130
M. Mikołajczyk et al. / Tetrahedron 68 (2012) 126e132
naphthylethyl auxiliary. The stereoselective and asymmetric syn-
thesis of the title salts paves the way for the synthesis of other
enantiomeric oxazaphosphorinanes and studies on the relationship
between chirality at phosphorus and bioactivity.
5.24 mmol) in chloroform (30 mL) was added dropwise. After 2 h the
solution was filtered through silica gel (5 g), concentrated under re-
duced pressure and purified by flash column chromatography (silica
gel, chloroformeethyl acetate, 98:2) to give the title compound 9
(1.49 g, 93%) as a pale yellow oil; [Found: C, 39.1; H, 5.0; N, 9.0; S,10.2.
4. Experimental
C10H15N2O5PSrequiresC,39.21;H, 4.90;N,9.15;S,10.45%];½a D22
þ28.4
ꢁ
(c 2.4, CHCl3); dH (200 MHz, CDCl3) 8.22 (2H, d, J 9.2 Hz, ArH), 7.35 (2H,
d, J 9.2 Hz, ArH), 3.80 (3H, d, JHeP 14.1 Hz, OCH3), 3.77 (2H, t, J 6.2 Hz,
OCH2), 3.25 (2H, dt, JHeH 6.4 Hz, JHeP 11.3 Hz, NCH2), 1.77 (2H, m,
OCH2CH2CH2N); dC (50 MHz, CDCl3) 155.9 (s, ArC),141.3 (s, ArC),125.2
(s, ArC),121.4 (s, ArC), 60.2 (s, CH2OH), 53.8 (d, JCeP 5.2 Hz, CH3O), 39.5
(d, JCeP 3.2 Hz, CCH2C), 33.1 (d, JCeP 5.9 Hz, NCH2); dP (81 MHz, CDCl3)
70.1.
4.1. General information
All solvents and chemicals were used as provided by the sup-
plier. Melting and boiling points are uncorrected. NMR spectra
were recorded on Bruker AC 200 and Bruker MSL spectrometers.
Chemical shifts are quoted in parts per million (ppm). 1H and 13C
chemical shifts are reported relative to TMS as an external stan-
dard. 31P NMR downfield chemical shifts are expressed with
a positive sign relative to an external standard of 85% H3PO4.
Optical rotations were measured at 22 ꢂC using PerkineElmer MC
241 photopolarimeter. Optical purity (op) values were calculated
based on specific rotations. Enantiomeric excesses (ee) were de-
termined by HPLC on a Varian Pro-Star instrument using Cyclo-
bond 2000 DMP, or by NMR via diastereoisomeric solvates.
Diastereoisomeric ratios (dr) were determined by integration of
the resonance signals in 1H and 31P NMR spectra. Mass spectra
were recorded on a Finnigan MAT 95 apparatus. Thin layer chro-
matography (TLC) was conducted on Silica Gel F254 TLC purchased
from Merck. Column chromatography was performed using Merck
silica gel (70e230 mesh).
4.2.4. (ꢀ)-(S)-Methyl p-nitrophenyl N-(3-hydroxypropyl)phosphoro-
amidothionate (9). When the thioacid (ꢀ)-(S)-8 (0.7 g, 2.81 mmol),
½
a 2D2
ꢁ
ꢀ23.4 (c 1.8, CHCl3), was used, the same procedure produced
the amidodiester (ꢀ)-(S)-9 (0.553 g, 87%) as a pale yellow oil, ½a D22
ꢁ
ꢀ25.2 (c 1.97, CHCl3).
4.2.5. (ꢀ)-(S)-2-Methoxy-1,3,2-oxazaphosphorinan-2-thione
(10). To a stirred solution of the phosphoroamidothionate (þ)-(R)-9
(c 2.4, CHCl3), (1.224 g, 4 mmol) in chloroform (40 mL) was added
tetramethylenediamine (TMEDA) (0.465 g, 4 mmol) at room tem-
perature. After 48 h the reaction solution was transferred into a sep-
aratory funnel, washed with water (4ꢃ5 mL), dried over anhydrous
potassium carbonate, filtered and evaporated under reduced pres-
sure. The crude product was purified by column chromatography
(silica gel 230e400 mesh, chloroform-n-heptane, 9:1) to give the
oxazaphosphorinane 10 (0.615 g, 92%) as a pale yellow oil; [Found: C,
29.1; H, 6.3; N, 8.4; P, 18.9. C4H10NO2PS requires C, 28.74; H, 6.02; N,
4.2. Stereoselective synthesis of (D)-(S)- and (L)-(R)-
tetramethylammonium 2-oxo-2-thio-1,3,2-
oxazaphosphorinane 5
8.38; P, 18.54%]; ½a D22
ꢀ35.2 (c 3.3, CHCl3, 85% ee); nmax (liquid fil)
ꢁ
4.2.1. (þ)-(R)-Methyl p-nitrophenyl phosphorothioic acid (8). To
a stirred suspension of (ꢀ)-(RP)-methostrychninium salt 7 (3.58 g,
3363e3291 (br), 2958e2843 (br), 1723, 1462, 1377, 1325, 1276, 1217,
1079, 1031, 969, 938, 873, 802, 663 cmꢀ1
; dH (200 MHz, CDCl3)
0.6 mmol), ½a 2D2
ꢁ
ꢀ15.3 (c 1.2, MeCN) in 50% methanol (25 mL), 2 N
4.38e4.24 (2H, m), 3.69 (3H, d, JHeP 13.6 Hz, OCH3), 3.41e3.14 (3H, m),
2.16e1.93 (1H, m),1.64e1.53 (1H, m); dC (50 MHz, CDCl3) 68.6 (d, JCeP
8.8 Hz, OCH2), 52.9 (d, JCeP 5.0 Hz, OCH3), 41.05 (d, JCeP 5.5 Hz, CCH2C),
26.0 (d, JCeP 6.9 Hz, CH2N); dP (81 MHz, CDCl3) 69.22.
hydrochloric acid (60 mL) was added slowly at room temperature.
After the salt was completely dissolved, the content was transferred
into separating funnel and extracted with dichloromethane
(3ꢃ60 mL). The organic layer was dried over sodium sulfate and
evaporated under reduced pressure. The crude phosphorothioic
acid 8 was obtained (1.47 g, 99% yield) as a pale yellow viscous oil
4.2.6. (þ)-(R)-2-Methoxy-1,3,2-oxazaphosphorinan-2-thione
(10). In a similar way phosphoroamidothionate (ꢀ)-9 (0.5 g,
and used without additional purification for further reactions. ½a D22
ꢁ
1.63 mmol), ½a 2D2
ꢀ25.2 (c 1.97, CHCl3), gave the oxazaphosphor-
ꢁ
þ26.7 (c.1.9, CHCl3, 86.6% ee); dH (200 MHz, CDCl3) 8.18 (2H, d, J
8.9 Hz, ArH), 7.37 (2H, d, J 8.9 Hz, ArH), 3.81 (3H, d, JHeP 13.8 Hz,
OCH3), dP (81 MHz, CDCl3) 59.35.
inane (þ)-10 (0.254 g, 90%), ½a D22
þ32.4 (c 2.5, CHCl3, 78% ee).
ꢁ
4.2.7. (þ)-(S)-Tetramethylammonium 2-oxo-2-thio-1,3,2-
oxazaphosphorinane (5). A mixture of (ꢀ)-10 (0.167 g, 1 mmol),
4.2.2. (ꢀ)-(S)-Methyl
p-nitrophenyl
phosphorothioic
acid
½
a 2D2
ꢁ
ꢀ35.2 (c 1, CHCl3) and trimethylamine (0.5 mL) in benzene
(8). According to the procedure described above from the salt
(3 mL) was kept at room temperature for 2 weeks. The white
(þ)-(SP)-7 (1.79 g, 3 mmol), ½a D22
ꢁ
þ14.2 (c 1.2, MeOH), the thioacid
crystalline salt (þ)-5 produced (0.137 g, 60%) was filtered off,
(ꢀ)-8 was obtained (0.71 g, 96%); ½a D22
ꢁ
ꢀ23.4 (c 1.8, CHCl3, 77% ee).
washed with benzene and dried over P2O5, mp 218e221 ꢂC; ½a D22
ꢁ
þ14.1 (c 1.26, MeOH, 85% ee); nmax (KBr) 3513e3340 (br), 3273,
4.2.3. (þ)-(R)-Methyl p-nitrophenyl N-(3-hydroxypropyl)phosphoro-
amidothionate (9). To a stirred phosphorus pentachloride (1.25 g,
6 mmol) in chloroform (50 mL) thioacid (þ)-(R)-8 (1.46 g, 5.86 mmol),
3013, 2952, 1650, 1608, 1487, 1199, 1163, 1075, 1040, 947, 856, 816,
759, 661, 591 cmꢀ1
; dH (200 MHz, CD3OD) 5.05e4.35 (3H, m, OCH2,
NH), 3.52 (12H, s, N(CH3)4), 3.28e2.85 (2H, m), 2.22e1.87 ( 1H, m,
CCH2C), 1.80e1.70 (1H, m, CeCH2eC); dP (81 MHz, D2O) 56.6.;
LSIMS, Csþ, 13 keV (NBA): ion (þ): m/z 74 (Me4Nþ), ion (ꢀ): m/z 152
(2-oxo-2-thio-1,3,2-oxazaphosphorinaneꢀ).
½
a 2D2
ꢁ
þ26.7, (c 1.9, CHCl3) in chloroform (10 mL) was added dropwise
at 0 ꢂC. The reaction mixture was stirred for 2 h and cooling bath was
removed. When room temperaturewasreached, thereaction mixture
was filtered. To the filtrate was added dry toluene (10 mL) and the
mixture evaporated to small volume under reduced pressure. Addi-
tion of toluene and evaporation was repeated to remove the traces of
phosphoryl chloride. A pale yellow oil obtained after evaporation was
pre-purified by flash column chromatography (5 g of silica gel, chlo-
roform-n-hexane, 1:1) to give phosphorochloridothionate (ꢀ)-(R)-6
(1.4 g, 90%); dP (81 MHz, CDCl3) 60.37. Without further purification it
4.2.8. (ꢀ)-(R)-Tetramethylammonium 2-oxo-2-thio-1,3,2-
oxazaphosphorinane (5). Demethylation of (þ)-10 (0.245 g,
1.46 mmol), ½a 2D2
þ32.4 (c 2.5, CHCl3), carried out as described above
ꢁ
afforded the title salt (ꢀ)-5 (0.183 g, 56%), ½a D22
ꢀ13.0 (c 1.24, MeOH,
ꢁ
78% ee).
was dissolved in chloroform (40 mL) and
aminopropanol (0.395 g, 5.24 mmol) and triethylamine (0.53 g,
a
mixture of 3-
4.2.9. (ꢀ)-(R)-Methyl p-nitrophenyl 3-azidopropyl phosphorothionate
(11). To an ethereal solution (5 mL) of phosphorochloridothionate