The Journal of Organic Chemistry
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67.3, 63.5, 63.5, 37.1, 36.9, 14.0 ppm. IR (neat): νmax 3392, 2918, 1729,
1524, 1443, 1278, 1168, 1002, 753, 701 cm−1. HRMS (ESI): m/z [M +
K]+ calcd for C29H26F3NO5S2K, 628.0842; found, 628.0844.
3273, 1737, 1699, 1655, 1450, 891 cm−1. HRMS (ESI): m/z [M + H]+
calcd for C37H30NO4S2, 616.1611; found, 616.1612.
2-(((9H-Fluoren-9-yl)methoxy)carbonylamino)-3-(2,2-diphenyl-
benzo-[d][1,3]dithiol-4-yl)propanoic Acid (19b). Starting from 6b,
19b was synthesized following the procedure of 19a. Compound 19b
was obtained as a white foamy solid product. Yield: 72% (Rf = 0.5,
DCM/MeOH, 92:8). 1H NMR (300 MHz, CDCl3): δ 7.71 (d, J = 7.5
Hz, 2H), 7.60 (t, J = 8.8 Hz, 4H), 7.48 (d, J = 7.2 Hz, 2H), 7.34 (t, J =
7.3 Hz, 2H), 7.23−7.13 (m, 8H), 7.07 (d, J = 7.5 Hz, 1H), 6.91 (t, J =
7.5 Hz, 1H), 6.84(m, 1H), 5.34 (d, J = 7.5 Hz, 1H), 4.68 (d, J = 5.4 Hz,
1H), 4.36−4.23 (m, 2H), 4.11 (m, 1H), 3.26−3.01 (m, 2H) ppm.
13C{1H} NMR (75 MHz, CDCl3): δ 175.8, 156.0, 143.9, 143.7, 143.2,
Diethyl 2-((2,2-Diphenylbenzo[d][1,3]dithiol-4-yl)methyl)-2-
(2,2,2-trifluoroacetamido)malonate (6b). Compound 6b was synthe-
sized from compound 7b (189 mg, 0.473 mmol), following the same
procedure of 6a. Compound 6b was obtained as a light yellowish
gummy product. Yield: 75% (209 mg) (Rf = 0.5, Pet-ether/EtOAc,
80:20). 1H NMR (400 MHz, CDCl3): δ 7.55−7.53 (m, 5H), 7.37−7.27
(m, 6H), 7.15 (d, J = 8 Hz, 1H), 7.0−6.9 (m, 1H), 6.7 (d, J = 7.6 Hz,
1H), 4.37−4.29 (m, 2H), 4.25−4.16 (m, 2H), 3.73 (s, 2H), 1.28 (t, J =
7.2 Hz, 6H) ppm. 13C{1H} NMR (100 MHz, CDCl3): δ 166.14,
166.11, 156.4 (q, 1C, J = 38 Hz), 155.1, 143.0, 142.9, 139.6, 138.9,
128.7, 128.6, 128.2, 128.16, 128.03, 127.97, 126.9, 126.3, 126.0, 124.3,
121.6, 116.8, 114.0, 110.2, 103.5, 66.9, 63.59, 63.55, 38.4, 37.5, 13.9
ppm. IR (neat): νmax = 3386, 3055, 2984, 1729, 1519, 1444, 1216, 1167,
696 cm−1. HRMS (ESI): m/z [M + H]+ calcd for C29H27F3NO5S2,
590.1277; found, 590.1276.
142.6, 141.3, 138.6, 130.8, 128.1, 127.9, 127.9, 127.8, 127.4, 127.2,
126.4, 125.3, 125.2, 121.2, 120.0, 77.3, 67.4, 54.0, 47.1, 38.1 ppm. IR
(neat): νmax 3068, 2928, 1714, 1508, 1447, 740 cm−1. HRMS (ESI): m/
z [M + Na]+ calcd for C37H29NO4S2Na, 638.1436; found, 638.1438.
Methyl-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,2-
diphenylbenzo[d][1,3]dithiol-5-yl)propanoate (1a). To a suspended
solution of compound 19a (212 mg, 0.34 mmol) in anhydrous DMF (3
mL) was added K2CO3 (94 mg, 0.68 mmol) portion wise at 0 °C. The
mixture was stirred at RT for 10 min and again cooled to 0 °C, treated
with CH3I (0.084 mL, 1.36 mmol), and allowed to stir at RT for 12 h.
After completion of reaction, the reaction mixture was quenched with
NH4Cl (5 mL) and extracted with EtOAc (3 × 5 mL). The organic
layers were combined, washed with brine, dried over Na2SO4, and
concentrated in vacuo. The crude product was purified by column
chromatography using ethyl acetate−petroleum ether (1:6) on silica gel
to afford 1a as a white solid (167 mg, 78% yield) (Rf = 0.5, Pet-ether/
Diethyl 2-Acetamido-2-((2-phenylbenzo[d][1,3]dithiol-5-yl)-
methyl)malonate (17a). Compound 17a was synthesized from 7a
(170 mg, 0.425 mmol) and malonate derivative 14, following the same
procedure of 6a, and was obtained as a white solid product. Yield: 65%
1
(148 mg) (Rf = 0.5, Pet-ether/EtOAc, 80:20). H NMR (300 MHz,
CDCl3): δ 7.53 (dd, J = 8.4, 1.8 Hz, 4H), 7.24−7.14(m, 6H), 7.0 (d, J =
5.4 Hz, 1H), 6,78 (s, 1H), 6.58 (dd, J = 7.8, 1.2 Hz, 1H), 6.47 (s, 1H),
4.23−4.10 (m, 4H), 3.47 (s, 2H), 1.91(s, 3H), 1.17 (t, J = 7.2 Hz, 6H)
ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 169.2, 167.4, 143.1, 138.2,
136.9, 133.5, 128.2, 128.0, 127.6, 123.6, 122.1, 78.3, 67.2, 62.8, 37.5,
23.1, 14.1 ppm. IR (neat): νmax 3405, 3064, 2983, 1740, 1680, 1493,
1443, 1276, 1198, 696 cm−1. HRMS (ESI): m/z [M + Na]+ calcd for
C29H29NO5S2Na, 558.1385; found, 558.1387.
Diethyl 2-(tert-Butoxycarbonylamino)-2-((2,2-diphenylbenzo[d]-
[1,3]dithiol-5-yl)methyl)malonate (18a). Compound 18a was synthe-
sized from 7a (165 mg, 0.413 mmol) and malonate derivative 15,
following the same procedure of 6a. A colorless oily product was
obtained. Yield: 32% (82 mg) (Rf = 0.5, Pet-ether/EtOAc, 80:20). 1H
NMR (300 MHz, CDCl3): δ 7.62 (dd, J = 7.8, 1.5 Hz, 4H), 7.32−7.24
(m, 6H), 7.07 (d, J = 8.1 Hz, 1H), 6.90 (s, 1H), 6.70 (d, J = 7.8 Hz, 1H),
5.74 (s, 1H), 4.29−4.12 (m, 4H), 3.52 (s, 2H), 1.46 (s, 9H), 1.24 (t, J =
7.2 Hz, 6H) ppm. 13C{1H} NMR (75 MHz, CDCl3): δ 167.6, 154.0,
143.2, 138.1, 136.7, 133.6, 128.20, 128.18, 128.1, 127.9, 127.6, 123.9,
122.0, 80.4, 78.2, 67.2, 62.7, 38.0, 28.4, 14.1 ppm. IR (neat): νmax 3431,
2979, 1740, 1715, 1489 cm−1. HRMS (ESI): m/z [M + Na]+ calcd for
C32H35NO6S2Na, 616.1804; found, 616.1805.
1
EtOAc, 75:25). H NMR (300 MHz, CDCl3): δ 7.77 (d, J = 7.5 Hz,
2H), 7.62 (d, J = 10.8 Hz, 4H), 7.57 (m, 2H), 7.40 (t, J = 7.5 Hz, 2H),
7.35−7.09 (m, 8H), 7.11 (d, J = 7.8 Hz, 1H), 6.96 (s, 1H), 6.75 (d, J =
7.8 Hz, 1H), 5.24 (d, J = 8.1 Hz, 1H), 4.61 (m, 1H), 4.47−4.32 (m,
2H), 4.21 (m, 1H), 3.65 (s, 3H), 2.99 (d, J = 5.7 Hz, 2H) ppm. 13C{1H}
NMR (75 MHz, CDCl3):δ = 171.8, 155.6, 143.9, 143.8, 143.1, 141.4,
138.5, 136.8, 134.0, 128.5, 128.2, 128.2, 127.9, 127.8, 127.2, 127.1,
127.0, 126.9, 125.2, 125.1, 123.7, 123.0, 120.1, 67.1, 54.8, 52.4, 47.3,
38.0 ppm. IR (neat): νmax 3333, 3064, 2951, 1723, 1521, 1445, 1213,
740 cm−1. HRMS (ESI): m/z [M + Na]+ calcd for C38H31NO4S2Na,
652.1592; found, 652.1593.
Methyl 2-(((9H-Fluoren-9-yl) methoxy) carbonylamino)-3-(2,2-
diphenylbenzo[d][1,3]dithiol-4-yl)propanoate (1b). Starting from
compound 19b (100 mg, 0.162 mmol), 1b was synthesized following
the procedure of 1a. Compound 1b was obtained as a white solid
1
product: yield 77% (78 mg) (Rf = 0.5, Pet-ether/EtOAc, 75:25). H
NMR (300 MHz, CDCl3): δ 7.76 (d, J = 7.5 Hz, 2H), 7.66−7.60 (m,
4H), 7.54 (d, J = 7.2 Hz, 2H), 7.39 (m, 2H), 7.30−7.18 (m, 8H), 7.12
(d, J = 7.5 Hz, 1H), 6.97 (m, 1H), 6.82 (d, J = 7.5 Hz, 1H), 5.34 (d, J =
7.2 Hz, 1H), 4.72 (q, J = 7.0 Hz, 1H), 4.41−4.15 (m, 2H), 4.17 (m,
1H), 3.69 (s, 3H), 3.22−3.04 (m, 2H) ppm. 13C{1H} NMR (75 MHz,
CDCl3): δ 172.0, 155.7, 144.0, 143.8, 143.3, 142.7, 141.3, 138.7, 138.6,
130.7, 128.5, 128.2, 128.2, 127.9, 127.8, 127.3, 127.2, 126.9, 126.3,
125.3, 125.2, 121.2, 120.0, 67.2, 54.0, 52.6, 47.2, 38.7 ppm. IR (neat):
νmax 3418, 3068, 2925, 1723, 1521, 1447, 740 cm−1. HRMS (ESI): m/z
[M + Na]+ calcd for C38H31NO4S2Na, 652.1592; found, 652.1593.
Optical Resolution by Preparative Chiral HPLC. Chiral amino acids
1a and 1b were analyzed and purified on Chiralpak IF and Chiralpak ID
columns. The two fractions collected were analyzed by analytical chiral
HPLC, a polarimeter, and ECD and VCD.
Chromatographic Conditions for 1a. Compound 1a was
prepurified on a preparative Chiralpak ID to remove ∼10% of
unidentified impurities. Then 380 mg of the purified racemic
compound was dissolved in 8 mL of a mixture of CH2Cl2/ethanol
(1:1). It was injected on a Chiralpak IF column (250 mm × 10 mm) in
160 × 50 μL stacked injections (every 4.2 min), using hexane/iPrOH/
DCM (80:10:10) as a mobile phase with a flow rate of 5 mL/min, and
detected with an UV detector at 280 nm. Two fractions were collected
and analyzed on an analytical Chiralpak IF column using heptane/
iPrOH/DCM (80:10:10) as an isocratic eluant. Compound 1a-R: 147
mg, tR = 9.8 (ee > 99.5%), [α]2D5 (CHCl3, c = 0.89) = −29. Crystals
could be grown by slow evaporation at 4 °C of a solution containing 110
2-(((9H-Fluoren-9-yl)methoxy)carbonylamino)-3-(2,2-
diphenylbenzo[d][1,3]dithiol-5-yl)propanoic Acid (19a). To an ice-
cold solution of malonate derivative 6a (247 mg, 0.42 mmol) in THF/
H2O (1:1) (10 mL) was added LiOH·H2O (120.38 mg, 5.016 mmol),
and the mixture was allowed to reflux for 12 h in a silicone oil bath. After
completion of reaction (TLC monitoring), THF was removed, the
remaining aqueous phase was first cooled to 0 °C, acidified to pH 2 with
0.1 N HCl, and then neutralized by adding solid NaHCO3 and diluted
with 5 mL of dioxane. A solution of Fmoc-OSu (282 mg, 0.84 mmol) in
7 mL of dioxane was then added dropwise to the suspension at the same
temperature, and the resulting mixture was allowed to stir at RT for 12
h. When the reaction was completed, the solvent was evaporated, and
the remaining aqueous phase was further acidified with 0.1 N HCl and
extracted with EtOAc (3 × 5 mL). The combined organic layers were
washed with water, followed by brine, dried over Na2SO4, and
concentrated to afford the product 19a as a white foamy solid (194 mg,
75% yield) (Rf = 0.5, DCM/MeOH, 92:8), which was used for the
esterification reaction without further purification. 1H NMR (300
MHz, CDCl3): δ 7.74 (d, J = 7.5 Hz, 2H), 7.608−7.577 (m, 4H), 7.52
(d, J = 6.6 Hz, 2H), 7.37 (t, J = 7.2 Hz, 2H), 7.30−7.19 (m, 8H), 7.06
(d, J = 7.8 Hz, 2H), 6.98 (s, 1H), 5.29 (d, J = 8.1 Hz, 1H), 4.61 (d, J =
6.3 Hz, 1H), 4.43−4.29 (m, 2H), 4.19−4.15 (m, 1H), 3.09−2.93 (m,
2H) ppm. 13C{1H} NMR (75 MHz, CDCl3):δ = 175.6, 155.9, 143.8,
143.7, 143.1, 141.4, 138.5, 136.8, 133.9, 127.8, 127.2, 125.2, 125.1,
123.0, 122.3, 120.1, 78.2, 67.2, 54.6, 47.2, 37.4 ppm. IR (neat): νmax
2219
J. Org. Chem. 2021, 86, 2210−2223