Asymmetric Total Synthesis Of Stemona Alkaloids(+)-Croomine And(-)-Sessilifoliamide,Exploratory Studies Of Poison Dart Frog Alkaloid(-)-Batrachotoxinin A

Most natural products exhibite biological activities,and many drugs have been directly or indirectly derived from them.However,due to the low content of natural products in nature,the direct isolation of natural products directly from nature cannot meet the needs of activity testing and medicinal research.Therefore,it is of great significance to carry out the total synthesis of complex natural products.The traditional Chinese medicine Stemona has long been used for the treatment of respiratory diseases,such as pertussis and tuberculosis,and its main active ingredient is Stemona alkaloids.Up to 2019,more than 215 Stemona alkaloids had been isolated.Due to their challenging structures and interesting biological activities,they have attracted synthetic interest of organic chemists around the word.We have chosen two Stemona alkaloids(+)-croomine(1)and(-)-sessilifoliamide J(2)with similar structures as our synthetic target molecular.Poison dart frog is also an important source of natural products.To date,more than 800 alkaloids have been isolated from the skin or secretions of poison dart frogs.Among them,batrachotoxin(3)has strong cardiac and neurotoxic activity,and is one of the most toxic non-peptide neurotoxins known to mankind,with an LD50 in mice only 2 μg/Kg.In addition to its strong toxicity,it is also a very important specific activator of sodium ion channels(Nav`s),which is of great value for studying the structure and function of cell ion channels.(-)-Batrachotoxinin A(4)is the analog of batrachotoxin with a free hydroxyl group on C-20,and its toxicity is reduced to onethousandth of the later.We selected the safer(-)-batrachotoxinin A(4)as our research object.Tertiary amines are an important class of chemical substance,which not only are important intermediates in organic synthesis,but also the structural feather of many drugs and pesticides.Amides are a class of highly stable and readily available compounds.Thus,it is of great significance to develop a new method for the synthesis of α-substituted tertiary amines by alkylation of tertiary amides.The main results and observations from these studies are listed as follows:1.Asymmetric total synthesis of two Stemona alkaloids(+)-croomine and(-)sessilifoliamide J.Starting from the known compounds aldehyde 5 and(R)-tert-butylsulfinamide 6,the key intermediate AD ring building block 10 was obtained in six steps,including vinylogous Mannich reaction,hydrogenation and oxidation.Then through the vinylogous Mannich reaction again,and intramolecular alkylation reaction,we have completed the asymmetric total synthesis of the stemona alkaloid(+)-croomine(1).The whole synthetic route requires 10 steps,with a 15%overall yield.The key building block 10 reacted with the other(trialkylsilyl)oxy furan 14 by vinylogous Mannich reaction under the catalysis of Lewis acid to give compound 15.Lactam 16 was obtained in four steps,and finally hydrogenated to complete the asymmetric total synthesis of(-)-sessilifoliamide J(2).Starting from the known compound 5,this synthetic route includes 12 steps,with a 19%overall yield.2.Preliminary investigation for the asymmetric total synthesis of the poison dart frog alkaloid(-)-batrachotoxinin A.Among more than 800 alkaloids isolated from skins of poison dart frog,batrachotoxin had attracted the most widespread attention of scientists from several fields,due to its potent cardio and nerve toxicity and challenging structure.Herein,we disclose a new strategy,which is different from all the previous total syntheses(one racemic and two enantioselective).Our strategy features the formation of B ring and thus ABCDE ring of batrachotoxin by a key Diels-Alder reaction between A ring and CDE ring skeleton.Because A ring segment is a known compound,the first key of our synthesis resides in the synthesis of CDE ring segment.Thus,in addition to the new synthetic strategy,we describe herein a synthetic study on the CDE segment.The synthesis started from the preparation of 2-allylcyclopentane-1,3-dione(17)and its Michael addition with hex-1-en-3-one(18).The Hajos-Wiechert type reaction of the adduct was investigated and under optimized conditions,using L-phenylalanine as an organocatalyst and D-CSA as an additive,the desired Robinson annulation proceeded smoothly to give the desired cyclization product 20 in 75%yield and in 81%ee.The latter was converted in seven steps into a functionalized CD ring 21 that bears all elements for the formation of E ring.3.Terminal alkynes as surrogate of alkyl reagent for chemoselective reductive functionalization of tertiary amides.Tertiary amide(22 or 23)is reduced by the combination of iridium/silane to obtain enamine or azaacetal,which was coupled with terminal alkynes under the catalysis of cuprous bromide to obtain propargylamine.Finally,the propargylamine is hydrogenated to give the alkylated product(24 or 25).In this process,the terminal alkynes play the role of the alkylation reagents.Compared with the alkylation methods previous reported in the literatures,this reaction has better chemical selectivity and functional group tolerance,and achieves moderate to excellent yields.