Short and Scalable Total Synthesis of Myrioneuron Alkaloids (±)-α,β-Myrifabral A and B

Abstract

The first total synthesis of the Myrioneuron alkaloids (±)-α,β-myrifabral A and B has been accomplished in only four steps from conveniently available starting materials. This short synthesis relied on the use of a key tandem Mannich/amidation reaction to rapidly construct the core framework and two carbon stereocenters. The synthetic route allows for large scale preparation of these promising natural products against the hepatitis C virus (HCV).

Enantioselective Total Synthesis of (–)-Myrifabral A and B

“…1 The first Myrioneuron alkaloids from Myrioneuron nutans were reported in 2002, with altogether 10 structures reported to date. 2 Since 2013, many new alkaloids have been isolated from Myrioneuron faberi, 3 Myrioneuron tonkinesis, 4 and Myrioneuron effusum. 5 In addition to their interesting structural features, a number of of these alkaloids possess a range of biological activities such as antimalarial properties, KB cell cytotoxicity, antimicrobial, and hepatitis C virus (HCV) replication inhibition.…”

“…5 In addition to their interesting structural features, a number of of these alkaloids possess a range of biological activities such as antimalarial properties, KB cell cytotoxicity, antimicrobial, and hepatitis C virus (HCV) replication inhibition. [1][2][3][4][5] Despite possessing promising biological properties and synthetically attractive motifs, relatively few of these alkaloids have been prepared by total synthesis efforts. 2d,e,6 Figure 1.…”

“…We became interested in (±)-myrifabral A (4) and (±)myrifabral B (5) in particular due to their unique cyclohexane fused octahydroquinolizine skeletons which contain four contiguous stereogenic centers, including an all-carbon quaternary center embedded in the cyclohexane fusion. Interestingly, both 4 and 5 are isolated as racemic mixtures of aand b-hydroxy epimers.…”

“…In devising our strategy, we targeted (-)-myrifabral A (4), which can be directly converted to (-)-myrifabral B (5), as reported by She (Scheme 1). 6c Retrosynthetically, we envisioned (-)-myrifabral A (4) could be simplified to tricyclic lactam (6).…”

Four new tetracyclic alkaloids with cis-decahydroquinoline motif from Myrioneuron effusum

“…(Rubiaceae) belong to the category of lysine-based structurally diverse natural products with various polycyclic skeletons (tricyclic-, tetracyclic-, pentacyclic-, hexacyclic-, octacyclic, and decacyclic-type), which have attracted much attention regarding their bioactivity and total synthesis [1][2][3][4][5][6][7][8][9][10][11][12][13]. In the past several years, we have isolated eighteen structurally unique and biosynthetically meaningful Myrioneuron alkaloids, including some with significant antihepatitis C virus (HCV) and antimicrobial activities [7][8][9][10][11][12].…”