Total synthesis of alpha-, beta- and gamma-naphthocyclinone

• Applicant: Dr. Mark Marcello Maturi
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 290521118

The aim of this research project is the first total synthesis of alpha-, beta- and gamma-naphthocyclinone, three natural products from the naphthocyclinone family. All three compounds were isolated in 1974 as the colorful pigments from the mycelium of streptomyces arenae and are strong antibiotics against gram-positive bacteria. The biosynthetic pathway of naphthocyclinones was intensively investigated and it was thereby discovered that mother nature uses the monomeric pyranonaphthoquinone unit for dimerization in order to construct the naphthocyclinones.The retrosynthetic analysis envisions one common intermediate, which bears the complete carbon skeleton with its bicyclic core structure. This bicyclic core structure can be constructed via an aldol-addition by reductive cyclization, a method that was developed in the group of Suzuki. The precursor for the cyclisation could be furnished by an asymmetric rhodium-catalyzed C-C-cross coupling reaction of a western and an eastern fragment. Inspired by the biosynthesis of the naphthocyclinones, both fragments could be synthesized from one key intermediate that is a pyranonaphthalene compound.In view of the synthetic strategy, the naphthalene core of the key intermediate should be accessible by annulation of a benzoic acid ester derivative and a literature know chiral dihydropyron building block, which bears on of the stereogenic centers of the key intermediate. The pyrane ring of the key intermediate could be fully functionalized by a diastereoselective alkylation reaction of a lactol. After modulation of the key intermediate into the western and eastern fragment, the common intermediate, bearing the full carbon skeleton, could be synthesized by a cross coupling reaction and a reductive cyclisation. Following a sequence of a) oxidation to a para-naphthoquinone moiety, b) generation of a carboxylic acid functionality and c) removal of all phenol protecting groups should furnish the target compound beta-naphthocyclinone. Reversing the order of the first two steps of this sequence (first generation of the carboxylic acid functionality and then oxidation to a para-naphthoquinone moiety) should allow for a literature known lactonisation. Again removal of all phenol protecting groups should lead to gamma-naphthocyclinone. In analogy to the biosynthesis, an epoxidation followed by photochemical rearrangement should finalize the synthesis of alpha-naphthocyclinone. In pursue of this research, the racemic synthetic strategy for the key intermediate, as well as its modulation into the western and eastern fragment, has been successfully established and thus opening the path for the enantioselective totals synthesis of the target natural compounds.

• DFG Programme: Research Fellowships
• International Connection: Japan
• Host: Professor Keisuke Suzuki, Ph.D.