Efficient enantiomeric synthesis of pyrrolidine and piperidine alkaloids from tobacco

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%).     

Cystic fibrosis: CFTR correctors to the rescue

Cystic fibrosis transmembrane conductance regulator (CFTR) correctors are small molecules that target the most common cause of cystic fibrosis: misfolded F508del-CFTR. Using differential scanning fluorimetry, Sampson et?al. (2010) identify a CFTR corrector that interacts directly with the CFTR domain affected by the F508del mutation.     

Cystic fibrosis proteins detected by electrophoretic techniques

For the detection of the cystic fibrosis protein (CFP) in serum of cystic fibrosis (CF) carriers, thin-layer polyacrylamide gel isoelectric focusing proved inappropriate as a diagnostic test, but was useful for screening fractions on purification of CFP by chromatofocusing on a Mono P column. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis an Mr 12,000 protein (P12) was found in most CFP-positive sera, indicating good correlation between these two CF-associated proteins. Detection of the P12 protein by sodium dodecyl sulfate-polyacrylamide gel electrophoresis was well reproducible and less delicate than IEF. The technique was also used to purify P12 from serum by two successive preparative electrophoresis steps in a 7.5-15% gradient and 15% homogeneous gel. The use of silver staining revealed that P12, which was present in all sera of CF patients and carriers with variable intensities, was also present in trace amounts in normal sera.     

Cystic fibrosis and fragile X syndrome: the arguments for antenatal screening

The ultimate public health aim of genetic screening is prevention. This can be achieved by reducing birth prevalence through primary or secondary methods such as pre-conceptional or antenatal screening. Tertiary prevention by neonatal screening is also an option where there is direct unbiased evidence for a substantial improvement in prognosis. In addition to this, the information provided during screening is also of value, enabling individuals to make choices that otherwise would not have been available. Having elucidated the natural histories and genetic defects underlying two common, serious genetic disorders, cystic fibrosis and fragile X syndrome, considerable efforts have been channelled into ascertaining the most efficacious method of prevention. To date there is only indirect evidence to suggest that neonatal screening improves prognosis in cystic fibrosis. Similarly, treatment for fragile X syndrome is limited and therefore early identification of the disorder by neonatal screening is unlikely to improve long term outlook. Thus the focus of this review is on primary and secondary preventive methods.     

Synthesis and biological evaluation of guanidine-type iminosugars

The preparation of carbohydrate mimics in which the endocyclic oxygen has been replaced by a guanidine-type nitrogen atom is reported. The synthetic strategy involves the furanose --> piperidine rearrangement of 5-deoxy-5-guanidino-L-idose precursors. The reaction proceeds through elimination of water to give 3-oxopiperidines, which were isolated as the corresponding hydrates. Biological evaluation of the new glycomimetics evidenced a strong influence of the nature of the substituents at the nitrogen atoms on the glycosidase inhibitory properties.     

Chiral ionic liquids: synthesis, properties, and enantiomeric recognition

We have synthesized a series of structurally novel chiral ionic liquids which have a either chiral cation, chiral anion, or both. Cations are an imidazolium group, while anions are based on a borate ion with spiral structure and chiral substituents. Both (or all) stereoisomeric forms of each compound in the series can be readily synthesized in optically pure form by a simple one-step process from commercially available reagents. In addition to the ease of preparation, most of the chiral ILs in this series are liquid at room temperature with a solid to liquid transformation temperature as low as -70 degrees C and have relatively high thermal stability (up to at least 300 degrees C). Circular dichroism and X-ray crystallographic results confirm that the reaction to form the chiral spiral borate anion is stereospecific, namely, only one of two possible spiral stereoisomers was formed. Results of NMR studies including 1H{15N} heteronuclear single quantum coherence (HSQC) show that these chiral ILs exhibit intramolecular as well as intermolecular enantiomeric recognition. Intramolecularly, the chiral anion of an IL was found to exhibit chiral recognition toward the cation. Specifically, for a chiral IL composing with a chiral anion and a racemic cation, enantiomeric recognition of the chiral anion toward both enantiomers of the cation lead to pronounced differences in the NMR bands of the cation enantiomers. The chiral recognition was found to be dependent on solvent dielectric constant, concentration, and structure of the ILs. Stronger enantiomeric recognition was found in solvent with relatively lower dielectric constants (CDCl3 compared to CD3CN) and at higher concentration of ILs. Also, stronger chiral recognition was found for anions with a relatively larger substituent group (e.g., chiral anion with a phenylmethyl group exhibits stronger chiral recognition compared to that with a phenyl group, and an anion with an isobutyl group has the weakest chiral recognition). Chiral anions were also found to exhibit intermolecular chiral recognition. Enantiomeric discrimination was found for a chiral IL composed of a chiral anion and achiral cation toward another chiral molecule such as a quinine derivative.     

Cystic fibrosis: a label-free detection approach based on thermally modulated electrochemical impedance spectroscopy

Cystic fibrosis is one of the most common genetically inherited diseases in northern Europe, with the DF508 mutation being the most common, and among the Caucasian population being responsible for almost 70% of cases. In this work, we report on the use of thermally modulated electrochemical impedance spectroscopy for the discrimination of the DF508 mutation from the wild-type sequence. DNA probes (15 and 21 bases long) were immobilised on the surface of gold electrodes and the variation of the charge-transfer resistance was monitored as a function of hybridisation. Two sets of targets were used in this work: synthetic 15-mer sequences and two single-stranded synthetic analogues of PCR products 82 (mutant) and 85 (wild type) bases long. Hybridisation with short targets resulted in very sequence specific charge-transfer-resistance variation with a discrimination factor at room temperature between fully complementary and mismatched sequences of approximately fivefold. However, in the case of the single-stranded synthetic PCR product analogues, a lower discrimination factor was recorded (1.5-fold). The effect of temperature was investigated to improve discrimination and the use of a posthybridisation wash at elevated temperature resulted in a fivefold improvement in the discrimination factor. Using an electrode array with probes immobilised against each of the mutant and wild-type sequences, we achieved an unequivocal detection of the DF508 mutation.     

Combinatorial approaches to iminosugars as glycosidase and glycosyltransferase inhibitors

Oligosaccharide processing enzymes such as glycosidases and glycosyltransferases are important classes of biocatalysts involved in synthesising specific oligosaccharide structures on proteins and lipids. These enzymes are known to be involved in a wide range of important biological processes, such as intestinal digestion, post-translational processing of glycoproteins, lysosomal catabolism of glycoconjugates and inter-cellular recognition events. Inhibition of these enzymes can disrupt biosynthesis of oligosaccharides, thus interfering in all of these processes. Hence, "glyco-enzyme" inhibitors might have enormous therapeutic potential in many diseases such as viral infection, cancer and diabetes. This very important prospect has led to increasing interest and demand for these compounds. Interference in oligosaccharide processing is the basis for the anti-influenza neuraminidase inhibitors that have recently been marketed and also for the potential use of glycosidase inhibitors against HIV, Gaucher's disease, hepatitis, and cancer. Since a rational design and synthesis of inhibitors are often extremely difficult due to the limited information regarding the structure of the active site, combinatorial approaches are particularly promising. This review will focus on synthetic efforts for the preparation of combinatorial libraries of glyco-enzyme inhibitors.     

Enantiopure alkaloid analogues and iminosugars from proline derivatives: stereocontrol in sequential processes

An alternative to the use of expensive auxiliaries or catalysts in the synthesis of chiral 2-substituted pyrrolidines is described. Thus, commercial, cheap 4-(S)-hydroxyproline was readily transformed into optically pure pyrrolidines, using a one-pot decarboxylation-alkylation reaction as the key step. In this reaction, an acyliminium intermediate was generated, which was trapped by carbon nucleophiles. As postulated by Woerpel, the addition of the nucleophiles to the five-membered ring iminium ions took place stereoselectively, affording 2,4-cis-disubstituted pyrrolidines in high de. The hydroxy group at C-4 can then be removed, or alternatively, it can be used to create new functionalities in the molecule. In this way, optically pure alkaloid analogues and iminosugars were prepared.     

Fluorinated piperidine iminosugars and their N-alkylated derivatives: Synthesis,conformational analysis,immunosuppressive and glycosidase inhibitory activity studies

The fluorinated piperidine iminosugars 2a-4a and their N-octyl and N-decyl derivatives 2b,c-4b,c were synthesized from d-mannose/d-xylose using nucleophilic fluorination as the key step. The conformation of iminosugars 2/3, either ²C₅ or ⁵C₂, was assigned based on the ¹H NMR studies at different pH. Immunomodulatory activity of 2a,c-4a,c was examined using Mixed Lymphocyte Reaction (MLR) and B-cell assay. The N-alkylated fluorinated d-manno-iminosugars 3b/4b were found to be better immunosuppressive agents (IC₅₀?=?5–6?μM) on T-cells. The fluorinated iminosugar 3a/4a act as potent and selective inhibitors of β-glucosidase (IC₅₀?=?4–8?μM). The N-alkyl-iminosugars 4b-c were found to be moderate inhibitors of α-glucosidase (yeast) and α-galactosidase (coffee beans), respectively.     

Ferrocene‐modified thiopyrimidines: synthesis,enantiomeric resolution,antitumor activity

Ferrocenylalkyl thiopyrimidines ( 6a–d to 9a–d ) were prepared via the reaction of the α‐(hydroxy)alkyl ferrocenes, FcCHR(OH) ( 1a–d ; Fc = ferrocenyl; R = H, Me, Et, Ph), with 2‐thiopyrimidines ( 2 – 5 ) in acetone at room temperature in the presence of TFA, yielding 50–95%. The resulting enantiomers were resolved using HPLC on modified cellulose as chiral selector. The antitumor activities of S‐ferrocenylethyl 2‐thiopyrimidine ( 6b ) against two murine solid tumor models, carcinoma 755 (Ca755) and Lewis lung carcinoma (LLC) were evaluated in vivo. The strong antitumor effect of compound 6b on Ca755 and LLC was demonstrated. The index of tumor growth inhibition on Ca755 equaled 95% in comparison with control. Copyright © 2010 John Wiley & Sons, Ltd.     

A silver-lined anniversary of Fleet iminosugars: 1984–2009, from DIM to DRAM to LABNAc

The synthesis of iminosugars, polyhydroxylated N-heterocylces, has profoundly influenced the understanding of carbohydrate-processing and other enzyme systems. This review examines the prescient work over 25 years of one of the leading protagonists in the synthesis of these powerful compounds, examining strategy, detail and outcome.     

Synthesis, enantiomeric conformations, and stereodynamics of aromatic ortho-substituted disulfones

[structure in text] Aromatic ortho-disulfone derivatives are readily accessible from diiodide precursors by Cu(I)-mediated reactions with sodium sulfinate salts. The sulfone substituents adopt C(2)-symmetric enantiomeric conformations (lambda and delta) as evidenced by X-ray structural analysis and (1)H and (31)P NMR on chiral bis(sulfonyl)veratrol derivatives and hexacoordinated tris(benzenediolato)phosphate anions. Slow dynamic conformational isomerism (DeltaG(++) > or = 19.8 kcal mol(-1)) was detected in solution.     

Cyclopolymerization: Cyclization of diallylcyanamide to pyrrolidine derivatives

Free-radical addition of perfluoroalkyl iodides (R_FI) to diallylcyanamide gave cis- and trans-1-cyano-3-iodomethyl-4-(perfluoroalkyl)methylpyrrolidine (Ia,b). Five-membered ring products were preferentially formed in this reaction by other 1,6-dienes having terminal vinyl groups. This strongly suggests that cyclopolymerization of such monomers occurs in analogous fashion, instead of leading to 6-membered rings as has been previously understood. Dehydrohalogenation of Ia,b gave 3-methylenepyrrolidine derivatives as expected. Infrared and NMR spectra clearly show the exocyclic CH₂? group. The influence of reaction conditions on the yield of cyclization product Ia,b and certain side products was investigated.     

A short, efficient, and stereoselective total synthesis of a pyrrolidine alkaloid: (-)-codonopsinine

An efficient total synthesis of antibiotic (-)-codonopsinine 1 with an overall yield of 44% was achieved from d-alanine as a chiral template. The key steps in our strategy are modified Sharpless asymmetric dihydroxylation reaction and the highly stereoselective intramolecular acid-catalyzed amidocyclization.