No abstract

The catalytic asymmetric synthesis of alkyl fluorides, particularly α-fluorocarbonyl compounds, has been the focus of substantial effort in recent years. While significant progress has been described in the formation of enantioenriched secondary alkyl fluorides, advances in the generation of tertiary alkyl fluorides have been more limited. Here, we describe a method for the catalytic asymmetric coupling of aryl alkyl ketenes with commercially available N-fluorodibenzenesulfonimide (NFSI) and C6F5ONa to furnish tertiary α-fluoroesters. Mechanistic studies are consistent with the hypothesis that the addition of an external nucleophile (C6F5ONa) is critical for turnover, releasing the catalyst (PPY*) from an N-acylated intermediate. The available data can be explained by a reaction pathway wherein the enantioselectivity is determined in the turnover-limiting transfer of fluorine from NFSI to a chiral enolate derived from the addition of PPY* to the ketene. The structure and the reactivity of the product of this proposed elementary step, an α-fluoro-N-acylpyridinium salt, have been examined.

The structurally unique polyketide mumbaistatin is the strongest naturally occurring inhibitor of glucose-6-phosphate translocase-1 (G6P-T1), which is a promising target for drugs against type-2 diabetes mellitus and angiogenic processes associated with brain tumor development. Despite its high relevance, mumbaistatin has so far withstood all attempts towards its total synthesis. In the present study an efficient total synthesis of a deoxy-mumbaistatin analogue containing the complete carbon skeleton and a spirolactone motif closely resembling the natural product in its cyclized form was elaborated. Key steps of the synthesis are a Diels-Alder cycloaddition for the construction of the fully functionalized anthraquinone moiety and an anionic homo-Fries rearrangement to build up the tetra-ortho-substituted benzophenone core motif, from which a spiroketal lactone forms in a spontaneous process. The elaborated strategy opens an entry to a variety of new analogs of mumbaistatin and cyclo-mumbaistatin and may be exploited for the total synthesis of the natural product itself in the future.

Lithium thioethoxide (LiSEt), a white solid easily prepared from EtSH and n-BuLi in hexane, was identified as a highly efficient reagent for the cleavage (O-demethylation) of aryl methyl ethers, i.e. methyl-protected phenols. Of particular synthetic value are applications in the double deprotection of 1,2-dimethoxyarenes (to give catechols) and in the selective monodeprotection of di-and trimethoxyarenes. The thermal reactions, which are usually performed in DMF as a solvent, can be greatly accelerated through microwave irradiation. In this case, the monodemethylated products are usually formed in high (80-99%) yield within only 15 minutes.

Studies on the total synthesis of mumbaistatin, the strongest natural inhibitor of G6P-T1, have culminated in the synthesis of a 4¢¢,8-dideoxy analogue. Key steps include a Diels-Alder reaction for the construction of the functionalized anthraquinone, a palladium-catalyzed Stille coupling to generate a tetra-ortho-substituted diarylmethane, and a titanium-mediated alkynylation of an aldehyde to complete the carbon skeleton of mumbaistatin. Radical bromination of the methylene bridge afforded a lactone, which resembles the target structure in its cyclized form.