Chemoenzymatic, biomimetic total synthesis of (−)-rugulosin B, C and rugulin analogues and their biosynthetic implications

Abstract

Flavoskyrins, (−)-rugulosin B, C and rugulin analogues are synthesized chemoenzymatically from anthraquinones in two, three and four steps, respectively.

Dothideomins A–D, Antibacterial Polycyclic Bisanthraquinones from the Endophytic Fungus Dothideomycetes sp. BMC-101

“…A plausible biosynthetic pathway of 1 – 4 was proposed as shown in Scheme S1. A growing list of reports have described that the anthraquinone scaffold is biosynthesized via a polyketide pathway. − The substrate of dothideomins A–D is proposed as a (a precursor of emodin, which often plays a crucial role as a biosynthetic precursor for fungal bisanthraquinones, including the unusual cage-like bisanthraquinones). , Herein, the precursor a is proposed to undergo reduction and dehydrogenation to form the intermediate b , and through ring-opening and decarboxylation to form the intermediates c and d . Then, b and d experience multistep Michael additions and enolization to obtain compound 3 .…”

Anthrol reductases: discovery, role in biosynthesis and applications in natural product syntheses

“…70 Similarly, (R)-3,4-dihydrolunatin (9b) and (R)-3,4-dihydrocitreorosein (9c) along with respective homodimeric analogues of (−)-avoskyrins, the (−)-lunaskyrin ( 49) and (−)-avoskyrin C (50) were also synthesized (Scheme 13B). 70,71 Furthermore, Mondal et al developed an alternate catalyst-free approach for the synthesis of dimeric (−)-avoskyrins (38), through the autoxidation of (R)-14a using molecular oxygen in KPi buffer of pH 6.0 in 72% yield. 72 Later, this method was applied to obtain various homo-and heterodimerized (−)-avoskyrins 49-53 and a mixture of heterodimeric (−)-avoskyrins 54/54 ′ , 55/55 ′ , and 56/56 ′ in 27-72% yield (Scheme 14).…”

“…This gave only (−)-rugulosin B ( 65 ) and (−)-dianhydrorugulosin B ( 66 ) in 60% and 18% yields, respectively (Scheme 16). 71 Based on the NMR studies of the cascade performed in pyridine- d 5 , the involvement of putative intermediates 62 / 62′ was proposed, which were not detected during the cascade. These might undergo a Michael reaction to form an inseparable mixture of diastereomeric intermediates 63 / 63′ , which on oxidation in the presence of molecular oxygen forms a trace amount of the oxidized intermediate 64 / 64′ .…”

Synthesis of (−)-Flavoskyrins by Catalyst-Free Oxidation of (R)-Configured Dihydroanthracenones in Aqueous Media and Its (Bio)synthetic Implications

“…11 This simple chemoenzymatic approach not only gave access to the putative biosynthetic intermediates (S)-2a and (R)-11a for the first time but also implicated the role of (R)-10a as an intermediate in the (bio)synthesis of (−)-flavoskyrin (1a) and (−)-rugulosin (3a) (Scheme 1). 11 Likewise, lunatin (9b, R = OCH 3 ) and citreorosein (9c, R = CH 2 OH) were used to obtain (−)-lunaskyrin (1b) 11 and (−)-flavoskyrin C (1c), 12 respectively (Scheme 1c). The spontaneous nature of stereocontrolled dimerization in the above process motivated us to investigate the catalyst-free oxidation of (R)-10a for the synthesis of (−)-flavoskyrin (1a) under aqueous ambient conditions.…”

“…Because our study supports the presence of other flavoskyrin-type molecules in nature, we believe that the reason not many of them have been isolated yet is due to the presence of the chemically sensitive β-hydroxy ketone group. Nevertheless, the flavoskyrins such as 1b , 1c , and 13a/13a ′ can be utilized toward the (bio)­synthesis of bisanthraquinones such as (−)-2,2′- epi -cytoskyrin ( 3b ), (−)-rugulosin C ( 3c ), and (−)-rugulosin B ( 3d ), which are yet to be isolated from natural sources (Scheme A).…”