A Three-Step Process to Facilitate the Enantioselective Assembly of Cis-Fused Octahydrophenanthrenes with a Quaternary Stereocenter

Abstract

A three-step process for the enantioselective assembly of cis-fused octahydrophenanthrenes with a quaternary stereocenter is reported. This synthetic strategy relies on a regioselective γ-alkylation, a one-pot sequence of asymmetric hydrogenation and oxidation, and an intramolecular enolate arylation to facilitate the rapid and enantioselective construction of cis-fused octahydrophenanthrene scaffolds with an arylated all-carbon quaternary stereocenter concisely and efficiently.

Aromatic Homo-Nazarov-Type Cyclization of Benzonorcaradienes: Stereoselective Synthesis of Hydrochrysenes

“…However, in the case of 3-methoxybenzoyl substrate 1a with a reactive ortho -position for Friedel–Crafts alkylation, the formation of intermediate 3a was completely interrupted by such alkylation reaction to give hydrochrysene 4a in a 93% yield (Scheme , b). Given the importance of the hydrochrysene and the cis -decalin segments in organic synthesis and bioactive natural products (Scheme , b), this stereoselective reaction cascade may serve as an attractive synthetic method for hydrochrysenes, with the advantages of modularity and simplicity. Interestingly, an unprecedented 1,2-shift of the acylium ions across the heteroaromatic ring occurred in reactions of the 2-heteroaroyl substrates to afford the same products as their 3-heteroaroyl analogues, which is indicative of a ring-opening/Friedel–Crafts alkylation sequence for the aromatic homo-Nazarov-type cyclization of in situ formed benzonorcaradienes.…”

Total Synthesis of the Alleged Structure of (+)-Fimbricalyxoid A

“…Furthermore, it shows significant cytotoxicity against human tumor cell lines, and its structure and absolute configuration are established by only NMR and ECD calculation . As part of our ongoing efforts to develop highly efficient asymmetric hydrogenations for the enantioselective synthesis of bioactive natural products, we have recently developed a three-step process for the rapid and enantioselective construction of cis- A/B-ring-fused tricyclic structures and completed the syntheses of a series of cis -fused octahydrophenanthrenes (Figure b). Encouraged by this work, we then embarked on a journey to the total synthesis of (+)-fimbricalyxoid A ( 4 ) (Figure c).…”

“…Because only moderate enantioselectivity (80% ee) was observed by catalyst ( R )- 10a in the asymmetric hydrogenation step of our previous synthetic protocol, our study began by screening the chiral iridium catalysts ( R )- 10 for the hydrogenation of enone 12 (Scheme ). Under the established reaction conditions [0.2 mol % ( R )- 10 , 10 mol % t BuOK at room temperature, and 10 atm of H 2 in EtOH/CH 2 Cl 2 ], a series of iridium catalysts ( R )- 10a–e available in our laboratory were evaluated .…”

“…The results showed that catalyst ( R )- 10 with a substitute at position 4 of the pyridine ring exhibited higher enantioselectivity, and 94% ee was observed by catalyst ( R )- 10e bearing a 4-(2,6-dimethylphenyl) group on the pyridine ring. With product (+)- 12 obtained by using catalyst ( R )- 10e at hand, (+)- 6 was successfully synthesized in 87% yield with 96% ee through a palladium-catalyzed intramolecular enolate arylation according to our previous protocol …”

“…With product (+)-12 obtained by using catalyst (R)-10e at hand, (+)-6 was successfully synthesized in 87% yield with 96% ee through a palladium-catalyzed intramolecular enolate arylation according to our previous protocol. 11 Subsequently, we started the enantioselective total synthesis toward (+)-fimbricalyxoid A ( 4) from (+)-6 via functional modification of the A-ring (Scheme 3). Accordingly, we initially intended to complete the introduction of an oxygen functionality at position C3 of the A-ring via enone epoxidation and Wharton oxygen transposition reaction.…”