(6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate → HCID 56601587, compound

HRID 406168Notes

Reaction equation

HRID 406168 reaction equation
[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[CH2:51]([Mg]Br)[CH3:52]>C1COCC1>[CH2:51]([C:13]1([OH:43])[C:12]2[CH:11]=[C:10]3[C:19]([C:20](=[O:27])[C@@:21]4([O:25][CH3:26])[C@@:8]([OH:45])([C:9]3=[O:44])[C:7]3[C:2]([OH:1])=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]([CH3:46])=[CH:5][C:6]=3[CH2:23][C@H:22]4[OH:24])=[C:18]([OH:28])[C:17]=2[C:16](=[O:29])[CH:15]=[C:14]1[NH:30][C@@H:31]1[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]1)[CH3:52]

Participants

4

Reactant 2

HCID 67121454(6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylateHCID 178418443HCID 178418443, compound

Product 1

HCID 56601587HCID 56601587, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a −78° C. solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.14 mmol) in THF (4 mL) was added a solution of ethylmagnesium bromide in THF (1M, 1.12 mL, 1.12 mmol) dropwise. The reaction mixture was stirred at −78° C. for 5 h, and then quenched with a saturated solution of ammonium chloride. The mixture was extracted with chloroform (3×20 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude was purified by preparative TLC (silica gel, 95:5 chloroform/methanol), and then the diastereomers were separated by preparative HPLC (Chiralpak AD column, 40:60 heptane/ethanol with 0.1% diethylamine) to afford (6R,6aS,14aR)-methyl 12-ethyl-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (diastereomer A, 29 mg, 28%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H), 6.80 (br s, 1H), 6.51 (s, 1H), 5.52 (s, 1H), 4.98 (d, J=5.0 Hz, 1H), 4.65 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.78-3.62 (m, 3H), 3.58 (s, 3H), 3.40 (s, 3H), 3.39-3.22 (m, 3H), 3.14 (t, J=9.0 Hz, 1H), 2.80 (br s, 1H), 2.36 (s, 3H), 2.12-2.01 (m, 2H), 1.35 (d, J=6.0 Hz, 3H), 0.72 (t, J=7.0 Hz, 3H); MS (ESI+) m/z 728 (M+H); HPLC 98.1% (AUC), tR 11.84 min; and (6R,6aS,14aR)-methyl 12-ethyl-1,6,8,12,14a-pentahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (diastereomer B, 11 mg, 10%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 15.09 (s, 1H), 12.08 (br s, 1H), 7.75 (s, 1H), 6.75 (d, J=9.0 Hz, 1H), 6.53 (s, 1H), 5.58 (s, 1H), 5.32 (s, 1H), 4.96 (s, 1H), 4.77 (d, J=8.0 Hz, 1H), 4.76-4.62 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.72 (dd, J=9.5, 3.0 Hz, 1H), 3.69 (s, 1H), 3.55 (s, 4H), 3.42 (s, 3H), 3.31 (d, J=19.0 Hz, 1H), 3.12-3.00 (m, 3H), 2.70 (br s, 1H), 2.40 (s, 3H), 1.98-1.80 (m, 2H), 1.31 (d, J=6.0 Hz, 3H), 0.57 (t, J=7.5 Hz, 3H); MS (ESI+) m/z 728 (M+H); HPLC 98.3% (AUC), tR 11.85 min.

Workup

  1. customquenched with a saturated solution of ammonium chloride
  2. extractionThe mixture was extracted with chloroform (3×20 mL)
  3. dry with materialThe combined organics were dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude was purified by preparative TLC (silica gel, 95:5 chloroform/methanol)
  7. customthe diastereomers were separated by preparative HPLC (Chiralpak AD column, 40:60 heptane/ethanol with 0.1% diethylamine)

Sources & evidence

ORD record
ord-ff72bbf392de4b9aa698057861775d2a
Source dataset
uspto-grants-2014_06
Patent number
US08754054B2

Reaction notes

Loading…