Symmetry-Driven Total Synthesis of Myrioneurinol

Abstract

We report a total synthesis of the Myrioneuron alkaloid myrioneurinol enabled by the recognition of hidden symmetry within its polycyclic structure. Our approach traces myrioneurinol’s complex framework back to a symmetrical diketone precursor, a double reductive amination of which forges its central piperidine unit. By employing an inexpensive chiral amine in this key desymmetrizing event, four stereocenters of the natural product including the core quaternary stereocenter are set in an absolute sense, providing the first asymmetric entry to this target. Other noteworthy strategic maneuvers include utilizing a bicyclic alkene as a latent cis-1,3-bis­(hydroxymethyl) synthon and a topologically controlled alkene hydrogenation. Overall, our synthesis proceeds in 18 steps and ∼1% yield from commercial materials.

Synthetic Studies toward the Myrioneuron Alkaloids

“…The most recent synthesis of myrioneurinol (3) was reported in 2022 by our own group (Scheme 12). 15 Our approach is distinct from these earlier syntheses, exploiting hidden symmetry…”

“…Under acidic conditions a key retro-Mannich The most recent synthesis of myrioneurinol (3) was reported in 2022 by our own group (Scheme 12). 15 Our approach is distinct from these earlier syntheses, exploiting hidden symmetry within the target to construct the polycy-clic piperidine core via a desymmetrizing double reductive amination. Our work also provides the first asymmetric entry to this natural product.…”

“…Under acidic conditions a key retro-Mannich The most recent synthesis of myrioneurinol (3) was reported in 2022 by our own group (Scheme 12). 15 Our approach is distinct from these earlier syntheses, exploiting hidden symmetry within the target to construct the polycy-Scheme 10 Completion of the Weinreb synthesis of (±)-myrioneurinol (3) J. M. Aquilina, M. W. Smith…”

Total Synthesis of the Myrioneuron Alkaloid (−)‐Schoberine B and Its Enantiomer (+)‐Schoberine B

“…To date, the enantioselective synthesis of (+)‐myroxazines A and B, [3a] as well as (−)‐myrionine, (−)‐myrionidine, and (−)‐schoberine has been reported by Bodo [3e] . More recently, the racemic synthesis of myrioxazine A by Coldham [6] and the more complex alkaloid myrioneurinol by the groups of Weinreb, [7] Smith, [8] and Ma [9] have been described.…”

Scalemic myrionsumamide A, tetracyclic skeleton alkaloids from Myrioneuron effusum

“… 1 Some structures of them showed significant biological activities such as antimalarial and anti-hepatitis C virus (HCV), 2–4 which along with their complex ring systems (up to 10 hexatomic rings) and amazing multiple chiral centers (up to 12 ones) within one structure have attracted great attention for total synthesis studies. 5–7 By July 2022, more than twenty Myrioneuron alkaloids had been obtained with various polycyclic structures (tricyclic-, tetracyclic-, pentacyclic-, hexacyclic-, octacyclic-, and decacyclic-type). 1,4,8–10 However, their stereochemistry control and polycyclic skeleton construction logic in nature remain elusive.…”