4
YAN ET AL.
2.2 | Preparation of
1-hydroxybenzotriazole (HOBT) (14.66 g, 108.5 mmol), and
triethylamine (24.95 g, 246.5 mmol) were added in
succession to the solution described above at
0ꢀC. 2-(Methylamino)-1-phenyl-1-ethanone hydrochloride
(18.25 g, 98.6 mmol) was added to the reaction solution in
small quantities. The reaction mixture was stirred at
0–10ꢀC and monitored by thin-layer chromatography.
Upon completion of the reaction, water was added to the
reaction mixture, and the mixture was stirred for 30 min.
The organic phase was subjected to successive washes with
saturated aqueous NaHCO3 and brine. The organic phase
was collected, dried over anhydrous Na2SO4, and concen-
trated by evaporation under reduced pressure. This was
used in the next reaction. The concentrate was purified by
column chromatography on silica gel using n-hexane/ethyl
acetate (1:1, v/v) as an eluent to produce the desired amide
compound (+)14 or (À)-14.
(À)-epineoclausenamide and
(+)-epineoclausenamide
2.2.1 | General procedure for the synthesis
of (2S,3R)-epoxycinnamate-(R)-
α-methylbenzylamine salt and (2R,3S)-
epoxycinnamate-(S)-α-methylbenzylamine salt
((+)-13 and (À)-13)
Compounds (+)-13 and (À)-13 were synthesized
according to the method used in literature.9 Figure 2
illustrates the reaction conditions and the reagents
employed.
(+)-13: white solid (39.4% yield), m.p. 164–166ꢀC. [α]
20 D = +125.8 (c = 1 in EtOH). 1H NMR (600 MHz,
DMSO-d6), δ: 7.49–7.48 (m, 2H), 7.39 (t, J = 6.69 Hz,
2H), 7.35–7.26 (m, 6H), 4.31 (q, J = 6.69 Hz, 1H), 3.75 (d,
J = 2.06 Hz, 1H), 3.16 (d, J = 2 Hz, 1H), 1.47
(d, J = 6.74 Hz, 3H). Enantiomeric ratio ((2S,3R)-
3-phenyloxirane-2-carboxylic acid (+)-12): 96.5(+):3.5
(À), determined by HPLC (Daicel Chiralpak AD-H, n-
hexane/IPA, 80:20 [v/v], flow rate 1.0 mL/min,
λ = 254 nm): retention time: 4.990 min.
(+)-14: yellow oil (79.6% yield), [α]D 20 = +161.2
1
(c = 1 in EtOH). H NMR (600 MHz, CDCl3) δ: 7.97 (d,
2H), 7.63–7.60 (m, 1H), 7.50 (t, 2H), 7.41–7.36 (m, 2H),
5.04–4.78 (dd, J = 17.74, 2H), 4.13 (d, J = 2.07 Hz, 1H),
3.80 (d, J = 1.65 Hz, 1H), 3.21 (s, 3H). 13C NMR
(151 MHz, CDCl3) δ: 193.55, 167.35, 135.58, 133.86,
128.98, 128.86, 128.72, 128.51, 128.00, 127.88, 125.81,
125.67, 57.84, 57.21, 54.40, 35.90. HRMS (ESI): m/z
[M + H]+, calculated: 296.1281, found: 296.1284. Enan-
tiomeric ratio: 100.0(+):0(À), determined by HPLC
(Daicel Chiralpak AD-H, n-hexane/isobutanol, 75:25
[v/v], flow rate 1.0 mL/min, λ = 254 nm): retention time:
16.658 min.
(À)-14: yellow oil (82.0% yield), [α]D 20 = À135.4
(c = 1 in EtOH). 1H NMR (600 MHz, CDCl3), δ: 7.95
(d, 2H), 7.60 (t, 3H), 7.48 (t, 3H), 7.37 (m, 5H), 4.89–4.77
(dd, J = 17.43 Hz, 2H), 4.12 (d, J = 2.06 Hz, 1H), 3.79
(d, J = 2.03 Hz, 1H), 3.21 (s, 3H); 13C NMR (151 MHz,
CDCl3) δ: 193.54, 167.35, 134.96, 133.86, 128.99, 128.86,
128.71, 128.51, 128.00, 127.88, 125.81, 125.68, 57.85,
57.21, 54.38, 35.90. HRMS (ESI): m/z [M + H]+, calcu-
lated: 296.1281, found: 296.1275. Enantiomeric ratio: 3.3
(+):96.7(À), determined by HPLC (Daicel Chiralpak
AD-H, n-hexane/isobutanol, 75:25 [v/v], flow rate
1.0 mL/min, λ = 254 nm): retention time: 13.387 min.
(À)-13: white solid (37.8% yield), m.p. 163–165ꢀC. [α]
D 20 = À124.7 (c = 1 in EtOH). 1H NMR (600 MHz,
DMSO-d6), δ: 7.49–7.47 (m, 2H), 7.40–7.39 (t,
J = 6.69 Hz, 2H), 7.35–7.26 (m, 6H), 4.30 (q, J = 6.69 Hz,
1H), 3.75 (d, J = 2.06 Hz, 1H), 3.15 (d, J = 2 Hz, 1H),
1.46 (d, J = 6.74, 3H). Enantiomeric ratio (((2R,3S)-
3-phenyloxirane-2-carboxylic acid (À)-12): 0.1(+):99.9
(À), determined by HPLC (Daicel Chiralpak AD-H, n-
hexane/IPA, 80:20 [v/v], flow rate 1.0 mL/min,
λ = 254 nm): retention time: 8.141 min
2.2.2 | General procedure for the synthesis
of (+)-N-methyl-N-benzoylmethyl-α,β-epoxy-
β-phenylpropionamide and (À)-N-methyl-N-
benzoylmethyl-α,β-epoxy-
β-phenylpropionamide ((+)14 and (À)-14)
CH2Cl2 (250 mL) was added to a solution of (2S,3R)-
epoxycinnamate-(R)-α-methylbenzylamine salt (+)-13
(28.12 g, 98.6 mmol) or (2R,3S)-epoxycinnamate-(S)-
α-methylbenzylamine salt (À)-13 (27.4 g, 96.0 mmol) in
deionized water (300 mL). The solution pH was adjusted
to 3–4 using 1-M HCl at 0ꢀC. The organic phase was iso-
lated. The aqueous layer was then extracted with CH2Cl2
(3 Â 150 mL). The combined organic phases were
washed with saturated brine, dried over Na2SO4, and
filtered. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
2.2.3 | General procedure for the synthesis
of (+)-neoclausenamidone and
(À)-neoclausenamidone ((+)-3 and (À)-3)
A solution of the concentrate obtained above was pre-
pared in CH2Cl2 (200 mL). To this solution, 3% aqueous
(CH3)4N+OHÀ (78 mmol, 100 mL) was added. The
resulting solution was stirred at room temperature for
25 h. The organic phase was separated. The aqueous
hydrochloride
(EDCI)
(20.79 g,
108.5
mmol),