William P. Unsworth

Synthesis of Spirocyclic Indolenines.

This Review provides an in-depth account of the synthesis of spirocyclic indolenines. Over the last 77 years, a wide array of diverse synthetic methods has been developed in order to generate these synthetically useful and biologically important spirocyclic scaffolds. The main synthetic strategies discussed are grouped into three main categories, namely interrupted Fischer indolisations, dearomatisation reactions of indoles and condensation reactions. The historical background, common synthetic challenges, current state-of-the-art and future perspectives of this field are examined.

Direct imine acylation: rapid access to diverse heterocyclic scaffolds.

A simple and efficient procedure to prepare a range of diverse heterocycles by the direct acylation of imines using a variety of functionalized benzoic acids is described. The methodology features a novel method for N-acyliminium ion generation followed by in situ intramolecular trapping by oxygen-, nitrogen-, sulfur- and carbon-based nucleophiles. Preliminary mechanistic studies, using ReactIR, are also reported.

Silver(I)- or copper(II)-mediated dearomatization of aromatic ynones: direct access to spirocyclic scaffolds.

A high-yielding silver(I)- or copper(II)-catalyzed dearomatizing spirocyclization strategy allows the conversion of simple aromatic compounds that contain ynone substituents, including indole, anisole, pyrrole, and benzofuran derivatives, into functionalized spirocyclic scaffolds. A high-yielding asymmetric variant furnishes spirocyclic indolenines in up to 89:11 e.r.

Silver(I)-Catalyzed Dearomatization of Alkyne-Tethered Indoles: Divergent Synthesis of Spirocyclic Indolenines and Carbazoles

A high-yielding, divergent approach to generate either spirocyclic indolenines or carbazoles from a common indole-tethered propargyl alcohol precursor is described, with mechanistic insight provided. Either product can be obtained upon treatment with different Ag(I) catalysts at rt. An unexpected hydration reaction to afford (±)-actinopolymorphol B is also reported.

Catalyst-Driven Scaffold Diversity: Selective Synthesis of Spirocycles, Carbazoles and Quinolines from Indolyl Ynones.

Abstract Medicinally relevant spirocyclic indolenines, carbazoles and quinolines can each be directly synthesised selectively from common indolyl ynone starting materials by catalyst variation. The high yielding, divergent reactions all proceed by an initial dearomatising spirocyclisation reaction to generate an intermediate vinyl–metal species, which then rearranges selectively by careful choice of catalyst and reaction conditions.

Total Synthesis of Spirobacillene A

The first total synthesis of spirobacillene A, an indole alkaloid isolated from Lysinibacillus fusiformis, is reported. A Lewis acid mediated spirocyclization of an anisole derivative onto a tethered ynone was used as a key step, drawing inspiration from a potential biosynthesis of the natural product.

Stereospecificity in the Au-catalysed cyclisation of monoallylic diols. Synthesis of (+)-isoaltholactone.

We describe a concise synthesis of (+)-isoaltholactone via a Au-catalysed cyclisation of a monoallylic diol to form the tetrahydrofuranyl ring. Analogous cyclisations show that the stereochemical outcome is dictated by the stereochemistry of the diol substrate.

From Heteroaromatic acids and Imines to Azaspirocycles : Stereoselective Synthesis and 3D Shape Analysis

Abstract Heteroaromatic carboxylic acids have been directly coupled with imines using propylphosphonic anhydride (T3P) and NEt(iPr)2 to form azaspirocycles via intermediate N‐acyliminium ions. Spirocyclic indolenines (3H‐indoles), azaindolenines, 2H‐pyrroles and 3H‐pyrroles were all accessed using this metal‐free approach. The reactions typically proceed with high diastereoselectivity and 3D shape analysis confirms that the products formed occupy areas of chemical space that are under‐represented in existing drugs and high throughput screening libraries.

Silica‐Supported Silver Nitrate as a Highly Active Dearomatizing Spirocyclization Catalyst: Synergistic Alkyne Activation by Silver Nanoparticles and Silica

Silica-supported AgNO3 (AgNO3 -SiO2 ) catalyzes the dearomatizing spirocyclization of alkyne-tethered aromatics far more effectively than the analogous unsupported reagent; in many cases, reactions which fail using unsupported AgNO3 proceed effectively with AgNO3 -SiO2 . Mechanistic studies indicate that this is a consequence of silver nanoparticle formation on the silica surface combined with a synergistic effect caused by the silica support itself. The remarkable ease with which the reagent can be prepared and used is likely to be of much synthetic importance, in particular, by making nanoparticle catalysis more accessible to non-specialists.

Selective Synthesis of Six Products from a Single Indolyl α-Diazocarbonyl Precursor

Indolyl α-diazocarbonyls can be selectively cyclized to give six distinct products through the careful choice of catalyst and reaction conditions. A range of catalysts were used, including complexes of Rh(II) , Pd(II) , and Cu(II) , as well as SiO2 , to promote diazo decomposition and subsequent cyclization/rearrangement through a range of mechanistic pathways.