1,2-Disubstituted bicyclo[2.1.1]hexanes as saturated bioisosteres of ortho-substituted benzene.

Bicyclo[2.1.1]hexanes have been synthesized, characterized, and biologically validated as saturated bioisosteres of the ortho-substituted benzene ring. The incorporation of the 1,2-disubstituted bicyclo[2.1.1]hexane core into the structure of fungicides boscalid (BASF), bixafen (Bayer CS), and fluxapyroxad (BASF) gave saturated patent-free analogs with high antifungal activity.

2-Oxabicyclo[2.1.1]hexanes as saturated bioisosteres of the ortho-substituted phenyl ring.

The ortho-substituted phenyl ring is a basic structural element in chemistry. It is found in more than three hundred drugs and agrochemicals. During the past decade, scientists have tried to replace the phenyl ring in bioactive compounds with saturated bioisosteres to obtain novel patentable structures. However, most of the research in this area has been devoted to the replacement of the para-substituted phenyl ring. Here we have developed saturated bioisosteres of the ortho-substituted phenyl ring with improved physicochemical properties: 2-oxabicyclo[2.1.1]hexanes. Crystallographic analysis revealed that these structures and the ortho-substituted phenyl ring indeed have similar geometric properties. Replacement of the phenyl ring in marketed agrochemicals fluxapyroxad (BASF) and boscalid (BASF) with 2-oxabicyclo[2.1.1]hexanes dramatically improved their water solubility, reduced lipophilicity and most importantly retained bioactivity. This work suggests an opportunity for chemists to replace the ortho-substituted phenyl ring in bioactive compounds with saturated bioisosteres in medicinal chemistry and agrochemistry.

Bicyclic Piperidines via [2 + 2] Photocycloaddition.

A synthetic strategy to fused bicyclic piperidines-building blocks for medicinal chemistry-is developed. The key step was an intramolecular [2 + 2]-photocyclization. The photochemical step was performed on a gram scale. Crystallographic analysis of the obtained compounds revealed that they occupy a novel chemical space and can be considered as elongated analogues of 3-substituted piperidines.

Saturated Bioisosteres of ortho-Substituted Benzenes.

Saturated bioisosteres of ortho-disubstituted benzenes (bicyclo[2.1.1]hexanes) were synthesized, characterized and validated. These cores were incorporated into the bioactive compounds Valsartan, Boskalid and Fluxapyroxad instead of the benzene ring. The saturated analogues showed a similar level of antifungal activity compared to that of Boskalid and Fluxapyroxad.

Convenient Access to Conformationally Rigid Sultams.

Synthesis of the previously unknown conformationally rigid sultams fused with the cyclobutane ring was developed. The key transformation was an intramolecular photochemical cyclization of linear sulfonamides. Crystallographic analysis showed that the obtained structures populated the uncharted region in the chemical space.

[2+2]-Photocycloaddition of N-Benzylmaleimide to Alkenes As an Approach to Functional 3-Azabicyclo[3.2.0]heptanes.

A one-step synthesis of functionalized 3-azabicyclo[3.2.0]heptanes by [2+2]-photochemical intermolecular cycloaddition of N-benzylmaleimide to alkenes was elaborated. The obtained compounds were easily transformed into the bi- and tricyclic analogues of piperidine, morpholine, piperazine, and GABA, which are advanced building blocks for drug discovery.

Photochemical Synthesis of 2-Azabicyclo[3.2.0]heptanes: Advanced Building Blocks for Drug Discovery. Synthesis of 2,3-Ethanoproline.

Intramolecular photochemical [2 + 2]-cyclization of acetophenone enamides gave 2-azabicyclo[3.2.0]heptanes, advanced building blocks for drug discovery. Synthesis of a conformationally restricted analogue of proline, 2,3-ethanoproline, was performed.

Photochemical Synthesis of 3-Azabicyclo[3.2.0]heptanes: Advanced Building Blocks for Drug Discovery.

We have developed a rapid two-step synthesis of substituted 3-azabicyclo[3.2.0]heptanes which are attractive building blocks for drug discovery. This new method utilizes very common chemicals, benzaldehyde, allylamine, and cinnamic acid, via intramolectular [2+2]-photochemical cyclization.

3-Benzyl-3-azabicyclo[3.1.1]heptan-6-one: a promising building block for medicinal chemistry.

An efficient two-step multigram synthesis of the previously unknown 3-benzyl-3-azabicyclo[3.1.1]heptan-6-one is described. The compound is shown to be a promising building block for further selective derivatization of the cyclobutane ring providing novel conformationally restricted piperidine derivatives.