A Carbene Catalysis Strategy for the Synthesis of Protoilludane Natural Products

Abstract

The Armillaria and Lactarius genera of fungi produce antimicrobial and cytotoxic mellolide, protoilludane, and marasmane sesquiterpenoids. Herein, we report a unified synthetic strategy to access the protoilludane, mellolide, and marasmane families of natural products. The significance of these syntheses lies in a) the organocatalytic, enantioselective construction of key chiral intermediates from a simple achiral precursor, b) the utility of a key 1,2-butanediol intermediate to serve as a progenitor to each natural product class, and c) a direct chemical conversion of a protoilludane to a marasmane via serendipitous ring contraction, providing experimental support for their proposed biosynthetic relationships.

Applications of the Horner–Wadsworth–Emmons Olefination in Modern Natural Product Synthesis

“…They reported the total synthesis of four sesquiterpenoids belonging to the protoilludane, mellolide, and marasmane families (Scheme 11). 77 The synthesis of these bioactive natural products was based on an HWE olefination of aldehyde 123 with phosphonate 124 in the presence of LiCl and isopropylethylamine, which produced enone 125 in good overall yield (70%). Intramolecular reductive pinacol coupling was subsequently employed to synthesize the key intermediate cis-cyclobutanediol 126.…”

“…Another example for the use of Masamune and Roush's HWE conditions for the synthesis of linear unsaturated carbonyl units in a natural product synthesis was described in 2017 by Scheidt and co-workers. 77 They reported the total synthesis of four sesquiterpenoids belonging to the protoilludane, mellolide, and marasmane families (Scheme 11). The synthesis of these bioactive natural products was based on an HWE olefination of aldehyde 123 with phosphonate 124 in the presence of LiCl and DIPEA, which produced enone 125 in good overall yield (70%).…”

Advances in N‐Heterocyclic Carbene Catalysis for Natural Product Synthesis

“…In these pathways, the EurJOC European Journal of Organic Chemistry difficult cis-fused octahydro-1H-indene ring is assembled using NHC-catalyzed asymmetric annulation (Scheme 16). [45] Exposing keto-enal 63 to the chiral NHC precursor 64 in the presence of the base DIPEA gave the key bicyclic vinyl lactone 65 in 80 % yield with excellent enantio-and diastereoselectivity (98 % ee, >20:1 dr). From this lactone, echinocidin B (66) was prepared in 15 steps, echinocidin D (67) in 13 steps, armillaridin (68) in 17 steps, and isovelleral (69) in 15 steps.…”

“…[43a], [43b], [43c], [43e], [43g], In 2017, Scheidt's group disclosed the syntheses of protoilludanes echinocidin B ( 66 ), echinocidin D ( 67 ), the mellolide armillaridin ( 68 ), and the marasmane isovelleral ( 69 ). In these pathways, the difficult cis ‐fused octahydro‐1H‐indene ring is assembled using NHC‐catalyzed asymmetric annulation (Scheme ) . Exposing keto‐enal 63 to the chiral NHC precursor 64 in the presence of the base DIPEA gave the key bicyclic vinyl lactone 65 in 80 % yield with excellent enantio‐ and diastereoselectivity (98 % ee, >20:1 dr).…”

Concise Access to the Skeleton of Protoilludane Sesquiterpenes through a Photochemical Reaction Cascade: Total Synthesis of Atlanticone C

“…[5] One set of syntheses aimed at ac onstruction of the tricyclic skeleton from acyclic or monocyclic precursors in amanner mimicking their biological genesis from humulene. [6] In several other approaches,t he rings were built consecutively, [7] with the construction of the cyclobutane ring requiring particular attention. Notable photochemical strategies [8] to secure formation of the four-membered ring include the common [2+ +2] photocycloaddition [9] but also some less frequently used methods such as the photochemical 1,3-acyl shift reaction of b,g-unsaturated enones.…”