Four Routes to 3-(3-Methoxy-1,3-dioxopropyl)pyrrole, a Core Motif of Rings C and E in Photosynthetic Tetrapyrroles.

The photosynthetic tetrapyrroles share a common structural feature comprised of a ß-ketoester motif embedded in an exocyclic ring (ring E). As part of a total synthesis program aimed at preparing native structures and analogues, 3-(3-methoxy-1,3-dioxopropyl)pyrrole was sought. The pyrrole is a precursor to analogues of ring C and the external framework of ring E. Four routes were developed. Routes 1-3 entail a Pd-mediated coupling process of a 3-iodopyrrole with potassium methyl malonate, whereas route 4 relies on electrophilic substitution of TIPS-pyrrole with methyl malonyl chloride. Together, the four routes afford considerable latitude. A long-term objective is to gain the capacity to create chlorophylls and bacteriochlorophylls and analogues thereof by facile de novo means for diverse studies across the photosynthetic sciences.

Preparation of Block Copolymer Nano-Objects with Embedded ß-Ketoester Functional Groups by Photoinitiated RAFT Dispersion Polymerization.

Herein, a photoinitiated reversible addition-fragmentation chain transfer (RAFT) dispersion polymerization of 2-(acetoacetoxy)ethyl methacrylate (AEMA) in ethanol/water at room temperature for in situ preparation of ß-ketoester-functionalized block copolymer nano-objects is reported. AEMA is also copolymerized with isobornyl methacrylate (IBOMA) to improve the colloidal stability of PIBOMA-based block copolymer nano-objects prepared by photoinitiated RAFT dispersion polymerization at low temperatures. A series of P(IBOMA-stat-AEMA)-based block copolymer nano-objects are prepared by changing reaction parameters. Finally, lanthanide-doped block copolymer nano-objects with luminescent and magnetic properties are also prepared based on the complexation of various lanthanide ions with the ß-ketoester group. It is expected that the current study will provide a facile platform for the in situ preparation of ß-ketoester-functionalized block copolymer nano-objects with different morphologies for specific applications.

Synthesis of chlorophyll-a homologs by C132-substitutions and their physico- and biochemical properties.

A mixture of pheophytins-a/a', metal-free forms of photosynthetically active chlorophyll(Chl)s-a/a' bearing the 132-methoxycarbonyl group, was substituted at the C132-position by bimolecular nucleophilic substitution with methyl bromoacetate or Michael addition with methyl acrylate, followed by C132-demethoxycarbonylation and magnesium insertion at the central position, to afford Chl-a/a' homologs possessing a methoxycarbonylmethyl or 2-methoxycarbonylethyl group at the C132-position, respectively. These C132-methylene- and ethylene-inserted homologs were characterized by 1D/2D 1H NMR spectroscopy, and the optical properties of their C132-epimerically pure samples are investigated using visible absorption, fluorescence emission, and circular dichroism spectroscopies. The stereochemistry at the C132-chiral center of these Chl-a/a' homologs was not inverted in a basic solution, and the Chl-a homologs were effective for the substrates for the chlorophyllase reaction, hydrolysis of the phytyl ester.

Photoredox Catalysis of Aromatic ß-Ketoesters for in Situ Production of Transient and Persistent Radicals for Organic Transformation.

Radical formation is the initial step for conventional radical chemistry. Reported herein is a unified strategy to generate radicals in situ from aromatic ß-ketoesters by using a photocatalyst. Under visible-light irradiation, a small amount of photocatalyst fac-Ir(ppy)3 generates a transient α-carbonyl radical and persistent ketyl radical in situ. In contrast to the well-established approaches, neither stoichiometric external oxidant nor reductant is required for this reaction. The synthetic utility is demonstrated by pinacol coupling of ketyl radicals and benzannulation of α-carbonyl radicals with alkynes to give a series of highly substituted 1-naphthols in good to excellent yields. The readily available photocatalyst, mild reaction conditions, broad substrate scope, and high functional-group tolerance make this reaction a useful synthetic tool.

Synthesis, modification, and cytotoxic evaluation of 2,3-secotriterpenic ß-ketoesters.

A set of ß-ketoesters was synthesized from 2,3-seco-18αH-oleanane and 2,3-secolupane bromomethyl ketones. Additionally, hydroxy derivatives with the A-seco- or five-membered A ring were obtained as a result of the reduction or of alkaline hydrolysis of acetic acid ß-ketoesters 4, 9. Cytotoxic screening revealed the compound 4 with marked activity (IC50 3.07-3.61 µM) against the HCT 116, MS, RD TE32 cancer cells. The studies of the cytotoxic mechanism enabled elucidating the fact that treatment of the HCT 116 cells with compound 4 for 18 h leads to induction of apoptosis in a dose-dependent manner. This observation was confirmed by registration of chromatin condensation, by the fluorescence increased during Annexin V-FITC staining, and by appearance of a sub-G0 peak in the cell cycle analysis with DAPI. Compound 4 also inhibited migration of cancer cells in the wound healing assay.

A Combination of Flow and Batch Mode Processes for the Efficient Preparation of mGlu2/3 Receptor Negative Allosteric Modulators (NAMs).

Benzodiazepinones are privileged scaffolds with activity against multiple therapeutically relevant biological targets. In support of our ongoing studies around allosteric modulators of metabotropic glutamate receptors (mGlus) we required the multigram synthesis of a ß-ketoester key intermediate. We report the continuous flow synthesis of tert-butyl 3-(2-cyanopyridin-4-yl)-3-oxopropanoate and its transformation to potent mGlu2/3 negative allosteric modulators (NAMs) in batch mode.

Functionalizing the γ-Position of α-Diazo-ß-ketoesters.

Although α-diazo-ß-ketoesters are synthetically versatile intermediates, methodology for introducing this functionality into complex molecules is still limited, most frequently involving a carboxylic acid precursor, which is then activated and transformed into a ß-ketoester, with the diazo group being subsequently added with a diazo transfer reagent. While introducing this highly functional moiety in a convergent one step process would be ideal, such an objective is limited by the relatively few studies which address functionalization of the α-diazo-ß-ketoester at the γ-position. In the present investigation, we evaluate strategies, both new and established, for functionalizing α-diazo-ß-ketoesters, particularly with regard to generating compounds prospectively useful in the synthesis of C1-substituted carbapenems. We report the first δ-aldehydo-α-diazo-ß-ketoester as well as a method for its oxidation to the corresponding methyl ester, and the formation of a new substituted pyrazole under basic conditions.

Coumarin-Synthetic Methodologies, Pharmacology, and Application as Natural Fluorophore.

Coumarins are secondary metabolites made up of benzene and α-pyrone rings fused together that can potentially treat various ailments, including cancer, metabolic, and degenerative disorders. Coumarins are a diverse category of both naturally occurring as well as synthesized compounds with numerous biological and therapeutic properties. Coumarins as fluorophores play a key role in fluorescent labeling of biomolecules, metal ion detection, microenvironment polarity detection, and pH detection. This review provides a detailed insight into the characteristics of coumarins as well as their biosynthesis in plants and metabolic pathways. Various synthetic strategies for coumarin core involving both conventional and green methods have been discussed comparing advantages and disadvantages of each method. Conventional methods discussed are Pechmann, Knoevenagel, Perkin, Wittig, Kostanecki, Buchwald-Hartwig, and metal-induced coupling reactions such as Heck and Suzuki, as well as green approaches involving microwave or ultrasound energy. Various pharmacological applications of coumarin derivatives are discussed in detail. The structural features and conditions responsible for influencing the fluorescence of coumarin core are also elaborated.

Cobalt(III)-py2en systems as potential carriers of ß-ketoester-based ligands.

Two cobalt(III) complexes containing different ß-ketoesters, namely [CoIII(L1)(py2en)](ClO4)2·H2O (1) and [CoIII(L2)(py2en)](ClO4)2 (2) (py2en = N,N'-bis(pyridin-2-ylmethyl)ethylenediamine; L1- = methylacetoacetate; L2- = ethyl 4-chloroacetoacetate) have been prepared and investigated as prototypes of bioreductive prodrugs. The presence of ß-ketoester and py2en ligands in 1 and 2, as well as the perchlorate counterions, was supported by IR spectroscopy and CHN elemental analysis. The composition molecular structure of both complexes was confirmed by NMR spectroscopy and ESI mass spectrometry. Structural information was also obtained for 2via X-ray diffraction analysis. The redox properties indicate that 1 and 2 are suitable for reduction under biological conditions. Investigation of DNA-interacting suggest that 1 and 2 bind DNA via electrostatic forces. Both complexes may be employed as possible platforms for the delivery of biologically active compounds, since their reaction with ascorbic acid in PBS at pH 6.2 and 7.4 at 37°C results in the release of the ß-ketoester ligands upon Co(III)/Co(II) reduction.

Recyclable fluorous cinchona alkaloid ester as a chiral promoter for asymmetric fluorination of ß-ketoesters.

A fluorous cinchona alkaloid ester has been developed as a chiral promoter for the asymmetric fluorination of ß-ketoesters. It has comparable reactivity and selectivity to the nonfluorous versions of cinchona alkaloids and can be easily recovered from the reaction mixture by simple fluorous solid-phase extraction (F-SPE) and used for the next round of reaction without further purification.

Whole cells in enantioselective reduction of benzyl acetoacetate.

The ß-ketoester benzyl acetoacetate was enantioselectively reduced to benzyl (S)-3-hydroxybutanoate by seven microorganism species. The best result using free cells was obtained with the yeast Hansenula sp., which furnished 97% ee and 85% of conversion within 24 h. After immobilization in calcium alginate spheres, K.marxianus showed to be more stable after 2 cycles of reaction.