Hyperpolarization is generated by dissolution dynamic nuclear polarization (d-DNP) using a polymer-based polarizing agent dubbed FLAP (filterable labeled agents for polarization). It consists of a thermo-responsive poly(N-isopropylacrylamide), also known as pNiPAM-COOH, labeled with nitroxide radicals. The polymer powder is impregnated with an arbitrary solution of interest and frozen as is. Dissolution is followed by a simple filtration, leading to hyperpolarized solutions free from any contaminants. We demonstrated the use of FLAP to hyperpolarize partially deuterated water up to P((1) H)=6 % with a long relaxation T1 >36 s characteristic of high purity. Water hyperpolarization can be transferred to drugs, metabolites, or proteins that are waiting in an NMR spectrometer, either by exchange of labile protons or through intermolecular Overhauser effects. We also show that FLAPs are suitable polarizing agents for (13) C-labeled metabolites such as pyruvate, acetate, and alanine.

Cyclization and annulation reactions initiated by ring-opening of small rings, especially cyclopropanes and cyclobutanes are now well-established in synthetic chemistry. Nevertheless, the potential of aminocyclopropanes and cyclobutanes, an important subclass for the synthesis of nitrogen-rich building blocks, has remained unexploited for a long time, despite important pioneering results. In the last decade, the situation has changed dramatically and new catalytic methods have emerged both for cyclization and annulation reactions. The purpose of this feature article is to present recent progress in this area, including our own work using donoracceptor substituted cyclopropanes and cyclobutanes.

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...

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