【作者】 张文；

【导师】 陈芬儿；

【作者基本信息】 四川大学 ， 药物化学， 2022， 博士

【摘要】 象牙胺-长春胺(eburnamine-vincamine)类吲哚生物碱主要分布于夹竹桃科(Apocynaceae)仔榄树属(Hunteria)、蔓长春花属(Vinca)及蕊木属(Kopsia)等植物中,迄今已发现超过60个分子。此类生物碱在结构上具有典型的五环稠合骨架,通常在DE环连接处包含两个相邻的立体中心,根据结构特点可分为四种主要类型:Eburnane-Vincane型、Tacaman型、Schizozygane型和Bisindole型。绝大多数表现出良好的生理活性,尤其是在中枢神经系统方面,目前已有4个药物[长春胺(vincamine)、长春西汀(vinpocetine)、长春布宁(eburnamonine)、溴长春胺(brovincamine)]作为脑血管扩张和神经保护药上市销售。还有5个化合物处于临床试验阶段以及数十化合物正在进行临床前研究。同时由于天然来源的有限性,近几十年来,该类生物碱的高效合成一直是天然产物学和药物化学领域的研究热点。本论文采用不对称氢化反应策略对eburnamine-vincamine生物碱展开全合成研究,主要分为三部分。第一部分:二氢-β-咔啉不对称氢化/内酰胺化策略合成eburnaminevincamine生物碱。以正丁醛为起始原料,经Storck烷基化,以及Pictet-Spengler环化得到外消旋的内酰胺中间体,接着在连续流促进下经氧化/内酰胺醇解串联反应制备对称的二氢-β-咔啉二酯,进而以高效的对映选择性和非对映选择性发生Ir/f-Binaphane催化的不对称氢化/内酰胺化串联反应,同时以溶剂依赖的方式分别获得反式[94%ee(trans),7.4:1 dr(trans:cis)]和顺式[91%ee(cis),1.8:1dr(cis:trans)]稠合骨架,然后通过选择性酰胺还原、分子内环化、Davis氧化制备得到羟内酰胺中间体,再经Parikh-Doering氧化和Benzilic acid型重排分别得到eburnamine-vincamine生物碱(+)-vincamine,(–)-20-epi-vincamine。进一步酯基还原以及氧化裂解分别完成(–)-eburnamonine和(–)-20-epi-eburnamonine的不对称全合成。此外,将(+)-vincamine进行脱水并酯交换,还可得到(+)-vinpocetine。第二部分,底物结构调控的eburnamine-vincamine生物碱立体选择性合成。尽管C20/C21反式选择性在前述Ir/f-Binaphane催化的氢化/内酰胺化串联反应中得到了很好的解决,但顺式选择性并不令人满意。我们据此分析在去对称内酰胺化时,相对较大的丙酸酯基团处于椅式过渡态的平伏键,从而生成具有两个相邻的C20/C21反式立体中心的热力学稳定产物。因此,我们推测这种转化的非对映选择性可能与底物的固有性质密切相关,而增加与C20相连基团的体积,则有利于顺式选择性。通过对具有不同C20相连基团的二氢-β-咔啉二酯底物的不对称氢化/内酰胺化串联反应进行筛选,最终优选出C20具有叔丁氧乙基基团的二氢-β-咔啉二酯底物,经不对称氢化/内酰胺化串联反应以优异的对映选择性和非对映选择性[98%ee(cis),>20:1 dr(cis:trans)]获得C20/C21顺式立体中心的通用四环内酰胺中间体,并通过该中间体发散式合成了(–)-larutenine,(+)-eburnaminol,(–)-cuanzine,(+)-vincamine和(–)-criocerine。第三部分:(–)-tacamine的不对称全合成。从δ-戊内酯开始,经醇解开环,Storck烷基化,以及Pictet-Spengler环化等数步转化得到外消旋内酰胺中间体,接着在次氯酸叔丁酯促进下氧化为前手性的环烯胺底物,进而以优异的对映选择性(96%ee)发生Ir/Zhao Phos催化的不对称氢化反应,获得关键的顺式稠合的四环手性内酰胺中间体。随后,采用Aldol反应/脱水/氢化序列反应立体选择性引入C20乙基取代基,并利用前述E环构建方法,完成(–)-tacamine的首次不对称全合成。综上,本论文成功利用铱催化的亚胺不对称氢化/内酰胺化串联反应策略,以高对映选择性和非对映选择性完成了9个eburnamine-vincamine生物碱的不对称全合成。此外,通过环烯胺的不对称氢化策略完成(–)-tacamine的不对称全合成。其中,(–)-cuanzine与(–)-tacamine为首次不对称全合成,本论文也为其他类型eburnamine-vincamine生物碱的合成提供思路。更多还原

【Abstract】 The eburnamine-vincamine class of natural products,isolated from the plants of Apocynaceae genus Hunteria,Vinca,Kopsia,and Criocerus,is a structurally diverse family of indole alkaloids feature a common,highly fused pentacyclic scaffold that typically contains two adjacent stereocenters at the D-E ring junction,more than 60 molecules have been discovered so far.According to the structural characteristics,eburnamine-vincamine alkaloids could be divided into four types:Eburnane-Vincane type,Tacaman type,Schizozygane type and Bisindole type.Notably,most of them exhibit significant physiological activities,especially in the central nervous system.There are 4 drugs(vincamine,vinpocetine,eburnamonine,and brovincamine)are marketed as cerebral vasodilators and neuroprotective drugs,5 compounds are in clinical trials and dozens of compounds are undergoing preclinical research.Due to their remarkable pharmacological activities and limited natural abundance,the eburnamine-vincamine indole alkaloids has aroused general interest in the fields of medicinal chemistry and natural products science for decades.This thesis focuses on the total syntheses of eburnamine-vincamine alkaloids,adopts the asymmetric hydrogenation strategy,which would be expounded with three parts.In the first part,enantioselective syntheses of eburnamine-vincamine alkaloids by asymmetric hydrogenation/lactamization cascade of dihydro-β-carboline.Our synthesis commenced with Storck alkylation of n-butyraldehyde and subsequent Pictet-Spengler cyclization to afford racemic lactam ester intermediate,which could undergo acid triggered continuous-flow oxidation/lactam alcoholysis tandem reaction to yield symmetric dihydro-β-carboline diester.In turn,a highly stereoselective solvent-dependent Ir/f-Binaphane catalyzed hydrogenation/lactamization cascade leading to the trans-(20R,21S)lactam ester scaffold [94% ee(trans),7.4:1 dr(trans:cis)] and the cis-(20S,21S)lactam ester scaffold [91% ee(cis),1.8:1 dr(cis:trans)] respectively,with high-level enantio-and diastereocontrol.As a result,selective amide reduction of the enantiomerically enriched lactam ester intermediate,which then through a one-pot lactamization/Davis oxaziridine oxidation,Parikh-Doering oxidation followed by alkali-promoted stereospecific ring-contraction benzilic acid rearrangement to deliver(+)-vincamine and(–)-20-epi-vincamine respectively.In addition,ester reduction and oxidative cleavage of adjacent glycols provided(–)-eburnamonine and(–)-20-epi-eburnamonine respectively.Finally,(+)-vincamine is suffered dehydration and transesterification sequence to obtain(+)-vinpocetine.The second part,asymmetric syntheses of eburnamine-vincamine alkaloids by substrate steric effects.Although C20/C21 trans-selectivity was addressed by Ir/f-Binaphane catalyzed hydrogenation/lactamization cascade,the diastereoselectivities,especially cis-selectivities,were unsatisfactory.Formation of the trans product plausibly due to the desymmetrizing lactamization preferentially occurring from the recognized chairlike conformation with the relatively larger propionic ester group in the equatorial position,generating the thermodynamic product with two adjacent stereogenic centers in the C20/C21 trans form.Hence,we speculated that the diastereoselectivity of this transformation could be closely connected with the substrate’s nature,thereby increasing the steric bulk of the group attached to C20 favored the cis-selectivity.Therefore,the asymmetric hydrogenation/lactamization cascade with excellent control of both the enantioselectivity and C20/C21 cis-selectivity [98% ee(cis),> 20:1 dr(cis:trans)]when the ethyl tert-butyl ether substrate was employed,by screening the dihydro-β-carboline diester substrates with different substituents.With a common tert-butyl ether intermediate as the branch point and by diversified transformations,concise total synthesis of eburnamine-vincamine alkaloids(–)-larutenine,(+)-eburnaminol,(–)-cuanzine,(+)-vincamine and(–)-criocerine.The third part,asymmetric total synthesis of(–)-tacamine.We take advantage of δ-valerolactone as the starting material,which is converted into a racemic tetracyclic lactam intermediate by lactone alcoholysis,oxidation,Storck alkylation and Pictet-Spengler cyclization sequence.Then,the tetracyclic lactam intermediate was oxidized to the prochiral cyclic enamine under the promotion of tert-butyl hypochlorite.Next,the crucial Ir/Zhao Phos-catalyzed asymmetric hydrogenation reaction of cyclic enamine with high enantioselectivity(96% ee)to yield enantiomerically enriched tetracyclic lactam.Subsequently,an Aldol reaction/dehydration/stereoselective hydrogenation sequence was employed to furnish the C20 stereocenter,and then use of our developed E-ring construction method at the late stage,thus completed the first enantioselective total synthesis of(–)-tacamine.In conclusion,we have accomplished the asymmetric total syntheses of 9eburnamine-vincamine alkaloids that features a highly enantio-and diastereoselective Ir-catalyzed hydrogenation/lactamization cascade to access the crucial tetracyclic lactam ester skeleton.Additionally,the total synthesis of(–)-tacamine was completed via an asymmetric hydrogenation strategy of cyclic enamine.O f note,(–)-cuanzine and(–)-tacamine are the first asymmetric total synthesis,and this synthetic strategy should be applicable for assembling other related eburnamine-vincamine alkaloids.更多还原