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5th December 2011 @ 05:14
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Coupling of carboxylic acid PMY 8-2 with glycolamide using propylphosphonic anhydride ( (T3P) and pyridine in ethyl acetate. Attempt to optimise coupling conditions. Method based on reference shown below.

Reaction Scheme

Reaction start time: 15.30 05/12/11
PMY 8-3 (50 mg, 0.21 mmol, 1 equiv.), glycolamide (18 mg, 0.24 mmol, 1.1 equiv.) were dissolved in EtOAc (approx. 1 mL) and DMF (0.2 mL), pyridine (0.1 mL, 1.3 mmol, 6 equiv.) and cooled in salt/ice. T3P 50% in EtOAc (0.26 mL, 0.43 mmol, 2 equiv.) was added dropwise over 3 minutes. 4-DMAP (a few crystals) were added as a solution in EtOAc (0.5 mL) and the reaction allowed to warm to room temperature overnight. After 17 hours, 0.5M HCl (4 mL) was added. The mixture was stirred for approx 1.5 hours. The mixture was diluted with EtOAc (approx 10 mL) and the layers were then separated and the organic washed again with 0.5M HCl (10 mL) followed by brine, then dried (MgSO4) and concentrated to a dark brown solid. 1H NMR shows mostly SM acid and a new product not consistent with desired product. The side reaction signals were observed in the crude mixture in PMY 10-2.

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC before quench


NMR:
1H NMR crude


Risk and Hazard Assessment:
See: Synthesis of TCMDC-123794 Side-chain (PMY 5-1)
Propylphosphonic anhydride is corrosive

Reference:
DOI:10.1021/ol201875q

See also:
Synthesis of TCMDC-123812 using DIC/DMAP (PMY 10-3)
Synthesis of TCMDC-123812 via acid chloride (PMY 10-2)
Synthesis of TCMDC-123812 via acid chloride (PMY 10-1)
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Reaction Scheme
1H NMR crude
TLC before quench
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