Facile Chemical Access to Biologically Active Norcantharidin Derivatives from Biomass

Abstract

Reductive amination of 2,5-diformylfuran (DFF) was used to implement the transition from bio-derived 5-hydroxymethylfurfural (HMF) to pharmaceuticals. The synthesized bis(aminomethyl)furans were utilized as building blocks for the construction of new derivatives with structural cores of naturally occurring biologically active compounds. Using the one-pot procedure, which included the Diels–Alder reaction followed by hydrogenation of the double bond, bio-derived analogues of the anticancer drug norcantharidin were obtained. The cyclization process was diastereoselective, and resulted in the formation of tricyclic products with the endo configuration. Analysis of cytotoxycity for the resulting tricyclic amine-containing compounds showed an increase of anticancer activity as compared with the unsubstituted norcantharimide.

Recent Advances on Diels‐Alder‐Driven Preparation of Bio‐Based Aromatics

“…Interestingly, the use of aqueous media is possible, but less efficient, as both the high solubility of BHMF‐7‐ONB and concomitant promotion of the retro‐DA complicate the isolation of pure product. Additionally, transformation of BHMF or HMF to the corresponding diamines by reductive amination with the dialdehyde, allowed production of derivates with two dialkylaminomethyl groups with increased anticancer activity [17] …”

“…Additionally, transformation of BHMF or HMF to the corresponding diamines by reductive amination with the dialdehyde, allowed production of derivates with two dialkylaminomethyl groups with increased anticancer activity. [17] …”

Chemical‐Switching Strategy for Synthesis and Controlled Release of Norcantharimides from a Biomass‐Derived Chemical

“…In particular, the electron‐withdrawing nature of aldehyde group inhibits the reactivity of diene group in HMF to undergo Diels‐Alder reactions with dienophiles. However, by converting the aldehyde group in HMF to an electron‐donating hydroxyl group, HMF can append maleimide‐based chemicals through Diels‐Alder coupling . Maleimides, containing a dienophilic C=C bond and imide functionalities, have served as sites to append additional chemicals for the synthesis of therapeutic molecules, such as norcantharimides and antibody‐drug‐conjugates, and for the production of novel polymers .…”

5-Hydroxymethylfurfural (HMF) in Organic Synthesis: A Review of its Recent Applications Towards Fine Chemicals

“…The authors also applied the Diels-Alder reaction on HMF-derived bis(aminomethyl)furans, and bis(alkoxymethyl)furans and maleic anhydride could be employed as dienophile to prepare analogues of the anticancer drug norcantharidin. [183] Scheme 61. Diels-Alder reaction of DHMF, bis(aminomethyl)furans and bis(alkoxymethyl)furans Sheppard's group reported a strategy to efficiently react HMF with dienophiles, without changing the oxidation state of the aldehyde (Scheme 62).…”