Stereodivergent dehydrative allylation of ß-keto esters using a Ru/Pd synergistic catalyst.

α-Alkylation of a ß-keto ester is a frequently used reaction for carbon-carbon bond formation. However, extension to a stereoselective reaction remains a significant challenge, because the product easily racemizes under acidic or basic conditions. Here, we report a hybrid system consisting of Pd and Ru complexes that catalyzes the asymmetric dehydrative condensation between cinnamyl-type allylic alcohols and ß-keto esters. α-Non-substituted ß-keto ester can be allylated to afford an α-mono-substituted product with high regio-, diastereo-, and enantioselectivity. No epimerization occurs owing to the nearly neutral conditions, which is achieved by a rapid proton transfer from Pd-enolate formation to Ru π-allyl complex formation. Four diastereomers can be synthesized on demand by changing the stereochemistry of the Pd or Ru complex. Eight stereoisomers with three adjacent stereogenic centers can be synthesized by employing diastereoselective reduction of the ketone in the products. The formal synthesis of (+)-pancratistatin demonstrates the utility of the reaction.

Asymmetric Dehydrative Cyclization of Allyl Alcohol to Cyclic Ether Using Chiral Brønsted Acid/CpRu(II) Hybrid Catalysts: A DFT Study of the Origin of Enantioselectivity.

To elucidate the reaction mechanism and the origin of the enantioselectivity of the asymmetric dehydrative cyclization of allyl alcohol to cyclic ether catalyzed by a Cp-ruthenium complex and a chiral pyridinecarboxylic acid, (R)-X-Naph-PyCOOH, density functional theory (DFT) calculations were performed. According to the DFT calculations, the rate-determining step is the dehydrative σ-allyl formation step with ΔG‡ = 18.1 kcal mol-1 at 80 °C. This agrees well with the experimental data (ΔG‡ = 19.01 kcal mol-1 at 80 °C). The DFT result showed that both hydrogen and halogen bonds play a key role in the high enantioselectivity by facilitating the major R,SRu-catalyzed reaction pathway via a σ-allyl Ru intermediate to generate the major (S)-product. In contrast, the reaction is sluggish in the presence of the diastereomeric R,RRu catalyst with an apparent activation energy of 33.1 kcal mol-1; the minor (R)-product is formed via a typical π-allyl Ru intermediate and via a minor pathway for the cyclization step. In addition, the calculated activation Gibbs free energies, 14.4 kcal mol-1 for I < 16.8 kcal mol-1 for Br < 18.1 kcal mol-1 for Cl, reproduced the observed halogen-dependent reactivity with the (R)-X-Naph-PyCOOH ligands. The origin of the halogen trend was clarified by a structural decomposition analysis.

Asymmetric Dehydrative Allylation Using Soft Ruthenium and Hard Brønsted Acid Combined Catalyst.

Asymmetric Pd-catalyzed Tsuji-Trost-type allylation is an important catalytic reaction toward chiral natural and unnatural product syntheses. We successfully modified a desalt-type reaction using allyl ester or halide to a dehydrative one using allylic alcohol via the establishment of two redox-mediated donor acceptor bifunctional catalyst systems. These systems were cationic CpRu-Cl-Napy-PyCOOH and cationic CpRu-Naph-diPIM-dioxo-iPr/p-TsOH and were designed on the basis of the soft ruthenium and hard Brønsted acid combined catalyst concept. The complementary use of the two chiral catalysts for dehydrative asymmetric allylation expands the application scope facilitating the utilization of both aliphatic and aromatic allylic alcohols with various nucleophiles in the substrate. In this account, the design, synthesis, and application of these catalysts were reported.

CpRu/Brønsted Acid-Catalyzed Enantioselective Dehydrative Cyclization of Pyrroles N-Tethered with Allylic Alcohols.

A cationic CpRu/halogen/Brønsted acid hybrid catalyst (R cat) with the axially chiral Cl-Naph-PyCOOH ligand (naph = naphthyl, py = pyridine) is highly efficient for dehydrative cyclization of pyrroles to construct 1,2-fused-2-allylated pyrroles that, so far, have not been achieved. The mechanistic study has implied that hydrogen and halogen bonds play a key role for facilitating the R,SRu-catalyzed reaction pathway via a σ-allyl intermediate and that the diastereomeric R,RRu cat slowly gives the minor enantiomer via a π-allyl intermediate.

Rapid Entry into Biologically Relevant α,α-Difluoroalkylphosphonates Bearing Allyl Protection-Deblocking under Ru(II)/(IV)-Catalysis.

A convenient synthetic route to α,α-difluoroalkylphosphonates is described. Structurally diverse aldehydes are condensed with LiF2CP(O)(OCH2CH═CH2)2. The resultant alcohols are captured as the pentafluorophenyl thionocarbonates and efficiently deoxygenated with HSnBu3, BEt3, and O2, and then smoothly deblocked with CpRu(IV)(π-allyl)quinoline-2-carboxylate (1-2 mol %) in methanol as an allyl cation scavenger. These mild deprotection conditions provide access to free α,α-difluoroalkylphosphonates in nearly quantitative yield. This methodology is used to rapidly construct new bis-α,α-difluoroalkyl phosphonate inhibitors of PTPIB (protein phosphotyrosine phosphatase-1B).

Short and Atom-Economic Enantioselective Synthesis of the σ1-Receptor Ligands (S)- and (R)-Fluspidine-Important Tools for Positron Emission Tomography Studies.

Aryl bromides 2a and 2b bearing an alkynyl substituent in the o-position reacted with n-butyllithium and 1-benzylpiperidin-4-one in a one-pot Domino reaction to form ester 3 and aldehyde 5, respectively. Enantiomeric alcohols (R)-8 and (S)-8 were obtained by conjugate NaBH4 reduction of α,ß-unsaturated ester 3 in the presence of chiral cocomplexes (R,R)-10 and (S,S)-10. Starting from orthoester 2a, the precursors (R)-8 and (S)-8 for the synthesis of fluspidine enantiomers (R)-1/[18F](R)-1 and (S)-1/[18F](S)-1 were obtained in only two reaction steps without additional steps for N-protection in an atom-economic manner in 95.6% ee and 97.2% ee, respectively.

Water, an Essential Element for a ZnII -Catalyzed Asymmetric Quinone Diels-Alder Reaction: Multi-Selective Construction of Highly Functionalized cis-Decalins.

A ZnII complex of a C2 -chiral bisamidine-type sp2 N bidentate ligand (LR ) possessing two dioxolane rings at both ends catalyzes a highly efficient quinone asymmetric Diels-Alder reaction (qADA) between o-alkoxy-p-benzoquinones and 1-alkoxy-1,3-butadienes to construct highly functionalized chiral cis-decalins, proceeding in up to a >99:1 enantiomer ratio with a high generality in the presence of H2 O (H2 O:ZnII =4-6:1). In the absence of water, little reaction occurs. The loading amount of the chiral ligand can be minimized to 0.02 mol % with a higher Zn/LR ratio. This first success is ascribed to a supramolecular 3D arrangement of substrates, in which two protons of an "H2 O-ZnII " reactive species make a linear hydrogen bond network with a dioxolane oxygen atom and one-point-binding diene; the ZnII atom captures the electron-accepting two-points-binding quinone fixed on the other dioxolane oxygen atom via an n-π* attractive interaction. The mechanisms has been supported by 1 H NMR study, kinetics, X-ray crystallographic analyses of the related ZnLR complexes, and ligand and substrate structure-reactivity-selectivity relationship.

Synthesis of the core structure of phalarine.

The core skeleton of phalarine was rapidly synthesised through novel palladium-catalysed dearomative spirocyclisation and a palladium-catalysed Wacker-carbonylative cyclisation cascade. The two key steps allowed for the efficient construction of a tricyclic propeller skeleton bearing contiguous tetrasubstituted carbon centres, within 3 steps from a topologically planar precursor.

Revisiting the CuII-Catalyzed Asymmetric Friedel-Crafts Reaction of Indole with Trifluoropyruvate.

A CuII complex of bisamidine ligand L S catalyzes the Friedel-Crafts (FC) reaction of indole with trifluoropyruvate with high generality, yielding the highly enantiomerically enriched FC adduct. Electron-rich indoles have high reactivity due to a dual activation mechanism showing second-order kinetics for CuII, whereas indoles with a soft substituent at C(4) proceed at a rate that is three orders of magnitude lower via a coordination mechanism, which reverses the sense of enantioselectivity.

Synthetic Study toward Total Synthesis of (±)-Germine: Synthesis of (±)-4-Methylenegermine.

The total synthesis of 4-methylenegermine is described.

Synthetic analogs of an Entamoeba histolytica glycolipid designed to combat intracellular Leishmania infection.

Intracellular pathogens belonging to the genus Leishmania have developed effective strategies that enable them to survive within host immune cells. Immunostimulatory compounds that counteract such immunological escape mechanisms represent promising treatment options for diseases. Here, we demonstrate that a lipopeptidephosphoglycan (LPPG) isolated from the membrane of a protozoan parasite, Entamoeba histolytica (Eh), shows considerable immunostimulatory effects targeted against Leishmania (L.) major, a representative species responsible for cutaneous leishmaniasis (CL). Treatment led to a marked reduction in the number of intracellular Leishmania parasites in vitro, and ameliorated CL in a mouse model. We next designed and synthesized analogs of the phosphatidylinositol anchors harbored by EhLPPG; two of these analogs reproduced the anti-leishmanial activity of the native compound by inducing production of pro-inflammatory cytokines. The use of such compounds, either alone or as a supportive option, might improve the currently unsatisfactory treatment of CL and other diseases caused by pathogen-manipulated immune responses.

Modular Construction of Protected 1,2/1,3-Diols, -Amino Alcohols, and -Diamines via Catalytic Asymmetric Dehydrative Allylation: An Application to Synthesis of Sphingosine.

A new enantioselective catalysis has been developed for the one-step construction of methylene-bridged chiral modules of 1,2- and 1,3-OH and/or NH function(s) from δ- or λ-OH/NHBoc-substituted allylic alcohols and "H2C═O"/"H2C═NBoc". A protonic nucleophile, either in situ-generated CH2OH or CH2NHBoc, is intramolecularly allylated to furnish eight possible 1,2- or 1,3-O,O, -O,N, -N,O, and -N,N chiral modules equipped with an ethenyl group in high yields and enantioselectivities. The utility of this method has been demonstrated in the five-step synthesis of sphingosine.

Synthesis and biological evaluation of chemokine receptor ligands with 2-benzazepine scaffold.

Targeting CCR2 and CCR5 receptors is considered as promising concept for the development of novel antiinflammatory drugs. Herein, we present the development of the first probe-dependent positive allosteric modulator (PAM) of CCR5 receptors with a 2-benzazepine scaffold. Compound 14 (2-isobutyl-N-({[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-1-oxo-2,3-dihydro-1H-2-benzazepine-4-carboxamide) activates the CCR5 receptor in a CCL4-dependent manner, but does not compete with [3H]TAK-779 binding at the CCR5. Furthermore, introduction of a p-tolyl moiety at 7-position of the 2-benzazepine scaffold turns the CCR5 PAM 14 into the selective CCR2 receptor antagonist 26b. The structure affinity and activity relationships presented here offer new insights into ligand recognition by CCR2 and CCR5 receptors.

Enantio- and Diastereoselective Dehydrative "One-Step" Construction of Spirocarbocycles via a Ru/H+ -Catalyzed Tsuji-Trost Approach.

Chiral spirocarbocyclic skeletons are ubiquitous in natural products. An intramolecular Tsuji-Trost (T-T) α-allylation of simple cyclic ketones is a reasonable approach to construct chiral spriocarbocyclic motifs; however, it has been a challenging approach despite many excellent intermolecular examples. For the first time, this has been achieved by a Ru/H+ combined catalyst that dehydratively cyclizes racemic allylic alcohols comprising a simple ketone via simultaneous activation of the C=O and OH groups. This chiral technology facilitates the construction of various spirocarbocycles containing two contiguous spiro all-carbon quaternary and tertiary stereocenters. Among four possible stereoisomers, one stereoisomer can be selectively produced in high yield, enhancing the feasibility of the T-T strategy, particularly in the synthesis of spirocarbocycles.

Do GluN2B subunit containing NMDA receptors tolerate a fluorine atom in the phenylalkyl side chain?

The influence of an F-atom in the side chain of benzo[7]annulen-7-amines on the affinity towards GluN2B subunit containing NMDA receptors and the selectivity over related receptors was investigated. The synthesis of 5a and 5b was performed by reductive amination of the ketone 6 with primary alkanamines 14a and 14b bearing an F-atom in ß-position. The GluN2B affinities of non-fluorinated and fluorinated ligands 4 and 5 are almost identical. The low impact of the F-atom on GluN2B affinity was unexpected, as it influences several chemical and physicochemical properties of the ligands. However, introduction of the F-atom led to reduced selectivity over σ receptors. Whereas 5a and 5b display still a 2-3-fold preference for GluN2B over σ1 receptors, they show almost the same affinity to GluN2B and σ2 receptors.

Enantioselective Total Synthesis of (+)-Hinckdentine A via a Catalytic Dearomatization Approach.

Optically pure hinckdentine A was synthesized on a 300 mg scale via an asymmetric catalysis-based strategy. The key steps to the first asymmetric synthesis involved (i) enantioselective dearomative cyclization of an achiral N-acyl indole that allowed for the efficient construction of the key polycyclic indoline intermediate with a crucial tetrasubstituted stereogenic carbon center, (ii) Beckmann fragmentation-mediated ring expansion, (iii) rearrangement-based introduction of an anilinic nitrogen atom, (iv) regioselective tribromination, and (v) final closure of the cyclic amidine moiety.

Development of a Divergent Synthetic Route to the Erythrina Alkaloids: Asymmetric Syntheses of 8-Oxo-erythrinine, Crystamidine, 8-Oxo-erythraline, and Erythraline.

A general synthetic methodology toward the erythrina alkaloids has been developed. Inspired by a proposed biosynthetic mechanism, the medium-sized chiral biaryl lactam was asymmetrically transformed into the common core A-D rings by a stereospecific singlet oxygen oxidation of the phenol moiety, followed by a transannular aza-Michael reaction to the dienone functionality. The late-stage manipulation of the oxidation and oxygenation states of the functional groups on the peripheral moieties enabled the flexible syntheses of the erythrina alkaloids.

Intramolecular Tsuji-Trost-type Allylation of Carboxylic Acids: Asymmetric Synthesis of Highly π-Allyl Donative Lactones.

Tsuji-Trost-type asymmetric allylation of carboxylic acids has been realized by using a cationic CpRu complex with an axially chiral picolinic acid-type ligand (Cl-Naph-PyCOOH: naph = naphthyl, py = pyridine). The carboxylic acid and allylic alcohol intramolecularly condense by the liberation of water without stoichiometric activation of either nucleophile or electrophile part, thereby attaining high atom- and step-economy, and low E factor. This success can be ascribed to the higher reactivity of allylic alcohols as compared with the allyl ester products in soft Ru/hard Brønstead acid combined catalysis, which can function under slightly acidic conditions unlike the traditional Pd-catalyzed system. Detailed analysis of the stereochemical outcome of the reaction using an enantiomerically enriched D-labeled substrate provides an intriguing view of enantioselection.

Mechanism of Asymmetric Hydrogenation of Aromatic Ketones Catalyzed by a Combined System of Ru(π-CH2C(CH3)CH2)2(cod) and the Chiral sp(2)N/sp(3)NH Hybrid Linear N4 Ligand Ph-BINAN-H-Py.

The combination of a Goodwin-Lions-type chiral N4 ligand, (R)-Ph-BINAN-H-Py ((R)-3,3'-diphenyl-N(2),N(2')-bis((pyridin-2-yl)methyl)-1,1'-binaphthyl-2,2'-diamine; L), with Ru(π-CH2C(CH3)CH2)2(cod) (A) (cod = 1,5-cyclooctadiene) catalyzes the hydrogenation of acetophenone (AP) to (R)-1-phenylethanol (PE) with a high enantiomer ratio (er). Almost no Ru complex forms, with A and L remaining intact throughout the reaction while generating PE quantitatively according to [PE] = k(obs)t(2). An infinitesimal amount of reactive and unstable RuH2L (B) with C2-Λ-cis-α stereochemistry is very slowly and irreversibly generated from A by the action of H2 and L, which rapidly catalyzes the hydrogenation of AP via Noyori's donor-acceptor bifunctional mechanism. A CH-π-stabilized Si-face selective transition state, CSi, gives (R)-PE together with an intermediary Ru amide, D, which is inhibited predominantly by formation of the Ru enolate of AP. The rate-determining hydrogenolysis of D completes the cycle. The time-squared term relates both to the preliminary step before the cycle and to the cycle itself, with a highly unusual eight-order difference in the generation and turnover frequency of B. This mechanism is fully supported by a series of experiments including a detailed kinetic study, rate law analysis, simulation of t/[PE] curves with fitting to the experimental observations at the initial reaction stage, X-ray crystallographic analyses of B-related octahedral metal complexes, and Hammett plot analyses of electronically different substrates and ligands in their enantioselectivities.