Mid Sweden University

A direct catalytic stereoselective synthesis of C4’ functionalized furanoside and nucleoside derivatives with a tetrasubstituted stereocenter is disclosed. The amine-catalyzed stereoselective α-aminomethylation reactions on furanoside-derived aldehyde derivatives gave the corresponding C4’ functionalized D- or L-ribose derivatives in good to excellent yields (67−94%) with up to >20:1 dr. 

Classical Crabbé type SN2' substitutions of propargylic substrates has served as one of the standard methods for the synthesis of allenes. However, the stereospecific version of this transformation often requires either stoichiometric amounts of organocopper reagents or special functional groups on the substrates, and the chirality transfer efficiency is also capricious. Herein, we report a sustainable methodology for the synthesis of diverse 1,3-di and tri-substituted allenes by using a simple and cheap cellulose supported heterogeneous nanocopper catalyst (MCC-Amp-Cu(I/II)). This approach represents the first example of heterogeneous catalysis for the synthesis of chiral allenes. High yields and excellent enantiospecificity (up to 97 % yield, 99 % ee) were achieved for a wide range of di- and tri-substituted allenes bearing various functional groups. It is worth noting that the applied heterogeneous catalyst could be recycled at least 5 times without any reduced reactivity. To demonstrate the synthetic utility of the developed protocol, we have applied it to the total synthesis of several chiral allenic natural products. 

Dynamic kinetic asymmetric transformations (DYKAT) are an important way of converting simple organic molecules into complex small molecules as single diastereo- and enantiomers. Herein we describe selected examples that are catalyzed by small organic molecules, which utilize activation mechanisms similar to enzymes for accomplishing the high stereoselectivity. The research area of DYKAT is growing and remarkable examples for producing important organic molecules and pharmaceuticals are demonstrated. In this context, organocatalysis will play an important role.

Functionalized triose-, furanose and chromane-derivatives were synthesized by the titled reactions. The sugar-assisted kinetic resolution/C−C bond-forming cascade processes generate a functionalized sugar derivative with a quaternary stereocenter in a highly enantioselective fashion (up to >99 % ee) by using a simple combination of metal and chiral amine co-catalysts. Notably, the interplay between the chiral sugar substrate and the chiral amino acid derivative allowed for the construction of a functionalized sugar product with high enantioselectivity (up to 99 %) also when using a combination of racemic amine catalyst (0 % ee) and metal catalyst. 

Herein, we describe an efficient nanocopper-catalyzed Alder-ene reaction of allenynamides. The copper nanoparticles were immobilized on amino-functionalized micro-crystalline cellulose. A solvent-controlled chemoselectivity of the reaction was observed, leading to the chemodivergent synthesis of pyrrolines (2,5-dihydropyrroles) and pyrroles. The heterogeneous copper catalyst exhibits high efficiency and good recyclability in the Alder-ene reaction, constituting a highly attractive catalytic system from an economical and environmental point of view.

The discovery and investigation of solvent dependency in stereoselective intramolecular amidation of chiral 5-aminofunctionalized-2-fluoromalonate ester derivatives, which gives access to highly functionalized δ-lactams with a quaternary fluorine-containing stereocenter, is disclosed. Experimental work together with density functional theory calculations led to understanding of how to direct and switch the stereochemical outcome of the stereoselective δ-lactam formation. The merging of this solvent-dependent stereoselective switch with asymmetric catalysis and cascade reactions gives access to an unprecedented strategy for stereodivergent synthesis of all possible stereoisomers of fluorine-containing stereocenters adjacent to tertiary stereocenters of a wide range of heterocyclic compounds with 95->99% ee in one-pot. It is also useful for application in total synthesis of fluorine-containing pharmaceuticals. 

The ability of intermolecular cooperative thiourea/oxime hydrogen-bond catalysis for improving and accelerating asymmetric aminocatalysis is presented. The two readily available hydrogen-bond-donating catalysts operates in synergy with a chiral amine catalyst to accomplish highly stereoselective transformations. The synergistic catalyst systems simultaneously activate both electrophiles and nucleophiles, and make the transformations more chemo- and stereoselective. This was exemplified by performing co-catalytic enantioselective direct intermolecular α-alkylation reactions of aldehydes, direct aldol reactions, and asymmetric conjugate reactions, which gave the corresponding products in high yields and enantiomeric ratios.

A versatile strategy for the enantioselective synthesis of bicyclic lactam N,S-acetals by one-pot cascade transformations is disclosed. The transformation of readily available substrates is promoted by chiral amines and creates bicyclic or tricyclic lactam N,S-acetals with high chemo- and stereoselectivity (up to > 99.5:0.5 dr and > 99 % ee) in one-pot operations.

A catalytic asymmetric strategy for the total synthesis of quinuclidine natural products, which includes the completed enantioselective synthesis of the classical targets quinine and quinidine is disclosed. It is based on catalytic asymmetric cascade transformations, which paves the road for the synthesis of both enantiomers of the crucial C4 stereocenter with high enantioselectivity (up to 99 % ee) in one pot. Next, developing a route to all possible stereoisomers of a common early-stage intermediate sets the stage for the total synthesis of different enantiomers or epimers of quinine, quinidine and analogues with high selectivity.