Diversity Through a Branched Reaction Pathway: Generation of Multicyclic Scaffolds and Identification of Antimigratory Agents

Abstract

A library of 91 heterocyclic compounds composed of 16 distinct scaffolds has been synthesized through a sequence of phosphine-catalyzed ring-forming reactions, Tebbe reactions, Diels–Alder reactions, and, in some cases, hydrolysis. This effort in diversity-oriented synthesis produced a collection of compounds that exhibited high levels of structural variation both in terms of stereochemistry and the range of scaffolds represented. A simple but powerful sequence of reactions thus led to a high-diversity library of relatively modest size with which to explore biologically relevant regions of chemical space. From this library, several molecules were identified that inhibit the migration and invasion of breast cancer cells and may serve as leads for the development of antimetastatic agents.

Diversity through phosphine catalysis identifies octahydro-1,6-naphthyridin-4-ones as activators of endothelium-driven immunity

“…S3) possess the scaffolds derived from the sequence of phosphine-catalyzed annulation, Tebbe methylenation, Diels-Alder reaction, and sometimes hydrolysis (scaffolds s24-s27, s31, s32, and s36 in Scheme 1). As reported earlier (24), tetrahydropyridine s1 and pyrrolidine s2 were formed through the phopshinecatalyzed [4 þ 2] and [3 þ 2] annulation reaction between allenoates and imines (11)(12)(13)(14) and converted into the corresponding ethoxy dienes via Tebbe reaction. The subsequent Diels-Alder reaction of the dienes with maleimides, N-phenyl triazolinedione, and N-sulfonamido arylimines provided multicyclic enol ethers s24, s25/s26, s27, s31, s32, each of which provided 9, 5, 5, 3, and 8 hits out of 10, 12, 5, 9, and 10 compounds, respectively, in confirmatory experiments (Fig.…”

“…At the same time, additional octahydro-1,6-naphthyridine analogs with different functional groups were synthesized in the solution phase (Scheme 3) for the further SAR analysis. The octahydro-1,6-naphthyridin-4-one analogs 11a-11ab with different substituents, Ar, R, Ar′, and R′, were synthesized according to procedures reported previously (Scheme 3A) (24). For the preparation of an octahydronaphthyridinone without the C7 substituent, a previously undescribed sequence of reactions was designed (Scheme 3B).…”

“…A stereoselective hydrolysis of the enol ether group in the Diels-Alder adducts further produced multicyclic ketones s36-s39. The library of 642 compounds of 39 distinctive scaffolds was tested in several bioassays and resulted in the identification of geranylgeranyltransferase type I (GGTase I) inhibitors (25,26), RabGGTase inhibitors (23), and antimigratory compounds (24). These outcomes powerfully demonstrate the premise behind DOS-the more structural diversity in the screening collection, the higher the probability of discovering small-molecule biomodulators.…”

“…The α,β-unsaturated ester functionality in tetrahydropyridine s1, dihydropyrrole s2, and bicyclic succinimide s3 was further utilized in a highly diastereoselective Michael addition of thiols to produce piperidine s21, pyrrolidine s22, and bicyclic succinimide s23 (23). The carbonyl group of the α,β-unsaturated ester was also methylenated using Tebbe reagent to provide alkoxy dienes, which upon exposure to dienophiles (imines, maleimides, triazolinediones, tetracyano ethylene, and benzoquinones) underwent diastereoselective Diels-Alder reaction and produced multicyclic compounds s24-s35 (24). A stereoselective hydrolysis of the enol ether group in the Diels-Alder adducts further produced multicyclic ketones s36-s39.…”

Phosphine catalysis of allenes with electrophiles

“…From this library, several molecules were identified as antimigratory agents of human breast cancer cells. 20 …”