A new tandem cross metathesis-intramolecular azaMichael reaction in which an α,α-difluorinated amide serves as a source of nucleophilic nitrogen is described. This process gives rise to a new family of fluorinated γ-and δ-lactams. The tandem protocol is catalyzed by the Hoveyda-Grubbs second-generation ruthenium catalyst with titanium(IV) tetraisopropoxide as a co-catalyst and it is highly efficient when conjugated ketones are used as the Michael acceptors. With conjugated esters, however, it is necessary to perform a step-by-step procedure in which the cyclization event is activated by the addition of a base. An asymmetric version of the process is also evaluated.Tandem processes usually generate high levels of molecular complexity in a single chemical operation thereby minimizing the use of solvents and reagents and reducing the time and number of steps involved in purification. These advantages make tandem transformations extremely appealing from both academic and industrial points of view. Indeed, tandem protocols have been extensively developed in recent decades, and they have found a wide variety of applications in natural-product synthesis. 1 Moreover, asymmetric versions greatly enhance the usefulness and relevance of tandem reactions and these have become extremely powerful and popular tools for synthetic organic chemists. 2The conjugated addition of nitrogen-centered nucleophiles to the β-carbon of electron-deficient olefins, the socalled aza-Michael reaction (AMR), is a particularly interesting transformation because it probably represents the shortest route to β-amino carbonyl derivatives, such as β-amino acids. Furthermore, a wide variety of nitrogen nucleophiles and Michael acceptors can participate in this process, which is also simple and displays significant atom economy. 3 The intramolecular version of the AMR is especially relevant because it permits the direct generation of nitrogen-containing heterocycles, yielding natural products and pharmaceutically relevant molecules in a relatively simple manner (Scheme 1). 4Olefin metathesis is one of the most powerful methods for the formation of carbon-carbon double bonds. 5 In comparison with the ring-closing metathesis reaction, the cross metathesis (CM) variant was initially underdeveloped because of a lack of predictability in the product distribution and the stereoselectivity of the reaction. However, the development of new ruthenium-based complexes that exhibit improved efficiency and tolerance to various functional groups changed the situation and it is now possible to achieve perfect control of E/Z selectivity in CM reactions. 6 Scheme 1 Intramolecular aza-Michael reactionsIn terms of their selectivities and yields, both azaMichael 3c,7 and olefin metathesis reactions 8 exhibit suitable properties for participation in effective tandem protocols. In fact, each of these reactions has been combined with other types of transformations in many tandem sequences. However, only a few examples of combinations of CM and AMR have been reported, probably...

The preparation of novel fluorinated allylamines and their use as key fragments for the stereoselective synthesis of hydroxyethyl secondary amine (HEA)-type peptidomimetics is described. Our strategy employs chiral sulfinyl imines as synthesis intermediates, by treatment of hemiaminal precursors with two equivalents of vinylmagnesium bromide. The subsequent oxidation of the allylic amines to the corresponding epoxides was achieved by treatment with methyl(trifluoromethyl)dioxirane. Finally, epoxide ring opening with a range of nitrogen nucleophiles provided a library of HEA-derived peptidomimetics with a phenyldifluoromethylene moiety. The biological evaluation of these derivatives revealed compounds with remarkable BACE1 inhibitory activity. Docking studies revealed the influence of the fluorine atoms in the binding mode of the synthesized ligands. Furthermore, the biological evaluation of our final products and synthesis intermediates led to the discovery of compounds with antimicrobial activity against Mycobacterium and Nocardia species.

In this work, we describe the asymmetric synthesis of a series of fluorinated and non-fluorinated quaternary α-amino acid derivatives. This methodology involves the diastereoselective addition of chiral 2-p-tolylsulfinyl benzylcarbanions to either imines containing a 2-furyl moiety or trifluoromethyl α-imino esters. Synthetic practicality of this method is demonstrated by short (two-steps) and convenient preparation of 2-(trifluoromethyl)indoline-2-carboxylates.

A New Tandem Cross Metathesis-Intramolecular Aza-Michael Reaction for the Synthesis of α,α-Difluorinated Lactams. -Difluorinated amides are treated with methyl vinyl ketone or analogous esters to produce the desired γand δ-lactam units including optically active versions. For the esters, a two-step procedure is required to achieve the cyclization by addition of base. -(FUSTERO, S.; BAEZ, C.; SANCHEZ-ROSELLO, M.; ASENSIO, A.; MIRO, J.; DEL POZO*, C.; Synthesis 2012, 12, 1863-1873, http://dx.