Total Synthesis of Linear Coumarniolignoids (+) and (−)-Sapiumin C, (−)-Moluccanin, and (−)-Hemidesminine

Abstract

Coumarinolignoids (CLs) are a class of natural products isolated from a diverse range of plant species. Due to their unique structural scaffold, they exhibit a wide range of interesting biological activities including hepatoprotective, antitumor, antiinflammatory, and antioxidant activities among others. In this research, key intermediate 10 was used to stereoselectively synthesize CLs (7′S,8′S)-and (7′R,8′R)-sapiumin C 1 and 2, (7′S,8′S)-moluccanin 3, and (7′S,8′S) hemidesminine 4 for the first time, establishing a versatile synthetic method for the stereoselective synthesis of linear CLs. The developed method includes a Mitsunobu coupling, a modified Miyaura arylation via a rhodium catalyst, and an acid-catalyzed cyclization in key bondforming steps. The developed synthetic route allows the synthesis of both enantiomers of a given natural product from the same chiral pool reagent (S)-solketal while allowing easy variation of aromatic substitution and hydroxymethyl/allylhydroxymethyl moieties that are common in this class of natural products.

Total Synthesis of (−)-Amovillosumin A and Structure Correction of (−)-Amovillosumin C Using Chemical Synthesis

“…In this work, it was decided to directly compare these two methods to assess the reliability and consistency. The aromatic bromides and boronic acids used in this work were prepared using reported methods (see Supporting Information, Scheme S1).…”

“…Cyclization under these conditions preferentially forms the more thermodynamically stable trans isomer. This is due to the quinonemethide intermediate generated by attacking the phenol from the least hindered side to favor the trans isomer . In this case, the acid cyclization of alcohols 16a and 16b led to a partially separable 7:1 mixture of trans -(7 R ,8 R )-amovillosumin A ( 1a ) and the isomer cis -(7 S ,8 R )- 1c in 86% overall yield.…”

“…With the desired aldehyde 15 in hand, the penultimate step was to introduce the second aromatic fragment to complete the phenylpropanoid unit. Traditionally, this has been achieved using common organometallic methods, such as aryl organolithiate addition. , However, in our previous synthesis, these conditions were unsuccessful on complex aliphatic aldehydes, which initiated the investigation to explore alternative methods, such as the modified Miyaura arylation via rhodium catalysis, for these systems . In this work, it was decided to directly compare these two methods to assess the reliability and consistency.…”

“…Recently, we reported methodology using a modified Miyaura arylation which was utilized in the total synthesis of coumarinolignoids, including 6 (Figure ). It was envisaged that a similar approach could be used for the synthesis of the amovillosumins.…”

“… Norlignans are known for displaying potent biological activities including antibacterial, antioxidant, phytotoxic, and platelet aggregation inhibitory effects . Furthermore, 1,4-benzodioxanes are an important neolignan subgroup containing a dioxane moiety (in purple), which were claimed to exhibit a diverse range of biological activities, such as hepatoprotective, , antiangiogenic, anti-inflammatory, , antitumor, , and antioxidant activities, among others. ,, These properties have led them to be desirable pharmacological ligands. Four norlignans, amovillosumins A–D ( 1 – 4 ), were isolated from the dried fruit of Amomum villosum (Amomi Fructus) by Ding et al, with some of these natural products shown to increase stimulation of glucagon-like peptide-1 (GLP-1) secretion.…”