Palladium-Catalyzed Cascade Assembly of Tricyclic Spiroethers from Diene-Alcohol Precursors.

Palladium-catalyzed carboetherification-Heck reactions to form tricyclic spiroethers, which are frequently observed as scaffold segments of various biochemical compounds, from simple diene-alcohols have been carried out in a cascade fashion. This is the first attempt to link simple alcohols with diverse, medium-sized spiroether architectures. The reported synthetic strategy is short and robust and offers rapid delivery of a broad spectrum of tricyclic spiranoid ethers.

Multifaceted α-Enaminone: Adaptable Building Block for Synthesis of Heterocyclic Scaffolds Through Conceptually Distinct 1,2-, 1,3-, 1,4-, and C-O Bond Forming Annulations.

The new reactivity of α,ß-unsaturated enaminones driven by their "dual electronic attitude" is reported. We introduce unexplored, α-enaminone synthones and reveal the unusual functionalities of these building blocks. The feasibility of this new concept is demonstrated in the direct functionalization of enaminone precursors, such as alkylation; 1,2- 1,3-, or 1,4-addition; and C-O bond formation. The general and potential applicability is presented through the collective synthesis of several important classes of heterocycles via controlled cyclizations of easily accessible common precursors. The rapid composition of novel key α-enaminone synthones yields an assembly of oxazines, azaspirones, quinolinones, and quinolinols in a regio- and chemoselective fashion.

Stereo- and Regioselective Synthesis of Tricyclic Spirolactones by Diastereoisomeric Differentiation of a Collective Key Precursor.

A general, parallel, and collective synthesis of 5/5/5- and 5/5/6-ring fusion topologies of tricyclic spiranoid lactones through the controlled cyclizations of easily accessible, common key precursors is described. The rapid composition of key cycloalkyl methylene precursors yielded an assembly of bicyclic diastereoisomeric iodolactones, which were individually converted into a wide range of tricyclic, angularly fused spiranoid lactones in a regioselective and stereodirected fashion through the diastereoisomeric differentiation of a collective key precursor. The critical stereochemical assignment of the bicyclic starting materials, as well as the tricyclic targets, was confirmed by X-ray crystal structure determination.

Synthesis of Tricyclic Spiranoid Lactones via I2/Sm(II)- and I2/Pd(0)-Mediated Cyclizations of a Common Cycloalkylmethylene Precursor.

A general synthesis of phylogenetically and structurally different tricyclic angularly fused spiranoid lactones, frequently observed as scaffold segments of various biochemical compounds and drugs of natural origin, is demonstrated via controlled cyclization of simple and easily accessible cycloalkylmethylene key precursors. The rapid composition of the key architecture yields an assembly of stable bicyclic iodolactones, which are converted to form a wide range of angularly fused tricyclic scaffolds.

Concise palladium-catalyzed synthesis of dibenzodiazepines and structural analogues.

A general and highly efficient protocol for the synthesis of dibenzodiazepines and their structural analogues is reported. In the presence of catalytic quantities of palladium, readily accessible precursors are cross-coupled with ammonia and then spontaneously undergo an intramolecular condensation to form the corresponding dibenzodiazepines in one step. This new strategy is applicable to the construction of a wide variety of dibenzooxazepines and other structurally related heterocycles.

Synthesis of heterocycles via Pd-ligand controlled cyclization of 2-chloro-N-(2-vinyl)aniline: preparation of carbazoles, indoles, dibenzazepines, and acridines.

The Pd-catalyzed condensation of 2-bromostyrene and 2-chloroaniline derivatives yields stable diphenylamine intermediates, which are selectively converted to five-, six-, or seven-membered heteroaromatics (indoles, carbazoles, acridines, and dibenzazepines). The selectivity of these intramolecular transformations is uniquely ligand-controlled and offers efficient routes to four important classes of heterocycles from a common precursor.

Neurotropic activity and safety of methylene-cycloalkylacetate (MCA) derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid.

Polyneuropathy is a disease involving multiple peripheral nerves injuries. Axon regrowth remains the major prerequisite for plasticity, regeneration, circuit formation, and eventually functional recovery and therefore, regulation of neurite outgrowth might be a candidate for treating polyneuropathies. In a recent study, we synthesized and established the methylene-cycloalkylacetate (MCAs) pharmacophore as a lead for the development of a neurotropic drug (inducing neurite/axonal outgrowth) using the PC12 neuronal model. In the present study we extended the characterizations of the in vitro neurotropic effect of the derivative 3-(3-allyl-2-methylenecyclohexyl) propanoic acid (MCA-13) on dorsal root ganglia and spinal cord neuronal cultures and analyzed its safety properties using blood biochemistry and cell counting, acute toxicity evaluation in mice and different in vitro "off-target" pharmacological evaluations. This MCA derivative deserves further preclinical mechanistic pharmacological characterizations including therapeutic efficacy in in vivo animal models of polyneuropathies, toward development of a clinically relevant neurotropic drug.

Proline-promoted dehydroxylation of α-ketols.

A new single-step proline-potassium acetate promoted reductive dehydroxylation of α-ketols is reported. We introduce the unexplored reactivity of proline and, for the first time, reveal its ability to function as a reducing agent. The developed metal-free and open-flask operation generally results in good yields. Our protocol allows the challenging selective dehydroxylation of hydroxyketones without affecting other functional groups.

Methylene-Cycloalkylacetate (MCA) Scaffold-Based Compounds as Novel Neurotropic Agents.

One of the main symptoms in degenerative diseases is death of neuronal cell followed by the loss of neuronal pathways. In neuronal cultures, neurite outgrowths are cell sprouts capable of transforming into either axons or dendrites, to further form functional neuronal synaptic connections. Such connections have an important role in brain cognition, neuronal plasticity, neuronal survival, and regeneration. Therefore, drugs that stimulate neurite outgrowth may be found beneficial in ameliorating neural degeneration. Here, we establish the existence of a unique family of methylene-cycloalkylacetate-based molecules (MCAs) that interface with neuronal cell properties and operate as acceptable pharmacophores for a novel neurotropic (neurite outgrowth inducing) lead compounds. Using an established PC12 cell bioassay, we investigated the neurotropic effect of methylene-cycloalkylacetate compounds by comparison to NGF, a known neurotropic factor. Micrographs of the cells were collected by using a light microscope camera, and digitized photographs were analyzed for compound-induced neurotropic activity using an NIH image protocol. The results indicate that the alkene element, integrated within the cycloalkylacetate core, is indispensable for neurotropic activity. The discovered lead compounds need further mechanistic investigation and may be improved toward development of a neurotropic drug.

Tricyclic Spirolactones as Modular TRPV1 Synthetic Agonists.

TRPV1 is a prominent signal integrator of the pain system, known to be activated by vanilloids, a family of endogenous and exogenous pain-evoking molecules, through the vanilloid-binding site (VBS). The extensive preclinical profiling of small molecule inhibitors provides intriguing evidence that TRPV1 inhibition can be a useful therapeutic approach. However, the dissimilarity of chemical species that activate TRPV1 creates a major obstacle to understanding the molecular mechanism of pain induction, which is viewed as a pivotal trait of the somatosensory system. Here, we establish the existence of a unique family of synthetic agonists that interface with TRPV1 through the VBS, containing none of the molecular domains previously believed to be required for this interaction. The overarching value obtained from our inquiry is the novel advancement of the existing TRPV1 activation model. These findings uncover new potential in the area of pain treatment, providing a novel synthetic platform.

Cascade Pd(II)-catalyzed Wacker lactonization-Heck reaction: rapid assembly of spiranoid lactones.

An unprecedented Pd-catalyzed cascade Wacker-Heck lactonization-cyclization sequence is reported. The process provides a facile approach to bi- and tricyclic spiranoid lactones in good yields. The reaction shows general substrate scope and a broad functional group tolerability. In addition, a rare 4-exo trig Heck-type cyclization is demonstrated.

Lanthanide-promoted ethylation of Schiff bases by triethylaluminum.

[reaction: see text] Schiff bases of aromatic aldehydes and anilines that fail to react with triethylaluminum are smoothly alkylated at room temperature in the presence of lanthanide catalysts. The alkylation takes place selectively at the vinylic carbon atom.

Palladium-catalyzed cross-alkynylation of aryl bromides by sodium tetraalkynylaluminates.

Sodium tetraalkynylaluminates (1-4), prepared from NaAlH4 and terminal alkynes, cross-couple with aryl bromides in the presence of Pd(0) and Pd(II) catalysts. The reactions take place in boiling THF or DME. The process is applicable to both homo- and heterocyclic aryl bromides and can be used for conversion of polybromo compounds into polyalkynes. The reactions are high yielding and selective, free of undesired homocoupling and hydrogenolysis processes. The reagents selectively react with the ring-bound bromine atoms but do not affect chloro, cyano, triflate, or ester functions.