Diastereoselective Synthesis of an Advanced Intermediate of Thapsigargin and Other 6,12-Guaianolides Using a RCEYM Strategy

Abstract

A new and flexible approach toward the synthesis of 6,12-guaianolide anticancer drugs such as trilobolides or thapsigargin has been developed that could be applied to the preparation of analogues with a modified ring system. The synthesis starts from commercial 2-methylcyclopentane-1,3-dione, only relying on diastereoselective reactions for the construction of the stereogenic centers at C1, C3, C6, and C10 and features a high-yielding ring-closing enyne metathesis (RCEYM) step for the formation of the [5,7] bicyclic core.

Function‐Oriented and Modular (+/−)‐cis‐Pseudoguaianolide Synthesis: Discovery of New Nrf2 Activators and NF‐κB Inhibitors

“…Finally, ring‐closing enyne metathesis [58] would yield an advanced intermediate 8 (via 7 ) that bears the enone (albeit deconjugated) and an allyl alcohol, which can be converted into the targeted acrylate moiety by straightforward functional group interconversions (deprotection then oxidation). Recently, ring‐closing enyne metathesis was used to synthesize the related guaianolide framework in ≈12 steps [49] . Notably, our proposal to synthesize terpenoid scaffolds from Knoevenagel adducts and allyl/propargylic electrophiles is in line with some of our recent work aimed at simple and modular cycloheptene‐scaffold synthesis [59–61] .…”

“…Recently,ring-closing enyne metathesis was used to synthesize the related guaianolide framework in % 12 steps. [49] Notably,o ur proposal to synthesize terpenoid scaffolds from Knoevenagela dducts and allyl/propargylic electrophiles is in line with some of our recent work aimed at simple and modular cycloheptene-scaffold synthesis. [59][60][61] We are targeting cis-pseudoguaianolides for af ew reasons (Figure 2B): (1) necessity-this route at presenty ields the cisfusion (vide infra).…”

“…[30][31][32][33][34][35][36] As such, the (pseudo)guaianolide family and their analogues have been implicated as leads in drug development. While the majority of medicinal chemistry and drug discoverye fforts re- lated to (pseudo)guaianolides involves isolation and/or semisynthesis, [37] there are numerous total syntheses(pseudoguaianolides [12][13][14][15] and guaianolides [38][39][40][41][42][43][44][45] )m ethods/approaches, [36,[46][47][48][49][50][51] and de novo analogue syntheses. [52,53] For drug discovery purposes, it would be ideal to have am odularr oute to pseudoguaianolide-analogues that retains the structural complexityo f the natural product family,c an tempert he reactivity of the Michael acceptors, [36] and allows for significant diversification aroundt he scaffold.…”

Metathesis Reactions in Natural Product Fragments and Total Syntheses

“…Thapsigargin is a 6,12‐guaianolide sesquiterpene (plant secondary metabolite) with anticancer activity. In this approach, total 12 steps were involved, where RCEM was one of the pivotal step brought into the action in last step to end‐up the synthesis of thapsigargin core [336a] . Alkynylation of an aldehyde 986 with methyl propiolate in presence of CeCl 3 and LiHMDS afforded an enyne compound 987 , a RCEM precursor.…”

Synthesis of Framework Structure of Guaiane

“…迄今为止, 已经开发出来了多种方法学用于 [5,7]并 环结构单元的愈创木烷型倍半萜类天然产物的合成研 究. 例如: 铑催化的 1,3 偶极环加成反应 [6] (Scheme 1, a)、铑催化的 Pauson-Khand 反应 [7] 、烯烃复分解反应 [8] 、 路易斯酸诱导的 Michael/coniaene 反应 [9] 、铂催化的[4 ＋3]环反应 [10] 、 SmI 2 诱导的单电子还原内酯环化反应 [11] 以及分子内羟醛缩合环化反应 [12] .…”