Recent advances in the total synthesis of monoterpenoid indole alkaloids enabled by asymmetric catalysis

Asymmetric catalysis has continued to enable the preparation of optically active natural products over the past decade.This minireview summarizes progress in the catalytic enantioselective total synthesis of complex monoterpenoid indole alkaloids covering the reports from 2019 to June 2021.In particular,the generation of the key chiral stereogenic centers with metal catalysts and organocatalysts has been highlighted,showcasing the power of asymmetric catalysis protocols in accessing complex molecular architectures.

Stereodivergent synthesis ofα-fluoroα-azaarylγ-butyrolactones via cooperative copper and iridium catalysis

The development of stereodivergent synthetic methods to access all four stereoisomers of biologically importantα-fluoroγ-butyrolactones containing vicinal stereocenters is of great importance and poses a formidable challenge owing to ring strain and steric hindrance.Herein,a novel asymmetric[3+2]annulation ofα-fluoroα-azaaryl acetates with vinylethylene carbonate was successfully developed through Cu/Ir-catalyzed cascade allylic alkylation/lactonization,affording a variety of enantioenrichedα-fluoroγ-butyrolactones bearing vicinal stereogenic centers with high reaction efficiency and excellent levels of both stereoselectivity and regioselectivity(up to 98%yield,generally>20:1 dr and>99%ee).Notably,all four stereoisomers of these pharmaceutically valuable molecules could be accessed individually via simple permutations of two enantiomeric catalysts.In addition,other azaaryl acetates bearingα-methyl,α-chlorine orα-phenyl group were tolerated well in this transformation.Reaction mechanistic investigations were conducted to explore the process of this bimetallic catalysis based on the results of reaction intermediates,isotopic labelling experiments,and kinetic studies.

Remote stereocontrol in the(4+2)cycloadditions of 1,7-zwitterions:Asymmetric synthesis of multifunctionalized tetrahydroquinoline derivatives

The scope of stereochemistry recognition usually occurs near the chiral scaffold of a ligand or catalyst.Remote stereocontrol,which can surpass the limits of stereorecognition of remote prochiral centers,has long been a challenging object of great interest in asymmetric catalysis.The current work realized the remote stereocontrol of 1,7-zwitterion intermediates formed from Huang's o-amino aryl MBH carbonates.With simple and easily accessibleβ-ICD as the bifunctional catalyst,multifunctionalized tetrahydroquinoline derivatives could be synthesized via(4+2)cycloadditions with excellent enantioselectivity and diastereoselectivity under mild conditions.The strategy possesses broad substrate scope,and three types of electron-deficient enones are successfully applied.Mechanistic studies disclosed the Lewis base-catalyzed reaction pathway,and H-bonding between the catalyst and enones is crucial for long-range stereocontrol.Scale-up reaction and transformations of the tetrahydroquinoline products demonstrated the potential of this strategy.

Asymmetric Synthesis of Anti-tuberculosis-specific Drug TBAJ-876 through Synergistic Li/Li Catalysis

TBAJ-876, developed by TB Alliance, a novel anti-tuberculosis-specific drug, has entered Phase II clinical trials. Herein, the first asymmetric synthesis of TBAJ-876 has been realized using synergistic Li/Li catalysis with excellent yield of 95% and 88 : 12 er (99.6 : 0.4 er, 10 : 1 dr after simple recrystallization). Furthermore, DFT calculations and 7Li-NMR analysis illustrated the mechanism of the synergistic reaction: a chiral Li-complex activates the nucleophile to control the stereoselectivity, while the other achiral Li-complex activates the electrophile to catalyze the carbonyl addition reaction. Additionally, this protocol has been successfully carried out at 5 gram-scale, showing its industrial potential.

Atroposelective Synthesis of 2-Arylindoles via Chiral Phosphoric Acid-Catalyzed Direct Amination of Indoles

Indole-based atropisomers are a very important class of axially chiral compounds.However,the atroposelective synthesis of axially chiral 2-arylindole remains largely unexplored.In this study,we report the successful synthesis of atropisomeric 2-arylindoles using direct amination of indoles with p-quinonediimines in the presence of chiral phosphoric acid as a catalyst.Quinonediimine acts as an aminating reagent through formal polarity inversion of imine.The malonate group on the 2-aryl of 2-indoles was found to be essen-tial for high enantioselectivity of the products.This could be due to the additional interaction between the ester group and the cata-lyst,as well as the intramolecular hydrogen bonding.Our findings provide a new strategy for the asymmetric construction of 2-arylindole atropisomers.

Recent trends and developments in the asymmetric synthesis of profens

The profens belong to a class of nonsteroidal anti-inflammatory drugs(NSAIDs),which exert significant antiinflammatory,analgesic,antipyretic and other pharmacological effects.A considerable number of catalytic asymmetric strategies for the synthesis of enantioenriched profens have been introduced.Herein are outlined recent trends and developments of promising catalytic enantioselective systems for the generation of profens and their derivatives.According to the reaction type,we divided these transformations into three categories:Transition metal-catalyzed asymmetric hydrogenations,transition metal-catalyzed asymmetric cross-couplings and organocatalytic asymmetric transformations.Overviews of generic reaction mechanisms are presented.Ideally,this tutorial review will motivate further interest in the catalytic asymmetric synthesis of highly enantioenriched profens.

Synergistic Copper and Chiral Lewis Base Catalysis for the Asymmetric Synthesis of Pyrrolo[1,2-a]indoles

The first asymmetric decarboxylative[3+2]-cycloaddition of ethynyl indoloxazolidones with carboxylic acids has been developed under synergistic catalysis of copper and chiral Lewis base.This protocol provides a direct and modular approach to biologically important pyrrolo[1,2-a]indoles bearing two vicinal stereogenic centers with excellent diastereo-and enantioselectivities(up to>20:1 dr and>99%ee).In addition,the utility of this methodology was demonstrated by scaled-up reaction and several synthetic transformations of the cycloadduct.

Transition-Metal-Catalyzed Carbon-Carbon Bond Activation in Asymmetric Synthesis

Catalytic asymmetric transformations involving carbon-carbon bond cleavages open intriguing strategies for the synthesis of chiral complex molecules.The transient organometallic species mainly generate from the oxidative addition of cyclic compounds with low valence metals or from β-carbon elimination of tert-alkoxyl metals.This overview covers the recent advances in transition-metal-catalyzed carbon-carbon bond activation in asymmet-ric synthesis.

Catalytic asymmetric dipolar cycloadditions of indolyl delocalized metal-allyl species for the enantioselective synthesis of cyclopenta[b]indoles and pyrrolo[1,2-α]indoles

The development of novel synthons and efficient methods to synthesize chiral polycyclic indoles has been a hot topic in organic synthesis and medicinal chemistry owing to their broad applications in medicines,pesticides,and other functional molecules.Here,we disclosed novel indolyl substituted metal-allyl zwitterionic intermediates through the decarboxylation of conveniently available vinyl indoloxazolidones,which could be regarded as two types of dipolar species through the anionic delocalization.The palladium-π-allyl species tended to serve as an all-carbon 1,3-dipole in the asymmetric[3+2]cycloaddition with electrondeficient alkenes,which furnished polysubstituted cyclopenta[b]indoles with high regio-and stereoselectivities.Meanwhile,the iridium-π-allyl species was recognized as an aza-1,3-dipole in asymmetric[3+2]cycloaddition with in situ generated C1 ammonium enolates,affording pyrrolo[1,2-α]indoles with high diastereo-and enantioselectivities.In addition,the dipolar cycloadditions could be easily scaled-up and several synthetic transformations of the cycloadducts were demonstrated for the rapid synthesis of diverse chiral polycyclic indoles.

Stereodivergently asymmetric synthesis of chiral phosphorus compounds by synergistic combination of ion-pair catalyst and base

Stereodivergently constructing the designed products having adjacent multi-stereocenters via a given reaction,with excellent control of both absolute and relative configurations,presents one of the substantial hurdles in asymmetric catalysis.Herein,we report a precisely stereodivergent asymmetric protocol by synergistic combination of phosphonium-involved ion-pair catalysis and base for accessing to chiral phosphorus compounds bearing two adjacent chiral centers particularly containing an acidic protonated enantioenriched carbon atom,having broad functional group compatibility in both dynamic and thermodynamic processes under mild reaction conditions.Two keys for the success in constructing these stereoisomers with high levels of regio-,diastereo-,and enantioselectivities were contained:firstly,the precise stereo-control in providing dynamic products was enabled by bifunctional phosphonium salt catalyst with semi-enclosed cavity;secondly,the readily stereospecific transformation of adducts from dynamic to thermodynamic version was initiated by achiral base.All four stereoisomers could be readily accessed even in gram-scale in high yields with maintaining excellent stereoselectivities,illustrating the potential of this synergistic catalytic methodology in organic synthesis.Moreover,mechanistic studies including density functional theory(DFT)calculations and control experiments provide insights into the mechanism.

Stereoselective Synthesis of （R）-Salmeterol via Asymmetric Cyanohydrin Reaction

The authors described a short and highly enantioselective route to （R）-salmeterol involving asymmetric synthesis of cyanohydrin followed by nucleophilic substitution with 6-（4-phenylbutoxy） hexyl methanesulfonate.

钯-手性磷酸接力催化的一锅三步串联反应合成手性四氢喹啉

设计钯-手性磷酸接力催化体系,以邻碘苯胺和苯基烯丙醇为原料,通过“一锅三步”串联反应高效合成手性2-苯基四氢喹啉,实验无需中间体分离,降低了手性四氢喹啉的合成难度并提高反应经济性,与单一催化反应相比,协同接力催化具有操作简单、反应高效等优点。将协同接力催化的科学前沿引入本科实验教学,融入节能减排和绿色化学等课程思政元素,能拓宽学生的科学视野,激发其学习兴趣并提升创新能力。此外,实验涵盖格氏反应、Heck反应、亚胺缩合反应、不对称氢转移反应等理论知识以及薄层色谱、柱层析色谱、旋转蒸发仪、核磁共振仪、高效液相色谱仪、旋光仪等分析分离设备的操作使用,能综合提升学生的理论水平、实验技能和科学思维能力,促进科研与教学相融合。

Amide Ionic Liquids(AILs)/L-Proline Synergistic Catalyzed Asymmetric Mannich Reactions

Amide ionic liquids （MLs）/L-proline synergistic catalyzed Mannich reactions of isovaleraldehyde, methyl ketones, and aromatic amines were carried out in moderate to high yields （ up to 96% ） and high stereo selectivities （ 〉99% e. e. ）. The products were easily isolated by extraction; and the catalyst system was readily recycled at least thrice without significant loss of efficiency. The scope of the substrates was studied and the interpretation of the manifest improvement of the reaction rates and enantio-selectivity of the novel catalyst system was speculated.

光酶催化混乱性反应的研究进展

光催化具有条件温和、可再生、反应性强等优点,然而由于自由基的高活性往往导致其选择性难以调控,限制了光催化在不对称有机合成中的广泛应用。酶催化虽具有高选择性和专一性的优势,但这也导致其存在反应类型单一和底物谱窄等缺陷。将反应性强的光催化与选择性高的酶催化相结合的光酶催化则可以提供一种全新的合成模式,实现优势互补,更加符合现代绿色有机合成的要求。狭义的光酶催化反应,也就是光酶协同反应一般包括以下四类:天然光酶反应,人工光酶反应,光催化与酶催化的偶联反应以及光酶催化混乱性反应。近年来,光酶催化的研究蓬勃发展,解决了许多传统有机合成中难以实现的问题,尤其是在不对称合成领域已占据重要地位。例如,脂肪酸光脱酸酶可以催化长链脂肪酸脱羧转化为相应烃类;结合光敏辅因子和蛋白骨架的人工光酶大大拓展了酶的应用范围,催化更多样化非天然有机化学品的生物合成;光催化剂催化光化学反应与酶催化反应的偶联方式可以实现一些复杂的有机合成过程;以及近年来一些含有光敏辅因子的氧化还原酶在光激发下催化新分子混乱性反应的功能。尽管已有许多文献对相关研究进行了总结,但是自2023年以来,光酶催化混乱性研究不断突破,涌现出许多全新的光酶催化反应类型和反应机理,立体选择性和区域选择性的精准调控更是满足了不对称合成的重大需求。对于这个飞速发展的领域,系统归纳其成果仍显得至关重要。因此本综述聚焦在光激发下光敏辅因子依赖型酶催化的混乱性反应最新研究成果,根据不同催化反应类型,分别介绍光酶通过自由基途径实现不对称脱卤、氢化、分子内环化、分子间C—C/C—N/C—S键交叉耦合等非天然反应。这些反应由于酶和底物的不同,展示了不同机理。例如在氧化还原起始过程中,包括单电子还原起始和单电子氧化起始两种类型;在自由基终止过程中,可能采用单电子还原终止和单电子氧化终止,而单电子还原终止方式中也存在氢原子转移和电子转移/质子转移耦合过程等不同情况。机理的多样性也为拓展更多的光酶催化混乱性反应提供了可能。在未来,新型的光酶催化方法将在快速发展的基因工程、合成生物学、酶工程,以及流动化学、人工智能等学科和技术的推动下,涌现出更多高效、高选择性的新分子新功能反应,显著拓展光酶催化方法在有机合成(尤其是绿色不对称合成)领域中的应用范围。

(S)-普萘洛尔的合成、应用及剂型研究进展

(S)-普萘洛尔是一种重要的β受体阻滞剂,用于治疗心血管疾病、焦虑症、甲状腺功能亢进等多种疾病。本文综述了迄今为止用于制备(S)-普萘洛尔的化学合成方法,如不对称拆分法、手性源合成法和不对称催化法。讨论了(S)-普萘洛尔口服和外用等多种新剂型,以及(S)-普萘洛尔在心血管疾病、焦虑症、甲状腺功能亢进、特发性震颤等疾病上的应用。本文期望为(S)-普萘洛尔的合成方法、应用和剂型研究提供参考。

2-甲酰基-1,1′-联萘手性醛催化剂的合成

目前报道的手性醛催化剂(3)的合成路线总收率较低,不适用于大量合成。通过对3的合成路线进行改进,以(S)-1,1′-联二萘酚((S)-BINOL)为原料,经磺酰化、插羰反应、偶联反应、硼化、氧化、甲氧基甲基保护、还原、氧化、脱除甲氧基甲基以及溴化10步反应合成了手性醛催化剂(3a~3i),其中大部分化合物的总收率大于20%。该合成路线可放大到10 mmol规模来进行,具有一定的应用前景。

手性磷酸催化非环状N,N′-缩酮的不对称合成

手性N,N′-缩酮是药物分子和生物活性化合物最重要的核心结构之一,也是有机合成中重要的催化剂或配体。因此,不对称合成N,N′-缩酮具有重要意义。通过手性磷酸、溶剂、催化剂负载量和投料比的筛选,确定了最佳的反应条件:在手性磷酸的催化下,以1,4-二氧六环作为溶剂,5-氨基异噁唑与β,γ-炔基-α-酮亚胺酯在室温下发生区域选择性的氮杂-曼尼希反应,实现异噁唑的不对称N—H烷基化,以中等至良好的收率(46%~83% yield)和较好的对映选择性(82%~92%ee)合成非环状的N,N′-缩酮。所有产物结构由^(1)H NMR,^(13)C NMR和HR-MS(ESI)确证,绝对构型通过X-射线晶体结构分析确定。

Enantioselective one-pot synthesis of β-sulfonyl ketones and trisubstituted tetrahydrothiophenes via β-elimination/cycloaddition sequence

A mild and efficient enantioselective one-pot synthesis of β-sulfonyl ketones and trisubstituted tetrahydrothiophenes via introducing 1,4-dithiane-2,5-diol to the simple kinetic resolution of β-sulfonyl ketones has been described herein. The one-pot reaction sequence including kinetic resolution and cascade sulfa-Michael/Aldol reaction proceeded successively to afford corresponding sulfonyl ketones and tetrahydrothiophenes with high enantioselectivities（85%-98% ee and 84%-95% ee）.

不对称催化构建轴手性化合物的研究进展

多数具有重要生理活性的天然产物和手性药物分子中都含具有轴手性骨架,研究如何构建具有轴手性化合物并将其应用于手性药物及天然产物的高效合成具有十分重大的实际意义。对联芳基、杂联芳基以及其他类型的轴手性化合物的研究进展进行了讨论,并对轴手性化合物的不对称催化合成策略作了重点介绍,同时举例说明所得轴手性化合物的潜在应用价值。