Dimeric Pyranonaphthoquinones: Isolation, Bioactivity, and Synthetic Approaches

Abstract

The dimeric pyranonaphthoquinones, “bis versions” of the naphtho[2,3‐c]pyran‐5,10‐dione moiety, comprises a group of antibiotics that have been isolated from a variety of sources including plants, bacteria, fungi, and insects. This review discusses the known naturally occurring dimeric pyranonaphthoquinones, their isolation and bioactivity, and synthetic approaches towards them that have helped to confirm their structures, as well as to resolve structural uncertainties such as stereochemistry. The major focus has been on the synthetic approaches adopted to complete the challenging total synthesis of the natural isolates and analogues.

The Dötz Benzannulation Reaction: A Booming Methodology for Natural Product Synthesis

“…It shows anti ‐bacterial activity against bacteria found in the human respiratory tract and on the skin known as Staphylococcusaureus . The Fernandes's group synthesized monomeric unit of actinorhodin and γ‐actinorhodin (i. e., hemi‐γ‐ actinorhodin 301 and hemi‐actinorhodin 302 ) using the Dötz benzannulation reaction between Fischer carbene complex 293 and terminal alkyne 294 to produce 295 which upon methylation and lactonization yield 297 (Scheme ) . Then oxa‐Pictet‐Spengler reaction was carried out and 298 was obtained which on oxidation gave a mixture of separable quinones 299 and 300 .…”

“…Crisamicin A is known to show excellent anti ‐tumor, immunomodulatory and antiviral activity . During the synthesis (Scheme ), Fernandes and co‐workers performed Dötz benzannulation with an aromatic chromium carbene complex 303 and an ester containing terminal alkyne 304 to afford the dimeric ester 305 which on oxa‐Pictet‐Spengler reaction in the presence of Lewis acid (TMSOTf) followed by oxidation with CAN produced two separate quinone 306 and 307 . Next, these compounds were transformed into the final product 309 as shown in Scheme .…”

“…Cardinalin 3 is yellow coloured pigment belonging to a series of dimeric pyranonaphthoquinones isolated from the purple‐red fruit bodies of New Zealand toadstool Dermocybe cardinalis, whose ethanolic extract exhibits significant cytotoxic activity against P388 murine leukaemia cell line. To this context, Fernandes and co‐workers synthesized regioisomeric core structure of cardinalin 3 in a way depicted in Scheme . The Fischer carbene complex 311 was derived from dibromophenyl compound 310 using n BuLi at room temperature which was then reacted with the chiral alkyne 312 to provide the dimer 313 .…”

“…Having both the alkyne and Fischer carbene complex in hand, they were then subjected to [3+2+1]‐benzannulation reaction to deliver the benzannulated product 319 in good yield. Finally, after performing several steps as displayed in the Scheme , they obtained the desired (+)‐demethoxycardinalin 3 ( 321 ) in overall good yield.…”

Dimeric Pyranonaphthoquinone Glycosides with Anti-HIV and Cytotoxic Activities from a Soil-Derived Streptomyces

“…Natural pyranonaphthoquinone antibiotics are widespread in bacteria and fungi and exhibit antitumor, antibacterial (mainly Gram-positive bacteria), antiviral, and antiprotozoan activities. − The biosynthesis of the naphtho­[2,3- c ]­pyran-5,10-dione moiety typically uses acetate/malonate units condensed via the type II polyketide synthase pathways. , Some natural pyranonaphthoquinone monomer units can produce symmetrical or asymmetrical dimers through a C–C bond, − an oxygen bridge, − or a sulfur bridge. − …”