Optically Active Flavaglines-Inspired Molecules by a Palladium-Catalyzed Decarboxylative Dearomative Asymmetric Allylic Alkylation

Abstract

With the aid of a class of newly discovered Trost-type bisphosphine ligands bearing a chiral cycloalkane framework, the Pd-catalyzed decarboxylative dearomative asymmetric allylic alkylation (AAA) of benzofurans was achieved with high efficiency [0.2–1.0 mol% Pd2(dba)3/L], good generality, and high enantioselectivity (>30 examples, 82–99% yield and 90–96% ee). Moreover, a diversity-oriented synthesis (DOS) of previously unreachable flavaglines is disclosed. It features a reliable and scalable sequence of the freshly developed Tsuji–Trost–Stoltz AAA, a Wacker–Grubbs–Stoltz oxidation, an intra-benzoin condensation, and a conjugate addition, which allows the efficient construction of the challenging and compact cyclopenta­[b]­benzofuran scaffold with contiguous stereocenters. This strategy offers a new avenue for developing flavagline-based drugs.

Palladium-Catalyzed Asymmetric Trifluoromethylated Allylic Alkylation of Pyrazolones Enabled by α-(Trifluoromethyl)alkenyl Acetates

“…The palladium-catalyzed asymmetric allylic alkylation (AAA) between a nucleophile and an allylic activated substrates is one of the most efficient methods to construct a chiral center in organic chemistry . Various allyl precursors, such as allyl esters, allyl alcohols, and some other propylene derivatives, have been used in the classic reaction.…”

Recent Advances in the Construction of Quaternary Stereocenters via Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation

“…In 2020, the Lu group designed and synthesized a new Trost-type bisphosphine ligand bearing a chiral cycloalkane structure. 47 With this Trost-type ligand L6, they developed a highly efficient Pd-catalyzed dearomative DAAA reaction of benzofurans with 0.2% catalyst loading, and the desired allylation product was generated in up to 96% ee (Scheme 13). Moreover, a diversity-oriented synthesis (DOS) of complex rocaglaol type flavaglines and rocaglamide-type flavaglines was accomplished based on this methodology.…”

Applications of Transition‐Metal‐Catalyzed Asymmetric Allylic Substitution in Total Synthesis of Natural Products: An Update

“…At the final, synthesis of two more flavaglines ( 215 and 216) was completed by the reaction of 3‐ epi ‐ 219 under different conditions (Scheme 42). [170] …”

“…[169] The . [170] The tetracyclic alcohol 220 resultant to the AÀ D system of (À )-gambieric acids A and C was synthesized in a novel, more efficient, and robust fashion in 23 longest linear steps and an overall yield of 1.45 %, calculating from the commercially available tri-O-acetyl-D -glucal. The key step of this approach included the DAAS reaction, which coupled the A-ring fragment 221 to the tricyclic BÀ D fragment 222.…”