Three-Component Betti Condensation for Synthesis of Aminomethylnaphthols Incorporating Deoxy-isoequilenine Scaffold-Absolute Configuration and Application

Chiral aminomethylnaphthols have been prepared highly diastereoselective by means of three-component `Betti condensation, using steroidal 2-naphthol analogue, synthesized from estrone. The use of 2-methoxybenzaldehyde or 2-pyridinecarboxaldehyde as aldehyde component and (S)-(-)-1-phenylethan-1-amine or (S)-(-)-1-(naphthalen-2-yl)ethan-1-amine, as chiral non-racemic amine component providing the diastereoselectivity, allowed the synthesis of structurally diverse aminomethylnaphthols. The latter easily form 1,3-dihydronaphthoxazines through reaction with formaldehyde. The absolute configurations of the new aminomethylnaphthols synthesized have been determined through advanced nuclear magnetic resonance (NMR) experiments and confirmed by X-ray crystallography. The chiral steroidal aminomethylnaphthols obtained as pure diastereoisomers have been evaluated as pre-catalysts in the enantioselective addition of diethylzinc to aldehydes with enantioselectivities of up to 97% ee.

Automated summary

Chiral aminomethylnaphthols have been synthesized using steroidal 2-naphthol analogue prepared from estrone via three-component `Betti condensation. By choosing appropriate aldehyde and chiral amine components, structurally diverse aminomethylnaphthols could be obtained. The absolute configurations of the synthesized aminomethylnaphthols were determined using advanced NMR experiments and confirmed by X-ray crystallography. These chiral steroidal aminomethylnaphthols showed good catalytic activity in the enantioselective addition of diethylzinc to aldehydes.