A flow process for the multi-step synthesis of the alkaloid natural product oxomaritidine: a new paradigm for molecular assembly.

A flow process for the multi-step synthesis of the alkaloid natural product (+/-)-oxomaritidine is described, mediated through the use of microfluidic pumping systems that progress material through various packed columns containing immobilized reagents, catalysts, scavengers or catch and release agents; our route involves the combination of seven separate synthetic steps linked into one continuous sequence utilizing flow chemistry.

Non-metal-catalysed intramolecular alkyne cyclotrimerization reactions promoted by focussed microwave heating in batch and flow modes.

A number of oligomeric alkynes underwent [2 + 2 + 2] intramolecular trimerization to afford arenes under metal-free conditions using focussed microwave heating.

The use of a continuous flow-reactor employing a mixed hydrogen-liquid flow stream for the efficient reduction of imines to amines.

Imines have been reduced to amines in high yield, and with excellent chemoselectivity, by catalytic hydrogenation in a continuous flow-reactor, utilising an electrochemically-generated hydrogen source to produce a mixed hydrogen-liquid flow stream.

Asymmetric construction of quaternary stereocenters by direct organocatalytic amination of alpha-substituted alpha-cyanoacetates and beta-dicarbonyl compounds.

The first organocatalytic highly enantioselective reactions of substituted alpha-cyanoacetates and beta-dicarbonyl compounds with azodicarboxylates are reported. In the presence of 0.1-5 mol % of a quinidine-derived alkaloid beta-ICD, optically active quaternary hydrazine adducts are obtained in very high yields and with enantioselectivities up to >98% ee. A two-step procedure for the cleavage of the hydrazine N-N bond using SmI2 is also demonstrated.

The first catalytic inverse-electron demand hetero-Diels-Alder reaction of nitroso alkenes using pyrrolidine as an organocatalyst.

The first catalytic inverse-electron demand hetero-Diels-Alder reaction of nitroso alkenes has been developed. Nitroso alkenes were generated in situ from alpha-halooximes and underwent [4 + 2]-cycloadditions with enamines as dienophiles formed from aldehydes and pyrrolidine (10 mol%) as an organocatalyst. The presence of a suitable heterogeneous buffer system was found to be essential and best results were obtained with sodium acetate trihydrate. The resulting 5,6-dihydro-4H-oxazines were obtained in moderate to good yields under mild reaction conditions. A catalytic cycle has been proposed and evidence for the cycloaddition mechanism has been obtained. Moderate asymmetric induction (42% ee) was observed when a chiral secondary amine was used.

The first catalytic highly enantioselective alkylation of ketimines--a novel approach to optically active quaternary alpha-amino acids.

A series of novel ketimines with intrinsic protecting group anchoring was synthesized and allowed to react with various silylketene acetals in the presence of 5-10 mol % of a chiral Zn(OTf)(2)-(R,R)-Ph-pybox-aqua complex. The corresponding optically active quaternary alpha-amino acid derivatives were obtained in high yields and with enantioselectivities ranging from 34 % up to 95 % ee. The catalyst was studied by (1)H NMR spectroscopy and X-ray crystallography, and a dynamic equilibrium of two species was identified in solution. These are a homo-chiral 1:2 metal-ligand complex and a 1:1 metal-ligand complex, of which the latter is expected to be the actual catalyst of the diastereo- and enantioselective reaction. A strong positive nonlinear effect was observed due to the formation of a catalytically inactive 1:2 metal-ligand hetero-chiral complex. On the basis of DFT calculations and the absolute stereochemistry of the products, simultaneous coordination of the imino electrophile and a single molecule of H(2)O to the chiral Lewis acid complex is proposed. Coordination of the imine-nitrogen atom in the axial position of an octahedral complex can account for the facial selectivity as well as the diastereoselectivity observed.

Optically active aromatic and heteroaromatic alpha-amino acids by a one-pot catalytic enantioselective addition of aromatic and heteroaromatic C-H bonds to alpha-imino esters.

The development of a practical one-pot catalytic enantioselective procedure for the synthesis of non-natural aromatic and heteroaromatic alpha-amino acids is reported. Starting from readily available starting materials and application of a chiral BINAP-Cu(I) catalyst, the optically active products are formed with readily removable N-protecting groups. The scope of the reaction is demonstrated by the addition of substituted furans, thiophenes, pyrroles, and aromatic compounds to N-alkoxycarbonyl-alpha-imino esters in good yields and with enantioselectivities up to 96% ee for the furans, 93% ee for the thiophenes, and 98% for the aromatic compounds. The protecting groups are readily removed, and various transformations of the aromatic and heteroaromatic alpha-amino acids are demonstrated. The coordination of the N-alkoxycarbonyl alpha-imino ester to the chiral BINAP-Cu(I) complex and the enantioselectivity of the catalyst is discussed on the basis of the DFT calculations and X-ray crystallographic data.