Design and De Novo Synthesis of 6-Aza-artemisinins

Abstract

Development of designer natural product variants, 6-aza-artemisinins, enabled us to achieve structural modification of the hitherto unexplored cyclohexane moiety of artemisinin and concise de novo synthesis of the tetracyclic scaffold in just four steps from the modular assembly of three simple building blocks. This expeditious catalytic asymmetric synthetic approach generated lead candidates exhibiting superior in vivo antimalarial activities to artemisinin.

Rapid and Systematic Exploration of Chemical Space Relevant to Artemisinins: Anti-malarial Activities of Skeletally Diversified Tetracyclic Peroxides and 6-Aza-artemisinins

“…Taking into account the SAR studies with skeletally diverse artemisinin analogs 15 – 19 , the second-generation molecular design featuring element implantation on the sp 3 -rich tetracyclic scaffold of 1 was then developed as reported in a previous study . We designed 6-aza-artemisinins by replacing a stereogenic carbon center at the C6 position of 1 with a nitrogen (Figure b).…”

“…First of all, we prepared building blocks bearing either an amino or an aldehyde group based on the reported procedure (Figure ). The amine building blocks 10a/10b were synthesized in two steps from the known sulfonamide 20 with improved yield of 10a . The aldehyde building block 12a was synthesized from commercially available ethyl levulinate ( 21 ) in two steps: Brønsted acid-mediated formation of cyclic ketal and subsequent reduction of the ethyl ester with DIBAL-H.…”

“…The four-step access to the tetracyclic scaffold of 6-aza-artemisinins began with Cu-catalyzed modular assembly of the three building blocks: amine 10a , aldehyde 12a , and commercially available trimethylsilylacetylene 11 (Figure ). To achieve a catalytic asymmetric de novo synthesis, Carreira’s chiral catalyst CuBr/( R , M )-PINAP was employed for Cu­(I)-mediated assembly . In the presence of only 1 mol % of the chiral catalyst and 4 Å molecular sieves in dimethyl carbonate, the three-component assembly underwent smoothly at room temperature to afford the ene-yne 13a in 92% yield with excellent enantioselectivity (93% ee).…”

“…The second approach features modular de novo synthesis of 6-aza-artemisinins (Figure b). Based on the molecular design concept of 6-aza-artemisinins, replacing a sp 3 stereogenic carbon center at the C6 position with a nitrogen revealed in a previous preliminary study, we report herein the development of the concise modular de novo synthetic approach generating substitutional variations at three positions (N6, C9, and C3). Structure–activity relationship (SAR) studies allowed selection of optimum substituents and led to generation of lead candidates exhibiting promising in vivo anti-malarial activities comparable to the natural product, artemisinin ( 1 ), and the semi-synthetic drug, artesunate ( 2 ).…”

Strategy and Problems for Synthesis of Antimalaria Artemisinin (Qinghaosu)

“…Bonepally and coworker recently reported the synthesis of 6‐aza‐artemisinins as an analogous of artemisinin [44] . They developed a catalytic asymmetric process in four steps which is initiated by assembly of PMB, an aldehyde and trimethylsilyl acetylene in presence of CuBr and chiral ligand ( R, M)‐ PINAP (Scheme 11).…”