Ipso-Type Regiocontrolled
Benzannulation for the Synthesis of Uniquely Substituted α‑Arylnaphthalenes:
Application to the First Total Synthesis of Chaihunaphthone
A distinctive method
for synthesizing a variety of multisubstituted
α-arylnaphthalenes utilizing novel regiocontrolled ipso-type [4 + 2] benzannulation is presented. Ortho- and para-substituted 1-Ar1-1-Ar2-2,2-dichlorocyclopropylmethanols (AACM) were transformed
to the corresponding ipso-type α-arylnaphthalenes.
(i) The reaction of ortho-AACM using TiCl4 or SnCl4 (1.0 equiv) proceeded smoothly to afford ipso-type α-arylnaphthalenes (seven examples; 49–69%
yield) exclusively, without producing conventional benzannulation
isomers. (ii) Para-AACM also underwent the reaction
successfully to afford the desired ipso-type α-arylnaphthalenes
(14 examples; 39–98% yield) without producing conventional
benzannulation isomers. (iii) In contrast, meta-AACM
underwent the previously reported conventional benzannulation. (iv)
The present method exhibited sufficient substrate generality for application
to ortho- and para-substituted AACM
substrates bearing Me-, Cl-, and MeO- groups. (v) The six key structures
were unambiguously confirmed by X-ray structure analyses. (vi) A plausible
reaction mechanism for the present ipso-type reaction
is proposed and supported by three careful cross-over and comparable
experiments. To demonstrate the utility of the present reaction, we
achieved the first total synthesis of chaihunaphthone, a uniquely
(highly congested) substituted and less accessible natural lignan
lactone with three contiguous trimethoxy substituents (total eight
steps, overall 6.4% yield).