The enantioselective synthesis of flavanones and chromanones is described. Bifunctional thiourea catalysts promote an asymmetric oxo-conjugate addition to a β-ketoester alkylidene in high yields with ...excellent enantioselectivity (80−94% ee) for aryl and alkyl substrates. Decarboxylation of the β-ketoester proceeds smoothly in a one-pot procedure to afford the enantioenriched flavanones and chromanones.
Multinuclear NMR spectroscopic studies at low temperature (−110 to −150 °C) revealed that lithium p-fluorophenolate and the lithium enolates of cyclohexanone, cyclopentanone and 4-fluoroacetophenone ...have tetrameric structures in THF/Et2O and THF/Et2O−HMPA by study of the effects of the addition of HMPA. The Z and E isomers of the lithium enolate of 1,3-bis-(4-fluorophenyl)-2-propanone (5F-Li) show divergent behavior. The Z isomer is completely dimeric in pure diethyl ether, and mostly dimeric in 3:2 THF/ether, where monomer could be detected in small amounts. TMTAN and PMDTA convert Z-5F-Li to a monomeric amine complex, and HMPA converts it partially to monomers, and partially to lithiate species (RO)2Li− and (RO)3Li2−. Better characterized solutions of these lithiates were prepared by addition of phosphazenium enolates (using P4-tBu base) to the lithium enolate in 1:1 ratio to form triple ion (RO)2Li− P4H+, or 2:1 ratio to form the higher lithiate (RO)3Li2− (P4H+)2) (quadruple ions). The E isomer of 5F-Li is also dimeric in 3:2 THF/Et2O solution, but is not detectably converted to monomer either by PMDTA or HMPA. In contrast to Z-5F-Li, the E isomer is tetrameric in diethyl ether even in the presence of excess HMPA. Thus for the two isomers of 5F six different enolate structures were characterized: tetramer, dimer, CIP-monomer, SIP-monomer, triple ion, and quadruple ion.
The first asymmetric syntheses of four members of the abyssinone class of natural products (I, II, III, and IV 4′-OMe) via quinine- or quinidine-derived thiourea-catalyzed intramolecular conjugate ...additions of β-keto ester alkylidenes are reported. This concise strategy delivers all four natural products and their corresponding antipodes. A preliminary evaluation of all of these small molecules against a metastatic human prostate cancer cell line has identified that these compounds selectively and differentially inhibit cell growth and downregulate the expression of matrix metalloproteinase-2 (MMP-2) at nontoxic concentrations.
The reactive species in fluoride-mediated carbon−carbon bond-forming reactions was investigated. The regio- and diastereoselectivities of silanes reacting with cyclohexenone in the presence of a ...catalytic amount of fluoride was compared to the reactivity of analogous solvent-separated lithium ion pairs. Closely analogous behavior was observed, showing that carbanions and not siliconate complexes are the reactive species in the fluoride-catalyzed reactions. Spectroscopic investigations unambiguously show that phenylthiobenzyl anion will form by reaction of silane with tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) or crypt2.1.1-solvated lithium enolates. The catalytic cycle runs smoothly with the crypt2.1.1 complex of α-(phenylthio)benzyllithium as the initiator and enolate as the carrier of the desilylation reaction.
Reaction of Metalated Nitriles with Enones Reich, Hans J; Biddle, Margaret M; Edmonston, Robert J
Journal of organic chemistry,
04/2005, Letnik:
70, Številka:
9
Journal Article
Recenzirano
There have been a number of reports of the kinetic conjugate (1,4) addition of metalated arylacetonitriles to enones. Several proposals have been made to explain this behavior based on nucleophile ...structure or aggregation state or on the HSAB properties of the reactants. A reexamination of these studies showed that in each case the 1,4 adducts resulted from equilibration of the kinetically formed 1,2 adducts to the more stable 1,4 adducts. Thus, no conclusions about the origins of 1,4 selectivity can be drawn from these experiments. The 1,2 addition, retro-1,2 addition, 1,4 addition, and retro-1,4 addition of lithiophenylacetonitrile to benzylideneacetone were examined, and a free energy level diagram was constructed for the reaction.
Conjugate additions to form carbon-carbon bonds are valuable methodologies in chemical synthesis. In an effort to better understand and be able to predict and control the regioselectivity of these ...reactions, we have conducted several studies in two areas: the regioselectivity of the addition of lithiated nitriles to α,β-unsaturated enones and mechanistic investigations of the catalytic cycle of fluoride-promoted conjugate addition reactions. There have been a number of reports of the kinetic conjugate addition of metalated arylacetonitriles to a, α,β-unsaturated enones rationalized by nucleophile structure, aggregation state, or the HSAB properties of the reactants. Chapter one focuses on our re-examination of these studies and shows that in each case the 1,4 adducts resulted from equilibration of the kinetically formed 1,2 adducts to the more stable 1,4 adducts. The 1,2 addition, retro-1,2 addition, 1,4 addition and retro-1,4 addition of lithiophenylacetonitrile to benzylideneacetone were examined and a free energy level diagram was constructed for the reactions. Electronic effects of different para substituents on lithiomethoxy( p-substituted-phenyl)acetonitriles were also explored. Fluoride-catalyzed cleavage of a carbon-silicon bond resulting in the transfer of the carbon moity to an electrophile is an attractive method for carbon-carbon bond formation. Two intermediates have been suggested as the reactive intermediate in such reactions: (1) a pentavalent, negatively charged silicon species which transfers the carbon moity and (2) a carbanion formed by dissociation from the pentavalent silicon which then adds to the electrophile. In chapter two we investigated the reactive intermediate in this process through comparison of the reactivity of known separated ion pairs with electrophiles and found the regio- and diastereoselectivity to be the same in most cases as that of the analogous fluoride-promoted silane reaction. Many of the equilibria of these reactions were probed by low temperature, heteronuclear NMR spectroscopy. It was shown that suitably solvated enolates can promote some of these reactions and there is spectroscopic evidence that these enolates form separated ion pairs when reacting with silanes, indicating that the reactive species is the separated ion pair. In the course of these studies, several fluoride sources were explored and their reactivity is discussed briefly in chapter three.
Nuclear speckles are prominent nuclear bodies that contain proteins and RNA involved in gene expression. Although links between nuclear speckles and gene activation are emerging, the mechanisms ...regulating association of genes with speckles are unclear. We find that speckle association of p53 target genes is driven by the p53 transcription factor. Focusing on p21, a key p53 target, we demonstrate that speckle association boosts expression by elevating nascent RNA amounts. p53-regulated speckle association did not depend on p53 transactivation functions but required an intact proline-rich domain and direct DNA binding, providing mechanisms within p53 for regulating gene-speckle association. Beyond p21, a substantial subset of p53 targets have p53-regulated speckle association. Strikingly, speckle-associating p53 targets are more robustly activated and occupy a distinct niche of p53 biology compared with non-speckle-associating p53 targets. Together, our findings illuminate regulated speckle association as a mechanism used by a transcription factor to boost gene expression.
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•The p53 transcription factor drives speckle association of a subset of target genes•p53-mediated speckle association of target genes boosts RNA expression•Regulated speckle association by p53 requires DNA binding, but not transcription•Speckle-associating and non-associating p53 gene targets are functionally distinct
Regulated association between genes and nuclear speckles remains poorly understood. Alexander et al. find that the p53 transcription factor regulates speckle association of certain target genes, demonstrating that speckle association by p53 governs gene expression. Thus, speckle association by transcription factors has the potential to be a major gene-regulatory mechanism.
The extent to which alteration of endogenous tRNA modifications may be exploited to improve genetic code expansion efforts has not been broadly investigated. Modifications of tRNAs are strongly ...conserved evolutionarily, but the vast majority of
E. coli
tRNA modifications are not essential. We identified queuosine (Q), a non-essential, hypermodified guanosine nucleoside found in position 34 of the anticodons of four
E. coli
tRNAs as a modification that could potentially be utilized to improve sense codon reassignment. One suggested purpose of queuosine modification is to reduce the preference of tRNAs with guanosine (G) at position 34 of the anticodon for decoding cytosine (C) ending codons over uridine (U) ending codons. We hypothesized that introduced orthogonal translation machinery with adenine (A) at position 34 would reassign U-ending codons more effectively in queuosine-deficient
E. coli
. We evaluated the ability of introduced orthogonal tRNAs with AUN anticodons to reassign three of the four U-ending codons normally decoded by Q34 endogenous tRNAs: histidine CAU, asparagine AAU, and aspartic acid GAU in the presence and absence of queuosine modification. We found that sense codon reassignment efficiencies in queuosine-deficient strains are slightly improved at Asn AAU, equivalent at His CAU, and less efficient at Asp GAU codons. Utilization of orthogonal pair-directed sense codon reassignment to evaluate competition events that do not occur in the standard genetic code suggests that tRNAs with inosine (I, 6-deaminated A) at position 34 compete much more favorably against G34 tRNAs than Q34 tRNAs. Continued evaluation of sense codon reassignment following targeted alterations to endogenous tRNA modifications has the potential to shed new light on the web of interactions that combine to preserve the fidelity of the genetic code as well as identify opportunities for exploitation in systems with expanded genetic codes.
Persons with Parkinson's disease (PwPD) suffer from motor and non-motor symptoms which significantly affect their quality of life (QoL), and the QoL of their care partners (CP). Tandem cycling ...reduces PwPD motor symptoms; however, no studies have examined other benefits or included PwPD CP. We conducted an 8-week community virtual reality (VR) tandem cycling intervention to assess the feasibility and efficacy for PwPD and their CP (i.e., PD dyads). We hypothesized that dyadic tandem cycling would improve (1) PwPD motor and non-motor symptoms and (2) dimensions of PD dyads' QoL and physiologic health.INTRODUCTIONPersons with Parkinson's disease (PwPD) suffer from motor and non-motor symptoms which significantly affect their quality of life (QoL), and the QoL of their care partners (CP). Tandem cycling reduces PwPD motor symptoms; however, no studies have examined other benefits or included PwPD CP. We conducted an 8-week community virtual reality (VR) tandem cycling intervention to assess the feasibility and efficacy for PwPD and their CP (i.e., PD dyads). We hypothesized that dyadic tandem cycling would improve (1) PwPD motor and non-motor symptoms and (2) dimensions of PD dyads' QoL and physiologic health.Ten PD dyads were recruited to complete 8 weeks of progressive intensity, bi-weekly tandem cycling. At pre- and post-testing, PwPD were assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-III (MDS-UPDRS-III), functional gait assessment (FGA), and 10-m gait speed test. PD dyads also completed emotional and cognitive status questionnaires e.g., Geriatric Depression Scale-Short Form (GDS-SF), and wore BodyGuard 2 heart rate (HR) monitors for 48 h to assess surrogate measures of heart rate variability. Statistical analyses were conducted using Student's t tests with significance set at p ≤ 0.05.METHODSTen PD dyads were recruited to complete 8 weeks of progressive intensity, bi-weekly tandem cycling. At pre- and post-testing, PwPD were assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-III (MDS-UPDRS-III), functional gait assessment (FGA), and 10-m gait speed test. PD dyads also completed emotional and cognitive status questionnaires e.g., Geriatric Depression Scale-Short Form (GDS-SF), and wore BodyGuard 2 heart rate (HR) monitors for 48 h to assess surrogate measures of heart rate variability. Statistical analyses were conducted using Student's t tests with significance set at p ≤ 0.05.Eight PD dyads and one PwPD completed the intervention. Retention of PwPD (90%) and CP (80%) was adequate, and PD dyad adherence ranged from 91.67 to 97.91%. PwPD demonstrated significant clinical improvements in MDS-UPDRS-III scores (- 7.38, p < 0.01), FGA scores (+ 3.50, p < 0.01), and 10-m gait speed times (+ 0.27 m/s, p < 0.01), in addition to significant self-reported improvements in mobility (- 13.61, p = 0.02), fatigue (- 5.99, p = 0.02), and social participation (+ 4.69, p < 0.01). CP depressive symptoms significantly decreased (- 0.88, p = 0.02), and PD dyads shared a significant increase in root mean square of the successive differences (RMSSD; p = 0.04).RESULTSEight PD dyads and one PwPD completed the intervention. Retention of PwPD (90%) and CP (80%) was adequate, and PD dyad adherence ranged from 91.67 to 97.91%. PwPD demonstrated significant clinical improvements in MDS-UPDRS-III scores (- 7.38, p < 0.01), FGA scores (+ 3.50, p < 0.01), and 10-m gait speed times (+ 0.27 m/s, p < 0.01), in addition to significant self-reported improvements in mobility (- 13.61, p = 0.02), fatigue (- 5.99, p = 0.02), and social participation (+ 4.69, p < 0.01). CP depressive symptoms significantly decreased (- 0.88, p = 0.02), and PD dyads shared a significant increase in root mean square of the successive differences (RMSSD; p = 0.04).Our pilot study demonstrated feasibility and multiple areas of efficacy supporting further investigation of community VR tandem cycling as a therapeutic intervention for PD dyads.CONCLUSIONOur pilot study demonstrated feasibility and multiple areas of efficacy supporting further investigation of community VR tandem cycling as a therapeutic intervention for PD dyads.
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