The gas-phase basicities (GBs) of nornicotine, nicotine, and model pyrrolidines have been measured by FT-ICR. These experimental GBs are compared with those calculated (for the two sites of protonation in the case of nicotine and nornicotine) at the B3LYP/6-311+G(3df,2p)//B3LYP/6-31G(d,p) level, or those estimated from substituent effects on the GBs of 2-substituted pyrrolidines, 2-substituted N-methylpyrrolidines, and 3-substituted pyridines. It is found that, in contrast to the Nsp(3) protonation in water, in the gas phase nornicotine is protonated on the pyridine nitrogen, because the effects of an intramolecular CH.Nsp(3) hydrogen bond and of the polarizability of the 3-(pyrrolidin-2-yl) substituent add up on the Nsp(2) basicity, while the polarizability effect of the 2-(3-pyridyl) substituent on the Nsp(3) basicity is canceled by its field/inductive electron-withdrawing effect. The same structural effects operate on the Nsp(3) and Nsp(2) basicities of nicotine, but here, the polarizability effect of the methyl group puts the pyrrolidine nitrogen basicity very close to that of pyridine. Consequently, protonated nicotine is a mixture of the Nsp(3) and Nsp(2) protonated forms.

This microreview focuses on recent applications of the ring‐closing metathesis reaction (RCM) to construct piperidine and pyrrolidine cores for the total synthesis of natural alkaloids. The most recent examples are described, from simple piperidine alkaloids to complex pentacyclic structures such as (+)‐tabersonine. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

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A new Ru complex containing the deprotonated 2,2':6',2''-terpyridine,6,6''-diphosphonic acid (H4tPa) and pyridine (py) of general formula, [Ru II (H3tPa--N 3 O)(py)2] + , 2 + , has been prepared and thoroughly characterized by means of spectroscopic, electrochemical techniques, X-ray diffraction analysis and with DFT calculations. Complex 2 + , presents a dynamic behavior in the solution that involves the synchronous coordination and the decoordination of the dangling phosphonic groups of the tPa 4ligand. However, at oxidation state IV complex 2 + , it becomes seven coordinated with the two phosphonic groups now bonded to the metal center. Further, at this oxidation state at neutral and basic pH, the Ru complex undergoes coordination of an exogenous OHgroup from the solvent that leads to an intramolecular aromatic O-atom insertion into the CH bond of one of the pyridyl groups forming the corresponding phenoxo-phosphonate Ru complex [Ru III (tPaO--N 2 OPOC)(py)2] 2 , 4 2 , where tPaO 5is 3-hydroxo-[2,2':6',2''-terpyridine]-6,6''-diyl)bis(phosphonate) ligand. This new in situ generated Ru complex, 4 2-, has been isolated and spectroscopically and electrochemically characterized. In addition, a crystal structure has been also obtained using single crystal X-ray diffraction techniques. Complex 4 2turns out to be an exceptional water oxidation catalyst achieving record high TOFmax in the order of 16,000 s -1 . A mechanistic analysis complemented with DFT calculations has also been carried out showing the critical role of intramolecular second coordination sphere effects exerted by the phosphonate groups in lowering the activation energy at the rate-determining step.

An enantiomeric synthesis of six piperidine and pyrrolidine alkaloids, (S)-nornicotine 1, (S)-nicotine 2, (S)-anatabine 3, (S)-N-methylanatabine 4, (S)-anabasine 5, and (S)-N-methylanabasine 6, known as natural products in tobacco, was established from a common chiral homoallylic (S)-3-(1-azido-but-3-enyl)-pyridine 15. An intramolecular hydroboration-cycloalkylation of the homoallylic azide intermediate 15 served as the key step in the pyrrolidine ring formation. A ring closing metathesis reaction (RCM) of a diethylenic amine intermediate (S)-allyl-(1-pyridin-3-yl-but-3-enyl)-carbamic acid benzyl ester 20 served as the key step in the piperidine ring formation. From the commercially available 3-pyridinecarboxaldehyde 13, a short and convenient enantiomeric synthesis of tobacco alkaloids is described: (S)-nornicotine 1 (5 steps, with an overall yield of 70%), (S)-nicotine 2 (6 steps, 65%), (S)-anatabine 3 (8 steps, 30%), (S)-N-methylanatabine 4 (8 steps, 25%), (S)-anabasine 5 (8 steps, 35%), and (S)-N-methylanabasine 6 (8 steps, 25%).

Since the discovery of nojirimycin, a glycosidase inhibitor, polyhydroxylated piperidines (also called azasugars: the ring O‐atom of a carbohydrate is replaced by nitrogen) have attracted considerable attention and have been the target of numerous synthetic strategies during the last decade. The efficient synthesis of naturally occurring azasugars and their analogs is of considerable importance due to their potential glycosidase inhibitor properties. Some of them have been widely investigated as candidates for drugs to treat a variety of carbohydrate‐mediated diseases such as diabetes, viral infections, including HIV, cancer metastasis, hepatitis, and Gaucher’s disease. This microreview focuses on recent syntheses of azasugars. In addition, the biology of these compounds is briefly considered. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

The thermodynamics of the hydrogen-bonding complexation of the acetylcholine agonists nicotine and nornicotine and of model pyridines, pyrrolidines, and N-methylpyrrolidines has been measured in CCl(4) by FTIR spectrometry toward a reference hydrogen-bond donor, 4-fluorophenol. Various methods are devised for measuring separately the hydrogen-bond acceptor strength of each nitrogen of nicotine and nornicotine: variation of the stoichiometry of complexation; correlations with electrostatic potentials on nitrogens and with substituent constants in the series of 3-substituted pyridines, 2-substituted pyrrolidines, and 2-substituted N-methylpyrrolidines; and linear free energy relationships between 4-fluorophenol and hydrogen fluoride hydrogen-bonded complexes. It is consistently found that nicotine and nornicotine have two active hydrogen-bond acceptor sites, the pyridine and pyrrolidine nitrogens, and that ca. 90% (for nicotine) and 80% (for nornicotine) of the 1:1 hydrogen-bonded complexes are formed to the pyridine nitrogen, although the pyrrolidine nitrogen is the first protonation site of nicotine and nornicotine in water. The low hydrogen-bond basicity of the pyrrolidine nitrogen in nicotine is mainly explained by the inductive electron-withdrawing and steric effects of the 2-(3-pyridyl) substituent. The partition of the Gibbs energy of the isomerism of complexation (AH...Nsp(2) <==> AH...Nsp(3)) into enthalpic and entropic contributions shows that the selectivity in favor of the pyridine nitrogen is driven by entropy. It is important to recognize the bifunctionality of nicotine in hydrogen bonding for understanding its lipophilicity and molecular recognition in non protonic media. When monoprotonated on their sp(3) nitrogen, nicotine and nornicotine keep, through their sp(2) nitrogen, a significant hydrogen-bond basicity which is greater than that of the ester group of acetylcholine.

The transacting transcriptional activator (Tat) is a viral protein essential for activation of the human immunodeficiency virus (HIV) genes, and it plays an important role in HIV induced immunodeficiency. We report the NMR structural characterization of the active Tat Mal variant that belongs to a highly virulent D-subtype HIV type-1 (HIV-1) strain (Mal) found mainly in Africa. A full Tat Mal protein (87 residues) is synthesized. This synthetic protein is active in a transactivation assay with HeLa cells infected with the HIV long terminal repeated noncoding sequences of the HIV-1 provirus (LTR) lac Z gene. Homonuclear (1)H-NMR spectra allows the sequential assignment of the Tat Mal spin systems. Simulating annealing generates 20 conformers with similar folding. The geometry of the mean structure is optimized with energy minimization to obtain a final structure. As the European variant (Tat Bru) the N-terminal region of Tat Mal constitutes the core, and there is a hydrophobic pocket composed of the conserved Trp 11 interacting with several aromatic residues. The two functional regions of Tat (basic and the cysteine-rich regions) are well exposed to the solvent. A short alpha-helix is observed in region V adjacent to the basic region. This alpha helix induces local structural variations compared to the NMR structure of Tat Bru, and it brings the cysteine-rich and basic regions closer. This study suggests that similar folding exists among Tat variants.