New avenues for asymmetric synthesis: N–H (+)-sparteine and analogues

Sparteine, a naturally occurring chiral N-centered diamine, has been employed as a useful chiral ligand in numerous synthetic transformations, but due to a shortage of accessible intermediates, its modification, development and utility have stalled. Herein we report the synthesis and assessment of a Sparteine-related (+)- N –H diamine L4 on a 100-g scale, commencing from (−)-cytisine. The performance of the (+)- N –H diamine is benchmarked against sparteine (and N –Me sparteine) across a range of 60 hydroarylation reactions, demonstrating an average improvement of 20 ​% yield and 20 ​% ee . The diamine L4 is also demonstrated competent in a variety of other asymmetric metal- and organo-catalyzed processes. In particular, L4 enables asymmetric catalysis in a pure aqueous phase under ambient to reflux conditions and aerobic atmosphere, exhibiting excellent enantioselectivity and operational simplicity, which highlights its industrial applicability. A divergent synthesis strategy to enantiomeric analogues of the (+)- N –H diamine scaffold is reported. The improved performance of these systems is explored using quantum mechanical calculations, shedding light on the causes of enantioselectivity of ligand-controlled reactions. We anticipate that further investigation into this scaffold will pave the way for the development of other catalysts for important but challenging stereoselective processes. Semi-synthesis of a Sparteine-related N-H diamine L4 on hundred-gram scale from (−)-cytisine is reported. This diamine L4 outperforms Sparteine analogue in hydroarylation reactions with up to 99 ​% yield and 98 ​% ee . Its versatility is shown in diverse asymmetric metal- and organo-catalyzed reactions. Quantum calculations reveal enhanced enantioselectivity mechanisms. Further exploration of this diamine scaffold would advance asymmetric catalysis field.