Asymmetric Total Synthesis Of Naphthospironone A, A Natural Naphthoquinone Produc

Naphthospironone A,a novel natural product in naphthoquinone family,was isolated by Zhu and Wen’s group in 2010 from the solid fermentation of an alkalophilic actinomycete which was found in a tin mine tailings area in Datun,Yunnan Province in southwest China.It exhibited moderate cytotoxicity and antibiotic activity against several Gram-positive and-negative bacteria.Unlike other reported naphthoquinones,Naphthospironone A has a unique spiro[bicyclo[3.2.1]octane-pyran]cage-like skeleton and contains five contiguous chiral carbons,four of which are quaternary oxygenated centers.Due to the synthetic challenge of naphthospironone A,only one study so far has constructed its racemic ABD ring model structure.In this thesis,an asymmetric synthetic route for Naphthospironone A was explored on the basis of retrosynthetic analysis.Firstly,the previous synthetic route of the spirolactone intermediate explored by our group was optimized.A convergent synthetic route was adopted to connect naphthoquinone with C-and D-ring precursors using a sequential two-step coupling reactions.The D-ring was efficiently constructed through epoxidation and epoxy-ring opening/lactonization under acidic condition to afford the key spirolactone intermediate.Secondly,we explored a series of strategies to construct the cage skeleton,including introducing the 19-OH group before and after B-ring cyclization,respectively.The skeleton was successfully constructed through the doublebond migration triggered by the reductive debromination of bromospirolactone under hydrogenation,followed by the intramolecular aldol reaction under basic conditions.And the 19-OH group was successfully introduced by the Mukaiyama hydration reaction.Lastly,we investigated the strategy to install the double bond on D-ring.After extensive investigation,we finally chose to introduce a thiophenyl group on the bromospironolactone intermediate and afforded the D-ring double bond through an oxidation-elimination process after cyclization to form the cage-like skeleton.In summary,we achieved the first asymmetric total synthesis of Naphthospironone A via a process containing 17 steps in the longest linear sequence.The successful work of the total synthesis of Naphthospironone A with a complex cage-like skeleton,not only paves the way for the next structure-activity relationship study and structure optimization,but also provides useful experience for the synthesis of other complex natural products in naphthoquinone family.