Reaction #2810

Reaction equation

sodium cyanoborohydride

sodium cyanoborohydride

L-leucine tert-butyl ester hydrochloride

2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-formyl-phenyl)-propionic acid, 2-trimethylsilanyl-ethyl ester

→

title compound

Yield 63.0%

2-{2-[2-(1,3-Dioxo-1,3,dihydro-isoindol-2-yl)-2-(2-trimethylsilanyl-ethoxycarbonyl)-ethyl]-benzylamino}-4-methyl-valeric acid, tert-butyl ester

Yield 63.0%

Solvents

tetrahydrofuran

methanol

Conditions

Workup

1. 1
   workup.STIRRINGstir for 5 hours
2. 2
   FiltrationFilter
3. 3
   Filtrationthrough filter aid
4. 4
   Otherevaporate the solvent in vacuo
5. 5
   Otherpartition the residue between methylene chloride (100 mL) and saturated sodium hydrogen carbonate (40 mL)
6. 6
   DryingDry (Na2SO4)
7. 7
   Otherevaporate the solvent in vacuo
8. 8
   Otherpurify by silica gel chromatography (5:1 hexane/ethyl acetate followed by 3:1 hexane/ethyl acetate)

Procedure

Dissolve 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-formyl-phenyl)-propionic acid, 2-trimethylsilanyl-ethyl ester (250 mg, 0.590 mmol) in methanol (15 mL) and treat with L-leucine tert-butyl ester hydrochloride (0.66 g, 3.0 mmol). Stir at room temperature for 2 hours with 3A molecular sieves, add sodium cyanoborohydride (0.6 mL of a 1.0M solution in tetrahydrofuran, 0.6 mmol), stir for 0.5 hours, add additional sodium cyanoborohydride (0.3 mL) and stir for 5 hours. Filter through filter aid, evaporate the solvent in vacuo and partition the residue between methylene chloride (100 mL) and saturated sodium hydrogen carbonate (40 mL). Dry (Na2SO4), evaporate the solvent in vacuo and purify by silica gel chromatography (5:1 hexane/ethyl acetate followed by 3:1 hexane/ethyl acetate) to give the title compound (221 mg, 63%).

Source