Journal of Medicinal Chemistry
Article
ninhydrin (0.3% w/v in ethanol) and observed under UV light when
applicable. Flash column chromatography was performed with Silica
gel 60 (VWR, 40−63 μm) with the solvent mixtures specified in the
corresponding experiment. Nuclear magnetic resonance (NMR)
spectra were recorded at room temperature on a Varian Direct
Drive (400 MHz or 500 MHz), Bruker AVANCE III HD NanoBay
chromatography (SiO , hexane/acetone 6:4) to afford 5 (454 mg,
2
1
78%) as oil. H NMR (400 MHz, CDCl ): δ 4.69−4.59 (m, 4H),
3
2.89−2.78 (m, 4H), 2.47 (t, J = 7.2 Hz, 2H), 2.29 (tt, J = 24.1, 5.8 Hz,
1
3
1H), 2.17 (s, 3H), 1.72 (p, J = 7.2 Hz, 2H), 1.20 (m, 24H). C NMR
(101 MHz, CDCl ): δ 195.6, 71.6 (m), 40.9 (t, J = 132.9 Hz), 32.0,
3
3
1
30.7, 29.2, 28.2 (t, J = 4.9 Hz), 28.1, 24.3 (m), 24.0 (m). P NMR
(162 MHz, CDCl ): δ 19.63. IR (neat): ν 2978, 1691, 1374, 1241,
(
400 MHz), Bruker AVANCE Neo (400 MHz or 500 MHz), or
3
−
1
+
+
Varian Direct Drive (600 MHz) spectrometers at a constant
temperature of 298 K with tetramethylsilane as an internal reference.
1102, 977 cm . HR-MS (ESI ) m/z: 529.1595 [M + Na] (calcd for
NaP , 529.1588).
S-(3-(Bis((diisopropoxyphosphoryl)methyl)amino)propyl) Etha-
C
H
19
O
40
S
2 2
7
1
Chemical shifts δ are reported in parts per million (ppm). H NMR
nethioate (9). Diisopropyl phosphite (875 μL, 5.26 mmol, 2.00
equiv) was added to a mixture of 8 (651 mg, 2.63 mmol, 1.00 equiv)
and paraformaldehyde (159 mg, 5.26 mmol, 2.00 equiv) in anhydrous
tetrahydrofuran (THF) (5 mL), dropwise at room temperature, under
an Ar atmosphere. The solution was refluxed overnight (16 h). The
solvent was evaporated under reduced pressure. The crude material
spectra were referenced to the residual partially nondeuterated solvent
signal of CHCl (δ = 7.27 ppm), D O (δ = 4.79 ppm), DMSO (δ =
3
2
2
.50 ppm), or MeOD (δ = 3.31 ppm) or to the signal of the residual
1
3
TMS (δ = 0.00 ppm). C NMR spectra were referenced to the
deuterated solvent signal of CDCl (δ = 77.00 ppm), DMSO-d (δ =
3
3
6
3
1
9.51 ppm), or MeOD (δ = 49.00 ppm). P NMR spectra are
was purified by column chromatography (SiO , CH Cl /MeOH
referenced according to the unified chemical shift scale as
2
2
2
1
66
13
31
9
5:5) to afford 9 (0.72 g, 57%) as light-yellow syrup. H NMR (400
recommended by the IUPAC. The collection of C and
P
1
MHz, CDCl ): δ 4.64 (m, 4H), 3.05 (d, J = 8.2 Hz, 4H), 2.87−2.79
NMR data was done with complete H decoupling. Coupling
constants J are reported in Hz, and splitting patterns are described
as m = multiplet, dd = double doublet, tt = triple triplet, td = triple
doublet, p = quintet, t = triplet, d = doublet, and s = singlet. 2D NMR
spectroscopy (HSQC) and diffusion ordered spectroscopy were used
to analyze the different species present. IR spectra were recorded with
a PerkinElmer Spectrum Two Fourier transform infrared attenuated
total reflection spectrometer. Electrospray (ESI) HRMS spectra were
recorded on a Waters Xevo G2-XS QTOF or a WATERS SYNAP G2.
Unless specified otherwise, the purity of all final compounds was
3
(
2
m, 4H), 2.23 (s, 3H), 1.67 (p, J = 7.1 Hz, 2H), 1.24 (d, J = 6.2 Hz,
4H). C NMR (101 MHz, CDCl ): δ 195.5, 70.2 (t, J = 3.5 Hz),
1
3
3
5
4.9 (t, J = 7.3 Hz), 50.8 (dd, J = 155.9, 5.9 Hz), 30.4, 27.4, 26.4, 24.0
3
1
(m). P NMR (162 MHz, CDCl ): δ 22.73. IR (neat): ν 2979, 1690,
3
−
1
+
1
375, 1210, 1140, 978 cm . HR-MS (ESI ) m/z: 512.1989 [M +
+
Na] (calcd for C H NO NaP S, 512.1977).
19 41
7
2
General Procedure for the Synthesis of Mercapto Diphos-
phonic Acids (6 and 10). Under an inert atmosphere, a solution of
HCl(aq) (6 M, 10 mL) was added to the appropriate ethane thionate
(5 or 9, 1 mmol, 1.00 equiv). The solution was refluxed overnight (16
h). The solvent was removed under reduced pressure to afford the
corresponding thiols 6 and 10 as colorless syrup. They were
characterized and used directly after evaporation of the solvent:
1
determined to be ≥95% by H NMR.
Chemical Synthesis. Tetraisopropyl Ethene-1,1-diylbis-
(
phosphonate) (2). Compound 2 was prepared modifying the
67
previously described procedure: A mixture of paraformaldehyde
4.36 g, 145 mmol, 5.00 equiv) and diethylamine (3.00 mL, 29.0
(
2-((3-Mercaptopropyl)thio)ethane-1,1-diyl)diphosphonic acid
(
1
(
6) (74 mg, Quantitative) as Colorless Syrup. H NMR (400
mmol, 1.00 equiv) in MeOH (50 mL) was refluxed until the complete
dissolution of the reactant. The solution was cooled to room
temperature and tetraisopropyl methylenediphosphonate (1, 10.0 g,
MHz, D O): δ 2.96 (td, J = 16.1, 6.4 Hz, 2H), 2.65 (t, J = 7.2 Hz,
2
2
=
H), 2.56 (t, J = 6.9 Hz, 2H), 2.50 (tt, J = 23.1, 6.4 Hz, 1H), 1.82 (p, J
7.0 Hz, 2H). Spectral data agree with previously reported values.
40
29.0 mmol, 1.00 equiv) was added. The resulting solution was
(
((3-Mercaptopropyl)azanediyl)bis(methylene))diphosphonic
refluxed for 6 days. The solution was cooled to room temperature,
and the solvent was eliminated under reduced pressure. The resulting
oil was dissolved in toluene (20 mL), and the solvent was evaporated
again under reduced pressure. The resulting crude material was
dissolved in dry toluene (250 mL), and a catalytic amount of p-
toluenesulfonic acid was added. The reaction mixture was refluxed in
a Soxhlet apparatus containing powdered calcium hydride (3 g) for 40
h. The mixture was cooled to room temperature, and the solvent was
removed under reduced pressure. The crude material was purified by
1
acid (10) (318 mg, Quantitative) as Colorless Syrup. H NMR (400
MHz, D O): δ 3.60−3.49 (m, 6H), 2.56 (t, J = 6.8 Hz, 2H), 2.03 (p, J
2
13
=
14.9, 7.0 Hz, 2H). C NMR (101 MHz, D O): δ 55.8 (t, J = 3.9
Hz), 51.3 (dd, J = 137.4, 4.3 Hz), 27.2, 20.5. P NMR (162 MHz,
2
31
D O): δ 7.84.
2
General Procedure for the Synthesis of Vinylsulfone
Bisphosphonates VS-BP (7 and 11). Divinyl sulfone (501 μL, 5
mmol, 5.0 equiv) and Na CO (263 mg, 2.5 mmol, 2.5 equiv) were
2
3
added to a solution of the corresponding mercapto diphosphonic
column chromatography (SiO , hexane/acetone 1:1) to afford 2 (7.62
2
acids (6 or 10, 1 mmol, 1.00 equiv) in H O (10 mL) under an Ar
2
1
1
g, 74%) as colorless oil. H NMR (400 MHz, CDCl ): δ H NMR
3
atmosphere. The reaction mixture was stirred for 16 h at room
(
1
400 MHz, CDCl ): δ 6.88 (dd, J = 37.9, 34.1 Hz, 2H), 4.70 (m, 4H),
.32 (d, J = 6.2 Hz, 12H), 1.29 (d, J = 6.2 Hz, 12H). C NMR (101
3
temperature. The solution was diluted with H O (20 mL) and washed
2
1
3
with CH Cl (5 × 20 mL). The aqueous phase was lyophilized to
2
2
MHz, CDCl ): δ 147.5, 134.9 (t, J = 168.7 Hz), 71.4 (m), 24.2 (m),
3
afford the corresponding vinyl sulfone derivatives 7 and 11 as white
solids:
2
3.9 (m).
S-(3-Mercaptopropyl) Ethanethioate (4). Under an inert atmos-
Sodium (2-((3-((2-(Vinylsulfonyl)ethyl)thio)propyl)thio) Ethane-
1
phere, acetic anhydride (1.89 mL, 20.0 mmol, 1.00 equiv) was added
to a solution of 1,3-propanedithiol (3, 2.00 mL, 20.0 mmol, 1.00
equiv) in anhydrous CH Cl /pyridine (1:1, 10 mL). The solution was
1,1-diyl)bis(phosphonate) (7) (522 mg, 96%) as a White Solid. H
NMR (400 MHz, D O): δ 6.90 (dd, J = 16.6, 10.1 Hz, 1H), 6.47 (d, J
2
2
2
= 16.7 Hz, 1H), 6.40 (d, J = 10.0 Hz, 1H), 3.58−3.50 (m, 2H), 3.06−
stirred for 16 h at room temperature. The solvent was removed under
reduced pressure. The crude material was purified by column
chromatography (SiO , CH Cl /hexane 1:1) to afford 4 (1.40 g,
2.89 (m, 4H), 2.77−2.63 (m, 4H), 2.06 (tt, J = 20.7, 7.0 Hz, 1H),
1
3
1.91 (p, J = 7.1 Hz, 2H). C NMR (101 MHz, D O): δ 134.3, 132.9,
2
2
2
2
53.3, 40.1 (t, J = 109.6 Hz), 30.9, 30.2, 28.6 (d, J = 3.8 Hz), 28.1, 23.1.
1
31
4
2
6%) as oil. H NMR (400 MHz, CDCl ): δ 2.96 (t, J = 7.1 Hz, 2H),
P NMR (162 MHz, D O): δ 17.94. IR (neat): ν 3098, 1650, 1360,
3
2
−
1
−
−
.56 (m, 2H), 2.31 (s, 3H), 1.86 (p, J = 7.1 Hz, 2H), 1.38 (t, J = 8.1
1083 cm . HR-MS (ESI ) m/z: 412.9706 [M − 4Na + 3H] (calcd
13
Hz, 1H). C NMR (101 MHz, CDCl ): δ 195.7, 33.7, 30.7, 27.6,
for C H O P S , 412.9717).
3
9
19
8 2 3
2
3.5.
Sodium (((3-((2-(Vinylsufonyl)ethyl)thio)propyl)azanediyl)bis
S-(3-((2,2-Bis(diisopropoxyphosphoryl)ethyl)thio)propyl) Ethane-
(methylene))bis (phosphonate) (11) (180 mg, Quantitative) as a
1
thioate (5). A solution of 4 (346 mg, 2.30 mmol, 2.00 equiv) in
anhydrous CH Cl (5 mL), 2-propanol (0.50 mL), and Et N (160 μL,
White Solid. H NMR (400 MHz, D O): δ 6.91 (dd, J = 16.5, 10.1
2
Hz, 1H), 6.48 (d, J = 16.6 Hz, 1H), 6.40 (d, J = 10.0 Hz, 1H), 3.70−
2
2
3
1
.15 mmol, 1 equiv) was added to 2 (410 mg, 1.15 mmol, 1.00 equiv)
under an Ar atmosphere. The resulting solution was stirred overnight
16 h) at room temperature under an Ar atmosphere. The solvent was
eliminated under vacuum. The crude material was purified by column
3.50 (m, 4H), 3.27 (d, J = 11.3 Hz, 4H), 2.97 (dd, J = 8.9, 6.4 Hz,
13
2H), 2.71 (t, J = 7.4 Hz, 2H), 2.24−2.01 (m, 2H). C NMR (126
(
MHz, D O): δ 134.3, 132.8, 55.3, 54.1 (dd, J = 125.5, 4.1 Hz), 53.2,
2
3
1
27.9, 23.5, 23.2. P NMR (202 MHz, D O): δ 6.33. IR (neat): ν
2
1
2255
J. Med. Chem. 2021, 64, 12245−12260