Development of a Terpenoid Alkaloid‐like Compound Library Based on the Humulene Skeleton

Abstract

Many natural terpenoid alkaloid conjugates show biological activity because their structures contain both sp -rich terpenoid scaffolds and nitrogen-containing alkaloid scaffolds. However, their biosynthesis utilizes a limited set of compounds as sources of the terpenoid moiety. The production of terpenoid alkaloids containing various types of terpenoid moiety may provide useful, chemically diverse compound libraries for drug discovery. Herein, we report the construction of a library of terpenoid alkaloid-like compounds based on Lewis-acid-catalyzed transannulation of humulene diepoxide and subsequent sequential olefin metathesis. Cheminformatic analysis quantitatively showed that the synthesized terpenoid alkaloid-like compound library has a high level of three-dimensional-shape diversity. Extensive pharmacological screening of the library has led to the identification of promising compounds for the development of antihypolipidemic drugs. Therefore, the synthesis of terpenoid alkaloid-like compound libraries based on humulene is well suited to drug discovery. Synthesis of terpenoid alkaloid-like compounds based on several natural terpenoids is an effective strategy for producing chemically diverse libraries.

Reagent-controlled regiodivergent ring expansions of steroids

“…Natural products represent valuable starting points for drug discovery, with late-stage diversification emerging as an attractive approach for generating new bioactive agents from complex scaffolds 1 – 6 . Despite many recent advances, a challenge common to late-stage natural product functionalization remains: complex structures often have profound biases that dictate the isomeric outcomes of reactions carried out on them.…”

Exploring sesquiterpene alkaloid-like scaffolds via Beckmann-transannular remodelling of beta-caryophyllene

“…Recently, creating complex small molecules directly from NPs has appeared as a convenience approach in diversity-oriented synthesis (DOS) area. [5][6][7][8][9] NPs are being considered as exceptional starting points due to the high abundance and structural variation. Additionally, NPs provide an excellent framework for site selective and stereoselective transformations.…”

“…The propensity of macrocyclic precursors to undergo transannular cyclization has been dely harnessed by nature to build thousands of polycyclic terpenoids and alkaloids with mediumsized rings. 9,[15][16][17] Our previous diversity-oriented transformation demonstrated the convenience protocol to build natural-like libraries containing medium-sized rings from macrocyclic caryophyllene. 18,19 In this paper, we consider applying Beckmann rearrangement associated with transannular cyclization to explore chemical space covering poly-N-heterocyclic skeletons.…”

Pd(OAc)2/Ph3P-catalyzed dimerization of isoprene and synthesis of monoterpenic heterocycles

“…Although the dimerization of isoprene is significantly more difficult compared to the dimerization of 1,3-butadiene, it would lead to synthetically useful linear monoterpenic structures that can be further transformed into interesting potential biologically active heterocyclic derivatives such as terpenoid pyranes, lactones, (hydro)chromenes or pyridines, among others [ 23 – 26 ]. Depending on the connection of the two isoprene units, four different kinds of dimers can be formed: tail-to-tail, head-to-tail, tail-to-head and head-to-head ( Fig.…”