Total Synthesis of the Tetracyclic Antimalarial Alkaloid (±)‐Myrioneurinol

Abstract

The first total synthesis of the tetracyclic antimalarial Myrioneuron alkaloid (±)-myrioneurinol has been accomplished using three highly diastereoselective reactions as pivotal steps: 1) an intramolecular Michael addition of a benzyloxycarbonyl-protected lactam titanium enolate to an α,β-unsaturated ester for construction of the spirocyclic C5 quaternary center and the a/d rings, 2) a malonate anion conjugate addition to a transient nitrosoalkene to install the requisite functionality and configuration at the C7 position, and 3) an intramolecular sulfonyliminium aza-Sakurai reaction to form the b ring and the attendant C9/C10 configuration of the natural product.

Synthetic Approaches to N‐Methoxy‐N‐methylamides

“…This synthetic method was utilized further for the preparation of N-methoxy-N-methyl 2-hydroxybenzamides (10). Thus, the reaction of methyl 2-hydroxybenzoates and (CH 3 O)NHCH 3 ÁHCl using 3 equiv of i-PrMgCl in THF 22 Alternatively, Lewis acids, such as trimethylaluminum 23 and dimethylaluminum chloride, 24 were useful for converting esters to amides. For example, lactam methyl ester (13) was transformed to the corresponding N-methoxy-Nmethylamide (14) by Me(MeO)NAl(Me)Cl, which was generated from a combination of (CH 3 O)NHCH 3 ÁHCl and dimethylaluminum chloride.…”

Conjugated nitrosoalkenes as Michael acceptors in carbon–carbon bond forming reactions: a review and perspective

“…Recently, Weinreb’s group used the advantage of nitrosoalkenes as Michael acceptors to accomplish total syntheses of several alkaloids, such as (+/−)-alstilobanines A and E, (+/−)-angustilodine [ 33 ] and (+/−)-myrioneurinol [ 34 – 35 ] ( Fig. 1 ).…”

“…Conjugate addition of malonate anion to a nitrosoalkene intermediate NSA9 was used as a key stage to construct an important C(7)–C(8) connection in the total synthesis of (+/−)-myrioneurinol ( Scheme 15 ) [ 34 – 35 ]. α-Chloroxime TBS ether 43 (prepared in 10 steps from δ-valerolactam) reacted with a dimethyl malonate anion under Denmark’s conditions via intermediate NSA9 to give the corresponding adduct 44 in 93% yield.…”

Organische Chemie 2014

“…Alkaloide sind nicht nur aufgrund ihrer strukturellen Komplexität, sondern auch durch ihre oftmals herausragenden biologischen Aktivitäten reizvolle Zielmoleküle für Totalsynthesen. Die Arbeitsgruppe Weinreb beschrieb im vergangenen Jahr einen Weg zur Totalsynthese des tetracyclischen Alkaloids Myrioneurinol (56) ,78 das gegen Malariaerreger wirkt. Ausgehend von Valerolactam gelang die Synthese in 23 Stufen.…”