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Fast Microwave Enhanced b,b-selective Heck Arylation of (2-ethenyloxiethyl)-
dialkylamines and the synthesis of a new class of melanocortin receptor ligands
By subjection of the (2-ethenyloxiethyl)-dialkylamine scaffold to aryl halides under Heck conditions, the incoming aryl moiety is typically b-directed due to chelatation control (right fig). The b,b-diarylated products has been found interesting from a medicinal point of view. A diverse set of aryl moieties has been introduced through in most cases expedient reactions (reaction time 20 minutes) giving rise to compounds of either two similar aryl moieties, or a phenyl and another moiety. The methodology allows the reaction to be tuned in favor of either geometric isomer. As a part of an industrial cooperation project, a series of compounds was synthesized utilizing the developed protocol rendering a diverse set of compounds (differing in R, R', Ar and Ar') suggested as melanocortin receptor ligands.

Potent GABAA-ligands have previously been synthesized based on the platform 5-(4-piperidyl)-3-isoxazol (4-PIOL, figure below). By substituting the 4-position with suitable substituents, high affinity GABAA-receptor antagonists can be assembled. A potent (Ki = 1.8 nM) 4-PIOL analog has been used as a template in the design of fluorescent GABAA-ligands. The ligand is believed to bind in the receptor cavity with the 4-substituent located in a pocket adjacent to the surrounding interstitial liquid.
Two approaches have been investigated in this project: In the one-component model, a fluorescent group is positioned in the 4-position of 4-PIOL resulting in a ligand with intrinsic fluorescent properties. Since the receptor affinity of the ligand can not be ensured, a series of compounds with different fluorescent groups have to be prepared. Since many of the fluorescent groups available are chemically labile, a route subjecting the fluorophore to a minimum of chemical tension has to be developed.
In the two-component approach, a suitable fluorescent group carrier will be positioned in the 4-position of 4-PIOL designed to render a high-affinity ligand, and at this platform, a nucleophilic handle will be positioned allowing the connection of an arbitrary fluorescent ligand to be positioned outside the receptor pocket in the surrounding interstitial fluid.

Catalytic role of palladacycles reveled
The inorganic palladium(II)salts commonly employed as palladium sources has gradually been replaced by palladacycles. The mechanistic rational for their catalytic role has however been debated. A PdII-PdVI catalytic cycle has been suggested to be operative in contrast to the classical Pd0-PdII cycle (right fig.). By ESI-MS investigations on aliquots taken from reaction mixtures of palladacycle catalyzed reactions, it has been possible to follow the successive degradation and release of active Pd0-species in the reaction mixture. All the reported palladium containing species has also been ambiguously determined by ESI-MSMS. We have also demonstrated that by subjecting the palladium catalyst to different ligand combinations, it has been possible to tune the catalytic effect in a manner that would not be possible if a PdII-PdIV catalytic cycle was operative.

New Carboxylic Acid Isostere by One pot Isomerization and 3-arylation of 1,2-cyclohexandione
The 1,2-cyclohexandione scaffold has been suggested as a prospective carboxylic acid isostere for medicinal applications. Palladium catalyzed reactions on 1,2-cyclohexane has however been problematic, suggestively due to its strong metal-chelating effect. The in-situ generation of 1,2-cyclohexandione from the precursor 2,3-epoxycyclohexandione followed by Heck arylation has thus been envisaged as an improved route to 3-aryl-1,2-cyclohexandiones. An expedient microwave-promoted protocol for the tandem isomerization/3-arylation of the starting epoxide has successfully been developed yielding the corresponding 3-aryl-1,2-cyclohexandiones through an environmentally benign procedure (NaOAc base, aqueous PEG reaction media, fig. right). A series of electronically and functionally diverse aryl bromides have been tested rendering in most cases high yields (moderate-poor for strongly electron-poor bromides). The utilization of PEG as solvent allows an expedient (~ 15 minutes) downstream workup and purification procedure. The mechanism has been pervasively investigated using a retarded model system.

First Spiro-cyclization of Highly Electron rich and Capto-dative Olefins and Vinyl Acetates
Spiro-compounds may play an important role in medicinal chemistry as conformationally restricted building blocks, although the usefulness is restricted due to lack of synthetic methods. Only moderately electron-rich olefinic precursors (N-carbonyl enamines) and no capto-dative olefins have previously been reported as substrates for Heck-cyclizations. A series of o-halobenzyl cyclohexenyl ether derivatives including highly electron-rich (vinyl ethers) and capto-dative olefins and surprisingly vinyl acetates (no p-allyl reactions found) was used as substrates for heck cyclization rendering the corresponding spiro-compound (fig. right). Most reactions were performed in no less than 10 minutes and double-bond migration could be controlled by the choice of conditions.

Inhibitors of Malarial Plasmepsin II
A route to a new class of Plasmepsin II inhibitors was developed (fig. 9). Most of the reactions were performed in high or excellent yields and without recemization of stereocenters. The epoxide opening turned out to be insensitive to the choice of amine. The alkylation step with methyl bromoacetate produced an ester/lacton mixture. The cyclization could neither be prevented nor brought to completion without decreased yield. Minimalistic model compounds however indicated that lacton 26 was considerably more reactive towards transamination than the starting ester which might explain the surprisingly high yield.

The 5-HT2C-receptor regulates a variety of behaviours such as cognition, emotion, attention and apatite. Consequently, the 5-HT2C-system has emerged as a promising target for the development of drugs with anxiolytic, antidepressive, antipsychotic and apatite reducing effects. In an ongoing project dedicated to develop therapeutic drugs targeting the 5-HT2C-receptor system, tranylcypromine has been found in a screening champagne to exert 5HT2C-agonistic properties. Initial SAR studies has revealed that potent and selective low molecular weight 5-HT2C-agonists can be derived from the trans-aminomethyl-2-phenylcyclopropane scaffold. Efforts are currently undertaken to optimize the scaffold in matter of potency, selectivity and drug properties.