HCID 102526939, compound → HCID 102526941, compound

HRID 1056862Notes

Reaction equation

HRID 1056862 reaction equation
[Si:1]([O:8][C@H:9]([C@@:11]1([NH:48][C:49]([N:51]([CH3:53])[CH3:52])=[O:50])[C:16](=[O:17])[C@@:15]2([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:13]([O:14]2)[C@@H:12]1[NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:54][Mg+].[Br-]>C1COCC1>[Si:1]([O:8][C@H:9]([C@@:11]1([NH:48][C:49]([N:51]([CH3:53])[CH3:52])=[O:50])[C@:16]([OH:17])([CH3:54])[C@@:15]2([CH2:18][O:19][Si:20]([C:33]([CH3:35])([CH3:34])[CH3:36])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:13]([O:14]2)[C@@H:12]1[NH:37][C:38](=[O:47])[O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]

Participants

4

Reactant 2

HCID 102526939HCID 102526939, compoundHCID 178418689HCID 178418689, compound

Product 1

HCID 102526941HCID 102526941, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A flame-dried 25-mL round-bottomed flask was charged with ketone 12 (1.7 g, 2.3 mmol, 1.0 equiv) and THF (23 mL). The solution was cooled to 0° C. and MeMgBr (3M in THF, 7.6 mL, 22.9 mmol, 10.0 equiv) was added dropwise. The reaction was stirred at 0° C. until TLC analysis indicated complete ketone consumption, typically 2 h. Saturated NH4Cl(aq.) (20 mL) was carefully added dropwise and the resulting mixture was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine (20 mL), dried with magnesium sulfate, and concentrated in vacuo. The crude product was purified via flash chromatography (90:10 to 70:30 hexanes:EtOAc) to afford carbinol 13 as a clear, viscous oil with >10:1 diastereoselection (1.3 g, 75%). The enantiomeric ratio was assayed at this intermediate and was found to be 95:5. This composition was determined by SFC analysis (Chiralcel, OD, 4.0% MeOH, 1.5 mL/min, 150 bar, 210 urn; tR-minor 34.4 min, tR-major 37.6 min). Analytical data: [α]D19 +7.2 (c=0.70, CHCl3); 1H NMR (600 MHz, CDCl3): δ 7.73 (d, J=7.8 Hz, 2H), 7.70 (d, J=7.2 Hz, 2H), 7.45-7.30 (m, 12H), 5.55 (br s, 1H), 5.21 (d, J=12.6 Hz, 1H), 5.17 (br s, 1H), 5.07 (d, J=12.0 Hz, 1H), 4.77 (br s, 1H), 4.64 (dd, J=8.4, 3.6 Hz, 1H), 4.21 (d, J=12.6 Hz, 1H), 4.12 (d, J=12.6 Hz, 1H), 3.90 (s, 1H), 2.75 (s, 6H), 1.30 (s, 3H), 1.25 (d, J=6.0 Hz, 3H), 1.07 (s, 9H), 0.97 (s, 9H), 0.11 (s, 3H), −0.01 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 158.8, 156.5, 136.3, 135.6, 135.5, 134.7, 133.3, 132.9, 129.6, 129.4, 128.4, 128.2, 128.1, 127.7, 127.6, 127.6, 67.1, 66.8, 62.1, 58.3, 36.1, 26.7, 26.5, 25.7, 23.8, 19.6, 19.2, 17.8, −4.2, −5.5; LRMS (ESI+) Calcd. for C42H61N3O7Si2+H, 776.41. Found, 776.36. IR (thin film, cm−1) 3430, 2429, 2359, 1716, 1635, 1506, 1456, 1112, 831, 700; TLC (90:10 hexanes/EtOAc): Rf=0.35.

Workup

  1. customketone consumption, typically 2 h
  2. additionSaturated NH4Cl(aq.) (20 mL) was carefully added dropwise
  3. extractionthe resulting mixture was extracted with EtOAc (3×15 mL)
  4. washThe combined organic extracts were washed with brine (20 mL)
  5. dry with materialdried with magnesium sulfate
  6. concentrationconcentrated in vacuo
  7. customThe crude product was purified via flash chromatography (90:10 to 70:30 hexanes:EtOAc)

Sources & evidence

ORD record
ord-15ab0820d9a94526b4fdf061b0b48481
Source dataset
uspto-grants-2016_07
Patent number
US09399652B2

Reaction notes

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