Update on the LA catalysed PS reaction

28 Mar
Published by KatB

It's now been about 3 weeks since I started working on the Lewis Acid (LAs) catalysed Pictet-Spengler project (see first post here). So far, I've been working on preparing the imine starting materials (1a-d) and getting them to cyclise (2a-d), just so I have a final product reference and a starting point for developing an assay to monitor the reaction.

The imines were very quick and easy to prepare and I now have a sufficient enough supply to start focussing more on the cyclisations and assays for the cyclisations.

 
Lab notes for the preparation of:
1a --> KAB18-1, KAB18-2
1b --> KAB19-1, KAB19-2
1c --> KAB22-1
1d --> KAB23-1
 I've also attempted the cyclisations mediated by superstoichiometric Bronsted acids to give 2a, 2b and 2d. The latest reaction in an attempt to produce 2a was performed under very harsh conditions (KAB20-4; neat methanesulfonic acid, 140C, 19 hours) and resulted in moderate yield (68%) and low conversion (10% by H-NMR). The reactions to give 2a (KAB21-2) and 2d (KAB24-1) were adapted from the literature [ref]. The final products for both those reactions are yet to be isolated and purified.
 
So far, monitoring of the reaction is somewhat different. I'm still working out the TLC eluents for checking the progress of the reactions and some of the spots have been unexpected - so far, the trend for the imines: very slow and polar (15-20% MeOH/DCM to get them to move with Rfs >0.05).
 
I haven't been able to find much background on the LA catalysed Pictet-Spengler (not acyl Pictet-Spengler) reaction to give the tetrahydroisoquinoline scaffold - but I'm still in the early stages of searching. I've started a page on OWW where I will be posting references (and some sort of summary) of what I can dig up that's relevant to the project. That page will also contain a running summary of what I've been up to in addition to any thoughts/comments/ideas/suggestions/etc that I get along the way. The project would really, really benefit from others' thoughts/comments/ideas/suggestions/etc as well - ideally posting here or on my Google+ page or the OWW talk page.
 
In other news, the BOX ligands arrived today, so motivation for getting the achiral cyclisations + assays in place is very high. And just for show: 7 g of recrystallised dimethoxy-nitro imine (1d, KAB23-1). Because I like crystals.
7 g of recrystallised KAB23-1