Synthesis of Heterocycles by isothiourea organocatalysis
异硫脲有机催化合成杂环化合物

1 INTRODUCTION  1 简介

Organocatalysis is the phenomena used to describe the event when the rate of a chemical transformation is accelerated by incorporating small organic molecules. Although, this type of reaction was known since 19th century from the discovery of amine catalyzed Knoevenagel reaction, only a few examples were known till the last decade of 20th century. This field of organic chemistry was rediscovered again at the very end of 20th century. The term “Organocatalysis” was popularized by MacMillan in late 1990s following which a number of new reactivities and complex cascade reactions utilizing several organocatalysts have been developed.
有机催化是用于描述通过掺入有机小分子来加速化学转化速率的事件的现象。尽管这种类型的反应自19世纪发现胺催化的Knoevenagel反应以来就为人所知，但直到20世纪最后十年，已知的例子还很少。有机化学这一领域在20世纪末再次被重新发现。 “有机催化”一词在 20 世纪 90 年代末由 MacMillan 推广，随后利用多种有机催化剂开发了许多新的反应性和复杂的级联反应。

Many organocatalytic reactions have been reported by several scientists over the past three decades involving various kinds of organic molecules as catalysts. In his pioneering article on organocatalysis, MacMillan divided the organocatalysts into seven major classes^[1]: (a) primary and secondary amines, (b) thioureas, (c) Brønsted acids like phosphoric acids, (d) Brønsted bases like chincona derivatives, (e) quaternary ammonium salts, (f) N-heterocyclic carbenes, etc. However, the article did not include amidine and other nucleophilic bases^{[2, 3]} as catalysts, possibly the chemistry with this class of organocatalysts was still underdeveloped. Among the nucleophilic bases, a relatively newly introduced and less highlighted class of organocatalysts are isothioureas. Mainly cyclic isothioureas have been explored in finding new chemical reactivities. The chemistry of isothiourea catalysis started with acyl transfer reaction in the course of kinetic resolution and desymmetrization studies. Later isothiourea was employed in several organic transformations including enantioselective versions. Complex cascade reactions catalyzed by chiral isothioureas affording various carbocycles and heterocyles have also been developed. The present review focuses on the synthesis of heterocyclic molecules employing isothiourea as catalysts in organic transformations.
在过去的三十年里，一些科学家报道了许多涉及各种有机分子作为催化剂的有机催化反应。在他关于有机催化的开创性文章中，MacMillan 将有机催化剂分为七大类¹ ：(a) 伯胺和仲胺，(b) 硫脲，(c) 布朗斯台德酸，如磷酸，(d) 布朗斯台德碱，如钦科纳衍生物，(e) )季铵盐、(f) N-杂环卡宾等。但该文章并未包含脒和其他亲核碱^{2 , 3}作为催化剂，可能此类有机催化剂的化学仍不发达。在亲核碱中，相对较新引入且不太突出的一类有机催化剂是异硫脲。主要探索了环状异硫脲以寻找新的化学反应性。异硫脲催化化学从动力学拆分和去对称化研究过程中的酰基转移反应开始。后来异硫脲被用于多种有机转化，包括对映选择性形式。还开发了由手性异硫脲催化的复杂级联反应，提供各种碳环和杂环。本综述重点关注使用异硫脲作为有机转化催化剂的杂环分子的合成。

The structural difference between famous and widely used organocatalyst thiourea and isothiourea lies in position of the carbon-heteroatom double bond. The structural feature and chemical properties of thioureas is determined by CS bond along with two adjacent amine substituents. In the thioureas, the electrophilic character of the carbon is largely diminished by the electron donating property of the the two adjacent nitrogens. On the other hand, the C-heteroatom π bond shifts to CN in isothioureas switching polarity of the molecule. Another common feature of isothiourea lies in its nucleophilic character as one of the two nitrogens can utilize its lone pair of electrons for the donation to an electrophile such as acyl cation, and the positive charge residing on the cationic intermediate gets stabilized by delocalization of charge over two nitrogens and one sulphur (Figure 1).
著名且广泛使用的有机催化剂硫脲和异硫脲之间的结构差异在于碳杂原子双键的位置。硫脲的结构特征和化学性质由C-S键以及两个相邻的胺取代基决定。在硫脲中，碳的亲电特性被两个相邻氮的给电子特性大大削弱。另一方面，在异硫脲中，C-杂原子 π 键转变为 C  N，从而改变了分子的极性。异硫脲的另一个共同特征在于其亲核特性，因为两个氮之一可以利用其孤对电子将其提供给亲电子试剂，例如酰基阳离子，并且阳离子中间体上的正电荷通过电荷离域而得到稳定。两个氮和一个硫（图1 ）。

2 THE REACTIVITY OF ISOTHIOUREA AS NUCLEOPHILE
2 异硫脲作为亲核试剂的反应活性

Isothioureas are nucleophilic in nature as well as possess Lewis base character. The reactivity of isothioureas in organocatalytic reactions depend on their nucleophilicities and Lewis basicities. Mayr and co-workers first reported a comparative study about the relative nucleophilicities and Lewis basicities of different cyclic isothiourea derivatives.^[4] To be noted, the SO interactions in the activated intermediates formed after reaction between catalyst and substrates led to the organized conformation furnishing the products with high stereocontrol which has been discussed later.
异硫脲本质上是亲核的并且具有路易斯碱特征。异硫脲在有机催化反应中的反应活性取决于其亲核性和路易斯碱性。 Mayr 和同事首先报道了关于不同环状异硫脲衍生物的相对亲核性和路易斯碱度的比较研究。 ⁴值得注意的是，催化剂和底物反应后形成的活化中间体中的 S  O 相互作用导致了有组织的构象，为产物提供了高度立体控制，这将在后面讨论。

The nucleophilic behavior of isothioureas empowers them with excellent catalytic activities and they readily form activated acyl isothiouronium intermediates from acyl halides or acid anhydrides. This intermediate acquires an enhanced electrophilicity with respect to starting carbonyl molecule and can be trapped by suitable nucleophiles which opens the window of a new organocatalysis. Employing a nucleophile in the reaction system facilitates nucleophilic substitution to generate a carbonyl molecule with the regeneration of isothiourea. This concept was previously utilized by several research groups who have successfully used a range of chiral organic Lewis bases as asymmetric acyl transfer catalysts to secondary alcohols as a route to the kinetic resolution.^[5
异硫脲的亲核行为使其具有优异的催化活性，并且它们很容易从酰基卤或酸酐形成活化的酰基异硫脲中间体。该中间体相对于起始羰基分子具有增强的亲电性，并且可以被合适的亲核试剂捕获，从而打开新有机催化的窗口。在反应体系中使用亲核试剂有利于亲核取代生成羰基分子并再生异硫脲。这个概念之前被几个研究小组利用，他们成功地使用一系列手性有机路易斯碱作为仲醇的不对称酰基转移催化剂，作为动力学拆分的途径。 ^5]

3 KINETIC RESOLUTION OF SECONDARY ALCOHOLS: ENTRY OF ISOTHIOUREA IN ORGANOCATALYSIS
3 仲醇的动力学拆分：异硫脲进入有机催化

As an alternative approach of enzymatic kinetic resolution of racemic secondary alcohols, several chiral organic bases have been developed as nucleophilic acyl transfer organocatalysts like chiral derivatives of guanidines, imidazoles,^[6] DMAPs,^[7] NHCs.^[8] In addition to that, Birman and co-workers developed an elegant method of acyl transfer to alcohols catalyzed by cyclic amidines.^[9] The study was extended to the kinetic resolution of racemic secondary alcohols via enantioselective acyl transfer catalyzed by chiral variant of cyclic amidines. In 2006, Kobyashi and Okamoto reported their investigations on the acyl transfer experiments promoted by cyclic isothiourea derivatives which had structural resemblences with amidines.^[10] A comparative analysis was carried out by employing two amidines (1a and 1b), two isothioureas (2a and 2b) and DMAP (3) as the acyl transfer agent to 1-phenylethyl alcohol. The reaction rate was very slow when amidines 1a and 1b were used as catalysts. With isothiourea 2a, reaction was completed within 15 hours whereas, reactions with both DMAP and 2b were accomplished within 15 minutes (Scheme 1). To investigate the reaction pathway, a 1:1 mixture of the isothiourea 2a and acetic anhydride in CDCl₃ was analyzed in 500 MHz NMR which showed the presence of acylated isothiouronium intermediate in considerable amount. This further support that acyl migration takes place to the alcohol via activated isothiouronium intermediate.
作为外消旋仲醇的酶动力学拆分的替代方法，已经开发了几种手性有机碱作为亲核酰基转移有机催化剂，如胍、咪唑、 ^{6 个}DMAP、 ^{7 个}NHC 的手性衍生物。 ⁸除此之外，Birman 和同事开发了一种由环脒催化的酰基转移到醇的优雅方法。 ⁹该研究扩展到通过环状脒的手性变体催化的对映选择性酰基转移进行外消旋仲醇的动力学拆分。 2006年，Kobyashi和Okamoto报道了他们对与脒结构相似的环状异硫脲衍生物促进的酰基转移实验的研究。^图10使用两种脒（ 1a和1b ）、两种异硫脲（ 2a和2b ）和DMAP（ 3 ）作为1-苯乙醇的酰基转移剂进行比较分析。当脒1a和1b用作催化剂时，反应速率非常慢。使用异硫脲2a ，反应在15小时内完成，而使用DMAP和2b两者的反应在15分钟内完成（方案1 ）。为了研究反应途径，在500 MHz NMR 中分析了异硫脲2a和乙酸酐在CDCl ₃中的1:1 混合物，结果显示存在大量酰化异硫脲中间体。 这进一步支持酰基通过活化的异硫脲中间体迁移到醇。

Birman and co-workers first employed a chiral isothiourea derivative as the enantioselective acyl transfer catalyst for the kinetic resolution of racemic secondary alcohol. A bicyclic isothiourea 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole, 4a (known as tetramisol) was used in this experiment which is cheap and commercially available owing to its frequent use in medicines and veterinary. 1-Phenyl propanol was resolved by using the catalyst 4a with s-factor of 31 (Scheme 2).^[11
Birman 和同事首先采用手性异硫脲衍生物作为对映选择性酰基转移催化剂，用于外消旋仲醇的动力学拆分。本实验使用双环异硫脲 6-苯基-2,3,5,6-四氢咪唑并[2,1- b ]噻唑, 4a （称为四胺醇），由于其经常用于药物和药物，因此价格便宜且可商业购买。兽医。使用s因子为31的催化剂4a拆分1-苯基丙醇（方案2 ）。 ^11]

In the line of previously developed nucleophilic catalysts of 2,3-dihydroimidazo[1,2-a]pyridine (DHIP) series^{[6, 9, 12]} for enantioselective acylation, authors have found that enantioselectivities were superior when benzene ring was incorporated in the DHIP core due to enhancement in π-π interaction. This observation tempted them to design benzannulated derivative of tetramisole, named 2-phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole (benzotetramisole, BTM), 5a. It is prepared by condensing 2-chlorobenzo[d]thiazole and (R)-2-amino-2-phenylethanol to afford 5aa which was led to an intramolecular cyclization to end up with (R)-benzotetramisole (Scheme 3).^{[11, 13}
在先前开发的用于对映选择性酰化的 2,3-二氢咪唑并[1,2-a]吡啶 (DHIP) 系列^{6 、 9 、 12}亲核催化剂中，作者发现当苯环掺入 DHIP 中时，对映选择性更优异核由于 π-π 相互作用的增强。这一观察结果促使他们设计了四咪唑的苯并环化衍生物，命名为2-苯基-2,3-二氢苯并[d]咪唑并[2,1 -b ]噻唑（苯并四咪唑，BTM）， 5a 。它是通过2-氯苯并[ d ]噻唑和( R )-2-氨基-2-苯基乙醇缩合得到5aa而制备的，5aa进行分子内环化最终得到( R )-苯并四咪唑（方案3 ）。 ^{11 , 13]}

A substantial increase in the s factor for kinetic resolution of 1-phenyl propanol was accomplished by (R)-BTM, 5a as the catalyst. The s factor increased greatly in the presence of bulkier alcohols (Scheme 4A).^[11] The enantioselective acyl transfer initiates with nucleophilic attack by isothiourea to carbonyl center of the acid anhydride producing activated acyl ammonium ion intermediate 8. Alcoholysis of this intermediate with secondary alcohol produces acetate. Enhanced enantioselectivity of the reaction with benzannulated catalyst 5a can be explained by π-π interaction between arene ring (from BTM) of activated electrophile 8 and arene moiety present on the secondary alcohol 8′ which forces the alcohol to undergo nucleophilic displacement selectively from one face of the intermediate (Scheme 4B).
( R )-BTM, 5a作为催化剂，显着提高了 1-苯基丙醇动力学拆分的s因子。当存在体积较大的醇时， s因子大大增加（方案4A ）。 ¹¹对映选择性酰基转移起始于异硫脲对酸酐羰基中心的亲核攻击，产生活化的酰基铵离子中间体8 。该中间体与仲醇醇解产生乙酸盐。苯并环化催化剂5a反应的对映选择性增强可以通过活化亲电子试剂8的芳烃环（来自 BTM）与仲醇8 ' 上存在的芳烃部分之间的 π-π 相互作用来解释，这迫使醇从一个面选择性地进行亲核置换中间体（方案4B ）。

Birman and co-workers prepared two new catalysts namely the homotetramisole (HTM) 6 and homo benzotetramisole (HBTM) 7a in which they have expanded the imidazoline moiety of their previously reported catalysts to tetrahydropyrimidine. Both of them were synthesized from (S)-3-amino-3-phenylpropanol. When enantiopure γ-amino alcohol is treated with 2-(methylthio)-4,5-dihydrothiazole·HI, a 4,5-dihydrothiazol-2-amine derivative 9 is produced in 50% yield which is then cyclized by Et₃N and SOCl₂ to prepare homo tetramisole 6 in 74% yield. Preparation of HBTM, 7a from the γ-amino alcohol was carried out via an another two-step protocol (Scheme 5).^[14
Birman 和同事制备了两种新催化剂，即均四咪唑 (HTM) 6和均苯四咪唑 (HBTM) 7a，其中他们将之前报道的催化剂的咪唑啉部分扩展为四氢嘧啶。两者都是由( S )-3-氨基-3-苯基丙醇合成的。当对映体纯γ-氨基醇用2-(甲硫基)-4,5-二氢噻唑·HI处理时，以50%的收率生成4,5-二氢噻唑-2-胺衍生物9 ，然后用Et ₃ N环化并SOCl ₂制备均四咪唑6 ，收率74％。通过另一个两步方案（方案5 ）从γ-氨基醇制备HBTM， 7a 。 ^14]

In 2013, a preparative method toward racemic HBTM was developed by Romo and co-workers.^[15] Their synthetic strategy involved annulation between 2-amino benzothiazole and α,β-unsaturated acid chloride to afford dihydropyrimidone. Next Grignard additon followed by reduction under Brønsted acid conditions provided a series of racemic HBTM derivatives. Both of these catalysts HTM and HBTM were more active in the kinetic resolution studies of racemic 1-phenylpropanol than the previously reported KR with BTM catalyst (Scheme 6).
2013年，Romo和同事开发了一种外消旋HBTM的制备方法。 ¹⁵他们的合成策略涉及 2-氨基苯并噻唑和α , β-不饱和酰基氯之间的环化，得到二氢嘧啶酮。接下来格氏加成，然后在布朗斯台德酸条件下还原，得到一系列外消旋 HBTM 衍生物。这两种催化剂 HTM 和 HBTM 在外消旋 1-苯基丙醇的动力学拆分研究中比之前报道的带有 BTM 催化剂的 KR 更活跃（方案6 ）。

The major isothiourea molecules which have been discussed in this review are depicted in the Figure 2. Any other isothiourea catalysts used in this review have been mentioned therein.
本综述讨论的主要异硫脲分子如图2所示。其中提到了本综述中使用的任何其他异硫脲催化剂。

4 REACTIVITIES OF ISOTHIOUREA IN CASCADE
4 异硫脲的级联反应活性

So far we have discussed representative examples on the isothiourea catalyzed kinetic resolution methods involving generation of an activated electrophile, acyl ammonium ion from the reaction between an acylating agent and an isothiourea catalyst.^[6] Basically, LUMO of carbonyl is stabilized upon formation of acylium cation and hence electrophilicity of the species is enhanced. Apart from this very usual mode of reactivity, another chemical activity promoted by isothiourea has been highlighted recently. Acidity of α-proton of the activated carbonyl of isothiourea bound acyl ammonium ion also increased markedly leading to the ready generation of enolate in the presence of a suitable base. Thus there occurs a rise in the HOMO energy level and enolate can act as a reactive nucleophile involving an inversion of reactivity (Scheme 7).^[16-18
到目前为止，我们已经讨论了异硫脲催化动力学拆分方法的代表性实例，涉及通过酰化剂和异硫脲催化剂之间的反应生成活化的亲电子试剂酰基铵离子。 ⁶基本上，羰基的 LUMO 在形成酰基阳离子时稳定，因此该物质的亲电性增强。除了这种非常常见的反应模式之外，最近还强调了异硫脲促进的另一种化学活性。异硫脲结合酰基铵离子的活化羰基的α-质子的酸性也显着增加，导致在合适的碱存在下容易生成烯醇化物。因此，HOMO 能级升高，烯醇化物可以充当反应性亲核试剂，涉及反应性反转（方案7 ）。 ^{16 - 18]}

The enolate and α,β-unsaturated acyl ammonium ion generated by isothiourea catalysis have been successfully employed in different cascade reactions to afford heterocyles. The present review focuses on the reaction methodologies catalyzed by isothioureas to synthesize diverse heterocylic moieties, the particular emphasis is given to their asymmetric synthesis by employing an enantiopure catalysts.
异硫脲催化产生的烯醇化物和α , β-不饱和酰基铵离子已成功用于不同的级联反应以提供杂环。本综述重点关注异硫脲催化合成不同杂环部分的反应方法，特别强调使用对映体纯催化剂进行不对称合成。

5 ISOTHIOUREA CATALYZED CASCADE PROCESSES TO FORM HETEROCYCLES VIA FORMAL [2 + 2] CYCLOADDITION
5 异硫脲催化级联过程通过形式 [2 + 2] CYCLOADDITION 形成杂环

The ammonium enolate derived from isothiourea and α-substituted acetic acids is nucleophilic enough to undergo nucleophilic addition with two π-electronic systems in [2 + 2] cycloaddition reactions. In 2010, Romo and co-workers first developed an isothiourea catalyzed cascade process to synthesize polycyclic β-lactones which proceeds through the formation of ammonium enolate. Previously developed Lewis base promoted intramolecular nucleophile catalyzed aldol-lactonization (NCAL) process in Romo's laboratory was applied for keto acid substrates with stoichiometric amount of 4-pyrrolidinopyridine (4-PPY) for the synthesis of racemic bicyclic and tricyclic β-lactones. Effort to make the process stereoselective was attempted by employing stoichiometric amount of (R)-tetramisole 4a as Lewis base catalyst with the keto acid substrate 11 to prepare tricyclic β-lactone 12 resulted in 53% chemical yield along with 97% enantiomeric excess. Their choice of starting substrate was 2,2-disubstituted cyclic 1,3-diketo molecule containing a carboxylic acid chain which was allowed to react with 1.5 equivalents of 1-bromo-N-propylpyridinium triflate as acid activator, 1.0 equivalent of (R)-tetramisole hydrochloride 4a, 5.0 equivalents of i-Pr₂NEt in DCM which afforded the cyclic lactone 12 in 27 hours of reaction time (Scheme 8).^[19
由异硫脲和α-取代的乙酸衍生的烯醇铵具有足够的亲核性，可以在[2 + 2]环加成反应中与两个π电子系统进行亲核加成。 2010年，Romo和同事首先开发了一种异硫脲催化级联工艺来合成多环β-内酯，该工艺通过烯醇铵的形成进行。 Romo实验室先前开发的路易斯碱促进的分子内亲核试剂催化羟醛内酯化（NCAL）工艺被应用于具有化学计量量的4-吡咯烷吡啶（4-PPY）的酮酸底物，用于合成外消旋双环和三环β-内酯。通过使用化学计量的( R )-四咪唑4a作为路易斯碱催化剂与酮酸底物11来制备三环β-内酯12 ，尝试使该过程具有立体选择性，结果是53%的化学产率和97%的对映体过量。他们选择的起始底物是含有羧酸链的2,2-二取代的环状1,3-二酮分子，使其与1.5当量的1-溴-N-丙基吡啶鎓三氟甲磺酸盐作为酸活化剂、1.0当量的( R )反应。 -盐酸四咪唑4a ，5.0当量的i -Pr ₂ NEt的DCM溶液，得到环内酯12在 27 小时的反应时间内（方案8 ）。 ^{19 号]}

In 2010, catalytic version of this process was published by same research group. The reaction of keto acid 11 in the presence of 20 mol% (S)-HBTM 7a catalyst, 1.25 equivalents of p-toluene sulfonyl chloride as activating agent, 4.0 equivalents of i-Pr₂NEt in DCM afforded β-lactone 12 as the single diastereomer with 58% chemical yield and 96% ee. Incorporation of 1.0 equivalent of LiCl as the Lewis acid activator in the reaction system enhanced the yield to 93% with a slight reduced ee of 90%. The substrate scope was wide as both five and six membered 1,3-dione acids participated in the reaction. Notably, this method was also well compatible with acyclic starting materials delivering bicyclic β-lactones (Scheme 9).^[20
2010年，同一研究小组发表了该过程的催化版本。酮酸11在20mol%( S )-HBTM 7a催化剂、1.25当量对甲苯磺酰氯作为活化剂、4.0当量i -Pr ₂ NEt的DCM溶液存在下反应，得到β-内酯12。单一非对映异构体，化学收率 58%，ee 96%。在反应体系中加入1.0当量的LiCl作为路易斯酸活化剂将收率提高至93%，同时ee略微降低至90%。底物范围很广，五元和六元1,3-二酮酸都参与反应。值得注意的是，该方法也与提供双环β-内酯的无环起始材料很好地兼容（方案9 ）。 ^20]

Activating agent produces acid-anhydride 13 after reacting with acid residue of the starting material 11. Next, catalyst displaces the tosylate to generate active acyl ammounium ion 14 as reaction intermediate. Due to enhanced acidity of methylene protons of the acylium intermediate 14, in the presence of excess amount of i-Pr₂NEt, spontaneous enolization occurs to provide enolate 15. Then enolate nucleophile undergoes intramolecular aldol-reaction with one of the ketone functional group leading to the desymmetrization of the 1,3-dione furnishing a five membered ring 16. Follow up lactonization provides tricyclic β-lactone 12 along with catalyst turnover. The process has been described as intramolecular nucleophile catalyzed aldol lactonization (NCAL) by the authors (Scheme 10). Stereochemical outcome of this process can be rationalized from the proposed transition state 18 adopting a chair like conformation stabilized by LiS chelation. Lithium ion also activates ketone moiety in the TS through coordination, thus increasing the product conversion. In comparison to 18, the transition state without LiCl, 17 lacking any LiS interaction, the arrangement is dictated by n_O→σ^*_CS interaction as proposed by Birman. This interaction restricts CN bond rotation, which results in a better stereochemical outcome. With LiCl, n_O→σ^*_CS interaction is replaced by lithium, which favors CN bond rotation thereby diminishing the enantioselectivity.
活化剂与原料11的酸残基反应后产生酸酐13 。接下来，催化剂置换甲苯磺酸盐，生成活性酰基铵离子14作为反应中间体。由于酰基中间体14的亚甲基质子的酸性增强，在过量的i -Pr ₂ NEt存在下，发生自发烯醇化以提供烯醇化物15 。然后烯醇化亲核试剂与酮官能团之一进行分子内羟醛反应，导致1,3-二酮去对称化，形成五元环16 。后续内酯化提供三环β-内酯12以及催化剂周转。作者将该过程描述为分子内亲核试剂催化的羟醛内酯化 (NCAL)（方案10 ）。该过程的立体化学结果可以从所提出的过渡态18合理化，过渡态 18 采用通过 Li - S 螯合稳定的椅状构象。锂离子还通过配位激活TS中的酮部分，从而提高产物转化率。与没有 LiCl 的过渡态18相比， 17缺乏任何 Li  S 相互作用，其排列由 Birman 提出的 n _O→ σ ^* _{C  S}相互作用决定。这种相互作用限制了 C  N 键旋转，从而产生更好的立体化学结果。 对于LiCl，n _O→ σ ^* _{C  S}相互作用被锂取代，这有利于C  N 键旋转，从而降低了对映选择性。

Few years later, NCAL process was successfully employed in asymmetric total synthesis of spirolactones, curcumanolide A and curcumalactone. These sesquiterpenes are found in the crud drug, zedoary used to treat cervical cancer and exhibits anti-inflammatory activity. The synthesis involved (R)-HBTM (ent-7a) catalyzed NCAL process carried on dione acid molecule 19 to prepare tricyclic β-lactone 20 in 65% yield in gram scale with >19:1 dr and 98% ee. Next, 20 was subjected to Baeyer-Villiger oxidation to expand the ring to δ-lactone 21 which was then treated with catalytic amount of TMSOTf in benzene to afford the spiro-γ-lactone 22 in 73% yield and 98% ee through a dyotropic rearrangement. This is the key intermediate compound for the first asymmetric synthesis of the targeted natural products. From 22, total synthesis of (−)-curcumanolide A was accomplished in 5 steps and (−)-curcumalactone was prepared in 6 steps (Scheme 11).^{[21, 22}
几年后，NCAL工艺成功应用于螺内酯、姜黄内酯A和姜黄内酯的不对称全合成。这些倍半萜存在于用于治疗宫颈癌的生药莪术中，并具有抗炎活性。该合成涉及 ( R )-HBTM ( ent - 7a ) 催化的 NCAL 过程，在二酮酸分子19上进行，以克级产率 65% 制备三环β-内酯20 ，dr > 19:1，ee 98%。接下来，将20进行Baeyer-Villiger氧化，将环扩环为δ-内酯21，然后用催化量的TMSOTf在苯中处理，通过双变反应得到螺-γ-内酯22 ，收率73%，ee 98%重新排列。这是首次不对称合成目标天然产物的关键中间体化合物。从22开始，(-)-姜黄内酯A的全合成通过5步完成，并且(-)-姜黄内酯通过6步制备(方案11 )。 ^{21 , 22]}

Another successful application of NCAL was reported for preparing N-heterocycle fused bicyclic β-lactones. The starting material was N-linked keto acid 23 which was treated with (S)-HBTM 7a as catalyst in presence of p-TsCl as activator, i-Pr₂NEt and LiCl as additive in CH₂Cl₂ to afford the bicyclic molecular scaffolds 24 in good chemical yields and high enantioselectivities (Scheme 12).^[23
NCAL 的另一个成功应用是制备N-杂环稠合双环β-内酯。起始材料为N-连接酮酸23 ，在CH ₂ Cl ₂中，在p -TsCl作为活化剂、 i -Pr ₂ NEt和LiCl作为添加剂的存在下，用( S )-HBTM 7a作为催化剂处理，得到双环分子支架24具有良好的化学产率和高对映选择性（方案12 ）。 ^23]

Smith et al reported an isothiourea catalyzed generation of ammonium dienolate from β-alkenoic acid 25. β-Alkenoic acid was employed as enolate precursor in combination with 3 equivalents of pivaloyl chloride, 5.5 equivalents of DIPEA and 10 mol% HBTM-2.1 7b as catalyst in CH₂Cl₂ to generate dienolate 28 as intermediate. This dienolate underwent smooth formal [2 + 2] cycloaddition reaction with N-tosyl aldimine 26 to afford the medicially important β-lactam 27. In the model experiment at room temperature, (E)-pent-3-enoic acid and aldimine 26 were used to isolate 27 as a 68:32 diastereomeric mixture in good enantioselectivities and yields. Notably, when reaction temeperature was lowered to −78°C enantioselectivity was dramatically improved as the major anti diastereomer was formed with 97% ee and the minor syn one with complete enantioselectivity (Scheme 13).^[24] Substrate scope was achieved by varying both acid and aldimine components. As the aldimine components, both electron donating and withdrawing groups were incorporated in benzene ring as well as naphthalene and heterocycle rings were also tested. Mostly (E) configured enoic acids were employed as acid components with methyl, ethyl, isopropyl and benzyl substituents at one end. The yields varies from 48-86% and diastereoselctivity (anti:syn) varies from 2.3:1 to 6.7:1. The major diastereomers were formed with 86-98% ees whereas minors were formed with 97 ≥ 99% ees. One example was reported with (Z)-acid affording syn diasteromer as the major one. (1.33:1 syn: anti).
Smith 等人报道了异硫脲催化从β-链烯酸生成二烯酸铵25 。使用β-烯酸作为烯醇化物前体，与3当量新戊酰氯、5.5当量DIPEA和10mol％HBTM-2.1 7b作为催化剂在CH ₂ Cl ₂中组合，生成作为中间体的二烯醇化物28 。该二烯醇化物与N-甲苯磺酰醛亚胺26进行顺利的正式[2 + 2]环加成反应，得到具有医学意义的β-内酰胺27 。在室温下的模型实验中，使用 ( E )-戊-3-烯酸和醛亚胺26以良好的对映选择性和产率分离出27作为 68:32 非对映异构体混合物。值得注意的是，当反应温度降低至 -78°C 时，对映选择性显着提高，因为主要的反式非对映异构体形成了 97% ee，而次要的顺式异构体则具有完全的对映选择性（方案13 ）。 ²⁴底物范围是通过改变酸和醛亚胺成分来实现的。作为醛亚胺组分，还测试了苯环以及萘和杂环中引入给电子基团和吸电子基团的情况。大多数( E )构型的烯酸被用作一端带有甲基、乙基、异丙基和苄基取代基的酸组分。产率从 48% 到 86% 不等，非对映选择性 ( anti:syn ) 从 2.3:1 到 6.7:1 不等。主要非对映体由 86-98% ee 形成，而次要非对映体由 97 ≥ 99% ee 形成。 报道的一个例子是( Z )-酸提供顺式非对映体作为主要的一种。 （1.33:1顺：反）。

Another isothiourea catalyzed enantioselective formal [2 + 2] cycloaddition toward β-lactam synthesis was reported by Smith and co-workers. The chiral catalyst HBTM-2.1 7b was their optimal choice in combination with simple aryl acetic acid or symmetrical aryl acetic anhydride to generate acyl isothiouronium intermediate which was coupled with N-sulfonyl aldimines 30 to afford anti-β-lactams 31 in moderate to good yields and appreciable stereoselectivities.^[25] The methodology with aryl acetic acid involves reaction of 1 equivalent of the acid component 29 with 1.5 equivalents of tosyl chloride and 1.5 equivalents of i-Pr₂NEt along with the catalyst in dichloromethane at ambient temperature to generate 3,4-disubstituted β-lactams 31. Discrepancy between the amount of conversion and isolated yield indicated the instability of lactam in chromatographic separation which required further in situ derivatization. The derivatization was achieved by methanolysis of the lactam moiety to afford β-amino esters (Scheme 14A).^[25
Smith 及其同事报道了另一种异硫脲催化的对映选择性形式 [2 + 2] 环加成反应来合成β-内酰胺。手性催化剂HBTM-2.1 7b是他们的最佳选择，与简单的芳基乙酸或对称的芳基乙酸酐结合生成酰基异硫脲中间体，该中间体与N-磺酰醛亚胺30偶联，以中等至良好的产率提供抗-β-内酰胺31和明显的立体选择性。 ²⁵使用芳基乙酸的方法涉及 1 当量的酸组分29与 1.5 当量的甲苯磺酰氯和 1.5 当量的i -Pr ₂ NEt 以及催化剂在二氯甲烷中在环境温度下反应，生成 3,4-二取代的β -内酰胺31 .转化率和分离收率之间的差异表明内酰胺在色谱分离中不稳定，需要进一步原位衍生化。通过内酰胺部分的甲醇分解来实现衍生化以提供β-氨基酯（方案14A ）。 ^25]

Although the protocol allows synthesis of amino esters via [2 + 2] annulation in reasonable yields over two-step, still, direct synthesis of structurally interesting β-lactam motif was challenging which was achieved by employing even simpler starting reagent as homo aryl acetic anhydrides 33 avoiding the use of any external activating agent. The anhydride reacted directly with aldimine 30, i-Pr₂NEt (1.5 equiv.) and HBTM-2.1 7b (5 mol%) in DCM at −78°C and the β-lactams were isolated with moderate to good yields supported by appreciable stereocontrol (Scheme 14B).
尽管该方案允许通过[2 + 2]环化以合理的产率通过两步合成氨基酯，但结构上有趣的β-内酰胺基序的直接合成仍然具有挑战性，这是通过使用更简单的起始试剂如同芳基乙酸酐来实现的33避免使用任何外部活化剂。酸酐在 -78°C 的 DCM 中直接与醛亚胺30 、 i -Pr ₂ NEt（1.5 当量）和 HBTM-2.1 7b （5 mol%）反应，以中等至良好的收率分离出β-内酰胺立体控制（方案14B ）。

Subsequently, Smith and co-workers reported an isothiourea (HyperBTM or HBTM-2.1, 7b) catalyzed enantioselective synthesis of isolable perfluoroalkyl-substituted β-lactones using bench-stable symmetric anhydrides 34 and perfluoroalkyl substituted ketones 35 with high degree of diastereo- and enantioselectivities. Derivatization of enantioenriched β-lactones into a variety of products proceeds through ring opening as well as two-step conversion to give perfluoroalkyl-substituted oxetenes, in good yields and with no loss in enantiopurity. The results from density-functional theory computations in tandem with ¹³C natural abundance KIE (Kinetic Isotope Effect) studies showed that a concerted asynchronous [2 + 2] cycloaddition mechanism is favored over a stepwise aldol-lactonization mechanism (Scheme 15).^[26
随后，Smith 及其同事报道了异硫脲（HyperBTM 或 HBTM-2.1, 7b ）催化对映选择性合成可分离的全氟烷基取代的β-内酯，使用稳定的对称酸酐34和全氟烷基取代的酮35 ，具有高度的非对映和对映选择性。对映体富集的β-内酯通过开环和两步转化衍生成各种产物，以良好的收率且不损失对映体纯度而得到全氟烷基取代的氧杂环丁烷。密度泛函理论计算与¹³ C 自然丰度 KIE（动力学同位素效应）研究相结合的结果表明，协同异步 [2 + 2] 环加成机制优于逐步羟醛内酯化机制（方案15 ）。 ^26]

Isothiourea, HBTM-2.1 was prepared in the laboratory by a seven step protocol starting from benzaldehyde. Multigram synthesis of the catalyst was accomplished in an overall yield of 38% in enantiopure form without any chromatographic purification (Scheme 16).^[27
异硫脲，HBTM-2.1 是在实验室中从苯甲醛开始通过七步方案制备的。催化剂的多克合成以对映体纯形式以38%的总产率完成，无需任何色谱纯化（方案16 ）。 ^27]

Recently, Deng and co-workers documented an enantioselctive isothiourea catalyzed formal [2 + 2] cycloaddition reaction between aryl acetic acid and isatin derived ketimines to prepare spiroxindole-β-lactams (Scheme 17).^[28
最近，Deng 和同事记录了芳基乙酸和靛红衍生的酮亚胺之间对映选择性异硫脲催化的正式 [2 + 2] 环加成反应，制备了螺吲哚-β-内酰胺（方案17 ）。 ^28]

6 SIX MEMBERED HETEROCYCLE FORMATION BY FORMAL AND CONCERTED [4 + 2] CYCLOADDITIONS
6 通过正式且一致的[4 + 2]环加成形成六元杂环

[4 + 2] Cycloaddition is a fundamental annulation strategy for constructing six membered carbo and heterocyles. Organocatalysis has been extensively employed in [4 + 2] cycloaddition in course of region, chemo and stereoselective synthesis of the cyclic molecular scaffolds. Isothiourea catalyzed formation of ammonium ion intermediate can be applied in [4 + 2] cycloaddition reaction which is very well explored by several research groups. The isothiouronium enolate has been employed as Michael donor to different α,β-unsaturated carbonyls which produces a variety of heterocycles in cascade processes. The overall transformation serves as [4 + 2] cycloaddition reaction. Alternatively, α,β-unsaturated acyl isothiouronium intermediate has been utilized as Michael acceptor toward several nucleophiles in the course of heterocycle synthesis.
[4 + 2] 环加成是构建六元碳和杂环的基本环化策略。有机催化已广泛应用于环状分子支架的区域合成、化学合成和立体选择性合成过程中的[4+2]环加成反应。异硫脲催化形成铵离子中间体可应用于[4+2]环加成反应，多个研究小组对此进行了很好的探索。异硫脲烯醇盐已被用作不同α ， β-不饱和羰基的迈克尔供体，在级联过程中产生各种杂环。整个转化为[4+2]环加成反应。或者， α , β-不饱和酰基异硫脲中间体已在杂环合成过程中用作几种亲核试剂的迈克尔受体。

Smith and co-workers showed an elegant application of isothiourea promoted enolate generation from acids in course of a cascade pathway to prepare polycyclic lactones. The process describes (S)-tetramisole 4a catalyzed highly stereoselective reaction of intramolecular Michael addition and lactonization of enone-acids to synthesize indane and dibenzofuran carboxylates after derivatization. Enone acid 37 was treated with 20 mol% of tetramisole hydrochloride 4a, 1.2 equivalent of pivaloyl chloride as the activator, 3.6 equivalents of Hünig's base in dichloromethane as solvent. The reaction afforded polycyclic lactone 38 containing two stereo centers in 62% yield with 99:1 diastereomeric ratio and 97% enantiomeric excess at room temperature within 1 hour reaction time. The lactone on methanolysis produced disubstituted indane derivative 39 in quantitative yield (Scheme 18).^[29
史密斯及其同事展示了异硫脲在制备多环内酯的级联途径中促进酸生成烯醇化物的巧妙应用。该工艺描述了( S )-四咪唑4a催化分子内迈克尔加成和烯酮酸内酯化的高度立体选择性反应，衍生后合成茚满和二苯并呋喃羧酸盐。将烯酮酸37用20mol％的盐酸四咪唑4a 、作为活化剂的1.2当量新戊酰氯、作为溶剂的二氯甲烷中的3.6当量的Hünig碱处理。该反应在室温下1小时反应时间内得到含有两个立体中心的多环内酯38，产率62%，非对映异构体比例为99:1，对映异构体过量为97%。内酯经甲醇分解产生定量产率的二取代茚满衍生物39 （方案18 ）。 ^29]

Exploration of substrate scope went smoothly with both electron-donating as well as electron-withdrawing substituents in the aromatic tethered enone acid and also with alkyl substituted starting material. The yield varies from 43% to 99% with diastereomeric ratio up to 99:1 and enantiomeric excess up to 99%. Further broadening of substrate scope was accomplished by employing an enone tethered with an oxy acetic acid 40 as the starting material which provided dihydrobenzofuran ester 41 after methanolysis of reaction product (Scheme 19).^[29
对于芳香族系链烯酮酸中的给电子取代基和吸电子取代基以及烷基取代的起始材料，底物范围的探索进展顺利。产率从 43% 到 99% 不等，非对映体比例高达 99:1，对映体过量高达 99%。通过使用与羟基乙酸40连接的烯酮作为起始材料来进一步拓宽底物范围，其在反应产物的甲醇解后提供二氢苯并呋喃酯41 （方案19 ）。 ^29]

Pivaloyl chloride generates mixed anhydride 42 upon reacting with the acid residue of starting substrate 37 or 40. Subsequent nucleophilic attack by isothiourea to carbonyl center of mixed anhydride generates acyl ammonium intermediate 43. Enhanced acidity of the protons adjacent to carbonyl moiety of 43 promotes formation of enolate intermediate 44 in presence of Hünig's base. Then 44 acts as Michael donor to enone moiety to facilitate subsequent intamolecular 1,4-addition reaction to generate intermediate 45 which on lactonization affords polyclic molecule 38/41 with necessary catalyst turnover. The transition state 46 involves a stabilizing interaction between enolate O and S atom of the catalyst which places O atom syn to S making the process highly enantioselctive (Scheme 20).
新戊酰氯在与起始底物37或40的酸残基反应时生成混合酸酐42 。随后异硫脲对混合酸酐的羰基中心进行亲核攻击，生成酰基铵中间体43 。在 Hünig 碱的存在下，与43的羰基部分相邻的质子的酸性增强促进了烯醇化物中间体44的形成。然后44充当烯酮部分的迈克尔供体以促进随后的分子内1,4-加成反应以生成中间体45 ，其在内酯化时提供具有必要的催化剂周转的多环分子38/41 。过渡态46涉及催化剂的烯醇化物O和S原子之间的稳定相互作用，其将O原子与S顺式放置，使得该过程具有高度对映选择性（方案20 ）。

Isothiourea mediated generation of enolate can also be employed in intermolecular Michael addition. In the same article, authors have shown the application of isothiourea enolate in intermolecular conjugate addition. The process involves reaction between aryl acetic acid 29 and Michael acceptor α-keto-β,γ-unsaturated ester 47 in combination with 1.5 equivalents of pivaloyl chloride as activating agent, 4.5 equivalents of i-Pr₂NEt and 10 mol% HBTM-2.1 7b as catalyst which afforded trisubstituted anti-dihydropyranone 48. In a tandem Michael-addition, lactonization and ring opening by methanolysis could furnish the the chiral building-block 49 in excellent overall yields and stereoselectivities (Scheme 21).

The mechanistic pathway can be depicted as follows - a mixed anhydride 50 is generated from initial reaction between the acid and pivaloyl chloride which produces an acyl ammonium ion pair 51 through nucleophilic substitution by isothiourea. The enolate 52 is generated from 51 via deprotonation (by the carboxylate counter ion). The enolate undegoes 1,4-addition to enone moiety of Michael acceptor 47 to afford addition product 53 as the next intermediate. Follow up lactonization produces dihydropyranone 48 with catalyst turn over (Scheme 22).

Intermolecular Michael addition-lactonization-nucleophilic ring opening cascade was successfully applied in course of synthesizing syn-2,3-substituted tetrahydrofurans 55 as well as syn-3,4-substituted tetrahydrofurans 57. Model substrates for this protocol were enone acids lacking any aryl ring joint and oxygen was incorporated into the chain of the molecule. (S)-Tetramisole hydrochloride 4a was found to be the optimal catalyst affording the products in appreciable yields and high stereoselectivities (Scheme 23).^[30]

The method was also successful for enone-acid joined by pyrrole ring which afforded 2,3-dihydropyrrolizine fused δ-lactone 58 in presence of (+)-BTM 5b as the catalyst. In situ methanolysis cleaved the lactone to provide disubstituted pyrrolizines 59 in good yields and excellent stereoselectivities (Scheme 24).^[31
该方法对于通过吡咯环连接的烯酮酸也成功，在(+)-BTM 5b作为催化剂存在下得到2,3-二氢吡咯嗪稠合的δ-内酯58 。原位甲醇解裂解内酯，以良好的产率和优异的立体选择性提供二取代的吡咯嗪59 （方案24 ）。 ^31]

The protocol was further extended for the synthesis of chiral chromenone derivatives by isothiourea catalyzed 6-exo trig Michael addition-lactonization process. The starting material was enone acetic acid tethered by aromatic ring 60 which was treated with pivaolyl chloride in presence of base and (S)-tetramisole·HCl 4a as catalyst to facilitate an intramolecular ring closure delivering cis-chromenone derivatives 63 in good yields and excellent stereoselctivities (Scheme 25).^[32
该方案进一步扩展为通过异硫脲催化的6- exo trig Michael加成-内酯化过程合成手性色烯酮衍生物。以芳环60束缚的烯酮乙酸为起始原料，在碱和 ( S )-四咪唑·HCl 4a催化剂存在下，用新戊酰氯处理，促进分子内闭环，以良好的收率和优异的性能生成顺式色烯酮衍生物63。立体选择性（方案25 ）。 ^32]

Smith and co-workers reported an intermolecular cascade by chiral isothiourea catalyzed enantioselective synthesis of dihydropyridones 65 from simple aryl acetic acid and N-tosyl α,β-unsaturated ketimine 64. This organic transformation could effectively produce chiral δ-lactams which are important building blocks and molecular scaffolds present in numerous natural and bioactive molecules. (Scheme 26).^[33
Smith 及其同事报道了通过手性异硫脲催化对映选择性合成二氢吡啶酮65从简单的芳基乙酸和N-甲苯磺酰基α , β-不饱和酮亚胺64的分子间级联。这种有机转化可以有效地产生手性δ-内酰胺，这是存在于许多天然和生物活性分子中的重要构建块和分子支架。 （方案26 ）。 ^33]

Mechanism of this reaction proceeds through the formation of acyl ammonium ion intermediate 66 from the in situ generated mixed anhydride. The acyl ammonium intermediate generates enolate 67 under basic conditions which continues the catalytic cycle through 1,4-addition to α,β-unsaturated ketimine, affording the next intermediate 68. Finally, lactamization affords the target molecule 65 along with catalyst turnover (Scheme 27).
该反应的机制是通过从原位生成的混合酸酐形成酰基铵离子中间体66来进行的。酰基铵中间体在碱性条件下生成烯醇化物67 ，通过1,4-加成至α , β-不饱和酮亚胺继续催化循环，得到下一个中​​间体68 。最后，内酰胺化提供目标分子65以及催化剂周转（方案27 ）。

Smith and co-workers employed isothiouronium enolate in the reaction with trifluoromethyl substituted enones 69 to prepare δ-lactone via Michael addition-lactonization sequence. For controlling the enantioselectivity of the reaction, HBTM-2.1 7b showed the best results to afford anti-6-trifluoromethyl dihydropyranones 71 with good yields and moderate to excellent stereoselctivities (Scheme 28A).^[27] They also extended the same protocol starting from benchstable α-substituted ester. Their choice of ester was trichlorophenyl ary acetic esters 70 which afforded the same products on reaction with trifluoromethyl substituted enones 69 in presence of 10 mol% (S)-tetramisole 4a as catalyst and DIPEA as base. Advantage of this method was avoiding further activation of the starting substrate 29 as 2,4,6-trichlorophenylate (TCPO) 70 acts as good leaving group to generate acyl ammonium ion intermediate on reaction with the catalyst (Scheme 28).^[34]

They have also conducted a detailed mechanistic investigation for this cascade process. A model reaction was set between the mixed anhydride of para-fluro phenylacetic acid and enone in presence of catalytic amount of HBTM-2.1 7b and 2.5 equivalents of Hünig's base in CD₂Cl₂ at - 78°C. The reaction mixture was directly analyzed by ¹⁹F NMR spectroscopy. Data analysis by varying the concentrations of enone and catalyst fit well in accordance with first order kinetics with respect to anhydride and catalyst. The proposed mechanistic pathway involves initial formation of acyl isothiouronium intermediate 72 through nucleophilic addition of isothiourea to the mixed anhydride. This was further supported by isolation of the acyl intermediate 73 in 92% yield from direct reaction between p-fluoro phenylacetyl chloride and HBTM-2.1 7b in DCM. Deprotonation of 73 produces (Z)-enolate 74 which undergoes Michael addition to the enone moiety followed by lactonization to afford final product (Scheme 29).
他们还对这个级联过程进行了详细的机制研究。在催化量的HBTM-2.1 7b和2.5当量的Hünig碱存在下，在CD ₂ Cl ₂中，在- 78℃下，在对氟苯乙酸和烯酮的混合酸酐之间建立模型反应。通过¹⁹ F NMR光谱直接分析反应混合物。通过改变烯酮和催化剂的浓度进行的数据分析非常符合酸酐和催化剂的一级动力学。所提出的机制途径涉及通过异硫脲与混合酸酐的亲核加成初步形成酰基异硫脲中间体72 。通过对氟苯乙酰氯与 HBTM-2.1 7b在 DCM 中的直接反应分离出酰基中间体73 ，产率 92%，进一步支持了这一点。 73的去质子化产生( Z )-烯醇化物74 ，其经历迈克尔加成至烯酮部分，然后内酯化以提供最终产物（方案29 ）。

The enolate was also utilized in intermolecular Michael-addition-catalyst elimination cascade sequence in combination with different types of suitable Michael acceptors in course of preparing several cyclic molecules like substituted δ-lactones and lactams (Scheme 30).^{[35, 36}
在制备几种环状分子如取代的δ-内酯和内酰胺的过程中，烯醇化物还与不同类型的合适迈克尔受体结合用于分子间迈克尔加成催化剂消除级联序列（方案30 ）。 ^{35 , 36]}

In this line, Smith group further extended the scope of cascade reactions with pyrrol acetic acid 75 to generate enolate intermediate which undergoes Michael addition toward α,β-unsaturated carbonyl containing trihaloalkyl substituent 69. Michael addition and subsequent lactonization provided an unstable dihydropyranone derivative 76. In situ treatment of the product by external nucleophile opened the ring and furnished ring opened molecules 77 with excellent diastero and enantioselectivities. The diseter 77 was further converted to dihydroindolizinones 78 by treatment with BBr₃ via iIntramolecular Fridel-Crafts acylation. The Fridel-Crafts acylation was successful with only aryl substituents (RAr) without any loss in the stereocontrol. The reaction was catalyzed by HBTM-2.1 (Scheme 31).^[37
在这条路线上，Smith小组进一步扩展了与吡咯乙酸75的级联反应范围，生成烯醇化物中间体，该中间体与含有三卤代烷基取代基的α , β-不饱和羰基69发生迈克尔加成。迈克尔加成和随后的内酯​​化提供了不稳定的二氢吡喃酮衍生物76 。通过外部亲核试剂对产物进行原位处理，开环并提供具有优异的非对映选择性和对映选择性的开环分子77 。通过分子内 Fridel-Crafts 酰化用 BBr ₃处理，将二酯77进一步转化为二氢吲哚嗪酮78 。仅用芳基取代基 (R-Ar) 进行的 Fridel-Crafts 酰化反应是成功的，且立体控制没有任何损失。该反应由HBTM-2.1催化（方案31 ）。 ^37]

This two-step protocol to prepare dihydroindilizinones were merged together by the same research group in a one-pot enantioselctive tandem reaction to provide highly functionalized tetrahydroindolizine derivatives comprising of three stereocenters. In the process, 2-(pyrrol-1-yl) acetic acid 75 was coupled with either trifluromethyl enones or α-keto-β,γ-unsaturated esters in the presence of HBTM-2.1 7b as catalyst. Michael addition and lactonization steps provided dihydropyranones 80 which were treated with a nucleophile in the same pot to open the ring generating 81 which was further cyclized in situ to produce tetrahydroindolizines 79 (Scheme 32).^[38
同一研究小组将这种制备二氢茚嗪酮的两步方案合并在一起，进行一锅对映选择性串联反应，以提供包含三个立体中心的高度功能化的四氢茚嗪衍生物。在此过程中，2-(吡咯-1-基)乙酸75在HBTM-2.1 7b作为催化剂的存在下与三氟甲基烯酮或α-酮-β , γ-不饱和酯偶联。迈克尔加成和内酯化步骤提供二氢吡喃酮80 ，将其在同一罐中用亲核试剂处理以打开环，生成81 ，其进一步原位环化以产生四氢中氮茚79 （方案32 ）。 ^38]

Another report on isothiourea catalyzed intermolecular 1,4-addition of enolate to α-keto phosphonates was published by Smith and co-workers. The ammonium enolate generation strategy from simple aryl acetic acids is the same as described above and the enolate produces dihydropyranone derivatives 83 after Michael addition followed by lactonization reactions. Alcoholysis of dihydropyranones affords diesters 84 (Scheme 33).^[39
Smith 及其同事发表了另一篇关于异硫脲催化烯醇化物与α-酮膦酸酯分子间 1,4-加成的报告。由简单芳基乙酸生成烯醇铵的策略与上述相同，并且烯醇化物在迈克尔加成和内酯化反应后产生二氢吡喃酮衍生物83 。二氢吡喃酮的醇解提供二酯84 （方案33 ）。 ^39]

Isothiourea catalyzed enolate generation was successfully applied by the same research group in α-amination of simple carboxylic acids. Aryl acetic acids were used as the enolate precursor in combination with super stoichiometric amount of p-methoxy benzoyl chloride and 1.0 mol% of catalyst 7b. Ketohydrazide 85 was employed in the reaction system as Michael acceptor toward enolate to produce 1,3,4-oxadiazin-6(5H) one 86 as the final product after ring closure.^[40] The heterocyclic rings were further cleaved by treatment with suitable nucleophiles allowing access to ketohzydrazides 87 (Scheme 34).
同一研究小组成功地将异硫脲催化烯醇化物的生成应用于简单羧酸的α-氨基化。芳基乙酸用作烯醇化物前体，与超化学计量的对甲氧基苯甲酰氯和1.0mol%的催化剂7b组合。反应体系中采用酮酰肼85作为烯醇化物的迈克尔受体，闭环后生成最终产物1,3,4-恶二嗪-6(5 H )一86 。 ⁴⁰通过用合适的亲核试剂处理进一步裂解杂环，从而获得酮肼87 （方案34 ）。

Isothiourea catalyzed enolate generation was also achieved from α-heteroatom substituted carboxylic acids. As α-substitution thiophenyl (PhS-) group was incorporated in acid molecule and resulting trisubstituted enolate 92 was generated in the reaction from acyl isothiouronium ion 91 via deprotonation. The enolate was coupled with N-sulfonyl substituted α,β-unsaturated imines 88 by Michael addition reaction and follow up CN bond formation produced δ-lactam derivative 94. Under reaction conditions, PhSH elimination and N to O sulfonyl transfer cascade sequence occurred to afford biologically important 2,4,6-trisubstituted pyridines 89 (Scheme 35).^[41
异硫脲催化烯醇化物的生成也可以由α-杂原子取代的羧酸实现。当α-取代苯硫基(PhS-)基团被引入酸分子中时，酰基异硫脲离子91通过去质子化反应生成三取代烯醇化物92 。该烯醇化物通过Michael加成反应与N-磺酰基取代的α , β-不饱和亚胺88偶联，随后形成C - N键生成δ-内酰胺衍生物94 。在反应条件下，PhSH 消除和 N 到 O 磺酰基转移级联序列发生，产生生物学上重要的 2,4,6-三取代吡啶89 （方案35 ）。 ^41]

In an extension of this method, α,α-disubstituted carboxylic acid 96 was used to generate the tetrasubstituted enolate which produces dihydropyridinones 98 after reacting with conjugated imine 97 via 1,4-addition followed by lactamization reactions. However this time, PhSH elimination occurred neither under the reaction conditions nor at higher temperature or in the presence of excess Lewis base. Isolated dihydropyridinones 98 were treated under oxidizing conditions to oxidize the sulphide to sulfoxide which was eliminated at room temperature, and follow up N to O sulfonyl transfer at elevated temperature afforded substituted pyridines 99. The three steps protocol opens access to tri and tetra-substituted pyridine tosylates in moderate to good yields (Scheme 36).^[42
在该方法的扩展中， α , α-二取代的羧酸96用于生成四取代的烯醇化物，其通过1,4-加成和内酰胺化反应与共轭亚胺97反应后产生二氢吡啶酮98 。然而，这一次，PhSH 消除既不在反应条件下发生，也不在较高温度下或在过量路易斯碱存在下发生。分离的二氢吡啶酮98在氧化条件下处理，将硫化物氧化成亚砜，亚砜在室温下消除，随后在升高的温度下进行N至O磺酰基转移，得到取代的吡啶99 。三步方案以中等至良好的产率获得三和四取代的吡啶甲苯磺酸盐（方案36 ）。 ^42]

A one-pot synthesis toward disubstituted pyrrolidines involving sequential reaction steps of ozonolysis, Witting olefination, isothiourea catalyzed intramolecular ring closure and alcoholysis was reported by Smith and co-workers. The valuable heterocyclic motif was prepared from N-allyl β-amino acid 100. The starting material was ozonolyzed to aldehyde followed by Witting olefination with a carbonyl substituted phosphorus ylide to afford enone amino acid 104. The enone amino acid was treated in the same pot with 1.5 equivalents of pivaloyl chloride, 1.5 equivalents of i-Pr₂NEt and 5 mol% (−)-tetramisole·HCl (4a·HCl) in CH₂Cl₂ to prepare the pyrrolidine moiety fused with δ-lactone 101. This step proceeds through the formation of chiral isothiourea bound enolate which undergoes intramolecular Michael addition to the enone moiety producing N-heterocycle. Follow-up lactonization forms 101 which was treated with methanol to cleave the lactone ring because of the instability of lactone moiety in column chromatography to prepare syn-3,4-disubstituted pyrrolidine ring 102a. Substrate scope was broadened by varying the carbonyl moiety of the ylide as well as N-protecting groups. Single column chromatography allowed the isolation of sole diastereomer with appreciable yields and excellent enantiocontrol.^[43] Generality of the above method was also tested with N-butenyl α-amino acid as the starting material affording syn-2,3-disubstituted pyrrolidines 103a as the sole diastereomer with yields ranging 61-80% and enantiomeric excess ranging 91-99%.
Smith 及其同事报道了二取代吡咯烷的一锅法合成，涉及臭氧分解、Witting 烯化、异硫脲催化分子内闭环和醇解的连续反应步骤。有价值的杂环基序是由N-烯丙基β-氨基酸100制备的。将起始原料臭氧解成醛，然后用羰基取代的磷叶立德进行Witting烯化，得到烯酮氨基酸104 。将烯酮氨基酸与1.5当量新戊酰氯、1.5当量i- Pr ₂ NEt和5mol%(-)-四咪唑·HCl( 4a ·HCl)的CH ₂ Cl ₂溶液在同一锅中处理，制备吡咯烷与δ-内酯101稠合的部分。该步骤通过形成手性异硫脲结合的烯醇化物进行，该烯醇化物经历分子内迈克尔加成到烯酮部分，产生N-杂环。后续内酯化形成101，由于内酯部分在柱色谱中不稳定，用甲醇处理以裂解内酯环，制备顺式-3，4-二取代吡咯烷环102a 。通过改变叶立德的羰基部分以及N-保护基团拓宽了底物范围。单柱色谱可以分离唯一的非对映异构体，具有可观的产率和出色的对映体控制。⁴³还使用N-丁烯基α-氨基酸作为起始原料测试了上述方法的普遍性，得到顺式-2,3-二取代吡咯烷103a作为唯一的非对映异构体，产率范围为 61-80%，对映体过量范围为 91-99% 。

As the substitute of Wittig olefination reaction, cross metathesis was also successfully used in the telescoped synthesis of pyrrolidine derivatives. In this case, N-butenyl α-amino ester 100a or N-allyl β-amino ester 100b would afford the intermediate 104 upon treatment with an enone in presence of Grubb's II catalyst. Tetramisole catalyzed intramolecular cascade on 104 followed by nucleophilic ring opening delivered syn-2,3 and syn-3,4-disubstituted heterocycles (102b or 103b, Scheme 37).
作为Wittig烯化反应的替代，交叉复分解也成功地应用于吡咯烷衍生物的叠层合成。在这种情况下， N-丁烯基α-氨基酯100a或N-烯丙基β-氨基酯100b在格鲁布II催化剂存在下用烯酮处理后将提供中间体104 。四咪唑催化104上的分子内级联，随后亲核开环产生syn -2,3和syn -3,4-二取代杂环（ 102b或103b ，方案37 ）。

Ammonium dienolate 106 was employed also in [4 + 2] cycloaddition with suitable 4π electron systems. As for example electron deficient trifluoromethyl substituted α,β-unsaturated carbonyl 69 was coupled with dienolate 25 to prepare δ-lactones 105 containing two chiral centers via Michael addition-lactonization cascade. This elegant approach led to the access of trifluormethyl containing lactones (Scheme 38).^[24
二烯醇铵106也可用于与合适的 4π 电子系统进行的 [4 + 2] 环加成反应。例如，缺电子三氟甲基取代的α ， β-不饱和羰基69与二烯醇化物25通过迈克尔加成-内酯化级联偶联制备含有两个手性中心的δ-内酯105 。这种优雅的方法导致获得了含有三氟甲基的内酯（方案38 ）。 ^24]

Further expansion of reaction scope was achieved by employing N-carbonyl substituted diazenes 85 as the 4π electron component affording 1,3,4-oxadiazene-6-one 107 as the product via a formal [4 + 2] cycloaddition which upon in situ ring opening by MeOH produces hydrazide 108. The reaction is tolerated by both E- and Z-configured alkenoic acids and hydrazides are formed in appreciable yields (71%-87%) with excellent enantioselectivities (91%-99%, Scheme 39).^[24
通过使用N-羰基取代的二氮烯85作为4π电子组分，进一步扩大了反应范围，通过正式的[4 + 2]环加成得到1,3,4-二氮烯-6-酮107 ，其在原位环加成通过MeOH打开产生酰肼108 。 E-和Z-构型链烯酸均能耐受该反应，并且酰肼以可观的产率(71%-87%)形成，具有优异的对映选择性(91%-99%，方案39 )。 ^24]

Smith and co-workers reported an isothiourea-catalyzed enantioselective Michael addition-annulation process using α,β-unsaturated acyl ammonium catalysis. A range of polyfluorinated dihydropyranone and dihydropyridinone products were synthesized with high enantioselectivities. Significantly, the in situ generated aryloxide group TCPO ^̶ was found to play various roles in the reaction, including acting as (i) a Brønsted base, overcoming the need of the addition of an auxiliary base; and (ii) a Lewis base, catalyzing the isomerization of dihydropyranone products 111 into thermodynamically-favored dihydropyridinones 112. Additionally upon protonation of the aryloxide, TCP-OH was formed which can act as a Brønsted acid promoting an isothiourea-catalyzed kinetic resolution of benzoxazole-derived dihydropyranones 111. A transition state 113 is proposed for the stereochemical rationale (Scheme 40).^[44
Smith 及其同事报道了使用α , β-不饱和酰基铵催化的异硫脲催化的对映选择性迈克尔加成环化过程。合成了一系列具有高对映选择性的多氟二氢吡喃酮和二氢吡啶酮产品。值得注意的是，原位生成的芳氧基^TCPO在反应中发挥着多种作用，包括充当 (i) 布朗斯台德碱，克服了添加辅助碱的需要； (ii)路易斯碱，催化二氢吡喃酮产物111异构化为热力学有利的二氢吡啶酮112 。此外，在芳氧化物质子化时，形成TCP-OH，它可以充当布朗斯台德酸，促进苯并恶唑衍生的二氢吡喃酮的异硫脲催化动力学拆分111 。出于立体化学原理提出了过渡态113 （方案40 ）。 ^44]

Another report on isothiourea catalyzed formal [4 + 2] cycloaddition was published involving catalyst bound enolate as 2π electron component and in situ generated 1,2-diaza-1,3-diene as 4π electron component. α-Halo N-boc hydrazone 114 generates diaza diene 116 under basic reaction condition which undergoes annulation with enolate 117 to deliver dihydropyridazinone 115 (Scheme 41).^[45
另一篇关于异硫脲催化的形式[4 + 2]环加成反应的报道已发表，涉及催化剂结合烯醇化物作为2π电子组分，并原位生成1,2-二氮杂-1,3-二烯作为4π电子组分。 α-卤代N -boc腙114在碱性反应条件下生成二氮杂二烯116 ，其与烯醇化物117进行成环反应，生成二氢哒嗪酮115 (方案41 )。 ^45]

Smith and co-workers reported enantioselective Michael-Michael-lactonization cascade reaction using enone-malonates 118 as Michael donor-acceptor species to furnish δ-lactones 119. Addition of isothiourea catalyst 7b into α,β-unsaturated acid chlorides led to the generation of α,β-unsaturated acyl ammonium intermediates. When treated with MeOH and DMAP, the δ-lactones 119 facilitated ring opening resulting in tetrasubstituted cyclopentanes 120. This protocol has been applied to a range of enone-malonates, affording δ-lactones and cyclopentanes 120 in good yields and diastereoselectivities (Scheme 42).^[46
Smith 及其同事报道了使用烯酮丙二酸酯118作为迈克尔供体-受体物种的对映选择性迈克尔-迈克尔-内酯化级联反应，以提供δ-内酯119 。将异硫脲催化剂7b加成到α , β-不饱和酰氯中导致生成α , β-不饱和酰基铵中间体。当用MeOH和DMAP处理时， δ-内酯119促进开环，产生四取代的环戊烷120 。该方案已应用于一系列烯酮丙二酸酯，以良好的产率和非对映选择性提供δ-内酯和环戊烷120 （方案42 ）。 ^46]

α,β-Unsaturated acyl ammonium ion intermediate is an excellent Michael acceptor toward a range of suitable Michael donors. Romo and co-workers employed α,β-unsaturated acyl ammonium intermediate in Michael reaction with γ-keto diester molecule to furnish a cyclopentane fused β-lactone molecule.^[47] The unsaturated acyl ammonium intermediate 123 was generated from α,β-unsaturated acyl chloride in presence of isothiourea catalyst under basic condition. This intermediate was coupled with γ-keto diester anion 124 containing two nucleophilic and one electrophilic sites. The final outcome of this cascade process is cyclopentane fused β-lactone 122 containing at least two chiral centers. The enantioselective cascade was set up with first enolate formation using LiHMDS on diester 121 and the final bicyclic products 122 was obtained in 54 to 80% yields, 19:1 diastereoselectivity and excellent enantioselectivities. The complex cascade allowed the synthesis of high functionalized cyclopentane scaffolds with three quaternary centers. (Scheme 43).
α , β-不饱和酰基铵离子中间体是一系列合适的迈克尔供体的优异迈克尔受体。 Romo及其同事在Michael反应中使用α , β-不饱和酰基铵中间体与γ-酮二酯分子进行环戊烷稠合β-内酯分子。 ⁴⁷在异硫脲催化剂存在下，碱性条件下，由α , β-不饱和酰氯生成不饱和酰基铵中间体123 。该中间体与含有两​​个亲核位点和一个亲电子位点的γ-酮二酯阴离子124偶联。该级联过程的最终结果是含有至少两个手性中心的环戊烷稠合β-内酯122 。使用LiHMDS在二酯121上首先形成烯醇化物，建立对映选择性级联，并以54%至80%的收率、19:1的非对映选择性和优异的对映选择性获得最终双环产物122 。复杂的级联允许合成具有三个四级中心的高功能化环戊烷支架。 （方案43 ）。

The mechanistic picture can be depicted as follows - a lithiated carbanion 124 is formed by deprotonation and α,β-unsaturated acyl azolium ion 123 is generated from unsaturated acyl chloride as discussed earlier. The cascade begins with 1,4-addition between carbanion and acyl azolium ion intermediate to generate the next intermediate 125 also having an (Z)-enolate moiety. Lithium ion binds to enolate oxygen atom and carbonyl oxygen at the other end of the tether thus locking the intermediate 125 to a particular conformation which is important for selectivity of the reaction. Ammonium enolate 125 undergoes a follow up nucleophilic attack to carbonyl carbon at the other end of intermediate 125 to produce the cyclic intermediate 126 which forms the final product via lactonization (Scheme 44). The novel organo-cascade has been described as a Nucleophile Catalyzed Michael Aldol Lactonization (NCMAL) by authors. The reaction was compatible with several ester functional groups like COOMe, COOBn, COOallyl as electron withdrawing groups. Only one example was reported for the enantioselective version with carbonyl as electron withdrawing group in place of ester in 121.
机理图可以描述如下——通过去质子化形成锂化碳负离子124 ，并且如前所述由不饱和酰氯产生α , β-不饱和酰基氮鎓离子123 。该级联从碳负离子和酰基氮鎓离子中间体之间的1,4-加成开始，生成下一个也具有( Z )-烯醇化物部分的中间体125 。锂离子与连接链另一端的烯醇化氧原子和羰基氧结合，从而将中间体125锁定在特定构象上，这对于反应的选择性很重要。烯醇铵125对中间体125另一端的羰基碳进行后续亲核攻击，产生环状中间体126 ，其通过内酯化形成最终产物（方案44 ）。作者将这种新颖的有机级联描述为亲核试剂催化迈克尔醇醛内酯化（NCMAL）。该反应与多种酯官能团（如 COOMe、COOBn、COO烯丙基）作为吸电子基团相容。仅报道了一个以羰基作为吸电子基团代替121中的酯的对映选择性版本的例子。

There occurs an interaction (n_O to σ^*_CS) between carbonyl O and S in the catalyst moiety of acyl ammonium intermediate and the half chair conformation of pyrimidine ring makes CNC moiety planar bringing phenyl ring of the catalyst in pseudoaxial conformation. This orientation blocks Si face of the intermediate and nucleophilic attack occurs from Re face predominantly via a proposed transition state 127. Diastereoselectivity of the process can be rationalized from 1,3-strain. Two conformations (127A and 127B) of intermediate 125 are possible but 127A is free of any A^1,3 strain and more favorable than the other (Figure 3).
酰铵中间体催化剂部分的羰基O与S之间发生相互作用(n _O to σ ^* _{C  S} )，嘧啶环的半椅构象使C  N  C部分平面化，使催化剂的苯环处于平面状态。假轴构象。该取向阻止了中间体的Si面，并且亲核攻击主要通过所提出的过渡态127从Re面发生。该过程的非对映选择性可以从1,3-应变来合理化。中间体125可能有两种构象（ 127A和127B ），但127A不含任何A ^1,3应变，并且比另一种构象更有利（图3 ）。

Isothiourea generated α,β-unsaturated acyl ammonium ions can act as good dienophile partner in [4 + 2] cycloaddition reaction. Research group of Romo showed the application of this type of dienophile in Diels-Alder cycloaddition with suitable dienes. α,β-Unsaturated acyl chlorides 128 were used as the precursor for generation of chiral acyl ammonium salt upon reaction with (−)-BTM 5a. As 4π electron component, diene 129 was employed in the reaction system. The reaction afforded cis and trans fused bicylic γ-and δ-lactones 130 in excellent diastereoselectivity (in all cases the endo/exo ratio is >19:1, Scheme 45).^[48
异硫脲生成的α , β-不饱和酰基铵离子可以作为[4+2]环加成反应中良好的亲双烯体伴侣。 Romo研究小组展示了这种类型的亲双烯体在与合适的二烯的Diels-Alder环加成反应中的应用。 α , β-不饱和酰基氯128用作与 (-)-BTM 5a反应生成手性酰基铵盐的前体。反应体系中使用二烯129作为4π电子成分。该反应以优异的非对映选择性提供了顺式和反式融合的双环γ-和δ-内酯130 （在所有情况下，内型/外型比率>19:1，方案45 ）。 ^48]

The reaction is competent with both (E,Z) and (Z,Z) configured dienes. When (E,Z) dienes are used, cis fused bicyclic lactones are formed as a sole diastereomer, whereas trans fused bicycles are obtained from (Z,Z)-dienes. Variation in the alkyl chain length of the alcohol substitution in diene generates bicyclic δ-lactones as well as γ-lactones. The reaction is well tolerated by various acid chloride component to provide products in 46% to 92% yields and 91% to 99% enantioselectivities. Synthetic utility of this method was further explored in preparing the core intermediate for the total synthesis of racemates of fraxinellolone, an antifeedant and ichthyotoxic agent. In addition to that the same intermediate can be employed in the synthesis of trisporic acids and trisporols, naturally occurring fungal pheromones (Scheme 46).^[22
该反应适用于( E , Z )和( Z , Z )构型的二烯。当使用( E , Z )二烯时，顺式稠合双环内酯作为唯一的非对映异构体形成，而反式稠合双环由( Z , Z )-二烯获得。二烯中醇取代的烷基链长度的变化产生双环δ-内酯以及γ-内酯。该反应对各种酰基氯组分具有良好的耐受性，可提供 46% 至 92% 的产率和 91% 至 99% 对映选择性的产物。进一步探讨了该方法在制备全合成拒食剂和鱼毒剂弗克内洛龙外消旋体的核心中间体中的合成用途。除此之外，相同的中间体还可用于合成天然存在的真菌信息素三孢酸和三孢醇（方案46 ）。 ^{22 号]}

Mechanism of the above methodology has been depicted as follows: α,β-unsaturated acyl ammonium ion 131, is primary intermediate formed to initiate the catalytic cycle. The [4 + 2] cycloaddition between acyl ammonium 131 and diene 132 affords cyclohexene ammonium ion 133 and follow up ring closure generates 134 as the next intermediate. Then 134 promotes another proton transfer cycle where protonated oxygen is deprotonated by the base, 2,6-lutidine, generating 135 as final intermediate of the cycle. Lutidine transfers the proton to heterogeneous base K₃PO₄. The catalyst is eliminated from 135 to deliver fused bicycle lactones. Stereo selectivity of the reaction was explained by analyzing transition state 136 of Diels Alder reaction which reveals that endo selective annulation is kinetically more favorable and the diene approaches from top face of the intermediate 131 delivering major enantiomer (Scheme 47).
上述方法的机理描述如下： α , β-不饱和酰基铵离子131是形成催化循环的主要中间体。酰基铵131和二烯132之间的[4+2]环加成得到环己烯铵离子133 ，随后闭环生成134作为下一个中间体。然后134促进另一个质子转移循环，其中质子化氧被碱2,6-二甲基吡啶去质子化，产生135作为循环的最终中间体。卢剔啶将质子转移至非均相碱基K ₃ PO ₄ 。催化剂从135中消除，得到稠合的自行车内酯。通过分析 Diels Alder 反应的过渡态136解释了反应的立体选择性，这表明内选择性成环在动力学上更有利，并且二烯从中间体131的顶面接近，传递主要对映体（方案47 ）。

Isothiourea catalyzed Diels-Alder lactonization cascade was applied to stereo divergent resolution of racemic diene bearing a secondary alcohol moiety to access tricyclic fused γ-lactones, with an yield of 85% along with two readily separable diastereomers (139a and 140a, 1.4:1 dr). Further extension of this method was applied to racemic dienes containing secondary and tertiary alcohols in the course of synthesizing bi- and tri-cyclic γ-lactones via a stereo divergent DAL cascade.^[49] The use of sterically hindered tertiary amine, 2,6-lutidine, delivered products with highest enantioselctivity. It is clearly understood that competitive background reaction between Lewis base (BTM) and Brønsted base to form the acyl ammonium ion reduces enantiocontrol of the reaction as evidenced by lowering of ee in cases of triethyl amine and DIPEA as Brønsted bases. Furthermore, the endo/exo selectivity was also improved in presence of 2,6-lutidine. (Scheme 48).
异硫脲催化的 Diels-Alder 内酯化级联用于带有仲醇部分的外消旋二烯的立体发散拆分，得到三环稠合γ-内酯，产率为 85%，同时还得到两个易于分离的非对映体（ 139a和140a ，1.4:1 dr） ）。该方法的进一步扩展应用于通过立体发散DAL级联合成双环和三环γ-内酯过程中含有仲醇和叔醇的外消旋二烯。 ⁴⁹使用位阻叔胺 2,6-二甲基吡啶可提供具有最高对映选择性的产品。可以清楚地理解，路易斯碱 (BTM) 和布朗斯台德碱之间形成酰基铵离子的竞争性背景反应减少了反应的对映体控制，如三乙胺和 DIPEA 作为布朗斯台德碱时 ee 的降低所证明的那样。此外，在 2,6-二甲基吡啶存在下，内切/外切选择性也得到改善。 （方案48 ）。

Enantioselective DAL cascade was tested using a furan based diene 141 as the 4π electron partner delivering oxa-bridged, trans-fused tricyclic γ-lactam 142 as product. The tricyclic molecule was further derivatized to fully substituted tetrahydrofuran moiety 143, the core structure of natural product, istisine A (Scheme 49).^[50
使用基于呋喃的二烯141作为 4π 电子伴侣测试对映选择性 DAL 级联，提供氧桥联、反式稠合的三环γ -内酰胺142作为产物。三环分子进一步衍生为完全取代的四氢呋喃部分143 ，即天然产物 istisine A 的核心结构（方案49 ）。 ^50]

An enantioselective complex cascade catalyzed by HBTM-2.1 7b has been reported from Romo's lab to prepare fused tricyclic molecules bearing a β-lactone moiety. The cyclic Michael donor 144 reacts with β,β-disubstituted alkylidene malonate 145 to afford lithium enolate 145′ intermediate. It was then treated with chiral isothiourea 7b and unsaturated acid chloride to afford a complex molecular scaffold 146. The process comprises of Michael Michael Aldol Lactonization (MMAL) cascade which has been successfully employed as Dynamic Kinetic Asymmetric Transformation (DYKAT) of five membered cyclic β-keto esters (Scheme 50).^[51
Romo 实验室报道了一种由 HBTM-2.1 7b催化的对映选择性复合级联，可制备带有β-内酯部分的稠合三环分子。环状迈克尔供体144与β , β-二取代亚烷基丙二酸酯145反应，得到烯醇锂145 '中间体。然后用手性异硫脲7b和不饱和酰基氯对其进行处理，得到复杂的分子支架146 。该过程包括 Michael Michael Aldol 内酯化 (MMAL) 级联，该级联已成功用作五元环β-酮酯的动态动力学不对称转化 (DYKAT)（方案50 ）。 ^51]

Smith and co-workers employed symmetrical anhydride with chiral isothiourea to generate α,β-unsaturated acyl ammonium ion as the intermediate. It was successfully utilized as Michael acceptor toward active methylene groups like 1,3-diketo or β-keto ester molecules to prepare dihydropyranone derivatives 149. The method involves the reaction of a symmetrical α,β-unsaturated anhydride 147 (1.4 equiv.) with 5 mol% of isothiourea catalyst 7b and 1.1 equiv. of PS-BEMP (polymer supported 2-t-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine) as base to furnish dihydrapyranone 149 in 5 to 18 hours. In situ methanolysis of 149 affords functionalized esters 150 with appreciable yields and excellent strereocontrol (Scheme 51).^[52
Smith 及其同事使用对称酸酐与手性异硫脲生成α , β-不饱和酰基铵离子作为中间体。它被成功地用作活性亚甲基如1,3-二酮或β-酮酯分子的迈克尔受体，制备二氢吡喃酮衍生物149 。该方法涉及对称α , β-不饱和酸酐147 （1.4当量）与5mol%异硫脲催化剂7b和1.1当量的反应。以PS-BEMP(聚合物负载的2-叔丁基亚氨基-2-二乙基氨基-1,3-二甲基全氢-1,3,2-二氮杂膦)作为碱，在5至18小时内提供二氢吡喃酮149 。 149的原位甲醇解提供具有可观产率和优异立体控制的官能化酯150 （方案51 ）。 ^52]

Two alternative mechanisms were proposed for the enantioselective cascade process. Initial nucleophililic substitution by isothiourea generates s-cis configured conjugated acyl ammonium intermediate 151. A 1,4-addition by active methylene group of the dicarbonyl produces enolate intermediate 152 which underwent rapid protonation and lactonization to afford dihydropyranones. Alternatively, the reaction may proceed via a 1,2-addition to acyl ammonium intermediate generating 153 as the intermediate. A [3,3]-sigmatropic rearrangement followed by protonation generates the next intermediate 154 which proceeds to the final product via lactonization (Scheme 52).
针对对映选择性级联过程提出了两种替代机制。异硫脲的初始亲核取代生成顺式构型的共轭酰基铵中间体151 。二羰基的活性亚甲基进行 1,4-加成，生成烯醇化物中间体152 ，该中间体经历快速质子化和内酯化，得到二氢吡喃酮。或者，反应可以通过与酰基铵中间体的1，2-加成进行，生成153作为中间体。 [3,3]-σ重排随后质子化产生下一个中间体154 ，其通过内酯化作用产生最终产物（方案52 ）。

Subsequently, Smith and co-workers reported an isothiourea catalyzed enantioselective nucleophile dependent complex domino reaction to produce trisubstituted indane moiety fused with various heterocycles. Their choice of starting material was α,β-unsaturated enone tethered to α,β-unsaturated ester by a benzene ring 155. The ester moiety of bench stable starting material produced α,β-unsaturated acyl ammonium ion on reaction with isothiourea catalyst 7b. Incorporation of a good leaving group (trichlorophenonate, TCPO⁻) in the ester functionality circumvents the use of external activator. A suitable nucleophile triggered three step domino reaction to afford polycyclic molecular scaffolds with appreciable stereocontrol. The method was tested by varying nucleophiles such as 1,3-dicarbonyls, acyl benzimidazoles and acyl benzothiazoles with multiple reactive sites promoting three different domino processes. The mechanistic pathway differes on changing the nucleophiles. With 1,3-diketone the reaction proceeds via Michael-addition-Michael-addition-lactonization whereas with 2-acyl benzothiazole and 2-acyl benzimidazole, the process undergoes Michael-Addition-Lactamization-Michael-Addition (Scheme 53).^[53] The high level of molecular complexity was attributed by nucleophile directed divergent domino reactions via formation of multiple bonds and contiguous stereocenters.
随后，史密斯和同事报道了异硫脲催化的对映选择性亲核试剂依赖性复合多米诺反应，产生与各种杂环稠合的三取代茚满部分。他们选择的起始材料是通过苯环155连接到α , β-不饱和酯上的α , β-不饱和烯酮。实验室稳定起始原料的酯部分与异硫脲催化剂7b反应生成α , β-不饱和酰基铵离子。在酯官能团中加入良好的离去基团（三氯酚酯，TCPO ^- ）可以避免使用外部活化剂。合适的亲核试剂引发三步多米诺骨牌反应，以提供具有明显立体控制的多环分子支架。该方法通过不同的亲核试剂（例如 1,3-二羰基、酰基苯并咪唑和酰基苯并噻唑）进行了测试，这些亲核试剂具有促进三种不同多米诺骨牌过程的多个反应位点。改变亲核试剂的机制途径不同。对于1,3-二酮，反应通过迈克尔-加成-迈克尔-加成-内酯化进行，而对于2-酰基苯并噻唑和2-酰基苯并咪唑，该过程经历迈克尔-加成-内酰胺化-迈克尔-加成(方案53 )。 ⁵³分子的高水平复杂性归因于亲核试剂通过形成多重键和连续立体中心而引导的发散多米诺骨牌反应。

Synthesis of heterocyles involving isothiourea catalysis mostly involves cascade processes that proceeds through either α,β-unsaturated acyl ammonium ion 156 or ammonium enolate 157 as the intermediates. Computational studies showed that the intermediates are stabilized by 1,5-OS interaction which is characterized as chalcogen bond. This interaction locks geometry of the intermediate which dictates the stereochemical outcome of the reaction. Internuclear distance between S and O was calculated which was found to be less than the sum of vanderwaal radii of two atoms as evidenced by crystallographic study. The covalent interaction increases the electrophilicity of carbonyl group enhancing the rate of the catalytic cycle (Figure 4).^[54
涉及异硫脲催化的杂环合成主要涉及级联过程，该过程通过α ， β-不饱和酰基铵离子156或烯醇铵157作为中间体进行。计算研究表明中间体通过1,5-O - S相互作用稳定，其特征为硫族键。这种相互作用锁定了中间体的几何形状，从而决定了反应的立体化学结果。计算了 S 和 O 之间的核间距，晶体学研究证明该距离小于两个原子的范德瓦尔半径之和。共价相互作用增加了羰基的亲电性，从而提高了催化循环的速率（图4 ）。 ^54]

Smith and co-workers also studied 1,5-SO interactions in unsaturated acyl ammonium ion intermediate for determining the steroselctivity and chemoselectivity of annulation reactions. Their model substrate was a symmetrical α,β-unsaturated anyhydride 158 which formed α,β-unsaturated acyl ammonium ion on treatment with catalyst 7b as catalyst. The intermediate preferentially forms a lactam 159 via N-cyclization on reaction with 2-acyl benzothiazole and 2-N,N-dialkylacetamidobenzothiazole, whereas lactone 160 is predominant through O-cyclization when the nuclephile was changed to 2-acyl benzoxazole (Scheme 54).^[55
Smith 及其同事还研究了不饱和酰基铵离子中间体中 1,5-S  O 的相互作用，以确定成环反应的立体选择性和化学选择性。他们的模型底物是对称的α ， β-不饱和酸酐158 ，其在用催化剂7b作为催化剂处理时形成α ， β-不饱和酰基铵离子。该中间体在与2-酰基苯并噻唑和2- N , N-二烷基乙酰胺苯并噻唑反应时优先通过N环化形成内酰胺159 ，而当亲核试剂变为2-酰基苯并恶唑时，通过O环化主要形成内酯160 （方案54 ） 。 ^55]

Computational studies were carried out to calculate energies of the intermediates separately for benzothiazole and benzoxazoles. 1,5-SO interaction governs the geometry of unsaturated acyl ammonium intermediate where carbonyl O and S become syn-coplanar which is energetically more favored than antiperiplanar geometry. The locked geometry favors nucleophilic attack preferentially from one face of the plane making the process highly enantioselective. 1,4-Addition (which is the stereo controlling step) occurs from less hindered face of the catalyst's stereo directing substituent. The enantiomeric excess obtained was up to >99% for both the nucleophiles. The study also explained how the chemoselectivity was dependent on the type of nucleophile used. In benzoxazole, lactonization is favored as the conformation 161 with 1,5-SO and CHO interaction is energetically more stabilized. In the case of benzothiazole (transition state 162), lactamization is favored due to (a) π-π interaction between the phenyl group present in catalyst and the benzothiazole ring, and (b) second SO interaction in the benzothiazole moiety in addition to the one already present in the acyl ammonium ion. The favored transition states for both the processes are shown below (Figure 5).
进行计算研究以分别计算苯并噻唑和苯并恶唑的中间体的能量。 1,5-S - O 相互作用控制着不饱和酰基铵中间体的几何形状，其中羰基 O 和 S 成为共面的，这在能量上比反围平面几何更有利。锁定的几何形状有利于优先从平面的一个面进行亲核攻击，从而使该过程具有高度对映选择性。 1,4-加成（立体控制步骤）从催化剂立体定向取代基的受阻较少的面发生。两种亲核试剂获得的对映体过量高达 >99%。该研究还解释了化学选择性如何取决于所用亲核试剂的类型。在苯并恶唑中，内酯化是有利的，因为具有 1,5-S  O 和 C  H  O 相互作用的构象161在能量上更加稳定。对于苯并噻唑（过渡态162 ），由于 (a) 催化剂中存在的苯基与苯并噻唑环之间存在 π-π 相互作用，以及 (b) 苯并噻唑部分中的第二个 S  O 相互作用，有利于内酰胺化到已经存在于酰基铵离子中的一个。这两个过程的首选过渡态如下所示（图5 ）。

Birman and co-workers reported an unprecedented isothiourea catalyzed enantioselctive synthesis of thiochromenes via an intramolecular cascade. The starting material was α,β-unsaturated thioester linked to aldehyde by an aromatic ring 163 which underwent smooth cascade in presence of 168 as the catalyst to produce thiochromenes 167 in an enantioselective fashion. The reaction begins with a nucleophilic attack of isothiourea 168 to the carbonyl carbon of thioester to afford α,β-unsaturated isothiouronium ion and an aromatic thiolate ion 164. Subsequent sulpha-Michael addition followed by lactonization produced the β-lactone fused sulphur-heterocylcle 166 which underwent further decarboxylation to form thiochromenes 166 with good yields and high enantioselectivities (Scheme 55).^[56
Birman 及其同事报道了前所未有的异硫脲通过分子内级联催化对映选择性合成硫色烯。起始原料是通过芳香环163与醛连接的α , β-不饱和硫酯，在168作为催化剂的存在下进行平稳级联，以对映选择性方式产生硫色烯167 。该反应开始于异硫脲168对硫酯的羰基碳进行亲核攻击，得到α , β-不饱和异硫脲离子和芳香族硫醇根离子164 。随后的磺胺-迈克尔加成和内酯化产生了β-内酯稠合硫杂环166 ，其进一步脱羧形成硫色烯166 ，具有良好的产率和高对映选择性（方案55 ）。 ^56]

This method was further expanded by using α,β-unsaturated thioester enone molecule 169 as the starting material which afforded δ-lactone fused sulphur heterocyle 170. The 20 mol% of an electron rich isothiourea 171 afforded the product with 83% yield, 96% ee and 98:2 dr. However the reaction was optimized using a different amidine catalyst which delivered the products with better yield (Scheme 56).^[57
通过使用α , β-不饱和硫酯烯酮分子169作为起始材料进一步扩展该方法，得到δ-内酯稠合硫杂环170 。 20 mol% 的富电子异硫脲171提供产率 83%、96% ee 和 98:2 dr 的产物。然而，使用不同的脒催化剂对反应进行了优化，从而获得了更高产率的产物（方案56 ）。 ^57]

7 FORMAL [4 + 3] CYCLOADDITION
7 正式 [4 + 3] 循环加载

Isothiourea catalyzed enantioselective [4 + 3] cycloaddition for synthesizing 1,5-benzothiazepines 174, a highly important class of molecules in medicinal chemistry, was published by Asano, Matsubara and co-workers.^[58] The net cycloaddition occurred between α,β-unsaturated acyl ammonium ion and amino thiophenol. A mixed anhydride 172 was treated with 2-amino thiophenol 173 and 5 mol% of (S)-BTM 5b in presence of 4 Å molecular sieves to form the cyclic products with good to excellent yields and high enantiomeric excesses. The reaction was well tolerated by both electron-rich and deficient amino thiophenols, however, the stereoselectivity is slightly better for electron rich components. The annulation strategy was further implemented in preparing an antidepressant drug, thiazesim. The cycloadduct 174 was treated with SmI₂ for tosyl deprotection to prepare cyclic secondary amine 175 which was then alkylated to get the targeted drug molecule without any loss in optical purity (Scheme 57).
Asano、Matsubara 及其同事发表了异硫脲催化对映选择性 [4 + 3] 环加成合成 1,5-苯并硫氮杂卓类化合物174 的文章，这是药物化学中非常重要的一类分子。 ⁵⁸净环加成发生在α , β-不饱和酰基铵离子和氨基苯硫酚之间。在 4 Å 分子筛存在下，用 2-氨基苯硫酚173和 5 mol% ( S )-BTM 5b处理混合酸酐172 ，形成环状产物，具有良好至优异的产率和高对映体过量。富电子和缺电子氨基苯硫酚都能很好地耐受该反应，但富电子组分的立体选择性稍好一些。环化策略进一步应用于制备抗抑郁药物噻嗪类药物。将环加合物174用SmI ₂处理以进行甲苯磺酰基脱保护以制备环状仲胺175，然后将其烷基化以获得目标药物分子，而光学纯度没有任何损失（方案57 ）。

The reaction occurs through the formation of α,β-unsaturated acyl ammonium ion 177 which reacts with amino thiophenol 173a from the opposite face of phenyl substiuent in 177. A sulfa-Michael reaction generates intermediate 178 following which a N-acylation occurs resulting in the formation of annulated products (Scheme 58).
该反应通过形成α , β-不饱和酰基铵离子177而发生，其与177中苯基取代基的相反面的氨基苯硫酚173a反应。磺胺-迈克尔反应生成中间体178 ，随后发生N-酰化，导致环状产物的形成（方案58 ）。

8 ISOTHIOUREA CATALYZED FORMAL [3 + 2] AND [3 + 3] CYCLOADDITION REACTIONS
8 异硫脲催化的缩甲醛[3 + 2]和[3 + 3]环加成反应

Although less explored in comparison to [4 + 2]; 1,3-dipolar cycloaddition has also been proved to be competent technique for construction of cyclic molecular structures. Few reports on isothiourea catalyzed 1,3-dipolar cycloaddition in reported this context. Isothiouronium enolate can be potential dipolarophile toward suitable 1,3-dipole to execute [3 + 2] cycloaddition in delivering five membered cyclic structures. Whereas α,β-unsaturated isothiouronium can be assembled with dipolar species in [3 + 3] cycloaddition to produce six membered cycles.
尽管与[4 + 2]相比探索较少； 1,3-偶极环加成也被证明是构建环状分子结构的有效技术。很少有关于异硫脲催化 1,3-偶极环加成反应的报道。烯醇异硫脲对于合适的 1,3-偶极子是潜在的亲偶极试剂，可在提供五元环状结构时执行 [3 + 2] 环加成。而α , β-不饱和异硫脲可以与偶极物质通过[3 + 3]环加成组装以产生六元循环。

An elegant approach toward isothiourea mediated [3 + 2] cycloaddition reaction between simple aryl acetic acid and azomethine imine 180 was reported by Studer and co-workers.^[59] In this method, 1.0 equivalent of aryl acetic acid was treated with 1.1 equivalents of Hünig's base and 1.0 equivalent of BzCl in dichloromethane for the in situ preparation of the mixed anhydride. After complete formation of the anhydride, 10 mol% isothiourea 5a and 1.2 equivalent of azomethine imine 180 were added which yielded pyrazolidinone derivative 181 in appreciable yields and excellent selectivities. The substrate scope was broadened by employing different aryl acetic acids as enolate precursor as well as by incorporating different substituents in the aryl moiety of azomethine imine (Scheme 59). The highly stereoselective approach efficiently promoted the synthesis of complex molecular topology containing pyrazolidinone with a tetrahydroisoquinoline core.
Studer 及其同事报道了一种简单的芳基乙酸和偶氮甲碱亚胺180之间异硫脲介导的 [3 + 2] 环加成反应的优雅方法。 ⁵⁹在该方法中，将 1.0 当量的芳基乙酸用 1.1 当量的 Hünig 碱和 1.0 当量的 BzCl 在二氯甲烷中处理，以原位制备混合酸酐。酸酐完全形成后，添加10mol%异硫脲5a和1.2当量偶氮甲碱亚胺180，以可观的产率和优异的选择性产生吡唑烷酮衍生物181 。通过使用不同的芳基乙酸作为烯醇化物前体以及在偶氮甲碱亚胺的芳基部分中引入不同的取代基，拓宽了底物范围（方案59 ）。高度立体选择性的方法有效地促进了含有四氢异喹啉核心的吡唑烷酮的复杂分子拓扑的合成。

DFT studies revealed that the reaction occurs in stepwise manner rather than a concerted pathway. Catalyst bound enolate 182 first undergoes 1,2-addition with the minimum moiety of 1,3-dipole, that is, azomethine imine 180 to form the intermediate 183 via CC bond formation. The next step is lactamization along with catalyst elimination which furnished the final product 181 (Scheme 60).
DFT 研究表明，反应是逐步发生的，而不是协调一致的途径。催化剂结合的烯醇化物182首先与最小的1,3-偶极部分即偶氮甲碱亚胺180进行1,2-加成，通过C - C键形成中间体183 。下一步是内酰胺化以及催化剂消除，提供最终产物181 （方案60 ）。

Isothiourea promoted [3 + 2] cycloaddition between ammonium enolate and N-substituted oxaziridines was reported by Smith and co-workers. Here, 1.5 equivalents of homoanhydride 184, 1.0 equivalent of racemic N-substituted oxaziridine 185, 10 mol% of HBTM-2.1 7b and 2.0 equivalents of Cs₂CO₃ were utilized to afford oxazolidine-4-one 186 bearing two chiral centers. However diastereomeric ratio, anti:syn were not promising as both diastereomers were equally formed (Scheme 61). Diastereoselectivity of the reaction greatly improved when enantiomerically pure (R,R)-N-tosylated oxaziridine was employed in the system keeping other parameters intact. The diastereomeric ratio for anti:syn isomers recorded in the range of 1.5:1-19:1 with excellent enantioselectivities.^[60
Smith 及其同事报道了异硫脲促进烯醇铵和N-取代的氮丙啶之间的 [3 + 2] 环加成。这里，使用1.5当量的高酸酐184、1.0当量的外消旋N-取代的恶氮丙啶185、10mol ％的HBTM-2.1 7b和2.0当量的Cs ₂ CO ₃来提供带有两个手性中心的恶唑烷-4-酮186 。然而，非对映异构体比率，抗：顺式并不乐观，因为两种非对映异构体均等形成（方案61 ）。当在系统中使用对映体纯的( R , R )-N-甲苯磺酰化氮丙啶并保持其他参数不变时，反应的非对映选择性大大提高。反式:顺式异构体的非对映异构体比例在1.5:1-19:1范围内，具有优异的对映选择性。 ^60]

Nucleophilic attack of chiral isothiourea to the carbonyl center of homo anhydride followed by α-deprotonation generates catalyst bound (Z)-enolate 187. Interaction between non-bonding electrons on the oxygen atom and antibonding CS orbital provides extra stability to the (Z)-enolate. Follow up intermolecular α-functionalization produces the next intermediate 188 which upon lactamization results in oxazolidinone ring (Scheme 61).
手性异硫脲对均酸酐的羰基中心进行亲核攻击，然后进行α-去质子化，生成催化剂结合的 ( Z )-烯醇化物187 。氧原子上的非键电子与反键C - S轨道之间的相互作用为( Z )-烯醇化物提供了额外的稳定性。随后的分子间α-官能化产生下一个中间体188 ，其在内酰胺化时产生恶唑烷酮环（方案61 ）。

Another enantioselective [3 + 2] cycloaddition reaction promoted by chiral isothiourea between γ-chloro cyclobutenone and azomethine imine was reported by Chi and co-workers. Enolate was generated from γ-chloro cyclobutenone 189 by (S)-benzotetramisole, 5b which underwent cycloaddition with azomethine imine 180 to afford pyrazolidinone ring 190 containing two contiguous stereo centers (Scheme 62).^[61
Chi和同事报道了另一种由手性异硫脲促进的γ-氯环丁烯酮和偶氮甲碱亚胺之间的对映选择性[3 + 2]环加成反应。烯醇化物由( S )-苯并四咪唑5b从γ-氯环丁烯酮189生成， 5b与甲亚胺亚胺180进行环加成，得到含有两个连续立体中心的吡唑烷酮环190 （方案62 ）。 ^61]

The reaction does not require any activating agent as there is no acid moiety present in the reaction system. Initiation of reaction occurs by attack of the nucleophilic catalyst to the carbonyl center of cyclobutenone molecule 189, affording catalyst bound α-oxy cyclobutene 191 as the intermediate. An electrocyclic ring opening would allow breaking of CC bond in the strained cyclic intermediate, producing a dienolate, 192. The final step is the cycloaddition between the α-selective dienolate and azomethine imine affording the final product (Scheme 63).
该反应不需要任何活化剂，因为反应体系中不存在酸部分。通过亲核催化剂攻击环丁烯酮分子189的羰基中心来引发反应，提供催化剂结合的α-氧基环丁烯191作为中间体。电环开环将允许应变环状中间体中的 C - C 键断裂，产生二烯醇化物192 。最后一步是α-选择性二烯醇化物和偶氮甲碱亚胺之间的环加成反应，得到最终产物（方案63 ）。

Very recently, isothiourea catalyzed [3 + 3] cycloaddition reaction has been reported by Smith and co-workers for preparing tetrahydro-α-carbolinone derivatives. They employed α,β-unsaturated ester 194 to generate the Michael acceptor, whereas α,β-unsaturated isothiouronium ion and indolin-2-imine 195 was used as the Michael donor. Michael addition followed by lactamization formed tetrahydro-α-carbolinone derivatives 196 in moderate to high yields and excellent enantioselctivities. α,β- Unsaturated ester containing p-nitrophenol moiety serves as a good leaving group in the generation of isohiouronium ion via nucleophilic substitution by the catalyst (Scheme 64).^[62] Peng and co-workers also demonstrated 7b catalyzed [3 + 3] annulation between indoline-2-thiones and α,β-unsaturated anhydrides in course of enantioselective synthesis of indolo[2,3-b]-dihydrothiopyranones.^[63
最近，Smith及其同事报道了异硫脲催化的[3+3]环加成反应用于制备四氢-α-咔啉酮衍生物。他们使用α , β-不饱和酯194生成迈克尔受体，而α , β-不饱和异硫脲离子和二氢吲哚-2-亚胺195用作迈克尔供体。迈克尔加成随后内酰胺化形成了四氢-α-咔啉酮衍生物196，具有中等至高产率和优异的对映选择性。含有对硝基苯酚部分的α , β-不饱和酯在催化剂通过亲核取代生成异硫脲离子时充当良好的离去基团（方案64 ）。 ⁶² Peng 及其同事还证明了在吲哚并[2,3-b]-二氢噻喃酮的对映选择性合成过程中， 7b催化了二氢吲哚-2-硫酮与α , β-不饱和酸酐之间的 [3 + 3] 环化。 ^63]

9 ISOTHIOUREA IN CO-OPERATIVE CATALYSIS
9 异硫脲的协同催化作用

Isothiourea has been coupled with other organocatalyst in enantioselective synthesis of heterocycles. In this context, isothiourea has also been employed as co-operative catalyst along with different metal-catalysts. In this present review, isothiourea-metal cooperativity is excluded. Recently, Song, Gong and co-workers showed an elegant approach of using isothiourea in co-operative catalysis along with Brønsted acid. α,β-Unsaturated ester was reacted with enamine in presence of chiral isothiourea and Brønsted acid to afford 3,4-dihydropyridin-2-one derivatives through an asymmetric formal [3 + 3] cycloaddition reaction.^{[1, 64]} β-Substituted α,β-unsaturated 2,4,6-trichlorophenyl (TCP) ester 197 was treated with enamine 198 in presence of 20 mol% chiral isothiourea 200 and 10 mol% diphenylphosphinic acid 201 to get 3,4-dihydropyridine-2-one derivatives 199 having excellent yields and enantioselectivities. Presence of 10 mol% of Brønsted acid drastically increased the rate as well as yield of the reaction. The reaction gave excellent yield and stereocontrol when R was electron withdrawing (ester, amide, CF₃, C₂F₅, p-nitrophenyl) compared to a decreased yield and enantioselctivity when R was alkyl and phenyl (Scheme 65).
异硫脲与其他有机催化剂偶联用于杂环的对映选择性合成。在这方面，异硫脲也已与不同的金属催化剂一起用作协同催化剂。在本综述中，异硫脲-金属协同作用被排除在外。最近，Song、Gong 和同事展示了一种使用异硫脲与布朗斯台德酸协同催化的优雅方法。 α , β-不饱和酯与烯胺在手性异硫脲和布朗斯台德酸存在下反应，通过不对称形式的[3+3]环加成反应得到3,4-二氢吡啶-2-酮衍生物。在20 mol%手性异硫脲200和10 mol%二苯基次膦酸201存在下，用烯胺198处理^{1 , 64} β-取代的α , β-不饱和2,4,6-三氯苯基(TCP)酯197 ，得到3,4-二氢吡啶-2-酮衍生物199具有优异的收率和对映选择性。 10 mol% 布朗斯台德酸的存在极大地提高了反应的速率和产率。当R为吸电子（酯、酰胺、CF ₃ 、C ₂ F ₅ 、对硝基苯基）时，该反应具有优异的产率和立体控制性，而当R为烷基和苯基时，反应产率和对映选择性降低（方案65 ）。

The nucleophilic catalysis by isothiourea delivered α,β-unsaturated acyl ammonium ion 202 as the intermediate after elimination of TCPO⁻. TCPO⁻ deprotonates Ph₂POOH to generate its conjugate base, thereby, reducing reversibility of the nucleophilic catalysis process. Furthermore, Ph₂POO⁻ is engaged in intermolecular H-bonding with enamine increasing the nucleophilicity. Thus, Ph₂POOH acts as a co-operative catalyst in the catalytic cycle. Enamine undergoes 1,4-addition to intermediate 202 and follow up lactamization generates 199 along with catalyst turnover (Scheme 66).^[64
异硫脲的亲核催化作用消除 TCPO ^-后产生α , β-不饱和酰基铵离子202作为中间体。 TCPO ^-将 Ph ₂ POOH 去质子化以生成其共轭碱，从而降低亲核催化过程的可逆性。此外，Ph ₂ POO ^-与烯胺形成分子间氢键，增加了亲核性。因此，Ph ₂ POOH 在催化循环中充当协同催化剂。烯胺经历 1,4-加成至中间体202 ，随后的内酰胺化随着催化剂周转生成199 （方案66 ）。 ^64]

Research group of Song merged isothiourea catalysis with photo activation as they reported a sequential protocol involving photo activation of α-diazoketones 204 followed by [4 + 2] cycloaddition with azadienes 205 to construct benzofuran fused tricyclic derivatives 206 with good stereoselctivities. α-Diazoketone undergoes Wolff rearrangement when irradiated with blue LED to produce ketene 208 as the intermediate. Presence of catalyst 207 afforded isothiouronium ion 209 from ketene which undergoes [4 + 2] cycloaddition with azadiene to form the tricyclic derivatives containing an all carbon quaternary stereo center (Scheme 67).^[65
Song的研究小组将异硫脲催化与光活化相结合，他们报道了一种顺序方案，涉及α-重氮酮204的光活化，然后与氮杂二烯205进行[4+2]环加成，构建了具有良好立体选择性的苯并呋喃稠合三环衍生物206 。 α-重氮酮在蓝光LED照射下发生Wolff重排，生成烯酮208作为中间体。催化剂207的存在从烯酮提供异硫脲离子209 ，其与氮杂二烯进行[4+2]环加成形成含有全碳季立体中心的三环衍生物(方案67 )。 ^65]

10 ISOTHIOUREA CATALYSIS IN TOTAL SYNTHESIS
10 异硫脲催化全合成

Isothiourea catalyzed enantioselective reaction was applied successfully in synthesizing a potent HIV inhibitor BMS-986001 showing its applicability in total synthesis.^[66] The synthesis starts from enantiopure (S)-3-substituted pyranone 211 which is accessed from its racemate 210 via levamisole 4a catalyzed dynamic kinetic resolution (DKR). Levamisole promoted DKR on 210 with isobutyric anhydride provides acylated (S)-enantiomer of the heterocycle with >95% yield and 88% ee. Whereas with 2-phenylacetic anhydride, the product was obtained with >95% yield and 79% ee. Dynamic kinetic asymmetric transformation (DYKAT) was further applied for the resolution of pyranose lactols, 212 (Scheme 68).
异硫脲催化的对映选择性反应成功应用于合成有效的 HIV 抑制剂 BMS-986001，显示了其在全合成中的适用性。 ⁶⁶合成从对映体纯 ( S )-3-取代的吡喃酮211开始，通过左旋咪唑4a催化的动态动力学拆分 (DKR) 从其外消旋体210获得。左旋咪唑用异丁酸酐促进210上的 DKR，提供杂环的酰化 ( S ) -对映异构体，产率 >95%，ee 为 88%。而使用 2-苯乙酸酐时，获得的产物具有 >95% 的产率和 79% ee。动态动力学不对称转化 (DYKAT) 进一步应用于吡喃糖乳醇的拆分， 212 （方案68 ）。

The conjugate thiolate addition was achieved on treatment of 211a with p-thiocresol and subsequently the resulting ketone was reacted with lithio-TMS-acytelene at - 78°C in same pot to afford trisubstituted pyranose 214 in 70% yield and > 20:1 dr. Upon hydrolysis, pyranose ring 215′ would equilibrate with furanose ring 215 via ring-chain tautomerism, and the furanose ring was selectively trapped by levamisole catalyzed benzylation. Five membered carbohydrate 216 is the key substrate for synthesizing the target molecule which was accessed by another four steps protocol affording the target compound in 44% overall yield. Here, isothiourea plays a vital dual role, firstly promotes DYKAT to prepare the building block and then directing carbohydrate ring chain tautomerization from six to five membered ring to facilitate the complete synthesis of BMS-986001 221 (Scheme 69).
用对硫甲酚处理211a时实现了共轭硫醇盐加成，随后所得酮与锂-TMS-乙炔在同一罐中于 78°C 下反应，得到三取代吡喃糖214 ，收率 70%，dr > 20:1 。水解后，吡喃糖环215 '将通过环链互变异构与呋喃糖环215平衡，并且呋喃糖环被左旋咪唑催化的苄基化选择性捕获。五元碳水化合物216是合成目标分子的关键底物，通过另一个四步方案获得目标分子，以 44% 的总产率提供目标化合物。在这里，异硫脲起着至关重要的双重作用，首先促进DYKAT制备结构单元，然后引导碳水化合物环链互变异构从六元环到五元环，以促进BMS-986001 221 （方案69 ）的完全合成。

11 HETEROGENOUS ISOTHIOUREA CATALYSIS IN HETEROCYLE SYNTHESIS
11 杂环合成中的多相异硫脲催化

Heterogenous organocatalysis has gained attention in developing stereoselective methods which focuses not only on the stereocontrol of the reaction but also on catalyst efficiency in promoting multiple catalytic cycles. The ease of separation and recyclability of the catalysts alleviates the large-scale production of the catalyst. Heterogeneous isothiourea catalyst has also been included in this context. Very recently, chiral benzotetramisole molecule was utilized to prepare an immobilized heterogeneous catalyst by attachment of the molecule on a polymeric support. The catalyst was prepared in a five-step reaction sequence starting from an enantiopure 1,2-disubstituted oxirane 222 containing propargyl ether linkage at one end. Epoxide ring of the oxirane molecule, was cleaved by aqueous ammonia to prepare 1,2-amino alcohol 223 which was further reacted with 2-chlorobenzothiazole under heating condition to obtain benzothiazole derivative 224. Secondary alcohol group in 224 was first mesylated, followed by subsequent base promoted ring closure provided benzotetramisole derivative 225. Finally, Cu (I) mediated click reaction was carried out between 225 and azidomethyl polystyrene 226 to achieve the polymer supported BTM derivative 227 (Scheme 70A).
多相有机催化在开发立体选择性方法方面引起了人们的关注，该方法不仅关注反应的立体控制，而且关注促进多个催化循环的催化剂效率。催化剂的易于分离和可回收性减轻了催化剂的大规模生产。非均相异硫脲催化剂也包括在本文中。最近，通过将分子附着在聚合物载体上，利用手性苯并四咪唑分子制备固定化非均相催化剂。该催化剂以一端含有炔丙基醚键的对映体纯1,2-二取代环氧乙烷222为原料，通过五步反应顺序制备。用氨水裂解环氧乙烷分子的环氧化物环，制备1，2-氨基醇223 ，再与2-氯苯并噻唑在加热条件下反应，得到苯并噻唑衍生物224 。 224中的仲醇基团首先被甲磺酸化，随后碱促进环闭合，提供苯并四咪唑衍生物225 。最后，在225和叠氮甲基聚苯乙烯226之间进行Cu(I)介导的点击反应以获得聚合物负载的BTM衍生物227 （方案70A ）。

The immobilized chiral isothiourea on polymer bed was employed in Michael addition-lactonization cascade between aryl acetic acid and ketimines to prepare anti-dihydropyridones in good yields and excellent stereoselctivities. The results obtained were comparable with reported homogenous isothiourea catalysis.^{[33, 67]} The heterogenous catalyst was found to be superior in delivering the product in much better yields and slightly enhanced selectivities with ortho substituted aryl acetic acids (Scheme 70B). The heterogenous catalyst can easily be separated from the reaction system by simple filtration. In addition, to the retainment of the catalytic activity without any significant loss in yield, the enantiopurity of the product was also maintained up to sixth catalytic cycle. The reaction was applied to flow process as well.^[68
将固定在聚合物床上的手性异硫脲用于芳基乙酸和酮亚胺之间的迈克尔加成-内酯化级联，以良好的收率和优异的立体选择性制备抗二氢吡啶酮。获得的结果与报道的均相异硫脲催化相当。 ^{33 , 67}发现多相催化剂在以更高的产率提供产物方面表现出色，并且对邻位取代的芳基乙酸的选择性略有提高（方案70B ）。通过简单的过滤可以很容易地将多相催化剂从反应体系中分离出来。此外，在保留催化活性且收率没有任何显着损失的情况下，产物的对映体纯度也保持到第六次催化循环。该反应也适用于流动过程。 ^68]

The activity of newly developed heterogenous catalyst was further explored by employing a different cascade comprising of Michael addition-lactonization sequence with cyclic sulphonyl imines in order to obtain tricyclic products 229 with good yields and excellent diastereo and enantio control. The catalyst was shown to be reactive up to seven consecutive catalytic cycles with different reagents in the same reaction pot maintaining the efficiency and allowing the formation of total 10 g of the different tricyclic derivatives. Turnover number of the catalyst was 51.
通过采用由迈克尔加成-内酯化序列与环状磺酰亚胺组成的不同级联，进一步探索了新开发的多相催化剂的活性，以获得具有良好产率和优异的非对映体和对映体控制的三环产物229 。该催化剂显示出在同一反应罐中与不同试剂进行长达七个连续催化循环的反应，保持了效率并允许形成总共 10 g 的不同三环衍生物。催化剂的周转数为51。

Pericas and co-workers have also reported the use of polymer supported chiral isothiourea catalyst in [4 + 2] cycloaddition reactions. The catalyst 227 was employed in [4 + 2] cycloaddition reaction between in situ generated mixed anhydride and alkylidene pyrazolone 230 or thiazolone 230′ leading to the formation of dihydropyranopyrazolones 231 or dihydropyranothiazolones derivatives 231′ bearing two chiral centers. The mixed anhydride used in this protocol was synthesized by the reaction between α-aryl acetic acids and pivaloyl chloride in presence of a base. The immobilized isothiourea catalyst employed in the reaction process forms isothiouronium ion on reaction with anhydride and subsequently the enolization leads to the formation of enolate intermediate which undergoes [4 + 2] cycloaddition reaction with alkylidene heterocycles to furnish products with good yields and stereoselctivities (Scheme 71A).^[69] The method was further extended using disubstituted alkylidene pyrazolones 232 to synthesize spiro heterocylic molecules 233 containing a tetrasubstituted chiral center (Scheme 71B). The authors also evaluated recyclability of the catalyst which was efficient enough to withhold up to 11 catalytic cycles without any loss in chemical yield and stereoselectivity of the product obtained.
Pericas 及其同事还报道了在[4 + 2]环加成反应中使用聚合物负载的手性异硫脲催化剂。催化剂227用于原位生成的混合酸酐与亚烷基吡唑啉酮230或噻唑啉酮230'之间的[4+2]环加成反应，导致形成带有两个手性中心的二氢吡喃并吡唑啉酮231或二氢吡喃并噻唑酮衍生物231' 。该方案中使用的混合酸酐是通过α-芳基乙酸和新戊酰氯在碱存在下反应合成的。反应过程中使用的固定化异硫脲催化剂与酸酐反应形成异硫脲离子，随后烯醇化形成烯醇化物中间体，该中间体与亚烷基杂环进行[4 + 2]环加成反应，得到具有良好收率和立体选择性的产物（方案71A） ）。 ⁶⁹该方法进一步扩展，使用二取代亚烷基吡唑啉酮232合成含有四取代手性中心的螺杂环分子233 （方案71B ）。作者还评估了催化剂的可回收性，该催化剂的效率足以承受多达 11 次催化循环，而不会损失化学产率和所获得产品的立体选择性。

In addition to [4 + 2] cycloaddition reaction, the same research group used the heterogenous isothiourea catalysis for [8 + 2] cycloaddition reaction. They employed α-substituted acetic acid derived mixed anhydride to generate ammonium enolate intermediate as dienophile toward an azaheptafulvenes 234 to accomplish the higher order cycloaddition aiding in the enantioselective synthesis of 7,5-fused heterocyclic molecules 235 (Scheme 72).^[70
除了[4+2]环加成反应外，同一研究小组还使用多相异硫脲催化进行[8+2]环加成反应。他们采用α-取代的乙酸衍生的混合酸酐来生成烯醇铵中间体作为氮杂七富烯234的亲二烯体，以完成有助于7,5-稠合杂环分子235的对映选择性合成的高阶环加成（方案72 ）。 ^70]

12 OTHER REACTION BY ISOTHIOUREA CATALYSIS
12 异硫脲催化的其他反应

Coquerel and Rodriguez reported an elegant approach of ring expansion of enantioenriched 2-oxocyclobutane carboxamide 236 to glutarimides 237 by isothiourea catalysis without any loss of stereoselectivity of the chiral centers. In the process, four membered ring was expanded to six membered in presence of achiral isothiourea (DHPB, 7c) as catalyst (Scheme 73).^[71
Coquerel 和 Rodriguez 报道了一种通过异硫脲催化将对映体富集的 2-氧代环丁烷甲酰胺236扩环至戊二酰亚胺237的优雅方法，且不损失手性中心的立体选择性。在此过程中，在非手性异硫脲（DHPB， 7c ）作为催化剂存在下，四元环扩展为六元环（方案73 ）。 ^71]

Mechanistic study reveals that the process occurs through nucleophilic catalysis which results in the formation of ring opened intermediate 238 which tautomerizes and subsequent lactamization produces the six-membered glutarimide derivatives 237 (Scheme 74).
机理研究表明，该过程通过亲核催化发生，导致开环中间体238的形成，中间体 238 互变异构，随后内酰胺化产生六元戊二酰亚胺衍生物237 （方案74 ）。

13 CONCLUSION  13 结论

In conclusion, isothioureas have been highlighted as important class of organ catalysts since 2006. Because of their applications in wide range of organic transformations, nucleophilic catalysis by isothioureas can be considered as separate category of organocatalysis. Primarily, isothioureas were employed as acyl transfer agent but later other activation modes by the catalysts have been utilized extensively. Enantoselective organic transformations by isothioureas have been well investigated including cycloaddition, complex cascade methodologies in the course of synthesizing several complex and interesting molecular scaffolds. In fact the chemistry with isothioureas is dominated by asymmetric methodologies with few reports on achiral variants. The present review has documented all reaction methods affording various heterocycles through isothiourea organocatalysis till May, 2020. These methods turn out through formation of two intermediates; either isothiouronium ion or isothiouronium enolate. Both the reactivities are well explored in synthesizing a range of N-, O- and S-heterocycles. A handful of research articles also reveal the applications of the heterocycles obtained through isothiourea catalysis, in preparing natural products and bioactive molecules. The applications are also included in the review. Recently, heterogenous isothioureas have been developed which opens another aspect in the field. By exploring the chemistry with isothioureas as catalysts, we envisage that isothiourea catalysis has a very promising future and many other organic transformations are yet to come involving isothioureas.
总之，自 2006 年以来，异硫脲已被强调为一类重要的有机催化剂。由于其在有机转化领域的广泛应用，异硫脲的亲核催化可被视为有机催化的一个单独类别。最初，异硫脲被用作酰基转移剂，但后来催化剂的其他活化模式被广泛使用。异硫脲的对映选择性有机转化已得到充分研究，包括在合成几种复杂且有趣的分子支架过程中的环加成、复杂级联方法。事实上，异硫脲的化学主要是不对称方法，关于非手性变体的报道很少。本综述记录了截至2020年5月通过异硫脲有机催化提供各种杂环的所有反应方法。这些方法通过形成两种中间体而得以实现；异硫脲离子或异硫脲烯醇盐。这两种反应性在合成一系列 N-、O- 和 S- 杂环时都得到了很好的探索。一些研究文章还揭示了通过异硫脲催化获得的杂环在制备天然产物和生物活性分子中的应用。这些申请也包含在审查中。最近，异质异硫脲的开发开辟了该领域的另一个方面。通过探索异硫脲作为催化剂的化学，我们设想异硫脲催化具有非常有前途的前景，并且许多其他涉及异硫脲的有机转化尚未出现。