The Journal of Organic Chemistry
Note
956, 914, 860, 776, 742 cm−1. Specific rotation [α]2D3 = −33.5 (c 0.23,
MeOH).
heated to 70 °C. Note that the thiosulfonate degrades when heated to
refluxing temperatures, or above approximately 85 °C. A reflux
condenser was attached, and the reaction was stirred for 2 h, turning
pale yellow in color. The reaction mixture was transferred to a
separatory funnel, diluted with ethyl acetate, and then washed with
half sat. NaHCO3. The aqueous layer was extracted with ethyl acetate,
and then the combined organic layers were washed with an aqueous
solution of saturated sodium chloride and dried (MgSO4). The
solvent was removed under reduced pressure, and the resulting oil was
purified by flash column chromatography on silica gel (10−100%
EtOAc/hexanes, Rf = 0.38, 50:50 EtOAc/hexanes) to yield the title
Preparation of (R)-1-Methoxy-3-((methylsulfonyl)thio)-1-
oxopropan-2-yl Benzoate (7b). The hydroxy acid 7 was
derivatized as described for chiral HPLC analysis: 7 (50 mg, 0.25
mmol) was dissolved in dry methanol (2 mL), heated to 60 °C, and
stirred overnight. The solvent was removed under reduced pressure.
The crude residue was diluted with ethyl acetate, washed with dilute
sodium bicarbonate, and then dried (MgSO4). The solvent was
removed under reduced pressure. The resulting oil (ca. 0.23 mmol)
was dissolved in 5 mL of dry dichloromethane in a flame-dried round-
bottom flask and then cooled in an ice−water bath. To the solution
was added triethylamine (39 uL, 0.28 mmol), followed by benzoyl
chloride (32 uL, 0.28 mmol) and 4-dimethylaminopyridine (5.6 mg,
0.05 mmol). The mixture was warmed to room temperature
overnight, and then the reaction was quenched with ammonium
chloride. The layers were separated, and the aqueous layer was
extracted three times with dichloromethane. The combined organic
extracts were washed with dilute HCl and then dried (MgSO4). The
resulting residue was purified by flash column chromatography (7−
40% EtOAc/hexanes, Rf = 0.14, 25% EtOAc/hexanes). 1H NMR (400
MHz, CDCl3): δ 8.11−8.05 (m, 2H), 7.68−7.56 (m, 1H), 7.48 (dd, J
= 8.5, 7.1 Hz, 2H), 5.65 (dd, J = 7.0, 4.1 Hz, 1H), 3.86 (dd, J = 14.8,
4.1 Hz, 1H), 3.82 (s, 3H), 3.74 (dd, J = 14.8, 7.1 Hz, 1H), 3.37 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 168.2, 165.5, 134.0, 130.1,
128.7, 128.7, 71.2, 53.2, 51.2, 37.2. HRMS (ESI-QTOF) m/z: [M +
H]+ calcd for C12H15O6S2, 319.0305; found, 319.0307. IR 3007, 1754,
1726, 1601, 1452, 1319, 1268, 1177, 1134, 1109, 1071, 1026, 957,
745, 713 cm−1. Specific rotation [α]D23 = +28.9 (c 1.7, CHCl3).
Enantiomeric ratio 96:4. HPLC chromatograms and method
information for assessment of enantiomeric ratio are included in the
Preparation of Methyl (R)-2-Hydroxy-3-((phenylsulfonyl)-
thio)propanoate (9). Amino acid 6 (261.3 mg, 1.0 mmol) was
dissolved in 4 mL of 1 M sulfuric acid in a 50 mL round-bottom flask
equipped with a magnetic stirrer. The reaction was run open to
ambient atmosphere. The mixture was cooled in an ice−water bath; 4
mL of acetone was then added. Sodium nitrite (276 mg, 4.0 mmol)
was dissolved in DI water (3 mL) and then added dropwise, using
additional DI water for rinsing (1 mL). The solution was warmed to
room temperature gradually over 4 h. The reaction mixture was
transferred to a separatory funnel. Saturated sodium sulfate was added
(8 mL), and then the aqueous layer was extracted with ethyl acetate
(4 × 5 mL). The combined organic extracts were dried (MgSO4) and
then filtered using a sintered glass funnel (medium porosity). The
solvent was removed under reduced pressure. The resulting yellow oil
containing 8 was dissolved in dry methanol in a flame-dried round-
bottom flask and stirred for 48 h at rt. The solvent was removed under
reduced pressure, and the resulting residue was purified by flash
column chromatography (7−40% EtOAc/hexanes) to yield a yellow
oil (168 mg, 0.61 mmol, 61%, 97:3 er). Alternatively, the crude oil
containing 8 was methylated with TMSCH2N2 (see Safety
Considerations) according to a general procedure12 and purified
analogously (143.2 mg, 0.52 mmol, 52%). 1H NMR (500 MHz,
CDCl3): δ 8.02−7.84 (m, 2H), 7.70−7.61 (m, 1H), 7.55 (dd, J = 8.4,
7.0 Hz, 2H), 4.42 (dd, J = 6.3, 4.1 Hz, 1H), 3.75 (s, 3H), 3.49 (dd, J =
14.0, 4.1 Hz, 1H), 3.30 (dd, J = 14.0, 6.3 Hz, 1H), 3.23 (s, 1H).
13C{1H} NMR (125 MHz, CDCl3): δ 172.4, 144.5, 134.0, 129.5,
1
compound as a yellow oil (1.49 g, 6.20 mmol, 60%). H NMR (400
MHz, CDCl3): δ 5.90 (ddt, J = 16.6, 10.4, 5.9 Hz, 1H), 5.39−5.25 (m,
2H), 4.69 (dt, J = 6.0, 1.3 Hz, 2H), 4.56 (dd, J = 6.0, 3.8 Hz, 1H),
3.66 (dd, J = 14.8, 3.8 Hz, 1H), 3.53 (dd, J = 14.8, 5.9 Hz, 1H), 3.42
(s, 3H), 3.39 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 171.8,
130.9, 120.0, 69.9, 67.1, 50.9, 40.2. HRMS (ESI-QTOF) m/z: [M +
Na]+ calcd for C7H12O5S2Na, 263.0018; found, 263.0022. IR 3477,
3011, 2930, 1735, 1648, 1449, 1411, 1312, 1185, 1128, 1093, 995,
956, 744 cm−1. Specific rotation [α]D23 = −56.2 (c 2.5, CHCl3).
Preparation of Allyl (R)-2-Hydroxy-3-((phenylsulfonyl)thio)-
propanoate (11). The title compound was prepared by the method
described for 10, starting from the crude hydroxy acid intermediate 8
described in the preparation of 9 on a 3.2 mmol scale. The crude oil
was purified by flash column chromatography (Rf = 0.49, 50:50
EtOAc/hexanes) to yield the title compound as a pearly yellow solid
(381 mg, 40% over 2 steps from 6). A single crystal was grown for X-
ray analysis by dissolving the material in a minimal amount of diethyl
ether, layering with hexanes, and allowing to stand at room
1
temperature for 48 h. H NMR (500 MHz, CDCl3): δ 7.97−7.91
(m, 2H), 7.69−7.62 (m, 1H), 7.56 (dd, J = 8.5, 7.1 Hz, 2H), 5.90
(ddt, J = 16.4, 10.4, 5.9 Hz, 1H), 5.42−5.26 (m, 2H), 4.67 (qdt, J =
12.9, 5.9, 1.4 Hz, 2H), 4.45 (dd, J = 6.3, 4.1 Hz, 1H), 3.51 (dd, J =
14.1, 4.1 Hz, 1H), 3.34 (dd, J = 14.0, 6.3 Hz, 1H), 2.77 (s, 1H).
13C{1H} NMR (125 MHz, CDCl3): δ 171.8, 144.6, 134.1, 131.1,
129.5, 127.2, 119.9, 69.3, 67.1, 39.8. HRMS (ESI-QTOF) m/z: [M +
Na]+ calcd for C12H14O5S2Na, 325.0175; found, 325.0177. IR 3482,
3067, 2948, 1736, 1648, 1582, 1447, 1415, 1322, 1243, 1203, 1139,
1095, 1075, 997, 937, 755, 715, 684 cm−1. Specific rotation [α]2D3
+6.3 (c 0.54, CHCl3). Melting point range 39−42 °C.
=
Preparation of Methyl (R)-2-Chloro-3-((phenylsulfonyl)-
thio)propanoate (13). Amino acid 6 (261 mg, 1.0 mmol) was
dissolved in 4 mL of 4 M HCl (aq) in a 25 mL round-bottom flask
equipped with a magnetic stirrer. The reaction was run open to
ambient atmosphere. The mixture was cooled in an ice−water bath,
and then 4 mL of acetone was added. Solid sodium nitrite (276 mg,
4.0 mmol) was added in portions with stirring. The solution was
gradually warmed to rt over 2 h. The reaction mixture was transferred
to a separatory funnel and diluted with 8 mL of saturated sodium
sulfate (aq). The aqueous mixture was extracted with ethyl acetate (4
× 5 mL). The combined organic layers were dried (MgSO4), then
filtered into a flame-dried 100 mL round-bottom flask, and
concentrated under reduced pressure. The resulting yellow oil
containing 12 was suspended in 1:1 anhydrous methanol/toluene
(14 mL) and cooled in an ice−water bath with stirring. The mixture
was capped with a rubber septum and vented with a needle. A
solution of TMSCH2N2 (2.0 M in diethyl ether) was added dropwise
through the septum until gas evolution ceased and yellow color
persisted (approximately 2.5 mL, 5 mmol). The mixture was then
stirred for 5 min at rt, and the reaction was quenched with 10 mL of
10% aqueous acetic acid (continue adding acetic acid until nitrogen
evolution ceases). The biphasic mixture was carefully transferred to a
separatory funnel, and 1 mL of 4 M HCl was added. The aqueous
phase was extracted with EtOAc (4 × 20 mL). The combined organic
fractions were dried (MgSO4) and concentrated under reduced
pressure at 40 °C and then diluted with toluene and concentrated
twice more. The resulting oil was purified by flash column
chromatography over silica gel (4−40% EA/hexanes, Rf = 0.4 in
50:50 EtOAc/hexanes) to yield the title compound as a yellow oil
(219 mg, 0.74 mmol, 74%, 99:1 er). 1H NMR (400 MHz, CDCl3): δ
127.1, 69.2, 53.2, 39.7. HRMS (ESI-QTOF) m/z: [M + Na]+ calcd
for C10H12O5S2Na, 299.0018; found, 299.0023. IR 3487, 3065, 2955,
1736, 1447, 1404, 1322, 1218, 1179, 1134, 1096, 1076, 1013, 969,
847, 755, 716, 685 cm−1. Specific rotation [α]2D3 = +7.8 (c 0.57,
CHCl3). Enantiomeric ratio 97:3. HPLC chromatograms and method
information for assessment of enantiomeric ratio are included in the
Preparation of Allyl (R)-2-Hydroxy-3-((methylsulfonyl)thio)-
propanoate (10). Hydroxy acid 7 (2.12 g, 10.6 mmol) was
suspended in dry toluene (10 mL) in a flame-dried 50 mL round-
bottom flask. Allyl alcohol (2.9 mL, 42 mmol) was added with
stirring. Sulfuric acid (4 drops) was added, and the reaction was
E
J. Org. Chem. XXXX, XXX, XXX−XXX