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19th February 2012 @ 22:03
PS = Pictet-Spengler

START: 20/02/12
FINISH: 02/03/12

Background
Continuation of the series of TfOH (10 mol%) catalysed Pictet-Spengler reactions to give PZQ and its analogues.




Hazard and Risk Assessment
Hazard and Risk Assessment KAB7-3


Previous Related Experiments
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 PS* reaction to give PZQ (KAB3-17)
TfOH catalysed PS* reactions to give the dimethoxy PZQ analogues (KAB8-14 & KAB1-5)
TfOH catalysed partial PS* reactions to give the enediamide intermediates of PZQ and the N-benzoyl analogue (KAB13-2 & KAB17-1)

Procedure
KAB6-1 (400 mg, 1.00 mmol) was dissolved in toluene (44 mL) before the addition of TfOH (8.90 μL, 0.10 mmol, 10 mol%) at rt. The mixture was immediately put in a pre-heated oil bath at 90 °C and refluxed from 10:35.
Reaction mixture before after the addition of TfOH
Reaction mixture (15 min)


Monitoring the Reaction Progress by TLC
All TLCs were eluted with EtOAc/hexane, 5:3, v/v and stained with KMnO4. The time noted is from the addition of the acid.
TLC of reaction mixture (5 min)
TLC of reaction mixture (15 min)
TLC of reaction mixture (30 min)
TLC of reaction mixture (1 h)
TLC of reaction mixture (2 h)


After 2 hours, the reaction mixture was removed from heat and allowed to cool. The solution was diluted with EtOAc (50 mL), then quenched with saturated sodium bicarbonate solution (50 mL).
Reaction mixture after removal from heat
After dilution with EtOAc
Quenched with NaHCO3

The organic layer was separated and the aqueous fraction extracted with EtOAc (3 × 30 mL). The organic fractions were combined, dried over magnesium sulfate, then passed through a silica pad.
First extraction with EtOAc
Second extraction with EtOAc
Third extraction with EtOAc
Left: aqueous fraction; Right: combined organic layers
Drying combined EtOAc fractions over MgSO4

Filtering through silica

The filtrate was collected and concentrated under reduced pressure to give crude KAB7-3 as a yellowish semi-solid (297 mg, 96%).
KAB7-3 filtrate
Concentrated KAB7-3

The crude sample was put under high vacuum for >2 hours before it was sealed and stored in the freezer overnight.

28/02/12
Attempt at recrystallisation from EtOAc/hexane.
Start: 295.4 mg
02/03/12
Recrystallisation failed. Product is a gel.

Raw H-NMR KAB7-3
Raw H-NMR KAB7-3


Summary and Conclusion
Triflic acid (10 mol%) catalyses partial Pictet-Spengler reaction to give the enamide intermediate. It is thought that loss of the ethoxy groups form the peptide acetal starting material results in the in situ formation of the iminium ion. Lack of electron density in the &del; aromatic group results in tautomerism of the iminium to the stable and isolatable enamide, KAB7-3.

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NOTES 20/02/12
- 15 min into the reaction and already complete consumption of the KAB6-1 starting material. Most of the product currently the enediamide intermediate (based on TLC). The enediamide spot immediately turned bright yellow on staining, with no heating required. The plate was still heated to develop the other spots.
- Flask 48.1329 g
- After standing under high vacuum, the oil showed signs of solidifying. Stored in freezer overnight.

NOTES 28/02/12
- Still not quite solid.
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Linked Posts
Attached Files
Scheme KAB7-3
Hazard and Risk Assessment KAB7-3
Reaction mixture before after the addition of TfOH
Reaction mixture (15 min)
TLC of reaction mixture (5 min)
TLC of reaction mixture (15 min)
TLC of reaction mixture (30 min)
TLC of reaction mixture (1 h)
TLC of reaction mixture (2 h)
Reaction mixture after removal from heat
After dilution with EtOAc
Quenched with NaHCO3
First extraction with EtOAc
Second extraction with EtOAc
Third extraction with EtOAc
Left: aqueous fraction; Right: combined organic layers
Drying combined EtOAc fractions over MgSO4
Filtering through silica
KAB7-3 filtrate
Concentrated KAB7-3
Table KAB7-3
Raw H-NMR KAB7-3
Raw H-NMR KAB7-3