Chiral polycyclic indoles are ubiquitous and important ring systems found in many bioactive alkaloids and pharmaceuticals. [1] As a result, extensive effort has been devoted to the development of efficient methods for their synthesis. Most approaches developed to date are based on the direct functionalization of the "privileged" indole core. [2] Representative strategies include asymmetric intramolecular alkylation of the C3, C2, or N1 positions of indoles, these reactions are exemplified by allylic alkylation, [3] Friedel-Crafts alkylation, [4] the Pictet-Spengler reaction, [5] and N-alkylation. [6] Most of these processes are governed by the nucleophilic character of the C3, C2, or N1 positions in the indole ring and require the substrates to be carefully designed. The latter requirement often limits the substrate scope of these reactions. Recently, indole-based cascade reactions driven by the nucleophilicity of the indole C3 position and the electrophilicity of the iminium species generated in situ, have served as the basis for alternative and robust methods of polycyclic indole synthesis. [7] Despite these recent advances, the development of new approaches to the construction of polycyclic indole derivatives, which take advantage of the unique reactivity profile of indoles, remains an important goal.The [a]-annelated indole system, particularly the pyrrolo-[1,2-a]indole scaffold, is present in a diverse family of structurally complex polycyclic indoles and has consequently become a primary target of synthetic efforts (Scheme 1). [8][9][10] In 2009, the groups of Chen [9c] and Hartwig [9b] uncovered regio and enantioselective N-allylation reactions of indoles that employed a cinchona alkaloid and an iridium/phosphoramidite complex, respectively. Routine elaboration of the products of these processes afforded highly substituted dihydropyrrolo[1,2-a]indoles in good overall yields. Recently, You and co-workers described another highly enantioselective N-allylation reaction of indoles that involved an iridiumcatalyzed allylic alkylation/oxidation cascade. [9a] The products of the reactions were also readily transformed, in this case into a diastereoisomer of naturally occurring methylyuremamine. Furthermore, Enders [6a] and Wang [6d] have also made significant contributions to the construction of these alkaloids by designing organocatalytic tandem N-alkylation/intramolecular cyclization reactions of modified indoles. However, to our knowledge, methods for the direct catalytic enantioselective assembly of structurally diverse and stereochemically complex pyrrolo[1,2-a]indole derivatives remain rare and, as a result, a challenging goal in the area of organic synthesis.In our recent research into the efficient asymmetric functionalization of indoles, [11] we envisaged that simple 3-substituted 1H-indoles might serve as N1 and C2 dinucleophiles in cascade reactions with suitable dielectrophiles to generate polycyclic indoles (Scheme 2). In elaborating this scenario, several issues had to be considered, including: ...

Through nearly 50 years of development, sulphur ylides have been established as versatile and powerful reagents for the construction of carbocycles and heterocycles. Despite advances, two important and yet elusive bottlenecks continue to inhibit the advancement of this chemistry: a limited number of reagents with polar groups to react with sulphur ylides, and the wide utilization of chiral auxiliaries or substrates to achieve asymmetric cycloaddition processes in the majority of known reports. Herein, we apply an asymmetric palladium catalysis strategy to the chemistry of sulphur ylides to address these two fundamental problems. We thus achieve an unprecedented decarboxylation-cycloaddition sequence of cyclic allylic esters with sulphur ylides through the enantioselective trapping of Pd-stabilized zwitterionic intermediates by the ylides. As a result, a series of biologically and synthetically important 3-vinyl indolines are rapidly assembled with a high reaction efficiency and stereoselectivity.

Batting the ylides: A simple procedure carried out under mild conditions allows the direct and efficient synthesis of structurally diverse indoles. This approach involves a cascade reaction of sulfur ylides and N-(ortho-chloromethyl)aryl amides.

A visible‐light‐induced cascade radical cyclization of aroyl chlorides with 2‐(allyloxy)‐benzaldehyde derivatives has been developed. The method takes advantages of unactivated C=C bonds as the acyl radical acceptors and offers a mild and green approach for the synthesis of 1,4‐diketones bearing biologically important chroman‐4‐one skeletons with moderate to good yields.

The present study examined horizontal saccades in healthy subjects: 9 adults (20-32 years) and 10 aged subjects (63-83 years), under gap (fixation target extinguishes prior to target onset) and overlap (fixation stays on after target onset). The gap paradigm is known to promote fast initiation of saccades while the overlap paradigm promotes voluntary saccades with longer latency. In real life we perform saccades at various distances. In this study each paradigm was run at three viewing distances-20, 40 and 150 cm, corresponding to a convergence angle of 17.1 degrees, 8.6 degrees and 2.3 degrees, respectively. Eye movements were recorded with the Chronos video eye tracker or with the photoelectric IRIS. The main findings are: (i) increase in latency of saccades with age, with distance and with the overlap condition; (ii) evidence for interaction between these factors, indicating the following anomaly: in the gap condition and at near, aged subjects show short latencies similar to those of young adults; (iii) express type of latencies (between 80 and 120 ms) occur most frequently at near in the gap condition and at similar rates in young (25%) and aged subjects (20%). The specificity of close distance combined with the gap for triggering short latency saccades could be related to both attention and oculomotor fixation disengagement. The strength of coupling between fixation-eye movement control and visual attention control varies for different locations in space, and its decline with aging can be also different.

The gold-catalyzed synthesis of methylidene 2,3-cyclobutane-indoles is documented through a combined experimental/computational investigation. Besides optimizing the racemic synthesis of the tricyclic indole compounds, the enantioselective variant is presented to its full extent. In particular, the scope of the reaction encompasses both aryloxyallenes and allenamides as electrophilic partners providing high yields and excellent stereochemical controls in the desired cycloadducts. The computational (DFT) investigation has fully elucidated the reaction mechanism providing clear evidence for a two-step reaction. Two parallel reaction pathways explain the regioisomeric products obtained under kinetic and thermodynamic conditions. In both cases, the dearomative CC bond-forming event turned out to be the rate-determining step.

How pain emerges from cortical activities remains an unresolved question in pain neuroscience. A first step toward addressing this question consists in identifying brain activities that occur preferentially in response to painful stimuli in comparison to non-painful stimuli. A key confound that has affected this important comparison in many previous studies is the intensity of the stimuli generating painful and non-painful sensations. Here, we compared the brain activity during iso-intense painful and tactile sensations sampled by functional MRI in 51 healthy participants. Specifically, the perceived intensity was recorded for every stimulus and only the stimuli with rigorously matched perceived intensity were selected and compared between painful and tactile conditions. We found that all brain areas activated by painful stimuli were also activated by tactile stimuli, and vice versa. Neural responses in these areas were correlated with the perceived stimulus intensity, regardless of stimulus modality. More importantly, among these activated areas, we further identified a number of brain regions showing stronger responses to painful stimuli than to tactile stimuli when perceived intensity was carefully matched, including the bilateral opercular cortex, the left supplementary motor area and the right frontal middle and inferior areas. Among these areas, the right frontal middle area still responded more strongly to painful stimuli even when painful stimuli were perceived less intense than tactile stimuli, whereas in this condition other regions showed stronger responses to tactile stimuli. In contrast, the left postcentral gyrus, the visual cortex, the right parietal inferior gyrus, the left parietal superior gyrus and the right cerebellum had stronger responses to tactile stimuli than to painful stimuli when perceived intensity was matched. When tactile stimuli were perceived less intense than painful stimuli, the left postcentral gyrus and the right parietal inferior gyrus still responded more strongly to tactile stimuli while other regions now showed similar responses to painful and tactile stimuli. These results suggest that different brain areas may be engaged differentially when processing painful and tactile information, although their neural activities are not exclusively dedicated to encoding information of only one modality but are strongly determined by perceived stimulus intensity regardless of stimulus modality.

Get asymmetric! Asymmetric [4+1] annulation of sulfur ylides and N-(ortho-chloromethyl)aryl amides allowed the formation of the desired cycloadduct with moderate to high yields and enantioselectivities (see scheme). The described strategy, taking advantage of chiral sulfur ylides, represents a direct procedure to access chiral 2-substituted indolines.