[Seanlet]

I have just read the fantastic paper on the simplified synthesis of sertraline which uses the insolubility of the imine to drive the ketone<->imine reaction to the right. No need for a dehydrating agent, no toxic byproducts.

I'm seriously looking for extra credits and rather than the complex chiral hydrogenation catalysts, it looks like L-selectride is the only chiral complex metal hydride for imine->amine reductions. Then a thought struck me - sodium triacetoxyborohydride l reduce ketimines BUT has anyone researched the use of other sodium borohydride derivatives to make chiral reducing agents? Quite a few natural carboxylic acids are chiral - lactic acid being one example? L-proline maybe?

I know benzoic acid has been substituted for acetic acid but that isn't chiral.

With it being a benzylic ketimine, it would require something both small & chiral - hence the idea of lactic acid (I also guess it's pretty soluble in the ethanol they use as solvent).

If this is just stupid - please be blunt and tell me so - it's 12:20AM here in the UK and I need to sleep. Thanks for reading.

[Dan]

Not a stupid idea at all.

Conceptually sound - chiral boranes, such as (Ipc)₂BH, have been used for asymmetric hydroboration for many years now. There was just recently a very cool paper in JACS using catalytic chiral boranes for asymmetric imine reduction with H₂, definitely worth a read:

J. Am. Chem. Soc. 2013, 35, 6810–6813

I am not aware of any chiral metal boron hydrides that have been successfully applied as stoichiometric chiral reducing agents. I think L-Selectride is sold as the racemate by the way. In principle it should be possible, however the fashion these days is for catalytic processes that generate less waste and do not require stoichiometric enantiopure ligands (which are often expensive) - there are a number of catalytic asymmetric reduction methods with transition metal hydrides.

[Seanlet]

Many thanks Dan. Is that a chiral catalyst I see on the first page? I was attempting to figure out a way where the actual hydride is chiral so that no catalyst is required. What do you think of:

Paper Asymmetric syntheses. Part 2. Reduction of ketones with chiral sodium borohydride-lactic acid derivative systems
Giorgio Bianchi,   Fiorella Achilli,   Anna Gamba and    Dina Vercesi 
J. Chem. Soc., Perkin Trans. 1, 1988, 417-422
DOI: 10.1039/P19880000417

They only claim a 38.3%ee but, if applied to the synthesis of sertraline, it could potentially reduce costs. Also, while sodium triacetoxyborohydride has very poor solubility in almost all solvents so I wonder if those 3 extra -OH groups would make it soluble in the ethanol used in that cool Green Chemistry route. OK, the imine is insoluble in ethanol, but will a dissolved reducing agent still work on the surface?

I REALLY appreciate your input. I slept 4 hours and used Reaxys, which misses SO much stuff and I will rind my buddy at a different uni where they have SciFinder to see what he can dig up.

Wouldn't it be great if we could knock off another 20% off the production costs for sertraline - just on this board ;-)