Gram-Scale Synthesis and Crystallographic Characterization of the Trans -Spanning Bisphosphine PhTRAP and Aryl-Modified Analogs

Abstract (S,S)-(R,R)-PhTRAP is a wide-bite-angle chiral bisphosphine initially reported by Ito and co-workers; despite its unique coordination geometry, prior catalytic applications have been largely limited to enantioselective hydrogenation and hydrosilylation. We recently leveraged the unique trans-spanning nature of this ligand in the Pd-catalyzed enantioselective anti-Michael (α-selective) hydroarylation of unsaturated carbonyl compounds. Previously reported syntheses of this ligand employ hygroscopic phosphorus building blocks and sensitive low-valent metal reagents and require hazardous reduction conditions, leading to operational challenges and variable yields. Here we describe an alternative synthesis of PhTRAP employing mild conditions, affording (+)-PhTRAP on a gram scale in 41% yield over four steps from the readily accessible planar-chiral scaffold iodo-Ugi amine. We further apply this synthetic route to access two previously unreported aryl-modified analogs in enantioenriched form, (S,S)-(R,R)-(3,5-Xyl)TRAP and (S,S)-(R,R)-(3,5-C6F2H3)TRAP. We determined the solid-state structures of this series of bisphosphines by X-ray crystallography and discuss the conformational differences across this series.