Studies toward the Total Syntheses of Calyciphylline D-Type Daphniphyllum Alkaloids

Abstract

An efficient construction of an aza-[5.7.6.5] tetracyclic core structure of calyciphylline D-type Daphniphyllum alkaloids has been achieved. The synthetic route features a diastereoselective cyclopropanation, efficient construction of the core bridged 8-aza-[3.2.1]­octane skeleton through a [3 + 2] IMCC strategy, oxidative dearomatization of phenol, and gram-scale preparation in each step.

Synthesis of Bridged Bicyclic Systems peri‐Annulated to the Indole Ring: Tropane‐Fused Indoles

“…We began this project by studying the Lewis acid‐induced reaction of the indole‐derived DA cyclopropane 1 [15] with primary amines 2 affording tropane derivatives peri ‐annulated to the indole ring 3 (Scheme 1c). It was earlier shown that aldehydes react with amines faster than DA cyclopropanes, [14b,16] this allows the goal process to be realised as a domino reaction. Our choice of substrates was motivated by their availability and the assumption that the resulting products 3 should have important physiological activities.…”

Highly efficient construction of an oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton and ring-opening of the bridged ring via C–O bond cleavage

“… 17 With this strategy, the fused 5–7 bicycle was efficiently constructed which matched the trans -stereochemisty, however a C-4 oxygen atom was not be direct. Following our previously developed [3 + 2] IMCC strategy, 18 a – h we have recently reported a novel and efficient construction of a bridged aza-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton with desirable substituents and stereochemistries toward total syntheses of calyciphylline D-type Daphniphyllum alkaloids ( Scheme 3 ). 18 i Herein, we report the application of the [3 + 2] IMCC strategy for efficient construction of the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle with stereochemistries on C-4, C-7 and C-10, as well as a methylene (methyl) group at C-6 matching those in neoglabrescin A, curcusones I/J and related rhamnofolane/tigliane/daphnane diterpenes.…”

Synthesis of the [6.6.7.5] Tetracyclic Core of Calyciphylline N via a Boc-Mediated Oxidative Dearomatization/Diels–Alder Approach

“…Due to their broad moderated biological activities as well as their unprecedented structures, the total synthesis of Daphniphyllum alkaloids came into focus in the 1980s when Heathcock and co-workers accomplished a landmark synthesis of six members in four subtypes by biomimetic synthesis . After that, a series of elegant total syntheses and constructive studies on the skeleton of Daphniphyllum alkaloids constantly updated our understanding of these molecules . Kobayashi and co-workers successfully reported the isolation of five novel hexacyclic daphniphyllum alkaloids: Daphmanidin A ( 1 ), E ( 3 ), and F ( 4 ), Daphtenidine C ( 5 ), and Calyciphylline N ( 2 ) from 2002 to 2009, composing as a new subtype of Daphmanidin A-type (Figure ).…”