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Comprehensive Summary: The first catalytic asymmetric total synthesis of (+)‐propolisbenzofuran B, enabled by a highly enantioselective rhodium‐catalyzed hydrogenation of a tetrasubstituted olefin, was described. Other noteworthy aspects include the construction of the central hydrodibenzo[b,d]furan core through a sequence of Zn(II)‐mediated regioselective benzofuran formation and Dieckmann condensation, as well as C‐H oxidations, involving a visible light‐induced Fe(III)‐catalyzed benzylic C(sp3)‐H oxidation. Additionally, the absolute configuration was confirmed by X‐ray analysis of a carbonate intermediate. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The first catalytic asymmetric total synthesis of (+)‐propolisbenzofuran B, enabled by a highly enantioselective rhodium‐catalyzed hydrogenation of a tetrasubstituted olefin, was described. Other noteworthy aspects include the construction of the central hydrodibenzo[b,d]furan core through a sequence of Zn(II)‐mediated regioselective benzofuran formation and Dieckmann condensation, as well as C‐H oxidations, involving a visible light‐induced Fe(III)‐catalyzed benzylic C(sp3)‐H oxidation. Additionally, the absolute configuration was confirmed by X‐ray analysis of a carbonate intermediate. [ABSTRACT FROM AUTHOR]

Planar‐chiral skeletons widely exist in natural products, bioactive compounds, and other functional molecules. Although significant progress has been made in the field of asymmetric synthesis of centrally or axially chiral molecules over the past years, enantioselective constructing of planar chirality is still a big obstacle and numerous efforts have been made in this field. Previous works have mainly focused on the assembly of planar‐chiral [2,2]‐paracyclophanes and metallocenes. This Minireview describes recent advancements in asymmetric catalytic synthesis of planar‐chiral macrocycles, including ansa chain construction, plane formation and asymmetric transformation strategies. It is anticipated that this Minireview will sever as a source of inspiration for developing new unconventional procedures for access to planar‐chiral skeletons. [ABSTRACT FROM AUTHOR]

Comprehensive Summary Salimabromide, a unique and scarce marine tetracyclic polyketide, was synthesized in both racemic and optically active forms. A novel carboxylic acid‐directed method for tandem oxidative difunctionalization of olefins was developed, whereby the formation of bridged butyrolactone and enone moieties occurs concurrently. Density functional theory (DFT) calculations indicate that this reaction follows a [3+2] process rather than the [2+2] process. In the meantime, the distinctive benzo‐fused [4.3.1] carbon skeleton and highly hindered vicinal quaternary stereocenters were simultaneously constructed through a challenging intramolecular Giese‐Baran radical cyclization. Furthermore, deuterium kinetic isotopic effects were utilized to enhance the efficacy of this pivotal step. This represents a new illustration of the application of kinetic isotope effects in natural product synthesis. Then, the short asymmetric synthesis of (+)‐salimabromide (13 or 15 steps) was accomplished by combing this method with rhodium‐catalyzed enantioselective hydrogenation of a cycloheptenone derivative (97% ee) or conjugate addition of an aryl boronic acid with 2‐cyclohepten‐1‐one (> 99% ee). [ABSTRACT FROM AUTHOR]

A highly effective enantioselective monobenzoylation of 1,3‐diols has been developed for the synthesis of 1,1‐disubstituted tetrahydro‐β‐carbolines. The chemistry has been successfully applied to the asymmetric total synthesis of (+)‐alstrostine G, which also features a cascade Heck/hemiamination reaction enabling facile construction of the pivotal pentacyclic core. [ABSTRACT FROM AUTHOR]

We describe a full account of our synthetic strategy leading to the first total synthesis of the manzamine alkaloid lissodendoric acid A. These efforts demonstrate that strained cyclic allenes are valuable synthetic building blocks and can be employed efficiently in total synthesis. [ABSTRACT FROM AUTHOR]

Axially chiral biaryl scaffolds are important in pharmaceuticals, natural products, and asymmetric synthesis. Atroposelective ring‐opening of configurationally labile biaryl reagents via dynamic kinetic asymmetric transformation provides a valuable approach to access axially chiral biaryl atropisomers. This review summarizes seminal contributions and recent advancements on this topic based on the use of different types of configurationally labile biaryl reagents. [ABSTRACT FROM AUTHOR]

The quest to explore chemical space is vital for identifying novel disease targets, impacting both the effectiveness and safety profile of therapeutic agents. The tangible chemical space, currently estimated at a conservative 108 synthesized compounds, pales in comparison to the theoretically conceivable diversity of 1060 molecules. To bridge this vast gap, organic chemists are spearheading innovative methodologies that promise to broaden this limited chemical diversity. A beacon of this progressive wave is Asymmetric Carbene Transfer (ACT), a burgeoning strategy that significantly boosts molecular diversity with efficient bond‐formation and precise chiral control. This review focuses on the capabilities of ACT in creating pharmaceutically significant molecules, encompassing an array of natural products and bioactive compounds. Through the lens of ACT, we discern its substantial influence on drug discovery, paving the way for novel therapeutic avenues by expanding the boundaries of molecular diversity. This review will shed light on prospective methodological developments of ACT and articulate their conceivable contributions to the medicinal chemistry arena. [ABSTRACT FROM AUTHOR]

Tetrahydro‐β‐carbolines (THβCs) also known as tryptolines serve as important structural elements in natural products and pharmaceutical compounds, and they are also utilized in drug discovery. They display diverse bioactivities, including anticancer, antifungal, antiparasitic, anti‐ischemic, anti‐inflammatory, and other activities. Besides their pharmacological and biological significance, these structural motifs are also extensively used in the production of other bioactive compounds. This review is intended to summarize recent advancements in the chemistry of this compound class, including the synthesis and the applications as organic synthetic intermediates and bioactive molecules. [ABSTRACT FROM AUTHOR]

Axially chiral biaryl ethers and related compounds hold valuable potential in natural products, medicinal chemistry, and catalysis; however, their asymmetric syntheses have always been overlooked compared to other biaryl/hetero-biaryl atropisomers. Unlike the later class molecules bearing a single chiral axis, the former category possesses a unique type of atropisomerism bearing two potential axes. Due to their great importance in diverse research domains, catalytic atropselective biaryl ether synthesis has recently witnessed an upsurge. This highlight article provides an elaborated view on the developments of catalytic synthetic methods that have been explored to achieve dual axial chirality in biaryl ethers and related scaffolds. [ABSTRACT FROM AUTHOR]

Here, a photocatalytic asymmetric multicomponent cascade Minisci reaction of β‐carbolines with enamides and diazo compounds is reported, enabling an effective enantioselective radical C─H functionalization of β‐carbolines with high yields and enantioselectivity (up to 83% yield and 95% ee). This enantioselective multicomponent Minisci protocol exhibits step economy, high chemo‐/enantio‐selective control, and good functional group tolerance, allowing access to a variety of valuable chiral β‐carbolines. Notably, diazo compounds are suitable radical precursors in enantioselective cascade radical reactions. Moreover, the efficiency and practicality of this approach are demonstrated by the asymmetric synthesis of bioactive compounds and natural products. [ABSTRACT FROM AUTHOR]

Asymmetric sequential hydrogenations of α‐methylene γ‐ or δ‐keto carboxylic acids are established in one‐pot using a bimetallic Ru/Ru catalyst system, achieving the stereodivergent synthesis of all four stereoisomers of both chiral γ‐ and δ‐lactones with two non‐vicinal carbon stereocenters in high yields (up to 99%) and with excellent stereoselectivities (up to >99% ee and >20:1 dr). The compatibility of the two chiral Ru catalyst systems is investigated in detail, and it is found that the basicity of the reaction system plays a key role in the sequential hydrogenation processes. The protocol can be performed on a gram‐scale with a low catalyst loading (up to 11000 S/C) and the resulting products allow for many transformations, particularly for the synthesis of several key intermediates useful for the preparation of chiral drugs and natural products. [ABSTRACT FROM AUTHOR]

A de novo asymmetric strategy for the synthesis of d‐bradyrhizose diastereomers from an achiral ketoenolester precursor is described. Key transformations used in the stereodivergent approach include two Noyori asymmetric reductions, an Achmatowicz rearrangement, diastereoselective alkene oxidations, and the first example of a palladium(0)‐catalyzed glycosylation of a vinylogous pyranone. The isomeric composition of the bicyclic reducing sugars obtained was analyzed and their behaviour was compared to the natural product, revealing key stereocentres that impact the overall distribution. [ABSTRACT FROM AUTHOR]

A de novo asymmetric strategy for the synthesis of d‐bradyrhizose diastereomers from an achiral ketoenolester precursor is described. Key transformations used in the stereodivergent approach include two Noyori asymmetric reductions, an Achmatowicz rearrangement, diastereoselective alkene oxidations, and the first example of a palladium(0)‐catalyzed glycosylation of a vinylogous pyranone. The isomeric composition of the bicyclic reducing sugars obtained was analyzed and their behaviour was compared to the natural product, revealing key stereocentres that impact the overall distribution. [ABSTRACT FROM AUTHOR]

Chirality constitutes an inherent attribute of nature. The catalytic asymmetric synthesis of molecules with central, axial, and helical chirality is a topic of intense interest and is becoming a mature field of research. However, due to the difficulty in synthesis and the lack of a prototype, less attention has been given to planar chirality arising from the destruction of symmetry on a single planar ring. Herein, we report the catalytic asymmetric synthesis of planar-chiral dianthranilides, a unique class of tub-shaped eight-membered cyclic dilactams. This protocol is enabled by cinchona alkaloid-catalyzed (dynamic) kinetic resolution. Under mild conditions, various C2- or C1-symmetric planar-chiral dianthranilides have been readily prepared in high yields with excellent enantioselectivity. These dianthranilides can serve as an addition to the family of planar-chiral molecules. Its synthetic value has been demonstrated by kinetic resolution of racemic amines via acyl transfer, enantiodivergent synthesis of the natural product eupolyphagin, and preliminary antitumor activity studies. Chirality has long fascinated chemists, but asymmetric synthesis has largely focused on central, axial, and helical chirality to date. Here, the authors synthesize dianthranilides with planar chirality, via cinchona alkaloid-catalyzed (dynamic) kinetic resolution. [ABSTRACT FROM AUTHOR]

In this study, the design and asymmetric synthesis of a series of chiral targets of orientational chirality were conducted by taking advantage of N-sulfinylimine-assisted nucleophilic addition and modified Sonogashira catalytic coupling systems. Orientational isomers were controlled completely using alkynyl/alkynyl levers [C(sp)-C(sp) axis] with absolute configuration assignment determined by X-ray structural analysis. The key structural element of the resulting orientational chirality is uniquely characterized by remote through-space blocking. Forty examples of multi-step synthesis were performed, with modest to good yields and excellent orientational selectivity. Several chiral orientational amino targets are attached with scaffolds of natural and medicinal products, showing potential pharmaceutical and medical applications in the future. [ABSTRACT FROM AUTHOR]

We have achieved the first total synthesis of pallamolides A−E. Of these compounds, pallamolides B−E possess intriguing tetracyclic skeletons with novel intramolecular transesterifications. Key transformations include highly diastereoselective sequential Michael addition reactions to construct the bicyclo[2.2.2]octane core with the simultaneous generation of two quaternary carbon centers, a one‐pot SmI2‐mediated intramolecular ketyl–enoate cyclization/ketone reduction to generate the key oxabicyclo[3.3.1]nonane moiety, and an acid‐mediated deprotection/oxa‐Michael addition/β‐hydroxy elimination cascade sequence to assemble the tetracyclic pallamolide skeleton. Kinetic resolution of ketone 14 through Corey–Bakshi–Shibata reduction enabled the asymmetric synthesis of pallamolides A−E. [ABSTRACT FROM AUTHOR]

General, catalytic and enantioselective construction of chiral α,α-dialkyl indoles represents an important yet challenging objective to be developed. Herein we describe a cobalt catalyzed enantioselective anti-Markovnikov alkene hydroalkylation via the remote stereocontrol for the synthesis of α,α-dialkyl indoles and other N-heterocycles. This asymmetric C(sp3)−C(sp3) coupling features high flexibility in introducing a diverse set of alkyl groups at the α-position of chiral N-heterocycles. The utility of this methodology has been demonstrated by late-stage functionalization of drug molecules, asymmetric synthesis of bioactive molecules, natural products and functional materials, and identification of a class of molecules exhibiting anti-apoptosis activities in UVB-irradiated HaCaT cells. Ligands play a vital role in controlling the reaction regioselectivity. Changing the ligand from bi-dentate L6 to tridentate L12 enables CoH-catalyzed Markovnikov hydroalkylation. Mechanistic studies disclose that the anti-Markovnikov hydroalkylation involves a migratory insertion process while the Markovnikov hydroalkylation involves a MHAT process. Catalytic and enantioselective construction of chiral α,α-dialkyl indoles represents an important yet challenging objective to be developed. Herein the authors describe a cobalt catalyzed enantioselective anti-Markovnikov alkene hydroalkylation via the remote stereocontrol for the synthesis of α,α-dialkyl indoles and other N-heterocycles. [ABSTRACT FROM AUTHOR]

Toward the total synthesis of natalamycin A, we have synthesized the C9-C21 segment corresponding to the northwestern part of the natural product. Key features of this synthesis were an asymmetric α-chlorination of an aldehyde using MacMillan's catalyst and stereoselective assembly of three contiguous stereocenters via a butenolide intermediate. [ABSTRACT FROM AUTHOR]

Axially chiral architectures exist widely in natural products, biologically relevant molecules, chiral ligands and catalysts as well as functional materials. Therefore, catalytic asymmetric synthesis of atropisomers has become one of the most fast‐growing fields in the community of chemistry and rapid advances have occurred. Among different methods reported, the organocatalytic atroposelective dynamic kinetic resolution (DKR) involving ring manipulations stands out as a cutting‐edge technology to construct axial chirality from the point of atom/step economy. In this DKR strategy, the configurational lability of starting materials originates from chirally‐labile ring structure of cyclic substrates/intermediates or transient ring formation through noncovalent interactions from acyclic substrates. The two atropisomers of starting material are in equilibrium in the reaction medium, ensuring the constant transformation of the less reactive atropisomer into the more reactive one, and then to a single enantiopure product in the presence of an appropriate organocatalyst. This review summarizes recent advancements on this topic, including their scopes, limitations, mechanisms, applications and provides some insights into further developments. [ABSTRACT FROM AUTHOR]

The synthesis of chiral organic molecules is a purity‐driven research that has become an essential part of our lives due to their applications in pharmaceuticals. Contemporary research focuses on the exploration of synthetic protocols that obviate the use/generation of hazardous chemicals. In this regard, dioxiranes are readily accessed as a reagent solution or catalyst (in situ) from the reaction of ketone with a co‐oxidant like Oxone® or H2O2; the latter makes the protocol very green and inexpensive. It has shown the potential to replace transition metal‐based oxygenation protocols. The dioxirane‐mediated asymmetric reactions include oxidations, epoxidations, C−H hydroxylations, etc. Both stoichiometric and catalytic protocols of dioxiranes are been explored for the oxyfunctionalization of chiral natural product derivatives such as Penicillin, nucleosides, amino acids, carbohydrates, etc. In addition, these are employed as key oxygenation agents during the synthesis of natural products like (+)‐Plagiogyrin A, Portimine, Taxol, Bryostatin, dafachronic acid, majucinoids, eldecalcitol, Spirochensilide A, etc. The review consolidates the development of both achiral and chiral dioxiranes in application to asymmetric synthesis and oxygenation of chiral molecules. [ABSTRACT FROM AUTHOR]

Chiral hydroxamic acid (HA) and bis-hydroxamic acid (BHA) ligands have made significant contributions to the field of asymmetric synthesis, particularly in the synthesis of natural products. These ligands possess unique molecular structures that allow for exceptional stereochemical control, leading to their widespread use in catalytic systems. This review highlights the advancements made in asymmetric synthesis using chiral hydroxamic acid and bis-hydroxamic acid ligands and their impact on the synthesis of complex natural products. This discussion encompasses their role in enantioselective C–C bond formation, the functionalization of C–H bonds, the asymmetric transformations involving heteroatoms, and their application in the total synthesis of natural products. The versatility and efficiency of chiral hydroxamic acid ligands and bis-hydroxamic acid ligands make them invaluable tools for synthetic chemists working towards the efficient and selective synthesis of natural products. This review provides a comprehensive overview of their contributions, showcasing their potential to expand the boundaries of chemical synthesis and access the diverse array of natural product scaffolds.

Isoxeniolide A is a highly strained xenicane diterpenoid of marine origin. This natural product is representative for a subfamily of xenicanes incorporating an allylic hydroxy group in the nine‐membered ring; members of this xenicane subfamily so far have not been targeted by total synthesis. Herein, we describe the first asymmetric total synthesis of isoxeniolide A. Key to forming the challenging E‐configured cyclononene ring was a diastereoselective intramolecular Nozaki–Hiyama–Kishi reaction. Other important transformations include an enzymatic desymmetrization for absolute stereocontrol, a diastereoselective cuprate addition and the use of a bifunctional vinyl silane building block. Our strategy also permits access to the enantiomer of the natural product and holds potential to access a multitude of xenicane natural products and analogs for structure–activity relationship studies. [ABSTRACT FROM AUTHOR]

α‐Methylene‐γ‐butyrolactone is an important skeleton in many natural products and pharmaceuticals. The factors influencing the palladium‐catalyzed asymmetric synthesis of α‐chloromethylene‐γ‐butyrolactones were investigated, including ligands, additives, the chlorine source, temperature, and solvents. We found that the reaction had broad substrate scope for the synthesis of the corresponding chiral products when the ligand, chlorine source and additives were optimized. The results will improve the catalytic synthesis of chiral α‐chloromethylene‐γ‐butyrolactones. [ABSTRACT FROM AUTHOR]

Pancratistatin and structurally related narciclasine are natural products of great interest as they display potent and selective activities against various diseases. A concise synthesis of a functionalised pancratistatin framework, via a Heck reaction and subsequent cyclisation, is reported. The unfunctionalised model core of pancratistatin was synthesised from 1‐cyclohexene‐1‐carboxylic acid in two steps in 50 % yield. A modified route was then successfully applied to (−)‐shikimic acid to afford a novel pancratistatin/shikimic acid hybrid analogue that possesses three stereo‐defined hydroxyl groups in the C‐ring. [ABSTRACT FROM AUTHOR]

Noncanonical amino acids (ncAAs) containing tertiary alcohols are valuable as precursors of natural products and active pharmaceutical ingredients. However, the assembly of such ncAA scaffolds from simple material by C−C bond formation remains a challenging task due to the presence of multiple stereocenters and large steric hindrance. In this study, we present a novel solution to this problem through highly selective enzymatic decarboxylative aldol addition. This method allows for the streamlined assembly of multifunctionalized ncAAs with γ‐tertiary alcohols from readily available materials, such as L‐aspartatic acid and isatins, vicinal diones and keto esters. The modularity of electrophiles furnished four classes of ncAAs with decent efficiency as well as excellent site and stereocontrol. Computational modeling was employed to gain detailed insight into the catalytic mechanism and to provide a rationale for the observed selectivities. The method offers a single‐step approach to producing multifunctionalized ncAAs, which can be directly utilized in peptide synthesis and bioactivity assessment. [ABSTRACT FROM AUTHOR]

Cyclobutene scaffolds occur in natural products and bioactive compounds. Their unique structural features and intrinsic ring strain make cyclobutene a type of important building block in synthetic chemistry. In recent years, considerable efforts have been dedicated to the synthesis of chiral cyclobutenes. Enantioselective [2+2] cycloadditions and functionalization of cyclobutene derivatives have emerged as powerful and reliable protocols for achieving this goal, resulting in significant progress in this field. This review provides a comprehensive summary of the recent advancements in the asymmetric synthesis of chiral cyclobutenes, and the discussion is logically divided into four parts according to the reaction mode. [ABSTRACT FROM AUTHOR]

Covering: 2013 to 2023 The α-tertiary amine moiety is a common structural motif in natural alkaloids and is frequently associated with intriguing biological activities and inherent synthetic challenges. A major hurdle in the total synthesis of these alkaloids is the asymmetric construction of the α-tertiary amine moiety. Temporary chirality inductions have been effective strategies employed to address this issue, particularly in natural product synthesis. The temporary chirality induction strategies in α-tertiary amine synthesis can be broadly classified into three categories based on the types of temporary chirality involved: Seebach's self-regeneration of stereocenters (SRS), C-to-N-to-C chirality transfer, and memory of chirality (MOC). This review highlights the recent advancements in temporary chirality induction strategies for the total synthesis of α-tertiary amine-containing natural products between 2013 and 2023. [ABSTRACT FROM AUTHOR]

N,N‐Dimethylaniline.borane (DMAB) is a stable, multifaceted electrophilic boron agent that displays hydroboration of C = C as well as selective reduction of functional groups under reflux, microwave, and ultrasound conditions. Natural products contain a plethora of functional groups that govern the specific bioactivity. It will be interesting to correlate the change in a functional group with the concern for change in bioactivity. Current research emphasizes the influence of microwave irradiation on moderately reactive DMAB reagent towards the functional group modification of selected limonoid‐phytochemicals of Meliaceae family viz. cedrelone, azadirone, nimbin, and azadiradione. DMAB conveniently reduces the ketone, epoxide group into alcohol, and does a hydroboration reaction on the C = C bond. It does not show interest to reduce the ester group irrespective of 30 min of MW irradiation. Except for these reducing properties, the reagent DMAB unveils chemo‐selective nature in respect of different functional groups and utilizes in an asymmetric synthesis. The coalescence of amine.borane with microwave irradiation brings forth a commodious and prompt method for the selective reduction of functional groups. The bioactive efficacy of modified phytochemicals is further taken for the antimicrobial studies. [ABSTRACT FROM AUTHOR]

This perspective article describes the recent progress in the total syntheses of iheyamines A and B. Since iheyamine A possesses a highly unique unsymmetrical azepino‐2,2'‐bisindole scaffold, novel strategies to construct the basic scaffold have been developed, and unique total syntheses have been reported based on these strategies. In addition, because iheyamine B bears vicinal 2‐oxopropyl moieties with a trans‐configuration in the azepine scaffold of iheyamine A, the first asymmetric total synthesis of iheyamine B took a substantially longer time than iheyamine A to complete. Due to the unusual structure of iheyamine B and some discrepancies in the experimental data between the isolated and synthesized iheyamine B, some controversial issues regarding whether iheyamine B is a natural product or an artifact have been raised and will be discussed. [ABSTRACT FROM AUTHOR]

16β‐Methylcorticoids are among the most important glucocorticoid steroids for the treatment of various dermatological disorders, respiratory infections, and other allergic reactions elicited during inflammatory responses of the human body. Betamethasone dipropionate, clobetasol propionate, and beclomethasone dipropionate are particularly noteworthy for their synthetic intractability. Despite five decades of research, these 16β‐methylcorticoids have remained challenging synthetic targets owing to insurmountable issues of reactivity, selectivity, and cost efficiency associated with all previously explored strategies. We herein report our practicability‐oriented strategy toward the unified stereoselective synthesis of 16β‐methylcorticoids in 12.6–14.0 % overall yield from commercially available 9α‐hydroxyandrost‐4‐ene‐3,17‐dione (9α‐OH‐AD). In this approach, the chiral C16β‐Me and C17α‐OH groups of the corticosteroid D ring were installed via a substrate‐controlled diastereo‐ and enantioselective Mn‐catalyzed oxidation‐reduction hydration of Δ4,9(11),16‐triene‐3,20‐dione. The C1−C2 double bond of the corticosteroid A ring was constructed using an unprecedented engineered 3‐ketosteroid‐Δ1‐dehydrogenase (MK4‐KstD)‐catalyzed regioselective Δ1‐dehydrogenation of Δ4,9(11)‐diene‐3,21‐dione. This strategy provides a general method and a key precursor for the divergent synthesis of a variety of glucocorticoids and related steroidal drugs. [ABSTRACT FROM AUTHOR]

Herein we report a structure‐unit‐based asymmetric total synthesis of sinulochmodin C, a norcembranoid diterpenoid bearing a transannular strained ether bridge β‐keto tetrahydrofuran moiety. Our synthetic route features an intramolecular double Michael addition to construct stereospecifically the [7,6,5,5] tetracyclic skeleton, a vinylogous hydroxylation/oxidation procedure or a stereospecific epoxide opening/oxidation sequence to establish the γ‐keto enone intermediate, a Lewis acid/Brønsted acid mediated transannular oxa‐Michael addition to fuse the β‐keto tetrahydrofuran moiety, a Mukaiyama hydration/Pd−C hydrogenation to reverse the C1‐configuration of the isopropenyl unit, and a bioinspired transformation of sinulochmodin C into scabrolide A. [ABSTRACT FROM AUTHOR]

Atropisomers have emerged as important structural scaffolds in natural products, drug design, and asymmetric synthesis. Recently, N−N biaryl atropisomers have drawn increasing interest due to their unique structure and relatively stable axes. However, its asymmetric synthesis remains scarce compared to its well‐developed C−C biaryl analogs. In this concept, we summarize the asymmetric synthesis of N−N biaryl atropisomers including N−N pyrrole−pyrrole, N−N pyrrole−indole, N−N indole−indole, and N−N indole−carbazole, during which a series synthetic strategies are highlighted. Also, a synthetic evolution is briefly reviewed and an outlook of N−N biaryl atropisomers synthesis is offered. [ABSTRACT FROM AUTHOR]

Macrocycles with bent π‐conjugation motif are extremely rare in nature and synthetically daunting and anticancer haouamines and spirohexenolides were representative of such rare natural products with synthetically challenging bent π‐conjugation within a macrocycle. While the total synthesis of haouamines has been elegantly achieved, spirohexenolides remains an unmet synthetic challenge due to the highly strained bent 1,3,5‐triene conjugation within C15 macrocycle. Inspired by the chemical synthesis of cycloparaphenylenes (CPPs) and haouamines, herein we devise a synthetic strategy to overcome the highly strained bent 1,3,5‐triene conjugation within the macrocycle and achieve the first, asymmetric total synthesis of spirohexenolides A (>20 mg) and B (>50 mg). Our synthesis features strategic design of ring‐closing metathesis (RCM) macrocyclization followed by double dehydration to achieve the C15 macrocycle with the deformed nonplanar 1,3,5‐triene conjugation. In addition, we have developed a new enantioselective construction of highly functionalized spirotetronate fragment (northeast moiety) through RCM and Ireland–Claisen rearrangement. Our in vitro bioassay studies reveal that both spirohexenolides are cytotoxic against a panel of human cancer cells with IC50 1.2–13.3 μM and spirohexenolide A is consistently more potent (up to 3 times) than spirohexenolide B, suggesting the importance of alcohol for their bioactivity and for medicinal chemistry development. [ABSTRACT FROM AUTHOR]

Covering: up to 2023 Huperzine alkaloids are a group of natural products belonging to the Lycopodium alkaloids family. The representative member huperzine A has a unique structure and exhibits potent inhibitory activity against acetylcholine esterase (AChE). This subfamily of alkaloids provides a great opportunity for developing synthetic methodologies and asymmetric synthesis. The efforts towards the synthesis of huperzine A have cultivated dozens of total syntheses and a rich body of new chemistry. Impressive progress has also been made in the synthesis of other huperzine alkaloids. The total syntheses of huperzines B, U, O, Q and R, structure reassignment and total syntheses of huperzines K, M and N have been reported in the past decade. This review focuses on the synthetic organic chemistry and the biosynthesis and medicinal chemistry of huperzines are also covered briefly. [ABSTRACT FROM AUTHOR]

Benzofuran‐ and benzopyran‐fused polycyclic acetals are found in a variety of biologically active natural products. The synthetic methods toward this class of polycyclic heterocycles have fascinated one of the most intensive pursuits in total synthesis. Nevertheless, stereoselective methods towards the rapid construction of such skeletons still remain challenging for organic chemists. Significant progress has been made in this research area in recent years, however, literature on enantioselective approaches to construct these molecules has not fully reviewed. Driven by their intriguing and complex scaffolds with potential usefulness, we compose the recent advances in this review covering all the important works in this field. We hope this review will promote future research in this area. [ABSTRACT FROM AUTHOR]

This article explores the synthesis of 3-lactone-substituted 2-oxindoles with vicinal quaternary carbon centers through vinylogous conjugate addition. These compounds have various bioactivities and are important intermediates in the synthesis of natural products and pharmaceuticals. The authors discuss different methods and catalysts used for this synthesis, including diastereo- and enantioselective versions that allow for the preparation of optically active natural products. They also propose a method to connect lactones and indol-2-ones to create new molecules. The article includes a table presenting the optimization of reaction conditions. The authors found that a chiral N,N'-dioxide/nickel(II) complex was effective in promoting the vinylogous addition reaction, yielding high diastereo- and enantioselectivities. They also conducted a gram-scale synthesis to demonstrate the practicality of the approach. [Extracted from the article]

The alkyne group is the key component of many bioactive molecules and versatile synthetic building block, thus the introduction of which into target molecules has attracted considerable interest from scientists. Moreover, tertiary and quaternary stereocenters are common motifs in natural products and drugs, however, the asymmetric construction of such motifs is one of the challenging tasks due to the steric congestion of multiple stereospecific substituents attached to one carbon. Metal–allenylidene are an excellent type of electrophilic species. The asymmetric addition of carbon‐nucleophiles at Cγ of the metal–allenylidene provides an effective way to construct tertiary and quaternary stereocenters as well as to introduce an alkyne group. In this review, the state‐of‐the‐art asymmetric propargylic C−C bond formation via metal‐allenylidene generated in situ from propargylic alcohol derivatives are presented. Synthetic applications, mechanistic insights are addressed. The challenges and opportunities of this field are also discussed. [ABSTRACT FROM AUTHOR]

Chiral hydroxamic acid (HA) and bis-hydroxamic acid (BHA) ligands have made significant contributions to the field of asymmetric synthesis, particularly in the synthesis of natural products. These ligands possess unique molecular structures that allow for exceptional stereochemical control, leading to their widespread use in catalytic systems. This review highlights the advancements made in asymmetric synthesis using chiral hydroxamic acid and bis-hydroxamic acid ligands and their impact on the synthesis of complex natural products. This discussion encompasses their role in enantioselective C–C bond formation, the functionalization of C–H bonds, the asymmetric transformations involving heteroatoms, and their application in the total synthesis of natural products. The versatility and efficiency of chiral hydroxamic acid ligands and bis-hydroxamic acid ligands make them invaluable tools for synthetic chemists working towards the efficient and selective synthesis of natural products. This review provides a comprehensive overview of their contributions, showcasing their potential to expand the boundaries of chemical synthesis and access the diverse array of natural product scaffolds. [ABSTRACT FROM AUTHOR]

Cephalotaxus diterpenoids are attractive natural products with intriguing molecular frameworks and promising biological features. As a structurally unusual member, (−)‐cephalotanin B possesses an extraordinarily congested heptacyclic skeleton, three lactone units, and nine consecutive stereocenters. Herein, we report an enantioselective total synthesis of (−)‐cephalotanin B based on a divergent asymmetric Michael addition reaction, a novel Pauson–Khand/deacyloxylation process discovered in the development of a second‐generation stereoselective Pauson–Khand reaction protocol, and an epoxide‐opening/elimination/dual‐lactonization cascade to construct the challenging propeller‐shaped A–B–C ring system as key transformations. [ABSTRACT FROM AUTHOR]

Axially chiral styrenes, a type of atropisomer analogous to biaryls, have attracted great interest because of their unique presence in natural products and asymmetric catalysis. Since 2016, a number of methodologies have been developed for the atroposelective construction of these chiral skeletons, involving both transition metal catalysis and organocatalysis. In this feature article, we aim to provide a comprehensive understanding of recent advances in the asymmetric synthesis of axially chiral styrenes catalyzed by transition metals, integrating scattered work with different catalytic systems together. This feature article is cataloged into five sections according to the strategies, including asymmetric coupling, enantioselective C–H activation, central-to-axial chirality transfer, asymmetric alkyne functionalization, and atroposelective [2+2+2] cycloaddition. [ABSTRACT FROM AUTHOR]

Axially chiral N-arylindoles bearing a stereogenic C-N axis are unique important scaffolds in natural products, advance materials, pharmaceuticals and privileged chiral ligands or catalysts. Herein, we report the direct synthesis of C-N axially chiral N-arylindoles through a Pd-catalyzed free amine-directed atroposelective C-H olefination enabled by a spiro phosphoric acid (SPA) ligand. A wide range of enantioenriched N-aromatic amine indoles were obtained in high yields with good enantioselectivities (35 examples, up to 91% yield and up to 96% ee). The chiral products with free amine group offer an effective functional handle for down-stream diversity-oriented synthesis. [ABSTRACT FROM AUTHOR]

The first total synthesis of (−)‐5‐deoxyenterocin has been accomplished starting from pentane‐1,3,5‐triol (16 steps in the longest linear sequence, 0.2 % overall yield). (−)‐Menthone served as the source of chirality to distinguish the enantiotopic hydroxymethyl groups of the substrate. Key steps of the synthesis include two aldol reactions to either end of the C5‐skeleton, a diastereoselective hydroxylation reaction and a biomimetic twofold intramolecular aldol reaction as the final step. Although this step suffered from geometrical constraints and was low yielding (10 %), enough synthetic material could be secured to substantiate the relative and absolute configuration of the natural product. Additional experiments were directed toward a C−H functionalization at carbon atom C5. Despite the fact that several protocols could be successfully applied to (3aR)‐(+)‐sclareolide as model substrate, (−)‐5‐deoxyenterocin withstood any selective functionalization. [ABSTRACT FROM AUTHOR]

Asymmetric organocatalytic 1,4‐conjugate addition is considered as an effective, powerful and sustainable method for carbon‐carbon bond formation. The core structure of maleimides or succinimides were found in several bioactive molecules as well as in natural products. Unprotected and protected maleimides were employed as an electrophile to construct novel succinimide based organic molecules. The rapid development of several new effective and prominent methodologies encourages us to write a review by summarizing the recent updates. In this review, we present an overview of the past 10 years progress on the asymmetric organocatalytic 1,4 conjugate additions using unprotected and protected maleimides. Special attention has been paid classifying the types of nucleophiles as well as catalysts employed for this asymmetric transformation along with substrate scope, limitation, mechanism, and synthetic utilities for each reaction. Knowing the versatility of maleimides, this review will encourage active researchers around the globe to put more efforts on the development of new methodologies including asymmetric photo redox catalysis for further functionalization of maleimides. [ABSTRACT FROM AUTHOR]

Thousands of coral terpenes originate from simple scaffolds that undergo oxidative tailoring. While corals are excellent sources of drug leads, the challenge of supplying structurally complex drug leads from marine organisms has sometimes slowed their development. Making this even more challenging, in comparison to other organisms, such as plants and microbes, for which the terpene literature is substantial, very little is known about how the unique coral terpenes are biosynthesized and elaborated in nature. In this study, we used a semisynthetic strategy to produce at gram scale in yeast the eunicellane scaffold that underlies >200 coral compounds. Synthetic oxidation reactions were explored, generating key scaffolds that reflect three of the four structural classes derived from eunicellane and enabling the first asymmetric syntheses of the natural products solenopodin C and klysimplexin Q. Biomimetic methods and detailed mechanistic studies of synthetic reactions shed light on potential enzymological reactivity, including the role of epoxide rearrangement in eunicellane biosynthesis. [ABSTRACT FROM AUTHOR]

We report here a homo‐Mannich reaction of cyclopropanol with an iminium ion, generated by an asymmetric allylic dearomatization of indole, to construct a tricyclic hydrocarbazole core, which is shared by a variety of monoterpenoid indole alkaloids across families. Through this approach, an all‐carbon quaternary stereogenic center as well as an allyl and a ketone group were installed. Using this functionalized hydrocarbazole as the structural platform, D ring and E rings of different sizes (i.e. five‐, six‐, and seven‐membered) were successively or simultaneously assembled, leading to a collective asymmetric synthesis of seven alkaloids belonging to the ibophyllidine, Aspidosperma, Kopsia, and Melodinus alkaloid families. [ABSTRACT FROM AUTHOR]

The residue was purified by column chromatography on silica gel (PE/EtOAc 1:1) to give sulfonamide B 26 b as a pale yellow syrup; yield: 5.55 g (95%); I R SB f sb i = 0.40 (PE/EtOAc 1:1). The residue was purified by column chromatography on silica gel (PE/EtOAc 6:1) to afford sulfinimine B 13 b as a pale-yellow syrup; yield: 12.15 g (95%); I R SB f sb i = 0.54 (PE/EtOAc 3:1). Keywords: macroline alkaloids; natural products; total synthesis; cyclizations; bridged rings EN macroline alkaloids natural products total synthesis cyclizations bridged rings 2648 2657 10 08/17/23 20230901 NES 230901 Graph Macroline-type alkaloids are mainly isolated from the plant family Apocynaceae, especially from the genera I Alstonia i and I Rauwolfia i . The residue was purified by column chromatography on silica gel (PE/EtOAc 5:1) to afford aldehyde B 15 b as a colorless oil; yield: 7.66 g (70%); I R SB f sb i = 0.30 (PE/EtOAc 6:1). [Extracted from the article]

We present a concise asymmetric total synthesis (5–8 steps) of nine sesquiterpenoid alkaloids featuring four different tetra‐/pentacyclic scaffolds. To this end, a novel, bioinspired indole N‐terminated cationic tricyclization has been developed, enabling the divergent synthesis of greenwayodendrines and polysin. Subtle variation of the C2‐substituted indole cyclization precursor allowed switching between indole N‐ and C‐termination. For the latter, a subsequent Witkop oxidation enabled conversion of the cyclopentene‐fused indole into the eight‐membered benzolactam to directly furnish the family of greenwaylactams. In addition, a diastereomeric C‐termination product has been elaborated to provide access to polyveoline. [ABSTRACT FROM AUTHOR]