Straightforward Access to the Dispirocyclic Framework via Regioselective Intramolecular Michael Addition

Abstract

In this article, an efficient and straightforward protocol for the construction of complex dispirocyclic skeletons via regioselective intramolecular Michael addition is presented. Diverse dispirocyclic compounds were synthesized under mild and transition-metal-free conditions with good to excellent yields. Most stereoisomers were conveniently separated by column chromatography, and their relative configurations were identified by single-crystal X-Ray diffraction of representative compounds. A scale-up experiment validated the practicality of this method. In an in vitro assay, some dispirocyclic compounds exhibited potent cytotoxicity with an IC₅₀ value of 10^-6 mol/L.

Keywords: regioselectivity; spiro compounds; transition-metal free.

Figure 1

Spiro compounds occur in natural products and pharmaceutical molecules.

Figure 2

Regioselective intramolecular Michael addition of quinones to construct dispirocyclic or fused polycyclic skeletons.

Figure 3

Investigation of substrate scope for the naphthoquinone derivatives. Treatment of compound 1 with a catalytic amount of NaOH (0.2 eq.) in a mixture of CH₂Cl₂ and CH₃OH (5:1) at −20 °C. ^a Determined by ¹H NMR. ^b Reaction was completed within 20 min.

Figure 4

Investigation of substrate scope for the indolequinone derivatives. Treatment of compound 4 with a catalytic amount of NaOH (0.2 eq.) in a mixture of CH₂Cl₂ and CH₃OH (5:1) at −20 °C. ^a Determined by ¹H NMR. ^b Reaction was completed within 20 min.