Discovery and Biomimetic Synthesis of a Polycyclic Polymethylated Phloroglucinol Collection from Rhodomyrtus tomentosa

Abstract

Inspired by a previously reported biomimetic synthesis study, four new naturally occurring phloroglucinol trimers 1–4 with unusual 6/5/5/6/6/6-fused hexacyclic ring systems, along with two known analogues (5 and 6) and two known biogenetically related dimers (10 and 11), were isolated from Rhodomyrtus tomentosa. Their structures and absolute configurations were unambiguously elucidated by spectroscopic analysis, X-ray diffraction, and electronic circular dichroism calculation. By mimicking two potentially alternative biosynthetic pathways, the first asymmetric syntheses of 1–4 and the racemic syntheses of 5 and 6 were achieved in only five to six steps without the need for protecting groups. Furthermore, phloroglucinol dimers 10 and 11 exhibited significant in vitro antiviral activity against the respiratory syncytial virus.

The Kornblum DeLaMare rearrangement in natural product synthesis: 25 years of innovation

“…This asymmetric approach was applied again by Deng et al in the synthesis of four unnamed phloroglucinol trimers ( 75a and 75b ) isolated again from Rhodomyrtus tomentosa . 103…”

Recent Advances in Chemistry and Antioxidant/Anticancer Biology of Monoterpene and Meroterpenoid Natural Product

“…Rhodomyrtone belongs to a large and diverse family of tricyclic meroterpenoid systems isolated from Rhodomyrtus tomentosa [ 66 , 67 , 68 , 69 , 70 ]. This set of compounds has been shown to have strong antibacterial activity, acting primarily against gram-positive strains.…”

“…In addition, the combined extracts of Rhodomyrtus tomentosa have shown anti-cancer and anti-tumoral effects in various models [ 66 , 67 ]. The synthesis of the unusual caryophyllene-derived meroterpenoids (CDMTs) including rhodotomentone A ( 127 ) and rhodotomentone B ( 128 ) was reported via a biomimetic pathway [ 68 , 69 , 70 ], ( Scheme 2 ). The synthesis began from the natural product leptospermone ( 22 ), a commonly occurring acylphloroglucinol, which was subjected to dehydration mediated by DIBAL-H, yielding the dearomatized ortho -quinone methide ( o -QM) intermediate 23 in gram-scale.…”

“…This produces rhodotomentone A( 127 ) and B( 128 ), along with two other rhodotomentone diastereoisomers, compounds 27 and 28 . Additionally, endoperoxide 24b was reacted with β-caryophyllene ( 25 ) to undergo the Kornblum-DeLamare rearrangement and Diels-Alder cycloaddition reaction sequence under thermal conditions to generate rhotomentodine A, B, Q and R ( 123 , 124 , 125 and 126 ), along with rhodomyrtusial A, B and C ( 120 , 121 and 122 ) and compound 29 [ 70 ] .…”

“…This was carried out under hetero-Diels-Alder (HDA) reaction conditions, requiring Lewis acid, ZnI 2 and heat, in relatively modest yields. The synthetic approach offers rapid access to impressively complex structures [ 70 ].…”