phosphoramidite and phosphine

Chemically modified oligonucleotides are being developed as a new class of medicines for curing conditions that previously remained untreatable. Three primary classes of therapeutic oligonucleotides are single-stranded antisense oligonucleotides (ASOs), double stranded small interfering RNAs (siRNAs), and oligonucleotides that induce exon skipping. Recently, ASOs, siRNAs, and exon skipping oligonucleotides have been approved for patients with unmet medical needs, and many other candidates are being tested in late stage clinical trials. In coming years, therapeutic oligonucleotides may match the promise of small molecules and antibodies. Interestingly, in the 1980s when we developed chemical methods for synthesizing oligonucleotides, no one would have imagined that these highly charged macromolecules could become future medicines. Indeed, the anionic nature and poor metabolic stability of the natural phosphodiester backbone provided a major challenge for the use of oligonucleotides as therapeutic drugs. Thus, chemical modifications of oligonucleotides were essential in order to improve their pharmacokinetic properties. Keeping this view in mind, my laboratory has developed a series of novel oligonucleotides where one or both nonbridging oxygens in the phosphodiester backbone are replaced with an atom or molecule that introduces molecular properties that enhance biological activity. We followed two complementary approaches. One was the use of phosphoramidites that could act directly as synthons for the solid phase synthesis of oligonucleotide analogues. This approach sometimes was not feasible due to instability of various synthons toward the reagents used during synthesis of oligonucleotides. Therefore, using a complementary approach, we developed phosphoramidite synthons that can be incorporated into oligonucleotides with minimum changes in the solid phase DNA synthesis protocols but contain a handle for generating appropriate analogues postsynthetically.This Account summarizes our efforts toward preparing these types of analogues over the past three decades and discusses synthesis and properties of backbone modified oligonucleotides that originated from the Caruthers' laboratory. For example, by replacing one of the internucleotide oxygens with an acetate group, we obtained so-called phosphonoacetate oligonucleotides that were stable to nucleases and, when delivered as esters, entered into cells unaided. Alternatively oligonucleotides bearing borane phos

Topics: Boranes; DNA; Foscarnet; Oligonucleotides; Organophosphonates; Organophosphorus Compounds; Phosphines; Phosphonoacetic Acid; Phosphorus

S-Nitrosothiols (RSNOs) have many biological implications but are rarely used in organic synthesis. In this work we report the development of proline-based phosphoramidite substrates that can effectively convert RSNOs to proline-based sulfenamides through a reductive ligation process. A unique property of this method is that the phosphine oxide moiety on the ligation products can be readily removed under acidic conditions. In conjugation with the facile preparation of RSNOs from the corresponding thiols (RSHs), this method provides a new way to prepare proline-based sulfenamides from simple thiol starting materials.

Topics: Nitric Oxide; Organophosphorus Compounds; Oxidation-Reduction; Phosphines; Proline; S-Nitrosothiols; Sulfamerazine

During the past decade, the use of Au(I) complexes for the catalytic activation of C-C π-bonds has been investigated intensely. Over this time period, the development of homogeneous gold catalysis has been extraordinarily rapid and has yielded a host of mild and selective methods for the formation of carbon-carbon and carbon-heteroatom bonds. The facile formation of new bonds facilitated by gold naturally led to efforts toward rendering these transformations enantioselective. In this Account, we survey the development of catalysts and ligands for enantioselective gold catalysis by our research group as well as related work by others. We also discuss some of our strategies to address the challenges of enantioselective gold(I) catalysis. Early on, our work with enantioselective gold-catalyzed transformations focused on bis(phosphinegold) complexes derived from axially chiral scaffolds. Although these complexes were highly successful in some reactions like cyclopropanation, the careful choice of the weakly coordinating ligand (or counterion) was necessary to obtain high levels of enantioselectivity for the case of allene hydroamination. These counterion effects led us to use the anion itself as a source of chirality, which was successful in the case of allene hydroalkoxylation. In general, these tactics enhance the steric influence around the reactive gold center beyond the two-coordinate ligand environment. The use of binuclear complexes allowed us to use the second gold center and its associated ligand (or counterion) to exert a further steric influence. In a similar vein, we employed a chiral anion (in place of or in addition to a chiral ligand) to move the chiral information closer to the reactive center. In order to expand the scope of reactions amenable to enantioselective gold catalysis to cycloadditions and other carbocyclization processes, we also developed a new class of mononuclear phosphite and phosphoramidite ligands to supplement the previously widely utilized phosphines. However, we needed to judiciously design the steric environment to create "walls" that enclose the gold center. We also successfully applied these same considerations to the development of binuclear carbene ligands for gold. Finally, we describe the design of bifunctional urea-monophosphine ligands used in a gold-catalyzed three-component coupling.

Topics: Alkadienes; Carbon; Catalysis; Gold; Ligands; Methane; Molecular Structure; Organic Chemistry Phenomena; Organogold Compounds; Organophosphorus Compounds; Phosphines; Stereoisomerism

A mild and general iridium-catalyzed, highly enantioselective hydrogenation of sterically hindered N-arylimines with a new H(8)-BINOL-derived phosphine-phosphoramidite ligand has been developed. The present catalytic system features high turnover numbers (up to 100000) and good to perfect enantioselectivities (up to 99% ee) for the hydrogenation of a variety of sterically hindered N-arylimines.

Topics: Catalysis; Hydrogenation; Imines; Iridium; Ligands; Molecular Structure; Organometallic Compounds; Organophosphorus Compounds; Phosphines

A class of chiral Rh(I) catalysts containing monodentate phosphorous acid diesters tautomerized from the corresponding secondary phosphine oxides was discovered by serendipitous hydrolysis of phosphoramidite ligands. The evolved catalysts demonstrated unprecedented enantioselectivities (98-99% ee) and high catalytic activities (as low as 0.01 mol% catalyst loading) in asymmetric hydrogenations of a wide variety of α-aryl-/alkyl-substituted ethenylphosphonic acids, providing a facile approach to the corresponding enantiopure phosphonic acids with significant biological importance.

Topics: Catalysis; Hydrogenation; Hydrolysis; Ligands; Models, Molecular; Organophosphorus Compounds; Oxides; Phosphines; Phosphorous Acids; Ruthenium; Stereoisomerism

A series of hybrid phosphine-phosphoramidite ligands has been designed and synthesized in moderate yields from chiral BINOL (1,1'-bi-2-naphthol) or NOBIN (2-amino-2'-hydroxy-1,1'-binaphthyl). They have achieved highly regio- and enantioselectivities in Rh-catalyzed asymmetric hydroformylations of styrene derivatives (branched/linear ratio up to 56.6, ee up to 99 %), vinyl acetate derivatives (up to 98 % ee), and allyl cyanide (up to 96 % ee). Systematic variation of ligand structure showed that the steric factor on the phsophoramidite moiety determined the performance of the ligand. With the increased hindrance, the branched/linear ratio rose, while the ee value dropped in the hydroformylation of styrene. However, the N-substituents did not influence the selectivities much.

Topics: Catalysis; Ligands; Naphthalenes; Naphthols; Nitriles; Organophosphorus Compounds; Phosphines; Rhodium; Stereoisomerism; Structure-Activity Relationship; Styrene; Vinyl Compounds

An X-ray diffraction experiment revealed an interesting triphosphorous bidentate coordination in a Pd(II) complex of a phosphine-phosphoramidite ligand 1, which showed excellent enantioselectivity (up to 99.4% ee) in Rh-catalyzed hydrogenation of alpha-dehydroamino esters in acetone. A dramatic solvent effect was found in the hydrogenation of itaconates, which induces opposite chiralities of the product with the same catalytic system by the use of different solvents (e.g., 99.6% ee (R) in TFE vs 71.2% ee (S) in methyl ethyl ketone).

Topics: Butanones; Catalysis; Esters; Hydrogenation; Ligands; Molecular Conformation; Organometallic Compounds; Organophosphorus Compounds; Palladium; Phosphines; Polytetrafluoroethylene; Solvents; Stereoisomerism; Succinates; X-Ray Diffraction

Hybrid bidentate phosphine-phosphoramidite ligands are prepared in a modular 2-step sequence and their rhodium complexes display high selectivity in rhodium catalysed hydrogenation and hydroformylation reactions.

Topics: Catalysis; Hydrogenation; Indicators and Reagents; Indoles; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Organometallic Compounds; Organophosphorus Compounds; Phosphines; Rhodium

Topics: Catalysis; Hydroxylation; Ligands; Models, Molecular; Molecular Structure; Organophosphonates; Organophosphorus Compounds; Phosphines; Rhodium; Stereoisomerism; Water

A new hybrid phosphorus ligand has been prepared starting from chiral NOBIN (2-amino-2'-hydroxy-1,1'-binaphthyl). Excellent enantioselectivities (up to 99% ee) have been achieved in the Rh-catalyzed asymmetric hydroformylations of styrene derivatives and vinyl acetate.

Topics: Aldehydes; Alkenes; Carbon Monoxide; Catalysis; Hydrogen; Ligands; Models, Molecular; Molecular Structure; Organophosphorus Compounds; Phosphines; Stereoisomerism; Styrene