Enantioselective Total Synthesis of (−)‐Jiadifenolide

Abstract

The first total synthesis of jiadifenolide (1), a potent neurotrophic modulator, has been reported. Highlights of the synthesis include: construction of the B ring via an asymmetric Robinson annulation; assembly of the E ring lactone via a novel acid-induced cascade reaction; and Pd(0)-mediated carbomethoxylation and methylation reactions for the construction of the C and A rings respectively.

Synthesis of the tetracyclic core of Illicium sesquiterpenes using an organocatalyzed asymmetric Robinson annulation

“…Among them, the Hajos–Wiechert and Wieland–Miescher ketones represent two of the most famous examples [59–65]. With this background information in mind, we devised an enantioselective synthesis of 8 starting from commercially available dione 12 , and the synthesis of 8 was previously published [25–26]. Tsuji–Trost allylation [66–68] of 12 produced compound 11 , which was readily converted to 13 by an acid-catalyzed Michael addition with methyl vinyl ketone (MVK) (two steps, 63% overall yield) [69–71].…”

“…Conversion of 10 to 9 was accomplished based on our previously reported strategy (Scheme 3) [25]. Treatment of 10 with magnesium methyl carbonate (MMC) [79–81] yielded the C-5 carboxylic acid that, without further purification, was esterified under Meerwein’s conditions to afford β-ketoester 17 .…”

Illicium Sesquiterpenes: Divergent Synthetic Strategy and Neurotrophic Activity Studies

“…We hypothesized that such a divergent strategy would provide access to a library of related molecules for subsequent structure-activity relationship studies. Herein, we describe this strategy that led to the first enantioselective synthesis [22] of 2 , 3 and 4 and related analogues. Biological evaluation of these compounds led to the identification of more potent neurotrophic agents and allowed to propose a critical pharmacophoric motif.…”

Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products

“…108 Among this large family, jiadifenolide ( 81 , Scheme 7) has recently attracted significant synthetic attention owing to its compact and highly oxidized molecular framework coupled with its ability to promote neurite outgrowth at very low concentrations. 109 To date, total syntheses of 81 have been disclosed by the groups of Theodorakis, 110,111 Paterson, 112 Sorensen, 113 Shenvi, 114 and Zhang, 115 in addition to a recent formal synthesis by Gademann. 116 Herein we discuss the three chiral pool-based total syntheses of 81 by Sorensen (2014), Zhang (2015), and Shenvi (2015).…”