Synthetic Studies Towards The Total Synthesis Of Two Types Of Polyketide Natural Antibiotics

There are many natural products of aromatic polyketones in nature,which often have broad antibacterial activity.This paper mainly introduces the total synthesis of two kinds of polyketide natural antibiotics.The first part of this paper mainly reviews the published theses of the synthesis of natural aromatic polyketones over the years.The second part of this paper mainly summarizes the total synthesis of fasamycins,naphthacemycins and anthrabenzoxocinones.The three natural antibiotics have the activity of anti Gram-positive bacteria,and they all have the gem-dimethyl group in structure.Fasamycins and naphthacemycins are five ring skeleton molecules,while anthrabenzoxocinones are six ring skeleton molecules.The synthesis of fasamycin and naphthacemycins can be divided into two stages:1)construction of molecular skeleton and adjustment of oxidation state;2)selective functionalization.These key reactions for the synthesis of fasamycins and naphthacemycins are as follows:1)using Lewis acid catalyzed intermolecular Diels-Alder reaction to construct D-ring;2)using PEDA reaction to construct B-ring;3)regioselectively introducing chlorine atom in different aromatic rings.We have synthesized naphthacemycin B₁ in 9 steps,the total yield is 2.3%;12 steps have been used to synthesize naphthacemycin B₂,the total yield is 9.6%;13 steps to synthesize naphthacemycin B₄,the total yield is 3.1%,and 14 steps to synthesize fasamycin B,the total yield is 1.0%,and we have also synthesized a variety of analogs.The synthesis of anthrabenzoxocinones molecules can be also divided into two stages:1)construction of molecular skeleton and adjustment of oxidation state,2)selective functionalization.The key reactions for the synthesis of anthrabenzoxocinones are as follows:1)using Diels-Alder reaction to construct C ring;2)using intramolecular hetero-Diels-Alder reaction to construct ketal ring E ring;3)using PEDA reaction to construct B ring;4)regioselectively introducing chlorine atoms.Finally we have used 9 steps to synthesize ABX-A,the total yield was 8.2%;11 steps to synthesize ABX-C,the total yield was 1.9%;10 steps to synthesize ABX-E,the total yield was 6.0%;10 steps to synthesize ABX-F,the total yield was 2.3%;10 steps to synthesize ABX-H,the total yield was 2.3%;11 steps to synthesize BABX,the total yield was 2.1%;In addition,some analogues have been synthesized,The synthesis of fasamycins,naphthacemycins,anthrabenzoxocinones is conducive to the later medicinal chemistry research.The third part of the paper mainly discusses the asymmetric total synthesis of natural antibiotics formicamycin O.Up to now,17 kinds of natural formicamycins antibiotics have been isolated.Formicamycins are five ring skeleton molecules in structure,which has two chiral centers and one axial chiral center.Moreover,there are several chlorine atoms in benzene ring,such as four chlorine atoms in formicamycin I,J,and bromine atoms in formicamycin K,L,M molecules.So the structure of these molecules are more complex.These molecules also have the activity of anti gram positive bacteria in biological activity.For the synthesis of this molecule,the key reactions we used are as follows:1)D-ring was constructed by Diels-Alder reaction with chiral substrate;2)C ring was constructed by intramolecular Aldol reaction;3)the molecular framework of formicamycin O was obtained by using PEDA reaction;4)using osmium tetroxide dihydroxylation strategy to construct the third-order chiral hydroxyl group between B-ring and C-ring;5)the chiral transfer strategy was used to construct the axial chiral center;6)the sulfonyl chloride reagent was used to introduce chlorine atoms into the E ring regioselectively.The total synthesis steps of formicamycin O were 19 and the total yield was 0.8%.This part of the work laid a foundation for the subsequent synthesis of a variety of formicamycin natural antibiotics.