Proton sponge → Monomethyl auristatin E intermediate-9

HRID 74717

Reaction equation

HRID 74717 reaction equation
[CH2:1]([O:8][C:9]([N:11]([CH3:27])[C@@H:12]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:13]([OH:22])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>ClCCCl>[CH2:1]([O:8][C:9]([N:11]([CH3:27])[C@@H:12]([C@@H:23]([CH3:26])[CH2:24][CH3:25])[C@H:13]([O:22][CH3:28])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 88675Proton spongeHCID 2735153Oxonium, trimethyl-, tetrafluoroborate(1-) (1:1)HCID 10022629tert-butyl (3R,4S,5S)-4-{[(benzyloxy)carbonyl](methyl)amino}-3-hydroxy-5-methylheptanoate

Product 1

HCID 10249994Monomethyl auristatin E intermediate-9

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a solution of #3 (8.4 g, 22 mmol, 1 eq.) in 1,2-dichloroethane (25 mL, 0.88 M) were added molecular sieves (4 Å, 0.7 g) and Proton sponge (1,8-bis(dimethylamino)naphthalene) (13.4 g, 59.2 mmol, 2.7 eq.), followed by trimethyloxonium tetrafluoroborate (9.10 g, 61.6 mmol, 2.8 eq.). After stirring overnight, the reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (Gradient: 0% to 40% 1:1 acetone:ethyl acetate in heptane) to give #@2 (8.7 g, 68%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers: δ 7.28-7.40 (m, 5H), 5.01-5.13 (m, 2H), 3.89-4.08 (br m, 1H), 3.70-3.82 (m, 1H), 3.18 and 3.26 (2 s, total 3H), 2.66 and 2.71 (2 br s, total 3H), 2.44-2.53 (m, 1H, assumed; partially obscured by solvent peak), 2.17-2.24 (m, 1H), 1.71-1.86 (br m, 1H), 1.39 and 1.39 (2 s, total 9H), 1.31-1.40 (m, 1H), 0.94-1.08 (m, 1H), 0.76-0.91 (m, 6H).

Workup

  1. filtrationthe reaction mixture was filtered through Celite
  2. concentrationThe filtrate was concentrated in vacuo
  3. customthe residue was purified by silica gel chromatography (Gradient: 0% to 40% 1:1 acetone:ethyl acetate in heptane)
  4. customto give #@2 (8.7 g, 68%) as a colorless oil
  5. additiona mixture of rotamers
  6. customδ 7.28-7.40 (m, 5H), 5.01-5.13 (m, 2H), 3.89-4.08 (br m, 1H), 3.70-3.82 (m, 1H), 3.18 and 3.26 (2 s, total 3H), 2.66 and 2.71 (2 br s, total 3H), 2.44-2.53
  7. custom2.17-2.24 (m, 1H), 1.71-1.86 (br m, 1H), 1.39 and 1.39 (2 s, total 9H), 1.31-1.40 (m, 1H), 0.94-1.08 (m, 1H), 0.76-0.91 (m, 6H)

Sources & evidence

ORD record
ord-111f1d0b2a3f47ec97e1e39c13b34151
Source dataset
uspto-grants-2014_09
Patent number
US08828401B2

Linked notes

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