A.D. Tiwari et al.
Bioorganic & Medicinal Chemistry 39 (2021) 116141
chloride solution followed by brine, separated, and dried over sodium
sulfate. Filtration and evaporation under reduced pressure provided the
crude products as oils. Flash silica gel column chromatography eluting
with 7–12% ethyl acetate: hexanes provided desired products in 45–95%
yields in > 95% purity. All new compounds were fully characterized by
ethyl acetate (50 mL) once, separated, and then water was removed by
lyophilization. Sep-Pak C-18 reverse phase column chromatography was
used for further purification in acetonitrile:water (8:2). Pure diacid
powders were obtained by lyophilization.
2-Hydroxy-4-methylenepentanedioic acid (2a): The compound ob-
1
13
1
H, C NMR, and HRMS.
tained as a white crystalline solid, yield 55%. H NMR (400 MHz,
1
Diethyl 2-hydroxy-4-methylenepentanedioate (1a): The obtained com-
pound was a clear oil, yield 95%. 1H NMR (500 MHz, Chloroform-d) δ
Deuterium Oxide) H NMR (400 MHz, Deuterium Oxide) δ 6.02 (d, J =
1.5 Hz, 1H), 5.61 – 5.57 (m, 1H), 4.20 (dd, J = 8.5, 4.0 Hz, 1H), 2.8 –
1
3
6
4
1
7
6
.29 (d, J = 1.3 Hz, 1H), 5.72 (q, J = 1.1 Hz, 1H), 4.42 – 4.37 (m, 1H),
.23 (qd, J = 7.1, 5.5 Hz, 4H), 3.13 (d, J = 5.5 Hz, 1H), 2.86 (ddd, J =
4.2, 4.5, 1.2 Hz, 1H), 2.64 (ddd, J = 14.3, 8.1, 1.0 Hz, 1H), 1.31 (q, J =
.2 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 174.4, 167.2, 136.0, 128.4,
9.7, 61.8, 61.2, 37.4, 14.3.14.2 HRMS (ESI + ) m/z 239.0887 [M +
2.75 (m, 1H), 2.54 (dd, J = 14.5, 8.5 Hz, 1H). C NMR (101 MHz, D
2
O)
δ 180.3, 174.1, 139.8, 125.4, 71.4, 37.4. HRMS (ESI-): m/z 159.0294
-
-
[Mꢀ H] ; calculated for C
6
8
H O
5
[Mꢀ H] 159.0299.
2-Hydroxy-2-methyl-4-methylenepentanedioic acid (2b): The com-
1
pound was obtained as an off white crystalline solid, yield 60%. H NMR
+
+
Na] ; calculated for C10
H
16
O
5
[M + Na] 239.0890.
(500 MHz, Methanol‑d
4
) δ 6.02 (d, J = 2.3 Hz, 1H), 5.44 (d, J = 2.2 Hz,
13
Diethyl 2-hydroxy-2-methyl-4-methylenepentanedioate (1b): The com-
pound was a clear oil, yield 80%. 1H NMR (400 MHz, Chloroform-d) δ
1H), 3.35 (s, 1H), 2.72 (q, J = 13.7 Hz, 2H), 1.33 (s, 3H). C NMR (126
MHz, MeOD) δ 183.0, 175.9, 143.0, 125.5, 77.5, 44.0, 26.9. HRMS (ESI-
-
-
6
3
1
1
.27 (d, J = 1.7 Hz, 1H), 5.68 (d, J = 1.8 Hz, 1H), 4.27 – 4.10 (m, 4H),
): m/z 173.0451 [Mꢀ H] ; calculated for C
7
H
10
O
5
[Mꢀ H] 173.0455.
.60 (s, 1H), 2.85 (d, J = 13.9, 1H), 2.68 (dd, J = 13.9, 1H), 1.44 (s, 3H),
2-Hydroxy-4-methylene-2-(trifluoromethyl)pentanedioic acid (2c): The
1
3
obtained compound was an off white solid, yield 40%. 1H NMR (400
.30 (td, J = 7.1, 4.6 Hz, 6H). C NMR (100 MHz, CDCl
3
) δ 176.0,
67.8, 135.9, 128.9, 74.3, 61.9, 61.2, 42.0, 25.7, 14.3(2C). HRMS (ESI
MHz, Deuterium Oxide) δ 5.95 (d, J = 1.5 Hz, 1H), 5.51 (s, 1H), 2.97 –
+
[M + H]+
13
+
) m/z 231.1229 [M + H] ; calculated for C11
H
18
O
5
2
2.85 (m, 2H). C NMR (101 MHz, D O) δ 175.7, 173.3, 138.9, 126.1,
-
2
31.1227.
125.4, 123.2, 78.8, 78.6, 34.9. HRMS (ESI-): m/z 227.0170 [Mꢀ H] ;
-
Diethyl 2-hydroxy-4-methylene-2-(trifluoromethyl)pentanedioate (1c):
calculated for C
7
H
7
3
F O
5
[Mꢀ H] 227.0173.
1
The compound was a clear oil, yield 60%. H NMR (400 MHz, Chloro-
form-d) δ 6.32 (d, J = 1.3 Hz, 1H), 5.78 (s, 1H), 4.39 (s, 1H), 4.37 – 4.32
2.1.4. Dess-Martin oxidation of selected alcohols
(
m, 1H), 4.28 (ddd, J = 10.5, 7.0, 3.3 Hz, 1H), 4.22 (qd, J = 7.1, 2.8 Hz,
The hydroxy derivatives were dissolved in dichloromethane (50 mL)
in a 100 mL round bottom flask and Dess-Martin-Periodinane (1.5 equiv.
mol ratio) was added to the solution. The heterogeneous mixture was
2
9
1
H), 3.12 (d, J = 14.3 Hz, 1H), 2.95 (d, J = 14.3 Hz, 1H), 1.32 (dt, J =
.6, 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl
) δ 168.7, 167.4, 133.4,
3
1
9
◦
30.2, 124.5, 122.2, 63.6, 61.5, 33.8, 33.7, 14.1, 13.9. F NMR (376
stirred at 20 C for 4 h. The reaction was monitored by TLC for the
+
MHz, CDCl
3
) δ ꢀ 78.41. HRMS (ESI + ) m/z 285.0947 [M + H] ;
complete oxidation of hydroxy derivative. The solvent was evaporated
under reduced pressure and residue was dissolved in ethyl acetate (100
+
calculated for C11
H
15
F
3
O
5
[M + H] 285.0944.
Diethyl 2-ethyl-2-hydroxy-4-methylenepentanedioate (1d): The com-
pound was a clear oil, 65% yield. 1H NMR (400 MHz, Chloroform-d) δ
mL). The organic layer was washed with 1:1 NaHCO
3
(10%) and
2 2 3
Na S O (10%) aqueous solution twice (50 mL each). The organic layer
6
.22 (d, J = 1.7 Hz, 1H), 5.65 (d, J = 1.9 Hz, 1H), 4.28 – 4.09 (m, 4H),
again washed with brine solution (50 mL) and dried over the sodium
sulfate, filtered and solvent were evaporated under reduced pressure.
The crude compounds were purified by the flash silica column chro-
matography and obtained in 80–90% yields.
3
.53 (s, 1H), 2.80 (d, J = 14.0 Hz, 1H), 2.70 (d, J = 13.9 Hz, 1H), 1.85
(
dt, J = 14.5, 7.2 Hz, 1H), 1.68 (dd, J = 14.7, 7.5 Hz, 1H), 1.28 (td, J =
1
3
7
.2, 1.7 Hz, 6H), 0.87 (t, J = 7.4 Hz, 3H). C NMR (101 MHz, CDCl
3
) δ
1
75.6, 167.8, 136.1, 128.5, 77.6, 61.8, 61.1, 40.9, 32.1, 14.4, 14.3, 8.0.
Diethyl 2-methylene-4-oxopentanedioate (3a): Off white solid, yield
+
1
HRMS (ESI + ) m/z 267.1198 [M + Na] ; calculated for C12
H
20
O
5
[M +
80%. H NMR (500 MHz, Chloroform-d) δ 6.39 (s, 1H), 5.70 (s, 1H), 4.33
+
Na] 267.1203.
(q, J = 7.1 Hz, 2H), 4.19 (q, J = 7.2 Hz, 2H), 3.82 (s, 2H), 1.36 (t, J = 7.2
Diethyl 2-hydroxy-2-isopropyl-4-methylenepentanedioate (1e): This
Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H).
1
compound was obtained as clear oil, yield 45%. H NMR (400 MHz,
Ethyl 1-(3-ethoxy-2,3-dioxopropyl)cyclopropane-1-carboxylate (7a):
1
Chloroform-d) δ 6.18 (d, J = 1.7 Hz, 1H), 5.64 (s, 1H), 4.27 – 4.08 (m,
Off white solid, yield 80%. H NMR (500 MHz, Chloroform-d) δ 4.33 (q,
4
H), 3.52 (s, 1H), 2.87 – 2.78 (m, 1H), 2.74 (d, J = 14.0 Hz, 1H), 2.05 (p,
J = 7.2 Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 3.04 (s, 2H), 1.40 – 1.37 (m,
J = 6.8 Hz, 1H), 1.29 (td, J = 7.2, 4.5 Hz, 6H), 1.01 (d, J = 6.9 Hz, 3H),
4H), 1.31 – 1.20 (m, 5H), 1.19 (t, J = 7.1 Hz, 3H), 0.82 (q, J = 4.4 Hz,
1
3
13
0
.88 (d, J = 6.8 Hz, 3H). C NMR (101 MHz, CDCl
3
) δ 175.7, 168.0,
3
2H). C NMR (126 MHz, CDCl ) δ 192.3, 174.0, 161.3, 62.6, 61.12,
1
36.8, 127.9, 80.0, 61.7, 61.1, 38.5, 35.7, 17.6, 16.1, 14.3, 14.2. HRMS
43.3, 19.7, 18.0, 15.4, 14.3, 14.12, 14.1.
+
[M + Na]+
(
ESI + ) m/z 281.1354 [M + Na] ; calculated for C13
H
22
O
5
Ethyl 1-(3-ethoxy-2-hydroxy-3-oxopropyl)cyclopropane-1-carboxylate
(5a): This derivative was synthesized according to previously published
literature.16 Clear oil, yield 45%. 1H NMR (500 MHz, Chloroform-d) δ
4.42 (dt, J = 9.3, 4.5 Hz, 1H), 4.23 (dtd, J = 21.1, 7.1, 3.6 Hz, 2H), 4.12
(q, J = 7.1 Hz, 2H), 3.39 (d, J = 6.2 Hz, 1H), 2.09 (dd, J = 14.7, 4.2 Hz,
1H), 1.90 (dd, J = 14.7, 8.7 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.24 (t, J =
2
81.1359.
Ethyl 4-hydroxy-2-methylenepentanoate (1f): This compound was a
1
white amorphous powder, yield 55%. H NMR (400 MHz, Chloroform-d)
δ 6.26 (d, J = 1.7 Hz, 1H), 5.66 (d, J = 1.8 Hz, 1H), 4.22 (q, J = 7.2 Hz,
2
1
6
4
H), 4.00 – 3.94 (m, 1H), 2.56 (dd, J = 14.0, 3.9 Hz, 1H), 2.38 (dd, J =
3.9, 8.0 Hz, 1H), 2.18 (d, J = 6.0, 1H), 1.31 (t, J = 7.2, 3H), 1.22 (d, J =
1
3
7.2 Hz, 3H), 0.91 (ddd, J = 9.7, 6.6, 3.8 Hz, 1H), 0.79 – 0.72 (m, 1H).
C
.3, 3H). 13C NMR (100 MHz, CDCl
) δ 167.8, 137.8, 127.7, 67.0, 61.2,
NMR (126 MHz, CDCl
16.2, 15.4, 14.3.
) δ 175.6, 174.9, 70.4, 61.6, 61.0, 39.1, 21.3,
3
3
+
2.1, 23.2, 14.3. HRMS (ESI + ) m/z 159.1013 [M + H] ; calculated for
+
C
H
8 14
O
3
[M + H] 159.1016.
Diethyl 2-fluoro-4-methylenepentanedioate (8a): This derivative was
1
6 1
synthesized according to previously published literature.
H NMR
2
.1.3. General method for saponification of diesters with aqueous lithium
(500 MHz, Chloroform-d) δ 6.34 (s, 1H), 5.76 (s, 1H), 5.16 – 5.04 (m,
1H), 4.44 (q, J = 7.2 Hz, 1H), 4.24 (dt, J = 14.8, 7.0 Hz, 3H), 2.99 (ddd,
J = 29.5, 14.7, 4.2 Hz, 1H), 2.82 (td, J = 16.3, 15.4, 8.6 Hz, 1H), 1.44 (t,
J = 7.2 Hz, 1H), 1.34 – 1.28 (m, 4H), 1.25 (d, J = 5.1 Hz, 1H).
hydroxide
The diesters (1.0 mmol) were saponified with lithium hydroxide
◦
(
LiOH, 1.0 M aqueous, 2–3 mol equiv.) in THF (50 mL) at 20 C for 6 h
with continuous stirring. Reactions were monitored by TLC for
completion. The crude reaction was concentrated under reduced pres-
sure and residue dissolved in 50 mL water and pH adjusted with 10%
HCl (1.2 M) till pH 4.0. The aqueous solution at pH 4.0 was washed with
2.1.5. General Pd/C hydrogenation of selected 4-methylene
pentanedicarboxylate esters
Selected 4-methylene derivatives were reduced in 50 mL absolute
3