【作者】 许佑君；

【导师】 钟大放； 柴崎 正勝；

【作者基本信息】 沈阳药科大学 ， 药学， 2003， 博士

【摘要】 以最简单的环己烯酮为起始原料，利用不对称Michael反应为关键步骤，预生产规模（公斤级）合成光学纯Michael加成物63，最终逐步实现了左旋士的宁（1）的不对称全合成。本研究的另一个关键步骤就是利用锌粉还原而引起的新型tandem环化反应来成功构筑B-和D-环系（Figure ab-1）。 （1）大规模合成光学纯Michael加成物 1996年，东京大学柴崎（M. Shibasaki）教授研究室研制出了多功能不对称催化剂（multifunctional asymmetric catalyst）—AlLibis（binaphthoxide）络合物（ALB），该催化剂高效催化环烯酮类与丙二酸酯类的不对称催化Michael反应。以后同一研究室又陆续报道了数个新型催化剂如LaNa₃tris（binaphthoxide）络合物、GaNabis（binaphthoxide）络合物和La-linked-BINOL络合物等，但从催化效率和催化剂的成本来看，ALB可以说是迄今最好的一个适用于Michael反应的催化剂。然而，为获得高化学收率、高光学纯度，即使经过优化改进，1mol％量的催化剂还是必需的。为拓宽这一成果在工业生产和天然产物如左旋士的宁不对称全合成研究领域的应用，本文进一步提高了催化剂的催化效率如催化剂的使用量、反应所需时间，而且也就反应的后处理作简化如革除了柱层析分离步骤等。我们详细讨论了添加剂、溶剂与配体的种类和加入量等因素的影响，最终发现，高浓度下可以显著提高该反应的速度，且化学收率和产品的光学纯度不受影响，从而使催化剂的用量从1.0降至0.1mol％，并于室温下、24 h即可反应完毕（scheme ab-1）。在实验室里我们即可逐渐将反应放大至预生产规模（公斤级），由于高浓度下进行反应，两升的烧瓶就可以完成该实验操作。普通后处理之后，以AcOEt／hexane为溶剂，从母液中三次析晶，得到白色晶状Michael加成物63，收率91％（1.24 kg），光学纯度大于99％ee。此外，结晶后所剩母液经萃取分离、回收约80％（R）-BINOL，其光学纯度不受影响。 据我们所知，上述反应是迄今最为实用、效率乃至选择性极高的不对称形成碳-碳键的一种方法。沈阳祷科大学博士李位论久:左谈士的宁的未对称全合成许佑君（2）光学选择性全合成左旋士的宁 有了大量光学纯的Michael加成物63，我们下一步着手来进行选择性全合成左旋士的宁的研究。选择左旋士的宁作为我们的目标分子，是因为它是strychno:生物碱类最具代表性的结构:虽然其结构较小，但仅有的24个原子却构成了7个骄环，6个手性中心紧密分布在一起，而且其中5个同处于一个环己基环上。就这种大小的分子来说，士的宁或许是最为复杂的一个。 此项工作具有一定难度，我们不得不数次更改研究方案。按照实验难度和进度，本文将研究工作分成三代。第一代研究工作集中于合成三环系中间体54（脱去PMB的中间体曾出现在Bosch报道的全合成路线中）的合成（Schemc ab一2）。首先要解决的问题就是在C一20位选择性地引入间一经乙叉基侧链，为此，以62为起始原料，我们尝试了几种方法:如syn一aldol/anti-消除由于选择性不高而不是很理想。最终发现，经络合机理以NaBH3CN/TICI;选择性还原日-酮基醋61制备anti一aldol，再与DCC/CuCI作用于中性条件下发生syn一消除反应，，.。at.:s。。石、3一一—一一兰兰 2 .LICI.HZO DMSO，140 OC （97%for 2 atePs） ^。。^，一7。。。。_自。一「1一。.一（^少冷丫cozMe ’^一一^N旧Me）Me土 肠2 610尸MB1 NaBH3CN T iC认，一55“C，COZMe2 DCC，CUCI benZ6ne re们UX介（72%.conv 82%）（70%for 2 stePs） 60 OPMBm ixture ofisomers （五了2.15.711）1 .01日^L一75 Oe2.一lpsoTf，E宝3N一75“e （日6%forZ鱿ePS）3 .eat.CSA.aCetone。介一1城)丫Mse一7。。e L，2 .eat.PdZ（dba）3 CHC13 d iallyl earbonate （90%for 2 stePs）1 .12.DMAp（BZ%）2 .eat.pdZ（dba）5 CHCI3 e乱Ph3As.eat.Culm ixtureofr铭ioisomers（》611）⑥SnMe3NOZ（quant）3 .3HF Et3N（q uant）一汉。户MB门les||esl||BIJ6匀OpMB…汤护N1尸日L 7oopMB_良萝、’一弄成气 OPMSOhemO BbweZ很顺利地解决了该问题。还原反应于THF中进行，并用CHZC12为co一solvent以溶解TIC14（比约为5/1）。该反应如果采用文献已报道的条件卜78’C)，产物的选择性不是很高（5 .7:1），经过系统研究，最终将反应温度升高至一55 OC，收率和选择性均显著提高（收率:75%，转化收率:88%选择性:15.7:1）（Figure ab一2）。第二个要解决的问题就是位置选择性地合成烯酮67（C3一c7）与它的异构体67，（C15一16），其中以高位阻的碱2，2，6，6一四甲基呱咙铿位置选择性形成烯醇硅醚（e7:ez6=>6:z），再经由”Pd”化学氧化即可完成。此saegusa一Ito反应:五{ ‘l一卜一斗-一卜^十一^J峭 -..一r，门o一temP tC]厂匆‘r..b宁经改进后，以PdZ（dba）3.cHcl:代替Pd（II），且不需要有机磷配体，可使反应由计更多还原

【Abstract】 An enantioselective total synthesis of (-)-strychnine (1) was achieved from easily accessible, optically pure Michael adduct 63, which was synthesized by the catalytic asymmetric Michael reaction on a greater than kilogram scale. Another key step in this entry was a novel tandem cyclization promoted by zinc reduction for the simultaneous construction of B- and D-rings (Figure ab-1).(1) Practical large-scale synthesis of enantiomerically pure Michael adductThe multifunctional asymmetric catalyst AlLibis(binaphthoxide) complex (ALB), which was developed by Prof. Shibasaki and co-workers in the University of Tokyo in 1996, is very effective for the catalytic Michael reaction of cyclic enones with malonates. Although several new catalysts including the LaNa3tris(binaphthoxide) complex, GaNabis(binaphthoxide) complex, and La-linked-BINOL complex have been developed in the above group, ALB is the most effective catalysts for the present Michael reaction in terms of catalyst efficiency and catalyst cost. Even improved procedure being used, however, 1 mol % of the catalyst was still required to obtain the product in excellent yield and high enentiomeric excess. In order to apply this chemistry to the synthesis of (-)-strychnine and a manufacturing scale synthesis, it was definitely necessary to further improve not only catalyst efficiency, such as catalyst loading and reaction time, but also the work-up procedure to eliminate the need for chromatographic separation. Thus, the effects of additive, solvent and ligand tuning were examined in this thesis and it was eventually discovered that the reaction was effectively accelerated under highly concentrated condition without lowering chemical yield or the high enantiomeric excess. Therefore, the catalyst loading was able to be decreased from 1.0 to 0.1 mol %. The reaction completed within 24 h at ambient temperature (Scheme ab-1) and was finally performed in pre-manufacturing scale (more than kilogram) synthesis, which was possible to be carried out in a two-literred flask due to the highly concentrated reaction condition. Followed an ordinary quenching procedure, theorganic layer was concentrated, and successively crystallized(total three times) from AcOEt/hexane to afford the Michael adduct 63 as a white crystal in 91% yield (1.24 kg) and morethan 99% ee. In addition, (R)-BINOL was recovered from the mother liquor by subsequent fractional extraction in about 80% yield without any loss of enantiomeric purity. To the best of our knowledge, the described method is one of the most practical and efficient catalytic asymmetric carbon-carbon bond formations in excellent enantioselectivity.(2) Enantioselective total synthesis of (-)-strychnineWith a large amount of the optically pure Michael adduct 63 in hand, our attention was then turned to the enantioselective total synthesis of (-)-strychnme, a flagship compound of strychnos alkaloids, ranking as one of themost complex natural products of its size: six contiguous asymmetric centers (five in the core cyclohexane ring) and a mere 24 skeletal atoms compactly arranged in its seven rings.The research proved to be challenging so that the synthetic strategies were modified for several times. In the first-generation strategy, the synthesis was directed to the key tricyclic intermediate 54 (similar to Bosch’s intermediate) (Scheme ab-2). The first challenging step was the (E)-selective introduction of the hydroxyethylidene moiety at C-20. Starting from 62, several methodologies were tried. For example, syn-aldol/anti-elimination proved to be fruitless due to their low selectivity. It was eventually found that the anti-aldol, obtained from the selectively chelatingreduction of the corresponding (3-ketoester 61 with NaBH3CN/TiCl4, and the following syn-elimination with DCC/CuCl under neutral condition, could tackle the problem. The reduction was carried out in THF using CH2C12 as a co-solvent for dissolving TiCl4 (ratio: ca. 5/1). Although it was moderate (5.7:1) under the original condition (-78℃),更多还原