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21st February 2012 @ 20:59
PS = Pictet-Spengler
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TO DO:
- Remove grease from final sample
- Upload NMR
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START: 22/02/12
FINISH:

Background
Reducing the catalyst load.

Scheme%20KAB13-2%20and%20KAB17-1.png


Hazard and Risk Assessment
As for KAB7-3 and KAB3-17.
Hazard and Risk Assessment KAB3-17
Hazard and Risk Assessment KAB7-3


Previous Related Experiments
TfOH catalysed PS* reactions to give the dimethoxy PZQ analogues (KAB8-14 & KAB1-5)
TfOH catalysed PS* reaction to give PZQ (KAB3-17)
TfOH catalysed PS* reaction to give the N-benzoyl PZQ analogue (KAB7-3)
Preparation of the PZQ peptide acetal Ugi-intermediate (KAB5-2)
Preparation of the N-benzoyl PZQ analogue Ugi-intermediate (KAB6-1)

Following Experiments
AgOTf catalysed partial PS reaction to give the N-benzoyl PZQ analogue enamide (KAB17-2)
AgOTf catalysed PS reaction to give the dimethoxy PZQ analogue (KAB1-6)
AgOTf catalysed PS reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-15)

Procedure
The peptide acetal Ugi-intermediate starting material was dissolved in toluene before the addtion of TfOH at rt. The mixture was immediately placed in a pre-heated oil bath (90 °C) and reflux heated. The reaction progress was monitored by TLC.

KAB17-1 (N-benzoyl PZQ analogue). Peptide Acetal KAB6-1: 373.1 mg (0.936 mmol), toluene: 37 mL, TfOH: 4.14 μL (0.047 mmol, 5 mol%).

KAB13-2 (PZQ). Peptide Acetal KAB5-2: 394.2 mg (0.974 mmol), toluene: 39 mL, TfOH: 4.32 μL (0.049 mmol, 5 mol%).

Reaction mixtures (5 min)
Reaction mixtures (15 min)
Reaction mixtures (30 min)
Reaction mixtures (1 h)
Reaction mixtures (2 h)

Reaction mixtures just removed from heat (at 3 h)


Monitoring the Reaction Progress by TLC
The progress was monitored by TLC of the reaction mixture against the relevant starting material, the expected product and the completely cyclised product. All TLCs were eluted with EtOAc/hexane, 5:3, v/v and stained with KMnO4.
TLC of KAB17-1 reaction mixture (5 min)
TLC of KAB13-2 reaction mixture (5 min)
TLC of KAB17-1 reaction mixture (15 min)
TLC of KAB13-2 reaction mixture (15 min)
TLC of KAB17-1 reaction mixture (30 min)

TLC of KAB13-2 reaction mixture (30 min)
TLC of KAB17-1 reaction mixture (1 h)
TLC of KAB13-2 reaction mixture (1 h)
TLC of KAB17-1 reaction mixture (2 h)
TLC of KAB13-2 reaction mixture (2 h)

TLC of KAB17-1 reaction mixture (3 h)
TLC of KAB13-2 reaction mixture (3 h)


Workup Procedure
Following removed from heat 3 hours after the addition of TfOH, the solution was diluted with EtOAc (50 mL) then quenched with saturated sodium bicarbonate solution (50 mL). The organic fraction was separated and the aqueous layer extracted with EtOAc (3 × 30 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure to give the crude products.
Crude KAB17-1, yield: 279 mg, 97%.
Crude KAB13-2, yield: 284 mg, 93%.
Crude KAB17-1
Crude KAB13-2


Purification
The crude products were dissolved in minimal EtOAc then passed through silica pads, eluting with neat EtOAc. The filtrates were collected then concentrated under reduced pressure to give KAB13-2 as a flaky solid (269 mg, 88%) and KAB17-1 as a yellow oil (282 mg, 98%), which showed signs of solidifying.

29/02/12. Recrystallisation of crude KAB13-2 from EtOAc/hexane. Dissolved in minimal EtOAc with heating. Hexane was added dropwise until a white precipitate began to appear momentarily. The flask was sealed and stored at rt.

02/03/12 - 1H-NMR of KAB17-1 recorded.
Raw H-NMR KAB17-1 (crude)
H-NMR KAB17-1 (crude)


08/03/12 - Attempting to remove grease and EtOAc traces from KAB17-1 sample. Washing with diethyl ether and hexane with sonication. Start Mass: 287 mg.

Summary and Conclusion


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NOTES 22/02/12
- KAB13-2 immediately turned yellow after adding the acid.
- KAB17-1 mostly finished by 30 minutes. KAB13-2 slower.

NOTES 29/02/12
- Successfully recrystallised KAB3-17. Will now attempt the reXST of KAB13-2. KAB17-1 is still semi-solid.

NOTES 01/03/12
- H-NMR of KAB17-1 indicates the product as a gel is pure. Aside form impurities between 0-3 ppm, the NMR is clean and as expected. The impurities are believed to originate from some of the solvent used. Will TLC the product to resolve any co-spotting. Will possibly require column chromatography.
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Linked Posts
Attached Files
Scheme KAB17-1 & KAB13-2
TLC of KAB17-1 reaction mixture (5 min)
TLC of KAB13-2 reaction mixture (5 min)
Reaction mixtures (5 min)
TLC of KAB17-1 reaction mixture (15 min)
TLC of KAB13-2 reaction mixture (15 min)
Reaction mixtures (15 min)
TLC of KAB17-1 reaction mixture (30 min)
TLC of KAB13-2 reaction mixture (30 min)
Reaction mixtures (30 min)
TLC of KAB17-1 reaction mixture (1 h)
TLC of KAB13-2 reaction mixture (1 h)
Reaction mixtures (1 h)
TLC of KAB17-1 reaction mixture (2 h)
TLC of KAB13-2 reaction mixture (2 h)
Reaction mixtures (2 h)
TLC of KAB17-1 reaction mixture (3 h)
TLC of KAB13-2 reaction mixture (3 h)
Reaction mixtures just removed from heat (at 3 h)
Crude KAB17-1
Crude KAB13-2
Scheme KAB17-1 & KAB13-2
Raw H-NMR KAB17-1 (crude)
H-NMR KAB17-1 (crude)