730
Chem. Pharm. Bull.
Vol. 64, No. 7 (2016)
(m, 1H), 2.05–1.95 (m, 1H); 13C-NMR (CDCl3, 125MHz) δ: thoxypyridin-3-yl)-3-(2-((4-methoxybenzyl)oxy)ethyl)pyr-
176.0, 175.1, 171.6, 171.5, 165.4, 161.4, 155.1, 154.3, 144.1, rolidine-1,2-dicarboxylate (29b) To a stirred solution of 28
136.6, 135.9, 128.5, 128.4, 128.2, 128.0, 127.7, 125.1, 125.0, (7.77g, 13.2mmol) in MeOH (65mL) was added Raney nickel
118.8, 118.6, 67.7, 67.6, 63.5, 63.0, 53.9, 52.6, 51.8, 49.0, 48.9, (23g, purchased from Aldrich, washed with water and MeOH)
42.8, 41.6, 39.2, 38.4, 33.1; HR-MS (ESI-TOF): Calcd for at room temperature. The resulting mixture was stirred under
C24H25N2O9 [(M−H)–] 485.1555. Found 485.1554.
hydrogen pressure (700 psi) at room temperature for 1.5h. The
Acromelic Acid A (1) To a stirred solution of 27 (271mg, mixture was filtered through a pad of Celite and concentrated
557 µmol) in H2O (1.5mL) was added 5M HBr in AcOH under reduced pressure. The crude materials including pyr-
(6.0mL) at room temperature. The resulting mixture was rolidines 39a and b were applied to the following reaction
stirred at 100°C for 12h. Then the reaction mixture was without further purification.
concentrated under reduced pressure. Purification of 1 was
To a solution of the crude materials including 39a and b in
carried out according to the reported procedure.4) The residue CH2Cl2 (70mL) were added Et3N (3.66mL, 26.4mmol) and
was charged onto a column containing Dowex-50 WX8 hy- CbzCl (2.81mL, 19.8mmol) at 0°C. The resulting mixture
drogen form (200–400 mesh). After elution with H2O (25mL) was stirred at the same temperature for 30min. Then the reac-
and 3% aqueous NH3 (25mL), the collected fractions were tion mixture was quenched with saturated aqueous NaHCO3
concentrated under reduced pressure. The resulting ammoni- and extracted with CH2Cl2. The organic layer was dried over
um was charged onto a column containing Amberlite IRC-50 anhydrous MgSO4, filtered and concentrated under reduced
hydrogen form. After elution with H2O, the collected fractions pressure. The residue was purified by column chromatogra-
were concentrated under reduced pressure to give free amino phy (SiO2, n-hexane–EtOAc=3:1) to afford 29a (2.30g, 26%
acid 1 (172mg, quant) as a colorless solid.
2steps) as a colorless oil and 29b (4.19g, 47% 2 steps) as a
1: mp >310°C (decomp.); [α]D25 +30.0 (c=1.11, H2O) [lit. colorless oil. These compounds exist as a mixture of rotamers
[α]D +27.8 (c=0.35, H2O)]4); IR (film, cm−1): 3422, 1618, 1381, in CDCl3 at 25°C.
1
787; H-NMR (D2O, 500MHz) δ: 7.52 (d, J=7.37Hz, 1H),
29a: [α]D20 −17.2 (c=1.03, CHCl3); IR (film, cm−1): 2978,
6.94 (d, J=7.37Hz, 1H), 4.12 (d, J=7.37Hz, 1H), 3.84–3.68 2938, 2870, 1736, 1709, 1599, 1512, 1481, 1414, 1368, 1356,
(m, 3H), 3.20–3.12 (m, 1H), 2.61 (dd, J=16.7, 5.10Hz, 1H), 1331, 1281, 1248, 1157, 1032, 824, 698; 1H-NMR (CDCl3,
2.15 (dd, J=16.7, 10.2Hz, 1H); 13C-NMR (D2O, 125MHz) δ: 500MHz) δ: 7.44–7.28 (m, 6H), 7.21–7.13 (m, 2H), 6.86–6.70
176.7, 173.6, 166.3, 163.1, 142.7, 139.5, 129.8, 108.9, 65.8, 47.5, (m, 3H), 5.22–5.07 (m, 2H), 4.36–4.33 (m, 2H), 4.26–4.21 (m,
42.5, 42.4, 35.7; HR-MS (ESI-TOF): Calcd for C13H13N2O7 1H), 4.11–4.04 (m, 1H), 3.96–3.85 (m, 4H), 3.80–3.62 (m, 4H),
[(M−H)−] 309.0717. Found 309.0715.
tert-Butyl
3.48–3.19 (m, 2H), 2.80–2.70 (m, 1H), 1.70–1.33 (m, 20H);
3-((2S,3S)-5-(tert-Butoxy)-3-(2-((4-methoxy- 13C-NMR (CDCl3, 125MHz) δ: 171.2, 165.9, 162.0, 159.1,
benzyl)oxy)ethyl)-1-nitro-4,5-dioxopentan-2-yl)-6-me- 154.8, 154.5, 148.2, 148.1, 138.5, 136.6, 136.4, 130.3, 129.2,
thoxypicolinate (28) To a stirred solution of 16 (400mg, 129.1, 128.5, 128.4, 128.0, 127.9, 127.8, 127.7, 124.9, 113.7,
1.43mmol) in IPA (0.4mL) were added Ni–diamine com- 112.4, 82.5, 82.4, 81.7, 81.6, 72.7, 68.3, 68.0, 67.1, 64.8, 64.4,
plex 20 (36.2mg, 71.4µmol), α-ketoester 7a40,43) (880mg, 55.2, 53.5, 50.0, 45.0, 43.6, 40.4, 39.5, 29.1, 29.0, 28.1, 28.0,
2.85mmol) in IPA (1.1mL) and Et3N (49mL, 357mmol) at 27.8; HR-MS (ESI-TOF) Calcd for C38H48N2O9Na [(M+Na)+]
−10°C. The resulting mixture was stirred at the same temper- 699.3252. Found 699.3263.
ature for 14h. Then the solvent was removed under reduced
29b: [α]D20 −31.0 (c=1.18, CHCl3); IR (film, cm−1): 3002,
pressure. The residue was purified by column chromatography 2977, 2941, 2904, 1740, 1721, 1709, 1698, 1601, 1513, 1480,
(SiO2, n-hexane–EtOAc=7:3) to afford 28 (887mg, quant.) as 1412, 1368, 1329, 1281, 1248, 1169, 1144, 1032, 847, 824,
1
a colorless oil. The ee value was determined by chiral HPLC 755, 698; H-NMR (CDCl3, 500MHz) δ: 7.89 (t, J=8.50Hz,
analysis.
1H), 7.40–7.27 (m, 5H), 7.21–7.08 (m, 2H), 6.85–6.72 (m,
28: HPLC (DAICEL CHIRALPAK AD-H, n-hexane– 3H), 5.22–5.08 (m, 2H), 4.49 (d, J=9.1Hz, 0.45H), 4.44 (d,
IPA=19:1, 1.0mL/min, 254nm, τminor 14.1min, tmajor 15.8 min); J=9.1Hz, 0.55H), 4.36–4.20 (m, 2H), 4.14–3.89 (m, 2H),
[α]D25 −33.0 (c=1.01, CHCl3, 91% ee); IR (film, cm−1): 2980, 3.93 (s, 3H), 3.83–3.70 (m, 1H), 3.78 (s, 3H), 3.40–3.00 (m,
2938, 2868, 1719, 1601, 1555, 1512, 1481, 1370, 1329, 1283, 3H), 1.66–1.54 (m, 11H), 1.44 (s, 4H), 1.29 (s, 5H); 13C-NMR
1250, 1171, 1148, 1098, 1030, 847, 826; 1H-NMR (CDCl3, (CDCl3, 125MHz) δ: 170.5, 170.4, 166.2, 162.0, 159.1, 154.8,
500MHz) δ: 7.57 (d, J=8.50Hz, 1H), 7.17 (d, J=8.50Hz, 2H), 154.4, 148.1, 147.9, 140.2, 140.1, 137.9, 136.5, 136.3, 130.5,
6.85 (d, J=8.50Hz, 2H), 6.74 (d, J=8.50Hz, 1H), 4.87 (dd, 129.2, 128.9, 128.5, 128.4, 128.0, 127.9, 126.4, 126.1, 113.7,
J=13.0, 5.10Hz, 1H), 4.81 (dd, J=13.0, 6.80Hz, 1H), 4.47–4.38 113.6, 112.6, 112.5, 82.6, 82.5, 82.2, 82.1, 72.5, 72.4, 68.3, 68.2,
(m, 1H), 4.30 (d, J=11.9Hz, 1H), 4.26 (d, J=11.9Hz, 1H), 4.09 67.2, 67.1, 63.4, 62.9, 55.2, 53.5, 52.4, 51.8, 41.9, 40.9, 40.8,
(dt, J=9.6, 4.0Hz, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 3.49–3.41 (m, 39.9, 28.2, 28.0, 27.8, 27.7, 27.6; HR-MS (ESI-TOF): Calcd for
2H), 2.18–2.00 (m, 2H), 1.64 (s, 9H), 1.36 (s, 9H); 13C-NMR C38H48N2O9Na [(M+Na)+] 699.3252. Found 699.3246.
(CDCl3, 125MHz) δ: 195.0, 165.3, 162.4, 159.8, 159.2, 147.3,
Epimerization of 29b to a To a stirred solution of 29b
139.2, 129.7, 129.3, 125.3, 113.7, 113.0, 83.7, 82.7, 77.6, 72.3, (60mg, 0.884µmol) in the 9:1 mixture of t-BuOH and ben-
67.3, 55.3, 53.5, 46.0, 39.9, 31.1, 28.1, 27.6; HR-MS (ESI- zene (total 2.0mL) was added t-BuOK (14.9mg, 0.133µmol)
TOF): Calcd for C30H40N2O10Na [(M+Na)+] 611.2575. Found at 0°C. The resulting mixture was stirred at room tempera-
611.2570.
ture for 6h. Then the reaction mixture was quenched with
1-Benzyl 2-(tert-Butyl) (2S,3S,4S)-4-(2-(tert-Butoxycar- saturated aqueous NH4Cl and extracted with EtOAc. The
bonyl)-6-methoxypyridin-3-yl)-3-(2-((4-methoxybenzyl)- organic layer was dried over anhydrous Na2SO4, filtered and
oxy)ethyl)pyrrolidine-1,2-dicarboxylate (29a) and 1-Ben- concentrated under reduced pressure. The residue was purified
zyl 2-(tert-Butyl) (3S,4S)-4-(2-(tert-Butoxycarbonyl)-6-me- by column chromatography (SiO2, n-hexane–EtOAc=3:1) to