Enantio‐ and Diastereodivergent Synthesis of Spirocycles through Dual‐Metal‐Catalyzed [3+2] Annulation of 2‐Vinyloxiranes with Nucleophilic Dipoles

Abstract

The development of efficient and straightforward methods for obtaining all optically active isomers of structurally rigid spirocycles from readily available starting materials is of great value in drug discovery and chiral ligand development. However,t he stereodivergent synthesis of spirocycles bearing multiple stereocenters remains an unsolved challenge owing to steric hindrance and ring strain. Herein, we report an enantioand diastereodivergent synthesis of rigid spirocycles through dual-metal-catalyzed [3+ +2] annulation of oxy p-allyl metallic dipoles with less commonly employed nucleophilic dipoles (imino esters). Aseries of spiro compounds bearing apyrroline and an olefin were easily synthesized in an enantio-and diastereodivergent manner (up to 19:1 dr, > 99 %e e), which showed great promise as an ew type of N-olefin ligand. Preliminary mechanistic studies were also carried out to understand the process of this bimetallic catalysis.

Nickel/Copper‐Cocatalyzed Asymmetric Benzylation of Aldimine Esters for the Enantioselective Synthesis of α‐Quaternary Amino Acids

“…Following our long‐standing interest in bimetallic catalysis, [2i, 3a,d,f,g,i,j] we envisaged the combination of the chiral Cu catalyst and the chiral Ni catalyst would realize the asymmetric benzylation of Schiff base activated amino acids (Scheme 1C). This benzyl substituted quaternary amino acid is ubiquitous in bioactive molecules (Figure 1).…”

Regio‐ and Enantioselective γ‐Allylic Alkylation of In Situ‐Generated Free Dienolates via Scandium/Iridium Dual Catalysis

“…Brønsted acids (trifluoroacetic acid, 4-chlorobenzoic acid) were evaluated as well, but failed to afford the target product 3 a (Table S2 in Supporting Information). Further screening of different solvents (entries [14][15][16][17][18] uncovered that tetrahydrofuran (THF) was optimal for the generation of the product 3 a in good yield (76 %) with excellent enantiopurity (97 % ee). Lowering the reaction temperature to 25 °C or 0 °C (entries 19 and 20) led to a slight decrease of the yields and did not affect the enantioselectivities.…”

“…reactions, vinyloxiranes usually undergo the oxidative addition producing π‐allyl‐TM species. Obviously, the potential Ir‐activated oxidative addition [17a,b] of vinyloxiranes would seriously disturb the generation of dienolates in this scenario. We hoped that using the appropriate Lewis acid could avoid this side pathway, leading to the exclusive chemoselectivity.…”

“…However, in common TM-catalyzed (Pd, [15] Rh, [16] Ir etc. [17] ) reactions, vinyloxiranes usually undergo the oxidative addition producing π-allyl-TM species. Obviously, the potential Ir-activated oxidative addition [17a,b] of vinyloxiranes would seriously disturb the generation of dienolates in this scenario.…”

Stereodivergent Desymmetrization of Simple Dicarboxylates via Branch‐Selective Pd/Cu Catalyzed Allylic Substitution

“…Recently, stereodivergent synthesis has gained significant attention in asymmetric catalysis [18] . Several types of catalytic model have been reported, including metal‐organo systems, [19] bimetallic systems, [12a,b,e,g,h,i,k,l,17b,20] and organo‐organo systems [21] . These elegant strategies provide tools to obtain all of the stereoisomers of one molecule by only changing the configurations of two chiral ligands.…”