Design of a Functional Chromene‐Type Kobayashi Precursor: Gram‐Scale Total Synthesis of Natural Xanthones by Highly Regioselective Aryne Annulation

Abstract

The 2,2‐dimethyl‐2H‐chromene motif is widely found in many bioactive molecules, and is a privileged structure in the pharmaceutical arena. We have developed a concise and regioselective approach to chromenes and chromanes through an aryne‐based synthetic strategy. A practical, gram‐scale synthetic route to a chromene‐type aryne precursor was explored. Subsequently, cyclization under mild conditions afforded tetracyclic xanthone skeletons with excellent regioselectivity. Our approach provides a concise strategy for the gram‐scale synthesis of chromene‐type xanthones such as 6‐deoxyisojacareubin, cylindroxanthone D, staudtiixanthone D, brasilixanthone A and cudracuspixanthone O.

Arynes as synthetic linchpins towards the construction of diversely functionalized natural product skeletons

“…In 2021, Wu and co-workers had developed efficient strategies employing chromene-type arynes as main intermediates in a gram-scale construction of five class of functionalized natural products namely, 6-deoxyisojacareubin 59 , cylindroxanthone D 58 , staudtiixanthone D 68a , cudracuspixanthone O 68b and brasilixanthone A 68c (Schemes 6 and 7). 42 The synthetic pathway that aimed to afford cylindroxanthone D 58 and 6-deoxyisojacareubin 59 (Scheme 6) involves the reaction of 2,3-dihydroxybenzaldehyde 52 with benzyl bromide (BnBr) gave rise to a benzylated adduct 53 , which on further selective debenzylation using MgBr 2 ·Et 2 O afforded salicylaldehyde 54 . Compound 54 underwent the subsequent Pinnick oxidation and methylation to form salicylate 55 over two steps.…”

Recent advances in the synthesis of natural products containing the phloroglucinol motif

“…Lately, Sha and Wu accomplished collective syntheses of five chromene-type xanthones, 6-deoxyisojacareubin ( 317 ), cylindroxanthone D ( 318 ), brasilixanthone A ( 325 ), staudtiixanthone D ( 326 ), and cudracuspixanthone O ( 327 ) (Scheme 56). 196 Through the use of trisubstituted 2,2-dimethyl-2 H -chromene 314 as a common intermediate, two divergent strategies were utilized to access the xanthone core in gram-scale. CsF-promoted cyclization between 314 and 315 proceeded via tandem intermolecular nucleophilic coupling of aryloxide (from 315 ) with in situ generated aryne intermediate (from 314 ), followed by intramolecular electrophilic cyclization to give 316 .…”

Microwave assisted L‐proline catalyzed one‐pot three–component reaction for the synthesis of 4‐aminoaryl‐2‐phenyl‐2H‐3‐nitrochromene hybrid via Domino Michael‐Henry‐Michael addition reaction

“…Among all the chromene derivatives, 2‐aryl‐3‐nitro‐2 H ‐chromenes are most important because they are highly reactive and related to conjugated nitro alkenes in chemical properties [2]. However, 2‐aryl‐3‐nitro‐2 H ‐chromene and 2,3,4 trisubstituted chromene are the most important precursor for the synthesis of various bioactive molecules, functional materials and natural products [3]. Moreover, chromene and their structural derivatives shows a number of importances in co‐ordination chemistry and serve as a good ligand in coupling reactions [4].…”