Piperidine → (2S,4S)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid

HRID 589259Notes

Reaction equation

HRID 589259 reaction equation
[C:1]([N:18]1[CH2:25][C@H:24]([OH:26])[CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C(N=C=NC(C)C)(C)C.[OH:36]N1C2C=CC=CC=2N=N1.N1CCCCC1.C(N=C=NC(C)C)(C)C.[OH:61]N1C2C=CC=CC=2N=N1>CN(C)C=O.CS(C)=O>[C:1]([N:18]1[CH2:25][C@@H:24]([OH:26])[CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[C:1]([N:18]1[CH2:25][CH2:24][C@@H:23]([OH:36])[C@H:19]1[C:20]([OH:22])=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[C:1]([N:18]1[CH2:25][CH2:24][C@H:23]([OH:61])[C@H:19]1[C:20]([OH:22])=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]

Participants

10

Reactant 5

HCID 8082PiperidineHCID 12734Diisopropylcarbodiimide3×HCID 757711-Hydroxybenzotriazole3×HCID 2756109(2S,4R)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acidHCID 22603587DIPCDI HOBt

Product 3

HCID 11902905(2S,4S)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acidHCID 45934220(2S,3S)-1-(((9H-Fluoren-9-yl)methoxy)carbonyl)-3-hydroxypyrrolidine-2-carboxylic acidHCID 69048672(2S,3R)-1-(((9H-Fluoren-9-YL)methoxy)carbonyl)-3-hydroxypyrrolidine-2-carboxylic acid

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 6228DimethylformamideSolvent2×

Procedure

Peptides were synthesised using a CS-Bio 336S, a CS-Bio 336X and a Multipep peptide synthesis machine (Intavis AG Bioanalytical Instruments, Germany). Standard amino acids were purchased from CS-Bio in their Fmoc-N-α-protected form. Fmoc-trans-4-hydroxy-(L)-proline was obtained from Merck. Fmoc-cis-4-hydroxy-(L)-proline, Fmoc-cis-3-hydroxy-(L)-proline and Fmoc-trans-3-hydroxy-(L)-proline were prepared as described in the synthetic section. Peptide synthesis was carried out in dimethylformamide (DMF) using diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBt) as activating reagents, and piperidine as Fmoc deprotection reagent. DIC was used as 0.5 M solution in DMSO, and HOBt as a 0.5 M solution in DMF. Typically, synthesis was carried out on a 0.1 mmol scale, using MBHA Rink Amide resin (loading 0.45 mmol/g), 1 mmol of protected amino acids (10× molar excess), and 1 mmol of activating reagents (DIC, HOBt). Parallel peptide synthesis for screening was performed on Tentagel S-RAM resin. Amino acids were pre-activated by addition of DIC/HOBt for 30 min prior to addition to the resin. After addition to the resin, the activated amino acid was allowed to react with the resin/growing peptide chain for 2 h, prior to removal and washing of the resin. Fmoc deprotection was performed using 20% piperidine, 20% DMSO in 60% DMF, followed by extensive washing of the resin, and addition of the next amino acid.

Workup

  1. customTypically, synthesis
  2. additionto addition to the resin
  3. additionAfter addition to the resin
  4. customto react with the resin/growing peptide chain for 2 h
  5. customto removal
  6. washwashing of the resin
  7. washby extensive washing of the resin, and addition of the next amino acid

Sources & evidence

ORD record
ord-f8d817ffd9114c4d81a330b8aca42354
Source dataset
uspto-grants-2016_01
Patent number
US09228224B2

Reaction notes

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