Oleksandr O. Grygorenko

Bicyclic Conformationally Restricted Diamines

CONTENTS

3-Haloquinolines by Friedländer Reaction of α-Haloketones

A general approach to 3-fluoro-, 3-chloro-, and 3-bromoquinolines which relies on organosilane-promoted Friedländer reaction of α-haloketones is described. The scope of the methylene component as well as influence of the organosilane component on the outcome of the reaction is studied. The method can be used under parallel synthesis conditions.

4-Fluoro-2,4-methanoproline.

The first fluorinated analogue of the naturally occurring 2,4-methanoproline, 4-fluoro-2,4-methanoproline, has been synthesized in five steps from commercially available methyl 2-fluoroacrylate through a photochemical cyclization as a key step in generating a 2-azabicyclo[2.1.1]hexane skeleton.

Approach to the library of fused pyridine-4-carboxylic acids by Combes-type reaction of acyl pyruvates and electron-rich amino heterocycles.

A library of fused pyridine-4-carboxylic acids (including pyrazolo[3,4-b]pyridines, isoxazolo[5,4-b]pyridines, furo[2,3-b]pyridines, thieno[2,3-b]pyridines, and pyrido[2,3-d]pyrimidines) was generated by Combes-type reaction of acyl pyruvates and electron-rich amino heterocycles followed by hydrolysis of the ester. The library members were also demonstrated to undergo the standard combinatorial transformations including amide coupling and esterification, as well as less common heterocyclizations to 1,2,4-triazoles and 1,2,4-oxadiazoles.

Toward lead-oriented synthesis: one-pot version of Castagnoli condensation with nonactivated alicyclic anhydrides.

One-pot variation of Castagnoli condensation, that is, reaction of cyclic anhydrides, amines, and aldehydes, has been developed as a combinatorial approach to 1,2-disubstituted 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids, as well as their benzo-analogues. Utility of the method to multigram preparation of building blocks and synthetic intermediates was also demonstrated. The final products are obtained in high yields and diastereoselectivity. The method fits well in the concept of lead-oriented synthesis; in particular, it can be used for the design of lead-like compound libraries, even if the strictest cut-offs are applied to the physicochemical properties of their members.

Cyclobutane-derived diamines: synthesis and molecular structure.

Cyclobutane diamines (i.e., cis- and trans-1,3-diaminocyclobutane, 6-amino-3-azaspiro[3.3]heptane, and 3,6-diaminospiro[3.3]heptane) are considered as promising sterically constrained diamine building blocks for drug discovery. An approach to the syntheses of their Boc-monoprotected derivatives has been developed aimed at the preparation of multigram amounts of the compounds. These novel synthetic schemes exploit classical malonate alkylation chemistry for the construction of cyclobutane rings. The conformational preferences of the cyclobutane diamine derivatives have been evaluated by X-ray diffraction and compared with the literature data on sterically constrained diamines, which are among the constituents of commercially available drugs.

An entry into hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide derivatives.

Hexahydro-2H-thieno[2,3-c]pyrrole is proposed as a low molecular weight polar scaffold to construct compound libraries used in the search for new drugs. Practical syntheses of derivatives of this bicyclic scaffold were developed, based on [3 + 2] cycloaddition of the ylide generated from N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine and 4-substituted 2,3-dihydrothiophene 1,1-dioxides. All of the 3-substituted hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide derivatives were obtained as single diastereomers. Conformational properties of the hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide derivatives were explored using X-ray diffraction studies. The potential of the scaffold to generate libraries of 3D-shaped molecules was demonstrated.

Conformationally restricted nonchiral pipecolic acid analogues.

Practical syntheses of 2-azabicyclo[3.1.1]heptane-1-carboxylic (2,4-methanopipecolic), 2-azabicyclo[2.2.2]octane-1-carboxylic (2,5-ethanopipecolic), and 9-azabicyclo[3.3.1]nonane-1-carboxylic (2,6-propanopipecolic) acids are reported. The synthetic schemes are short (five, seven, and five steps, respectively) and result in reasonably high yields of the title compounds. The key step in the syntheses is the tandem Strecker reaction and intramolecular nucleophilic cyclization of ketones possessing a leaving group at the delta-position.

Approach to the Library of 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones through a Three-Component Condensation

A convenient procedure for the parallel synthesis of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones through a three-component condensation of active methylene compounds, aldehydes, and amines was developed. It was shown that the use of acetic acid as the reaction medium was suitable for the considerably reactive substrates with no additional functionalities. The substrates with low reactivity and those possessing carboxylic groups or additional basic centers required the use of DMF as the solvent and chlorotrimethylsilane as the reaction promoter was necessary. More than 3000 pyrrolones were synthesized by the developed procedure. To demonstrate the scope of the described approach 114 library representatives were fully characterized.

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.