Antiprotozoal Activity of Azabicyclo-Nonanes Linked to Tetrazole or Sulfonamide Cores.

N-(Aminoalkyl)azabicyclo[3.2.2]nonanes possess antiplasmodial and antitrypanosomal activity. A series with terminal tetrazole or sulfonamido partial structure was prepared. The structures of all new compounds were confirmed by NMR and IR spectroscopy and by mass spectral data. A single crystal structure analysis enabled the distinction between isomers. The antiprotozoal activities were examined in vitro against strains of Plasmodium falciparum and Trypanosoma brucei rhodesiense (STIB 900). The most active sulfonamide and tetrazole derivates showed activities in the submicromolar range.

Efficacy of Four-Channel Functional Electrical Stimulation on Moderate Arm Paresis in Subacute Stroke Patients-Results from a Randomized Controlled Trial.

This preliminary randomized clinical trial explores the efficacy of task-oriented electromyography (EMG)-triggered multichannel functional electrical stimulation (EMG-MES) compared to single-channel cyclic neuromuscular electrical stimulation (cNMES) on regaining control of voluntary movements (CVM) and the ability to execute arm-hand-activities in subacute stroke patients with moderate arm paresis. Twelve ischemic stroke patients (Fugl-Meyer Assessment Arm Section (FMA-AS) score: 19-47) with comparable demographics were block-randomized to receive 15 sessions of cNMES or EMG-MES over three weeks additionally to a conventional neurorehabilitation program including task-oriented arm training. FMA-AS, Box-and-Block Test (BBT), and Stroke-Impact-Scale (SIS) were recorded at baseline and follow-up. All participants demonstrated significant improvement in FMA-AS and BBT. Participants treated with EMG-MES had a higher mean gain in FMA-AS than those treated with cNMES. In the SIS daily activities domain, both groups improved non-significantly; participants in the EMG-MES group had higher improvement in arm-hand use and stroke recovery. EMG-MES treatment demonstrated a higher gain of CVM and self-reported daily activities, arm-hand use, and stroke recovery compared to cNMES treatment of the wrist only. The protocol of this proof-of-concept study seems robust enough to be used in a larger trial to confirm these preliminary findings.

Enantioselective iridium-catalyzed allylic amination of ammonia and convenient ammonia surrogates.

Iridium-catalyzed, asymmetric allylation of ammonia as a nucleophile occurs with stereoselectivity to form a symmetric diallylamine, and related allylation of the inexpensive ammonia equivalent potassium trifluoroacetamide or the highly reactive ammonia equivalent lithium di-tert-butyliminodicarboxylate forms a range of conveniently protected, primary, alpha-branched allylic amines in high yields, high branched-to-linear regioselectivities, and high enantiomeric excess. The reactions of ammonia equivalents were conducted with a catalyst generated from a phosphoramidite containing a single stereochemical element.

Effects of catalyst activation and ligand steric properties on the enantioselective allylation of amines and phenoxides.

[reaction: see text] The yields, enantioselectivities, and regioselectivities of the reactions of amines and phenoxides with allylic carbonates in the presence of a metallacyclic iridium catalyst were compared. These data show that both preactivation of the catalyst and the size of the ligand affect the yield, enantioselectivity, and regioselectivity. With the activated catalyst containing a bis-naphthethylamino group, the allylic amination and etherification of a broad range of allylic carbonates occurred in high yields and with high regioselectivities and enantioselectivities.

Sequential catalytic isomerization and allylic substitution. Conversion of racemic branched allylic carbonates to enantioenriched allylic substitution products.

A catalytic protocol for the conversion of readily accessible racemic, branched aromatic allylic esters to branched allylic amines, ethers, and alkyls has been developed. Palladium-catalyzed isomerization of branched allylic esters to terminal allylic esters, followed by sequential iridium-catalyzed allylic substitution, gave the branched allylic products in good yield with high regioisomeric and enantiomeric selectivity. Both electron-rich and electron-poor branched allylic esters gave products in >90% ee. High enantiomeric excesses were also observed for the products from the reactions of 2-thienyl acetates and dienyl carbonates.

A simple iridium catalyst with a single resolved stereocenter for enantioselective allylic amination. Catalyst selection from mechanistic analysis.

A study of the relationship between the stereochemical elements of a phosphoramidite ligand and the stereoselectivity of iridium-catalyzed amination of allylic carbonates is reported. During catalyst activation, a complex of a phosphoramidite ligand possessing one axial chiral binaphtholate group and two resolved phenethyl substituents converts to a more reactive cyclometalated complex containing one distal chiral substituent at nitrogen, one substituent that becomes part of the metalacycle, and one unperturbed binaphtholate group. Systematic changes were made to the different stereochemical elements. Replacement of the distal chiral phenethyl substituent with a large achiral cycloalkyl group led to a catalyst that reacts with rates and enantioselectivities that are similar to those of the original catalyst with the phenethyl group. Studies of the reactions of diastereomeric ligands containing (R) or (S) binaphtholate groups on phosphorus, along with one (R)-phenethyl and one achiral cyclododecyl group on nitrogen, show that the complexes of the two diastereomeric ligands undergo cyclometalation at much different rates. To access both diastereomeric catalysts and to determine if the reaction can occur selectively with an even simpler ligand containing a phenethyl substituent at nitrogen as the only resolved stereochemical element, the catalyst derived from a phosphoramidite containing a biphenolate group was studied. Catalysts generated from this ligand were shown to react in all cases examined with nearly the same rates, regioselectivities, and enantioselectivities as catalysts derived from the original more elaborate ligand. The absolute stereochemistry of the product implies that the major enantiomer is formed from the (R(a),R(c))-atropisomer of the catalyst containing the biphenolate group.

Iron-catalyzed cross-coupling reactions.

Simple iron salts such as FeCl(n), Fe(acac)(n) (n = 2,3) or the salen complex 4 turned out to be highly efficient, cheap, toxicologically benign, and environmentally friendly precatalysts for a host of cross-coupling reactions of alkyl or aryl Grignard reagents, zincates, or organomanganese species with aryl and heteroaryl chlorides, triflates, and even tosylates. An "inorganic Grignard reagent" of the formal composition [Fe(MgX)(2)] prepared in situ likely constitutes the propagating species responsible for the catalytic turnover, which occurs in many cases at an unprecedented rate even at or below room temperature. Because of the exceptionally mild reaction conditions, a series of functional groups such as esters, ethers, nitriles, sulfonates, sulfonamides, thioethers, acetals, alkynes, and -CF(3) groups are compatible. The method also allows for consecutive cross-coupling processes in one pot, as exemplified by the efficient preparation of compound 12, and has been applied to the first synthesis of the cytotoxic marine natural product montipyridine 8. In contrast to the clean reaction of (hetero)aryl chlorides, the corresponding bromides and iodides are prone to a reduction of their C-X bonds in the presence of the iron catalyst.

Palladium-catalyzed addition of mono- and dicarbonyl compounds to conjugated dienes.

An intermolecular, palladium-catalyzed addition of the alpha-C-H bond of monocarbonyl and 1,3-dicarbonyl compounds to dienes has been developed, and an exploration of the scope of these reactions with a broad range of carbonyl compounds and nitriles was conducted. The combination of CpPd(allyl) and the commercially available 1,3-bis(dicyclohexylphosphino)propane (DCyPP) catalyzed the 1:1 addition of the C-H bonds of these substrates to dienes in high yields. These reactions included unusual additions of the C-H bonds of ketones, lactones, esters, and nitriles to dienes, as well as the more common additions of cyanoesters, malononitrile, and alpha-sulfonyl esters. Reactions of these substrates with both cyclic and acyclic dienes are reported. Reactions catalyzed by complexes of nonracemic chiral ligands were also conducted, and the first enantioselective version of this reaction was achieved with a Josiphos ligand with enantioselectivities up to 81%.

Editing the stereochemical elements in an iridium catalyst for enantioselective allylic amination.

Individual diastereomeric phosphoramidites and mixtures of diastereomeric phosphoramidites were evaluated in the iridium-catalyzed amination of allylic carbonates. The original process was conducted with a phosphoramidite ligand containing a resolved 2,2-dihydroxy-1,1-binaphthyl (BINOL) group and a diastereomerically and enantiomerically pure bis(phenethyl)amino group. Evaluation of the structure of the active catalyst and relative rates for reactions in the presence of catalysts containing diastereomeric ligands led to the identification of a phosphoramidite that provided the amination product with enantiomeric excess similar to the original, more structurally and stereochemically complex ligand and that contains a racemic BINOLate and an N-benzylphenethylamino group on phosphorus.

Catalysis-based enantioselective total synthesis of the macrocyclic spermidine alkaloid isooncinotine.

A concise and efficient total synthesis of the spermidine alkaloid (-)-isooncinotine (1) incorporating a 22-membered lactam ring is outlined. The approach is largely catalysis-based, involving a selective iron-catalyzed alkyl-aryl cross-coupling reaction of a difunctionalized pyridine substrate, a heterogeneous asymmetric hydrogenation step to set the chiral center of the target, and a highly integrated ring-closing metathesis/hydrogenation sequence to forge the saturated macrocyclic edifice in a single operation.