Enantioselective Organocatalytic Michael/Aldol Sequence: Anticancer Natural Product (+)‐trans‐Dihydrolycoricidine

Abstract

A total synthesis of the anticancer natural product (+)-trans-dihydrolycoricidine is reported from α-azidoacetone and cinnamaldehyde precursors. Key elements include an asymmetric organocatalytic sequence proceeding by a regiospecific secondary-amine-catalyzed syn Michael addition followed by an intramolecular aldol reaction. The sequence results in the formation of an advanced intermediate, containing three stereogenic centers, in one step which and was converted into the title compound in eight steps.

Total Synthesis of the Natural Product (+)‐trans‐Dihydronarciclasine via an Asymmetric Organocatalytic [3+3]‐Cycloaddition and discovery of its potent anti‐Zika Virus (ZIKV) Activity

“…We were inspired by recent enantioselective organocatalytic approaches toward six member carbacycles to develop a stepwise [3+3]‐type Michael‐aldol sequence,– involving an α‐nitrogen‐substituted acetone moiety reacting with an unsaturated aldehyde, as a rapid entry to the amaryllidaceae core. Such an approach proved successful in our recent synthesis of alkaloid 2 , which provided access to the natural product and structural analogs that permitted investigation of the antiviral activity against herpes viruses …”

“…Commercially available 5‐methoxypiperonal was subject to a two‐carbon aldehyde to alkenal homologation using a diethylacetal‐functionalized Wittig reagent yielding the cinnamaldehyde derivative 7 in 82 % yield (Scheme ). The crucial iminium ion‐mediated [3+3]‐Michael‐aldol sequence of 7 with azidoacetone 8 proved highly effective using the Jørgensen ( R )‐diphenylsilaprolinol secondary amine catalyst in combination with the tertiary amine quinidine, providing the cycloadduct 9 in 58 % isolated yield and >99 % enantiomeric excess (e.e.). The mirror‐image reaction employing ( S )‐diphenylsilaprolinol in the presence of quinidine gave ent ‐ 9 also in 99 % e.e.…”

DualPhos: a versatile, chemoselective reagent for two-carbon aldehyde to latent ( E )-alkenal homologation and application in the total synthesis of phomolide G

“…The intermediate latent alkenals may be cleaved immediately, revealing synthetically useful α,β-unsaturated aldehydes, or may be carried through a wide range of synthetic transformations intact. The robust nature of these latent alkenals contrasts sharply with dialkyl- and cyclic acetals obtained using standard reagents such as 4 and 5 [57,58], and permits a multitude of chemoselective transformations demonstrated in a new synthesis of the natural product macrolactone phomolide G. Further developments on the use of DualPhos and applications of the readily available alkenals in organocatalytic cascade sequences [59,60] are under active investigation in our laboratories.…”

Bifunctional Tripeptide with a Phosphonic Acid as a Brønsted Acid for Michael Addition: Mechanistic Insights

“…Moreover these methodsh ave been successfully employed for the synthesis of biologically active compounds. [6] Due to their multifunctional structure,a mino acids and peptides are espe-cially efficient at multi-activating easily accessible or natural molecules. The combination of either amino-, H-bonding, or Lewis-base catalysis with hydrophobic effects andi n-solvent organization has been knownt om imic enzyme behavior and selectively interactw ith substrates.…”