叶松
论文题目：叶立德环丙烷化和环氧化反应的立体化学控制
作者简介：叶松，男，1973年01月出生，1997年09月师从于中国科学院上海有机化学研究所戴立信教授，于2002年08月获博士学位。
摘
要
烯基环丙烷结构单元广泛存在于天然和非天然的生物活性分子之中，并且烯基环丙烷衍生物也是非常重要的有机合成中间体。为此，人们发展了多种多样的合成此类化合物的方法学。然而由于此类反应往往涉及区域选择性、非对映选择性（包含顺反选择性）和对映选择性等问题，因而，多取代、多官能团光学活性烯基环丙烷衍生物的直接合成依然是有机合成中的难点之一。
1．立体化学开关：HMPA对烯丙型碲叶立德和a，b-不饱和酯、酰胺环丙烷化反应的顺反选择性调控作用。
黄耀曾等报道，烯丙基碲叶立德易于制备，当它和a，b-不饱和酯反应，能以高收率、高顺反选择性地得到相应的烯基环丙烷衍生物。有趣的是，选择不同的碱，能够控制该叶立德环丙反应的立体化学。当采用KHMDS作碱时，反应受热力学控制，得到顺式为主的环丙烷化产物；而当反应体系存在锂离子时，反应可能通过锂离子和底物及叶立德配位，形成六元环过渡态，从而得到反式为主的环丙烷化产物。由此我们设想，通过添加锂离子络合剂，阻止锂离子和底物及叶立德的配位，从而调控该反应的立体化学。
HMPA是一种高极性的非质子溶剂，它能够和锂离子发生很强的络合作用。实验表明，碲盐在LDA作用下，现场生成的含硅烯丙基碲叶立德和肉桂酸甲酯反应，高产率、高选择性地得到以酯基和烯基成反式的环丙烷化产物。而相同的反应，在HMPA存在下，高产率、高选择性地得到酯基和烯基成顺式的环丙烷化产物。HMPT、TMEDA、PMDETA和12-冠-4等络合剂对此反应立体化学的影响也进行了研究。同时研究表明，HMPA的用量对反应的产率和顺反选择 性亦有较大影响。通过对一系列底物研究表明，对于b-芳基或b-烷基的a，b-不饱酯、酰胺和该烯丙基型碲叶立德的环丙烷化反应，HMPA都能调控反应产物的立体化学。
这一工作，为合成两种顺反异构的烯基环丙烷衍生物中的任意一种提供了较为简便的途径；给出一个文献中很少见的利用添加剂调控反应立体化学的实例。
2. (-)-8-Phenylmenthol为手性辅基的光学活性烯基环丙烷衍生物的高选择性合成。
文献报道，(-)-8-phenylmenthol辅基在Michael加成反应中常表现出的优秀手性诱导效果。考虑到叶立德环丙烷化反应的第一步也是叶立德碳负离子对Michael受体的加成，我们着手研究这一辅基在不对称叶立德环丙烷化的应用。研究发现，烯丙型碲叶立德能够和(-)-8-phenylmenthol的a，b-不饱和酯反应，高产率、高非对映选择性地得到光学活性的烯基环丙烷衍生物。研究了温度、反应物比例、加料方式、溶剂、碱等反应条件对此不对称叶立德环丙烷化反应的影响；考察了底物a, b-不饱和化合物的适用范围，a-位可以是氢也可以是芳基，芳环上取代基的电子效应不明显。
通过对比了(-)-menthyl、(-)-8-(2-naphthyl)menthyl和(-)-8-Phenylmenthyl作手性辅基的情况，认为手性辅基上的芳基和a, b-不饱和酯的双键可能存在π-Stacking作用是此反应能取得良好的手性诱导效果的关键。
该反应手性辅基易于回收、选择性好，产率高，这一工作为合成多取代的光学活性乙烯基环丙烷衍生物的提供了一种较为简便的方法。
3．手性硫叶立德控制的高对映选择性合成多取代烯基环丙烷衍生物。
前述工作中，我们发现锂离子对烯丙型碲叶立德和a，b-不饱和酯、酰胺反应的立体化学控制起着重要的作用。基于此，我们设想在叶立德的杂原子（X）附近引入一个可供配位的基团（比如羟基、胺基等），利用这类基团与金属离子的配位作用形成较为刚性的过渡态，从而可能提高反应选择性。从价廉易得的手性源D-樟脑出发，合成了硫原子b-位含有羟基的手性硅基烯丙基硫盐。
为了稳定生成的烯丙基硫叶立德，并抑制它的2, 3-sigma重排反应，在硫叶立德结构上做了两方面的考虑：一是在烯丙基双键的未端引入硅基，利用硅原子对a-碳负离子的稳定作用来稳定烯丙基硫叶立德；二是在硫原子的b-位引入羟基，利用羟基氧对硫正离子的作用来稳定硫叶立德。
在反应条件上也做了相关考察：一是在加料方式上采用的一锅煮的方法，避免的了高浓度叶立德的存在；二是采用了固液相转移的技术，加入固体碱降低了溶液中碱的浓度。研究了温度、碱的种类和用量、溶剂和添加剂等对反应的影响，给出较为适宜的反应条件。反应的底物适用范围较宽：a, b-不饱和酯、酰胺、酮、腈均能较好地反应；b-位为氢或芳基时反应的顺反选择性很好，b-位为烷基时，反应的顺反选择性中等；所有例子的对映选择性都高于92%，最高可达99%。
考察了硫盐结构对反应的影响，当硫盐中碳-硫键位于樟脑骨架endo位置和碳-硫键位于exo位置时所得环丙烷化反应主产物的绝对构型相反。
根据硫盐晶体结构和硫盐在反应中所表现的性质，认为硫叶立德b-位的羟基可能是反应取得高对映选择性的关键。
对映选择性的合成1，2，3-三取代的乙烯基环丙烷衍生物目前文献中还缺乏有效的方法。在这一章中，我们利用易得的手性烯丙基硫叶立德为对映选择性的合成这类化合物提供了简便有效的方法。
4．手性硫叶立德控制的高对映选择性合成烯基环氧化合物
光学活性烯基环氧化合物是一类非常有用的有机合成中间体。由于烯基环氧化合物中存在多种官能团，因而往往需要采用间接的方法来合成。烯丙型叶立德对醛的加成是为数多不多的直接方法之一。然而对于叶立德途经的烯基环环氧化合物的对映选择性合成，文献中还很少有报道。
我们发现上述烯丙型硫叶立德能够和芳香醛反应，以良好的顺反选择性，优异的对映选择性得到相应的烯基环氧化合物。
根据反应条件对反应的影响并结合通过单晶测定的反式环氧化产物的绝对构型，我们提出了氢键起主导作用的手性诱导机制。
综上述，本论文主要研究了烯丙型硫、碲叶立德与Michael受体环丙烷化反应的立体控控制。先后通过三种途经（添加剂、手性辅基、手性试剂）分别实现了叶立德环丙烷化反应的顺反选择性、非对映选择性以及对映选择性控制。论文对手性烯丙型硫叶立德不对称环氧化反应也做了初步的研究。
Abstract
The occurrence of vinylcyclopropane subunit in many natural and synthetic biologically active compounds, as well as its utility as a synthetic intermediate, has promoted many strategies for its construction. In view of the difficulty associated with the regioselectivity, diastereoselectivity (cis/trans) and enantioselectivity, the highly selective synthesis of optically active multisubsituted vinylcyclopropanes in one step remains a challenging problem.
1. Switching of stereochemistry: Dramatic effect of HMPA on the stereoselectivity of the cyclopropanation reaction of telluronium allylides with α,β-unsaturated esters and amides.
Huang et al. reported that the telluronium allylides were readily available and reacted with α,β-unsaturated esters to provide the vinylcyclopropane derivatives in high yields with high stereoselectivity. Interestingly, the stereoselectivity of ylide cyclopropanation could be controlled by the choice of the base used for the formation of ylide. When KHMDS is used as the base, this cyclopropanation reaction is subject to thermodynamic control and the cis-isomer is the major product. In the presence of lithium salts, however, the reaction may proceed via a chelating six-membered ring transition state, which is formed by coordination of lithium ion with carbonyl oxygen and ylidic carbanion simultaneously. This coordination can change the stereochemical course of the reaction. This mechanistic insight suggested that it is possible to tune the stereoselectivity of such reactions by inhibition of the coordination in situ.
HMPA is a highly polar aprotic solvent which coordinates very well to the lithium ion. As expected, silylated telluronium allylide, which was generated in situ from the corresponding telluronium salt and LDA, reacted with methyl cinnamate to afford trans-2-phenyl-trans-3-((trimethylsilyl)vinyl)cyclopropyl ester in high yield with high selectivity in the absence of HMPA. The same reaction provided trans-2-phenyl-cis-3-((trimethylsilyl)vinyl)cyclopropyl ester in the presence of HMPA. The ability of HMPT, TMEDA, PMDETA and 12-crown-4 to affect the stereochemical course were also studied. Further studies showed that the amount of HMPA used in this reaction also influenced the stereoselectivity and the yield. The generality of this tuning reaction was established by investigating a variety of α,β-unsaturated carbonyl compounds as substrates. Either β-aryl-substituted or β-alkyl substituted α,β-unsaturated esters or amides were used, these reactions proceeded smoothly. HMPA, like a switch of stereochemistry, could play a crucial role to tune the stereoselectivity of these cyclopropanation reactions.
The switch-like method for the stereocontrol of ylide cyclopropanation provides a facile means for the synthesis of the two geometrical isomers of multifunctionlized 3-vinylcyclopropane derivatives.
2. Highly Diastereoselective synthesis of vinylcyclopropane derivatives with (-)-8-phenylmenthol as chiral auxiliary
It was reported that (-)-8-phenylmenthol is powerful chiral auxiliary in Michael addition reaction. The first step of ylide cyclopropanation is usually considered to be a Michael addition step, so we carried out the asymmetrical ylide cylcopropanation with (-)-8-phenylmenthol as a chiral auxiliary. It was found that silylated telluronium allylide could react with (-)-8-phenylmenthyl α,β-unsaturated esters to afford vinylcyclopropanes with high diastereoselectivity in high yields. The scope the substances was also investigated. It was found a variety of α,β-unsaturated esters can react smoothly to afford the corresponding products.
Based on the different reaction results with (-)-menthyl, (-)-8-(2-naphthyl)menthyl or (-)-8-phenylmenthyl as the chiral auxiliary, it is was proposed that the possible p-stacking effect between the aryl of chiral auxiliary and dienyl group of α,β-unsaturated esters is involved in the diastereoselectivity of these reactions.
The easy recovery of chiral auxiliary, good selectivity and high yield of this reaction make it a potential method in the synthesis of multifunctional optically active cyclopropane derivatives.
3. A novel chiral sulfonium ylide: Highly enantioselective synthesis of vinylcyclopropanes
In our previous research, we found lithium ion played a crucial role on the stereoselective tuning of the cyclopropanation reaction of telluronium allylides with α,β-unsaturated esters or amides. On the basis of its mechanistic insight, we proposed that it is possible to enhance its selectivity by formation of a rigid transition state if a coordination group (such as hydroxy or amino) is introduced into a chiral ylide molecule in the presence of a metal ion. Thus, the corresponding chiral sulfonium ylide was designed and its precursor was found to be readily available from the coresponing sulfide that was easily prepared from D-camphor in two steps.
Two special structural features of the sulfonium salt were proved to stabilize its corresponding ylide and depress the 2,3-sigma rearrangement. One is that there is a trimethylsilyl in the end of the allylic double band. This silicon atom can stabilize a α-carbon anion and the corresponding ylide. Another is that there is hydroxy group in the beta-position of sulfonium atom. The oxygen of this hydroxy group may stabilize the sulfonium cation.
The cyclopropantion reaction conditions were optimized. The one-pot approach was used to avoid the existence of high concentration of ylide, and Solid-Liquid phase transfer system was used to reduce the concentration of the base in the solution. It was found that a variety of α,β-unsaturated esters, amides, ketones and nitriles are all worked well to afford the cyclopropanation products in good yields. The trans/cis selectivities are excellent with the β-hydrogen or β-aryl substrates, while the selectivity is good with β-alkyl substrate. All reaction’s ee is higher than 92%, and up to 99%.
Several stereo-isomers of the sulfonium salt were also investigated. It was found that the endo-type sulfonium salts were also worked but afforded the corresponding cyclopropanes with opposite absolute configuration compared with that from the exo-type salt.
Based on the crystal structure of sulfonium salt and the reaction results, it was proposed that the β-hydroxy of the sulfonium salt play a key role in the highly stereoselective cyclopropantion reation.
Thus, we have developed an efficient method for one-step enantioselective synthesis of 1,3-disubsituted-2-silylvinylcyclopropanes. As a result, both diastereoselectivity(cis/trans) and enantioselectivity are excellent in most cases studied. Since the ylide is readily available from cheap D-camphor and the enantioselectivity is partially tunable, the current method has a high potential for practical use in organic synthesis.
4. Highly enantioselective synthesis of vinylepoxides via chiral sulfonium ylide
Optically active vinylepoxides are very useful intermediates in organic synthesis. Due to the multifunctional groups in the vinylepoxides, they are usually synthesized by indirect methods. The epoxidation reaction of allylide with aldehyde is one of the direct methods. However, the enantioselective synthesis of vinylepoxides by allylides is still rare in the literatures.
It was found that the allylide of sulfonium salt could react with aryl aldehydes to afford corresponding trans-epoxides in good yield with good trans/cis selectivity and excellent enantioselectivity.
Based on the results with several reaction conditions and the absolute configuration of epoxidation products, it was proposed that the excellent enantioselectivity was owed to the hydrogen bond between hydroxyl group and aldehyde.
In conclusion, three strategies (additive agent, chiral auxiliary or chiral reagent) were developed to improve the trans/cis selectivity, diastereoselectivity or enantioselectivity of the ylide cyclopropanation reactions. The success of these strategies provided facile and effective methodologies to the highly stereoselective synthesis of multisubstituted vinylcyclopropanes. The highly enantioselective synthesis of vinyl epoxide via chiral sulfonium ylide was also developed.
