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Sulfur can form diverse S(IV) and S(VI) stereogenic centers, of which some have gained significant attention recently due to their increasing use as pharmacophores in drug discovery programs. The preparation of these sulfur stereogenic centers in their enantiopure form has been challenging, and progress made will be discussed in this Perspective. This Perspective summarizes different strategies, with selected works, for asymmetric synthesis of these moieties, including diastereoselective transformations using chiral auxiliaries, enantiospecific transformations of enantiopure sulfur compounds, and catalytic enantioselective synthesis. We will discuss the advantages and limitations of these strategies and will provide our views on how this field will develop. Nanyang Technological University Published version X.Z. acknowledges financial support from the start-up funding from Sichuan University. C.H.T. acknowledges financial support from Nanyang Technological University (Tier 1 RG2/20).

International audience; This review updates the field of enantioselective domino reactions promoted by chiral catalysts derived from noble metals, including palladium, silver, rhodium, ruthenium, iridium and gold, published since the beginning of 2019. It illustrates how much a diversity of these catalysts allow unprecedented asymmetric domino reactions of many types to be achieved with excellent enantioselectivity, giving a direct access to a wide variety of complex chiral molecules.

The development of micellar catalysis offers a sustainable alternative to organic solvents, and represents an environmental milestone in organic synthesis. Here, the first Michael addition of masked acetaldehyde under neutral, cationic and anionic micellar catalysis is reported, affording the products in high yields and enantiomeric excess, despite the use of water as solvent.

Chiral N-heterocycles are a common motif in many active pharmaceutical ingredients; however, their synthesis often relies on the use of heavy metals. In recent years, several biocatalytic approaches have emerged to reach enantiopurity. Here, we describe the asymmetric synthesis of 2-substituted pyrrolidines and piperidines, starting from commercially available ω-chloroketones by using transaminases, which has not yet been comprehensively studied. Analytical yields of up to 90% and enantiomeric excesses of up to >99.5% for each enantiomer were achieved, which has not previously been shown for bulky substituents. This biocatalytic approach was applied to synthesize (R)-2-(p-chlorophenyl)pyrrolidine on a 300 mg scale, affording 84% isolated yield, with >99.5% ee.

The activation of molecules through intramolecular hydrogen-bond formation to promote chemical reactions appears as a suitable strategy in organic synthesis, especially for the preparation of chiral compounds under metal and organocatalytic conditions. The use of this interaction has enabled reactivity enhancement of reagents, as well as stabilization of the chemical species and enantiocontrol of the processes, Financial support was provided by the European Research Council (ERC-CoG, Contract No. 647550, ERC-PoC, Contract No. 861930), the Spanish Government (RTI2018- 095038-B-I00), “Comunidad de Madrid”, and European Structural Funds (S2018/NMT-4367) and proyectos sinérgicos I+D (Y2020/NMT-6469). A.G.-C. acknowledges a predoctoral FPI fellowship

International audience; Enantioselective construction methods of chiral derivatives of α-tertiary amines using acyclic and cyclic trifluoromethylketimines are considered. The importance of a trifluoromethyl group in the structure of ketimine substrates for effective asymmetric addition of C-nucleophilic reagents in the presence of metal complex catalysts or organocatalysts is emphasized. The practical application of these chiral products in medicinal chemistry is covered.

In this personal account, we summarize our investigations on the asymmetric direct addition of C(sp2)–H bonds to unsaturated bonds, such as C=O and C=C, using cationic iridium/chiral O-linked bidentate phosphoramidite (Me-BIPAM) and S-linked bidentate phosphoramidite (S-Me-BIPAM) catalyst systems.1 Introduction2 Highly Enantioselective Intramolecular Hydroarylation of α-Keto Amides3 Highly Enantioselective Intermolecular Hydroarylation of Bicyclo­alkenes4 Conclusion

This study reported an asymmetric synthesis of 1,2-limonene epoxides. The absolute stereochemistry was controlled by a Jacobsen epoxidation of cis-1,2-limonene epoxide (with diastereomeric excess of 98%) and trans-1,2-limonene epoxide (with diastereomeric excess of 94%), which could be used as important raw materials for the preparation of related cannabinoid drugs.

An unusual diastereodivergent stereoselective allylation reaction is presented. It consists of a palladium-catalyzed allylation reaction of an organocatalytically generated amino isobenzofulvene, where the diastereoselectivity is controlled by the electronic properties of a monodentate, achiral ligand on palladium. One major diastereoisomer is formed using triarylphosphines substituted with neutral or electron-donating substituents of the aryl group, while those with electron-withdrawing substituents favor the other diastereoisomer. The diastereoselectivity correlates with the Taft inductive parameter of substituents on the triarylphosphine ligand on palladium. The synergistic reaction involves both a catalytic secondary amine catalyst for the indene-aldehyde activation and the monodentate phosphine ligands on palladium, affording a highly enantioselective reaction with up to 98 % enantiomeric excess. Based on computational investigations, the role of the monodentate phosphine ligand on the diastereoselectivity is discussed.

In dynamic covalent chemistry, reactions follow a thermodynamically controlled pathway through equilibria. Reversible covalent‐bond formation and breaking in a dynamic process enables the interconversion of products formed under kinetic control to thermodynamically more stable isomers. Notably, enantioselective catalysis of dynamic transformations has not been reported and applied in complex molecule synthesis. We describe the discovery of dynamic covalent enantioselective metal‐complex‐catalyzed 1,3‐dipolar cycloaddition reactions. We have developed a stereodivergent tandem synthesis of structurally and stereochemically complex molecules that generates eight stereocenters with high diastereo‐ and enantioselectivity through asymmetric reversible bond formation in a dynamic process in two consecutive Ag‐catalyzed 1,3‐dipolar cycloadditions of azomethine ylides with electron‐poor olefins. Time‐dependent reversible dynamic covalent‐bond formation gives enantiodivergent and diastereodivergent access to structurally complex double cycloadducts with high selectivity from a common set of reagents., A highly enantioselectively catalyzed dynamic covalent one‐pot‐tandem 1,3‐dipolar cycloaddition of azomethine ylides to α′‐alkylidene‐2‐cyclopentenones is described. Time‐dependend enantio‐ and diastereodivergent synthesis was achieved by using the same set of reagents. A reversible cycloaddition of the kinetically favored product enables the interconversion to its more stable thermodynamically favored product through a chiral complex‐mediated process.

Coumarin derivatives are essential scaffolds in medicinal and synthetic chemistry. Compounds of this class have shown important activities, such as anticancer and antiparasitic, besides the commercially available drugs. These properties led to the development of efficient and greener synthetic methods to achieve the 2H-chromen-2-one core. In this context, the advances in asymmetric organocatalyzed synthesis of coumarin derivatives are discussed in this review, according to the mode of activation of the catalyst.

Nowadays, the selective introduction of fluorine into bioactive compounds is a mature strategy in the design of drugs allowing to increase efficiency, biological half-life and bio-absorption. On the other hand, amino acids (AAs) represent one of the most ubiquitious classes of naturally occurring organic compounds, which are found in over 40% of newly marked small-molecule pharmaceutical drugs and medical formulations. The primary goal of this work is to underscore two major trends in the design of modern pharmaceuticals. The first is dealing with the unique structural characteristics provided by the structure of amino acids featuring an abundance of functionality and the presence of a stereogenic center, all of which bodes well for the successful development of targeted bioactivity. The second is related to fine-tuning the desired activity and pharmacokinetics by selective introduction of fluorine. Historically, both trends were developed separately as innovative and prolific approaches in modern drug design. However, in recent decades, these approaches are clearly converging leading to an ever-increasing number of newly approved pharmaceuticals containing both structural features of amino acids and fluorine. This work was funded by the National Natural Science Foundation of China (No. 21761132021), and IKERBASQUE, Basque Foundation for Science. The financial support from the University of the Basque Country UPV/EHU (UFIQOSYC11/22), Basque Government (GVgrant IT1236-19), and Ministerio de Ciencia e Innovación (grant PID2019-109633GBC21) for. A. L. are also acknowledged.

The synthesis of nitrogen-containing heterocycles, including natural alkaloids and other compounds presenting different types of biological activities have proved to be successful employing chiral sulfinyl imines derived from tert-butanesulfinamide. These imines are versatile chiral auxiliaries and have been extensively used as eletrophiles in a wide range of reactions. The electron-withdrawing sulfinyl group facilitates the nucleophilic addition of organometallic compounds to the iminic carbon with high diastereoisomeric excess and the free amines obtained after an easy removal of the tert-butanesulfinyl group can be transformed into enantioenriched nitrogen-containing heterocycles. The goal of this review is to the highlight enantioselective syntheses of heterocycles involving the use of chiral N-tert-butanesulfinyl imines as reaction intermediates, including the synthesis of several natural products. The synthesis of nitrogen-containing heterocycles in which the nitrogen atom is not provided by the chiral imine will not be considered in this review. The sections are organized according to the size of the heterocycles. The present work will comprehensively cover the most pertinent contributions to this research area from 2012 to 2020. We regret in advance that some contributions are excluded in order to maintain a concise format. We thank the continuous financial support from the Spanish Ministerio de Economía y Competitividad (MINECO; project CTQ2014-53695-P, CTQ2014-51912-REDC, CTQ2016-81797-REDC, CTQ2017-85093-P), Ministerio de Ciencia, Innovación y Universidades (RED2018-102387-T, PID2019-107268GB-100), FEDER, the Generalitat Valenciana (PROMETEOII/2014/017), and the University of Alicante (VIGROB-068). We are also grateful for the financial support from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

The short lifetime and high reactivity of the molecular excited states were the main culprits for the low achieved enantioselectivity of the excited-state photoreactions. Supramolecular strategies by confining the prochiral substrates in a chiral microenvironment prior to photoexcitation were excellent solutions for the challenges mentioned above. In the present review, endeavors to enhance the enantioselectivities of the photoreactions by pre-arranging the conformations of the substrate(s) were summarized, and the photoreactions accelerated by substoichiometric amount of mediums were paid special attention from atom economy and green chemistry points of view. For the sake of brevity, we mainly focused on the advances of supramolecular chiral photochemistry in chiral pre-arrangements reported in the recent 5 years.

Carbohydrate-based crown ethers represent a special group of chiral phase transfer catalysts. Several derivatives of these macrocycles have been synthesized in our research group. Among these compounds, monoaza-15-crown-5 lariat ethers proved to be effective phase transfer and enantioselective catalysts in certain reactions. Those chiral azacrown ethers incorporating various carbohydrate moieties in the macrocyclic structure are reviewed, which generated asymmetric induction in reactions, such as Michael addition, epoxidation of enones, Darzens condensation and Michael-initiated ring-closure (MIRC) reaction. Effects on the catalytic activity of the structural changes are the focus.

Asymmetric access to γ‐lactams is achieved via a cyclobutanone ring expansion using widely available (1S,2R)‐1‐amino‐2‐indanol for chiral induction. Mechanistic analysis of the key N,O‐ketal rearrangement reveals a Curtin–Hammett scenario, which enables a downstream stereoinduction (up to 88:12 dr) and is corroborated by spectroscopic, crystallographic, and computational studies. In combination with an easy deprotection protocol, this operationally simple sequence allows the synthesis of a range of optically pure γ‐lactams, including those bearing all‐carbon quaternary stereocenters. In addition, the formal synthesis of drug molecules baclofen, brivaracetam, and pregabalin further demonstrates the synthetic utility and highlights the general applicability of the presented method., (1S,2R)‐2‐Amino‐1‐indanol was identified as a chiral nitrogen source in an oxidative rearrangement of prochiral cyclobutanones. Building on strain release as the driving force, this downstream stereoinduction enables a variety of γ‐lactams to be synthesized including those bearing quaternary stereocenters. In addition, drug molecules pregabalin, baclofen, and brivaracetam are accessible, which underlines the broad applicability of this method.

Strain relief of oxetanes offers a plethora of opportunities for the synthesis of chiral alcohols and ethers. In this context, enantioselective desymmetrization has been identified as a powerful tool to construct molecular complexity and this has led to the development of elegant strategies on the basis of transition metal, Lewis acid, and Brønsted acid catalysis. This review highlights recent examples that harness the inherent reactivity of prochiral oxetanes and offers an outlook on the immense possibilities for synthetic application., Prochiral oxetanes are excellent candidates for the synthesis of chiral alcohols and ethers via enantioselective desymmetrization. Recent methods relying on transition metal, Lewis acid, and Brønsted acid catalysis allow access to a remarkably diverse set of compounds, which are highlighted and put into context.

Atropisomeric styrenes are a class of optically active compounds, the chirality of which results from restricted rotation of the C(vinyl)–C(aryl) single bond. In comparison with biaryl atropisomers, the less rigid skeleton of styrenes usually leads them to have lower rotational barriers. Although it has been overlooked for a long time, scientists have paid attention to this class of unique molecules in recent years and have developed many methods for the preparation of optically active atropisomeric styrenes. In this article, we review the development of the concept of atropisomeric styrenes, along with their isolation, asymmetric synthesis, and synthetic applications.1 Introduction2 The Concept of Styrene Atropisomerism3 Early Research: Separation of Optically Active Styrenes4 Synthesis of Optically Active Styrenes5 Stability of the Chirality of Atropisomeric Styrenes6 Outlook

1. Procedure (Note 1) A. 3-Ammoniopropylsulfate (1). An oven-dried single-necked 100 mL round-bottomed flask (14/23 joint), equipped with a 2.5-cm Teflon-coated magnetic stirbar, is charged with 3-amino-1-propanol (11.5 mL, 150 mmol, 1 equiv) (Note 2) and anhydrous dichloromethane (35 mL) (Note 3). A 50 mL pressure-equalizing addition funnel (14/23 joint) equipped with a CaCl2 tube is attached to the round-bottomed flask and is then charged with chlorosulfonic acid (10.5 mL, 159 mmol, 1.06 equiv) (Note 4) using a 20 mL glass luer-lock syringe. The flask is immersed in an ice/water bath and the solution is stirred for 5 min. The chlorosulfonic acid is added dropwise over 30 min, allowing the fumes to escape. A white precipitate is formed during the addition. Once the addition is complete, the reaction is stirred at 0 °C for 20 min and left to warm slowly to room temperature over 30 min (Note 5). Once at room temperature, the reaction mixture is stirred for 1 h. The resulting mixture is filtered through a 70 mm diameter Number 3 Glass filter funnel with a Büchner setup. A bent spatula and methanol (25 mL) (Note 6) are used to remove remaining product from the flask walls. The mixture in the filter funnel is triturated with methanol (40 mL, then 2 × 20 mL) (Note 6), using a spatula to break up the lumps each time. The resulting white solid is broken up into a coarse powder and transferred to a 100 mL round-bottomed flask (29/32 joint), where it is placed on a rotary evaporator (40 °C, 12 mmHg pressure) for 1 h. The resulting white solid is ground to a fine white powder using a 10 cm diameterglass mortar and pestle, retransferred to a 100 mL round-bottomedflask and dried on a high vacuum line (25 °C, 0.1 mmHg pressure) for 2 h giving the title compound 1 (20.72 g, 134 mmol, 89% yield) (Note 7) as a fine white powder.

The asymmetric Pictet-Spengler reaction (PSR) with aldehydes is well known. However, PSR involving ketones as electrophilic partners is far-less developed. We report herein the first examples of catalytic enantioselective PSR of tryptamines with α-ketoamides. A new class of easily accessible prolyl-urea organocatalysts bearing a single H-bond donor function catalyzes the title reaction to afford 1,1-disubstituted tetrahydro-β-carbolines in excellent yields and enantioselectivities. The kinetic isotope effect using C2-deuterium-labelled tryptamine indicates that the rearomatization of the pentahydro-β-carbolinium ion intermediate might be the rate- and the enantioselectivity-determining step.

Non-covalent interactions are routinely used by enzymes to control selectivity of chemical reactions during biosynthesis. This prevalence in nature has inspired chemists to adapt these interactions to control selectivity in small molecule catalysis. This thesis describes efforts towards utilising non-covalent interactions to influence site-selectivity and enantioselectivity during palladium-catalysed cross-coupling reactions ��� a category of transformations used widely by synthetic chemists for many purposes. This thesis focuses on members of the privileged dialkylbiarylphosphine ligand class, specifically sSPhos, which is the commercially available sulfonated variant of SPhos. The first part investigates the use of this ligand to impart site-selectivity in the cross-coupling of 3,4-dichloroarenes containing an acidic directing group. Selectivity was proposed to arise from an electrostatic interaction between the deprotonated substrate, the cation of the base and the anionic ligand. An intriguing characteristic of sSPhos is that it is a chiral molecule due to its desymmetrisation upon sulfonation. Resolution of the two enantiomers was achieved initially by preparative supercritical fluid chromatography in collaboration with AstraZeneca, and later by chemical resolution using a chiral auxiliary, work described in this thesis. The second half of this thesis evaluates the efficacy of this new chiral ligand in two classes of asymmetric Suzuki-Miyaura coupling: desymmetrisation, and formation of atropisomers. Desymmetrisation was investigated on protected benzyhydrylamines resulting in good to excellent enantioselectivities being observed. The formation of atropisomeric biaryls was investigated with a wide range of coupling partners, with moderate to good enantioselectivity observed for coupling partners containing polar functionality. Excellent enantioselectivity was observed for the synthesis of 2,2���-biphenols: a scaffold prevalent in natural products as well as in numerous privileged catalysts. Overall, this work demonstrates the utility of the privileged ligand sSPhos on controlling site- and enantio- selectivity in palladium-catalysed cross-coupling reactions using non-covalent interactions., AstraZeneca Funded

Purpose: The main purpose of the article is to identify factors that may affect the course of inflation processes in Poland after the adoption of the single European currency. Design/Methodology/Approach: The mechanism triggering an inflationary spiral in the first years after the adoption of the euro was especially visible in Spain, which became the subject of comparative analysis. Based on literature, it was determined that the price increase in Spain resulted from an asymmetric demand shock. Its sources should be sought in Spain's adoption of a lower interest rate and in the structural features of the country’s economy. Similarly, Poland’s submission to the single monetary policy regime imposed by the European Central Bank may affect the course of inflationary processes. This study made use of the document analysis, comparative analysis, and statistical analysis methods. Findings: Factors that may affect inflation processes in Poland after the adoption of the single currency will be the adoption of a lower interest rate, and expansionary fiscal policy. Lending policy and inflation expectations will be less likely to stimulate price increases. These factors may contribute to the occurrence of asymmetric shock, i.e. surplus of global demand over supply. Reduction of the inflation risk will require a tightening of lending and fiscal policy. Otherwise, the Polish economy will be exposed to the occurrence of crises. Practical Implications: Reflections on the importance of the single European currency in the course of inflation processes can be a valuable source of information for decision makers in preventing crisis phenomena. The more so because six Central and Eastern European countries have committed themselves in the Accession Treaties to the introduction of the euro and will face similar dilemmas. Originality/Value: The authors of this article draw attention to the importance of domestic factors in correcting inflation processes in the event of the loss of independence of national monetary policy., peer-reviewed

A series of cholesterol and based hydrophobic urea and thiourea compounds were synthesized and successfully used as a cocatalyst for L-proline catalyzed aldol reactions in the presence of water. The anticonfigured products were obtained with good yields (up to 94%), high diastereoselectivities (up to 95:5), and high enantiomeric excesses (up to 93% ee). The successful results for catalytic efficiency of L-proline in the presence of water reveal the importance of the hydrophobic nature of cholesterol and diosgenin parts of thiourea on the reactivity and selectivity in the presence of water.

A catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines is reported. A chiral Brønsted acid promotes aza‐Michael addition to fluoroalkenyl heterocycles to give a prochiral enamine intermediate that undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C−F stereocentre in high enantioselectivity, and is also amenable to stereogenic C−CF3 bonds. Extensive DFT calculations provided evidence for stereocontrolled proton transfer from catalyst to substrate as the rate‐determining step, and showed the importance of steric interactions from the catalyst's alkyl groups in enforcing the high enantioselectivity. Crystal structure data show the dominance of noncovalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran‐type analysis of conformer distribution and Protein Data Bank mining indicated that benzylic fluorination by this approach has the potential to improve the potency of several marketed drugs., Chiral Brønsted acid catalysis enables the synthesis of heterocyclic vicinal fluoroamines by asymmetric protonation. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C−F stereocentre in high enantioselectivity, and allows the formation of chiral C−CF3 bonds. DFT calculations provided insight into the reaction mechanism, and conformational control of the products is elucidated.

A novel asymmetric phase-transfer-catalyzed γ-alkylation of phthalide 3-carboxylic esters has been developed, giving access to 3,3-disubstituted phthalide derivatives, which present a chiral quaternary γ-carbon in good to excellent yields and good enantioselectivities (74–88% ee). The enantiomeric purity could be substantially enhanced to 94–95% ee by recrystallization. Both electron-withdrawing and electron-releasing substituents are well tolerated on the phthalide core as well as on the aromatic moiety of the alkylating agent. This methodology, enabling the introduction of an unfunctionalized group at the phthalide γ-position, fully complements previously reported organocatalytic strategies involving functionalized electrophiles, thus expanding the scope of accessible 3,3-disubstituted products. The high synthetic value of this asymmetric reaction has been proven by the formal synthesis of the naturally occurring alkaloid (+)-(9S,13R)-13-hydroxyisocyclocelabenzine.

We report the first examples of catalytic enantioselective benzilic ester rearrangement reaction. In the presence of a catalytic amount of Cu(OTf)(2) and a chiral box ligand under mild conditions, reaction of 2,3-diketoesters with alcohols afforded structurally diverse alpha-aryl(alkyl) substituted-alpha-hydroxy malonates (tartronic esters) in good to excellent yields with high enantioselectivities. Preliminary mechanistic studies indicated that hemiketalization, rather than the dynamic kinetic resolution of hemiketal, was the enantiodetermining step under our reaction conditions.

We describe herein a highly diastereo‐ and enantioselective [4+3]‐cycloannulation of ortho‐quinone methides and carbonyl ylides to furnish functionalized oxa‐bridged dibenzooxacines with excellent yields and stereoselectivity in a single synthetic step. The combination of rhodium and chiral phosphoric acid catalysis working in concert to generate both transient intermediates in situ provides direct access to complex bicyclic products with two quaternary and one tertiary stereogenic centers. The products may be further functionalized into valuable and enantiomerically highly enriched building blocks., It takes two: A combination of Rh2(OAc)4 and a chiral phosphoric acid catalyzes the in situ generation of transient carbonyl ylides and chiral hydrogen‐bonded ortho‐quinone methides through cooperative catalytic cycles. These transient species then undergo a highly diastereo‐ and enantioselective cycloannulation to afford a broad range of functionalized oxa‐bridged dibenzooxacines featuring two quaternary and one tertiary stereogenic centers.

Four differently substituted chiral Ni(II)‐complexes of dehydroalanine Schiff base were prepared and reacted with BrCF2COOEt/Cu under the standard reaction conditions. The observed diastereoselectivity was found to depend on the degree and pattern of chlorine substitution for hydrogen in the structure of the dehydroalanine complexes. The unsubstituted complex gave the ratio of diastereomers (S)(2S)/(S)(2R) of 66/34. On the other hand, introduction of chlorine atoms in the strategic positions on the chiral ligands allowed to achieve a practically attractive diastereoselectivity of (∼98.5/1.5). Diastereomerically pure major product was disassembled to prepare 9‐fluorenylmethyloxycarbonyl (Fmoc) derivative of (S)‐4,4‐difluoroglutamic acid., The secret is in the structure! An asymmetric Cu‐promoted Michael addition reaction between chiral Schiff base Ni(II)‐complexes and BrCF2COOEt is developed providing an easy method for the synthesis of (S)‐4,4‐difluoroglutamic acid.

For the enantioselective diversification of a single starting material, a different chiral catalyst is usually required for each transformation. Herein, we extend the concept of catalytically formed chiral auxiliary from hydrogenation to the asymmetric cyclopropanation and epoxidation of tetra-substituted olefins, alleviating the need for different chiral catalysts in the alkene functionalization step. The chiral auxiliary is catalytically constructed from propargylic amines in a Pd-catalyzed enantioselective carboetherification step using a commercially available trifluoroacetaldehyde hemiacetal tether. The installed auxiliary is then controlling the stereochemistry of the cyclopropanation and the epoxidation using standard highly reactive reagents to give enantioenriched spirocyclic aminomethylcyclopropanols and alpha-amino-alpha-hydroxy ketones.

The Mitsunobu Reaction allows the conversion of primary and secondary alcohols to esters, phenyl ethers, thioethers and some other compounds. The nucleophile employed should be acidic, since one of the reagents, diethylazodicarboxylate (DEAD) must be protonated during the course of the reaction, preventing from the formation of unwanted side products. In this review, we try to focus on the scope and preparative synthetic applications of Mitsunobu reaction as a key step in the total synthesis of biologically active natural products.

The asymmetric synthesis of bicyclic highly substituted tetrahydropyrans is described. The reaction is catalyzed by unnatural γ-dipeptides based on densely substituted l- and d-proline derivatives. This organocatalytic one-pot reaction takes place among a ketone, a nitroalkene, and an aldehyde to yield an octahydro-2H-chromene scaffold. Monomeric species, from which the corresponding γ-dipeptides are synthesized, cannot catalyze the reaction, thus confirming the emergent nature of the catalytic behavior of these dimeric species. Financial support for this work was provided by the Spanish Ministerio de Ciencia, Innovacion y Universidades (MICINNFEDER, Grants PID2019-104772GB-I00 and RED2018-102387-T) and the Gobierno Vasco/Eusko Jaurlaritza (GV/EJ, Grant IT-1553-22). M.d.G.R. thanks the DIPC and UPV/EHU for her postdoctoral contract. M.A. thanks the Gobierno Vasco/Eusko Jaurlaritza for her Ph.D. grant. J.Z. thanks the China Scholarship Council for his Ph.D. grant (CSC 201908390051). The authors also thank the SGI/IZO-SGIker of the UPV/EHU and the DIPC for the generous allocation of analytical and computational resources.

During the last decade, a wide spectrum of applications and advantages in the use of deep eutectic solvents for promoting organic reactions has been well established among the scientific community. Among these synthetic methodologies, in recent years, various examples of biocatalyzed processes have been reported, making use of eutectic mixtures as reaction media, as an improvement in terms of selectivity and sustainability. This review aims to show the newly reported protocols in the field, subdivided by reaction class as a ‘toolbox’ guide for organic synthesis.

Partially reduced aromatic polyketides are bioactive secondary metabolites or intermediates in the biosynthesis of deoxygenated aromatics. For the antibiotic GTRI‐02 (mensalone) in different Streptomyces spp., biosynthesis involving the reduction of a fully aromatized acetyltrihydroxynaphthalene by a naphthol reductase has been proposed and shown in vitro with a fungal enzyme. However, more recently, GTRI‐02 has been identified as a product of the ActIII biosynthetic gene cluster from Streptomyces coelicolor A3(2), for which the reduction of a linear polyketide precursor by ActIII ketoreductase, prior to cyclization and aromatization, has been suggested. We have examined three different ketoreductases from bacterial producer strains of GTRI‐02 for their ability to reduce mono‐, bi‐, and tricyclic aromatic substrates. The enzymes reduced 1‐ and 2‐tetralone but not other aromatic substrates. This strongly suggests a reduction of a cyclized but not yet aromatic polyketide intermediate in the biosynthesis of GTRI‐02. Implications of the results for the biosynthesis of other secondary polyketidic metabolites are discussed., One ring to rule: In contrast to the case of reduction of fully aromatic naphthols or a linear polyketide, monocyclized polyketides are proposed as the substrates of ketoreductases in the biosynthesis of bacterial aromatic polyketides such as GTRI‐02.

The asymmetric synthesis of chiral-at-cage o-carboranes, whose chirality is associated with the substitution patterns on the polyhedron, is of great interest as the icosahedral carboranes have wide applications in medicinal and materials chemistry. Herein we report an intermolecular Ir-catalyzed enantioselective B−H alkenylation for efficient and facile synthesis of chiral-at-cage o-carboranes with new skeletons under mild reaction conditions. Generally very good to excellent yields with up to 99% ee can be achieved in this Ir-catalyzed B−H alkenylation. The enantiocontrol model is proposed based on Density Functional Theory calculations in which the use of chiral phosphoramidite ligand is essential for such asymmetric o-carborane B−H alkenylation., Chiral-at-cage o-carboranes are clusters of carbon and boron atoms that, when functionalized, can lower the symmetry of the cluster. Here the authors present a method to alkenylate B–H bonds on ocarboranes enantioselectively via iridium catalysis.

By varying the steric and electronic surroundings of the hydrogen-bonding motif, the novel chiral Cinchona-alkaloid based selenoureas were developed. Acting as bifunctional catalysts, they were applied in the Michael reactions of dithiomalonate and nitrostyrene providing chiral adducts with up to 96% ee. The asymmetric Michael–-hemiacetalization reaction of benzylidene pyruvate and dimedone, performed with the assistance of 5 mol% of selenoureas, furnished the product with up to 93% ee and excellent yields. The effectiveness of the new hydrogen-bond donors was also proved in solvent-free reactions under ball mill conditions, supporting the sustainability of the devised catalytic protocol.

Viral infections inflict many serious human diseases, being responsible for remarkably high mortality rates. In this sense, both the academy and the pharmaceutical industry are continuously searching for new compounds with antiviral activity, and in addition, face the challenge of developing greener and more efficient methods to synthesize these compounds. This becomes even more important with drugs possessing stereogenic centers as highly enantioselective processes are required. In this minireview, the advances achieved to improve synthetic routes efficiency and sustainability of important commercially antiviral chiral drugs are discussed, highlighting the use of organocatalytic methods.

Derivatization of spirooxindole having triazole and ferrocene units was achieved by the [3 + 2] cycloaddition (32CA) reaction approach. Reacting the respective azomethine ylide (AY) intermediate generated in situ with the ethylene derivative produced novel asymmetric cycloadducts with four contiguous asymmetric carbons in an overall high chemical yield with excellent regioselectivity and diastereoselectivity. X-Ray single-crystal structure analyses revealed, with no doubt, the success of the synthesis of the target compounds. The 32CA reaction of AY 5b with ferrocene ethylene 1 has been studied within MEDT. This 32CA reaction proceeds via a two-stage one-step mechanism involving a high asynchronous transition state structure, resulting from the nucleophilic attack of AY 5b on the β-conjugated position of ferrocene ethylene 1. The supernucleophilic character of AY 5b and the strong electrophilic character of ferrocene ethylene 1 account for the high polar character of this 32CA reaction. Further, Hirshfeld analyses were used to describe the molecular packing of compounds 4b, 4e, 4h and 4i.

Herein, we report the application of an efficient and practical K2CO3 promoted cascade reaction of 2-acetylbenzonitrile in the synthesis of novel 3-methylated analogs of Pazinaclone and PD172938, belonging to isoindolinones heterocyclic class bearing a tetrasubstituted stereocenter. Organocatalytic asymmetric synthesis of the key intermediate and its transformation into highly enantioenriched 3-methylated analog of (S)-PD172938 was also developed. These achievements can be of particular interest also for medicinal chemistry, since the methyl group is a very useful structural modification in the rational design of new and more effective bioactive compounds.

Background Chiral furfuryl alcohols are important precursors for the synthesis of valuable functionalized pyranones such as the rare sugar L-rednose. However, the synthesis of enantiopure chiral biobased furfuryl alcohols remains scarce. In this work, we present a chemoenzymatic route toward enantiopure nitrogen-containing (R)- and (S)-3-acetamido-5-(1-hydroxylethyl)furan (3A5HEF) from chitin-derived N-acetyl-D-glucosamine (NAG). Findings 3-Acetamido-5-acetylfuran (3A5AF) was obtained from NAG via ionic liquid/boric acid-catalyzed dehydration, in an isolated yield of approximately 31%. Carbonyl reductases from Streptomyces coelicolor (ScCR) and Bacillus sp. ECU0013 (YueD) were found to be good catalysts for asymmetric reduction of 3A5AF. Enantiocomplementary synthesis of (R)- and (S)-3A5HEF was implemented with the yields of up to > 99% and the enantiomeric excess (ee) values of > 99%. Besides, biocatalytic synthesis of (R)-3A5HEF was demonstrated on a preparative scale, with an isolated yield of 65%. Conclusions A two-step process toward the chiral furfuryl alcohol was successfully developed by integrating chemical catalysis with enzyme catalysis, with excellent enantioselectivities. This work demonstrates the power of the combination of chemo- and biocatalysis for selective valorization of biobased furans. Graphic abstract

In the presence of a suitable acid or base, α-hydroxyaldehydes, ketones, and imines can undergo isomerization that features the 1,2-shift of an alkyl or aryl group. In the process, the hydroxy group is converted to a carbonyl and the aldehyde/ketone or imine is converted to an alcohol or amine. Such α-ketol/α-iminol rearrangements are used in a wide variety of synthetic applications including asymmetric synthesis, tandem reactions, and the total synthesis and biosynthesis of natural products. This review explores the use of α-ketol rearrangements in these contexts over the past two decades.

The synthesis of phosphines is based on white phosphorus, which is usually converted to PCl3, to be afterwards substituted step by step in a non-atomic efficient manner. Herein, we describe an alternative efficient transition metal-mediated process to form asymmetrically substituted phosphines directly from white phosphorus (P4). Thereby, P4 is converted to [Cp*Fe(η5-P5)] (1) (Cp* = η5-C5(CH3)5) in which one of the phosphorus atoms is selectively functionalized to the 1,1-diorgano-substituted complex [Cp*Fe(η4-P5R′R″)] (3). In a subsequent step, the phosphine PR′R″R‴ (R′ ≠ R″ ≠ R‴ = alky, aryl) (4) is released by reacting it with a nucleophile R‴M (M = alkali metal) as racemates. The starting material 1 can be regenerated with P4 and can be reused in multiple reaction cycles without isolation of the intermediates, and only the phosphine is distilled off., Asymmetrically substituted phosphine ligands play a decisive role in catalysis, but their synthesis is rather challenging and often involves hazardous chemicals such as PCl3 or PH3. Here, the authors report the one-pot preparation of asymmetric phosphines from white phosphorus via a pentaphosphaferrocene based modular system, in which the transition metal complex can be reused.

Orientadores: Luiz Carlos Dias, Jean-Marc Campagne Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química Resumo: SÍNTESE DO FRAGMENTO C1-C9 DA (-)-DICTIOSTATINA: A (-)-dictiostatina é uma macrolactona de origem marinha que apresenta uma potente atividade antitumoral, inibindo a proliferação de células cancerígenas em concentrações na ordem de nanomolar. Propusemos desenvolver uma nova rota sintética para o fragmento C1-C9 deste produto natural. Conseguimos sintetizar o fragmento C1-C9 da (-)-dictiostatina em 15 etapas a partir do 1,3-propanodiol com 3,57% de rendimento global. Nossa rota sintética utilizou como etapas chaves a epoxidação assimétrica de Sharpless e a abertura de epóxido nas condições de Myashita para formar os centros estereogênicos. Este fragmento compreende os carbonos C1-C9 da (-)-dictiostatina, no qual está contido o dieno 2Z,4E e dois centros estereogênicos (C6R, C7S do produto natural). ESTUDOS VISANDO A SÍNTESE TOTAL DA (+)-TAUTOMICETINA: A (+)-tautomicetina é um policetídeo natural isolado em 1989 a partir de Streptomyces griseochromogenes como um antifúngico. Atualmente, TTN é mais conhecida pela sua atividade em proteínas serina/treonina fosfatases. Propusemos desenvolver uma rota sintética convergente para este produto natural. Conseguimos sintetizar dois fragmentos da tautomicetina, sendo o fragmento B2 correspondendo a parte C1-C12 e o composto 260 que consiste na parte C7¿-C13 da (+)-tautomiceina. A síntese do fragmento B2 teve como etapa chave a abertura estereosseletiva de epóxido quiral, o que consiste uma estratégia inédita para construir a parte desoxipropionato da TTN. A síntese do composto 260 teve como etapa chave, uma metodologia inédita de bis-esterificação de anidridos desenvolvida em nosso grupo de pesquisa Abstract: SYNTHESIS OF THE C1-C9 FRAGMENT OF (-)-DICTYOSTATIN: (-)-Dictyostatin is a marine macrolactone with potent antitumor activity. Herein, we report the development of a new synthetic route for the C1-C9 fragment of this natural product. The C1-C9 fragment of (-)-dictyostatin was synthesized in 15 steps and 3.57% overall yield from 1,3-propanediol. Our synthetic route employed Sharpless asymmetric epoxidation and epoxide opening under Myashita's conditions as key steps to form the stereogenic centers. The C1-C9 fragment contains the 2Z,4E diene and two stereogenic centers (C6R, C7S) contained in the natural product. STUDIES TOWARD THE TOTAL SYNTHESIS OF (+)-TAUTOMYCETIN: (+)-Tautomycetin is a polyketide natural product isolated in 1989 from Streptomyces griseochromogenes with antifungal activity. Currently, TTN is best known for its activity in serine/threonine phosphatase proteins. We developed a convergent synthetic route to this natural product. Two key fragments of (+)-tautomycetin were synthesized, the B2 fragment containing the C1-C12 chain and the compound 260, corresponding to the C7'-C13 fragment of (+)-tautomycetin. The synthesis of fragment B2 employed a stereoselective chiral epoxide opening reaction as a key step, which consist of a novel strategy to prepare the desoxypropionate moiety of TTN. The synthesis of 260 employed a novel method for bis-esterification of anhydrides developed in the Dias-Campagne groups Doutorado Química Orgânica Doutor em Ciências

Orientador: Paulo José Samenho Moran Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química Resumo: Nesse projeto estudaram-se reducoes biocataliticas de alcenos ativados diversos. Na primeira etapa do projeto realizaram-se reducoes de enonas estruturalmente semelhantes, contendo ou nao halogenios em posicao alilica. A introducao do halogenio nos substratos serviu como estrategia de controle da estereoquimica das reacoes, e foi possivel produzir tanto o isomero (R) quanto o (S) dos produtos de biorreducao. Nos casos de ¿À-haloenonas que tinham carbocations benzilicos particularmente estabilizados, a solvolise do substrato foi a reacao exclusiva. Para contornar esse problema, sintetizaram-se ¿À-acetoxienonas, que se mostraram comportamento identico ao das ¿À-haloenonas quanto a estereoquimica das reducoes, mas que nao sofreram solvolise em nenhum dos casos. Sintetizaram-se ambos os isomeros do TropionalR a partir de duas enonas semelhantes, contendo um grupo metil ou acetoximetil em posicao ¿¿ a carbonila. Verificou-se, ainda, que quando o grupo acetoxi alilico estava situado em um centro estereogenico, apenas um dos enantiomeros produziu um produto em que havia manutencao do grupo acetoxi. Em uma etapa seguinte, realizaram-se reducoes de enonas contendo outros grupos abandonadores em posicao alilica, e no caso de uma ¿À-azidocetona verificou-se que em sua biotransformacao ha a formacao de dois produtos: um com a manutencao do grupo azido em posicao ¿À, e outro sem o grupo azido. Verificou-se, ainda, que a eliminacao da ¿À-azidocetona e bastante lenta, e nao justifica a formacao da cetona sem o grupo azido. Finalmente, realizaram-se reducoes de alcenos contendo grupos retiradores de eletrons diversos. Constatou-se que os micro-organismos empregados sao ineficazes em reducoes de acidos e esteres ¿¿,¿À-insaturados, mas uma levedura testada foi capaz de reduzir o acilfosfonato derivado do acido cinamico. Infelizmente, devido a instabilidade desse subtrato em agua, sua hidrolise competiu com a biorreducao, e produziram-se misturas do acido ¿¿,¿À-insaturado e do acido saturado. Em seguida, constatou-se que uma levedura e capaz de realizar a hidrogenacao de um acilsilano insaturado. A ultima etapa do trabalho consistiu em biotransformacoes de alcoois alilicos, que produziram o alcool ou o acido saturado, dependendo das condicoes empregadas Abstract: This project¿s main focus was the study of biocatalytic reductions of activated alkenes. In the first stage of this work reductions of structurally related enones were performed: the presence or absence of an allylic halogen in the substrate acted as a stereocontrol strategy for these hydrogenations. Thus, ketones with both (R) and (S) configurations could be obtained from different substrates using the same biocatalyst. In cases where the â-haloenones¿ benzylic carbocations were particularly stabilized, however, substrate solvolysis was the exclusive reaction, and no bioreduction was observed. To overcome this limitation, â-acetoxienones were synthesized and subjected to the same biotransformation conditions. These substrated showed the same stereochemical behavior as their â-halo counterparts, but did not undergo solvolysis, providing the bioreduction products evenin the cases of electron rich aromatic rings. This strategy was employed in the synthesis of both isomers of Tropional® from related enones bearing a methyl or acetoxymethyl group á to the carbonyl. In the next stage of this project, we performed biotransformations of enones bearing other leaving groups in allylic position. In particular, a â-azidoketone produced a mixture of reduction products: one with the azido group in the â position, and the other one without it. We found out that elimination of hydrazoic acid from the potential â-azidoketone intermediate was very slow, and did not justify the formation of the ketone without the azido group. Finally, biotransformations of miscellaneous activated alkenes were performed. We found out that the microorganisms used in this work were not successful in the reduction of á,â-unstaturated acid and esters, but one yeast was capable of reducing an á,â-unsaturated acylphosphonate. Unfortunately, due to competing hydrolysis to the corresponding acid, both the saturated and unsaturated acids were observed in the reaction medium. The same yeast was capable of reducing an á,â-unsaturated acylsilane. In the last stage of this work, we performed biotransformations of allylic alcohols, which produced the saturated alcohol or acid depending on the employed reaction conditions Doutorado Química Orgânica Doutor em Ciências FAPESP 2012/08385-6

Chiral tertiary boronic esters are important precursors to bioactive compounds and versatile synthetic intermediates to molecules containing quaternary stereocenters. The development of conjugate boryl addition to α,β-unsaturated amide has been hampered by the intrinsic low electrophilicity of the amide group. Here we show the catalytic asymmetric synthesis of enantioenriched tertiary boronic esters through hydroboration of β,β-disubstituted α,β-unsaturated amides. The Rh-catalyzed hydroboration occurs with previously unattainable selectivity to provide tertiary boronic esters in high enantioselectivity. This strategy opens a door for the hydroboration of inert Michael acceptors with high stereocontrol and may provide future applications in the synthesis of biologically active molecules., The development of conjugate boryl addition to α,β-unsaturated amide has been hampered by the intrinsic low electrophilicity of the amide group. Here the authors show a catalytic asymmetric synthesis of enantioenriched tertiary boronic esters through hydroboration of β,β-disubstituted α,β-unsaturated amides.

The history of fragrances is closely associated with the chemistry of terpenes and terpenoids. For thousands of years mankind mainly used plant extracts to collect ingredients for the creation of perfumes. Many of these extracts contain complex mixtures of terpenes, that show distinct olfactoric properties as pure compounds. When organic synthesis appeared on the scene, the portfolio of new scents increased either in order to substitute natural fragrances without change of olfactoric properties or to broaden the scope of scents. This short review describes the story of the most successful synthetic fragrance ever which is called Iso E Super®as it is an ingredient in a large number of perfumes with varying percentages and is the first example being used as a pure fragrance. Structurally, it is related to natural terpenes like many other synthetic fragrances. And indeed, the story began with a classic in the field of fragrances, the natural product ionone.

Propargylamines are versatile compounds for heterocyclic synthesis, some of which are current drugs prescribed to treat patients with Parkinson’s disease. There are different methods to synthesize propargylamines, however, modern chemistry has moved progressively to rely on new strategies that meet the principles of Green Chemistry. In this context, propargylamines are readily accessible by the cross-dehydrogenative coupling (CDC) of two C-H bonds (i.e., NCsp3-H and Csp-H bonds); surely, CDC can be considered the most atom-economic and efficient manner to form C-C bonds. The aim of this review is to provide a comprehensive survey on the synthesis of propargylamines by the CDC of amines and terminal alkynes from three fronts: (a) transition-metal homogeneous catalysis, (b) transition-metal heterogeneous catalysis and (c) photoredox catalysis. A section dealing with the asymmetric synthesis of chiral propargylamines is also included. Special attention is also devoted to the proposed reaction mechanisms. This work was generously supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (MICIU; grant no. CTQ2017-88171-P), the Generalitat Valenciana (GV; grant no. AICO/2017/007) and the Instituto de Síntesis Orgánica (ISO). I.B. is also grateful to the Spanish MICIU for a Juan de la Cierva-incorporación grant (no. IJCI-2017-33706).

The catalytic enantioselective addition of glyoxylate cyanohydrin to imines to afford α-keto-β-amino acid equivalents is reported. Sterically tuned aminobenzothiadiazine catalysts provided high yields and stereoselectivities (up to 100% yield, 99% ee, >99:1 dr) for both aromatic and aliphatic imines, and the stereodivergent synthesis of both diastereomers was achieved. The optimal catalytic system was scalable, even with a low catalyst loading. The resulting adducts were converted into various chiral building blocks, including β-amino acid analogues, which are important motifs in medicinal chemistry, while maintaining a high enantiomeric excess.