Concise Synthesis of a Potential 5-Lipoxygenase Activating Protein (FLAP) Inhibitor and Its Analogs through Late-Stage Alkene Dicarbofunctionalization

Abstract

We report a five-step synthesis of the biologically important 1,1-diarylalkane 1, a potential 5-lipoxygenase activating protein (FLAP) inhibitor that was synthesized previously in 12 steps. In this synthesis, we apply a three-component alkene dicarbofunctionalization reaction as a key final step to assemble the potential FLAP inhibitor 1 from commercially available starting materials. In addition, we also report the synthesis of a variety of new analogs of the inhibitor 1 and its regioisomer.

Multicomponent, Tandem 1,3- and 1,4-Bisarylation of Donor–Acceptor Cyclopropanes and Cyclobutanes with Electron-Rich Arenes and Hypervalent Arylbismuth Reagents

“…Among the different reaction manifolds developed with D–A cyclopropanes, exploration on 1,3-bisfunctionalization to acyclic systems has picked up significantly in recent years . In fact, such functionalization correlates well as a homologous variant of 1,2-difunctionalization process of olefins, which is a highly sought-after area in organic synthesis. , Unarguably, olefin 1,2-carbodifunctionalization to two new C–C bond formation provides a fascinating route for increasing molecular complexity and affords a highly functionalized structure . A similar process, when applied to a cyclopropane ring, would render one-carbon homologated products (Scheme a).…”

Nickel-Catalyzed Dicarbofunctionalization of Alkenes

“…An alkylarylation of vinylarenes combines alkyl halides and arylzinc reagents to form 1,1-diarylalkane products (Table , entry 2) . This reaction has been applied as the final step to assemble a potential inhibitor for the 5-lipoxygenase activating protein (FLAP) . Recently, the scope of the electrophile has been extended to include α-halocarbonyl compounds (Table , entry 3) .…”

“…Recently, hydrofunctionalization and difunctionalization of alkenes have emerged as useful methods with some enantioselective variants . These new reactions have streamlined the preparation of the anti-inflammatory medicine naproxen and a potential inhibitor for the 5-lipoxygenase activating protein (FLAP) …”

Recent developments in nickel-catalyzed intermolecular dicarbofunctionalization of alkenes

“…Giri and coworkers also reported the utility of this method toward the synthesis of FLAP inhibitors. 22 The Brown lab simultaneously reported a 1,2-diarylation of terminal and internal vinyl arenes using 7.5 mol% NiCl 2 with aryl bromides and aryl boronic acid neopentyl glycol esters (ArB(nep)) ( Fig. 6B).…”