The isoxazolidine ring represents one of the privileged structures in medicinal chemistry, and there have been an increasing number of studies on isoxazolidine and isoxazolidine-containing compounds. Optimization of the 1,3-dipolar cycloaddition (1,3-DC), original methods including electrophilic or palladium-mediated cyclization of unsaturated hydroxylamine, has been developed to obtain isoxazolidines. Novel reactions involving the isoxazolidine ring have been highlighted to accomplish total synthesis or to obtain bioactive compounds, one of the most significant examples being probably the thermic ring contraction applied to the total synthesis of (±)-Gelsemoxonine. The unique isoxazolidine scaffold also exhibits an impressive potential as a mimic of nucleosides, carbohydrates, PNA, amino acids, and steroid analogs. This review aims to be a comprehensive and general summary of the different isoxazolidine syntheses, their use as starting building blocks for the preparation of natural compounds, and their m...

Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry

Development of efficient sequences for the total syntheses of (±)-actinophyllic acid (rac-1) and (−)-actinophyllic acid (1) are described. The central step in these syntheses is the aza-Cope/Mannich reaction, which constructs the previously unknown hexacyclic ring system of actinophyllic acid in one step from much simpler tetracyclic precursors. The tetracyclic hexahydro-1,5-methano-1H-azocino[4,3-b]indole ketone rac-37 is assembled from o-nitrophenylacetic acid in four steps, with oxidative cyclization of a dienolate derivative of tricyclic precursor rac-35 being the central step. In the first-generation synthesis, this intermediate is transformed in two steps to homoallyl amine rac-43, whose formaldiminium derivative undergoes efficient aza-Cope/Mannich reaction to give pentacyclic ketone rac-44. In four additional steps, this intermediate is advanced to (±)-actinophyllic acid. The synthesis is streamlined by elaborating ketone rac-37 to β-hydroxyester intermediate rac-53, which is directly transformed ...

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Total Synthesis of (±)- and (−)-Actinophyllic Acid

Described herein is a catalytic asymmetric total synthesis of (-)-actinophyllic acid, with the key step being a chiral phosphine-catalyzed [3 + 2] annulation between an imine and an allenoate to form a pyrroline intermediate in 99% yield and 94% ee. The synthesis also features CuI-catalyzed coupling between a ketoester and a 2-iodoindole to shape the tetrahydroazocine ring; intramolecular alkylative lactonization; SmI2-mediated intramolecular pinacol coupling between ketone and lactone subunits to assemble the complex skeleton of (-)-actinophyllic acid; and an unprecedented regioselective dehydroxylation.

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Catalytic Asymmetric Total Synthesis of (-)-Actinophyllic Acid.

A desymmetrization strategy was developed involving iridium-catalyzed allylic dearomatization of indoles. The six-membered-ring spiroindolenines contain three contiguous stereogenic centers, including an all-carbon quaternary center, and were obtained in up to 99 % yield with 99 % ee and >95:5 d.r. When treated with a catalytic amount of tosylic acid, six-membered spiroindolenine undergoes an unprecedented six-to-seven-membered ring expansion, affording the corresponding hexahydroazepino[4,5-b]indole.

Iridium-Catalyzed Asymmetric Allylic Dearomatization by a Desymmetrization Strategy.

Indole alkaloids: 2012 until now, highlighting the new chemical structures and biological activities.

Alsmaphorazines A and B, novel indole alkaloids from Alstonia pneumatophora.

Alstilobanines A-E, new indole alkaloids from Alstonia angustiloba

Alpneumines A–H, new anti-melanogenic indole alkaloids from Alstonia pneumatophora

Alsmaphorazines C–E, indole alkaloids from Alstonia pneumatophora

Two new methyl chanofruticosinate-type indole alkaloids, flavisiamines E (1) and F (2), and an aspidofractinine-type indole alkaloid, fruticosiamine A (3), have been isolated from Kopsia flavida and K. fruticosa, respectively and their structures were elucidated by NMR spectral analysis using 2D techniques.

Teh Chin Hoe

Papers

Alsmaphorazines A and B, novel indole alkaloids from Alstonia pneumatophora.

Alstilobanines A-E, new indole alkaloids from Alstonia angustiloba

Alpneumines A–H, new anti-melanogenic indole alkaloids from Alstonia pneumatophora

Alsmaphorazines C–E, indole alkaloids from Alstonia pneumatophora

Flavisiamines e -f and fruticosiamine a, new methyl chanofruticosinate-and aspidofractinine-type indole alkaloids, from two species of kopsia