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19th January 2012 @ 00:40
*****Experiment concluded on 23/01/12


Performed simultaneously with the The copper(II) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-3)

Background
Previous experiments KAB11-1, KAB11-2 and KAB11-3 were intended to isolate the enediamide intermediate of the Pictet-Spengler (PS) reaction to give the dimethoxy N-benzoyl PZQ analogue (i.e. KAB8), using catalytic amounts of metal triflates; see also ref [1].
The reaction of the peptide acetal starting material in the stoichometric acid-mediated PS resulted in rapid formation of the expected product (<30 min, see KAB8-1). It was expected that use of proton deficient metal triflates would result in the partial PS to give the iminium ion, which would then tautomerise to the stable enediamide intermediate.
Surprisingly, the reactions KAB11-2 and KAB11-3 produced the complete PS product, the dimethoxy N-benzoyl PZQ analogue (at least, by TLC), in less than 18 hours.
This experiment is an attempt to reproduce the results obtained in the experiment KAB11-2 on a slightly larger scale, in order to determine if the final product is N-benzoyl PZQ analogue.

Scheme
Scheme%20KAB8-4.png
Table%20KAB8-4.jpg

Hazard and Risk Assessment
As for KAB11-2 (here)

Following Experiments
The metal triflate catalysed Pictet-Spengler to give racemic PZQ (KAB3-9 & KAB3-10)

Procedure

19/01/12

11:20 - MNR10-1 (112 mg, 0.244 mmol) was dissolved in toluene (32 mL) before the addition of AgOTf (38.1 mg, 61 mol%) at rt. The reaction mixture was then reflux heated at 90 °C.

A 0.1 mL aliquot was extracted at ~13:05 and analysed by TLC (EtOAc/hexane, 4:1, v/v; KMnO4 stain). The sample was not diluted.
TLC of reaction mixture (1)

From left to right:
8-3 = KAB8-3 reaction mixture aliquot 1.
Co = Co-spot of KAB8-3 aliquot 1, the starting material MNR10-1 and the expected product, KAB8-1.
SM = The MNR10-1 starting material
8-1 = The expected product KAB8-1 (made previously)
Co = Co-spot of the simultaneously prepared KAB8-4 reaction mixture aliquot 1, MNR10-1 and KAB8-1.
8-4 = Aliquot 1 of the KAB8-4 reaction mixture.


The TLC of the KAB8-4 aliquot 1 showed 4 distinct spots, which were particularly clear under short wave UV light.

Another 0.1 mL aliquot was extracted at 15:45 and analysed by TLC.
TLC of reaction mixture (2)

From left to right:
Co = Co-spot of KAB8-3 aliquot 2, the starting material MNR10-1 and the expected product, KAB8-1.
8-3 = KAB8-3 reaction mixture aliquot 2.
SM = The MNR10-1 starting material.
8-1 = The expected product KAB8-1 (made previously).
Co = Co-spot of KAB8-4 reaction mixture aliquot 2, MNR10-1 and KAB8-1.
8-4 = Aliquot 2 of the KAB8-4 reaction mixture.


Reaction mixture after removal from heat


At 16:45, the reaction mixture was allowed to cool, before concentrated under reduced pressure. The residue was dissolved in EtOAc then passed through a silica pad. The filtrate was collected and concentrated under reduced pressure to give KAB8-4 (116 mg, 130%)

TLC of crude KAB8-4

From left to right:
8-3 = Crude KAB8-3.
Co = Co-spot of crude KAB8-3 and the expected product
8-1 = The expected product KAB8-1 (made previously).
Co = Co-spot of crude KAB8-4 and the expected product
8-4 = Crude KAB8-4.


Expected product KAB8-4 has Rf = 0.3 in EtOAc/hexane, 4:1, v/v.
Enediamide intermediate (see KAB11-2) has Rf = 0.5 in EtOAc/hexane, 4:1, v/v.

20/01/12

The crude KAB8-4 was dissolved in EtOAc (50 mL) and washed with citric acid solution (30 mL, pH 1). The EtOAc layer was then washed with saturated sodium bicarbonate solution (30 mL) and some gas was released. The aqueous layer was separated then extracted further with EtOAc (2 × 30 mL). The organic layers were combined, dried over magnesium sulfate, then concentrated under reduced pressure to give an off-white residue (64 mg, 72%).

Crude KAB8-4
H-NMR of crude KAB8-4
Raw H-NMR KAB8-4


The product was recrystallised from EtOAc and hexane - Start: 58 mg.

Recrystallising KAB8-4


23/01/12

White crystals formed over the weekend and were filtered, then washed with hexane to give KAB8-4, the dimethoxy N-benzoyl PZQ analogue as small white crystals (58 mg, 65%). The recovery from the recrystallisation was ~99%.

Re-crystallised KAB8-4
Re-XST mother liquor
Final KAB8-4


Conclusion
The silver catalysed Pictet-Spengler cyclisation of the to give KAB8-4 was a very clean reaction. Yield could possibly be improved by performing the reaction under an inert atmosphere, to minimise poisoning of the catalyst. The NMR of the crude product obtained in KAB11-2 was fairly clean, reflecting the small amount of impurities removed on crystallisation of the final KAB8-4 product. The crystals are white, as opposed to the pale yellow to off white colour of KAB8-1, which was prepared using stoichiometric methanesulfonic acid (MSA).
This procedure was both more efficient (i.e. catalytic as opposed to acid-mediated) and produced greater yield than the method that uses MSA.


References
Todd, M. H., Ndubaku, C. & Bartlett, P. A., J. Org. Chem. 2002, 67, 3985-3988 - DOI: 10.1021/jo010990m (Paper)

Related Experiments
The copper(II) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-3)
Copper(II) triflate catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-3)
Lewis acid catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-1)
Silver(I) triflate catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-2)


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NOTES 19/01/12
- AgOTf was a beige crystalline solid.
- Worried about losing product during the filtration step, like I did with KAB8-3, that I may have over filtered the solution, which may have allowed some AgOTf to end up in the final product, hence the >100% yield.

NOTES 23/01/12
Will NMR the final white crystals tomorrow (which is when the next available booking is).
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Linked Posts
Attached Files
Scheme KAB8-4
Table KAB8-4
TLC of reaction mixture (1)
TLC of reaction mixture (2)
TLC of crude KAB8-4
Reaction mixture after removal from heat
H-NMR of crude KAB8-4
Raw H-NMR KAB8-4
Crude KAB8-4
Recrystallising KAB8-4
Re-crystallised KAB8-4
Re-XST mother liquor
Final KAB8-4