Hydrochloric Acid → cis-methyl (1R,3R)-1-amino-3-(4-prop-1-ynylphenyl)cyclopentane-1-carboxylate;(2R,3R)-2,3-dihydroxybutanedioic acid

HRID 1511847Notes

Reaction equation

HRID 1511847 reaction equation
[CH3:1][O:2][C:3]([C@@:5]1([NH2:17])[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)[CH2:6]1)=[O:4].Cl.[CH:19]#[C:20][CH2:21]CCCCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1.[C:52]([OH:61])(=[O:60])[C@@H:53]([C@H:55]([C:57]([OH:59])=[O:58])[OH:56])[OH:54]>CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOCC.C1COCC1>[OH:56][C@H:55]([C@@H:53]([OH:54])[C:52]([OH:61])=[O:60])[C:57]([OH:59])=[O:58].[CH3:1][O:2][C:3]([C@@:5]1([NH2:17])[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][C:13]([C:19]#[C:20][CH3:21])=[CH:12][CH:11]=2)[CH2:6]1)=[O:4]

Participants

12

Reactant 6

HCID 313Hydrochloric AcidHCID 8082PiperidineHCID 11776TriphenylphosphineHCID 123701-Octyne2×HCID 444305L-Tartaric acidHCID 25002100(1R,3R)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate

Product 1

HCID 131729811cis-methyl (1R,3R)-1-amino-3-(4-prop-1-ynylphenyl)cyclopentane-1-carboxylate;(2R,3R)-2,3-dihydroxybutanedioic acidYield 60%

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 887MethanolSolvent2×HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a three-neck round bottom flask was added (1R,3R)-1-amino-3-(4-bromo-phenyl)-cyclopentanecarboxylic acid methyl ester; hydrochloride (4.00 g, 12.0 mmol), 1-octyne (3.54 mL, 24.0 mmol), triphenylphosphine (314 mg, 1.20 mmol), piperidine (7.13 ml, 72.0 mmol), and THF (100 mL). The mixture was degassed, and Pd(PPh3)2Cl2 (421 mg, 0.60 mmol) was added and the mixture was stirred for a few minutes under an atmosphere of nitrogen before addition of the copper(I) iodide (114 mg, 0.60 mmol). The reaction was stirred under an atmosphere of nitrogen at 60° C. for 4 hours. More 1-octyne (5.31 mL, 36.0 mmol) was added in two portions and the reaction mixture was heated at 60° C. for a total of about 30 hours. The solvent was then removed and crude material was partitioned between EtOAc and saturated NaHCO3. The aqueous layer was back-extracted once with EtOAc. Organic layers were combined, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography using 1 L of EA followed by 1 L of 2% MeOH in EtOAc to give 3.52 g (90%) crude product as a yellow oil. A portion of the crude product (60.0 mg, 0.126 mmol) was dissolved in minimum amount of MeOH, to which L-tartaric acid (1.69 g) in MeOH was added. Ether was then added dropwise until solution just turned turbid. The mixture was left to crystallize. The solid was collected by filtration, washed with ether to give 45.0 mg (60%) (1R,3R)-1-amino-3-(4-prop-1-ynyl-phenyl)-cyclopentanecarboxylic acid methyl ester; compound with (2R,3R)-2,3-dihydroxy-succinic acid.

Workup

  1. customThe mixture was degassed
  2. temperaturethe reaction mixture was heated at 60° C. for a total of about 30 hours
  3. customThe solvent was then removed
  4. customcrude material was partitioned between EtOAc and saturated NaHCO3
  5. extractionThe aqueous layer was back-extracted once with EtOAc
  6. dry with materialdried over MgSO4
  7. customthe solvent was removed under reduced pressure
  8. customThe residue was purified by silica gel chromatography
  9. customto give 3.52 g (90%) crude product as a yellow oil
  10. additionwas added
  11. waitThe mixture was left
  12. customto crystallize
  13. filtrationThe solid was collected by filtration
  14. washwashed with ether

Sources & evidence

ORD record
ord-c6d907585f5e491fbfd5e5fd61896cde
Source dataset
uspto-grants-2012_07
Patent number
US08217027B2

Reaction notes

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