Nanaomycins

Nanaomycin A 103 and deoxyfrenolicin 108 are members of a group of naphthoquinone antibiotics based on the isochroman skeleton. The therapeutic potential of these natural products has attracted considerable attention, and different approaches towards their synthesis have been reported [65,66]. The key step in the total synthesis of racemic nanaomycin A 103 is the chemo-and regioselective benzannulation reaction of carbene complex 101 and allylacety-lene 100 to give allyl-substituted naphthoquinone 102 after oxidative workup in 52% yield [65] (Scheme 47). The allyl functionality is crucial for a subsequent intramolecular alkoxycarbonylation to build up the isochroman structure. However, modest yields and the long sequence required to introduce the... 

For that reason an intramolecular benzannulation was developed, which incorporates all components for the intramolecular alkoxycarbonylation into the naphthoquinone 105 [65]. Based on that strategy a short and convergent pathway for the synthesis of racemic deoxyfrenolicin 108 was accomplished. Xu et al. replaced the allylacetylene 100 in the reaction sequence for nanaomycin A by alkynoate 106. The benzannulation product 107 was an appropriate precursor for a subsequent tandem oxa-Pictet-Spengler cyclisation/DDQ-induced coupling reaction [66]. Following this strategy the total synthesis of enan-tiomerically pure deoxyfrenolicin could be accomplished (Scheme 48). 

This reaction is applied to the intramolecular regioselective cyclization of the 3-alkoxybenzoeyelobutenedione 60 to 61, a precursor of nanaomycin A 62 [33], (Scheme 23)... 

Tanaka Y, Kamei K, Otoguro K, Omura S (1999) Heme-Dependent Radical Generation Possible Involvement in Antimalarial Action of Non-Peroxide Microbial Metabolites, Nanaomycin A and Radicicol. J Antibiot 52 880... 

This regioselective synthesis of benzannelated rings, which, unlike its Friedel Crafts equivalent, is not perturbed by the nature of other directing groups carried by the ring, has been used in several syntheses. Indanone 76 from cyclisation of 75 is an intermediate in a synthesis of nanaomycin A,44 and tetralone 77 is an intermediate in a synthetic study towards daunomycin 45... 

Pyranonaphthoquinones. The reaction of phthaloylmetal complexes with alkynes to give naphthoquinones (10, 221-222) has been extended to a synthesis of pyrano-naphthoquinones. An intramolecular version of the reaction is used to control the regio-selectivity. The method is outlined in Scheme (1) for a synthesis of nanaomycin (6) and the cw-epimer (7). 

Nanaomycin A (128), an antibiotic pyranonaphthoquinone, has been synthesized via this route starting from (127). This method has also been applied to the synthesis of royleanone (129), an abietanoid diteipene quinone possessing antitumor cytotoxicity, in which the highly substituted quinone skeleton has been efficiently constmcted by using the maleoylcobalt complex. ... 

Isochroman-5,8-diones (300) were prepared by oxidation of 5,8-dimethoxy-isochromans with AgO and nitric acid (82SC279). This system is present as a structural moiety in some natural quinones, such as eleutherin (51HCA561), kalafungin (68MI1), nanaomycins (75MI2, 75MI3 76CC320), and other compounds. 

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