Application of aldolases for the asymmetric synthesis of multifunctional chiral products is hampered by their reputed strict nucleophile (=aldol donor) specificity owing to a mechanistic requirement for creating a carbanion nucleophile in aqueous medium. Here we report that a minimalist engineering can extensively broaden the substrate scope of native D-fructose-6-phosphate aldolase (FSA) from Escherichia coli, for which hydroxyacetone is the most proficient substrate, to accept an unprecedented wide variety of alternative nucleophiles. By single-or double-space-generating mutations using simple conservative Leu to Ala replacement of active site residues, we found enzyme variants to efficiently convert larger ketols and bioisosteric ether components with up to seven skeletal atoms, including linear and branched-chain structures. All reactions occurred with full retention of the natural D-threo diastereospecificity. These FSA variants open new avenues toward the synthesis of novel product families that hitherto were inaccessible by biological catalysis.

A trisilenediide: The reduction of dichlorotrisilene 1 with active magnesium leads to α,ω‐dianionic trisilene 2, which is characterized by NMR spectroscopy and X‐ray diffraction. The potential of 2 as a precursor in the synthesis of heterocycles incorporating a SiSi double bond is demonstrated by the formation of stannatrisilacyclobutene 3.

A structure for the self-condensation product of 2-(1H-indol-2-yl)ethyl tosylate 2a, previously proposed as 6,7,14,15-tetrahydro-15aH-azocino[1,2-a:6,5-b]diindole 3a, was revised based on the (13)C-2D-INADEQUATE experiment, and proved to be 7,7a,13,14-tetrahydro-6H-cyclobuta[b]pyrimido[1,2-a:3,4-a']diindole 4a. A mechanism for the unexpected formation of this novel hexacyclic heterocycle was proposed and its NMR solution structure was elucidated. Five derivatives of the title ring skeleton 12-16 designed as melatonin receptor ligands were synthesized and their affinities for the human MT(1) and MT(2) receptors were determined. Both butyramides 13 and 15, as well as the non-methoxy acetamide 12 exhibited micromolar binding affinities for both receptors being slightly MT(2) selective. The methoxy acetamide 14 showed the best pharmacological profile exhibiting a five times higher affinity for MT(1) (K(i) = 49 nM) than for MT(2) (K(i) = 246 nM) receptor.

Ein α,ω‐dianionisches Trisilen wurde durch Reduktion von Dichlortrisilen 1 mit aktivem Magnesium hergestellt. Das Trisilendiid 2 wurde durch NMR‐Spektroskopie und Kristallstrukturanalyse charakterisiert. Sein Potenzial als Ausgangsverbindung in der Synthese von Heterocyclen mit Si‐Si‐Doppelbindung wird durch die Bildung des Stannatrisilacyclobutens 3 aus 2 und Me2SnCl2 betont.