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PubMed2002

Obsessive-compulsive-bipolar comorbidity: a systematic exploration of clinical features and treatment outcome.

BACKGROUND: Notwithstanding the emerging literature on comorbidity between obsessive-compulsive disorder (OCD) and bipolar disorder, relatively few systematic data exist on the clinical characteristics of this interface and its treatment. The aim of the present study is to address this challenge as it appears in a setting of routine clinical practice. METHOD: The sample comprised 68 patients with comorbid DSM-IV diagnoses of OCD and major depressive episode admitted and treated at the day-hospital in the Department of Psychiatry at the University of Pisa (Pisa, Italy) during a 3-year period (January 1995-December 1998). Thirty-eight patients (55.8%) showed lifetime comorbid bipolar disorder (12 [31.6%] bipolar I and 26 [68.4%] bipolar II). Diagnoses and clinical features were collected by means of structured (Structured Clinical Interview for DSM-IV) and semistructured interviews (OCD-Interview). Assessments of drug treatments, clinical outcome, and adverse effects were made prospectively as part of routine clinical care throughout the course of their day-hospitalization. RESULTS: In contrast with non-bipolar OCD patients, OCD-bipolar patients showed a more episodic course with a greater number of concurrent major depressive episodes. They reported a significantly higher rate of sexual obsessions and significantly lower rate of ordering rituals. Furthermore, they reported more frequent current comorbidity with panic disorder-agoraphobia and abuse of different substances (alcohol, sedatives, nicotine, and coffee). Drug treatment with clomipramine and, to a lesser extent, with selective serotonin reuptake inhibitors was associated with hypomanic switches in OCD-bipolar patients, especially in those not concomitantly treated with mood stabilizers. A combination of multiple mood stabilizers was necessary in 16 OCD-bipolar patients (42.1%) and a combination of mood stabilizers with atypical antipsychotics was required in 4 cases (10.5%). OCD-bipolar patients tended to show a less positive outcome for mood symptomatology and general functioning. Three patients required hospitalization for severe mixed episode. CONCLUSION: In a tertiary care center, comorbidity between OCD and bipolar disorder is a significant clinical problem affecting a large number of patients and has a substantial impact on the clinical characteristics and treatment outcome of both disorders.

Adolescent↗

PubMed1992

[Intravenous peripheral digital subtraction angiography after stabilization of medial femoral neck fractures. Results and value].

In patients with medial femoral neck fractures the condition of the blood vessels is the decisive factor as to whether or not femoral capital necrosis will develop. Therefore, conventional angiography has been used both preoperatively for the diagnostic work-up and for selecting the best mode of management and postoperatively for prognostic purposes. Its routine use has, however, been limited by the long examination time, the complexity of the technique and the potential complications. Peripheral intravenous digital subtraction angiography (DSA) for imaging peripheral vessels is a far less demanding procedure. Its usefulness was studied postoperatively in 7 patients. The vascular information obtained was inferior to that of conventional angiography because of the inherently poorer vessel imaging qualities. Moreover, since its applicability is limited to patients with a completely intact cardiovascular system and normal cardiac output, it is not suitable for most geriatric patients. It is, therefore, concluded that peripheral intravenous DSA cannot (yet) be recommended as a routine procedure. It remains to be seen whether technical improvements in system features will improve the diagnostic performance.

Adult↗

PubMed1989

Buoyant density and lipid composition of purified myelin of aging human brain.

Purified myelin of human brain from 15 young adult (below 50 years of age) and old (above 70 years of age) autopsy cases each was examined by isopycnic centrifugation in continuous sucrose gradients, and for lipid composition. The mean buoyant density of myelin was the same in both groups. Apparent features of old age were a wide range of density values, less compact myelin bands, and the dissociation of myelin into two bands in six of 15 old cases. Lipid analyses of randomly selected myelin samples of each group revealed an inverse relationship between the total lipid to protein ratio and density of myelin. In old age total lipids decreased by an average 10 mol lipid per mol protein. This decrease was accounted for by cholesterol, phosphatidylserine and cerebrosides. Changes in fatty acid moieties mainly affected sphingolipids. C20:0 and C24:0 of sphingomyelin increased, as did even more markedly the more hydrophilic OH-fatty acids of cerebrosides. Correlations with buoyant density existed for the ratios of cholesterol to protein in young adult cases, and those of galactolipids to protein in old cases. The results suggest that old age is associated with impaired stability and altered lipid composition of myelin.

Adolescent↗

PubMed1999

An internal open reading frame triggers nonsense-mediated decay of the yeast SPT10 mRNA.

Yeast cells containing a temperature-sensitive mutation in the PRT1 gene were found to selectively stabilize mRNAs harboring early nonsense codons. The similarities between the mRNA decay phenotypes of prt1-1 cells and those lacking the nonsense-mediated mRNA decay (NMD) factor Upf1p led us to determine whether both types of mutations cause the accumulation of the same mRNAs. Differential display analysis and mRNA half-life measurements demonstrated that the HHF2 mRNA increased in abundance in prt1-1 and upf1Delta cells, but did not manifest a change in decay rate. In both mutant strains this increase was attributable to stabilization of the SPT10 transcript, an mRNA encoding a transcriptional regulator of HHF2. Analyses of chimeric mRNAs used to identify the cis-acting basis for NMD of the SPT10 mRNA indicated that ribosomes scan beyond its initiator AUG and initiate at the next downstream AUG, resulting in premature translation termination. By searching a yeast database for transcripts with sequence features similar to those of the SPT10 mRNA, other transcripts that decay by the NMD pathway were identified. Our results demonstrate that mRNAs undergoing leaky scanning are a new class of endogenous NMD substrate, and suggest the existence of a novel cellular regulatory circuit.

5' Untranslated Regions↗

PubMed2002

Fluorescence data analysis on gel-based biochips.

A series of biochip readers developed for gel-based biochips includes three imaging models and a novel nonimaging biochip scanner. The imaging readers, ranging from a research-grade versatile reader to a simple portable one, use wide-field objectives and 12-bit digital large-coupled device cameras for parallel addressing of multiple array elements. This feature is valuable for monitoring the kinetics of sample interaction with immobilized probes. Depending on the model and the label used, the sensitivity of these readers approaches 0.3 amol of a labeled sample per gel element. In the selective scanner, both the spot size of the excitation laser beam and the detector field of view match the size of the biochip array elements so that the whole row of the array can be read in a single scan. The portable version reads 50-mm long, 150-element, one-dimensional arrays in 5 s. With a dynamic range of 4000:1, a sensitivity of 1-5 amol of a labeled sample per gel element, and a data format facilitating online processing, the scanner is an attractive, inexpensive solution for biomedical diagnostics. Fluorophores for sample labeling were compared experimentally in terms of detection sensitivity, influence on duplex stability, and suitability for multilabel analysis and thermodynamic studies. Texas Red and tetracarboxyphenylporphyn proved to be the best choice for two-wavelength analysis using the imaging readers.

Fluorescent Dyes↗

PubMed2003

[Clinical study on applying brainstem auditory evoked potential to monitor anesthesia depth and awaken in children].

OBJECTIVES: To study applying auditory brainstem reaction (ABR) to monitor the general anesthesia depth and awaken degree in children as an objective guide. METHODS: Forty-five infant or children patients, American Society of Anesthesiologists(ASA) graded I-II, with normal audition, were selected and divided into 3 groups (15 cases per group) to receive propofal venous anesthesia, fentanyl venous anesthesia, or isoflurane anesthesia, respectively. During anesthesia, peak latencies (PL) of I, III, V wave, and interpeak latencies (IPL) of I-III, III-V, I-V were monitored and recorded after short sound stimulation of 90 db which accumulated 1,000 times with Madsen. The changing of PL and IPL with time passing and anesthesia dosage was studied to discuss the feature of ABR in each anesthesia procedure as above. RESULTS: There is a significant positive correlation between PL and IPL of ABR waves as above and the dosage of propofol or the concentration of isoflurane. The dosage or the concentration increased, and PL and IPL prolonged. It is important of PL of wave I to reflect anesthesia degree. It is wave V with the best stability and correlation to monitor anesthesia degree. After anesthesia period or patients almost awaken, PL and IPL of some ABR waves were still more than normal values, which is detention reaction. For the fentanyl anesthesia, ABR is not sensible enough, i.e. has little correlation. CONCLUSION: The changing of PL and IPL of ABR waves could conclude anesthesia degree in children and be treated as reference of whether awaken or not in some certain, but have possibility of detention reaction.

Anesthesia Recovery Period↗

PubMed2005

An active enzyme constructed from a 9-amino acid alphabet.

Nature employs a set of 20 amino acids to produce a repertoire of protein structures endowed with sophisticated functions. Here, we combined design and selection to create an enzyme composed entirely from a set of only 9 amino acids that can rescue auxotrophic cells lacking chorismate mutase. The simplified protein captures key structural features of its natural counterpart but appears to be somewhat less stable and more flexible. The potential of a dramatically reduced amino acid alphabet to produce an active catalyst supports the notion that primordial enzymes may have possessed low amino acid diversity and suggests that combinatorial engineering strategies, such as the one used here, may be generally applied to create enzymes with novel structures and functions.

Amino Acid Sequence↗

PubMed1996

In vivo repair of 3'-end deletions in a TCV satellite RNA may involve two abortive synthesis and priming events.

RNA viruses that do not have the stabilizing features of poly(A) tails or amino acids covalently linked to their 3' ends must develop other means for protecting or repairing their genomes from damage caused by cellular RNases. We previously found that deletions in the single-stranded tails of a satellite RNA (sat-RNA D) associated with turnip crinkle virus are repaired in vivo (C. D. Carpenter and A. E. Simon, 1996, J. Virol. 70, 478-486). We now extend this analysis to show that sat-RNA D transcripts with 3'-end deletions of 5 bases give rise to wild-type sat-RNA, while deletions of 6 to 11 bases result in sat-RNA with additional deletions to the -14 position joined to internal TCV genomic RNA (or other) sequence followed by replacement of the terminal C1-2UGC1-3 motif. In addition, we have determined that the selection of internal TCV sequence used in the repair of sat-RNA D 3' ends is not random and generation of these short TCV segments likely involves primer-mediated synthesis of abortive products facilitated by base-pairing between internal regions of TCV genomic RNA and oligoribonucleotides generated by abortive cycling from the 3' end of the TCV genome.

Carmovirus↗

PubMed2003

Early-age-at-onset colorectal cancer and microsatellite instability as markers of hereditary nonpolyposis colorectal cancer.

PURPOSE: Early-age-at-onset colorectal cancer and microsatellite instability are characteristic features of hereditary nonpolyposis colorectal cancer. Our aim was therefore to investigate whether these features might be useful markers in screening for hereditary nonpolyposis colorectal cancer and mismatch repair gene mutations. METHODS: From 1,132 consecutive patients who underwent surgery for colorectal cancer at our department between 1980 and 1999, we selected all patients 40 years of age or younger (study group, n = 59) and a subset of patients 40 years of age or older (control group, n = 60) who were matched for gender and pathologic TNM stage. Patients for whom a complete family cancer history or microsatellite status was unavailable were excluded from the study. Family cancer histories, retrieved from archival charts, were reassessed. Microsatellite status was investigated with the five microsatellites from the Bethesda recommended panel (BAT-26, BAT-25, D2S123, D5S346, and D17S250). On the basis of the number of altered microsatellites (> or = 2, 1, or 0), tumors were considered as having high or low instability or microsatellite stability, respectively. Mutation analysis for MLH1 and MSH2 genes was performed only in cases of high instability. DNA was investigated for mutations by single-strand conformational polymorphism and sequencing analysis. RESULTS: Data from 95 patients (study group: n = 37, 18 males, mean age 35 years; control group: n = 58, 29 males, mean age 62 years) were available for analysis. Four patients (study group, n = 3; control group, n = 1) fulfilled the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. Of the 37 study group tumors, 12 (32.4 percent) showed high-frequency microsatellite instability, and 25 had microsatellite stability, whereas among the 58 control group tumors, 4 (7 percent) showed high-frequency microsatellite instability, and 54 had microsatellite stability (P < 0.002). Mismatch repair gene mutation analysis was performed in 12 cases (study group, n = 7; control group, n = 5). We found four mutations (MSH2 119delG, MLH1 ex9 684insT, MSH2 Gln239Stop, and MLH1 del0.8 Kb) in the study group patients and none in the control group. Of four hereditary nonpolyposis colorectal cancer patients who underwent mismatch repair gene mutation analysis, one had a mutation. CONCLUSIONS: Early-age-at-onset colorectal cancer is significantly correlated with high-frequency microsatellite instability tumor status and is a useful criterion to identify hereditary nonpolyposis colorectal cancer patients. Moreover, when used in association with high-frequency microsatellite instability status, it is effective in selecting patients for mismatch repair gene mutation analysis.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Solution structural study of a DNA duplex containing the guanine-N7 adduct formed by a cytotoxic platinum-acridine hybrid agent.

[PtCl(en)(ACRAMTU-S)](NO(3))(2) (PT-ACRAMTU; en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea) is a dual metalating/intercalating DNA binding drug conjugate that shows cytotoxicity at micromolar to nanomolar concentrations in a wide range of solid tumor cell lines. In approximately 80% of its adducts, PT-ACRAMTU binds to guanine-N7 in the major groove, selectively at 5'-CG sites [Budiman, M. E. et al. (2004) Biochemistry 43, 8560-8567]. Here, we report the synthesis, physical characterization, and NMR solution structure of a site-specifically modified octamer containing this adduct, 5'-CCTCGTCC-3'/3'-GGAGCAGG-5', where the asterisk indicates the [Pt(en)ACRAMTU)](3+) fragment. The structure was determined by a combination of high-resolution 2-D NMR spectroscopy and restrained molecular dynamics/molecular mechanics (rMD/MM) calculations using 179 NOE distance restraints and refined to an r(6) weighted residual (R(x)) of 9.2 x 10(-)(2) using the complete relaxation matrix approach. An average structure was calculated from the final ensemble of 19 rMD geometries showing pairwise root-mean-square deviations of <1.05 A. The dual binding increases the thermal stability of the octamer compared to the unmodified duplex (DeltaT(m) = 13.2 degrees ). The modified sequence shows structural features reminiscent of both B- and A-type DNA. Watson-Crick hydrogen bonding is intact at and beyond the adduct site. Platinum is bound to the N7 position of G5 in the major groove, and ACRAMTU intercalates into the central 5'-C4G5/C12G13 base-pair step on the 5'-face of the platinated nucleobase. The chromophore's long axis is aligned with the long axes of the adjacent base pairs, maximizing intermolecular pi-pi stacking interactions. PT-ACRAMTU lengthens (rise, 6.62 A) and unwinds (twist, 15.4 degrees ) the duplex at the central base-pair step but does not cause helical bending. No C3'-endo deoxyribose pucker and no significant roll are observed at the site of intercalation/platination, which clearly distinguishes the PT-ACRAMTU-induced damage from the 1,2-intrastrand cross-link formed by cisplatin. Overall, the DNA perturbations produced by PT-ACRAMTU do not appear to mimic those caused by the major cisplatin lesion. Instead, intriguing structural similarities are observed for PT-ACRAMTU's monoadduct and the N7 adducts of dual major-groove alkylating/intercalating antitumor agents, such as the pluramycins.

Acridines↗

PubMed2001

Synthesis and evaluation of novel fluorogenic substrates for the detection of bacterial beta-galactosidase.

AIMS: A widely used coumarin derivative is 7-hydroxy-4-methylcoumarin-beta-D-galactoside (4-methylumbelliferone-beta-D-galactoside; 4-MU-GAL). This galactoside is utilized as a substrate for the detection of the beta-galactosidase activity of coliform bacteria in water analysis. The intense fluorescence of coumarin-based molecules has enabled them to be incorporated into enzyme-based tests for the quantitative assay of indicator bacteria. The aim of this present study was to evaluate the potential of other coumarin derivatives, by synthesis of a selection of core coumarin molecules. METHODS AND RESULTS: Several coumarin derivatives were found to be more promising than 4-MU, with ethyl-7-hydroxycoumarin-3-carboxylate (EHC) giving a combination of greater fluorescence over a broad pH range and reduced growth inhibition with 12 representative coliform strains. On conversion to a beta-galactoside derivative, EHC-GAL generated a more rapid fluorescence than any other tested substrate. CONCLUSIONS: When tested in a broth assay format, based on most probable number (MPN), low numbers of coliforms were detected with EHC-GAL around 1 h earlier than with 4-MU-GAL. SIGNIFICANCE AND IMPACT OF THE STUDY: The present study suggests that EHC-GAL should be evaluated as a substrate for the detection of coliforms in water analysis, due to a combination of the following favourable features: (i) reduced toxicity; (ii) increased fluorescence; (iii) pH stability of fluorescence; and (iv) rapid detection.

Bacteriological Techniques↗

PubMed2000

Tertiary core rearrangements in a tight binding transfer RNA aptamer.

Guided by an in vitro selection experiment designed to obtain tight binding aptamers of Escherichia coli glutamine specific tRNA (tRNAGln) for glutaminyl-tRNA synthetase (GlnRS), we have engineered a tRNA mutant in which the five-nucleotide variable loop sequence 5'-44CAUUC48-3' is replaced by 5'-44AGGU48-3'. This mutant tRNA binds to GlnRS with 30-fold improved affinity compared to the wild type. The 2.7 A cocrystal structure of the RNA aptamer-GlnRS complex reveals major rearrangements in the central tertiary core of the tRNA, while maintaining an RNA-protein interface identical to the wild type. The repacked RNA core features a novel hydrogen bonding arrangement of the trans Levitt pair G15-U48, a new sulfate binding pocket in the major groove, and increased hydrophobic stacking interactions among the bases. These data suggest that enhanced protein binding to a mutant globular RNA can arise from stabilization of RNA tertiary interactions rather than optimization of RNA-protein contacts.

Amino Acyl-tRNA Synthetases↗

PubMed2000

Potential diagnostic, prognostic and therapeutic implications of some new regulatory proteins in hematologic malignancies.

Multiple cell surface receptors play an important role in the biology of hematological malignant cells. Like already clustered monoclonal antibodies, the use of new markers of differentiation provide some new information about their structure and function. Here we consider the role of few selected regulatory proteins that are most frequently involved in the processes of activation, cell differentiation and proliferation of human hematological malignant cells. These molecules, being either lineage-restricted or multi-lineage cell activation ones, are involved in cell-cell and cell-matrix communications. They are involved in various leukocyte functions such as mobility, interaction with endothelium, and homing. Since physiologic cell growth involves not only cell division, but also programmed-cell death, we considered some apoptosis-regulatory molecules implicated in the clinical heterogeneity of hematological malignancies. The presence or absence of staining for these molecules is not only an important discriminatory immunophenotypic feature, but it appears useful also for prognosis and particularly in an experimental therapeutical setting. The prognostic significance of cell-expression of these molecules has not yet been clearly established, but it might be helpful in the evaluation of stability and progression of the disease.

Antigens, CD↗

PubMed2005

The novel lipophilic camptothecin analogue gimatecan is very active in vitro in human neuroblastoma: a comparative study with SN38 and topotecan.

Neuroblastoma is one of the most common extracranial solid tumours in childhood with a poor prognosis in its advanced stage. Treatment failure is often associated to the occurrence of drug resistance. To date, treatment of paediatric neuroblastoma is still dismal, and therefore novel effective drugs are awaited. In recent years, an increasing interest has concentrated on camptothecin analogues. Topotecan and irinotecan, the only two clinically relevant camptothecin derivatives to date, have entered clinical trials in neuroblastoma but so far the results have been disappointing. Gimatecan (ST1481, LBQ707; 7-t-butoxyiminomethylcamptothecin), is a novel lipophilic camptothecin derivative that was selected from a series of lipophilic analogues rationally designed and synthesized in order to overcome some of the main drawbacks of conventional camptothecins, limiting their clinical efficacy. Gimatecan is endowed with potent antitumour activity, strong topoisomerase I inhibition, stable drug-target interactions and a better pharmacological profile. The present study deals with the comparative evaluation of cellular pharmacology features of gimatecan, topotecan and SN38 in neuroblastoma cell lines. We show that, despite the lowest intracellular accumulation, gimatecan was the most active among the camptothecin analogues studied. Our findings suggest that the high activity of gimatecan in neuroblastoma is related to the ability of this novel analogue to cause a very high number of DNA breaks as assessed by the Comet assay in both cellular or sub-cellular systems. We propose that DNA strand breaks efficiency as measured by the Comet assay might provide important information about the stability of the ternary complexes induced by camptothecin compounds.

Antineoplastic Agents↗

PubMed2006

IR spectra of photopolymerized C60 films. Experimental and density functional theory study.

IR spectra of photopolymerized fullerene films obtained by simultaneous deposition and UV irradiation were measured in the range of 1500-450 cm(-1). The degree of the polymerization of the C60 films was estimated to be about 95%. To assist the assignment of the experimental IR spectra of the films, quantum chemical calculations of the equilibrium structures of the C60 dimers and trimers were performed at the DFT(B3LYP)/3-21G level of theory. Next, IR frequencies and intensities for those structures were calculated. For the five-trimer structures found in the calculations, the relative stabilities were determined at the B3LYP/4-31G and B3LYP/6-31G levels and used to select the lowest-energy trimers, which are Trimer A (angle between monomer centers is 90 degrees ) and Trimer B (angle between monomer centers is 120 degrees). Next, the IR spectra of the polymerized fullerene films were compared with the calculated frequencies of the lowest-energy dimer and the two lowest-energy trimers. On the basis of this analysis and on the comparison of the film spectra with the IR spectra of the C60 dimer and trimer spectra obtained by other methods, it was shown that the main components of the films are C60 dimers and the orthorhombic (O) polymer phase. The tetragonal (T) and rhombohedral (R) polymers, as well as small amounts of monomers, were also found. Although vibrational frequencies of different C60 phases are similar in most cases, we found several unique spectral features of the C60 dimer and other polymers that may be used to determine the composition of the polymerized C60 film.

Fullerenes↗

PubMed2001

Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia.

Dementia lacking distinctive histopathology (DLDH) or frontotemporal lobe degeneration (FTLD) is the most common neuropathological diagnosis for sporadic frontotemporal dementias (FTDs). The hallmarks of DLDH are neuron loss and gliosis in the absence of any disease-specific brain lesion. Similar brain pathology is also seen in a familial FTD pedigree known as hereditary dysphasic disinhibition dementia 2 (HDDD2). Abnormality in the function or isoform composition of the microtubule binding protein tau is a prominent feature in the brains of many patients with sporadic and hereditary FTDs. Therefore, we studied the tau protein in different brain regions from DLDH and HDDD2 patients. Our results indicate that a selective loss of all six tau isoforms, but not tau mRNA, occurs in these brains compared to normal control and Alzheimer's disease brains. Loss of tau protein was identified by Western blot analysis of protein extracts from DLDH and HDDD2 brains in regions both with and without neuronal degeneration. Functionally, this loss of tau protein may be equivalent to pathogenic mutations in the tau gene identified in familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). Thus, DLDH and HDDD2 are novel tauopathies with a unique mechanism of pathogenesis. The presence of tau mRNA in these brains suggests that the level of tau protein may be controlled posttranscriptionally, at the level of either translation or mRNA stability.

Aged↗

PubMed2006

Phagocytosis in atherosclerosis: Molecular mechanisms and implications for plaque progression and stability.

Macrophages play a key role in atherosclerotic plaque destabilization and rupture. In this light, selective removal of macrophages may be beneficial for plaque stability. However, macrophages are phagocytic cells and thus have an important additional role in scavenging of modified lipoproteins, unwanted or dead cells and cellular debris via phagocytosis. The concept of phagocytosis as well as the underlying mechanisms is well defined but the effect of phagocytosis in terms of plaque stability remains poorly understood. Recent findings point towards a complex role of macrophage phagocytosis in atherogenesis. Macrophages are necessary for removal of apoptotic cells from plaques, but exert strong proatherogenic properties upon phagocytosis of lipoproteins, erythrocytes and platelets. Apart from heterophagy, autophagocytosis better known as autophagy may occur in advanced atherosclerotic plaques. Several lines of evidence indicate that autophagy is initiated in plaque smooth muscle cells as a result of cellular distress. Since autophagy is well recognized as a survival mechanism, autophagic smooth muscle cells in the fibrous cap may reflect an important feature underlying plaque stability. All together, phagocytosis is a crucial process involved in atherogenesis that may significantly affect the stability of the atherosclerotic plaque.

Animals↗

PubMed2006

Intramolecular Diels-Alder reactions of ester linked 1,3,9-decatrienes: cis/trans selectivity in thermal and Lewis acid promoted reactions of ethylene-tethered and benzo-tethered systems.

High cis (i.e., endo) diastereoselectivities are witnessed in heat-promoted intramolecular Diels-Alder (IMDA) reactions of ethylene-tethered hexadienyl acrylates. The cis stereoselectivity is improved by promotion with Et2AlCl. The first examples of Et2AlCl catalyzed intramolecular Diels-Alder reactions of ester-activated dienophiles are reported. In contrast, the corresponding benzo-tethered hexadienyl acrylates undergo moderately trans (i.e., exo) selective IMDA reactions. Very high trans stereoselection is obtained upon promotion with ATPH. The outcomes of these reactions are essentially insensitive to dienophile (C10) geometry and substitution. DFT (B3LYP/6-31+G(d)) computed cis/trans product distributions-based on Boltzmann transition structure populations-are in good agreement with the experimental results. These computational investigations provide useful insights into the origins of stereoselection in these systems. The stereoselectivity exhibited by the ethylene-tethered hexadienyl acrylates is ascribed to stabilizing secondary orbital interactions at play in the cis-transition structures (TSs). In the benzo-tethered series, this effect is overridden by stabilizing pi-conjugative interactions, between the benzo moiety and the 1,3-diene component, which are stronger in trans TSs, compared to the cis TSs. The computed TS geometries generally exhibit advanced peripheral bond forming asynchronicity, with the tether carbonyl group in conjugation with the dienophile. Such TS features significantly weaken the stereodirecting influence of terminal dienophile substituents.

Acids↗