Marion Barbazanges

Total Synthesis of (+)-Amphidinolide J

The marine natural product amphidinolide J has been synthesized according to a convergent strategy. The key steps of this synthesis include a B-alkyl Suzuki-Miyaura coupling and the addition of an alkynyllithium reagent to a Weinreb amide to build the C4-C5 and C12-C13 bonds, respectively, and a Yamaguchi macrolactonization.

Synthesis of 1,2-Amino Alcohols by Sigmatropic Rearrangements of 3-(N-Tosylamino)allylic Alcohol Derivatives

Sigmatropic rearrangements of 3-(N-tosylamino)allylic alcohol derivatives, a particular subclass of functionalized enamides, have been investigated. Whereas the presence of the nitrogen atom alters the stereochemical outcome of Ireland-Claisen rearrangements of glycolates derived from such substrates, [2,3]-Wittig rearrangements of α-allyloxy acetamides or propargylic ethers derivatives provide access to a wide variety of functionalized 1,2-amino alcohols usually with high levels of stereocontrol, as well as to heterocyclic compounds. The stereoselectivity issues of these rearrangements (1,2-diastereoselectivity, auxiliary-induced diastereoselection, chirality transfer, and double stereodifferentiation) were thoroughly investigated.

Double-Stereodifferentiation in Rhodium-Catalyzed [2 + 2 + 2] Cycloaddition: Chiral Ligand/Chiral Counterion Matched Pair.

The first enantioselective metal-catalyzed [2 + 2 + 2] cycloaddition involving a double asymmetric induction has been devised. It relies on the use of an in situ generated chiral cationic rhodium(I) catalyst with a matched chiral ligand/chiral counterion pair. Careful optimization of the catalytic system, as well as of the reaction conditions, led to atroposelective [2 + 2 + 2] pyridone cycloadducts with high ees up to 96%. This strategy outperformed those previously described involving a chiral ligand only or a chiral counterion only.

Chiral Acyclic Diaminocarbene Complexes: a New Opportunity for Gold Asymmetric Catalysis

Over the last decade, gold catalysis has emerged as a very fecund field of research featuring outstanding advances from gold coordination chemistry to applications in the total synthesis of natural products. Interestingly, asymmetric gold catalysis has not followed these developments at the same pace, although as early as 1986, Hayashi in a very pioneering work reported the highly enantioselective addition of isocyanoacetate to aldehydes catalyzed by a chiral ferrocenylphosphinegold(I) complex. In 2005, three independent and seminal reports on asymmetric gold(I)-catalyzed alkoxycyclization by Echavarren, hydrogenation by Corma, and intermolecular cyclopropanation by Toste paved the way for further developments. Although gold(III) chiral catalytic systems can be used, the vast majority of the subsequent reports have relied on gold(I) catalytic complexes, presumably because of their higher redox stability toward the engaged substrates in the reaction conditions. However, the linear coordination keeps the ligand and the coordinated substrate on opposite sides of the metal and renders the task of asymmetric induction presumably difficult. Nevertheless, three types of solutions have been proposed. As pioneered by Echavarren, the first one relies on the use of dinuclear complexes of chiral biaryldiphosphines. A cooperative effect resulting from the p–p interaction between aryl rings of the phosphines has been invoked, which creates an opportune chiral environment around the metal. The second consists of the use of phosphoramidite ligands. Finally, a striking alternative featuring chiral phosphate anions has been proposed by Toste. Interestingly, carbenes, which are versatile ligands for gold(I) complexes, have not so far proven to be high-performance in asymmetric catalysis. In this context, the recent report in Angewandte Chemie by Handa and Slaughter marks a major step forward towards enantioselective catalysis, by using suitably substituted acyclic diaminocarbenes (ADC), also known as N-acyclic carbenes (NAC). Compared to NHC-ligands, ADC-ligands possess a larger NC-N angle (116–1218), bringing chiral information closer to the metal center. However, the preparation of ADC-based complexes has long suffered from the high reactivity of the corresponding free carbenes. As a consequence, studies of their promising potential are still in their infancy. In their work, Handa and Slaughter developed and crystallized a series of four new chiral ADC-gold(I) catalysts derived from 2-binaphthyl-isocyanides, differently substituted at the 2’-binaphthyl position [H, C6H5, and 3,5-(CF3)2C6H3]. Interestingly, when the binaphthyl core is substituted at the 2’-position, two different conformers were observed by X-ray diffraction analysis, depending on the electronic nature of the substituent. While a phenyl substituent is expelled from the coordination sphere (“out”-rotamer), introduction of an electron-poor 3,5-bis(trifluoro)phenyl led to the corresponding “in”-rotamers for which the steric hindrance is maximized. In these cases, Xray enlightened a weak Au-arene electrostatic interaction (Au– arene = 3.5 0.1). This interaction presumably stabilizes the molecular assembly and increases the chiral environment at the metal center. The authors hypothesized that these differences in solid state may reflect different catalytic abilities in solution and investigated enantioselective catalysis. Indeed, these new gold complexes were successfully employed in the first catalytic enantioselective tandem cycloisomerization/acetalization. With use of optimized conditions, gold(I) chloride complex (5 mol %) required a pre-treatment with LiNTf2 (4.5 mol %) as an additive (45 8C) to generate the active species (Scheme 1). Treatment of ortho-alkynylbenzaldehydes in the presence of a nucleophilic alcohol led then to the optically enriched 1H-isochromene derivatives (DCE, RT or 60 8C). The authors demon-

Mechanism of action of the cytotoxic macrolides amphidinolide X and J.

Microtubules and actin filaments play important biological roles in mitosis, cytokinesis, cell signaling, intracellular transport, and cell motility of eukaryotic cells. 2] Molecules that target these cytoskeleton proteins are potential antitumor or anti-HIV agents. In fact, there are several clinical drugs that target the stabilization (paclitaxel-like behavior) or destabilization (vinca-like or colchicine-like behavior) of microtubules, specifically their heterodimeric component, a,b-tubulin. On the other hand, no actin-targeting drug has yet entered clinical studies. Amphidinolides are a series of structurally dissimilar cytotoxic macrolides isolated from dinoflagellates (Amphidinium sp.). Their mechanisms of action are unknown, except that for one that has one of the largest rings, the 26-membered macrolide amphidinolide H (Amp-H, MW = 562.73) ; this shows cytotoxicity in the nanomolar range against several carcinoma cell lines. Amp-H drastically and irreversibly deformed actin fibers; the actin fibers completely disappeared, and only a few disorganized aggregates remained in the cells. Amp-H induced multinucleated cells by disrupting actin organization (polyploid cells). In vitro assays on purified actin indicated that Amp-H stimulates actin polymerization, and stabilizes the actin filaments (F-actin). 11] In contrast, most of the smallest amphidinolides are cytotoxic in the micromolar range. For example, amphidinolide X (1, MW = 448.59) [12] and amphidinolide J (4, MW = 390.56) [13] have IC50 values of 1.3 and 6.9 mm, respectively, against the lymphocytic leukemia cell line L1210, although their mechanisms of action have not been reported. As these small amphidinolides are easier to synthesize than the larger molecules, 16] it would be desirable to identify their binding sites. Appropriate chemical modifications of these natural products might afford leads with activities below 0.1 mm that might eventually give rise to new antitumor agents. We report here biological studies of 1, the structurally related synthetic diolides 2 and 3, and 4 (Scheme 1). We examined their effect on the proliferation of A2780 (human ovarian carcinoma) and of LoVo (human colon carcinoma) cell lines, as well as on the cytoskeleton proteins tubulin, actin, and intermediate filaments in A549 (lung carcinoma) and PtK2 cells. Their effects on actin polymerization was then studied in vitro.

Chiral Phosphate in Rhodium-Catalyzed Asymmetric [2+2+2] Cycloaddition: Ligand, Counterion, or Both?

Investigations based on NMR spectroscopy, mass spectrometry, and DFT calculations shed light on the metallic species generated in the rhodium-catalyzed asymmetric [2+2+2] cycloaddition reaction between diynes and isocyanates with the chiral phosphate TRIP. The catalytic mixture comprising [{Rh(cod)Cl}2 ], 1,4-diphenylphosphinobutane (dppb), and Ag(S)-TRIP actually gives rise to two species, both having an effect on the stereoselectivity. One is a rhodium(I) complex in which TRIP is a weakly coordinating counterion, whereas the other is a bimetallic Rh/Ag complex in which TRIP is a strongly coordinating X-type ligand.

Organometallic catalysis for applications in radical chemistry and asymmetric synthesis

Abstract Two organometallic catalysis studies are presented. The first one deals with the development of a new catalytic agent based on the mixture of a hydride and an iron salt to trigger efficient radical cyclization processes. In a second line of research, we have shown that the use of chiral anions can outperform chiral ligands in a carbocyclization reaction and a [2 + 2 + 2] cycloaddition.