Cu(OTf)2-Catalyzed Pummerer Coupling of ß-Ketosulfoxides.

The copper(II) trifluoromethanesulfonate-catalyzed Pummerer reaction of ß-ketosulfoxides with 1,3-dicarbonyl compounds or π-nucleophiles such as phenols, arenes, and tetraallylsilane is reported. The mild conditions provide an efficient entry to a novel class of polysubstituted 3-alkylthiofuran and polysubstituted 3-thiobenzofuran heterocycles from readily available materials.

Enantioselective Oxidative Homocoupling and Cross-Coupling of 2-Naphthols Catalyzed by Chiral Iron Phosphate Complexes.

Novel chiral iron phosphate complexes were prepared as catalysts for asymmetric oxidative coupling reactions. These catalysts were applied for the synthesis of enantio-enriched C1- and C2-symmetric BINOLs, in which the 3 and 3' positions are available for chemical modifications. It was proposed that the reaction takes place via an oxidative radical-anion coupling mechanism. A destructive BINOL racemization that competes with the enantioselective oxidative coupling of 2-naphthols was revealed, thereby offering new insights into this highly important reaction.

Reductive Alkylation of Arenes by a Thiol-Based Multicomponent Reaction.

A simple and highly chemo- and regioselective method for introducing primary alkyl substituents into aromatic compounds was developed. The method is based on an electrophilic aromatic substitution of an aldehyde, promoted by a thiol, to afford 1-(alkylthio)alkylarenes, which can either be reduced in situ with triethylsilane or reacted further. This multicomponent reaction enables the direct introduction of both aromatic and linear and branched aliphatic alkyl groups into arenes. The above one-pot protocol may be performed in air and in the presence of water and is compatible with various functional groups.

Thiol-promoted selective addition of ketones to aldehydes.

A simple and efficient thiol-mediated addition of ketones to aromatic and aliphatic aldehydes is reported. This thermodynamically controlled Pummerer/aldol reaction, which can tolerate both moisture and protic functional groups, provides a direct entry to syn-ß-thioketones in high chemo- and regioselectivity. Mechanistic studies revealed that selective transformation of the aldehyde to an electrophilic thionium ion species concurrent with the generation of a nucleophilic vinyl sulfide coupling partner from the ketone is imposing cross-coupling over dimerization.

Aerobic iron-based cross-dehydrogenative coupling enables efficient diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators.

An iron-based cross-dehydrogenative coupling (CDC) approach was applied for the diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators (SERMs), representing the first application of CDC chemistry in natural product synthesis. The first stage of the two-step synthesis of coumestrol involved a modified aerobic oxidative cross-coupling between ethyl 2-(2,4-dimethoxybenzoyl)acetate and 3-methoxyphenol, with FeCl3 (10 mol%) as the catalyst. The benzofuran coupling product was then subjected to sequential deprotection and lactonization steps, affording the natural product in 59% overall yield. Based on this new methodology other coumestrol analogues were prepared, and their effects on the proliferation of the estrogen receptor (ER)-dependent MCF-7 and of the ER-independent MDA-MB-231 breast cancer cells were tested. As a result, new types of estrogen receptor ligands having an acetamide group instead of the 9-hydroxyl group of coumestrol were discovered. Both 9-acetamido-coumestrol and 8-acetamidocoumestrol were found more active than the natural product against estrogen-dependent MCF-7 breast cancer cells, with IC50 values of 30 and 9 nM, respectively.

Iron-catalyzed oxidative cross-coupling of phenols and alkenes.

A novel bioinspired iron-catalyzed oxidative cross-coupling reaction between phenols and conjugated alkenes was developed. This method enables the direct coupling of phenols with styrene, α-alkyl- and α-arylstyrenes, ß-alkyl styrenes, and stilbenes, thereby providing a new strategy for the preparation of the pharmacologically important 2,3-dihydrobenzofuran motif. In addition, this study revealed that under a different set of conditions an oxidative/addition dearomatization reaction of 1,1'-bi-2-naphthol (BINOL) with styrene can take place.

Ligand-controlled iron-catalyzed coupling of α-substituted ß-ketoesters with phenols.

A chemo-, regio-, and stereoselective FeCl(3)/1,10-phenanthroline-catalyzed cross dehydrogenative coupling (CDC) reaction between phenols and α-substituted ß-ketoesters was developed. The reaction creates a new quaternary carbon center within a polycyclic hemiacetal or polycyclic spirolactone architecture. The applicability of the new method to the synthesis of natural products was demonstrated by a possible biomimetic synthesis of the lachnanthospirone core.