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Pictet-Spengler Route to (R)-PZQ
Thu, 2007-11-29 13:21 — MatTodd
The Pictet-Spengler reaction is used in the current industrial synthesis of rac-PZQ, and these reactions have been looked at on the Synaptic Leap here.
The PS has been used in the synthesis of PZQ, and we used it as the final step in our solid phase synthesis of PZQ, but both these syntheses were racemic.
Catalytic, asymmetric
General aim is this:
We have now started an Electronic Lab Notebook for the raw data for this specific aspect of the project here. Comments can be left here or there.
Essentially we need to start with literature catalysts for the catalytic, asymmetric Pictet-Spengler reaction. We therefore need to assemble a list of these catalysts here (literature help needed from anyone please!):
1996 Nakagawa
1998 Nakagawa
2004 Jacobsen
2007 Jacobsen
2009 Franzen
2010 Wu et al.
2010 Jacobsen
Need more candidate catalysts!
We are looking for people to help screen known catalysts for the relevant reaction. If your lab has any such catalysts we can send you starting material to screen. Substantial contributors to the project will be invited to be authors on the resulting papers.
Log of labs contacted for help with screening: (Important note: declining a request to participate will never be criticised - people may have very valid reasons for not wanting to participate, or may just be too busy. This log is here purely for record, to stimulate readers to suggest alternative/additional collaborating labs, and to avoid duplication of effort. If you know of a lab working on the asymmetric Pictet-Spengler reaction please feel free to contact them and leave a note of the request here.)
Diastereoselective
Wayne Best of Epichem has suggested an alternative approach based on a PS reaction of a chiral phenylethanolamine. This is an interesting idea, since 1 to 2 (below) might work well with asymmetric induction, and the products resemble PZQ. The use of a chiral starting material, in the generation of some analogue of PZQ that contains an extra stereocentre, could be an interesting project, but it's not clear these analogs would be active. Anyone have a suggestion for a suitable commercially-available chiral starting material? Anyone want to try this?
A chiral auxiliary-mediated PS was reported by Ma et al. (J. Chem. Res. 2004, 2004, 186-187 - paper doesn't seem to have a DOI?) where the key asymmetric step is shown below.
Other examples: Comins 1991
The use of an auxiliary is of course atom-inefficient, however, and likely to be expensive.
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BINOL phosphoric acids
Another class of chiral Broensted acids, which are able to catalyze a Pictet-Spengler cyclisation in an enantioselective manner, are BINOL-phosphoric acids 6.
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Enantioselective Broensted acid-catalyzed reactions with derivatives of those phosphoric acids are one hot spot in recent literature and here are some examples for asymmetric Pictet-Spenger reactions.
2006 List
2008 van Maarseveen, Hiemstra
The problem of the less acidity of the proton donors (compared to sulfonic acids) we are dealing with could be solved by using strong acidic N-triflylphosphoamides 7.
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2006 Yamamoto
2008 Rueping
2009 Nakamura
2010 Rueping
Asymmetric synthesis
Any asymmetric synthesis will probably be expensive. If you are aiming for very large quantities of product this still requires, even at 1 - 5 mol%, lots of catalyst, expensive! And you need to dispose of it from the product, probably to very low levels <10ppm?
The resolution approach should not be discarded, I would go for that route it may be cheaper in the long run.
Traceless auxiliary
Just thinking a bit latterly, what about the idea of using a chiral auxiliary, with a traceless linker, on the benzene ring. There's lots of traceless linker methodology in the solid-phase literature that might be adapated. So for example a silyl group on the benzene ring either chiral itself or with a homochiral substituent... That might be enough to give some asymmetry in the Pictet–Spengler, but even if it didn't the product would be a diastereomeric mix (and hence maybe separable). Then clip off the traceless auxiliary. All just hand-waving of course.
Traceless auxiliary - cost?
Sure, why not. An interesting idea. The auxiliary would need to be close to the site of interest in the transition state. So two comments immediately, now you've stuck your head over the battlements...:
a) Do you know of any example of this kind of auxiliary?
b) Without completely pre-judging the economics, the extra steps involved, as well as a need for a homochiral component that is probably not naturally available, would be negatives to this approach?
What about: 1. PS of
What about:
1. PS of phenylalanine, followed by isolation of appropriate diastereomer
2. Decarboxylation of resulting alpha aminoacid using 2-cyclohexon-1-one (See A)
(A) M. Hashimoto, Y. Eda, Y. Osanai, T. Iwai, and S. Aoki
Chemistry Letters 893-896 (1986)
Decarboxylation idea
That's a neat suggestion. You mean this:
where the cyclization of that acyliminium ion is guided by the stereocentre? Issue: the carboxylic acid would need to be protected during the synthesis of this P-S precursor, right?