L-Tyrosine → 2-Methoxybenzaldehyde

HRID 2188419Notes

Reaction equation

HRID 2188419 reaction equation
O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C[O-].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].N[C@H](C(O)=O)CC1C=CC(O)=CC=1.C(OC(C1C=C(C[C@H](NC(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)C(O)=O)C=CC=1OCC(OCC)=O)=O)C.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:11][O:10][C:4]1[CH:3]=[CH:2][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]

Participants

9

Reactant 7

HCID 6057L-TyrosineHCID 12734DiisopropylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 5195414-Hydroxy-2-MethoxybenzaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 10942334Sodium MethoxideHCID 59897163HCID 59897163, compound

Product 1

HCID 86582-Methoxybenzaldehyde

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

The production of this library required seven steps using solid support. Three steps were carried out in a 96 well format. The AMEBA (acid sensitive methoxy benzaldehyde) linker was prepared by reacting Merrifield resin and 4-hydroxy-2-methoxybenzaldehyde with sodium methoxide (see Scheme I). The AMEBA resin was then treated with the corresponding amine and NaBH(OAc)3 to give the corresponding reductive amination product. The tyrosine scaffold (5) was then coupled to the various amine resins using DIC and HOBT in DMF. The Fmoc protecting group was then removed with piperidine/DMF (1:1). The resin was then plated in a 96 well Robbins block then coupled to the corresponding acid with DIC and HOBT in DMF. The diethyl ester was hydrolyzed with excess LiOH in THF: MeOH (1:1) for 5-14 h at rt to yield the dicarboxylic acid on resin. The use of THF: MeOH (1:1) is crucial for this hydrolysis. The use of excess LiOH and neat MeOH, THF and DMF failed to yield the diacid. The product was then cleaved from the resin with 20% TFA/CH2Cl2 solution. The resin was cleaved twice to yield the maximum possible product. The second cleavage resulted in approximately 10-20% more product without any change in purity levels.

Workup

  1. customto give the corresponding reductive amination product
  2. customThe Fmoc protecting group was then removed with piperidine/DMF (1:1)

Sources & evidence

ORD record
ord-6c85f033aa4d44e5ae31ec80c725d897
Source dataset
uspto-grants-2002_06
Patent number
US06410585B1

Reaction notes

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