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ABSTRACT:In this communication, we report the first example of dynamic kinetic asymmetric [3+2] annulation reaction of aminocyclopropanes with both enol ethers and aldehydes. Using a copper catalyst and a commercially available bisoxazoline ligand, cyclopentyl-and tetrahydrofurylamines were obtained in 69-97% yield and up to a 98:2 enantiomeric ratio using the same reaction conditions. The method gives access to important enantioenriched nitrogen building blocks for the synthesis of bioactive compounds.The combination of nitrogen functionalities and cyclic structures is omnipresent in bioactive compounds. From the ten most sold pharmaceutical products based on small molecules in 2009, nine contain nitrogen atoms embedded in ring systems. Among the multitude of reported nitrogen-rich cyclic scaffolds, tetrahydrofurylamines and cyclopentylamines occupy a privileged position ( Figure 1). Tetrahydrofurylamines are especially important in the form of aminosugars, such as aminodeoxyriboses 1, which are at the core of DNA and many bioactive synthetic nucleoside analogues. Cyclopentylamines are well-represented in bioactive compounds, such as the bicyclic drug Ramipril (2) used to treat hypertension and heart diseases. 1 They are also at the core of numerous bioactive natural products, such as the antibiotic Pactamycin (3). 2 A stereoselective synthetic access to tetrahydrofuryl-and cyclopentylamines would be consequently highly valuable in order to discover new bioactive compounds. Since 2010, our group has examined the use of donor-acceptor substituted aminocyclopropanes and aminocyclobutanes for the synthesis of nitrogen-rich molecules (Scheme 1, A). 3 This approach is particularly attractive as the nitrogen atom plays a dual role: it is not only an essential structural element of the product, but also a steering group to control regioselective ring opening upon release of ring strain. Despite important progress in the use of donor-acceptor substituted cyclopropanes, 4 only few examples on the use of aminocyclopropanes had been reported prior to our own work. 5 In our hands, the ring-opening of aminocyclopropanes was highly successful for the inter-and intramolecular addition of nucleophiles 3a-c and the development of new annulation reactions, in particular for the synthesis of cyclopentyl-and tetrahydrofurylamines ((1) in Scheme 1, B). 3d-g The reaction of enol ethers and ketones using a tin catalyst was enantiospecific, whereas the ironcatalyzed annulation of aldehydes gave racemic products. An approach allowing the complete conversion of easily accessible racemic aminocyclopropanes into enantiopure cyclopentylamines -a dynamic kinetic asymmetric transformation (DYKAT)-6 would be much more straightforward. Such reactions have been realized for other classes of donor-acceptor cycloproThis document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the pub...

A careful interplay between the π electrophilicity of a cationic Au(I) center and the basicity of the corresponding counterion allowed for the chemo- and regioselective inter- as well as intramolecular de-aromatization of 2,3-disubstituted indoles with allenamides. The silver-free bifunctional Lewis acid/Brønsted base complex [{2,4-(tBu)2C6H3O}3PAuTFA] assisted the formation of a range of densely functionalized indolenines under mild conditions.

The first Lewis acid catalyzed enantioselective ring-opening desymmetrization of a donor-acceptor meso-diaminocyclopropane is reported. The copper(II)-catalyzed Friedel-Crafts alkylation of indoles and one pyrrole with an unprecedented meso-diaminocyclopropane delivered enantioenriched, diastereomerically pure urea products, which are structurally related to natural and synthetic bioactive compounds. The development of a new ligand through the investigation of an underexplored subclass of bis(oxazoline) ligands was essential for achieving high enantioselectivities.

ABSTRACT:The first [4+2]-annulation between aminocyclobutanes and aldehydes to access tetrahydropyranyl amines is reported. With phthalimido cyclobutane dicarboxylates and aromatic aldehydes, tetrahydropyrans were obtained in 53-92% yield and 3:1-17:1 dr using scandium triflate or iron trichloride as catalyst. The use of thymine-or fluorouracil-substituted cyclobutanes gave direct access to six-membered ring nucleoside analogues. Finally, the [4+2]-annulation between aminocyclobutanes and enol ethers led to the corresponding cyclohexylamines.Six-membered nitrogen-substituted carbo-and heterocycles are among the most frequently encountered scaffolds in natural and synthetic bioactive compounds (Figure 1). A cyclohexylamine or a tetrahydropyranylamine ring for example can be found in the core of the natural alkaloids strychnine (1) and staurosporine (2) respectively. The synthetic antiviral drug Tamiflu (3) is constituted by a cyclohexenyldiamine core. Synthetic methods giving access to these important scaffolds with high efficiency and broad scope are desirable to accelerate the discovery of new bioactive compounds. Whereas the Diels-Alder reaction has emerged as a powerful method to synthesize cyclohexenylamines and dihydropyranylamines, 1 there is currently a lack of transformations giving straightforward access to saturated ring systems with high convergence. The use of annulation reactions of donor-acceptor substituted strained rings constitutes a valuable alternative for the synthesis of saturated carbo-or heterocycles. In the case of sixmembered rings, the [4+2]-annulation between donor-acceptor cyclobutanes and olefins or carbonyl compounds appears particularly attractive (Scheme 1, A). Nevertheless, the chemistry of donor-acceptor cyclobutanes has been much less developed than for the corresponding cyclopropanes. 2 It is only very recently that more general catalytic methods have been developed in the groups of Johnson, Christie and Pritchard, and Pagenkopf in particular (Scheme 1, B). 3 However, these works focused on the use of oxygen and carbon as electron-donating groups, and the scope of substituents on the cyclobutanes was often limited. In the case of nitrogen as donor, an important pioneering result has been reported by Saigo and co-workers in 1991. 4 Unfortunately, the precious nitrogen functionality could not be conserved in the final product, as hydrolysis occurred upon work-up. Scheme 1.[4+2]-Annulations for the Synthesis of SixMembered Rings.Recognizing the underexploited potential of nitrogensubstituted strained rings for the synthesis of bioactive compounds, 5 our group has initially focused on the discovery of new types of donor-acceptor systems which could be broadly applied in annulation reactions. In particular, we reported that imido-substituted cyclopropane dicarboxylates can be used in [3+2]-annulations with both enol ethers and carbonyl compounds under mild catalytic conditions. 6 In 2013, we reported a new method to access the corresponding imido substituted cyclobutane dicarbo...