Artur Noole

Enantioselective Henry Reaction Catalyzed by CuII Salt and Bipiperidine

A complex derived from the enantiomeric bipiperidine and copper(II) acetate hydrate is an efficient catalyst for the enantioselective Henry reaction. The easy availability of both catalyst components, mild reaction conditions, high yield, and good to excellent enantioselectivity make the catalyst useful for everyday practice.

Highly Enantio‐ and Diastereoselective Generation of Two Quaternary Centers in Spirocyclopropanation of Oxindole Derivatives.

Spirocyclopropanes: Only one out of eight possible stereoisomers was obtained in the asymmetric cascade cyclopropanation of alkylidene oxindoles with ethyl 2-chloroacetoacetate. Improved catalyst design ensured that spirocyclopropyl oxindoles featuring two quaternary centers were synthesized in high yield and high enantio- and diastereoselectivity (see scheme).

Enantioselective Organocatalytic Aza-Ene-Type Domino Reaction Leading to 1,4-Dihydropyridines

A new general methodology was developed to access highly enantiomerically enriched 1,4-dihydropyridines (DHPs) 3 via an organocatalytic asymmetric aza-ene-type cascade reaction, cocatalyzed by (S)-diarylprolinol-TMS ether V and benzoic acid (BA). Both aliphatic and aryl enals 1 reacted smoothly with enaminones and β-enamino esters 2, affording highly functionalized 1,4-DHPs 3 in high enantioselectivities and good yields.

Asymmetric synthesis of congested spiro-cyclopentaneoxindoles via an organocatalytic cascade reaction.

Starting from simple alkylidene oxindoles and nitroketones, a highly stereoselective methodology was developed for the synthesis of spiro-cyclopentaneoxindoles with four consecutive stereogenic centers. Using an organocatalytic cascade of Michael and aldol reactions in the presence of a chiral thiourea catalyst products were obtained in moderate to high yields and excellent enantioselectivities. Nitro, ester, and hydroxyl groups were introduced to the spiro ring, which could be used to facilitate further functionalization of the products.

INDOLE-LIKE TRK RECEPTOR ANTAGONISTS

The virtual screening for new scaffolds for TrkA receptor antagonists resulted in potential low molecular weight drug candidates for the treatment of neuropathic pain and cancer. In particular, the compound (Z)-3-((5-methoxy-1H-indol-3-yl)methylene)-2-oxindole and its derivatives were assessed for their inhibitory activity against Trk receptors. The IC50 values were computationally predicted in combination of molecular and fragment-based QSAR. Thereafter, based on the structure-activity relationships (SAR), a series of new compounds were designed and synthesized. Among the final selection of 13 compounds, (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-N-methyl-2-oxindole-5-sulfonamide showed the best TrkA inhibitory activity using both biochemical and cellular assays and (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-2-oxindole-5-sulfonamide was the most potent inhibitor of TrkB and TrkC.