Radical S-Adenosyl-l-Methionine Enzyme PylB: A C-Centered Radical to Convert l-Lysine into (3R)-3-Methyl-d-Ornithine.

PylB is a radical S-adenosyl-l-methionine (SAM) enzyme predicted to convert l-lysine into (3R)-3-methyl-d-ornithine, a precursor in the biosynthesis of the 22nd proteogenic amino acid pyrrolysine. This protein highly resembles that of the radical SAM tyrosine and tryptophan lyases, which activate their substrate by abstracting a H atom from the amino-nitrogen position. Here, combining in vitro assays, analytical methods, electron paramagnetic resonance spectroscopy, and theoretical methods, we demonstrated that instead, PylB activates its substrate by abstracting a H atom from the Cγ position of l-lysine to afford the radical-based ß-scission. Strikingly, we also showed that PylB catalyzes the reverse reaction, converting (3R)-3-methyl-d-ornithine into l-lysine and using catalytic amounts of the 5'-deoxyadenosyl radical. Finally, we identified significant in vitro production of 5'-thioadenosine, an unexpected shunt product that we propose to result from the quenching of the 5'-deoxyadenosyl radical species by the nearby [Fe4S4] cluster.

Exploring the Biosynthetic Potential of TsrM, a B12 -dependent Radical SAM Methyltransferase Catalyzing Non-radical Reactions.

B12 -dependent radical SAM enzymes are an emerging enzyme family with approximately 200,000 proteins. These enzymes have been shown to catalyze chemically challenging reactions such as methyl transfer to sp2- and sp3-hybridized carbon atoms. However, to date we have little information regarding their complex mechanisms and their biosynthetic potential. Here we show, using X-ray absorption spectroscopy, mutagenesis and synthetic probes that the vitamin B12 -dependent radical SAM enzyme TsrM catalyzes not only C- but also N-methyl transfer reactions further expanding its synthetic versatility. We also demonstrate that TsrM has the unique ability to directly transfer a methyl group to the benzyl core of tryptophan, including the least reactive position C4. Collectively, our study supports that TsrM catalyzes non-radical reactions and establishes the usefulness of radical SAM enzymes for novel biosynthetic schemes including serial alkylation reactions at particularly inert C-H bonds.

Unbiased C3-Electrophilic Indoles: Triflic Acid Mediated C3-Regioselective Hydroarylation of N-H Indoles.

The direct dearomative addition of arenes to the C3 position of unprotected indoles is reported under operationally simple conditions, using triflic acid at room temperature. The present regioselective hydroarylation is a straightforward manner to generate an electrophilic indole at the C3 position from unbiased indoles in sharp contrast to previous strategies. This atom-economical method delivers biologically relevant 3-arylindolines and 3,3-spiroindolines in high yields and regioselectivities from both intra- and intermolecular processes. DFT computations suggest the stabilization of cationic or dicationic intermediates with H-bonded (TfOH)n clusters.

Au(I)-Catalyzed Pictet-Spengler Reactions All around the Indole Ring.

Au(I) complexes catalyze iso-Pictet-Spengler reactions. Ethylamine or methylamine chains were introduced at C2, C4, or the nitrogen atom of the indole ring, and the corresponding substrates were reacted in the presence of aldehydes and catalytic amounts of Au(I) complexes, leading to a variety of polycyclic scaffolds. Selectivity could be achieved in the course of a double iso-Pictet-Spengler reaction involving two successive aldehydes, leading to highly complex molecules.

Tethered Counterion-Directed Catalysis: Merging the Chiral Ion-Pairing and Bifunctional Ligand Strategies in Enantioselective Gold(I) Catalysis.

Tethering a metal complex to its phosphate counterion via a phosphine ligand enables a new strategy in asymmetric counteranion-directed catalysis (ACDC). A straightforward, scalable synthetic route gives access to the gold(I) complex of a phosphine displaying a chiral phosphoric acid function. The complex generates a catalytically active species with an unprecedented intramolecular relationship between the cationic Au(I) center and the phosphate counterion. The benefits of tethering the two functions of the catalyst are demonstrated here in a tandem cycloisomerization/nucleophilic addition reaction, by attaining high enantioselectivity levels (up to 97% ee) at an unusually low 0.2 mol % catalyst loading. Remarkably, the method is also compatible with a silver-free protocol.

Gold-catalyzed enantioselective functionalization of indoles.

Gold catalysis and indole chemistry are two mature and prolific fields. The gold-catalyzed functionalization of indoles has produced numerous results and paved the way for novel strategies in the building of molecular complexity. However - and curiously - though enantioselective gold catalysis is now a well-established field, it has been relatively little applied to the modification of indoles. This review highlights most of the enantioselective gold-catalyzed examples of the functionalization of indoles in order to emphasize the strengths and limitations of the method.

Dissecting the Gold(I)-Catalyzed Carboaminations of N-Allyl Tetrahydro-ß-carbolines to Allenes.

N-Allyl tetrahydro-ß-carbolines undergo gold-catalyzed cyclizations that lead to tetracyclic compounds, resulting from both ring closure and the transfer of the allylic group from the nitrogen to the carbon backbone. The final skeleton obtained depends on the nature of both the R2 group of the allene and the R3 group of the allylic residue. Mechanistic studies and DFT calculations allowed the determination of all the mechanistic pathways involved in these processes, stemming from a common intermediate that evolves differently according to the substituents nature.

Stereoselective Synthesis of Chiral Polycyclic Indolic Architectures through Pd(0) -Catalyzed Tandem Deprotection/Cyclization of Tetrahydro-ß-carbolines on Allenes.

Enantioenriched N-allyl tetrahydro-ß-carbolines were prepared by chiral phosphoric acid-catalyzed Pictet-Spengler reactions. The compounds undergo Pd(0) -catalyzed cyclizations through a tandem deprotection/cyclization process. The regioselectivity of the attack is controlled by the chain length and by the substitution pattern of the allene function. Products resulting from 5-exo- or 6-exo-attack were obtained with diastereoisomeric ratio up to 95:5. Azepinopyrrido[3,4-b]indoles were obtained by 7-endo-cyclizations.

Self-Relay Gold(I)-Catalyzed Pictet-Spengler/Cyclization Cascade Reaction for the Rapid Elaboration of Pentacyclic Indole Derivatives.

Gold-catalyzed cascade reactions allow the rapid elaboration of pentacyclic indolo[2,3-a]quinolizidines from N-allyl tryptamines and ortho-alkynylarylaldehydes. The tandem process combines a gold-catalyzed Pictet-Spengler reaction and a cyclization occurring concomitantly with an allyl transfer from the nitrogen atom to the stilbene function. Various substituted allyls were successfully transferred, furnishing the products in yields typically ranging from 60-98 % in high diastereoselectivity. Tryptamines bearing a butenol chain undergo an additional cyclization to chiral hemiaminals in high diastereoselectivities.

When Phosphosugars Meet Gold: Synthesis and Catalytic Activities of Phostones and Polyhydroxylated Phosphonite Au(I) Complexes.

The synthesis and characterization of P-chiral phosphonite-, phosphonate- and thiophosphonate-Au(I) complexes are reported. These novel ligands for Au(I) are based on glycomimetic phosphorus scaffolds, obtained from the chiral pool. The catalytic activities of these complexes are shown in the cyclization of allenols and the hydroamination of 2-(2-propynyl)aniline combined with an organocatalyzed reduction to the corresponding 2-phenyl tetrahydroquinoline. All described gold complexes present excellent catalytic activities.

Synthesis and evaluation of di- and trimeric hydroxylamine-based ß-(1→3)-glucan mimetics.

Di- and trimeric hydroxylamine-based mimetics of ß-(1→3)-glucans have been accessed by an asymmetric synthesis route featuring an iterative double ring-closing reductive amination reaction. These oligomeric hydroxylamines are demonstrated to inhibit the staining of human neutrophils and of mouse macrophages by fluorescent anti-CR3 and anti-dectin-1 antibodies, respectively, and to stimulate phagocytosis, all in a linkage-dependent manner suggestive of binding to the lectin domains of complement receptor 3 (CR3) and dectin-1. The ability of these relatively short mimetics to bind to CR3 and dectin-1, as compared to the greater degree of polymerization required in ß-(1→3)-glucans, is discussed in terms of the increased hydrophobicity of the α-face on replacement of the glycosidic bond by the hydroxylamine linkage.

N-O bond as a glycosidic-bond surrogate: synthetic studies toward polyhydroxylated N-alkoxypiperidines.

A series of novel polyhydroxylated N-alkoxypiperidines has been synthesized by ring-closing double reductive amination (DRA) of highly functionalized 1,5-dialdehydes with various hydroxylamines. The required saccharide-based dialdehydes were prepared efficiently from sodium cyclopentadienylide in seven steps. A two-step protocol has been developed for the DRA; it led, after deprotection, to isofagomine, 3-deoxyisofagomine, and numerous other N-alkoxy analogues. The barrier to inversion in these polyhydroxylated N-alkoxypiperidine derivatives was found by variable-temperature NMR methods to be approximately 15 kcal mol(-1). With the exception of N-hydroxyisofagomine itself, none of the compounds prepared showed significant inhibitory activity against sweet almond ß-glucosidase.

Alternative synthesis of P-chiral phosphonite-borane complexes: application to the synthesis of phostone-phostone dimers.

An improved strategy for the synthesis of P-chiral gluco- and manno-phosphonite-borane complexes is described on the basis of the addition of diethyl phosphonite-borane to a glucal-derived aldehyde, followed by a cyclization coupled with an ethyl/methyl exchange. This direct P(III) strategy facilitates the obtention of various P-chiral phosphonite-boranes, of which further coupling reactions are described leading to the selective synthesis of two phostone dimers.

Synthesis, characterization, and coupling reactions of six-membered cyclic P-chiral ammonium phosphonite-boranes; reactive H-phosphinate equivalents for the stereoselective synthesis of glycomimetics.

Stereoselective syntheses of P-chiral ammonium phosphonite-borane complexes in the gluco- and manno-like series have been developed from P(V) phostone derivatives. The coupling reactions of these phostone donors with alcohols have been investigated with particular emphasis on the influence of protecting groups and conditions on stereoselectivity. The phosphonite-borane complexes may be applied directly in the coupling reactions and the products oxidized in situ to give phostone-mimetics of disaccharides. On the basis of these studies, successful protocols were established for the synthesis of ß-gluco and α- and ß-manno-configured phostones of primary alcohols. Deprotection of the dimeric compounds leads to novel families of α- or ß-(1→6)-linked glycomimetics.

Study of the total synthesis of (-)-exiguolide.

In this article, we disclose the various routes and strategies we had to explore before finally achieving the total synthesis of (-)-exiguolide ((-)-1). Two first types of approaches were set, both relying on the Trost's domino ene-yne coupling/oxa-Michael reaction that we choose for its ability to control the geometry of the methylacrylate-bearing tetrahydropyrane ring B. In our first approach, we expected to assemble the two main fragments (C14-C21 and C1-C13) by creating the C13-C14 bond through a palladium(0)-catalyzed cross-coupling, but this step failed, unfortunately. In the second approach, which was more linear, we created the C16-C17 bond through condensation of a lithium acetylide on a Weinreb amide, and we assembled the C1-C5 and C6-C21 subunits through Trost's domino ene-yne coupling/oxa-Michael reaction. These two approaches served us to design an ameliorated third strategy, which finally led to the total synthesis of (-)-exiguolide.

Synthesis and evaluation of 1-(1H-indol-3-yl)ethanamine derivatives as new antibacterial agents.

A collection of 3-substituted indole derivatives was prepared using nucleophilic addition of indoles to nitrones. The compounds were then tested for their antibacterial activity against almost thirty bacterial strains representative of common human pathogens. Two types of indolic molecules inhibit the growth of Staphylococcus aureus, including MRSA and VISA strains, with MIC values ranging from 8 to 16 mg/L.

Enantioselective Au(I)-catalyzed dearomatization of 1-naphthols with allenamides through Tethered Counterion-Directed Catalysis.

The Tethered Counterion-Directed Catalysis (TCDC) approach has been applied to the enantioselective Au(I) catalyzed dearomatizations of 1-naphthols with allenamides. Stereocontrol is ensured by the intramolecular ion-pairing between the chiral gold-tethered phosphate and an iminium unit, that provides a rigid, well-defined chiral environment to the key electrophilic intermediate.

Synthesis of the landomycinone skeleton.

The synthesis of the highly functionalized tetracyclic skeleton of landomycinone (2), the aglycon of landomycins, was performed using two pivotal steps relying on metal-catalyzed reactions. They are (1) a [2 + 2 + 2] cycloaddition of alkynes promoted by Wilkinson's catalyst to build rings B and C concomitantly and (2) a ring-closing metathesis followed by aromatization to build ring D.

Gold-Catalyzed Spirocyclization Reactions of N-Propargyl Tryptamines and Tryptophans in Aqueous Media.

N-Propargyl tryptamine and tryptophan derivatives that are readily available from both synthetic and biocatalytic approaches undergo gold-catalyzed dearomative cyclizations in aqueous media to the corresponding spirocyclic derivatives. In addition to the efficiency of the method, operating in aqueous media affords a selective entry to C2-unsubstituted spiroindolenines that have long remained unattainable by Au(I) catalysis. Moderate to excellent yields of the desired spirocyclic products bearing various substituents were obtained.

Palladium(0)-catalyzed cross-coupling of potassium (Z)-2-chloroalk-1-enyl trifluoroborates: a chemo- and stereoselective access to (Z)-chloroolefins and trisubstituted alkenes.

We describe the preparation of a series of new potassium trifluoroborates 1 and the study of their behaviour in a Pd(0)-catalyzed cross-coupling reaction. We found that compounds 1 are endowed with original properties as they behave as nucleophilic cross-coupling partners chemoselectively but also as ambivalent synthons. The usefulness of this methodology has been successfully illustrated by the first total synthesis of an N-acyl spermidine.