50 (μM)b
5
Me
–
n.a.
19
n.a.
n.a.
n.a.
n.a.
9.8
n.a.
n.a.
20
n.a.
n.a.
n.a.
n.a.
6
]O
]S
]Se
eBH3
–
(36%)c
(24%)c
(24%)c
(16%)c
n.a.
7
(24%)c
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
4.4
d
8
(30%)
3. Conclusion
9
2.5
n.a.
n.a.
13
10
11
12
13
14
15
16
Ph
In this study, using the phosphinophenol structure as a common
platform, we investigated the structure-property relationship and ER-
modulating potency of phosphine derivatives. The phosphine deriva-
tives examined showed a wide range of hydrophobicity parameters, and
these results suggest that phosphine-based substructures provide a
versatile option to generate a series of compounds with a wide range of
hydrophobicity. Phosphine boranes 9 and 14 exhibited significant ER-
antagonistic activity, suggesting that phosphine boranes can function as
isosteric building blocks of alkanes and silanes with a less hydrophobic
nature. The results indicate the potential of phosphine boranes as new
structural options for drug discovery. The parameters and structure–-
activity relationship presented here should be helpful in the application
of such phosphorus-containing compounds for drug development.
]O
]S
]Se
eBH3
n.a.
n.a.
20
n.a.
10
12
n.a.
2.0
13
–
–
24
(38%)c
(20%)c
> 30
13
5.0
a
b
c
Concentration showing 50% of the maximal activity of E2.
concentration inhibiting the activity of 0.3 nM E2 by 50%.
percentage of the maximal activation of E2 at 30 µM.
% inhibition at 30 µM, n.a: no activity.
d
results indicated the synthesized phosphine boranes can permeate
through the lipid membrane (Table S1).
Among the synthesized phosphine derivatives, phosphine boranes
exhibited the most potent activity. Therefore, we conducted a docking
simulation of 9 with the X-ray crystal structure of the antagonist-bound
form of hERβ ligand-binding domain (LBD) (PDB ID: 1L2J),19 using
AutoDock 4.2.20 Compound 9 has two stereoisomers depending on the
chirality of the phosphorus atom, and both isomers were docked.
Fig. 3A shows the docking model of the phosphine borane 9 in the hERβ
LBD as a superimposition of the two isomers. In the calculated struc-
ture, the two isomers occupy the same region of the ligand-binding
pocket and take almost the same conformation. Namely, the phenolic
hydroxyl group interacts with Glu305 and Arg346, with which estradiol
forms key hydrogen bonds, and the methylphenylphosphine borane
moiety occupies the hydrophobic cavity of the ligand-binding pocket.
Next, we docked silane 16, which is isoelectronic with phosphine
borane 9, to the hERβ LBD, and compared the binding mode with that
of phosphine borane. Fig. 3B and 3C shows the docked structure of 16
superimposed on that of each isomer of 9. In the docked structure, si-
lane 16 adopts the same conformation as phosphine borane (Fig. 3). We
also conducted a docking simulation of the compounds with hERαLBD
(PDB ID: 3UUA),21 and the results similar to those of hERβ were ob-
tained from the calculation, namely, silane 16 adopts the same
4. Experimental
4.1. Chemistry
4.1.1. General remarks. All reagents were purchased from Sigma-
Aldrich Chemical Co., Tokyo Kasei Kogyo Co., FUJIFILM Wako Pure
Chemical Industries, or Kanto Kagaku Co., Inc. Silica gel for column
chromatography was purchased from Kanto Kagaku Co., Inc. 1H NMR,
13C NMR and 31P NMR spectra were recorded on a JEOL JNM-GX500
(500 MHz, 125 MHz, and 202 MHz respectively) spectrometer.
Chemical shifts for 1H NMR and 13C NMR are reported as parts per
million (ppm) relative to chloroform (7.26 ppm for 1H NMR and
77.00 ppm for 13C NMR) or DMSO (2.50 ppm for 1H NMR and
39.52 ppm for 13C NMR) or methanol (3.31 ppm for 1H NMR and
49.00 ppm for 13C NMR). The following abbreviations are used:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
dd = double doublet, td = triple doublet, br = broad. Electrospray
ionization mass spectra (ESI-MS) were recorded on a Bruker micrOTOF
II spectrometer with Low Concentration Tuning mix (G1969-85000).
Fig. 3. Docking models of phosphine borane 9 with hERβ LBD (PDB ID: 1L2J) obtained with AutoDock 4.2. The protein surface is indicated as a blue mesh. A)
Superimposition of docking models of (R)-9 (pink) and (S)-9 (green) in the hERβ LBD. B). Superimposition of docking models of (R)-9 (pink) and silane 16 (white). C)
Superimposition of docking models of (S)-9 (green) and silane 16 (white). (For interpretation of the references to colour in this figure legend, the reader is referred to
the web version of this article.)
4

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Fig. 4. Docking models of phosphine borane 9 with hERα LBD (PDB ID: 3UUA) obtained with AutoDock 4.2. The protein surface is indicated as a cyan mesh. A)
Superimposition of docking models of (R)-9 (pink) and (S)-9 (green) in the hERα LBD. B). Superimposition of docking models of (R)-9 (pink) and silane 16 (white). C)
Superimposition of docking models of (S)-9 (green) and silane 16 (white). (For interpretation of the references to colour in this figure legend, the reader is referred to
the web version of this article.)
4.1.1. General procedure a for preparation of phosphine oxides 19 and 20.
To a solution of dialkylphosphinic chloride (17 or 18) in dry THF, 4-
methoxyphenylmagnesium bromide solution (0.5 M in THF, 1.1 or
2.0 eq) was added dropwise at 0 °C under an argon atmosphere. The
mixture was stirred at room temperature for 2 h, and then 1.0 M aqu-
eous HCl was added. Stirring was continued for 10 min, and the mixture
was extracted with CHCl3. The organic layer was washed with saturated
brine, dried over with sodium sulfate and concentrated under reduced
pressure. The resulting residue was purified by flash column chroma-
tography on silica gel (ethyl acetate/methanol = 10/1) to isolate the
product.
dry THF and the mixture was stirred for 30 min at 100 °C under mi-
crowave irradiation. The reaction mixture was filtered and the filtrate
was concentrated under reduced pressure. The resulting residue was
purified by flash column chromatography on silica gel (hexane/ethyl
acetate = 2/1) to isolate the product.
4.1.6. General procedure F for preparation of phosphine boranes 9 and 14.
To the solution of 5 or 10 in dry THF, BH3 in THF (1.0 M, 3 eq) was
added at room temperature under an argon atmosphere. The reaction
mixture was stirred for 3 h at room temperature, then quenched with
water and extracted with CHCl3. The organic layer was washed with
saturated brine, dried over with sodium sulfate and concentrated under
reduced pressure. The resulting residue was purified by flash column
chromatography on silica gel (chloroform:ethyl acetate = 10:1) to
isolate the product.
4.1.2. General procedure B for cleavage of methoxy groups to afford
compounds 6, 7, 11, and 12.
To a solution of 13, 14, 17, or 18 in dry CH2Cl2, boron tribromide
(1.0 M in CH2Cl2, 5 eq) was added dropwise at 0 °C under an argon
atmosphere. The reaction mixture was stirred at room temperature for
15 h, then quenched with water, and the mixture was extracted with
CHCl3. The organic layer was washed with saturated brine, dried over
with sodium sulfate and concentrated under reduced pressure. The re-
sulting residue was purified by flash column chromatography on silica
gel (ethyl acetate/methanol = 10/1) to isolate the product.
4.1.7. (4-Methoxyphenyl)(methyl)(phenyl)phosphine oxide (19)
Prepared by general procedure A (97%) as a white powder. 1H NMR
(500 MHz, CDCl3) δ 7.71 (m, 2H), 7.66 (m, 2H), 7.53 (td, J = 7.5,
1.8 Hz, 1H), 7.48 (td, J = 7.5, 2.9 Hz, 2H), 6.99 (dd, J = 8.6, 2.9 Hz,
2H), 3.85 (s, 3H), 2.04 (d, J = 13.2 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 162.5 (d, JCP = 2.4 Hz), 134.3 (d, JCP = 101.3 Hz), 132.5 (d,
JCP = 10.5 Hz), 131.7 (d, JCP = 2.4 Hz), 130.5 (d, JCP = 10.7 Hz),
128.6 (d, JCP = 11.9 Hz) , 124.9 (d, JCP = 107.3 Hz), 114.3 (d,
4.1.3. General procedure C for reduction of phosphine oxide to afford
phosphines 5, 10, 21, and 22.
J
CP = 11.9 Hz), 55.4 (s), 16.8 (d, JCP = 73.9 Hz). 31P NMR (202 MHz,
To a solution of 6, 11, 19, or 20 in a mixture of dry THF and toluene
(1:1), trichlorosilane (12–20 eq) was added at room temperature under
an argon atmosphere. The reaction mixture was stirred for 2 h at 110 °C,
then quenched with 10% aqueous NaOH solution, and extracted with
CHCl3. The organic layer was washed with saturated brine, dried over
sodium sulfate, and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography on silica gel
(chloroform/methanol = 10/1) to isolate the desired compounds.
DMSO-d6) δ 28.9 (s).
4.1.8. (4-Methoxyphenyl)diphenylphosphine oxide (20)
Prepared by general procedure A (quant.) as a white powder. 1H
NMR (500 MHz, CDCl3) δ 7.66 (m, 4H), 7.58 (m, 2H), 7.53 (t,
J = 7.5 Hz, 2H), 7.46 (m, 4H), 6.97 (dd, J = 8.6, 2.9 Hz, 2H), 3.85 (s,
3H). 13C NMR (125 MHz, CDCl3) δ 162.6 (s), 134.1 (d, JCP = 10.7 Hz),
132.9 (d, JCP = 103.7 Hz), 132.1 (d, JCP = 9.5 Hz), 131.9 (d,
JCP = 2.4 Hz), 128.6 (d, JCP = 11.9 Hz) , 123.5 (d, JCP = 109.3 Hz),
114.2 (d, JCP = 13.1 Hz), 55.4 (s). 31P NMR (202 MHz, DMSO-d6) δ
4.1.4. General procedure d for preparation of phosphine sulfides 23 and
24.
26.1(s). ESIMS (positive) m/z 331 [M+Na]+
.
Compound 21 or 22 and elemental sulfur (15 eq) were dissolved in
dry THF and the mixture was stirred for 30 min at 120 °C under mi-
crowave irradiation. The reaction mixture was washed with water and
extracted with CHCl3. The organic layer was washed with saturated
brine, dried over sodium sulfate and concentrated under reduced
pressure. The resulting residue was purified by flash column chroma-
tography on silica gel (hexane/ethyl acetate = 10/1) to isolate the
product.
4.1.9. (4-Hydroxyphenyl)(methyl)(phenyl)phosphine oxide (6)
Prepared by general procedure B (quant.) as a white powder. 1H
NMR (500 MHz, CDCl3) δ 7.66 (m, 2H), 7.51 (m, 1H), 7.46–7.41 (m,
4H), 6.98 (dd, J = 8.6, 2.3 Hz, 2H), 1.97 (d, J = 13.2 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 161.9 (s), 133.1 (d, JCP = 102.5 Hz), 132.4 (d,
JCP = 10.7 Hz), 132.1 (s), 130.6 (d, JCP = 9.5 Hz), 128.9 (d,
JCP = 11.9 Hz), 120.1 (d, JCP = 114.6 Hz), 116.5 (d, JCP = 13.1 Hz),
16.5 (d, JCP = 73.9 Hz). 31P NMR (202 MHz, DMSO-d6) δ 29.2 (s).
4.1.5. General procedure e for preparation of phosphine selenides 8 and 13.
Compound 5 or 10 and selenium powder (10 eq) were dissolved in
ESIMS (positive) m/z 255 [M+Na]+
.
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4.1.10. (4-Hydroxyphenyl)diphenylphosphine oxide (11)
3H), 6.85 (dd, J = 8.6, 2.3 Hz, 2H), 2.23 (d, J = 13.2 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 159.0 (d, JCP = 2.4 Hz), 134.0 (d, JCP = 83.5 Hz),
132.8 (d, JCP = 13.1 Hz), 131.6 (s), 130.8 (d, JCP = 10.7 Hz), 128.8 (d,
JCP = 13.1 Hz), 124.1 (d, JCP = 89.4 Hz), 116.0 (d, JCP = 14.3 Hz),
21.9 (d, JCP = 59.6 Hz). 31P NMR (202 MHz, DMSO-d6) δ 35.6 (s).
Prepared by general procedure B (86%) as a white powder. 1H NMR
(500 MHz, CD3OD) δ 7.62 (m, 6H), 7.54–7.51 (m, 4H), 7.46–7.42 (m,
2H), 6.92 (dd, J = 8.6, 2.3 Hz, 2H). 13C NMR (125 MHz, CD3OD) δ
161.7 (s), 133.9 (d, JCP = 11.9 Hz), 132.2 (d, JCP = 2.4 Hz) 131.9 (d,
JCP = 104.9 Hz), 131.7 (d, JCP = 10.7 Hz), 128.6 (d, JCP = 11.9 Hz),
120.2 (d, JCP = 113.3 Hz), 115.6 (d, JCP = 13.1 Hz). 31P NMR
ESIMS (negative) m/z 247 [MeH]−
.
(202 MHz, DMSO-d6) δ 26.3 (s). ESIMS (negative) m/z 293 [MeH]−
4.1.11. (4-hydroxyphenyl)(methyl)(phenyl)phosphine (5)
.
4.1.18. (4-Hydroxyphenyl)diphenylphosphine sulfide (12)
Prepared by general procedure B (91%) as a white powder. 1H NMR
(500 MHz, CD3OD) δ 7.67–7.63 (m, 4H), 7.52–7.49 (m, 4H), 7.50–7.43
(m, 4H), 6.85 (dd, J = 8.6, 2.3 Hz, 2H). 13C NMR (125 MHz, CD3OD) δ
160.9 (d, JCP = 2.4 Hz), 134.1 (d, JCP = 84.7 Hz), 133.6 (d,
JCP = 84.7 Hz), 131.9 (d, JCP = 10.7 Hz), 131.4 (d, JCP = 2.4 Hz),
128.3 (d, JCP = 11.9 Hz), 121.4 (d, JCP = 93.0 Hz), 115.2 (d,
JCP = 13.1 Hz). 31P NMR (202 MHz, DMSO-d6) δ 42.6 (s). ESIMS
Prepared by general procedure C (81%) as a white powder. 1H NMR
(500 MHz, CDCl3) δ 7.40–7.26 (m, 7H), 6.86 (d, J = 6.9 Hz, 2H), 1.61
(br, 3H). 13C NMR (125 MHz, CDCl3)
δ 161.0 (s), 134.4 (d,
JCP = 19.1 Hz), 132.5 (d, JCP = 11.9 Hz), 131.7 (d, JCP = 16.7 Hz),
130.6 (d, JCP = 9.5 Hz), 128.9 (d, JCP = 11.9 Hz), 121.8 (d,
J
CP = 109.7 Hz), 116.4 (d, JCP = 13.1 Hz), 16.5 (d, JCP = 73.9 Hz). 31
P
(negative) m/z 309 [MeH]−
.
NMR (202 MHz, DMSO-d6) δ −30.0 (s). ESIMS (positive) m/z 217
[M + H]+
.
4.1.19. (4-Hydroxyphenyl)(methyl)(phenyl)phosphine selenide (8)
Prepared by general procedure E (97%) as an amorphous oil. 1H
NMR (500 MHz, DMSO-d6) δ 7.83–7.79 (m, 2H), 7.70 (dd, J = 13.2,
2.3 Hz, 2H), 7.52–7.47 (m, 3H), 6.87 (dd, J = 11.5, 2.3 Hz, 2H), 2.45
(d, J = 13.7 Hz, 3H). 13C NMR (125 MHz, DMSO-d6) δ 161.1 (s), 134.6
(d, JCP = 68.2 Hz), 133.6 (d, JCP = 11.9 Hz), 131.7 (s), 131.2 (d,
JCP = 10.7 Hz), 129.0 (d, JCP = 13.1 Hz), 121.6 (d, JCP = 79.9 Hz),
116.0 (d, JCP = 14.3 Hz), 21.7 (d, JCP = 53.7 Hz). 31P NMR (202 MHz,
4.1.12. (4-hydroxyphenyl)diphenylphosphine (10)
Prepared by general procedure C (93%) as a clear oil. 1H NMR
(500 MHz, CD3OD) δ 7.29 (m, 6H), 7.21 (m, 4H), 7.13 (t, J = 8.0 Hz,
2H), 6.78 (d, J = 8.6 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 158.5 (s),
138.2 (d, JCP = 10.7 Hz), 135.5 (d, JCP = 21.5 Hz), 133.1 (d,
JCP = 19.1 Hz), 128.2 (d, JCP = 4.8 Hz), 128.1 (s), 125.8 (d,
JCP = 6.0 Hz), 115.4 (d, JCP = 8.4 Hz). 31P NMR (202 MHz, DMSO-d6)
DMSO-d6) δ 23.6 (s). ESIMS (negative) m/z 295 [MeH]−
4.1.20. (4-Hydroxyphenyl)diphenylphosphine selenide (13)
.
δ −8.10 (s). ESIMS (negative) m/z 277 [MeH]−
.
4.1.13. (4-Methoxyphenyl)(methyl)(phenyl)phosphine (21)
Prepared by general procedure E (89%) as a white powder. 1H NMR
Prepared by general procedure C (74%) as an amorphous yellow oil.
1H NMR (500 MHz, CDCl3) δ 7.43–7.38 (m, 4H), 7.35–7.30 (m, 3H),
6.91 (d, J = 8.6 Hz, 2H), 3.82 (s, 3H), 1.63 (d, J = 2.9 Hz, 3H). 13C
NMR (125 MHz, DMSO-d6) δ 160.4 (s), 141.5 (d, JCP = 23.6 Hz), 134.3
(d, JCP = 21.5 Hz), 131.7 (d, JCP = 17.9 Hz), 130.3 (d, JCP = 9.5 Hz),
128.9 (d, JCP = 6.0 Hz), 128.5 (s), 114.8 (d, JCP = 8.3 Hz), 55.6 (s),
12.4 (d, JCP = 13.1 Hz).
(500 MHz, DMSO-d6) δ 7.65–7.46 (m, 12H), 6.91 (dd, J = 13.8, 2.3 Hz,
2H). 13C NMR (125 MHz, DMSO-d6)
δ 161.4 (s), 131.9 (d,
JCP = 13.1 Hz), 132.7 (d, JCP = 76.3 Hz), 132.5 (d, JCP = 10.7 Hz),
132.2 (s) , 129.2 (d, JCP = 11.9 Hz), 119.7 (d, JCP = 82.3 Hz), 116.3 (d,
JCP = 13.1 Hz). 31P NMR (202 MHz, DMSO-d6) δ 34.4 (s). ESIMS
(negative) m/z 357 [MeH]−
.
4.1.21. (4-hydroxyphenyl)(methyl)(phenyl)phosphine borane (9)
4.1.14. (4-Methoxyphenyl)diphenylphosphine (22)
Prepared by general procedure F (quant.) as an amorphous oil. 1H
NMR (500 MHz, CDCl3) δ 7.61 (m, 2H), 7.54 (m, 2H), 7.47–7.41 (m,
3H), 6.90 (dd, J = 8.6, 1.7 Hz, 2H), 1.82 (d, J = 10.4 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 158.6 (d, JCP = 2.4 Hz), 133.9 (d, JCP = 10.7 Hz),
131.6 (d, JCP = 9.6 Hz), 131.2 (d, JCP = 56.0 Hz) 131.1 (s), 128.9 (d,
JCP = 10.7 Hz), 120.8 (d, JCP = 62.0 Hz) , 116.2 (d, JCP = 10.7 Hz),
12.3 (d, JCP = 40.5 Hz). 31P NMR (202 MHz, DMSO-d6) δ 7.68 (q).
Prepared by general procedure C (93%) as a white powder. 1H NMR
(500 MHz, CDCl3) δ 7.35–7.31 (m, 12H), 6.91 (m, 2H), 3.81 (s, 3H). 13
C
NMR (125 MHz, CDCl3) δ 160.7 (s), 137.0 (d, JCP = 6.0 Hz), 135.7 (d,
JCP = 21.5 Hz), 133.5 (d, JCP = 17.9 Hz), 128.9 (s), 128.6 (d,
JCP = 7.2 Hz) , 126.7 (d, JCP = 2.4 Hz), 126.7 (s), 114.4 (d,
JCP = 8.4 Hz), 55.4 (d, JCP = 19.1 Hz).
ESIMS (negative) m/z 229 [MeH]−
.
4.1.15. (4-Methoxyphenyl)(methyl)(phenyl)phosphine sulfide (23)
Prepared by general procedure D (90%) as an amorphous oil. 1H
NMR (500 MHz, CDCl3) δ 7.80–7.72 (m, 4H), 7.48–7.44 (m, 3H), 6.96
(dd, J = 8.6, 2.3 Hz, 2H), 3.84 (s, 3H), 2.24 (d, J = 13.2 Hz, 3H). 13C
NMR (125 MHz, CDCl3) δ 162.3 (s), 134.7 (d, JCP = 82.3 Hz), 132.8 (d,
JCP = 11.9 Hz), 131.4 (d, JCP = 2.4 Hz), 130.7 (d, JCP = 10.7 Hz),
128.7 (d, JCP = 13.1 Hz), 124.7 (d, JCP = 88.2 Hz), 114.3 (d,
JCP = 13.1 Hz), 55.5 (s), 22.1 (d, JCP = 59.6 Hz).
4.1.22. (4-Hydroxyphenyl)diphenylphosphine borane (14)
Prepared by general procedure F (95%) as an amorphous oil. 1H NMR
(500 MHz, CDCl3) δ 7.57–7.53 (m, 4H), 7.49–7.47 (m, 4H), 7.45–7.41
(m, 4H), 6.89 (dd, J = 8.6, 1.8 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ
158.5 (s), 135.4 (d, JCP = 10.7 Hz), 133.1 (d, JCP = 9.5 Hz), 131.2 (d,
J
CP = 2.4 Hz), 129.7 (d, JCP = 57.2 Hz) 128.8 (d, JCP = 10.7 Hz), 119.7
(d, JCP = 62.0 Hz), 116.1 (d, JCP = 11.9 Hz). 31P NMR (202 MHz,
DMSO-d6) δ 18.8 (q). ESIMS (negative) m/z 291 [MeH]−
.
4.1.16. (4-Methoxyphenyl)diphenylphosphine sulfide (24)
Prepared by general procedure D (92%) as a white powder. 1H NMR
(500 MHz, CDCl3) δ 7.71–7.61 (m, 6H), 7.47 (m, 2H), 7.41 (m, 4H),
6.93 (dd, J = 8.6, 2.3 Hz, 2H), 3.81 (s, 3H). 13C NMR (125 MHz, CDCl3)
δ 162.4 (d, JCP = 2.4 Hz), 134.2 (d, JCP = 11.9 Hz), 133.5 (d,
JCP = 85.9 Hz), 132.3 (d, JCP = 10.7 Hz), 131.5 (d, JCP = 2.4 Hz),
128.6 (d, JCP = 11.9 Hz), 123.7 (d, JCP = 90.6 Hz), 114.2 (d,
JCP = 13.1 Hz), 55.5 (s).
4.2. Determination of logP values
The 1-octanol/water partition coefficient, log P, was determined by
means of an HPLC method based on the OECD Guideline for Testing
Chemicals.14 An Inertsil ODS-4 (5 μm, 4.6 × 150 mm, GL Sciences Inc.,
Japan) column was fitted on an HPLC instrument (Photodiode Array
detector, MD-2018 Plus, JASCO) equipped with a pump (PU-980,
JASCO) and oven (SSC-2120, Senshu Scientific Co., Ltd.). The injection
volume was 10 μL, and the flow rate was 1.0 mL/min in all cases. The
compounds were detected by measuring UV absorption at 240 and
230 nm. The temperature of the column was kept at 40.0 ( 0.1) °C
4.1.17. (4-Hydroxyphenyl)(methyl)(phenyl)phosphine sulfide (7)
Prepared by general procedure B (95%) as an amorphous oil. 1H
NMR (500 MHz, CDCl3) δ 7.77 (m, 2H), 7.58 (m, 2H), 7.47–7.42 (m,
6

H. Saito, et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxxx
during the measurement. The mobile phase was a methanol–water
system, and the methanol concentration was changed from 75% (v/v)
to 60% (v/v) in 5% (v/v) steps.22,23 The dead time t0 was measured
with thiourea as the unretained compound. Each measurement was
performed in triplicate, and the mean value was used for further cal-
culations. The capacity factor of each compound in 100% aqueous
eluent, log kw, was calculated by extrapolation of the line fitted to the
measured log k values in the methanol–aqueous mobile phase. For the
reference compounds (4-methoxyphenol, phenol, p-cresol, 4-chlor-
ophenol, 4-phenylphenol, diphenylether), the calculated log kw values
were plotted against log P values to prepare a calibration graph (log
P = 1.1155 log kw + 0.0433, R2 = 0.9968). The log P values of tested
phenols were obtained by interpolation of the calculated capacity fac-
tors log kw on the calibration graph.
Acknowledgments
This work described in this paper was partially supported by Grants
in-Aid for Scientific Research from JSPS (KAKENHI Grant Nos.
17H03887 and 19K22486 (S.F.)). We thank Dr. Prof. Minoru Ishikawa
(Graduate School of Life Sciences, Tohoku University, Japan) for
helpful discussion on evaluation of membrane permeability using IAM
column.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmc.2020.115310.
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Declaration of Competing Interest
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The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
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