Search

In this communication, we report on the use of deep eutectic solvents (DESs) for processing nuclear waste, with a view to selectively recovering minor actinides (MA) from highly active raffinate solutions. DESs are an interesting new class of green and eco-sustainable solvents. Herein, a representative family of DES was tested as a co-solvent for MA/lanthanides partitioning based on Selective ActiNide EXtraction (SANEX)-like hydrometallurgical processes. The reference system exploits the CyMe4-BTBP lipophilic extractant for selective MA recovery, but the slow kinetics is the main limitation toward the industrial implementation. A selection of hydrophilic DESs has been proposed as a phase transfer catalyst and tested to improve the process performances. In this work, the radiochemical stability and the extraction behavior of these DESs have been ascertained. Moreover, a preliminary optimization of system composition has been achieved. This study underlines a catalytic effect of DES that can be proficiently exploited to enhance CyMe4-BTBP extraction and selectivity.

Plasmonic nanoparticles (NPs) are exploited to concentrate light, provide local heating and enhance drug release when coupled to smart polymers. However, the role of NP assembling in these processes is poorly investigated, although their superior performance as nanoheaters has been theoretically predicted since a decade. Here we report on a compound hydrogel (agarose and carbomer 974P) loaded with gold NPs of different configurations. We investigate the dynamics of light-heat conversion in these hybrid plasmonic nanomaterials via a combination of ultrafast pump-probe spectroscopy and hot-electrons dynamical modeling. The photothermal study ascertains the possibility to control the degree of assembling via surface functionalization of the NPs, thus enabling a tuning of the photothermal response of the plasmon-enhanced gel under continuous wave excitation. We exploit these assemblies to enhance photothermal release of drug mimetics with large steric hindrance loaded in the hydrogel. Using compounds with an effective hydrodynamic diameter bigger than the mesh size of the gel matrix, we find that the nanoheaters assemblies enable a two orders of magnitude faster cumulative drug release toward the surrounding environment compared to isolated NPs, under the same experimental conditions. Our results pave the way for a new paradigm of nanoplasmonic control over drug release.

Using mechanochemistry by grinding TPB and ZnBr2 an amorphous poly-[n]-catenane of interlocked M12L8 nanocages is obtained in good yields (⁓ 80 %) and within 15 minutes. The mechanical bond among icosahedral M12L8 cages in the amorphous phase has been demonstrated by single crystal XRD, powder XRD and FT-IR spectroscopy following an amorphous-to-crystalline transformation by guest uptake of the amorphous phase. High-resolution solid-state 13C NMR spectroscopy gives insights in the local structure of the amorphous catenane focusing on TPB aromatic-aromatic interactions.

Reactive microgliosis is a pathological hallmark that accompanies neuronal demise in many neurodegenerative diseases, ranging from acute brain/spinal cord injuries to chronic diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and age-related dementia. One strategy to assess and monitor microgliosis is to use positron emission tomography (PET) by exploiting radioligands selective for the 18 kDa translocator protein (TSPO) which is highly upregulated in the brain in pathological conditions. Several TSPO ligands have been developed and validated, so far. Among these, PBR28 has been widely adopted for PET imaging at both preclinical and clinical levels, thanks to its high brain penetration and high selectivity. For this reason, PBR28 represents a good candidate for functionalization strategies, where this ligand could be exploited to drive selective targeting of TSPO-expressing cells. Since the PBR28 structure lacks functional moieties that could be exploited for derivatization, in this work we explored a synthetic pathway for the synthesis of a PBR28 derivative carrying an alkyne group (PBR-alkyne), enabling the fast conjugation of the ligand through azide-alkyne cycloaddition, also known as click-chemistry. As a proof of concept, we demonstrated in silico that the derivatized PBR28 ligand maintains the capability to fit into the TSPO binding pocked, and we successfully exploited PBR-alkyne to decorate zwitterionic biodegradable polymer nanoparticles (NPs) resulting in efficient internalization in cultured microglia-like cell lines., Nanoletters, 11 (7), ISSN:2079-4991

Ivabradine (Corlanor&reg, ), is a chiral benzocycloalkane currently employed and commercialized for the treatment of chronic stable angina pectoris and for the reduction in sinus tachycardia. The eutomer (S)-ivabradine is usually produced via chiral resolution of intermediates, by employing enantiopure auxiliary molecules or through preparative chiral HPLC separations. Recently, more sustainable biocatalytic approaches have been reported in literature for the preparation of the chiral amine precursor. In this work, we report on a novel biocatalyzed pathway, via a resolution study of a key alcohol intermediate used as a precursor of the chiral amine. After screening several enzymatic reaction conditions, employing different lipases and esterases both for the esterification and hydrolysis reactions, the best result was achieved with Pseudomonas cepacia Lipase and the final product was obtained in up to 96:4 enantiomeric ratio (e.r.) of an ivabradine alcohol precursor. This enantiomer was then efficiently converted into the desired amine in a facile three step synthetic sequence.

MOFs, (the acronym for Metal-Organic Frameworks) are a quite new family of materials resulting from the combination of organic ligands and metal ions. The coordination between the metal centers and the organic scaffolds give rise to complex assemblies which can develop into coordination polymers from 1D to 3D structures. These materials are usually porous with well-defined channels or pores. For this reason, MOFs are able to absorb a number of molecules with very high efficiency. Depending on the combination of the metal and organic components, selectivity toward different classes of gases or organic molecules (guests) can be achieved. The interaction of the MOF with the guest often results in a modification of the MOF crystalline structure which eventually produce a change in the physical properties of the materials. These variations can be exploited to detect the presence of a specific guest. In this chapter, the application of MOFs for the sensing of chemical species will be briefly illustrated. After an introduction on of the structures and synthesis of MOFs, the different mode of sensing will be described. Then a number of examples from the recent literature will be discussed. The focus will be on two issues: the sensing of small molecules as gases, VOC and organic compounds, and the sensing of biomolecules. The former can find many uses in the industry, whereas the latter is a promising topic for biomedical applications.

The selective formation of the heterocyclic salt ((1,4-dioxane-2,5-diyl)-bis-(methylene))-bis-(triphenylphosphonium) chloride was observed when epichlorohydrin and triphenylphosphine were reacted in CH2Cl2 at room temperature. Slow evaporation from a mixture of ethanol and ethyl acetate allows to isolate monocrystals of the heterocyclic phosphonium salt. Mechanistic investigations point to the formation of the zwitterionic intermediate 1-chloro-3-(triphenylphosphonio)-propan-2-olate, which can dimerize and generate the 1,4-dioxane derivative. In the exclusive presence of a Brønsted acid as HCl, which usually facilitates epoxide ring opening, the exclusive formation of 1,3-dichloro-2-propanol was although observed. Also, when epichlorohydrin, PPh3, and a stoichiometric amount of HCl were mixed, (2-chloro-3-hydroxypropyl)-triphenylphosphonium chloride was formed and its isolation in pure form provides monocrystals subjectable to X-ray analysis.

Targeted drug delivery is currently emerging as a promising approach to overcome the limits of currently employed administration techniques. The most convenient methodology to control drug delivery is the application of stimuli-responsive materials, which can release drugs only when required, to remotely controlled microdevices able to navigate human body. Thanks to this synergy, release can be controlled both spatially and temporally. Spatial control is guaranteed by the maneuverability of the devices, which can be precisely guided to release in targeted locations. Temporal control, conversely, is guaranteed by the functionalization introduced in the stimuli-responsive material. In this context, the present work describes the coating of magnetically controlled microdevices with functionalized alginate-based hydrogels able to release drugs at pH values lower than 4.5. Hydrogels are functionalized binding the drug with either an azidoethyl ester bond or an amidic bond, following an innovative synthesis route. After fabrication, release from hydrogel coated microdevices as a function of the environmental pH is characterized. Finally, devices are magnetically actuated and the possibility to achieve spatially and temporally controlled release is demonstrated. The functional microtransporters described in the present work are particularly promising for in-vivo applications in environments where pH differences are present, like the digestive apparatus., Materials & Design, 197, ISSN:0264-1275, ISSN:1873-4197

The expression of multidrug resistance P-glycoprotein (P-gp) by cancer cells represents one of the major drawbacks to successful cancer therapy. Accordingly, the development of drugs that inhibit the activity of this transporter remains a major challenge in cancer drug discovery. In this context, several new ecdysteroid derivatives have been synthesized and evaluated as P-gp inhibitors. Two of them (compounds 9 and 14) were able to resensitize CEMVbl100 and LoVoDoxo resistant cell lines to vinblastine and doxorubicin, respectively. Indeed, both compounds 9 and 14 increased the cellular accumulation of rhodamine 123 in cells expressing P-gp and stimulated basal P-glycoprotein-ATPase activity at a 1 μM concentration, demonstrating their interference with the transport of other substrates in a competitive mode. Moreover, in a medulloblastoma cell line (DAOY), compounds 9 and 14 reduced the side population representing cancer stem cells, which are characterized by a high expression of ABC drug transporters. Further, in DAOY cells, the same two compounds synergized with cisplatin and vincristine, two drugs used commonly in the therapy of medulloblastoma. Molecular docking studies on the homology-modeled structure of the human P-glycoprotein provided a rationale for the biological results, validating the binding mode within the receptor site, in accordance with lipophilicity data and observed structure–activity relationship information. Altogether, the present results endorse these derivatives as promising P-gp inhibitors, and they may serve as candidates to reverse drug resistance in cancer cells.

Drug delivery systems for the controlled and targeted release of drugs are in continuous development nowadays, allowing to benefit of ever better and more effective therapies. Chemical engineers th...

In the last years, nanogels have emerged as one of the most promising classes of novel drug delivery vehicles since they can be employed in multiple fields, such as various therapeutics or diagnostics, and with different classes of compounds and active molecules. Their features, such as a high volume to surface ratio, excellent drug loading and release ability, as well as biocompatibility and tunable behavior, are unique, and, nowadays, great efforts are made to develop new formulations that can be employed in a wider range of applications. Polyethylene glycol (PEG)-polyethylenimine (PEI) nanogels probably represent the baseline of this class of biomaterials and they are still largely employed and studied. In any way, the possibility to exploit new core formulations for nanogels is certainly very interesting in order to understand the influence of different polymer chains on the final properties of the system. In this research, we explore and make a comparison between PEG-PEI nanogels and two other different formulations: pluronic F127-PEI nanogels and PEG-Jeffamine nanogels. We propose nanogels synthesis methods, their chemical and physical characterization, as well as their stability analysis, and we focus on the different drug delivery ability that these structures exhibit working with different typologies of drug mimetics.

Ene reductases from the Old Yellow Enzyme (OYE) family are industrially interesting enzymes for the biocatalytic asymmetric reduction of alkenes. To access both enantiomers of the target reduced products, stereocomplementary pairs of OYE enzymes are necessary, but their natural occurrence is quite limited. A library of wild type ene reductases from different sources was screened in the stereoselective reduction of a set of representative alpha-alkyl-beta-arylenones to investigate the naturally available biodiversity. As far as the bioreduction of the ethyl ketone derivatives concerns, the results confirmed the distinctiveness of the OYE3 enzyme in affording the reduced product in the (S) configuration, while all the other tested ene reductases from the Old Yellow Enzymes family showed the same stereoselectivity toward the formation of corresponding (R) enantiomer. A possible determinant role of the "hot spot" residue in position 296 for the stereoselectivity control of these reactions was confirmed by the replacement of Phe296 of OYE1 with Ser as found in OYE3. Further investigations showed that the same stereoselectivity switch in OYE1 could be achieved also by the replacement of Trp116 with Ala and Val, these experimental results being rationalized by structural and docking studies. Moreover, an additive effect on the stereoselectivity of OYE1 was observed when coupling the selected mutations in position 296 and 116, thus providing two extremely enantioselective variants of OYE1 (W116A-F296S, W116V-F296S) showing the opposite stereoselectivity of the wild type enzyme. Lastly, the effects of the mutations on the bioreduction of carvone enantiomers were investigated as well.

Polymer functionalization strategies have recently attracted considerable attention for several applications in biomaterials science. In particular, technological advancements in medical imaging have focused on the design of polymeric matrices to improve non-invasive approaches and diagnostic accuracy. In this scenario, the use of microwave irradiation of aqueous solutions containing appropriate combinations of polymers is gaining increasing interest in the synthesis of sterile hydrogels without using monomers, eliminating the need to remove unreacted species. In this study, we developed a method for the in situ fabrication of TEMPO-labeled hydrogels based on a one-pot microwave reaction that can then be tracked by magnetic resonance imaging (MRI) without using toxic compounds that could be hostile for the target tissue. Click chemistry was used to link TEMPO to the polymeric scaffold. In an in vivo model, the system was able to preserve its TEMPO paramagnetic activity up to 1 month after hydrogel injection, showing a clear detectable signal on T1-weighted MRI with a longitudinal relaxivity value of 0.29 mM s−1, comparable to a value of 0.31 mM s−1 characteristic of TEMPO application. The uncleavable conjugation between the contrast agent and the polymeric scaffold is a leading point to record these results: the use of TEMPO only physically entrapped in the polymeric scaffold did not show MRI traceability even after few hours. Moreover, the use of TEMPO-labeled hydrogels can also help to reduce the number of animals sacrificed being a longitudinal non-invasive technique.

Ligands L1 and L2 have been designed, synthesized, and used to build for the first time bispidine-based coordination polymers (CPs) in combination with MnII . The novel CPs have been structurally characterized by single-crystal (SC) and powder X-ray diffraction (P-XRD) techniques, showing that they are composed of 1D ribbon-like chains that adopt various arrangements depending on the trapped solvent species. These materials show highly dynamic behavior as they undergo heterogeneous solid/liquid and solid/vapor multiple solvent exchange processes, comprising crystalline-amorphous-crystalline, selective adsorption and SC-to-SC transformations, where major structural reorganization of the 1D ribbons are observed. By tuning inter-ribbon interactions through expansion of the ligand's accessible surface, the dynamic behavior can be effectively modulated.

3-Substituted oxindoles are very interesting molecules both for their potential biological activity and for their role as starting materials toward more complex oxindole-based structures. These molecules can be prepared by the reduction of a 3-ylidene oxindole precursor by classical metal-catalysed chemical reductions of the olefin. In this work we present a biocatalytic approach for the reduction of oxindole-based olefins using baker's yeast. All the substrates were efficiently reduced in high yields. When an α,β-unsaturated ketone was used, the corresponding saturated alcohol was obtained in high yield and ee. To further investigate the enzyme-substrate interactions a molecular docking study was also performed.

The development of nanogels as nanoscale multifunctional polymer-based matrices for controlled drug and gene delivery purposes has been the subject of intense research during the last decades. Indeed, polymeric nanoparticles are capable to interact with cells to different extents, depending on their size, shape, surface properties and ligands tagged to the surface. Moreover, coating these devices using appropriate functionalization strategies can greatly improve or not their adhesion and uptake by cells. In this work, we proposed different coatings and then we studied their ability to improve or reduce microglia internalization. Nanogels (NGs) were composed by polyethylene glycol (PEG) and polyethyleneimine (PEI) conjugated with rhodamine through click chemistry reaction. Coatings were prepared using PEG monomethyl ether (mPEG), modifying its terminal hydroxyl groups with different linkers to evaluate the amount of mPEG layer chemically bond to the nanogel and its effect over microglia internalization. Nanogels were also investigated to identify which procedure is able to form networks with adequate dimensions and stability, according to the physicochemical parameters for the microglia applications in vitro . The biological experimental results showed that NGs were efficiently internalized by cells and the coating-microglia interactions allowed different cellular uptake. This outcome could be considered a promising perspective of nanogels use as carriers for drugs or genes delivery within microglia environment, improving their therapeutic effect through polymer surface modifications.

An efficient Ugi three-component reaction of a preformed chiral ketimine derived from isatin with various isonitrile and acid components has been developed. The reactions proceeded smoothly and in a stereocontrolled manner with regard to the new center of the Ugi products due to the stereoinduction of the amine chiral residue. A wide variety of novel chiral 3,3-disubstituted 3-aminooxindoles were obtained, a selection of which were subjected to post-Ugi transformations, paving the way to application as peptidomimetics.

Chiral products play an important role particularly in the field of medicinal chemistry, where it is known that enantiomers often have very different biological properties and effects. One of the most powerful tool to obtain a product as a single enantiomer is asymmetric catalysis. Recently, organocatalysis, i.e. the use of small organic molecules to catalyze enantioselective transformations, has emerged as a prominent field in asymmetric synthesis. In this work, the use of hydrogels as a support for a chiral imidazolidinone organocatalyst (MacMillan catalyst) and its application in the reduction of activated olefins mediated by the Hantzsch ester is reported for the first time. Results showed a good activity of hydrogels in respect to both yield and enantioselection.

A series of 1,4-disubstituted piperazine-based compounds were designed, synthesized, and evaluated as dopamine D2/D3 receptor ligands. The synthesis relies on the key multicomponent split-Ugi reaction, assessing its great potential in generating chemical diversity around the piperazine core. With the aim of evaluating the effect of such diversity on the dopamine receptor affinity, a small library of compounds was prepared, applying post-Ugi transformations. Ligand stimulated binding assays indicated that some compounds show a significant affinity, with K i values up to 53 nM for the D2 receptor. Molecular docking studies with the D2 and D3 receptor homology models were also performed on selected compounds. They highlighted key interactions at the indole head and at the piperazine moiety, which resulted in good agreement with the known pharmacophore models, thus helping to explain the observed structure-activity relationship data. Molecular insights from this study could enable a rational improvement of the split-Ugi primary scaffold, toward more selective ligands.

A multistep stereoselective synthesis of each stereoisomer of Nicotiana tabacum lactone is reported. A two steps reduction of an α,β-unsaturated ketoester gives the corresponding key intermediate ethyl 4-hydroxy-3-methylpentanoate. This one pot synthesis was catalyzed by a multienzymatic system comprising an ene-reductase (ER) and an alcohol dehydrogenase (ADH). This cascade process was highly chemoselective and stereoselective. In the last step, treatment of the hydroxyester with trifluoroacetic acid gives the γ-lactone in a very high overall yield (up to 78%) and with an excellent stereoselectivity (de > 94%, ee > 98%). The access to each stereoisomer was achieved by a substrate engineering approach and by selecting a Prelog or an anti-Prelog ADH. Furthermore, computational studies of the binding modes of the substrates into the catalytic site of ene-reductases have been carried out, giving an insight of the observed enantiodivergence.

A small family of structural analogues of the antimitotic tripeptides, hemiasterlins, have been designed and synthesized as potential inhibitors of tubulin polymerization. The effectiveness of a multicomponent approach was fully demonstrated by applying complementary versions of the isocyanide-based Ugi reaction. Compounds strictly related to the lead natural products, as well as more extensively modified analogues, have been synthesized in a concise and convergent manner. In some cases, biological evaluation provided evidence for strong cytotoxic activity (six human tumor cell lines) and for potent inhibition of tubulin polymerization.

This study reports on our ongoing investigation on hybrid EM-2 analogues, in which the great potential of β-amino acids was exploited to generate multiple conformational modifications at the key positions 3 and 4 of the parent peptide. The effect on the opioid binding affinity was evaluated, by means of ligand stimulated binding assays, which indicated a high nanomolar affinity toward the μ-receptor, with appreciable μ/δ selectivity, for some of the new compounds. The three-dimensional properties of the high affinity μ opioid receptor (MOR) ligands were investigated by proton nuclear magnetic resonance, molecular dynamics, and docking studies. In solution, the structures showed extended conformations, which are in agreement with the commonly accepted pharmacophore model for EM-2. From docking studies on an active form of the MOR model, different ligand–receptor interactions have been identified, thus confirming the ability of active compounds to assume a biologically active conformation.

The synthesis of novel spirocyclic lactams, embodying D-tryptophan (Trp) amino acid as the central core and acting as peptidomimetics, is presented. It relies on the strategic combination of Seebach's self-reproduction of chirality chemistry and Pictet-Spengler condensation as key steps. Investigation of the conformational behavior by molecular modeling, X-ray crystallography, and NMR and IR spectroscopies suggests very stable and highly predictable type II' β-turn conformations for all compounds. Relying on this feature, we also pursued their application to two potential mimetics of the hormone somatostatin, a pharmaceutically relevant natural peptide, which contains a Trp-based type II' β-turn pharmacophore.

A stereoselective synthesis of bicyclic primary or secondary amines, based on tetralin or chroman structural moieties, is reported. These amines are precursors of important active pharmaceutical ingredients such as rotigotine (Neupro), robalzotan, and ebalzotan. The key step is based on a multienzymatic reduction of an alpha,beta-unsaturated aldehyde or ketone to give the saturated primary or secondary alcohol, in a high yield and with a high ee. The catalytic system consists of the combination of an ene-reductase (ER; i.e., OYE2 or OYE3 belonging to the Old Yellow Enzyme family) with an alcohol dehydrogenase (ADH), applying the in situ substrate feeding product removal technology. By this system the formation of the allylic alcohol side product and the racemization of the chirally unstable alpha-substituted aldehyde intermediate are minimized. The primary alcohols were elaborated via a Curtius rearrangement. The combination of OYE2 with a Prelog or an anti-Prelog ADH allowed the preparation of the secondary alcohols with ee > 99% and de > 87%. The absolute configuration of the primary amines was unambiguously assigned by comparison with authentic samples. The stereochemistry of secondary alcohols was assigned by X-ray crystal structure and NMR analysis of Mosher esters.

To overcome the usually low productivities of the C=C bond bioreduction of alpha,beta-unsaturated aldehydes we combined the in situ substrate feeding product removal (SFPR) technology with a cascade system comprising an isolated ene-reductase and a chemoselective alcohol dehydrogenase.

The bakers yeast (BY)-mediated reduction of a set of a-substituted derivatives of cinnamaldehyde to give the corresponding saturated alcohols was investigated. Our study demonstrates that the ene reductases of BY (OYE?2 or OYE?3) preferentially reduce the C?C double bond of stereoisomers with the phenyl group trans to the carbonyl group. Moreover, the alcohol dehydrogenases (ADHs) chemoselectively reduce (oxidise) the carbonyl group (hydroxyl group) of saturated aldehydes (alcohols) if the side chain does not contain a heteroatom such as oxygen or sulphur and is longer than an ethyl group. Using isolated OYEs instead of BY, the saturated aldehydes partially lost their optical purity during the biotransformation, even with the in situ substrate feeding product removal (SFPR) technology. This limitation can be overcome by the combination of an isolated ene reductase (OYE?2 or OYE?3) together with an ADH (horse liver alcohol dehydrogenase) in a cascade system which allowed both yields and enantioselectivities to improve.

A simple and straightforward synthesis of a tetranuclear copper(I)–pyridine–iodide cluster is described as a laboratory experiment for advanced inorganic chemistry undergraduate students. The product is used to demonstrate the fascinating and visually impressive phenomenon of luminescence thermochromism: exposed to long-wave UV light, the crystalline solid shows a bright yellow fluorescence at room temperature and an equally intense blue-violet fluorescence when cooled in liquid nitrogen. The procedure was also extended to several other pyridine ligands to allow students to synthesize different clusters and compare their photophysical behavior.

A series of novel hybrid compounds obtained by the attachment of anhydrovinblastine, vinorelbine, and vindoline to thiocolchicine, podophyllotoxin, and baccatin III are described. Two types of diacyl spacers are introduced. The influence of the hybrid compounds on tubulin polymerization is reported. The results highlight the importance of the length of the spacer. Immunofluorescence microscopy and flow cytometry measurements that compound with the best in vitro activity could disrupt microtubule networks in cell and prevent the formation of the proper spindle apparatus, thereby causing cell cycle arrest in the G2/M phase. The newly synthesized compounds were tested in the human lung cancer cell line A549.

A dynamic combinatorial library of thiocolchicine-podophyllotoxin derivatives based on the disulfide bond exchange reaction is described. The influence of a biological target on the composition of the reaction mixture has been demonstrated. Use of high-resolution ESI mass spectrometry to evaluate the composition of the mixture shows promise for the design of new large libraries. The biological evaluation demonstrates that formation of a divalent compound affords a new chemical entity whose biological activity is not merely the sum of the single ligands activities, thus reflecting a different interaction with the biological target.

An efficient RCM-based approach was applied to the total asymmetric synthesis of a tricyclic diamine and, formally, of its enantiomer, widely known as efficient and versatile chiral ligands of the sparteine-like type.

The preparation of collections of structurally diverse small molecules is a useful tool for studying biology and medicine with chemistry. Herein, we demonstrate the versatility of the pure enantiomers of 2-(2-oxo-ethyl)-piperidine-1-carboxylic acid tert-butyl ester to prepare the biological active alkaloids sedridine, allosedridine, methylsedridine, methylallosedridine, ethylnorlobelol, and coniine in two steps and in a stereoselective way via a reagent-based differentiation. The described syntheses are a demonstration of the versatility of 2-(2-oxo-ethyl)-piperidine-1-carboxylic acid tert-butyl esters as chiral building blocks.

The equilibrium structures of the lupine alkaloid sparteine, its diastereoisomers (alpha-sparteine and beta-sparteine), and two related tricyclic diamines were investigated with the density functional theory ansatz B3LYP and HF-MP2 method. With the exception of beta-sparteine, these free molecules are structurally simple, since one conformer predominates both in the gas phase and in solution. The mono-protonated forms of all these molecules are characterized by intramolecular asymmetric hydrogen bonds. The di-protonated species have the same structural preferences as the parent free bases. All the theoretical structural predictions are consistent with the available experimental results. The NMR chemical shifts, calculated by the continuous set of gauge transformations formalism with the DFT/B3LYP method, are fairly consistent with NMR observation. The He(I) photoelectron spectra were measured and assigned by means of ab initio outer valence Green's function calculations. The overwhelming predominance of the lowest-energy conformer of all compounds is confirmed by various spectroscopic results. However, the structure of beta-sparteine is very special. The C-13 NMR spectra in solution at room temperature are indicative of an effective C-2 molecular symmetry. From the analysis of the NMR spectra from +20 to -85degreesC it is inferred that the most stable C-1 conformer of beta-sparteine is almost exclusively present in solution. At room temperature, it rapidly interconverts between two enantiomeric forms to produce the NMR spectrum of a time-averaged C-2 conformer. (C) 2003 Elsevier B.V. All rights reserved.