An oxidopyrylium cyclization/ring-opening route to polysubstituted α-hydroxytropolones

Abstract

α-Hydroxytropolones are a class of molecules with therapeutic potential against several human diseases. However, structure-activity relationship studies on these molecules have been limited due to a scarcity of efficient synthetic methods to access them. It is demonstrated herein that α-hydroxytropolones can be generated through a BCl(3)-mediated ring-opening/aromatization/demethylation process on 8-oxabicyclo[3.2.1]octenes. Used in conjunction with an improved method based on established oxidopyrylium dipolar cycloadditions, several polysubstituted α-hydroxytropolones can be accessed in three steps from readily available α-hydroxy-γ-pyrones.

Figure 1

Examples of bioactive natural α-hydroxytropolones

Scheme 1

General route toward polysubstituted α-hydroxytropolones from commercially available kojic acid

Scheme 2

Established oxidopyrylium cyclization and relevant observations used for reaction optimization

Scheme 3

Substrate studies for oxidopyrylium cyclization ^a Condition A: 2 equiv of N,N-dimethylaniline, CH₂Cl₂, rt. Condition B: 1.2 equiv of N,N-diisopropylaniline, CHCl₃, 100 °C, µwave. Unless otherwise indicated, 20 equiv of alkyne were used. ^b 5 equiv of alkyne were used. ^c Reaction run without solvent.

Scheme 4

Select results comparing BBr₃ and BCl₃ along with crystal structure of α-hydroxytropolone 6a

Scheme 5

Ring-expansion substrate scopea ^a Reactions were run with 7 equiv of BCl₃ unless otherwise noted. Reaction yields are reported following aqueous workup with ratios of 6a–i to 10a–i being calculated by 1H NMR integration. ^b15 equiv of BCl₃ were used.

Scheme 6

Example of homogenizing α-methoxy and α-hydroxytropolone mixture by HBr/AcOH demethylation

Scheme 7

Proposed mechanism