Asymmetric synthesis of N-bridged [3.3.1] ring systems by phosphonium salt/Lewis acid relay catalysis

Abstract

Optically pure pseudo-natural products (PNPs), particularly exemplified by azabicyclo[3.3.1]nonane molecules and their analogs provide an attractive platform for structure−activity relationship studies, and also lead new compound discovery in drug development. However, there are currently no examples of guiding catalytic asymmetric strategies available to construct such important PN-scaffolds, thus limiting their broad use. Here, we report a general and modular method for constructing these pseudo-natural N-bridged [3.3.1] ring systems via cascade process by bifunctional phosphonium salt/Lewis acid relay catalysis. A wide variety of substrates bearing an assortment of functional groups (59 examples) are compatible with this protocol. Other features include a [3 + 2] cyclization/ring-opening/Friedel-Crafts cascade pathway, excellent reactivities and stereoselectivities, easily available starting materials, step economy and scalability. The obtained enantioenriched products showed potential of preliminary anticancer activities. Insights gained from our studies are expected to advance general efforts towards the catalytic synthesis of challenging even unprecedented chiral PNPs, offering new opportunities for bioactive small-molecule discovery.

Enantioselective Synthesis of Atropisomeric Biaryl Phosphorus Compounds by Chiral‐Phosphonium‐Salt‐Enabled Cascade Arene Formation

“…In connection to our previous findings, [16c–g] we also believed that the hydrogen‐bonding interactions as well as ion‐pair activation contributed significantly to the asymmetric induction for this cascade reaction. In this context, we carried out studies to demonstrate its importance.…”

“…The idea of constructing arene rings with axial chirality by organocatalysis through a one‐pot operation was very appealing to us, we were mindful that these molecules are inherently synthetic challenging and additionally such cascade procedure has never been disclosed so far. We reasoned that our highly tunable multifunctional phosphonium halide catalysts, particularly which possess semi‐enclosed cavities and also have fascinating electrostatic potentials (ESPs) with an electropositive region [16d,g] may be able to address the reactivity and selectivity issues towards controlling the chemo‐ and enantioselectivities of this novel cascade process, providing an intriguing but not available cascade strategy for accessing atropisomeric biaryl phosphorus molecules. In response to this assumption, herein, we disclose the first organocatalytic enantioselective cascade reaction involving formal [4+2] cycloaddition, oxidative hydroxylation, and aromatization via central‐to‐axial chirality conversion, providing novel and facile access to valuable axially chiral biaryl monophosphorus compounds in high stereoselectivity.…”

Design and Application of Peptide‐Mimic Phosphonium Salt Catalysts in Asymmetric Synthesis

“…[32] Inspired by acid-promoted retro-Mannich fragmentations, [33] we developed the first catalytic asymmetric protocol for the synthesis of chiral pseudo-natural N-bridged [3.3.1] ring systems via a novel [3 + 2] cyclization/ring-opening/Friedel-Crafts cascade reaction by APS/Lewis acid relay catalysis (Scheme 7A). [34] With this methodology, consistently high enantiomeric excesses and yields could be obtained over a wide range of commonly available indole-based α,β-unsaturated ketones and sixmembered cyclic azomethine ylides under mild reaction conditions. Computational analysis revealed the origin of this ring expansion, wherein Lewis acids, such as BF 3 •Et 2 O, could promote the intramolecular retro-Mannich reaction of the chiral pseudo-[5 + 2] adducts, followed by a Friedel-Crafts-type process to afford the desired eight-membered Nbridged ring products without any loss of the stereoselectivities.…”

Enantioselective Synthesis of Atropisomers by Oxidative Aromatization with Central-to-Axial Conversion of Chirality

“…Recently, in 2022, Wang and co-workers employed an asymmetric thiourea-based phosphonium salt dual catalyst 117 in a cascade procedure for the atroposelective synthesis of aminophosphine-type ligands 116 ( Scheme 27 ) [ 145 ]. This represents the first report on the use of such a dual catalyst in a central-to-axial chirality conversion, although the same group already employed it in other catalytic cyclizations [ 146 ] as well as for the synthesis of atropisomeric biaryls via kinetic resolution [ 147 ]. In this case, the reaction between a nitroolefin 111 and a substituted 2-(3,4-dihydronaphthalen-1(2H)-ylidene)malononitrile 112 provided a chiral intermediate 113 containing four rings.…”