Structures of the Most Twisted Thioamide and Selenoamide: Effect of Higher Chalcogens of Twisted Amides on N-C(X) Resonance.

Amide bond replacement with planar isosteric chalcogen analogues has an important implication for the properties of the N-C(X) linkage in structural chemistry, biochemistry and organic synthesis. Herein, we report the first higher chalcogen derivatives of non-planar twisted amides. The synthesis of twisted thioamide in a versatile system has been accomplished by direct thionation without cleavage of the σ N-C bond. The synthesis of twisted selenoamide has been accomplished by selenation with Woollins' reagent. The structures of higher chalcogen analogues of non-planar amides were unambiguously confirmed by X-ray crystallography. Reactivity studies were conducted to determine the effect of isologous N-C(O) to N-C(X) replacement on the properties of the amide linkage. Computational studies were employed to evaluate structural and energetic parameters of amide bond alteration in higher chalcogen amides. The study provides the first experimental evidence on the effect of chalcogen isologues on the structural and electronic properties of the non-planar amide N-C(X) linkage.

Structural Insights into JAK2 Inhibition by Ruxolitinib, Fedratinib, and Derivatives Thereof.

The discovery that aberrant activity of Janus kinase 2 (JAK2) is a driver of myeloproliferative neoplasms (MPNs) has led to significant efforts to develop small molecule inhibitors for this patient population. Ruxolitinib and fedratinib have been approved for use in MPN patients, while baricitinib, an achiral analogue of ruxolitinib, has been approved for rheumatoid arthritis. However, structural information on the interaction of these therapeutics with JAK2 remains unknown. Here, we describe a new methodology for the large-scale production of JAK2 from mammalian cells, which enabled us to determine the first crystal structures of JAK2 bound to these drugs and derivatives thereof. Along with biochemical and cellular data, the results provide a comprehensive view of the shape complementarity required for chiral and achiral inhibitors to achieve highest activity, which may facilitate the development of more effective JAK2 inhibitors as therapeutics.

The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes share their E2 and E3 components for their function and both generate reactive oxygen species.

Herein are reported unique properties of the novel human thiamin diphosphate (ThDP)-dependent enzyme 2-oxoadipate dehydrogenase (hE1a), known as dehydrogenase E1 and transketolase domain-containing protein 1 that is encoded by the DHTKD1 gene. It is involved in the oxidative decarboxylation of 2-oxoadipate (OA) to glutaryl-CoA on the final degradative pathway of L-lysine and is critical for mitochondrial metabolism. Functionally active recombinant hE1a has been produced according to both kinetic and spectroscopic criteria in our toolbox leading to the following conclusions: (i) The hE1a has recruited the dihydrolipoyl succinyltransferase (hE2o) and the dihydrolipoyl dehydrogenase (hE3) components of the tricarboxylic acid cycle 2-oxoglutarate dehydrogenase complex (OGDHc) for its activity. (ii) 2-Oxoglutarate (OG) and 2-oxoadipate (OA) could be oxidized by hE1a, however, hE1a displays an approximately 49-fold preference in catalytic efficiency for OA over OG, indicating that hE1a is specific to the 2-oxoadipate dehydrogenase complex. (iii) The hE1a forms the ThDP-enamine radical from OA according to electron paramagnetic resonance detection in the oxidative half reaction, and could produce superoxide and H2O2 from decarboxylation of OA in the forward physiological direction, as also seen with the 2-oxoglutarate dehydrogenase hE1o component. (iv) Once assembled to complex with the same hE2o and hE3 components, the hE1o and hE1a display strikingly different regulation: both succinyl-CoA and glutaryl-CoA significantly reduced the hE1o activity, but not the activity of hE1a.

Ruthenium(II)-Catalyzed Direct C-H Arylation of Indoles with Arylsilanes in Water.

The ruthenium(II)-catalyzed, heteroatom-directed C-H arylation of indoles with arylsilanes in water has been developed. The method represents the first example of a ruthenium(II)-catalyzed oxidative C-H arylation in water/aqueous media as a sustainable solvent for C-H functionalization. The reaction enables the synthesis of a wide range of indoles with exquisite selectivity for arylation at the C-2 position. Preliminary mechanistic studies indicate reversibility of the C-H ruthenation step under the developed reaction conditions.

Highly chemoselective ruthenium(ii)-catalyzed direct arylation of cyclic and N,N-dialkyl benzamides with aryl silanes.

The ruthenium(ii)-catalyzed oxidative cross-coupling of C(sp2)-H bonds with organosilanes has been accomplished for the first time. This novel protocol enlists challenging cyclic and N,N-dialkyl benzamides as weakly-coordinating substrates to achieve highly regioselective C(sp2)-H arylation as a proof-of-concept, taking advantage of the attractive features of organosilanes as coupling partners. This innovative method is characterized by very high chemoselectivity, installing halide functional groups (I, Br, Cl) that are incompatible with Ru(ii)-carboxylate systems employing halides as cross-coupling partners, while obviating the need for sensitive organometallic reagents and cryogenic temperatures typical to the classic directed-ortho-metallation (DoM) techniques, employing benzamides to afford bioactive structural motifs.

Ruthenium(ii)-catalyzed ortho-C-H arylation of diverse N-heterocycles with aryl silanes by exploiting solvent-controlled N-coordination.

We report the first method for the direct, regioselective Ru(ii)-catalyzed oxidative arylation of C-H bonds in diverse N-heterocycles with aryl silanes by exploiting solvent-controlled N-coordination. The reaction takes advantage of the attractive features of organosilanes as coupling partners, providing proof of concept for N-directed Ru(ii)-catalyzed C-H arylation. This novel, operationally-simple and versatile protocol utilizes the Ru(ii)/CuF2 reagent system in which CuF2 serves as a dual activator/oxidant in non-coordinating solvents to accommodate for ligand N-coordination. This first Ru(ii)-catalyzed N-directed Hiyama C-H arylation offers broad implications to achieve numerous C-H bond functionalizations by versatile ruthenium(ii) catalysis manifold.

σ N-C Bond Difunctionalization in Bridged Twisted Amides: Sew-and-Cut Activation Approach to Functionalized Isoquinolines.

A rare example of highly selective σ N-C bond difunctionalization in bridged twisted lactams through N-C cleavage has been achieved. In combination with the intramolecular Heck cyclization, this method affords a two-step bond reorganization event ("sew-and-cut") to access functionalized isoquinoline ring systems directly with high atom economy. C-H bond functionalizations directed by a weakly coordinating bridged amide bond increase scaffold diversity. Preliminary mechanistic studies on the effect of amide distortion and the role of electrophile in this unusual σ N-C amide difunctionalization are described.

The human Krebs cycle 2-oxoglutarate dehydrogenase complex creates an additional source of superoxide/hydrogen peroxide from 2-oxoadipate as alternative substrate.

Recently, we reported that the human 2-oxoglutarate dehydrogenase (hE1o) component of the 2-oxoglutarate dehydrogenase complex (OGDHc) could produce the reactive oxygen species superoxide and hydrogen peroxide (detected by chemical means) from its substrate 2-oxoglutarate (OG), most likely concurrently with one-electron oxidation by dioxygen of the thiamin diphosphate (ThDP)-derived enamine intermediate to a C2α-centered radical (detected by Electron Paramagnetic Resonance) [Nemeria et al., 2014 [17]; Ambrus et al. 2015 [18]]. We here report that hE1o can also utilize the next higher homologue of OG, 2-oxoadipate (OA) as a substrate according to multiple criteria in our toolbox: (i) Both E1o-specific and overall complex activities (NADH production) were detected using OA as a substrate; (ii) Two post-decarboxylation intermediates were formed by hE1o from OA, the ThDP-enamine and the C2α-hydroxyalkyl-ThDP, with nearly identical rates for OG and OA; (iii) Both OG and OA could reductively acylate lipoyl domain created from dihydrolipoyl succinyltransferase (E2o); (iv) Both OG and OA gave α-ketol carboligaton products with glyoxylate, but with opposite chirality; a finding that could be of utility in chiral synthesis; (v) Dioxygen could oxidize the ThDP-derived enamine from both OG and OA, leading to ThDP-enamine radical and generation of superoxide and H2O2. While the observed oxidation-reduction with dioxygen is only a side reaction of the predominant physiological product glutaryl-CoA, the efficiency of superoxide/ H2O2 production was 7-times larger from OA than from OG, making the reaction of OGDHc with OA one of the important superoxide/ H2O2 producers among 2-oxo acid dehydrogenase complexes in mitochondria.

A highly enantioselective, organocatalytic [3+2]-cycloannulation reaction towards the de novo-synthesis of 1-cyclopentenyl-α-keto esters.

We disclose herein a highly enantioselective de novo-synthesis of chiral 1-cyclopentenyl-α-keto esters starting from a simple bis-silyl-1,3-dienediolate and α,ß-unsaturated aldehydes via a domino vinylogous Michael-intramolecular Knoevenagel-type condensation. The cyclopentenes proved to be highly versatile and were readily converted into various structural motifs.

Highly modular C(1) -symmetric chiral (P,N) ligands with a stereolabile P center: experimental and theoretical studies.

An improved synthesis of a novel class of bidentate (P,N) ligands is presented, the structures of which are characterized by three distinct elements of chirality. The stereoselective installation of the elements of central chirality (at the benzylic carbon and the phosphorus atom) depends on the size of the phosphorus substituent. Thermal inversion of the phosphorus center has been studied experimentally and further correlated by DFT calculations. The potential of these ligands and the role of the phosphorus atom in the asymmetric α-arylation of aldehydes (Pd) and hydrogenation of allylic alcohols (Ir) have also been investigated.

Atropoisomeric (P,N) ligands for the highly enantioselective Pd-catalyzed intramolecular asymmetric α-arylation of α-branched aldehydes.

Three-in-one: a short synthetic route readily gives access to a new class of chiral (P,N) ligands characterized by three distinct elements of chirality. These ligands are highly enantioselective in the challenging Pd-catalyzed intramolecular asymmetric α-arylation of α-branched aldehydes.

Rauhut-Currier type homo- and heterocouplings involving nitroalkenes and nitrodienes.

Reaction of nitroalkenes or nitrodienes with methyl vinyl ketone (MVK) or acrylate in the presence of the imidazole-LiCl catalyst system provides Rauhut-Currier (vinylogous Morita-Baylis-Hillman) adducts in moderate yield. Under similar conditions (imidazole-hydroquinone), nitroalkenes and nitrodienes undergo self-dimerization to afford the Rauhut-Currier adducts in varying yields. An alternative self-dimerization-nitro group elimination pathway in the presence tricyclohexylphosphine was observed with heteroaromatic nitroalkenes. A synthetically useful one-pot two step transformation of Rauhut-Currier adducts of nitroalkenes with MVK to 2,3-disubstituted cyclopentenones is also described.