Synthetic Studies toward Actinorhodin and γ‐Actinorhodin by using a Homo‐coupling Strategy: Synthesis of Hemiactinorhodin and Hemi‐γ‐actinorhodin

Abstract

A homo‐coupling strategy toward the synthesis of actinorhodin and γ‐actinorhodin has been explored. The monomeric unit was synthesized by employing an efficient combination of Dötz benzannulation and oxa‐Pictet–Spengler reactions. Attempts towards oxidative homo‐coupling of the pyranonaphthalene monomer intermediate to give dimer were unsuccessful. Later, monomer pyranonaphthalene was carried forward to complete the synthesis of hemiactinorhodin and hemi‐γ‐actinorhodin.

First Stereoselective Total Synthesis of a Dimeric Naphthoquinonopyrano‐γ‐lactone: (+)‐γ‐Actinorhodin

“…For example, the combined synthetic efforts towards (−)‐crisamycin A ( 7 a ) ended prematurely with the synthesis of dimeric precursors, a 1:1 mixture—not referred to as such by the authors—of rac ‐crisamycin A ( 7 b ) and meso ‐crisamycin A ( 8 b ), or the synthesis of a compound that resisted demethylation in what would have been the final step . Endeavors towards γ‐actinorhodin ( 5 ) and actinorhodin ( 6 ) came to a halt at the stage of precursors, “half‐sized molecules”, or earlier . In fact, our total synthesis of γ‐actinorhodin ( 5 ) described in the following is the very first synthesis of a dimeric naphthoquinonopyrano‐γ‐lactone natural product in isomerically pure form …”

“…[3] Them onomeric naphthoquinonopyrano-g-lactones (+ +)-kalafungin (1), [4,5] (+ +)-frenolicin B( 2), [6, 4c, 5c, 7] and (À)-griseusin A (3) [8,9] have been obtained by total synthesis.M uch less is known about the synthesis of naturally occurring naphthoquinonopyrano-g-lactone dimers.F or example,the combined synthetic efforts towards (À)-crisamycin A( 7a) [10] ended prematurely with the synthesis of dimeric precursors, [11] a1 :1 mixture-not referred to as such by the authors-of rac-crisamycin A(7b)and meso-crisamycin A(8b), [12] or the synthesis of acompound that resisted demethylation in what would have been the final step. [13] Endeavors towards g-actinorhodin (5)a nd actinorhodin (6)c ame to ah alt at the stage of precursors, [14] "half-sized molecules", [15] or earlier. [16] In fact, our total synthesis of g-actinorhodin (5) described in the following is the very first synthesis of ad imeric naphthoquinonopyrano-g-lactone natural product in isomerically pure form.…”

A Decade with Dötz Benzannulation in the Synthesis of Natural Products

“…Scheme 22 Synthetic studies on -actinorhodin, actinorhodin and crisamicin A Considering the possible oxidative homocoupling of monomeric units to the dimeric molecules actinorhodin and -actinorhodin, we planned to synthesize the former monomers (Scheme 23). 59 Dötz benzannulation of the Fischer carbene 121 (prepared from 120) with alkyne 79 gave the naphthol 122 in 52% yield. Conversion of the phenol group into a methyl ether and lactonization provided 123 (74% over two steps).…”

Die erste stereoselektive Totalsynthese eines dimeren γ‐Lacton‐ anellierten Pyranonaphthochinons: (+)‐γ‐Actinorhodin

“…Bemühungen um eine Synthese von (−)‐Crisamycin A ( 7 a ) endeten immer vorzeitig: Sie erreichten dimere Vorstufen, 1:1‐Gemische aus rac ‐Crisamycin A ( 7 b ) und meso ‐Crisamycin A ( 8 b ) – welche die Autoren nicht als solche bezeichneten – oder eine Verbindung, die sich im letzten Syntheseschritt nicht demethylieren ließ . Syntheseanstrengungen Richtung γ‐Actinorhodin ( 5 ) und Actinorhodin ( 6) kamen bereits auf der Stufe von Vorstufen, Molekülhälften oder früher zum Stillstand. Unsere nachfolgend beschriebene Totalsynthese von γ‐Actinorhodin ( 5 ) ist daher die erste Synthese eines strukturell einheitlichen dimeren γ‐Lacton‐anellierten Pyranonaphthochinons überhaupt…”