Journal of Medicinal Chemistry
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obtained as a white solid (11.8 g, 30%). After filtration, a saturated
aqueous solution of sodium chloride was added to the filtrate and the
solution was extracted by dichloromethane. After drying of organic
layers over sodium sulfate, filtration, and evaporation under vacuum, the
final residue was purified by chromatography on silica gel column with as
eluent a mixture of ether/ethyl acetate (100/0 to 20/80), affording both
different fractions enriched with 3.1b and 3.1d. Each fraction was
recrystallized in a mixture diethyl ether/pentane, affording compounds
3.1b (6.81 g, 17%) and 3.1d (1.8 g, 4%).
(d, J = 2.9 Hz), 109.71, 110.09, 127.90 (d, J = 140.2 Hz), 128.50 (d, J =
13.2 Hz), 132.26 (d, J = 10.9 Hz), 133.30 (d, J = 2.9 Hz) ppm. HRMS
(ESI) m/z calcd for C18H26O7P (M + H)+, 385.1416; found, 385.1429.
[α]D25 +40 (c 10 g/L, MeOH). HPLC: tR = 5.45 min; >99% purity at 254
nm.
(SPRSRR)-3-Hydroxy-4-(2.2-dimethyl[1.3]dioxolan-4-yl)-2.2-
dimethyl-2-oxo-2-ethyltetrahydro-2λ5-[1.2]oxaphosphinane
(3.2a).
(SPRSRR)-3-Hydroxy-4-(2.2-dimethyl[1.3]dioxolan-4-yl)-2.2-
dimethyl-2-oxo-2-phenyltetrahydro-2λ5-[1.2]oxaphosphinane
(3.1a).
2.3:5.6-Di-O-isopropylidene-α-D-mannofuranose 2 (2 g, 7.68 mmol)
was added under nitrogen to a solution of ethyl ethylphosphinate 1 (830
mg, 7.68 mmol) in THF (25 mL), and then freshly sublimated
potassium tert-butoxide (175 mg, 0.2 equiv) was added to the solution.
After a 24 h stirring and addition of a saturated solution of NaCl (25
mL), the mixture was extracted with chloroform (50 mL). 1 was
completely consumed and three diastereomers were obtained in 63%
yield.
1
31P NMR (161.97 MHz, CDCl3): δ = 30.43 ppm. H NMR (400.13
MHz, CDCl3): δ = 1.41 (s, 3H), 1.44 (s, 3H), 1.47 (s, 3H), 1.71 (s, 3H),
3.25 (dd, 1H, J = 11.7, 3.1 Hz), 4.04 (dd, 1H, J = 11.7, 3.1 Hz), 4.13 (m,
1H), 4.17 (m, 2H), 4.47 (q, 1H, J = 12.1, 5.5 Hz), 4.65 (dd, 1H, J = 7.9,
1.3 Hz), 4.84 (ddd, 1H, J = 24.6, 7.9, 4.1 Hz), 7.50−7.86 (m, 5H) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 24.54, 25.19, 25.60, 26.86, 66.11 (d,
J = 97.33 Hz), 66.22, 73.27 (d, J = 3.7 Hz), 74.44 (d, J = 8.0 Hz), 75.25
(d, J = 3.7 Hz), 76.20 (d, J = 8.0 Hz), 109.78, 111.21, 128.93 (d, J = 13.2
Hz), 130.62 (d, J = 131.73 Hz), 130.85 (d, J = 10.2 Hz), 132.93 ppm.
HRMS (ESI) m/z calcd for C18H26O7P (M + H)+, 385.1416; found,
385.1404. [α]D25 +58 (c 10 g/L, MeOH). HPLC: tR = 4.29 min; >99%
purity at 254 nm.
3.2a was separated and recovered pure by chromatography on silica
gel with as eluent a mixture of dichloromethane/ethyl acetate (80/20 to
1
50/50). 31P NMR (161.97 MHz, CDCl3): δ = 46.6 ppm. H NMR
(400.13 MHz, CDCl3): δ = 1.24 (dt, 3H, J = 15.2, 7.6 Hz), 1.36 (s, 3H),
1.38 (s, 3H), 1.42 (s, 3H), 1.59 (s, 3H), 1.79−1.97 (m, 2H), 3.69 (dd,
1H, J = 10.6, 5.1 Hz), 3.77 (ddd, 1H, J = 7.3, 3.1, 1.3 Hz), 3.91 (ddd, 1H,
J = 10.8, 3.5, 1.8 Hz), 3.99 (dd, 1H, J = 9.1, 4.3 Hz), 4.12 (dd, 1H, J = 9.1,
6.1 Hz), 4.37(m, 1H), 4.54 (d, 1H, J = 8.8 Hz), 4.79 (ddd, 1H, J = 22.7,
7.6, 3.5 Hz) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 5.25 (d, J = 5.8
Hz), 20.74 (d, J = 90.7 Hz), 24.66, 25.09, 25.72, 26.90, 64.46 (d, J = 90.8
Hz), 66.31, 73.32 (d, J = 2.9 Hz), 73.96 (d, J = 8.8 Hz), 75.37 (d, J = 7.3
Hz), 75.65 (d, J = 5.1 Hz), 109.79, 110.98 ppm. m/z for C14H26O7P (M
+ H)+: 337.18. HPLC was not possible, as no chromophore group is
(RPRSRR)-3-Hydroxy-4-(2.2-dimethyl[1.3]dioxolan-4-yl)-2.2-
dimethyl-2-oxo-2-phenyltetrahydro-2λ5-[1.2]oxaphosphinane
(3.1b).
1
present for UV detection. Purity was determined using 31P NMR, H
NMR, and 13C NMR.
(SPRSRR)-3-Hydroxy-4-(2.2-dimethyl[1.3]dioxolan-4-yl)-2.2-
dimethyl-2-oxo-2-butyltetrahydro-2λ5-[1.2]oxaphosphinane
(3.3a).
1
31P NMR (161.97 MHz, CDCl3): δ = 40.00 ppm. H NMR (400.13
MHz, CDCl3): δ = 1.31 (s, 3H), 1.33 (s, 3H), 1.40 (s, 3H), 1.45 (s, 3H),
4.04−4.14 (m, 2H), 4.17 (dt, 1H, J = 8.1, 1.8 Hz), 4.35−4.43 (m, 1H),
4.50−4.60 (m, 2H), 4.77 (ddd, 1H, J = 27.0, 7.6, 1.3 Hz), 7.25−7.35 (m,
2H), 7.35−7.50 (m, 1H), 7.85−7.95 (m, 2H) ppm. 13C NMR (100.6
MHz, CDCl3): δ = 24.23, 25.07, 25.65, 27.08, 66.73, 68.48 (d, J = 106.8
Hz), 73.56 (d, J = 9.5 Hz), 73.85, 74.51 (d, J = 5.9 Hz), 75.84, 110.21 (d,
J = 17.6 Hz), 126.38 (d, J = 136.85 Hz), 128.13 (d, J = 13.9 Hz), 132.98,
2.3:5.6-Di-O-isopropylidene-α-D-mannofuranose 2 (3 g, 11.52 mmol)
was added under nitrogen to a solution of ethyl n-butylphosphinate 1
(1.56 g, 11.52 mmol) in THF (25 mL), and then freshly sublimated
potassium tert-butoxide (260 mg, 0.2 equiv) was added to the solution.
After 24 h stirring and addition of a saturated solution of NaCl (25 mL),
the mixture was extracted with chloroform (50 mL). Compound 1 was
completely consumed, and three diastereomers were obtained in 47%
yield.
25
133.25 (d, J = 11.0 Hz) ppm. [α]D +56 (c 10 g/L, MeOH). HRMS
(ESI) m/z calcd for C18H26O7P (M + H)+, 385.1416; found, 385.1424.
HPLC: tR = 4.74 min; >95% purity at 254 nm.
(RPSSRR)-3-Hydroxy-4-(2.2-dimethyl[1.3]dioxolan-4-yl)-2.2-
dimethyl-2-oxo-2-phenyltetrahydro-2λ5-[1.2]oxaphosphinane
(3.1d).
3.3a was separated and recovered pure using normal phase
chromatography on silica gel with as eluent a mixture of dichloro-
methane/ethyl acetate (50/50 to 0/100). 31P NMR (161.97 MHz,
CDCl3): δ = 45.43 ppm. 1H NMR (400.13 MHz, CDCl3): δ = 0.93 (t,
3H, J = 7.3 Hz), 1.36 (s, 3H), 1.38 (s, 3H), 1.42 (s, 3H), 1.43 (sext, 2H, J
= 7.3 Hz), 1.59 (s, 3H), 1.60−1.97 (m, 4H), 3.35 (dd, 1H, J = 10.8, 3.3
Hz), 3.77 (ddd, 1H, J = 7.3, 3.0, 1.3 Hz), 3.82 (dd, 1H, J = 8.3, 3.3 Hz),
3.98 (dd, 1H, J = 9.1, 5.5 Hz), 4.12 (dd, 1H, J = 9.1, 6.1 Hz), 4.35 (m,
1H), 4.54 (d, 1H, J = 7.8 Hz), 4.76 (ddd, 1H, J = 22.9, 7.8, 3.8 Hz) ppm.
13C NMR (100.6 MHz, CDCl3): δ = 13.58, 23.14 (d, J = 5.1 Hz), 23.88
(d, J = 5.4 Hz), 27.91(d, J = 88.5 Hz), 24.79, 25.08, 25.71, 26.90, 64.95
(d, J = 89.3 Hz), 66.37, 73.25 (d, J = 2.9 Hz), 73.98 (d, J = 8.8 Hz), 75.23
(d, J = 7.3 Hz), 75.49 (d, J = 4.4 Hz), 109.79, 111.03 ppm. m/z for
C16H30O7P (M + H)+: 365.19. HPLC was not possible, as no
1
31P NMR (161.97 MHz, CDCl3): δ = 36.19 ppm. H NMR (400.13
MHz, CDCl3): δ = 1.40 (s, 3H), 1.42 (s, 3H), 1.47 (s, 3H), 1.49 (s, 3H),
4.14 (d, 1H, J = 5.0 Hz), 4.33 (dd, 1H, J = 6.6, 3.8 Hz), 4.45 (dt, 1H, J =
9.8, 4.2 Hz), 4.54 (ddd, 1H, J = 8.1, 6.1, 1.8 Hz), 4.61 (dm, 1H, J = 7.3
Hz), 4.88 (ddd, 1H, J = 24.5, 7.3, 3.8 Hz), 7.44−7.53 (m, 2H), 7.56−
7.65 (m, 1H), 7.88−8.00 (m, 2H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 24.12, 25.18, 25.76, 26.97, 64.23 (d, J = 90.0 Hz), 66.83,
71.90 (d, J = 4.4 Hz), 73.59 (d, J = 8.1 Hz), 74.00 (d, J = 5.1 Hz), 75.36
H
dx.doi.org/10.1021/jm500522y | J. Med. Chem. XXXX, XXX, XXX−XXX