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28th February 2012 @ 22:19
PS = Pictet-Spengler

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Summary and Conclusion
Successful AgOTf catalysed Pictet-Spengler reaction to give the dimethoxy N-benzoyl PZQ analogue. Isolated yield was 87%. Incomplete isolation of product after 3 recrystallisation crops - some product remained in mother liquor. Recommend column before recrystallisation of product in future attempts to remove the enamide intermediate.
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START: 29/02/12
FINISH: 06/03/12

Background

Scheme%20KAB8-15.png
Table%20KAB8-15.png

Hazard and Risk Assessment
Hazard and Risk Assessment KAB8-15


Previous Related Experiments
AgOTf catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-10)
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-12)
The silver(I) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-4)

Following Experiments
AgOTf catalysed PS reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-16)
AgOTf catalysed PS reaction to give the dimethoxy PZQ analogue (KAB1-6)

Procedure
Reaction performed under anhydrous conditions. MNR10-2 (618 mg, 1.35 mmol) was dissolved in dry toluene (62 mL) before the addition of AgOTf (33.4 mg, 0.130 mmol, 10 mol%). The reaction mixture was immediately placed in a pre-heated oil bath at 90 °C and refluxed from 09:40 in the dark. The reaction progress was monitored by TLC against the MNR10-2 starting material and the expected product (identical to KAB8-4).
Reaction Setup
Reaction mixture (5 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 AgOTf. TLC Legend (from L to R): (1)Reaction mixture at time indicated at the bottom, (2)Co-spot of reaction mixture, MNR10-2 starting material and the expected product, (3)MNR10-2 starting material, (4)Expected product identical to KAB8-4.
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)

TLC of reaction mixture (3 h)
TLC of reaction mixture (4 h)


Workup Procedure
Four hours after the addition of AgOTf, the reaction mixture was taken out of the oil bath and allowed to cool. The mixture was transferred to a separating funnel then diluted with EtOAc (50 mL).
Reaction mixture after removal from heat
Silver residue stuck in the flask
Dilution with EtOAc

After washing with citric acid solution (0.5 M, 50 mL), the organic fraction was separated. The acidic aqueous fraction was adjusted to pH 10 by the addition of sodium hydroxide solution (2 M) turning the solution a dark grey colour.
Washed with citric acid solution
Acidic aqueous fraction
Aqueous fraction after basification

The aqueous mixture was extracted with EtOAc (3 × 50 mL). The organic fractions were combined then dried over magnesium sulfate, which turned the cloudy orange solution a clear golden colour.
First extraction with EtOAc
Second extraction with EtOAc
Third extraction with EtOAc
Left: aqueous fraction; Right: combined organic layers
Drying combined organic fractions over MgSO4

After removal of the drying agent by filtration, the solution was concentrated under reduced pressure to give crude KAB8-15 as a dark brown sticky oil (657 mg, 133%).
Dried combined organic fractions
Crude KAB8-15


Purification 29/02/12
The crude product was dissolved in minimal EtOAc then filtered through a short silica column. The filtrate was concentrated under reduced pressure to give an off-white foam (509 mg, 103%).
Filtering through silica
Filtered KAB8-15

The foam was dissolved in minimal EtOAc with heating. Hexane was added dropwise until a white precipitate began to momentarily appear as the hexane was added to the solution. The flask was sealed and put in the freezer overnight.

Purification (cont'd) 02/03/12
The white crystals were filtered out and washed with hexane. Crystals continued to form in the filtrate, which was transferred to a weighed container, sealed and put back into the freezer.
Yield so far: 245 mg (50%).

Purification (cont'd) 05/03/12
Filtered crystals then washed with hexane. Product still crashing out. The filtrate was concentrated under reduced pressure and the residue recrystallised with EtOAc/hexane.
Yield so far: 340 mg (69%).

Purification (cont'd) 06/03/12
Crystals were filtered and washed with hexane. TLC of the crystals against the mother liquor suggested product still remained in the mother liquor. The products were taken no further.

Summary and Conclusion
Successful AgOTf catalysed Pictet-Spengler reaction to give the dimethoxy N-benzoyl PZQ analogue. Isolated yield was 87%. Incomplete isolation of product after 3 recrystallisation crops - some product remained in mother liquor. Recommend column before recrystallisation of product in future attempts to remove the enamide intermediate.

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NOTES 29/02/12
- Slightly concerned that good AgOTf (i.e. right out of the bottle) is white. The AgOTf that I've been using up until now has been beige.
- Reaction mixture turned brownish within 5 min. At 15 minutes, very brown - Silver reduced?
- 4 hours. Silver got reduced.
- Flask: 59.4272 g
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21st February 2012 @ 20:59
PS = Pictet-Spengler
=======================================
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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21st February 2012 @ 20:58
PS = Pictet-Spengler

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This experiment has been put on hold. No further work performed as of 24/02/12.
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START: 23/02/12
FINISH:

Background

Scheme%20KAB16-1.png


Hazard and Risk Assessment
Hazard and Risk Assessment KAB16-1


Previous Related Experiments
Preparation of Imidobis(sulfuryl chloride) (KAB15-1)

Following Experiments


Procedure

23/02/12 - Saturation of diethyl ether with gaseous HCl
Neat sulfuric acid in a pressure equalising dropping funnel was added dropwise in portions to a 3-necked round bottom flask containing sodium chloride. The generated hydrogen chloride gas was sparged through diethyl ether (1 L) at -78 °C. The sodium chloride flask required changing after excessive formation of sodium bisulfate.
Saturation of ether setup
Saturation of ether setup (annotated)



Summary and Conclusion


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NOTES 23/02/12
- After about half of the H2SO4 was added, the NaOH solution backflowed into the ether solution. The process was terminated and while the ice was still frozen in the ether solution, the acidic ether was canulated into an oven-dried 1 L pyrex jar. The ether will require further acidification before use in the column.
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21st February 2012 @ 02:16
PS = Pictet-Spengler

=======================================
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

Scheme%20KAB8-14.png
Table%20KAB8-14.jpg

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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20th February 2012 @ 22:12
PS = Pictet-Spengler

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Summary and Conclusion
No reaction of the dimethoxy N-benzoyl PZQ analogue peptide acetal in the presence of silver chloride.
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START: 21/02/12
FINISH: 21/02/12

Background

Scheme%20KAB8-13.png
Table%20KAB8-13.jpg

Hazard and Risk Assessment
Hazard and Risk Assessment KAB8-13


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

Following Experiments
TfOH catalysed PS* reactions to give the dimethoxy PZQ analogues (KAB8-14 & KAB1-5)

Procedure
MNR10-2 (253.6 mg, 0.553 mmol) was dissolved in toluene (25 mL) before the addition of AgCl (29.1 mg, 0.203, 37 mol%) at rt. The mixture was immediately placed in a pre-heated oil bath at 90 °C and reflux heated from 10:55.

Taken off heat after 1 hour.

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


Summary and Conclusion
No reaction of the dimethoxy N-benzoyl PZQ analogue peptide acetal in the presence of silver chloride.

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NOTES 21/02/12
- Suspect the silver has been reduced - Black solid in flask.
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