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21st February 2012 @ 02:16
PS = Pictet-Spengler

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TO DO:
- Remove grease from final sample
- H-NMR both samples
- KAB8-14 has been concluded. Still finalising KAB1-5.
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***Experiment still in progress with regular updates. Last updated 12/03/12.

START: 21/02/12
FINISH:

Background




Hazard and Risk Assessment
As for KAB8-11 and KAB1-3.
Hazard and Risk Assessment KAB8-11
Hazard and Risk Assessment KAB1-3


Previous Related Experiments
AgCl catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-13)
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-12)
TfOH catalysed PS* reaction to give the dimethoxy PZQ analogue (KAB1-4)

Following Experiments
TfOH catalysed partial PS* reactions to give the enediamide intermediates of PZQ and the N-benzoyl analogue (KAB13-2 & KAB17-1)
AgOTf catalysed PS reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-15)
AgOTf catalysed PS reaction to give the dimethoxy PZQ analogue (KAB1-6)

Procedure

21/02/12
General procedure. The peptide acetal Ugi-intermediate was dissolved in toluene before the addition of triflic acid at rt. The reaction vessel was immediately fitted with a condensing tube and placed in a pre-heated oil bath at 90 °C. The reaction mixture was reflux heated and the progress monitored by TLC against the relevant starting material and the expected product.

KAB8-14. Peptide acetal MNR10-2 (302.4 mg, 0.659 mmol), toluene (30 mL), TfOH (2.92 μL, 0.033 mmol, 5 mol%).

KAB1-5. Peptide acetal MNR8-3 (381.6 mg, 0.821 mmol), toluene (38 mL), TfOH (3.64 μL, 0.041 mmol, 5 mol%).

Reaction mixtures (5 min)
Reaction mixtures (15 min)
Reaction mixtures (30 min)
Reaction mixtures (1 h)
Reaction mixtures (3 h)


Monitoring the Reaction Progress by TLC
All TLCs were eluted with EtOAc/hexane, 5:3, v/v and stained with KMnO4. Time noted is the amount elapsed since the addition of acid.
TLC of KAB8-14 reaction mixture (5 min)
TLC of KAB1-5 reaction mixture (5 min)
TLC of KAB8-14 reaction mixture (15 min)
TLC of KAB1-5 reaction mixture (15 min)
TLC of KAB8-14 reaction mixture (30 min)

TLC of KAB1-5 reaction mixture (30 min)
TLC of KAB8-14 reaction mixture (1 h)
TLC of KAB1-5 reaction mixture (1 h)
TLC of KAB8-14 reaction mixture (2 h)
TLC of KAB1-5 reaction mixture (2 h)

TLC of KAB8-14 reaction mixture (3 h)
TLC of KAB1-5 reaction mixture (3 h)


Workup Procedure
After 3.5 hours the reaction mixture was allowed to cool. After the mixture was diluted with EtOAc (50 mL) then quenched with saturated sodium bicarbonate solution (50 mL), the organic layer was separated. The aqueous fraction was extracted with EtOAc (3 × 30 mL) before the organic layers were combined then dried over magnesium sulfate and filtered.
The pale yellow KAB8-14 and the yellow KAB1-5 solutions were concentrated under reduced pressure to give the crude products. KAB8-14 as a orangish semi-solid (249.8 mg, 103%) and KAB1-5 as a reddish semi-solid (312.0 mg, 102%).
Crude KAB8-14
Crude KAB1-5


Purification
Both crude KAB8-14 and KAB1-5 residues were dissolved in EtOAc. The solutions were passed through silica pads then concentrated under reduced pressure.
KAB8-14 (233 mg, 96%).
KAB1-5 (279 mg, 91%).
Filtered KAB8-14
Filtered KAB1-5


Recrystallisation from EtOAc/hexane.
KAB8-14 Start: 226 mg
Pure KAB8-14: 211 mg (93%).

07/02/12 - Attempt at reXST of KAB1-5 from EtOAc/Et2O

Summary and Conclusion


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NOTES 21/02/12
- KAB8-14 Flask: 49.1531 g
- Forgot to weigh out KAB1-5 flask. Will weigh it out after the filtration step tomorrow.

NOTES 28/02/12
- Still testing a recrystallisation of crude KAB1-2 before any attempting with the KAB1-5 sample.
- KAB8-13 filter paper: 1.1914 g

NOTES 29/02/12
- Still attempting to recrystallise an old sample of KAB1-2. Unsuccessful so far. No attempt at the recrystallisation of KAB1-5 as of yet.


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Linked Posts
Attached Files
Scheme KAB8-14 & KAB1-5
Table KAB8-14 & KAB1-5
TLC of KAB8-14 reaction mixture (5 min)
TLC of KAB1-5 reaction mixture (5 min)
Reaction mixtures (5 min)
TLC of KAB8-14 reaction mixture (15 min)
TLC of KAB1-5 reaction mixture (15 min)
Reaction mixtures (15 min)
TLC of KAB8-14 reaction mixture (30 min)
TLC of KAB1-5 reaction mixture (30 min)
Reaction mixtures (30 min)
TLC of KAB8-14 reaction mixture (1 h)
TLC of KAB1-5 reaction mixture (1 h)
Reaction mixtures (1 h)
TLC of KAB8-14 reaction mixture (2 h)
TLC of KAB1-5 reaction mixture (2 h)
Reaction mixtures (3 h)
TLC of KAB8-14 reaction mixture (3 h)
TLC of KAB1-5 reaction mixture (3 h)
Crude KAB8-14
Crude KAB1-5
Filtered KAB8-14
Filtered KAB1-5