In this article strategies for the design and synthesis of natural product analogues are summarized and illustrated with some selected examples. Proven strategies include diverted total synthesis ...(DTS), function-oriented synthesis (FOS), biology-oriented synthesis (BIOS), complexity to diversity (CtD), hybrid molecules, and biosynthesis inspired synthesis. The latter includes mutasynthesis, the synthesis of natural products encoded by silent genes, and propionate scanning. Most of the examples from our group fall in the quite general concept of DTS. Thus, in case an efficient strategy to a natural product is at hand, modifications are possible at almost any stage of a synthesis. However, even for compounds of moderate complexity, organic synthesis remains a bottle neck. Unless some method for predicting the biological activity of a designed molecule becomes available, the design and synthesis of natural product analogues will remain what it is now, namely it will largely rely on trial and error.
The regulatory approval of Onpattro, a lipid nanoparticle-based short interfering RNA drug for the treatment of polyneuropathies induced by hereditary transthyretin amyloidosis, paves the way for ...clinical development of many nucleic acid-based therapies enabled by nanoparticle delivery.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
An extensive experimental study of the mechanism of gold(I)‐catalyzed hydroalkoxylation of internal alkynes has been conducted by using NMR spectroscopy. This study was focused on the organogold ...intermediates, observations of actual catalytic intermediates in situ, and the reaction kinetics that are involved in this reaction. Based on the experimental results, a complete mechanistic picture was established, including on‐ and off‐cycle processes that explain the role of diaurated species. We have shown that gold‐catalyzed hydroalkoxylation of internal alkynes is a reaction that requires only one gold atom for the catalytic cycle, disproving a recent hypothesis regarding the involvement of cooperative gold catalysis.
Golden mechanism: An extensive experimental study of the mechanism of gold(I)‐catalyzed hydroalkoxylation of internal alkynes (see scheme) has been carried out by using NMR spectroscopy. This study is focused on the organogold intermediates, observations of actual catalytic intermediates in situ, and the reaction kinetics.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
An experimental mechanistic study of the gold(I)‐catalyzed hydroamination shows the formation of conformationally flexible auro‐iminium salts Au‐Im, which originate from the protonation of a vinyl ...gold species. Rotation around the CCAu bond is the reason for the loss of stereospecificity of protodeauration, which explains the stereochemical result of the Stradiotto reaction. The ambiguity about inner or outer sphere mechanism is thus resolved in favor of the outer sphere mechanism.
Which way is right? Experimental mechanistic study of hydroamination reveals the formation of conformationally flexible auro‐iminium salts Au‐Im, which originate from protonation of the vinyl gold species B. Rotation around the CCAu bond is the reason for the loss of stereospecificity of protodeauration, which explains earlier stereochemical results. This shows that the reaction proceeds through the outer sphere mechanism.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
An extensive experimental NMR study of gold-catalyzed hydroalkoxylation was conducted to explain the influence of a silver salt additive on the gold-catalyzed process (silver effect). Addition of ...silver salt may have no effect or a negative or positive effect on gold-catalyzed hydroalkoxylation. However, silver was shown to be essentially innocent (plays no role) with regard to the mechanism of the catalytic process itself. The effect occurs only if silver induces variations in the fraction of in-cycle organogold intermediates and H+. This is associated with the formation of the argento vinyl gold species G, which was shown to be an off-cycle intermediate. This species is formed by trapping the vinyl gold species B with Ag+; in the same way, the diaurated species D (another possible off-cycle intermediate) is formed by trapping B with LAu+. The argento vinyl gold species G1 was extensively characterized in solution by various NMR techniques at different temperatures. Furthermore, bringing together our results and the topical research of others, we introduced classification of silver effects to eliminate the confusion around the interpretation of erratic effects. Reactions that are separately catalyzed either by silver or by gold were beyond the scope of this study (for those reactions a “true” silver effect would take place).
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IJS, KILJ, NUK, PNG, UL, UM
Using gold(I)-catalyzed hydroalkoxylation of alkynes as a model reaction with a well-known mechanism, a systematic experimental study was conducted to disclose the influence of the counterion X– of ...a gold catalyst LAuNCMe+ X– on every step of the catalytic cycle. The overall ion effect is determined as a superposition of several effects, operating on different steps of the reaction mechanism. All effects were explained from a position of hydrogen bonding, coordination chemistry at gold, and affinity for a proton.
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IJS, KILJ, NUK, PNG, UL, UM
Errors in human behavior elicit a cascade of brain activity related to performance monitoring and error detection. Whereas the early error-related negativity (Ne/ERN) has been assumed to reflect a ...fast mismatch or prediction error signal in the medial frontal cortex, the later error positivity (Pe) is viewed as a correlate of conscious error processing. A still open question is whether these components represent two independent systems of error monitoring that rely on different types of information to detect an error. Here, we investigated the prediction that the Ne/ERN but not the Pe requires a representation of the correct response to emerge. To this end, we created a condition in which no information about the correct response was available while error detection was still possible. We hypothesized that a Pe, but no Ne/ERN should be obtained in this case. Participants had to classify targets but ignore flankers that were always associated with an incorrect response. Targets but not flankers were masked with varying target-masking intervals. Crucially, on some trials no target at all was presented, thus preventing the representation of a correct response and the emergence of an Ne/ERN. However, because flankers were easily visible and responses to the flankers were always incorrect, detection of these flanker errors was still possible. In line with predictions of a multiple-systems account, we observed a robust Pe in the absence of an Ne/ERN for these errors. Moreover, this Pe relied on the same neural activity as that on trials with a visible target, as revealed by multivariate pattern analysis. These findings demonstrate that the mechanisms reflected by the two components use different types of information to detect errors, providing evidence for independent systems of human error monitoring.
•Two components (Ne/ERN and Pe) of error-related brain activity are investigated.•Error processing in both components relies on different types of information.•The Ne/ERN but not the Pe requires a representation of the correct response.•A Pe can emerge in the absence of an Ne/ERN.•Pe and Ne/ERN reflect independent monitoring processes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The optimization of human performance requires the continuous monitoring of behavioral conflicts. According to conflict monitoring theory, the dorsal anterior cingulate cortex registers response ...conflict which is reflected by two electrophysiological signatures, the N2 and the Ne/ERN. The theory assumes that, if a stimulus activates an incorrect response that competes with the correct response, pre-response conflict on correct trials (reflected by the N2) is enhanced but post-response conflict on error trials (reflected by the Ne/ERN) is reduced. Here, we asked whether response conflict depends on the number of competing incorrect responses activated by a stimulus, that is, whether the N2 is further enhanced and the Ne/ERN is further reduced if two incorrect responses are activated as compared to one. To this end, we used a modified flanker paradigm, in which the two flankers were associated either with the same incorrect response or with different incorrect responses. Our results indicate an increased N2 on correct trials and a reduced Ne/ERN on error trials in the latter as compared to the former condition. These results confirm central predictions of conflict monitoring theory and demonstrate that response conflict is directly related to the number of competing incorrect responses.
•Activating more competing incorrect responses leads to a larger N2.•Activating more competing incorrect responses leads to smaller Ne/ERN.•Results provide support for conflict monitoring theory.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Current Gigabit-class passive optical networks (PONs) evolve into next-generation PONs, whereby high-speed 10+ Gb/s time division multiplexing (TDM) and long-reach wavelength-broadcasting/routing ...wavelength division multiplexing (WDM) PONs are promising near-term candidates. On the other hand, next-generation wireless local area networks (WLANs) based on frame aggregation techniques will leverage physical-layer enhancements, giving rise to Gigabit-class very high throughput (VHT) WLANs. In this paper, we develop an analytical framework for evaluating the capacity and delay performance of a wide range of routing algorithms in converged fiber-wireless (FiWi) broadband access networks based on different next-generation PONs and a Gigabit-class multiradio multichannel WLAN-mesh front end. Our framework is very flexible and incorporates arbitrary frame size distributions, traffic matrices, optical/wireless propagation delays, data rates, and fiber faults. We verify the accuracy of our probabilistic analysis by means of simulation for the wireless and wireless-optical-wireless operation modes of various FiWi network architectures under peer-to-peer, upstream, uniform, and nonuniform traffic scenarios. The results indicate that our proposed optimized FiWi routing algorithm (OFRA) outperforms minimum (wireless) hop and delay routing in terms of throughput for balanced and unbalanced traffic loads, at the expense of a slightly increased mean delay at small to medium traffic loads.
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