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In this study, the preparation of 4-imidoyl-, 4-oxiranyl-, and 4-propargyloxyphenyl-substituted beta-lactams as versatile building blocks in heterocyclic chemistry was realized. Efforts were made to deploy these polyvalent compounds for ensuing cyclization reactions en route to new bi- or polycyclic frameworks, which, in the case of a 3-chloro-4-propargyloxyphenyl-beta-lactam substrate, enabled the preparation of an unprecedented beta-lactam-fused benzotriazolo-oxazocane scaffold. The chemical structure of the latter polyheterocycle was unequivocally secured by means of X-ray analysis.

A stereoselective [10 + 2] cycloaddition for the reaction of homologated indenecarbaldehydes with α,β-unsaturated aldehydes, providing tetrahydrocyclopenta[a]indenes, has been developed and investigated mechanistically. The reaction proceeds via an aminocatalytic double Michael addition in high formal peri-, diastereo-, and enatioselectivity (up to 99% enantiomeric excess). Mechanistic investigations conclude that the reaction takes advantage of the in situ generation of a highly reactive amino isobenzofulvene intermediate via an aromative aminocatalytic strategy. A significant nonlinear effect is observed, consistent with a dual-activation model. Kinetic studies suggest a stepwise mechanism which is further supported by the identification and isolation of diastereomeric precyclization intermediates. These intermediates showed that in the presence of the aminocatalyst, they re-enter the catalytic cycle and afford the [10 + 2] cycloadduct with the same stereoselectivity observed in the prototypical reaction. Density functional theory calculations identified a Curtin-Hammett scenario where the stereoisomer of the [10 + 2] cycloadduct is determined by downstream species. These mechanistic investigations provide an understanding of the reaction pathway and stereoselectivity and continue to increase the knowledge of higher-order cycloadditions.

Aspartic acid derivatives with branched N‐alkyl or N‐arylalkyl substituents are valuable precursors to artificial dipeptide sweeteners such as neotame and advantame. The development of a biocatalyst to synthesize these compounds in a single asymmetric step is an as yet unmet challenge. Reported here is an enantioselective biocatalytic synthesis of various difficult N‐substituted aspartic acids, including N‐(3,3‐dimethylbutyl)‐l‐aspartic acid and N‐[3‐(3‐hydroxy‐4‐methoxyphenyl)propyl]‐l‐aspartic acid, precursors to neotame and advantame, respectively, using an engineered variant of ethylenediamine‐N,N′‐disuccinic acid (EDDS) lyase from Chelativorans sp. BNC1. This engineered C–N lyase (mutant D290M/Y320M) displayed a remarkable 1140‐fold increase in activity for the selective hydroamination of fumarate compared to that of the wild‐type enzyme. These results present new opportunities to develop practical multienzymatic processes for the more sustainable and step‐economic synthesis of an important class of food additives.

A novel continuous flow reactive crystallization process for the in situ on-demand access of single enantiomer crystals is reported and exemplified for a chiral pharmaceutical intermediate that crystallizes as a racemic conglomerate. During this process, a nearly racemic feed suspension with a racemization catalyst is circulated through a tubular coiled milli-reactor immersed in two thermostatic baths set at different temperatures. This flow configuration enables rapid heat transfer, which in turn results in successive spatial cycles of dissolution and re-crystallization carried out at extremely short residence times, unattainable in batchwise operations. By tuning the number of cycles, residence time per cycle and feed suspension density we show that unprecedented productivities (>20 g L−1 h−1) of the preferred enantiomer at purities >98% can be attained that could easily suit industrial demand in a directly scalable process.

The compatibility between gold(I) catalysts and amine transaminases has been explored to transform racemic propargylic alcohols into enantioenriched allylic amines in a straightforward and selective manner. The synthetic approach consists of a gold(I)-catalysed Meyer-Schuster rearrangement of a series of 2-arylpent-3-yn-2-ols and a subsequent stereoselective enzyme-catalysed transamination of the resulting alpha,beta-unsaturated prochiral ketones. The design of cascade processes involving sequential or concurrent approaches has been studied in our search for ideal reaction conditions to produce the desired amines. Thus, the N-heterocyclic carbene complex [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-[bis(trifluoromethanesulfonyl)-imide]gold(I) ([Au(IPr)(NTf2)] (A) in aqueous medium was found to be an ideal catalyst, while selective, made-in-house and commercial amine transaminases permitted the asymmetric synthesis of both (E)-4-arylpent-3-en-2-amine enantiomers in good isolated yields (53-84%) and excellent stereoselectivities (97 to >99% enantiomeric excess).

Synthesis of enantioenriched Betti base precursors containing a congested quaternary stereocenter is described. In a chiral phosphoric acid-catalyzed reaction, a series of in situ generated isoindolinone- derived ketimines and phenol derivatives yield products in good to excellent yields, and moderate enantioselectivities. Conversion of the obtained products into chiral Betti bases with the retention of the optical purity is demonstrated.

Theoretical calculations, associated with control experiments, were carried out to gain insights into the mechanism and origin of enantioselectivity in the phosphoric-acid-catalyzed dynamic kinetic resolution of azlactones. The results revealed a Münchnone intermediate as the key species involved in the isomerization of azlactone rings. The developed model was successfully employed in the comprehension and prediction of enantioselectivity under diverse of reaction conditions, including alcoholysis and aminolysis protocols.

A straightforward, user-friendly, efficient protocol for the one pot, ZnI2-catalyzed allenylation of terminal alkynes with pyrrolidine and ketones, toward trisubstituted allenes, is described. Trisubstituted allenes can be obtained under either conventional heating or microwave irradiation conditions, which significantly reduces the reaction time. A sustainable, widely available, and low-cost metal salt catalyst is employed, and the reactions are carried out under solvent-free conditions. Among others, synthetically valuable allenes bearing functionalities such as amide, hydroxyl, or phthalimide can be efficiently prepared. Mechanistic experiments, including kinetic isotope effect measurements and density functional theory (DFT) calculations, suggest a rate-determining [1,5]hydride transfer during the transformation of the intermediate propargylamine to the final allene. The research project was supported by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the "1st Call for H.F.R.I. Research Projects to support Faculty Members & Researchers and the procurement of high-cost research equipment grant" (Project Number: 16.Acronym: SUSTAIN). We thank Professor Thomas Mavromoustakos for his advice and support concerning the calculation of the relaxation delay times for the NMR analysis related to the kinetic isotope effect measurements. We also acknowledge the contribution of COST Action CA15106 (C-H Activation in Organic Synthesis.CHAOS). We also thank the Spanish Ministerio de Ciencia e Innovacion (PID2019-110008GB-I00) and IZO-SGI SGIker of UPV/EHU for financial and human support. The Special Account for Research Grants of the National and Kapodistrian University of Athens is also gratefully acknowledged for funding (research program 70/4/17454).

Here we show trapping of chiral enolates with carbenium ions, Michael acceptors, and bromine. Silyl ketene aminals, disilyl acetals, and aza-enolates were obtained via Lewis acid mediated enantioselective conjugate addition of Grignard reagents to unsaturated amides, carboxylic acids and alkenyl heterocycles.

General methods to prepare chiral N‐heterocyclic molecular scaffolds are greatly sought after because of their significance in medicinal chemistry. Described here is the first general catalytic methodology to access a wide variety of chiral 2‐ and 4‐substituted tetrahydro‐quinolones, dihydro‐4‐pyridones, and piperidones with excellent yields and enantioselectivities, utilizing a single catalyst system.

N‐cycloalkyl‐substituted amino acids have wide‐ranging applications in pharma‐ and nutraceutical fields. Here we report the asymmetric synthesis of various N‐cycloalkyl‐substituted L‐aspartic acids using ethylenediamine‐N,N'‐disuccinic acid lyase (EDDS lyase) and a previously engineered variant of methylaspartate ammonia lyase (MAL‐Q73A) as biocatalysts. Particularly, EDDS lyase shows broad non‐natural substrate promiscuity and excellent enantioselectivity, allowing the selective addition of homo‐ and heterocycloalkyl amines (comprising four‐, five‐ and six‐membered rings) to fumarate, giving the corresponding N‐cycloalkyl‐substituted L‐aspartic acids with >99% e.e. This biocatalytic methodology offers an alternative synthetic choice to prepare difficult N‐cycloalkyl‐substituted amino acids. Given its very broad amine scope, EDDS lyase is an exceptionally powerful synthetic tool that nicely complements the rapidly expanding toolbox of biocatalysts for asymmetric synthesis of noncanonical amino acids.

Over the past few years, nickel catalysis "encountered" allenes in organic transformations, opening direct access to a plethora of chemical scaffolds in straightforward manner. The activation of allenes or their reaction partners by means of [Ni(0)] as well as [Ni(II)] species enabled chemical diversity and complexity to be achieved simultaneously through desirable concepts like selectivity, functional group tolerance and mildness. An overview of the most recent findings in the area is presented herein.

The novel di((camphorsulfonyl)oxy)iodo]benzene (DCIB) was synthesized from [Bis(trifluoroacetoxy)iodo]benzene in the mild conditions. The alpha-sulfonoxylation of various ketones with novel hypervalent iodine was reported in excellent yield. alpha-Hydroxyketones were synthesized from alpha-sulfonoxy compounds (caphorsulfonoxy ketones) with Li/NH3(g) at -20 degrees C in THF. Then, some biochemical studies including several enzyme inhibition linked some global diseases were carried out. For this purpose, the inhibitory potentials of synthesized novel camphorsulfonoxy ketones were investigated against hCA I, and hCA II isoenzymes, AChE, and BChE enzymes. When the results were evaluated, novel alpha-sulfonoxy ketones were found to have strong inhibition effects on these metabolic enzymes. IC50 values and K-i values were determined for each compounds and compared with putative and positive controls. The synthesized alpha-sulfonoxy ketone compounds showed K-i values of in range of 73.2-406.0 mu M against hCA I, and 57.12-526.05 mu M against hCA II closely associated with various physiological and pathological processes in living organisms. On the other hand, K-i values were found in range of 28.80-140.3 mu M against AChE, and 7.186-40.0 mu M against BChE enzymes. Within the scope of the study, the inhibition types of the alpha-sulfonoxy ketones with novel hypervalent iodine were evaluated. Camphorsulfonoxy moiety caused to inhibition of the enzymes through hydrophobic interaction and hydrogen bond. (C) 2021 Elsevier B.V. All rights reserved., TUBITAK [107T390], Financial support from the TUBITAK (107T390) is gratefully acknowledged. The authors are grateful to Dr. Muhammet Karaman for providing his technical guidance while processing docking study of this article and for supporting small drug discovery suite software.

A copper(I)-catalyzed vinylation of diazo compounds with vinylbenziodoxolone reagents (VBX) as partners is reported. The transformation tolerates diverse functionalities on both reagents delivering polyfunctionalized vinylated products. The strategy was successfully extended to a three-component/intermolecular version with alcohols. The obtained products contain synthetically versatile functional groups, such as an aryl iodide, an ester, and an allylic leaving group, enabling further modification.

Cross-coupling of two alkyl fragments is an efficient method to produce organic molecules rich in sp(3)-hybridized carbon centres, which are attractive candidate compounds in drug discovery. Enantioselective C(sp(3))-C(sp(3)) coupling is challenging, especially of alkyl electrophiles without an activating group (aryl, vinyl, carbonyl). Here, we report a strategy based on nickel hydride addition to internal olefins followed by nickel-catalysed alkyl-alkyl coupling. This strategy enables the enantioselective cross-coupling of non-activated alkyl halides with alkenyl boronates to produce chiral alkyl boronates. Employing readily available and stable olefins as pro-chiral nucleophiles, the coupling proceeds under mild conditions and exhibits broad scope and high functional-group tolerance. Applications for the functionalization of natural products and drug molecules, as well as the synthesis of chiral building blocks and a key intermediate to (S)-(+)-pregabalin, are demonstrated. Methods for producing organic molecules rich in sp(3)-hybridized carbon centres can be particularly useful for drug development. Now, it has been shown that the enantioselective cross-coupling of non-activated alkyl halides with alkenyl boronates enables the synthesis of chiral alkyl boronates. The reaction proceeds via nickel hydride insertion into an internal alkene followed by nickel-catalysed alkyl-alkyl cross-coupling.

Aromatic β-hydroxyaldehydes, 1,3-diols, and α,β-unsaturated aldehydes are valuable precursors to biologically active natural products and drug molecules. Herein we report the biocatalytic aldol condensation of acetaldehyde with various aromatic aldehydes to give a number of aromatic α,β-unsaturated aldehydes using a previously engineered variant of 4-oxalocrotonate tautomerase [4-OT(M45T/F50A)] as carboligase. Moreover, an efficient one-pot two-step chemoenzymatic route toward chiral aromatic 1,3-diols has been developed. This one-pot chemoenzymatic strategy successfully combined a highly enantioselective aldol addition step catalyzed by a proline-based carboligase [4-OT(M45T/F50A) or TAUT015] with a chemical reduction step to convert enzymatically prepared aromatic β-hydroxyaldehydes into the corresponding 1,3-diols with high optical purity (e.r. up to >99:1) and in good isolated yield (51-92%). These developed (chemo)enzymatic methodologies offer alternative synthetic choices to prepare a variety of important drug precursors.

Aspartic acid derivatives with branched N‐alkyl or N‐arylalkyl substituents are valuable precursors to artificial dipeptide sweeteners such as neotame and advantame. The development of a biocatalyst to synthesize these compounds in a single asymmetric step is an as yet unmet challenge. Reported here is an enantioselective biocatalytic synthesis of various difficult N‐substituted aspartic acids, including N‐(3,3‐dimethylbutyl)‐l‐aspartic acid and N‐[3‐(3‐hydroxy‐4‐methoxyphenyl)propyl]‐l‐aspartic acid, precursors to neotame and advantame, respectively, using an engineered variant of ethylenediamine‐N,N′‐disuccinic acid (EDDS) lyase from Chelativorans sp. BNC1. This engineered C–N lyase (mutant D290M/Y320M) displayed a remarkable 1140‐fold increase in activity for the selective hydroamination of fumarate compared to that of the wild‐type enzyme. These results present new opportunities to develop practical multienzymatic processes for the more sustainable and step‐economic synthesis of an important class of food additives.

A series of aminocarboxylic acid analogues of aspergillomarasmine A (AMA) and ethylenediamine-N,N'-disuccinic acid (EDDS) were chemoenzymatically synthesized via the addition of various mono- and diamine substrates to fumaric acid catalyzed by the enzyme EDDS lyase. Many of these novel AMA and EDDS analogues demonstrate potent inhibition of the bacterial metallo-β-lactamase NDM-1. Isothermal titration calorimetry assays revealed a strong correlation between the inhibitory potency of the compounds and their ability to bind zinc. Compounds 1a (AMA), 1b (AMB), 5 (EDDS), followed by 1d and 8a, demonstrate the highest synergy with meropenem resensitizing an NDM-1 producing strain of E. coli to this important carbapenem of last resort.

Access to vitamin B5 [(R)‐pantothenic acid] and both diastereoisomers of α‐methyl‐substituted vitamin B5 [(R)‐ and (S)‐3‐((R)‐2,4‐dihydroxy‐3,3‐dimethylbutanamido)‐2‐methylpropanoic acid] was achieved using a modular three‐step biocatalytic cascade involving 3‐methylaspartate ammonia lyase (MAL), aspartate‐α‐decarboxylase (ADC), β‐methylaspartate‐α‐decarboxylase (CrpG) or glutamate decarboxylase (GAD), and pantothenate synthetase (PS) enzymes. Starting from simple non‐chiral dicarboxylic acids (either fumaric acid or mesaconic acid), vitamin B5 and both diastereoisomers of α‐methyl‐substituted vitamin B5, which are valuable precursors for promising antimicrobials against Plasmodium falciparum and multidrug‐resistant Staphylococcus aureus, can be generated in good yields (up to 70 %) and excellent enantiopurity (>99 % ee). This newly developed cascade process may be tailored and used for the biocatalytic production of various vitamin B5 derivatives by modifying the pantoyl or β‐alanine moiety.

The field of synthetic molecular machines has quickly evolved in recent years, growing from a fundamental curiosity to a highly active field of chemistry. Many different applications are being explored in areas such as catalysis, self-assembled and nanostructured materials, and molecular electronics. Rotary molecular motors hold great promise for achieving dynamic control of molecular functions as well as for powering nanoscale devices. However, for these motors to reach their full potential, many challenges still need to be addressed. In this paper we focus on the design principles of rotary motors featuring a double-bond axle and discuss the major challenges that are ahead of us. Although great progress has been made, further design improvements, for example in terms of efficiency, energy input, and environmental adaptability, will be crucial to fully exploit the opportunities that these rotary motors offer.

Various flavoprotein oxidases were recently shown to oxidize primary thiols. Herein, this reactivity is extended to sec-thiols by using structure-guided engineering of 5-(hydroxymethyl) furfural oxidase (HMFO). The variants obtained were employed for the oxidative kinetic resolution of racemic sec-thiols, thus yielding the corresponding thioketones and nonreacted R-configured thiols with excellent enantioselectivities (E >= 200). The engineering strategy applied went beyond the classic approach of replacing bulky amino acid residues with smaller ones, as the active site was additionally enlarged by a newly introduced Thr residue. This residue established a hydrogen-bonding interaction with the substrates, as verified in the crystal structure of the variant. These strategies unlocked HMFO variants for the enantioselective oxidation of a range of sec-thiols.

The natural aminocarboxylic acid product ethylenediamine- N, N'-disuccinic acid [( S, S)-EDDS] is able to form a stable complex with metal ions, making it an attractive biodegradable alternative for the synthetic metal chelator ethylenediaminetetraacetic acid (EDTA), which is currently used on a large scale in numerous applications. Previous studies have demonstrated that biodegradation of ( S, S)-EDDS may be initiated by an EDDS lyase, converting ( S, S)-EDDS via the intermediate N-(2-aminoethyl)aspartic acid (AEAA) into ethylenediamine and two molecules of fumarate. However, current knowledge of this enzyme is limited because of the absence of structural data. Here, we describe the identification and characterization of an EDDS lyase from Chelativorans sp. BNC1, which has a broad substrate scope, accepting various mono- and diamines for addition to fumarate. We report crystal structures of the enzyme in an unliganded state and in complex with formate, succinate, fumarate, AEAA, and ( S, S)-EDDS. The structures reveal a tertiary and quaternary fold that is characteristic of the aspartase/fumarase superfamily and support a mechanism that involves general base-catalyzed, sequential two-step deamination of ( S, S)-EDDS. This work broadens our understanding of mechanistic diversity within the aspartase/fumarase superfamily and will aid in the optimization of EDDS lyase for asymmetric synthesis of valuable (metal-chelating) aminocarboxylic acids.

A new study opens a route to convert lignin, the world largest natural source of aromatics, into valuable bioactive compounds.

The reactivity of 3-oxo-β-lactams with respect to primary amines was investigated in depth. Depending on the specific azetidin-2-one C4 substituent, this reaction was shown to selectively produce 3-imino-β-lactams (through dehydration), α-aminoamides (through CO elimination), or ethanediamides (through an unprecedented C3-C4 ring opening). In addition to the experimental results, the mechanisms and factors governing these peculiar transformations were also examined and elucidated by means of DFT calculations.

The regioselective conversion of C-H bonds into C-Si bonds is extremely important owing to the natural abundance and non-toxicity of silicon. Classical silylation reactions often suffer from poor functional group compatibility, low atom economy, and insufficient regioselectivity. Herein, we disclose a template-assisted method for the regioselective para silylation of toluene derivatives. A new template was designed, and the origin of selectivity was analyzed experimentally and computationally. An interesting substrate-solvent hydrogen-bonding interaction was observed. Kinetic, spectroscopic, and computational studies shed light on the reaction mechanism. The synthetic significance of this strategy was highlighted by the generation of a precursor of a potential lipophilic bioisostere of gamma-aminobutyric acid (GABA), various late-stage diversifications, and by mimicking enzymatic transformations.

A series of prenyl-containing malonates are kinetically benchmarked against the standard allyl-containing congeners using a ruthenium benzylidene precatalyst for ring-closing metatheses. The prenyl grouping is found to be a superior acceptor olefin compared to an allyl group in RCM processes with ruthenium alkylidenes derived from terminal alkenes. The prenyl group is also found to be a highly competent acceptor for a ruthenium alkylidene derived from a 1,1-disubstituted olefin in a RCM process.

Treatment of urea or carbamate derived benzomorpholines with lithium diisopropylamide generates N-vinyl ureas or N-vinyl carbamates by elimination of a phenoxide anion, cleaving the benzomorpholine ring. Simultaneous formation of a carbanion a to a stabilising aryl or nitrile group allows migration of the newly formed N-vinyl substituent to the carbanionic centre, in some cases with high enantiospecificity. Mild hydrolysis of the resulting urea or carbamate returns a C-vinylated amine, alcohol or hydantoin, in some cases with high enantiomeric purity. This 'masked' vinylation strategy avoids the need to use the reactive and volatile vinyl isocyanate as a starting material. (C) 2017 Academie des sciences. Published by Elsevier Masson SAS. All rights reserved.

Due to the emerging resistance against classical beta-lactam-based antibiotics, a growing number of bacterial infections has become harder to treat. This alarming tendency necessitates continued research on novel antibacterial agents. Many classes of b- lactam antibiotics are characterized by the presence of the 3- aminoazetidin-2-one core, which resembles the natural substrate of the target penicillin-binding proteins. In that re-spect, this Review summarizes the different synthetic pathways toward this key structure for the development of new antibacterial agents. The most extensively applied methods for 3-amino-beta-lactam ring formation are discussed, in addition to a few less common strategies. Moreover, approaches to introduce the 3-amino substituent after ring formation are also covered.

The biodegradation of the nylon-6 precursor caprolactam by a strain of Pseudomonas jessenii proceeds via ATP-dependent hydrolytic ring-opening to 6-aminohexanoate. This non-natural ω-amino acid is converted to 6-oxohexanoic acid by an aminotransferase (PjAT) belonging to the fold type I PLP enzymes. To understand the structural basis of 6-aminohexanoatate conversion, we solved different crystal structures and determined the substrate scope with a range of aliphatic and aromatic amines. Comparison with the homologous aminotransferases from Chromobacterium violaceum (CvAT) and Vibrio fluvialis (VfAT) showed that the PjAT enzyme has the lowest KM values (highest affinity) and highest specificity constant (kcat /KM ) with the caprolactam degradation intermediates 6-aminohexanoate and 6-oxohexanoic acid, in accordance with its proposed in vivo function. Five distinct three-dimensional structures of PjAT were solved by protein crystallography. The structure of the aldimine intermediate formed from 6-aminohexanoate and the PLP cofactor revealed the presence of a narrow hydrophobic substrate-binding tunnel leading to the cofactor and covered by a flexible arginine, which explains the high activity and selectivity of the PjAT with 6-aminohexanoate. The results suggest that the degradation pathway for caprolactam has recruited an aminotransferase that is well adapted to 6-aminohexanoate degradation. This article is protected by copyright. All rights reserved.

A central goal of chemical biology is to develop molecular probes that enable fundamental studies of cellular systems. In the hierarchy of bioactive molecules, the so-called ionophore class occupies an unflattering position in the lower branches, with typical labels being "non-specific" and "toxic". In fact, the mere possibility that a candidate molecule possesses "ionophore activity" typically prompts its removal from further studies; ionophores-from a chemical genetics perspective-are molecular outlaws. In stark contrast to this overall poor reputation of ionophores, synthetic chemistry owes some of its most amazing achievements to studies of ionophore natural products, in particular the carboxyl polyethers renowned for their intricate molecular structures. These compounds have for decades been academic battlegrounds where new synthetic methodology is tested and retrosynthetic tactics perfected. Herein, we review the most exciting recent advances in carboxyl polyether ionophore (CPI) synthesis and in addition discuss the burgeoning field of CPI chemical biology.

Unprecedented alpha-imino N-acyl pyrazoles were efficiently and selectively prepared through the 1,5,7-triazabicyclo [4.4.0]dec-5-ene (TBD)-catalyzed reaction of nitrosoarenes with N-acyl pyrazoles via an N-nitroso aldol reaction/dehydration sequence. The alpha-imino acyl pyrazoles were demonstrated to be new versatile intermediates for practical one-pot syntheses of alpha-imino amides, dipeptide precursors, esters, and beta-amino alcohols. The synthetic method competes with known protocols in terms of ready availability of the reagents and catalyst, mild and catalytic reaction conditions, gram-scale applicability, and scope of the alpha-imino acid derivatives achievable.

The activity of a simple, commercially available copper salt, [Cu(NCMe)4](BF4) in intramolecular hydroamination reactions of alkynes and allenes is presented. Reactions were successfully carried out in technical acetonitrile in the presence of air. While attempts of alkene hydroamination failed, this catalysts was also found active in intermolecular aza‐Michael reactions.

Asymmetric metal-catalyzed C–H functionalization is a powerful strategy for the rapid generation of complex target molecules from simple precursors. While aryl (pseudo)halides have been used as electrophilic substrates in enantioselective Pd(0)-catalyzed syntheses of N-heterocycles, alternative partners for C–H functionalizations remain underexplored. Herein we describe the first application of ketene aminal phosphates as competent electrophiles in a Pd(0)-catalyzed desymmetrization. This transformation allowed the efficient synthesis of chiral isoindolines in a highly enantioselective fashion. Furthermore, intending to introduce sought-after perfluoroalkyl substituents, we explored intramolecular C–H functionalization of imidoyl chlorides resulting in the asymmetric preparation of previously inaccessible 1H-isoindoles. Tailored chiral monodentate ligands afforded high levels of enantioinduction in both transformations.

A Cu(II)-catalyzed diastereoselective Michael/aldol cascade approach is used to accomplish concise total syntheses of cardiotonic steroids with varying degrees of oxygenation including cardenolides ouabagenin, sarmentologenin, 19-hydroxysarmentogenin, and 5-epi-panogenin. These syntheses enabled the subsequent structure activity relationship (SAR) studies on 37 synthetic and natural steroids to elucidate the effect of oxygenation, stereochemistry, C3-glycosylation, and C17-heterocyclic ring. Based on this parallel evaluation of synthetic and natural steroids and their derivatives, glycosylated steroids cannogenol-L-alpha-rhamnoside (79a), strophanthidol-L-alpha-rhamnoside (92), and digitoxigenin-L-alpha-rhamnoside (97) were identified as the most potent steroids demonstrating broad anticancer activity at 10-100 nM concentrations and selectivity (nontoxic at 3 mu M against NIH-3T3, MEF, and developing fish embryos). Further analyses indicate that these molecules show a general mode of anticancer activity involving DNA-damageupregulation that subsequently induces apoptosis.

Practical methods for the preparation of selectively fluorinated compounds are in extremely high demand in nearly every sector of the pharmaceutical and agrochemical industries. Here we provided an account of the recent methodological breakthrough dealing with detrifluoroacetylative in situ generation of cyclic fluoro-enolates and their application for the preparation of various polyfunctional compounds featuring quaternary C-F stereogenic carbon. The reactions include aldol, Mannich, Michael addition reactions, S(N)2/S(N)2' alkylations, and the additions to azo compounds. The detrifluoroacetylative protocol for in situ generation of cyclic fluoro-enolates is operationally simple and scalable and proceeds at ambient temperature. Generally, the stereochemical outcome, controlled by the stoichiometric chiral auxiliary of the chiral catalyst, is synthetically useful, allowing preparation of enantiomerically pure compounds of high pharmaceutical potential. We gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 21761132021) and IKERBASQUE, Basque Foundation for Science.

[EN] An organocatalytic enantioselective functionalization in the carbocyclic ring of indoles with benzoxathiazine 2,2-dioxides is described using a quinine-derived bifunctional organocatalyst. This aza-Friedel-Crafts reaction provides 4-indolyl, 5-indolyl and 7-indolyl sulfamidate derivatives in good yields (up to 99%) and with moderate to high enantioselectivities (up to 86% ee)., Financial support from the Agencia Estatal de Investigación (AEI, Spanish Government) and Fondo Europeo de Desarrollo Regional (FEDER, European Union) (CTQ2017-84900-P) is acknowledged. C. V. thanks the Spanish Government for the RyC contract (RYC-2016-20187).

Microbial enzymes from pristine niches can potentially deliver disruptive opportunities in synthetic routes to Active Pharmaceutical Ingredients and intermediates in the Pharmaceutical Industry. Advances in green chemistry technologies and the importance of stereochemical control, further underscores the application of enzyme-based solutions in chemical synthesis. The rich tapestry of microbial diversity in the oceanic ecosystem encodes a capacity for novel biotransformations arising from the chemical complexity of this largely unexplored bioactive reservoir. Here we report a novel ω-transaminase discovered in a marine sponge Pseudovibrio sp. isolate. Remote stereoselection using a transaminase has been demonstrated for the first time using this novel protein. Application to the resolution of an intermediate in the synthesis of sertraline highlights the synthetic potential of this novel biocatalyst discovered through genomic mining. Integrated chemico-genomics revealed a unique substrate profile, while molecular modelling provided structural insights into this ‘first in class’ selectivity at a remote chiral centre.

Various (activated and non-activated) aziridines with diverse substitution patterns have been deployed successfully as starting materials for the synthesis of a wide variety of alkaloids via suitable functionalization and aziridine ring transformation. Alternatively, the preparation and interception of reactive aziridine intermediates has also been shown to constitute a valid approach toward alkaloid synthesis. This review summarizes aziridine-mediated syntheses of alkaloids, in which the aziridine is mobilized as either a substrate or an advanced synthetic intermediate.1 Introduction2 Alkaloids Synthesis from Aziridine Starting Materials2.1 (2R)- and (2S)-Hydroxymethyl-N-(1-phenylethyl)aziridines2.2 N-Benzylaziridine-2-carboxylates2.3 2-Substituted N-Tosyl- or N-Tritylaziridines2.4 2,3-Disubstituted N-Cbz- or N-Tosylaziridines2.5 N-DMB-aziridines3 Alkaloids Synthesis from Aziridines as Key Advanced Synthetic Intermediates3.1 Alkylative Aziridine Ring Opening3.2 Arylative Aziridine Ring Opening3.3 Ring Expansion3.4 Oxidative Aziridine Ring Opening3.5 Heteroatomic Nucleophilic Aziridine Ring Opening3.6 Reductive Aziridine Ring Opening4 Conclusion

[Image: see text] The Pomeranz–Fritsch reaction and its Schlittler–Müller modification were successfully applied in the Ugi postcyclization strategy by using orthogonally protected aminoacetaldehyde diethyl acetal and complementary electron rich building blocks. Several scaffolds, including isoquinolines, carboline, alkaloid-like tetrazole-fused tetracyclic compounds, and benzo[d]azepinone scaffolds, were synthesized in generally moderate to good yield. All our syntheses provide a short MCR-based sequence to novel or otherwise difficult to access scaffolds. Hence, we foresee multiple applications of these synthesis technologies.

The applications of Morita-Baylis-Hillman (MBH) and Rauhut-Currier (RC) adducts of nitroalkenes in the synthesis of various carbo- and heterocycles are summarized in this review. In recent years, the MBH adducts and their derivatives such as acetates and bromides have served as efficient synthons for the synthesis of bioactive compounds including natural products. The close proximity of various functional groups makes the MBH and RC adducts extremely valuable substrates in multicomponent and cascade reactions, including annulations, organocatalysis, and kinetic resolution, to name a few.