Discovery of a Novel Pseudo-Natural Product Aurora Kinase Inhibitor Chemotype through Morphological Profiling.

The pseudo-natural product (pseudo-NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. The resulting compounds retain the biological relevance of NPs but are not yet linked to bioactivities and may therefore be best evaluated by unbiased screening methods resulting in the identification of unexpected or unprecedented bioactivities. Herein, various NP fragments are combined with a tricyclic core connectivity via interrupted Fischer indole and indole dearomatization reactions to provide a collection of highly three-dimensional pseudo-NPs. Target hypothesis generation by morphological profiling via the cell painting assay guides the identification of an unprecedented chemotype for Aurora kinase inhibition with both its relatively highly 3D structure and its physicochemical properties being very different from known inhibitors. Biochemical and cell biological characterization indicate that the phenotype identified by the cell painting assay corresponds to the inhibition of Aurora kinase B.

A divergent intermediate strategy yields biologically diverse pseudo-natural products.

The efficient exploration of biologically relevant chemical space is essential for the discovery of bioactive compounds. A molecular design principle that possesses both biological relevance and structural diversity may more efficiently lead to compound collections that are enriched in diverse bioactivities. Here the diverse pseudo-natural product (PNP) strategy, which combines the biological relevance of the PNP concept with synthetic diversification strategies from diversity-oriented synthesis, is reported. A diverse PNP collection was synthesized from a common divergent intermediate through developed indole dearomatization methodologies to afford three-dimensional molecular frameworks that could be further diversified via intramolecular coupling and/or carbon monoxide insertion. In total, 154 PNPs were synthesized representing eight different classes. Cheminformatic analyses showed that the PNPs are structurally diverse between classes. Biological investigations revealed the extent of diverse bioactivity enrichment of the collection in which four inhibitors of Hedgehog signalling, DNA synthesis, de novo pyrimidine biosynthesis and tubulin polymerization were identified from four different PNP classes.

Synthesis of Indofulvin Pseudo-Natural Products Yields a New Autophagy Inhibitor Chemotype.

Chemical and biological limitations in bioactive compound design based on natural product (NP) structure can be overcome by the combination of NP-derived fragments in unprecedented arrangements to afford "pseudo-natural products" (pseudo-NPs). A new pseudo-NP design principle is described, i.e., the combination of NP-fragments by transformations that are not part of current biosynthesis pathways. A collection of indofulvin pseudo-NPs is obtained from 2-hydroxyethyl-indoles and ketones derived from the fragment-sized NP griseofulvin by means of an iso-oxa-Pictet-Spengler reaction. Cheminformatic analysis indicates that the indofulvins reside in an area of chemical space sparsely covered by NPs, drugs, and drug-like compounds and they may combine favorable properties of these compound classes. Biological evaluation of the compound collection in different cell-based assays and the unbiased high content cell painting assay reveal that the indofulvins define a new autophagy inhibitor chemotype that targets mitochondrial respiration.

Imine as a linchpin approach for meta-C-H functionalization.

Despite the widespread applications of C-H functionalization, controlling site selectivity remains a significant challenge. Covalently attached directing groups (DGs) served as ancillary ligands to ensure ortho-, meta- and para-C-H functionalization over the last two decades. These covalently linked DGs necessitate two extra steps for a single C-H functionalization: introduction of DG prior to C-H activation and removal of DG post-functionalization. Here we report a temporary directing group (TDG) for meta-C-H functionalization via reversible imine formation. By overruling facile ortho-C-H bond activation by imine-N atom, a suitably designed pyrimidine-based TDG successfully delivered selective meta-C-C bond formation. Application of this temporary directing group strategy for streamlining the synthesis of complex organic molecules without any necessary pre-functionalization at the meta position has been explored.

Palladium-Catalyzed meta-C-H Allylation of Arenes: A Unique Combination of a Pyrimidine-Based Template and Hexafluoroisopropanol.

Controlling remote selectivity and delivering novel functionalities at distal positions in arenes are an important endeavor in contemporary organic synthesis. In this vein, template engineering and mechanistic understanding of new functionalization strategies are essential for enhancing the scope of such methods. Herein, meta-C-H allylation of arenes has been achieved with the aid of a palladium catalyst, pyrimidine-based auxiliary, and allyl phosphate. 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) was found as a critical solvent in this transformation. The role of HFIP throughout the catalytic cycle has been systematically studied. A broad substrate scope with phenethyl ether, phenol, benzylsulfonyl ester, phenethylsulfonyl ester, phenylacetic acid, hydrocinnamic acid, and 2-phenylbenzoic acid derivatives has been demonstrated. Interestingly, conformationally flexible arenes have also been selectively allylated at the meta-position using allyl phosphate. A combination of 1H NMR, 31P NMR, ESI-MS, kinetic experiments, and density functional theory (DFT) computations suggested that reaction proceeds through a ligand-assisted meta-C-H activation, allyl addition forming a Pd-π-allyl complex which is then followed by a turnover determining the C-C bond formation step leading to the meta-allylated product.

Direct meta-C-H Perfluoroalkenylation of Arenes Enabled by a Cleavable Pyrimidine-Based Template.

The development of efficient and mild methods for the synthesis of organofluorine compounds is of foremost interest in various fields of chemistry. A direct pyrimidine-based selective meta-C-H perfluoroalkenylation of arenes involving several commercially available perfluoroolefins is described. The synthetic versatility of the protocol is demonstrated by an extensive substrate scope including different benzylsulfonyl, alkylarene and phenylacetic acid scaffolds. The generality of this methodology including the meta-C-H perfluoroalkenylation of Ibuprofen, the facile cleavage of the directing group and gram-scale reactions are presented.

Palladium-Catalyzed Selective meta-C-H Deuteration of Arenes: Reaction Design and Applications.

Deuterium-labeled compounds find wide applications in kinetic studies, and within the pharmaceutical industry. An easily removable pyrimidine-based auxiliary has been employed for the meta-C-H deuteration of arenes. The scope of this Pd-catalyzed deuteration using commercially available [D1 ]- and [D4 ]-acetic acid has been demonstrated by its application in phenylacetic acid and phenylmethanesulfonate derivatives. A detailed mechanistic study led us to explore the reversibility of the non-rate determining C-H activation step. The present study of meta-deuterium incorporation illustrates the template morphology in terms of selectivity. The applicability of this method has been demonstrated by the selective deuterium incorporation into various pharmaceuticals.

Diverse meta-C-H Functionalization of Arenes across Different Linker Lengths.

Arenes containing conformationally flexible long alkyl chains have been successfully functionalized at the meta-position. Good to excellent meta selectivity is achieved for systems with up to 20 atoms between the target C-H bond and the coordinating heteroatom of the directing group. The palladium-catalyzed functionalization reactions include alkylation, cyanation, olefination, and acetoxylation. The meta selectivity is exclusively governed by the design of flexible pyrimidine-based scaffolds.

Remote meta-C-H Cyanation of Arenes Enabled by a Pyrimidine-Based Auxiliary.

An easily removable pyrimidine-based auxiliary has been employed for the remote meta-C-H cyanation of arenes. The scope of this Pd-catalyzed cyanation reaction using copper(I) cyanide as the cyanating agent was demonstrated with benzylsilanes, benzylsulfonates, benzylphophonates, phenethylsulfonates, and phenethyl ether derivatives. The method was utilized for the synthesis of pharmaceutically valuable precursors.

Template-Assisted meta-C-H Alkylation and Alkenylation of Arenes.

To expand the scope of meta-functionalization, a pyrimidine-based template effective for the formation of ß-aryl aldehydes and ketones, using allyl alcohols, by meta-C-H activation of benzylsulfonyl esters is described. In addition, α,ß-unsaturated aldehydes were generated by in situ olefination and deprotection of allyl benzyl ethers. These new functionalizations at the meta-position of an arene have also been successfully implemented in benzylphosphonate, phenethyl carbonyl, and phenethylsulfonyl ester scaffolds. Key to these successful new functionalizations is the creation of an electropositive palladium center by accepting the electron cloud from the metal to the energetically low-lying π-orbitals of pyrimidine ring, and it favors coordination of allyl alcohol to the metal center.

Palladium-Catalyzed Directed para C-H Functionalization of Phenols.

Various practical methods for the selective C-H functionalization of the ortho and recently also of the meta position of an arene have already been developed. Following our recent development of the directing-group-assisted para C-H functionalization of toluene derivatives, we herein report the first remote para C-H functionalization of phenol derivatives by using a recyclable silicon-containing biphenyl-based template. The effectiveness of this strategy was illustrated with different synthetic elaborations and by the synthesis of various phenol-based natural products.

Remote para-C-H Functionalization of Arenes by a D-Shaped Biphenyl Template-Based Assembly.

Site-selective C-H functionalization has emerged as an efficient tool in simplifying the synthesis of complex molecules. Most often, directing group (DG)-assisted metallacycle formation serves as an efficient strategy to ensure promising regioselectivity. A wide variety of ortho- and meta-C-H functionalizations stand as examples in this regard. Yet despite this significant progress, DG-assisted selective para-C-H functionalization in arenes has remained unexplored, mainly because it involves the formation of a geometrically constrained metallacyclic transition state. Here we report an easily recyclable, novel Si-containing biphenyl-based template that directs efficient functionalization of the distal p-C-H bond of toluene by forming a D-shaped assembly. This DG allows the required flexibility to support the formation of an oversized pre-transition state. By overcoming electronic and steric bias, para-olefination and acetoxylation were successfully performed while undermining o- and m-C-H activation. The applicability of this D-shaped biphenyl template-based strategy is demonstrated by synthesizing various complex molecules.

Palladium-catalyzed aryl C-H olefination with unactivated, aliphatic alkenes.

Palladium-catalyzed coupling between aryl halides and alkenes (Mizoroki-Heck reaction) is one of the most popular reactions for synthesizing complex organic molecules. The limited availability, problematic synthesis, and higher cost of aryl halide precursors (or their equivalents) have encouraged exploration of direct olefination of aryl carbon-hydrogen (C-H) bonds (Fujiwara-Moritani reaction). Despite significant progress, the restricted substrate scope, in particular noncompliance of unactivated aliphatic olefins, has discouraged the use of this greener alternative. Overcoming this serious limitation, we report here a palladium-catalyzed chelation-assisted ortho C-H bond olefination of phenylacetic acid derivatives with unactivated, aliphatic alkenes in good to excellent yields with high regio- and stereoselectivities. The versatility of this operationally simple method has been demonstrated through drug diversification and sequential C-H olefination for synthesizing divinylbenzene derivatives.

Significant influence of coligands toward varying coordination modes of 2,2'-bipyridine-3,3'-diol in ruthenium complexes.

The varying coordination modes of the ambidentate ligand 2,2'-bipyridine-3,3'-diol (H2L) in a set of ruthenium complexes were demonstrated with special reference to the electronic features of the coligands, including σ-donating acac(-) (= acetylacetonate) in Ru(III)(acac)2(HL(-)) (1), strongly π-accepting pap (= 2-phenylazopyridine) in Ru(II)(pap)2(L(2-)) (2)/[(pap)2Ru(II)(µ-L(2-))Ru(II)(pap)2](ClO4)2 ([4](ClO4)2), and reported moderately π-accepting bpy (= 2,2'-bypiridine) in [Ru(II)(bpy)2(HL(-))]PF6 ([5]PF6)/[(bpy)2Ru(µ-L(2-))Ru(bpy)2](PF6)2 ([7](PF6)2). The single-crystal X-ray structures reveal that, in paramagnetic and electron paramagnetic resonance active 1 and reported diamagnetic [5]PF6, nearly planar monoanionic HL(-) coordinates to the metal ion via the N,N donors forming a five-membered chelate ring with hydrogen-bonded O-H···O function at the backbone of the ligand framework, as has also been reported in other metal complexes. However, structurally characterized diamagnetic 2 represents O(-),O(-) bonded seven-membered chelate of fully deprotonated but twisted L(2-). The nonplanarity of the coordinated L(2-) in 2 does not permit the second metal fragment {Ru(pap)2} or {Ru(bpy)2} or {Ru(acac)2} to bind with the available N,N donors at the back face of L(2-). Further, the deprotonated form of the model ligand 2,2'-biphenol (H2L') yields Ru(II)(pap)2(L'(2-)) (3); its crystal structure establishes the expected O(-),O(-) bonded seven-membered chelate of nonplanar L'(2-) as in reported Ru(II)(bpy)2(L'(2-)) (6), although {Ru(acac)2} metal precursor altogether fails to react with H2L'. All attempts to make diruthenium complex from {Ru(acac)2} and H2L failed; however, the corresponding {Ru(pap)2(2+)} derived dimeric [4](ClO4)2 was structurally characterized. It establishes the symmetric N,O(-)/N,O(-) bridging mode of nonplanar L(2-) as in reported [7](PF6)2. Besides structural and spectroscopic characterization of the newly developed complexes, the ligand (HL(-), L(2-), L'(2-), pap)-, metal-, or mixed metal-ligand-based accessible redox processes in 1(n) (n = +2, +1, 0, -1), 2(n)/3(n) (n = +2, +1, 0, -1, -2), and 4(n) (n = +4, +3, +2, +1, 0, -1) were analyzed in conjunction with density functional theory calculations.