Synthesis of a Retinoic Acid Receptor Agonist

Key words

retinoic acid receptor agonist - nickel-catalyzed cross-coupling - α-(methylthio)acetate esters - dimethylzinc

Significance

The target molecule I is a retinoic acid receptor γ (RARγ) agonist that is of interest for the treatment of acne, psoriasis and melanoma. The synthesis depicted features the first nickel-catalyzed stereospecific Negishi alkyl–alkyl cross-coupling reaction of secondary benzylic α-(methylthio)acetate esters with dimethylzinc.

Comment

The mild reaction conditions are compatible with a variety of functional groups including alkenes, protected alkynes, acetals, and esters. Heterocycles, amines, and imides are also well tolerated. Cross-coupling with diethylzinc is also possible but the reaction is more complex owing to additional competitive reaction pathways.