Organocatalytic desymmetrisation reactions involving prochiral or meso compounds are powerful ways to introduce multiple stereocentres into a molecule with high enantioselectivity. Many impressive advances have been made in this area over the past few decades.

Cyclohexadienone is a commonly used substrate for such desymmetrisation reactions, as it can undergo a Michael addition reaction with a pronucleophile. A cyclohexadienone with a pendant carbon pronucleophile can undergo an intramolecular reaction, forming a bicyclic system with three contiguous stereogenic centres. There has been a growing interest in such reactions, as existing methods have mostly involved aldehydes or heteroatoms as pronucleophiles, and using high pK_a pronucleophiles such as amides for these reactions has remained a challenge.

In 2013, the Dixon group disclosed a new class of chiral organocatalysts, termed bifunctional iminophosphorane (BIMP) catalysts due to their ability to function both as a superbase and a hydrogen bond donor. Prepared in situ in a Staudinger reaction with a chiral azide and a trivalent phosphine, these catalysts have been proven over the years to be effective in various enantioselective Michael addition reactions, including challenging sulfa-Michael additions.

With an amide-based BIMP catalyst, we have achieved the formation of bicyclic enantioenriched oxindole derivatives using amide-tethered cyclohexadienones in high yields, diastereomeric ratios and enantiomeric excesses of up to 93%, which can be increased to 99% after recrystallisation. We have expanded the substrate scope with variations at 3 different positions on the substrate, with around 20 examples. With a gram-scale synthesis of a substrate, we have also performed a series of transformations on this product to demonstrate its synthetic utility.

BIMP catalysed desymmetrisation of amide-tethered cyclohexadienones

Ying Xuan Charmaine Poh

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