Philippe Dauban

Nitrene Chemistry in Organic Synthesis: Still in Its Infancy?

The element nitrogen is essential to life. Considerable attention is thus paid to the development of synthetic methods for its introduction into molecules. Nitrenes, long regarded as highly reactive but poorly selective species, have recently emerged as useful tools for the formation of C-N bonds. Practical metal-catalyzed protocols are now available for the preparation of amines through either the aziridination of alkenes or the C-H amination of alkanes. Recent results highlighted in this Minireview suggest that synthetic nitrene chemistry is maturing with a wider scope not limited to these two reactions.

Evidence in Favor of a Calcium-Sensing Receptor in Arterial Endothelial Cells: Studies With Calindol and Calhex 231

Small increases in extracellular Ca2+ dilate isolated blood vessels. In the present study, the possibility that a vascular, extracellular Ca2+-sensing receptor (CaSR) could mediate these vasodilator actions was investigated. Novel ligands that interact with the CaSR were used in microelectrode recordings from rat isolated mesenteric and porcine coronary arteries. The major findings were that (1) raising extracellular Ca2+ or adding calindol, a CaSR agonist, produced concentration-dependent hyperpolarizations of vascular myocytes, actions attenuated by Calhex 231, a negative allosteric modulator of CaSR. (2) Calindol-induced hyperpolarizations were inhibited by the intermediate conductance, Ca2+-sensitive K+ (IKCa) channel inhibitors, TRAM-34, and TRAM-39. (3) The effects of calindol were not observed in the absence of endothelium. (4) CaSR mRNA and protein were present in rat mesenteric arteries and in porcine coronary artery endothelial cells. (5) CaSR and IKCa proteins were restricted to caveolin-poor membrane fractions. We conclude that activation of vascular endothelial CaSRs opens endothelial cell IKCa channels with subsequent myocyte hyperpolarization. The endothelial cell CaSR may have a physiological role in the control of arterial blood pressure.

Studies in catalytic C-H amination involving nitrene C-H insertion.

Stereoselective catalytic intermolecular C-H amination of complex molecules is reported. Site-selective functionalizations occur with very good yields up to 91% and excellent d.e.s up to 99%. However, the precise nature of the nitrene C-H insertion remains a matter of debate despite several physical organic experiments.

A Masked 1,3‐Dipole Revealed from Aziridines

Heterocycles are thought to be part of more than half of the known organic compounds. A large number of them are natural products and many synthetic derivatives are used as drugs, agrochemicals, dyes, or materials. A recent review has highlighted that the heterocyclic chemical space is far from having been fully explored and hundreds of simple structures, predicted to be tractable, still remain to be conquered. Needless to say the search for innovative routes towards their formation is still a field of intense investigation. Among the several strategies available, cycloadditions offer unequaled opportunities since multiple bonds can be created in one step with high degrees of efficiency, selectivity, and atom economy. Of particular significance is the 1,3-dipolar cycloaddition which has been claimed to be “the single most important method for the construction of heterocyclic fivemembered rings in organic chemistry”. Azomethine ylides are common 1,3-dipoles especially useful for the preparation of five-membered nitrogen heterocycles, N-alkylor N-arylaziridines being one of their most widely used synthetic precursors. Heine and Peavy, Padwa and Hamilton, and Huisgen et al. first reported azomethine ylide formation by thermal aziridine ring-opening, which proceeds through a conrotatory C C bond-breaking process according to the Woodward–Hoffmann rules. The cisand trans-aziridines 1 therefore lead to transand cisazomethine ylides 2, respectively, which can then be trapped by various dipolarophiles (e.g., alkynes) in concerted 1,3dipolar cycloadditions to give nitrogen heterocycles (e.g., 3 ; Scheme 1a). A noteworthy application of this reaction is the concise enantioselective synthesis of acromelic acid A (6) which was successfully developed by Takano et al. (Scheme 1b). The chemistry of aziridines is centered on ring-opening reactions with a wide range of nucleophiles as a consequence of their ring strain. These reactions have led to the formation of various important 1,2-difunctionalized scaffolds such as amino acids, amino sugars, and b-lactams. Interestingly, this reactivity has been elegantly applied to the formation of five-membered nitrogen heterocycles through a formal [3+2] cycloaddition involving C N bond breaking. Hiyama and co-workers, and then Zwanenburg and coworkers described the reaction of aziridines (7) with nitriles in the presence of boron trifluoride etherate for the preparation of imidazolidines. Scheme 2a shows as an example the reaction of 7 with acetonitrile to 9. These Lewis acid mediated transformations have been proposed to proceed in a Ritter fashion by an initial SN2-type aziridine ring-opening to give intermediates such as 8. The use of p nucleophiles such as allylsilanes (e.g., 10 ; Scheme 2b), alkenes, and alkynyltungsten complexes in the presence of a Lewis acid has also been shown to induce similar stepwise cycloadditions thereby suggesting that aziridines may behave as masked 1,3-dipoles. 9] The synthetic potential of this methodology is demonstrated by its application to the total synthesis of physostigmine (15 ; Scheme 2c). This formal [3+2] cycloaddition is generally observed with simple aliphatic aziridines. In contrast, the introduction of substituents, likely to stabilize a positive charge, onto one of the carbon atoms of an N-sulfonylated aziridine generates a very different reactivity. Mann and co-workers have been the first to investigate the formation of the uncommon zwitterScheme 1. a) Aziridines in 1,3-dipolar cycloadditions involving azomethine ylides. b) Application of methodology to natural product synthesis. EWG = electron-withdrawing group, Bn = benzyl.

The expression and function of Ca2+‐sensing receptors in rat mesenteric artery; comparative studies using a model of type II diabetes

The extracellular calcium‐sensing receptor (CaR) in vascular endothelial cells activates endothelial intermediate‐conductance, calcium‐sensitive K+ channels (IKCa) indirectly leading to myocyte hyperpolarization. We determined whether CaR expression and function was modified in a rat model of type II diabetes.

Calindol, a Positive Allosteric Modulator of the Human Ca2+ Receptor, Activates an Extracellular Ligand-binding Domain-deleted Rhodopsin-like Seven-transmembrane Structure in the Absence of Ca2+

The extracellular calcium-sensing human Ca2+ receptor (hCaR),2 a member of the family-3 G-protein-coupled receptors (GPCR) possesses a large amino-terminal extracellular ligand-binding domain (ECD) in addition to a seven-transmembrane helical domain (7TMD) characteristic of all GPCRs. Two calcimimetic allosteric modulators, NPS R-568 and Calindol ((R)-2-{1-(1-naphthyl)ethyl-aminom-ethyl}indole), that bind the 7TMD of the hCaR have been reported to potentiate Ca2+ activation without independently activating the wild type receptor. Because agonists activate rhodopsin-like family-1 GPCRs by binding within the 7TMD, we examined the ability of Calindol, a novel chemically distinct calcimimetic, to activate a Ca2+ receptor construct (T903-Rhoc) in which the ECD and carboxyl-terminal tail have been deleted to produce a rhodopsin-like 7TMD. Here we report that although Calindol has little or no agonist activity in the absence of extracellular Ca2+ for the ECD-containing wild type or carboxyl-terminal deleted receptors, it acts as a strong agonist of the T903-Rhoc. In addition, Ca2+ alone displays little or no agonist activity for the hCaR 7TMD, but potentiates the activation by Calindol. We confirm that activation of Ca2+ T903-Rhoc by Calindol truly the is independent using in vitro reconstitution with purified Gq. These findings demonstrate distinct allosteric linkages between Ca2+ site(s) in the ECD and 7TMD and the 7TMD site(s) for calcimimetics.

Intermolecular C–H Amination of Complex Molecules: Insights into the Factors Governing the Selectivity

Transition-metal-catalyzed C-H amination via nitrene insertion allows the direct transformation of a C-H into a C-N bond. Given the ubiquity of C-H bonds in organic compounds, such a process raises the problem of regio- and chemoselectivity, a challenging goal even more difficult to tackle as the complexity of the substrate increases. Whereas excellent regiocontrol can be achieved by the use of an appropriate tether securing intramolecular addition of the nitrene, the intermolecular C-H amination remains much less predictable. This study aims at addressing this issue by capitalizing on an efficient stereoselective nitrene transfer involving the combination of a chiral aminating agent 1 with a chiral rhodium catalyst 2. Allylic C-H amination of terpenes and enol ethers occurs with excellent yields as well as with high regio-, chemo-, and diastereoselectivity as a result of the combination of steric and electronic factors. Conjugation of allylic C-H bonds with the π-bond would explain the chemoselectivity observed for cyclic substrates. Alkanes used in stoichiometric amounts are also efficiently functionalized with a net preference for tertiary equatorial C-H bonds. The selectivity, in this case, can be rationalized by steric and hyperconjugative effects. This study, therefore, provides useful information to better predict the site of C-H amination of complex molecules.

Molecular determinants of non-competitive antagonist binding to the mouse GPRC6A receptor

GPRC6A displays high sequence homology to the Ca2+-sensing receptor (CaSR). Here we report that the calcimimetic Calindol and the calcilytic NPS2143 antagonize increases in inositol phosphate elicited by L-ornithine-induced activation of mouse GPRC6A after transient coexpression with Galpha(qG66D) in HEK293 cells. The calcilytic Calhex 231 did not modulate this response. A three-dimensional model of the GPRC6A seven transmembrane domains (TMs) was constructed. It was used to identify seven residues strictly conserved within the CaSR and GPRC6A allosteric binding pockets, and previously demonstrated to interact with calcilytics or calcimimetics. The mutations F666A(3.32), F670A(3.36), W797A(6.48) caused a loss of L-ornithine ability to activate GPRC6A mutants. The F800A(6.51) mutant was not implicated in either Calindol or NPS 2143 recognition. The E816Q(7.39) mutation led to a loss of Calindol antagonist activity but was without effect on NPS2143 inhibitory response. In summary, these data suggest that Calindol is primarily anchored through an H-bond to E816(7.39) in TM7 and highlight important local differences at the level of the CaSR and GPRC6A allosteric binding pockets. We have identified the first antagonists of GPRC6A that could represent new tools to analyze GPRC6A functions and serve as chemical leads for the development of more specific modulators.

One-Pot Double Suzuki−Miyaura Couplings: Rapid Access to Nonsymmetrical Tri(hetero)aryl Derivatives

We describe a one-pot, simultaneous Suzuki-Miyaura cross-coupling of two different aryl boronic acids with symmetrical dibromo aryl and heterocyclic substrates to give as major products the unsymmetrical disubstituted tri(hetero)aryl derivatives. Yields of unsymmetrical dicoupled products were generally in the 52-75% range. This methodology is particularly suited to the generation of chemical libraries, as well as to the synthesis of biologically active or natural product analogs.

Stereoselective Rhodium-Catalyzed Imination of Sulfides

The preparation of optically active sulfilimines via the catalytic diastereoselective imination of sulfides using a chiral nitrene is described. Excellent yields up to 97% and good diastereoselectivities up to 96% have been obtained. Oxidation of the sulfilimines then stereospecifically affords the corresponding sulfoximines with very good yields in the 88-96% range.