Stereodivergent Total Synthesis of Tacaman Alkaloids

This paper describes a concise, asymmetric and stereodivergent total synthesis of tacaman alkaloids. A key step in this synthesis is the biocatalytic Baeyer-Villiger oxidation of cyclohexanone, which was developed to produce seven-membered lactones and establish the required stereochemistry at the C14 position (92 % yield, 99 % ee, 500 mg scale). Cis- and trans-tetracyclic indoloquinolizidine scaffolds were rapidly synthesized through an acid-triggered, tunable acyl-Pictet-Spengler type cyclization cascade, serving as the pivotal reaction for building the alkaloid skeleton. Computational results revealed that hydrogen bonding was crucial in stabilizing intermediates and inducing different addition reactions during the acyl-Pictet-Spengler cyclization cascade. By strategically using these two reactions and the late-stage diversification of the functionalized indoloquinolizidine core, the asymmetric total syntheses of eight tacaman alkaloids were achieved. This study may potentially advance research related to the medicinal chemistry of tacaman alkaloids. The asymmetric total synthesis of eight tacaman alkaloids was accomplished. A chemoenzymatic Baeyer-Villiger reaction was used to produce seven-membered lactones, establishing a stereogenic center at the C14 position. Acid-regulated cyclization cascades involving the Pictet-Spengler reaction afforded cis- and trans-fused tetracyclic cores. DFT calculations indicated that the stereochemistry of this cascade was controlled via hydrogen bonding. image