ConspectusCycloaddition reactions are among the most powerful methods for the synthesis of complex compounds. In particular, the development and application of the 1,3-dipolar cycloaddition, an important member of this reaction class, has grown immensely due to its powerful ability to efficiently build various five-membered heterocycles. Azomethine ylides are commonly used as dipoles for the synthesis of the pyrrolidine scaffold, which is an important motif in natural products, pharmaceuticals, and biological probes. The reaction between azomethine ylides and cyclic dipolarophiles allows access to polycyclic products with considerable complexity. The extensive application of the 1,3-dipolar cycloaddition is based on the fact that the desired products can be obtained with high yield in a regio- and stereocontrolled manner. The most attractive feature of the 1,3-dipolar cycloaddition of azomethine ylides is the possibility to generate pyrrolidines with multiple stereocenters in a single step. The development of enantioselective cycloadditions became a subject of intensive and impressive studies in recent years. Among many modes of stereoinduction, the application of chiral metal–ligand complexes has emerged as the most viable option for control of enantioselectivity.In chemical biology research based on the principle of biology-oriented synthesis (BIOS), compound collections are prepared inspired by natural product scaffolds. In BIOS, biological relevance is employed as the key criterion to generate hypotheses for the design and synthesis of focused compound libraries. In particular, the underlying scaffolds of natural product classes provide inspiration for BIOS because they define the areas of chemical space explored by nature, and therefore, they can be regarded as “privileged”. The scaffolds of natural products are frequently complex and rich in stereocenters, which necessitates the development of efficient enantioselective methodologies.This Account highlights examples, mostly from our work, of the application of 1,3-dipolar cycloaddition reactions of azomethine ylides for the catalytic enantioselective synthesis of complex products. We successfully applied the 1,3-dipolar cycloaddition in the synthesis of spiro-compounds such as spirooxindoles, for kinetic resolution of racemic compounds in the synthesis of an iridoid inspired compound collection and in the synthesis of a nitrogen-bridged bicyclic tropane scaffold by application of 1,3-fused azomethine ylides. Furthermore, we performed the synthesis of complex molecules with eight stereocenters using tandem cycloadditions. In a programmable sequential double cycloaddition, we demonstrated the synthesis of both enantiomers of complex products by simple changes in the order of addition of chemicals. Complex products were obtained using enantioselective higher order [6 + 3] cycloaddition of azomethine ylides with fulvenes followed by Diels–Alder reaction. The bioactivity of these compound collections is also discussed.
Two birds, one stone: Semisynthetic derivatives of the ribosomal inhibitor thiostrepton display up to ten times higher antiplasmodial activity than the natural product itself. This activity was correlated with selective functional inhibition of the 20S proteasome. Thiostrepton derivatives are now established as novel antimalarials with a dual mode of action and highly promising scaffolds for proteasome inhibitor development.
A solid phase-based strategy gave access to DNA-tagged heterocycles by metal-mediated imine chemistry, exemplified by Cushman- and 1,3-dipolar cycloaddition reactions.
DNA-encoded compound libraries are a highly attractive technology for the discovery of small molecule protein ligands. These compound collections consist of small molecules covalently connected to individual DNA sequences carrying readable information about the compound structure. DNA-tagging allows for efficient synthesis, handling and interrogation of vast numbers of chemically synthesized, drug-like compounds. They are screened on proteins by an efficient, generic assay based on Darwinian principles of selection. To date, selection of DNA-encoded libraries allowed for the identification of numerous bioactive compounds. Some of these compounds uncovered hitherto unknown allosteric binding sites on target proteins; several compounds proved their value as chemical biology probes unraveling complex biology; and the first examples of clinical candidates that trace their ancestry to a DNA-encoded library were reported. Thus, DNA-encoded libraries proved their value for the biomedical sciences as a generic technology for the identification of bioactive drug-like molecules numerous times. However, large scale experiments showed that even the selection of billions of compounds failed to deliver bioactive compounds for the majority of proteins in an unbiased panel of target proteins. This raises the question of compound library design.
Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions DNA-encoded compound libraries are a widely used technology for target-based small molecule screening. Initiating encoded compound synthesis with solid phase -coupled DNA barcodes does benefi t from choice of organic solvents. Screening of more than 50 metal salts and organic reagents for DNA compatibility suggested reactions for encoded compound synthesis. A ZnCl2-mediated aza-Diels-Alder reaction with Danishefsky's diene and diphenyl phosphate-promoted tetrahydroquinoline and pyrimidinone syntheses by Povarov and Biginelli reactions, respectively, showed a broad substrate scope and were well tolerated by a DNA oligonucleotide.DNA-encoded compound libraries are a widely used technology for target-based small molecule screening. Generally, these libraries are synthesized by solution phase combinatorial chemistry requiring aqueous solvent mixtures and reactions that are orthogonal to DNA reactivity. Initiating library synthesis with readily available controlled pore glass-coupled DNA barcodes benefits from enhanced DNA stability due to nucleobase protection and choice of dry organic solvents for encoded compound synthesis. We screened the compatibility of solid-phase coupled DNA sequences with 53 metal salts and organic reagents. This screening experiment suggests design of encoded library synthesis. Here, we show the reaction optimization and scope of three sp 3 -bond containing heterocyclic scaffolds synthesized on controlled pore glass-connected DNA sequences. A ZnCl 2 -promoted aza-Diels-Alder reaction with Danishefsky's diene furnished diverse substituted DNA-tagged pyridones, and a phosphoric acid organocatalyst allowed for synthesis of tetrahydroquinolines by the Povarov reaction and pyrimidinones by the Biginelli reaction, respectively. These three reactions caused low levels of DNA depurination and cover broad and only partially overlapping chemical space though using one set of DNA-coupled starting materials. † Electronic supplementary information (ESI) available: Synthesis and additional tables for screening experiments, reaction optimization experiments and reaction scope. Copies of HPLC traces and MALDI-MS spectra are shown for all discussed DNA conjugates. See a For each: 20 nmol DNA, 200 equiv. (transition) metal salt or organocatalyst A-H, 50 mL dry solvent, r.t., 22 h. b 50 mL of the indicated aqueous acid. c 5 equiv. of metal salt were used. hexT 7 ¼ 5 0 -AcN-(CH 2 ) 6 -TTT TTT-3 0 -CPG, TC 8 ¼ 5 0 -TTC CTC TCC T-3 0 -CPG, ATC 9 ¼ 5 0 -TTA CTA CCT A-3 0 -CPG, ATGC 10 ¼ 5 0 -GTC ATG ATC T-3 0 -CPG, ACN ¼ acetonitrile, MeOH ¼ methanol. This journal is View Article Online c 1000 equiv. of amine 12 were used. d Yb(OTf) 3 was used instead of ZnCl 2 . e The 2 nd step of the reaction was performed overnight at 35 C. 10mer ATGC ¼ 5 0 -GTC ATG ATC T-3 0 , ACN ¼ acetonitrile. This journal isFig. 7 Cheminformatics analysis: A ¼ PCA plot of the DA-1(red), P (blue) and B (green) lib...
DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or "hot spot", regions of protein-protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide "hexT", encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.
We developed an enantioselectively catalyzed tandem synthesis of structurally and stereochemically complex molecules that forms four carbon-carbon bonds and sets eight stereocenters with high regio-, diastereo- and enantioselectivity. It can be programmed to yield different stereoisomers by varying only the order of combination of a common set of reagents and catalysts. We report what is to our knowledge the first synthesis of both enantiomers of a chiral compound using the same chiral catalyst.
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