A modular, stereodiversified and scalable synthesis of 5-membered cyclic N-hydroxylamidines endowed with three contiguous stereogenic centres is reported. The synthesis utilizes 2-cyano-3-aryl-4-nitroalkynoates as key building blocks, which are provided by a novel 3-component Knoevenagel -Michael addition manifold carried out as an aqueous emulsion (on water). The key building blocks are obtained as separable mixtures of two series of diastereomers: 2,3,4-syn,syn and 2,3,4-syn,anti. Both series were separately transformed into the corresponding 5-membered 3,4,5-trisubstituted N-hydroxylamidines by a tandem hydrogenation cyclization reaction (stereodiversification phase). These N-hydroxylamidines are functionalized at C 3 -methinic position of the ring (alpha to the amidine function) by a robust and unprecedented Namidinoxyl radical-mediated auto-oxidation process (hydroxylation), or by a diastereoselective enaminebased CÀC bond forming manifold (creation of an all-carbon quaternary centre). The outcome of the latter is biased by the relative disposition of substituents in the ring, affording C 3 -quaternized 5-membered cyclic Nhydroxylamidines or 2,9-diazabicyclo[4.3.0]non-1-en motives. Finally, the Ti(III)-reduction of these quaternized N-hydroxylamidines generates the corresponding amidines in excellent yields.

A convenient, instrumentally simple, and efficient methodology to transform 1,2-dihydropyridines into benzoic esters is described. The generated multisubstituted benzoic esters feature different topologies spanning from simple aromatic rings to fused benzocycloalkane systems. As an extension of this methodology, these benzoic esters are efficiently transformed into an array of fluorenone frameworks featuring interesting and novel topological patterns.

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