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Ipso -Type Regiocontrolled Benzannulation for the Synthesis of Uniquely Substituted α-Arylnaphthalenes: Application to the First Total Synthesis of Chaihunaphthone.

ABSTRACT: 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).

SUBMITTER: Moriguchi K

PROVIDER: S-EPMC8296562 | biostudies-literature |

REPOSITORIES: biostudies-literature

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