Enantiodivergent Cyclization by Inversion of the Reactivity in Ambiphilic Molecules.

Inverting the reactivity of the functional groups in ambiphilic molecules provides a new synthetic strategy to perform late-stage enantiodivergence. Both enantiomers of the final compound can be obtained from a common chiral precursor. As a proof of concept, the synthesis of substituted five- and six-membered oxacycles is described. The key step is the cyclization of an ambiphilic linear precursor bearing a propargylic alcohol and an epoxide linked through an alkyl chain. Through a slight modification of these linear precursors and employing different reaction conditions, these functional groups can inverse their chemical reactivity, producing one enantiomer or another of the final product. This enantiodivergent cyclization involves three stereogenic centers that can undergo fully controlled retention or inversion of their configuration depending on the cyclization pathway that is activated. The cyclization provides late-stage enantiodivergence, enabling the synthesis of either enantiomers of the oxacycles from a common chiral substrate with total transfer of the enantiomeric purity.

Chemoenzymatic Total Synthesis and Structural Revision of Ampelomins B, D, E, and epi-Ampelomin B.

Enantioselective synthesis of ampelomin B and epi-ampelomin B, D, and E was accomplished starting from toluene, through a chemoenzymatic sequence, in which stereoselective hydrogenation, Mitsunobu reaction, and regio- and stereoselective nucleophilic opening of an epoxide were used as the main transformations. Structural revision and absolute configuration of the natural compounds were carried out.

Chemoenzymatic synthesis of trans-tetrahydrofuran cores of annonaceous acetogenins from bromobenzene.

Two types of trans-THF cores, present in acetogenins, have been synthesized by an intramolecular iodoetherification reaction. The starting alkenol was obtained in a few steps from a chiral cis-diol resulting from microbial oxidation of bromobenzene. The cyclization gave complete stereoselectivity for trans-THF cores with either (S,S) or (R,R) configurations at the THF chiral carbons.

Insecticidal properties of annonaceous acetogenins and their analogues. Interaction with lipid membranes.

The interactions were studied by FTIR and DSC of the terminal lactone of annonaceous acetogenins (ACGs) and synthetic analogues, such as THF, with POPC bilayers, as well as the toxic effect produced by these compounds on Spodoptera frugiperda larvae. The aim of this work was to find a relationship between ACG insecticidal properties and the specific sites of interaction with lipid membranes. ACGs interact to different extents with the phosphate of lipid membranes and differences in the antisymmetric stretching of the phosphate groups were found in the presence of water that indicate water loss and further hydrogen bonding.The ACG tested produced more than 70% larval mortality. Rolliniastatin-1 (3) proved to have the most toxic effects (100%) on early larval instars when incorporated in the larval diet at a dose of 100 microg per g of diet. Additionally, it produced a significant decrease in growth rate (GR) and consumption index (CI), and reduced the efficiency with which larvae converted ingested food into biomass (ECI). The destabilization that occurs in the membrane due to dehydration around the phosphate groups caused by interaction with ACGs and their synthetic analogues would account for ACGs' insecticidal action.

Stereoselective synthesis of 3-oxygenated-cis-dialkyl-2,5-substituted tetrahydrofurans from cyclohexadienediols.

The 3-oxygenated-cis-dialkyl-2,5-substituted tetrahydrofuran system, present in several natural products, was prepared with good selectivity by acidic cyclization of 5-alkene-1,2,4-triol derivatives. The starting alkenol was obtained in few steps from a chiral cis-diol resulting from microbial oxidation of bromobenzene. The study of the cyclization allowed the rationalization of all experimental results by assuming a complete ionization at the allylic position and a model close to the one proposed by Labelle for homoallylic induction in five-membered ring closures.

Concise chemoenzymatic synthesis of epi-inositol.

epi-Inositol was synthesized in six steps in 40% overall yield from a bacterial bromobenzene metabolite. The chemoenzymatic route involved toluene dioxygenase oxidation, substrate-directed catalytic osmylation, m-CPBA epoxidation, radical debromination, and Amberlite-catalized hydrolysis. The route described is amenable to scaleup and could allow access to cis-inositol, and deoxy derivatives of epi-inositol.