An expedient strategy for the synthesis of polycyclic small molecules is described. The method first joins together two achiral building blocks (an enyne and an aldehyde or a ketone) using an alkynyl ...halo-Prins protocol. Then, in the same reaction vessel, acidic conditions initiate a cationic cascade that includes a stereospecific halo-Nazarov electrocyclization and a diastereoselective Friedel–Crafts allylation. The entire sequence forms three carbon–carbon bonds and a carbon–halogen bond, generating halocyclopentene adducts in one pot from simple precursors. The process occurs with excellent diastereocontrol, providing highly functionalized polycycles containing three tertiary or quaternary stereogenic centers in a linear array. It is even possible to install three contiguous all-carbon quaternary centers using this method.
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A diastereoselective two‐step strategy for the synthesis of densely functionalized 1‐halocyclopentenes with several chiral centers has been developed. In the first step, a multicomponent alkynyl ...halo‐Prins reaction joins an enyne, a carbonyl derivative, and either a chloride, bromide, or iodide to produce a cyclic ether intermediate. In the subsequent step, the intermediate is ionized to generate a halopentadienyl cation, which undergoes an interrupted halo‐Nazarov cyclization. The products contain three new contiguous stereogenic centers, generated with a high level of stereocontrol, as well as a vinyl halide allowing for additional functionalization. The strategy creates two new carbon–carbon bonds, one carbon–halide bond, and one carbon–oxygen bond.
A two‐step strategy has been developed for the synthesis of densely functionalized 1‐halocyclopentenes with a high level of stereocontrol. First, a multicomponent alkynyl halo‐Prins reaction joins an enyne, a carbonyl derivative, and either chloride, bromide, or iodide to produce a cyclic ether intermediate. Then, the intermediate is ionized to generate a halopentadienyl cation, which undergoes an interrupted halo‐Nazarov cyclization.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this report, we describe a halo-Prins/aryl halo-Nazarov cyclization strategy that employs readily available starting materials, inexpensive reagents, and convenient reaction procedures to generate ...functionalized haloindenes and indanones. The scope and limitations of the method are outlined, demonstrating that aromatic systems readily react under mild, catalytic conditions when this strategy is implemented. Furthermore, we present both experimental and computational data supporting the notion that cyclizations of 3-halopentadienyl cationic intermediates are more kinetically accessible, as well as more thermodynamically favorable, than cyclizations of the analogous 3-oxypentadienyl cationic systems. The energetic advantage imparted by the halo-Nazarov cyclization design was found to be especially valuable in the cyclizations of arylallyl cationic intermediates, which require disruption of aromaticity.
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Abstract
The cannabinoid CB
2
receptor (CB
2
R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed ...and widely used to target CB
2
R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB
2
R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB
2
R agonists to study the role of CB
2
R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research.
A novel metal-free double-annulation cascade for the construction of unusual fused heterocyclic systems is described. This simple protocol enables the sequential assembly of two rings in one pot from ...two simple precursors. Acidic conditions promote the condensation and the intramolecular alkynyl Prins reaction of an enyne or arenyne alcohol with a cyclic hemiaminal to form a five-, six-, or seven-membered oxacycle followed by a seven- or eight-membered azacycle. In this transformation, chemical complexity is rapidly generated with the formation of three new bonds (one C-O, one C-C, and one C-N) in one synthetic operation. The strategy is modular and relatively general, providing access to a series of unique fused bicyclic scaffolds.
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A stereocontrolled halo-Prins/halo-Nazarov cyclization protocol is reported, where chiral information from a secondary alcohol is relayed through several intermediates yielding halocyclopentene ...products diastereoselectively. An enantiopure product is obtained when a nonracemic secondary alcohol is used. Experimental and computational studies are described, enabling the design and synthesis of systems that ionize and cyclize with >95% chirality transfer through a mechanism involving the creation and preservation of transient helical chirality in a pentadienyl cation intermediate. First, a diastereoselective alkynyl Prins cyclization is executed to synthesize a conformationally distorted dihydropyran intermediate with a curved backbone and high reactivity. This chiral precursor adopts a specific helical alignment early in the subsequent cationic ionization/halo-Nazarov cyclization process, dictating the direction of conrotation in the electrocyclization. Notably, despite the ablation of an sp3 stereogenic center during ionization, the low halo-Nazarov barrier enables efficient capture of a cationic intermediate with dynamic conformational chirality. The ionization and electrocyclization thus occur with “memory of chirality”.
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Photolabile protecting groups (PPGs) enable the precise activation of molecular function with light in many research areas, such as photopharmacology, where remote spatiotemporal control over the ...release of a molecule is needed. The design and application of PPGs in recent years have particularly focused on the development of molecules with high molar absorptivity at long irradiation wavelengths. However, a crucial parameter, which is pivotal to the efficiency of uncaging and which has until now proven highly challenging to improve, is the photolysis quantum yield (QY). Here, we describe a novel and general approach to greatly increase the photolysis QY of heterolytic PPGs through stabilization of an intermediate chromophore cation. When applied to coumarin PPGs, our strategy resulted in systems possessing an up to a 35-fold increase in QY and a convenient fluorescent readout during their uncaging, all while requiring the same number of synthetic steps for their preparation as the usual coumarin systems. We demonstrate that the same QY engineering strategy applies to different photolysis payloads and even different classes of PPGs. Furthermore, analysis of the DFT-calculated energy barriers in the first singlet excited state reveals valuable insights into the important factors that determine photolysis efficiency. The strategy reported herein will enable the development of efficient PPGs tailored for many applications.
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Using light as an external stimulus to control (bio)chemical processes offers many distinct advantages, most importantly it allows for the spatiotemporal control simply through operating the light ...source. Photocleavable protecting groups (PPGs) are a cornerstone class of compounds that are used to achieve photocontrol over (bio)chemical processes. PPGs are able to release a payload of interest upon light irradiation. The successful application of PPGs hinges on their efficiency of payload release, captured in the uncaging Quantum Yield (QY). Heterolytic PPGs efficiently release low pKa payloads, but their efficiency drops significantly for payloads with higher pKa values, such as alcohols. For this reason, alcohols are usually attached to PPGs via a carbonate linker. The self-immolative nature of the carbonate linker results in concurrent release of CO2 with the alcohol payload upon irradiation. We introduce herein novel PPGs containing sulfites as self-immolative linkers for photocaged alcohol payloads, for which we discovered that the release of the alcohol proceeds with higher uncaging QY than an identical payload released from a carbonate-linked PPG. Furthermore, we demonstrate that uncaging of the sulfite-linked PPGs results in the release of SO2 and show that the sulfite linker improves water solubility as compared to the carbonate based systems.Using light as an external stimulus to control (bio)chemical processes offers many distinct advantages, most importantly it allows for the spatiotemporal control simply through operating the light source. Photocleavable protecting groups (PPGs) are a cornerstone class of compounds that are used to achieve photocontrol over (bio)chemical processes. PPGs are able to release a payload of interest upon light irradiation. The successful application of PPGs hinges on their efficiency of payload release, captured in the uncaging Quantum Yield (QY). Heterolytic PPGs efficiently release low pKa payloads, but their efficiency drops significantly for payloads with higher pKa values, such as alcohols. For this reason, alcohols are usually attached to PPGs via a carbonate linker. The self-immolative nature of the carbonate linker results in concurrent release of CO2 with the alcohol payload upon irradiation. We introduce herein novel PPGs containing sulfites as self-immolative linkers for photocaged alcohol payloads, for which we discovered that the release of the alcohol proceeds with higher uncaging QY than an identical payload released from a carbonate-linked PPG. Furthermore, we demonstrate that uncaging of the sulfite-linked PPGs results in the release of SO2 and show that the sulfite linker improves water solubility as compared to the carbonate based systems.
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Photolabile Protecting Groups (PPGs) are molecular tools used, for example, in photopharmacology for the activation of drugs with light, enabling spatiotemporal control over their potency. Yet, ...red‐shifting of PPG activation wavelengths into the NIR range, which penetrates the deepest in tissue, has often yielded inefficient or insoluble molecules, hindering the use of PPGs in the clinic. To solve this problem, we report herein a novel concept in PPG design, by transforming clinically‐applied NIR‐dyes with suitable molecular orbital configurations into new NIR‐PPGs using computational approaches. Using this method, we demonstrate how Cy7, a class of NIR dyes possessing ideal properties (NIR‐absorption, high molecular absorptivity, excellent aqueous solubility) can be successfully converted into Cy7‐PPG. We report a facile synthesis towards Cy7‐PPG from accessible precursors and confirm its excellent properties as the most redshifted oxygen‐independent NIR‐PPG to date (λmax=746 nm).
The computational design and synthesis of Cy7‐PPG, a new oxygen‐independent novel near‐infrared photolabile protecting group (PPG) is reported. Cy7‐PPG is the most redshifted PPG to date (λmax=746 nm), with unmatched near‐infrared molecular absorptivity and aqueous solubility, and excellent uncaging efficiency, paving the way for the use of PPGs in the clinic.
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Photocleavable protecting groups (PPGs) enable the precise spatiotemporal control over the release of a payload of interest, in particular a bioactive substance, through light irradiation. A crucial ...parameter that determines the practical applicability of PPGs is the efficiency of payload release, largely governed by the quantum yield of photolysis (QY). Understanding which parameters determine the QY will prove crucial for engineering improved PPGs and their effective future applications, especially in the emerging field of photopharmacology. The Contact Ion Pair (CIP) has been recognized as an important intermediate in the uncaging process, but the key influence of
its fate
on the quantum yield has not been explored yet, limiting our ability to design improved PPGs. Here, we demonstrate that the CIP escape mechanism of PPGs is crucial for determining their payload- and solvent-dependent photolysis QY, and illustrate that an intramolecular type of CIP escape is superior over diffusion-dependent CIP escape. Furthermore, we report a strong correlation of the photolysis QY of a range of coumarin PPGs with the DFT-calculated height of all three energy barriers involved in the photolysis reaction, despite the vastly different mechanisms of CIP escape that these PPGs exhibit. Using the insights obtained through our analysis, we were able to predict the photolysis QY of a newly designed PPG with particularly high accuracy. The level of understanding of the factors determining the QY of PPGs presented here will move the ever-expanding field of PPG applications forward and provides a blueprint for the development of PPGs with QYs that are independent of payload-topology and solvent polarity.
Improving the efficiency of photocleavable protecting groups is crucial for their application. Here we reveal how the fate of the contact ion pair intermediate plays a key role in defining this efficiency.
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