Fig. 1: Challenges in the construction of C2-symmetric axially spirocyclic scaffolds.
From: Bis-indole chiral architectures for asymmetric catalysis
A The key synthesis step of forming spirocyclic architectures from phenol and naphthol is fundamentally challenging due to inherent site selectivity and low reactivity. These issues often require additional steps, such as employing directing group strategies and using large amounts of hazardous acids. B Strategies to achieve intramolecular spirocyclization of phenols include (i) Enhanced reactivity observed with ketals, (ii) A strategy involving 2-naphthol rather than phenol, (iii) Spirocyclization using Ir-catalyzed pre-formed chiral ketones, and (iv) Spirocyclization employing Rh-catalyzed pre-formed chiral ketones. C The construction of 1,1’-spirobisindane-6,6’-diols has also been explored by rearranging bisphenols formed via the condensation of phenols and acetone under acidic conditions. D Construction of Spiro-bisindoles with strategies as applied to SPINOLs. E In this work, a simpler approach is introduced using a confined chiral Brønsted acid-catalyzed process with readily available and inexpensive indole and acetone. This method provides a direct route to C2-symmetric spirocycles, addressing the thermodynamic challenges of bis-indole structures, as demonstrated by relative energy data.
