Molecules 2018, 23, 1440
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3.4. Synthesis of Di-tert-butyl 3,8-Dibenzyl-5,10-dihydroxy-1,6,2,7-dioxadiazecane-2,7-dicarboxylate (3)
(E)-4-phenylbut-2-enal 1a (146 mg, 1 mmol) was dissolved in dichloromethane (5 mL), and then
N-Boc-hydroxylamine 2 (199 mg, 1.5 mmol), piperidine (17 mg, 0.2 mmol), and benzoic acid (24 mg,
0.2 mmol) were added to the resulting solution at 0 ◦C. The reaction mixture was stirred for 8 h at
0 ◦C. The mixture solution was diluted with dichloromethane (20 mL) and washed with saturated
sodium bicarbonate aqueous solution (5 mL) and brine (5 mL). The resulting organic phase was dried
over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified over
silica gel column chromatography (PE/EtOAc, 10:1–4:1) to give
3 as a white solid (254 mg, 91%). mp:
123–124 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
7.32–7.22 (m, 10H), 5.73–5.69 (m, 2H), 4.66–4.59 (m, 1H),
4.31–4.24 (m, 1H), 3.43 (s, 1H), 3.21–3.17 (m, 2H), 3.11 (dd, J = 4.2 Hz, 12 Hz, 1H), 2.94 (dd, J = 4.2 Hz,
12 Hz, 1H), 2.74 (dd, J = 4.1 Hz, 12 Hz, 1H), 2.58–2.51 (m, 1H), 2.24 (dd, J = 4.1 Hz, 12 Hz, 1H), 2.16–2.09
(m, 1H), 2.06–1.99 (m, 1H), 1.53 (s, 9H), 1.51 (s, 9H) (Supplementary Material Figure S3); 13C-NMR
(100 MHz, CDCl3)
81.5, 79.8, 41.8, 41.0, 39.2, 38.8, 28.3, 28.2 (Supplementary Material Figure S4); HR-MS (C30H42N2O8Na)
calcd. 581.2833 ([M + Na]+), Found 581.2798. Compound
was further characterized by heteronuclear
δ 155.0, 154.0, 137.0, 136.8, 129.2, 129.2, 128.5, 128.5, 126.7, 126.6, 83.5, 82.5, 82.5, 81.9,
3
multiple quantum coherence (HMQC) and heteronuclear multiple bond correlation (HMBC).
3.5. Synthesis of (3R,5S)-Tert-butyl 3-benzyl-5-hydroxyisoxazolidine-2-carboxylate (4a)
(E)-4-phenylbut-2-enal 1a (146 mg, 1 mmol) was dissolved in dichloromethane (5 mL), and
then N-Boc-hydroxylamine
2 (199 mg, 1.5 mmol), (S)-diphenylprolinol-TMS II (33 mg, 0.1 mmol),
and p-nitrobenzoic acid (16 mg, 0.1 mmol, 10 mol %) were added to the resulting solution at
◦
◦
0 C. The reaction mixture was stirred for 15 h at 0 C. The mixture solution was diluted with
dichloromethane (20 mL) and washed with saturated sodium bicarbonate aqueous solution (5 mL)
and brine (5 mL). The resulting organic phase was dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified over silica gel column chromatography (PE/EtOAc,
◦
D
10:1–4:1) to give 4a as a white solid (251 mg, 90%). mp: 138–139 C; [
1H-NMR (400 MHz, CDCl3)
7.29–7.18 (m, 5H), 5.71 (d, J = 4.4 Hz, 1H), 4.49–4.42 (m, 1H), 3.00 (dd,
J = 8.3 Hz, 12 Hz, 1H), 2.70 (dd, J = 8.3 Hz, 12 Hz, 1H), 2.28 (dd, J = 8.4 Hz, 12 Hz, 1H), 2.00–1.94 (m,
1H), 1.35 (s, 9H) (Supplementary Material Figures S5 and S7); 13C-NMR (100 MHz, CDCl3)
158.8,
α
]
+16.50 (c 1.0, CHCl3);
22
δ
δ
138.2, 129.4, 128.3, 126.4, 98.7, 82.0, 59.4, 42.1, 41.3, 28.0 (Supplementary Material Figures S6 and S8);
HR-MS (C15H21NO4Na) calcd. 302.1363 ([M + Na]+), Found 302.1370; 92% ee; Chiral HPLC condition:
SHIMADZU Essentia LC-16 HPLC, Chiralcel AD-H column (250
×
4.6 mm, i.d.) with a mixture of
hexane and 2-propanol (95:5) at a flow rate of 1.0 mL/min as the mobile phase, oven temperature was
◦
28 C, 210 nm, tminor = 6.66 min, tmajor = 6.00 min. A quintuple scale of this reaction was also carried
out and a similar result was observed (88% yield, 92% ee).
3.6. Synthesis of (3R)-Tert-butyl 3-benzyl-5-(tert-butoxycarbonyloxy)isoxazolidine-2-carboxylate (5)
(E)-4-phenylbut-2-enal 1a (146 mg, 1 mmol) was dissolved in dichloromethane (5 mL), and then
N-Boc-hydroxylamine
2 (199 mg, 1.5 mmol), (S)-diphenylprolinol-TMS II (33 mg, 0.1 mmol),
and p-Toluenesulfonic acid (34 mg, 0.2 mmol, 10 mol %) were added to the resulting solution at 0 ◦C.
◦
The reaction mixture was stirred for 8 h at 0 C. The mixture solution was diluted with dichloromethane
(20 mL) and washed with saturated sodium bicarbonate aqueous solution (5 mL) and brine (5 mL).
The resulting organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified over silica gel column chromatography (PE/EtOAc, 10:1–4:1) to give
D
5
as a wax solid (246 mg, 65%); [
α
]
22 +13.80 (c 1.0, CHCl3); 1H-NMR (400 MHz, CDCl3)
δ
7.30–7.20
(m, 5H), 6.11–6.08 (m, 1H), 4.62–4.55 (m, 1H), 2.99 (dd, J = 8.6 Hz, 12 Hz, 1H), 2.71 (dd, J = 8.5 Hz,
12 Hz, 1H), 2.63–2.57 (m, 1H), 2.25–2.19 (m, 1H), 1.50 (s, 9H), 1.39 (s, 9H) (Supplementary Material
Figure S11); 13C-NMR (100 MHz, CDCl3)
δ
158.3, 155.6, 137.7, 129.3, 128.3, 126.4, 88.5, 82.8, 82.2, 61.2,
41.3, 35.2, 28.1, 27.9; HR-MS (C20H29NO6Na) calcd. 402.1893 ([M + Na]+), Found 402.1891. 43% ee;