Formic Acid → HCID 5358230, compound

HRID 2218491Notes

Reaction equation

HRID 2218491 reaction equation
[CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([O:30]C(CC(C)C)=O)[CH2:24][C:22](=[O:23])[N:21]([CH3:37])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:38])=[CH:9][CH:8]=[CH:7][CH:6]([O:39][CH3:40])[C:5]2([OH:45])[NH:41][C:42]([O:44][CH:3]1[CH2:4]2)=[O:43].C(O)=O.O1CCCC1.C(OCC)(=O)C>O>[CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:37])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:38])=[CH:9][CH:8]=[CH:7][CH:6]([O:39][CH3:40])[C:5]2([OH:45])[NH:41][C:42]([O:44][CH:3]1[CH2:4]2)=[O:43]

Participants

6

Reactant 4

HCID 284Formic Acid2×HCID 8028Tetrahydrofuran2×HCID 8857Ethyl AcetateHCID 99958HCID 99958, compound2×

Product 1

HCID 5358230HCID 5358230, compound

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
-57 °C

Procedure

This example describes preparation of the bridged acetal compound shown in Formula (I), where R1 is CH(CH3)2, reduction of ansamitocins with LiAl(OMe)3H, followed by aqueous formic acid quench. Ansamitocins (3.0 g, 4.72 mmol) were weighed into a three necked flask equipped with a thermometer. Tetrahydrofuran (15 mL) was added to the flask with stirring, and the flask was cooled in a −57° C. cooling bath. Once the contents of the flask reached −35° C., a solution of 0.67 M LiAl(OMe)3H in tetrahydrofuran (56 mL, 37.7 mmol) was added dropwise by syringe using a syringe pump. The temperature of the reaction was maintained between −30° C. and −40° C. throughout the addition. After addition was complete the reaction was stirred for 2 hours at between −34° C. and −37° C. A solution of 88% formic acid (1.85 mL, 2.16 g, 41.5 mmol) in 23 mL of deionized water was added dropwise to the flask at a rate that did not produce excessive frothing, followed by 66 mL of ethyl acetate. The cooling bath was removed and the mixture was allowed to warm to room temperature. The pH of the mixture was checked with pH paper and found to be approximately pH 6. Precipitated aluminum-based byproducts were removed by vacuum filtration and the solvent was removed from filtrate by rotary evaporation under vacuum. Butyl acetate (10 mL) was added to the residue, and the solvent was then evaporated in order to remove residual water. The residue was purified by silica chromatography using dichloromethane:methanol 95:5 (v:v) giving a later eluting band (maytansinol) and an early eluting band. The maytansinol band was collected and solvent was removed by rotary evaporation to give 1.55 g of maytansinol (58% yield by weight). Solvent was removed from the earlier eluting band, and the material was dissolved in a minimum volume of acetonitrile, then purified by preparative reverse phase HPLC. The compound of Formula (I) (retention time 26 min) was recovered, and solvent was removed by rotary evaporation to give 440 mg (15% yield by weight). Characterization of maytansinol: 1H NMR (CDCl3) δ 0.83 (s, 3H), 1.20 (m, 1H), 1.30 (d, 3H, J=6.0 Hz), 1.50 (m, 2H), 1.69 (s, 3H), 2.10 (d, 1H, J=9.4 Hz), 2.52 (d, 1H, J=9.4 Hz), 2.88 (d, 1H, J=5.4 Hz), 3.12 (d, 1H, J=12.7 Hz), 3.2 (s, 3H), 3.36 (s, 3H), 3.46 (m, 2H), 3.54 (d, 1H, J=9.3), 3.64 (br s, 1H), 3.99 (s, 3H), 4.36 (dd, 1H, J=12, 1.0 Hz), 5.53 (dd, 1H, J=15, 9.3 Hz), 6.14 (d, 1H, J=11 Hz), 6.14 (d, 1H, J=11 Hz), 6.27 (s, 1H), 6.44 (dd, 1H, J=15, 11 Hz), 6.81 (d, 1H, J=1.8 Hz), 6.96 (d, 1H, J=1.8 Hz); Characterization of the compound of Formula (I): R1═CH(CH3)2: 1H NMR (CDCl3) δ 0.78 (s, 3H), 0.97 (d, 3H, J=6.9), 1.04 (d, 3H, J=6.7), 1.23 (m, 1H), 1.28 (d, 3H, J=6.4), 1.54 (m, 1H), 1.66 (s, 3H), 1.72 (m, 2H) 2.03 (dd, 1H, J=14, 3.6 Hz), 2.3 (d, 1H, J=14), 2.49 (dd, 1H, J=11.7, 14), 2.92 (d, 1H, J=9.5 Hz), 3.14 (s, 3H), 3.12 (m, 1H), 3.37, (s, 3H), 3.52 (m, 3H), 3.65 (m, 1H), 3.75 (m, 1H), 3.97 (s, 1H), 4.31 (m, 2H), 5.52 (dd, 1H, J=16, 8.7 Hz), 6.13(d, 1H, J=11 Hz), 6.34 (s, 1H), 6.45 (dd, 1H, J=16, 11 Hz), 6.80 (d, 1H, J=1.5 Hz), 6.92 (d, 1H, J=1.5 Hz); MS (M+1 found: 619.3 M+1 calculated: 619.2)

Workup

  1. customquench
  2. customequipped with a thermometer
  3. temperaturecooling bath
  4. customreached −35° C.
  5. temperatureThe temperature of the reaction was maintained between −30° C. and −40° C. throughout the addition
  6. additionAfter addition
  7. stirringwas stirred for 2 hours at between −34° C. and −37° C
  8. customdid not produce excessive frothing
  9. customThe cooling bath was removed
  10. temperatureto warm to room temperature
  11. customwere removed by vacuum filtration
  12. customthe solvent was removed from filtrate by rotary evaporation under vacuum
  13. additionButyl acetate (10 mL) was added to the residue
  14. customthe solvent was then evaporated in order
  15. customto remove residual water
  16. customThe residue was purified by silica chromatography

Sources & evidence

ORD record
ord-ba04dec3d42b49b3be3e8c1e85c0246d
Source dataset
uspto-grants-2008_08
Patent number
US07411063B2

Reaction notes

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