Fluorous Parallel Synthesis of a Piperazinedione-Fused Tricyclic Compound Library

Abstract

A fluorous-linker-assisted solution-phase protocol has been developed and applied to parallel synthesis of a piperazinedione-fused tricyclic compound library. The one-pot [3 + 2] cycloaddition of fluorous amino esters, aldehydes, and maleimides afforded bicyclic proline derivatives. The intermediates were subjected to N-acylation with chloroacetyl chloride, followed by displacement reactions with amines. Linker cleavage with concomitant lactamization yielded the final products. Microwave heating was employed to facilitate several reaction steps and fluorous solid phase extraction (F-SPE) was employed to purify the intermediates. During the method development, a small library containing sixteen analogs was prepared. The optimized conditions were applied to the synthesis of a production library containing ninety analogs.

Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2009

“…In a joint work conducted by the Werner and the Zhang groups, fluorous amino esters 184 were used for solution-phase parallel synthesis of novel piperazinedione-fused tricyclic library compounds 189 (Figure 17). 328 The compounds are structurally similar to the tricyclic thrombin inhibitors and diketopiperazine-based inhibitors of human hormone-sensitive lipase. At the first library synthesis step, azomethine ylides generated from 184 and aldehydes 185 underwent microwave-assisted 1,3-dipolar cycloadditions with maleimides to form 186 in stereoselective fashion.…”

“…289 and substituted pyrimidines via a 3-component reaction; 158 and (d) fluorous technology: displaceable fluorous dihydropyran 322 and isonnitrile linkers, 327 fluorous synthesis of 1,4-benzodiazepine-2,5-dione, 327 piperazinedion-fulsed tricyclic 328 compound libraries and a fluorous mixture synthesis of natural product resorcyclic acid lactone library. 329 …”

Microwave Multicomponent Synthesis

“…A fluorous synthesis was developed [ 43 ] involving a three-component one-pot [3+2] cycloaddition of fluorous amino esters, aldehydes and maleimides with MW irradiation yielded bicyclic proline products ( Scheme 42 ) which were transformed by acylation, nucleophilic substitution and lactamization reactions to deliver a 90 member library piperazinedione-fused tricyclic analogues.…”

Comprehensive Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2008

“…328 Fluorous amino esters are useful linkers for library synthesis. In a joint work conducted by the Werner and the Zhang groups, fluorous amino esters 184 were used for solution-phase parallel synthesis of novel piperazinedione-fused tricyclic library compounds 189 ( Figure 17).…”