Construction of the Myrioneuron Alkaloids: A Total Synthesis of (±)-Myrioneurinol

Abstract

A strategy has been developed that culminated in a stereoselective total synthesis of the tetracyclic antimalarial Myrioneuron alkaloid myrioneurinol. The synthesis relies on three highly diastereoselective reactions, including an intramolecular chelation-controlled Michael spirocyclization of an N-Cbz-lactam titanium enolate to an α,β-unsaturated ester for construction of the A/D-ring system and the attendant C5 (quaternary), C6 relative stereochemistry; a malonate enolate conjugate addition to a nitrosoalkene in order to install the appropriate functionality and establish the configuration at C7; and an intramolecular aza-Sakurai reaction to form the B-ring and the accompanying C9 and C10 stereocenters.

Synthesis of α-Substituted Enoximes with Nucleophiles via Nitrosoallenes

“… Thus, we anticipated that 1,4-additions of nucleophiles to 1 would proceed to afford α-functionalized enoximes. The nitroso group is a well-known strong electron-withdrawing substituent, and applications of nitrosoalkenes have been extensively documented. , However, to the best of our knowledge, no synthetic report of compounds 1 is found, and their chemical reactivity should be explored. , Additionally, enoximes are efficient precursors for construction of various amino compounds through cascade reactions and for the assembly of functionalized heterocycle cores like pyridines and isoxazolines in agrochemicals and anticancer agents . We herein describe the study of novel chemical species nitrosoallenes and the nucleophilic addition reaction affording α-functionalized enoximes.…”

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.…”

Titanium Enolate Chemistry at the Beginning of the 21st Century

“…The products were formed in good yields and with excellent diastereoselectivities. Diastereoselective Michael addition of chiral titanium(IV) enolates to acrylonitrile was later mentioned in a multistep synthesis of macrolide antibiotic rutamycin B99a and, more recently, in the preparation of the antimalarial tetracyclic alkaloid myrioneurinol 99b. However, sterically crowded and less reactive Michael acceptors such as methacrylates did not react with titanium(IV) enolates.…”