Asymmetric Synthesis of Remotely Chiral Naphthols and Naphthylamines via Naphthoquinone Methides

Quinone methides are well-established
intermediates in
asymmetric
synthesis. In contrast, their extended analogues with the carbonyl
and methide units distributed across two different rings have not
been exploited in asymmetric synthesis. Herein, we achieved the first
asymmetric process involving such intermediates. Specifically, the
use of suitable chiral phosphoric acids enabled in situ generation of 2-naphthoquinone 8-methides and the corresponding
aza counterparts for mild one-pot asymmetric nucleophilic addition.
These processes provided rapid access to a wide range of previously
less accessible remotely chiral naphthols and naphthylamines with
both high efficiency and excellent enantioselectivity. Control experiment
and DFT calculations provided important insights into the reaction
mechanism, which likely involves two phosphoric acid molecules in
the enantiodetermining transition states. This work serves as a proof
of concept for the exploitation of new types of extended quinone methides
as versatile intermediates for asymmetric synthesis, thus providing
a new platform for the efficient construction of remote benzylic stereogenic
centers of aromatic compounds.