Molecular Basis of Lysosomal Enzyme Recognition: Three-Dimensional Structure of the Cation-Dependent Mannose 6-Phosphate Receptor

AbstractTargeting of newly synthesized lysosomal hydrolases to the lysosome is mediated by the cation-dependent mannose 6-phosphate receptor (CD-MPR) and the insulin-like growth factor II/cation-independent mannose 6-phosphate receptor (IGF-II/CI-MPR). The two receptors, which share sequence similarities, constitute the P-type family of animal lectins. We now report the three-dimensional structure of a glycosylation-deficient, yet fully functional form of the extracytoplasmic domain of the bovine CD-MPR (residues 3–154) complexed with mannose 6-phosphate at 1.8 Å resolution. The extracytoplasmic domain of the CD-MPR crystallizes as a dimer, and each monomer folds into a nine-stranded flattened β barrel, which bears a striking resemblance to avidin. The distance of 40 Å between the two ligand-binding sites of the dimer provides a structural basis for the observed differences in binding affinity exhibited by the CD-MPR toward various lysosomal enzymes

[2,2′-Bis(diphenyl­phosphan­yl)-1,1′-binaphthyl-κ2 P,P′]chlorido(4-methyl­phenyl­sulfon­yl-κS)palladium(II) dichloro­methane tris­olvate monohydrate

In the title compound, [Pd(C7H7O2S)Cl(C44H32P2)]·3CH2Cl2·H2O, the geometry around the metal atom is distorted square planar, with a twist angle between the P—Pd—P and S—Pd—Cl planes of 28.11 (2)°. The two Pd—P bond lengths differ by about 0.04 Å and the biphosphane bite angle is slightly obtuse [92.92 (2)°]. There are three dichloro­methane and one water mol­ecule co-crystallized with the palladium mol­ecule, all with atoms in general positions. Alternating water and palladium mol­ecules form four-membered cyclic units through O—H⋯Cl and O—H⋯O hydrogen bonding. One of the dichloromethane solvent molecules is disordered over two positions in a 0.55:0.45 ratio

Nickel-catalyzed electrophile cross-coupling of aryl halides with alkyl halides

Thesis (Ph. D.)--University of Rochester. Dept. of Chemistry, 2013.This thesis details the author’s contributions to the emerging field of electrophile cross-couplings. This new field is related to the well-established field of conventional cross-coupling that uses transition metal-catalysts to facilitate coupling reactions between electrophile-nucleophile pairs. Electrophile cross-coupling uses a conceptually different approach because it seeks to selectively join two different electrophiles with a transition metal-catalyst. The issue of developing cross-selective reactions is the central challenge addressed. Chapter 1 details recent advances and the state-of-the-art in conventional cross-coupling only for the purpose of conceptual comparison to electrophile cross-coupling. Additionally, a review of similar coupling reactions and their mechanisms are presented with the earliest examples of the unique reactivity that guided development of the reactions in this thesis. Chapter 2 details the first cross-selective nickel-catalyzed electrophile cross-coupling of iodoarenes with iodoalkanes. The new method displays exceptional functional group compatibility (-C(O)Me, -NHBoc, 1° and 2° alkyls, -OH) and the catalyst shows chemoselective reaction at C-I bonds over C-B bonds on bifunctional substrates. Mechanistic studies reveal that the reaction likely proceeds without the intermediacy of a carbon nucleophile, and that dimeric by-products arise from disproportionation of nickel intermediates. Chapter 2 also summarizes a detailed mechanistic study conducted in our lab that indicates the cross-coupled product is formed by a radical chain mechanism. Chapter 3 expands on the results of Chapter 2 by increasing the scope of the method to include bromo- and chloroarenes for the first time. Additional competition experiments reveal that the new catalysts and reaction conditions are chemoselective for the cross-coupling of two electrophilic C-Br bonds over conventional cross coupling of C-Br bonds with C-B, C-Sn, or C-Si bonds. Further mechanistic work reveals that υ ∝ [bromoalkane]x[catalyst]y/[bromoarene]z (x, y, and z are positive numbers and could be non-integers). Chapter 4 presents the first electrophile cross-couplings of halogenated pyridines with alkyl bromides. Scope and limitations are discussed in the context of improving the method. Chapter 5 details the effect of additives on other related electrophile coupling reactions

Nickel-catalyzed reductive coupling of epoxides and aziridines

Thesis (Ph. D.)--University of Rochester. Department of Chemistry, 2015.In this thesis, nickel-catalyzed reductive coupling reaction with epoxides and aziridines is described with details. Chapter 1 delves into the development of nickel/iodide-catalyzed epoxide arylation reaction. The broad utilization and nucleophilic ring opening of epoxides are both covered. In particular, the chapter presents the challenges and practicality associated with the catalysis. In-depth discussion is devoted to the discovery of the catalysis and detailed optimization and substrate scope are also covered. Chapter 2 introduces the history of Nugent’s reagent and its application in epoxide-related chemistry. It also explains the logic and design for the Ni/Ti co-catalyzed epoxide arylation reaction. Chapter 3 deepens the discussion in Chapter 2 by extending the Ni/Ti co-catalysis to enantioselective synthesis. Chiral catalyst synthesis, kinetic resolution, and heterocyclic arene application are all covered Chapter 4 details the application of Ni/Iodide catalysis to aziridines. Interesting Lewis acid effect and protecting group screen are explained with details. The substrate scope of this reaction is also briefly discussed

Nickel-catalyzed reductive ketone synthesis and stoichiometric reactivity of nickel(II) acyl halide complexes with organic halides

Thesis (Ph. D.)--University of Rochester. Dept. of Chemistry, 2016Chapter one focuses on the formation of ketones by nickel-catalyzed cross electrophile coupling of activated carboxylic acid derivatives and functionalized alkyl halides to give functionalized alkyl alkyl ketones. Use of this method allows for functionalized substrates to be used, including amines alcohols and even boronic esters. Stearicly hindered ketones can also be made by this method, a significant challenge for other procedures. The published work demonstrates 16 examples with 71% average yield and several more that are unpublished. Chapter two discusses a catalytic carbonylative cross-electrophile coupling of alkyl and aryl halides to form ketones. Only a small hand full of catalytic carbonylative cross-electrophile coupling reactions have been published. This method provides a convenient alternative to electrochemical and stoichiometric methods. The procedure allows for the rapid construction of aryl alkyl ketones from stable starting materials. The published work includes eight examples with 60% average yield. Chapter three, covers the previously unknown stoichiometric reactivity of bipyridine ligated acylnickel(II) halide complexes with alkyl and aryl halides. Acylnickel(II) complexes have been implicated as intermediates in several nickelcatalyzed reactions including acylation and carbonylation reactions discussed in chapters 1 and 2. This work reveals that these intermediates may be involved in the catalytic cycles for both carbonylation and acylation reactions. Selectivity for cross-ketone in the reactions of acylnickel complexes with organic halides ranges from 3:1 up to 20:1 with yields of the cross ketone up to 76% isolated

Ruthenium-Catalyzed C–H Arylation of Diverse Aryl Carboxylic Acids with Aryl and Heteroaryl Halides

Ruthenium ligated to tricyclohexylphosphine or di-<i>tert</i>-butylbipyridine catalyzes the arylation of carboxylic acids with diverse aryl halides (iodide, bromide, and triflate; aryl and heteroaryl). In addition, arylations with 2-iodophenol formed benzochromenones, carboxylate was shown to be a stronger donor than an amide, and the arylation of a pyridine carboxylate was demonstrated. Stoichiometric studies demonstrated that the added ligand is required for reaction with the electrophile but not the C–H bond

Nickel-Catalyzed Regiodivergent Opening of Epoxides with Aryl Halides: Co-Catalysis Controls Regioselectivity

Epoxides are versatile intermediates in organic synthesis, but have rarely been employed in cross-coupling reactions. We report that bipyridine-ligated nickel can mediate the addition of functionalized aryl halides, a vinyl halide, and a vinyl triflate to epoxides under reducing conditions. For terminal epoxides, the regioselectivity of the reaction depends upon the cocatalyst employed. Iodide cocatalysis results in opening at the less hindered position via an iodohydrin intermediate. Titanocene cocatalysis results in opening at the more hindered position, presumably via Ti^III-mediated radical generation. 1,2-Disubstituted epoxides are opened under both conditions to form predominantly the trans product

Enantioselective Cross-Coupling of <i>meso</i>-Epoxides with Aryl Halides

The first enantioselective cross-electrophile coupling of aryl bromides with <i>meso</i>-epoxides to form <i>trans</i>-β-arylcycloalkanols is presented. The reaction is catalyzed by a combination of (bpy)­NiCl₂ and a chiral titanocene under reducing conditions. Yields range from 57 to 99% with 78–95% enantiomeric excess. The 30 examples include a variety of functional groups (ether, ester, ketone, nitrile, ketal, trifluoromethyl, sulfonamide, sulfonate ester), both aryl and vinyl halides, and five- to seven-membered rings. The intermediacy of a carbon radical is strongly suggested by the conversion of cyclooctene monoxide to an aryl [3.3.0]­bicyclooctanol

Multimetallic catalytic methods for the formation of carbon-carbon bonds

Thesis (Ph. D.)--University of Rochester. Department of Chemistry, 2016.This thesis describes the use of multiple transition metal catalysts for the selective formation of carbon-carbon bonds. While the majority of cross coupling reactions rely on one transition-metal catalyst which reacts with a stoichiometric metal reagent, the combination of two metal catalysts in reactions has the potential to significantly increase the expediency towards synthetic targets, eliminating the need for stoichiometric metal reagents and improving functional group compatibility. There are many precedents for the combination of catalysts in organic methodology, however relatively few examples of multimetallic catalyzed reactions exist, and even fewer examples exist where the mechanism between the two catalytic metals is understood. The aim of the projects communicated in this thesis is two-fold: (1) To design new and efficient ways to form useful carbon-carbon bonds (Csp²-Csp³, Csp²-Csp², and Csp³-Csp³) from readily available starting materials and (2) to provide insight into how two transition metal catalysts can cooperate in a reaction to achieve high selectivity and yield. Chapter 1 reviews the importance of carbon-carbon bond formation and introduces the main methods of cross coupling, including the concept of multimetallic catalysis. Previous examples of dual metal catalysis are summarized in the literature and the advantages and challenges of using two metals in a catalytic system are discussed. Chapter 2 presents a nickel and cobalt catalyzed strategy for the formation of Csp²-Csp³ bonds. The first attempted cross electrophile couplings to form diarylmethanes from benzyl halides and aryl iodides is reported in moderate selectivity, followed by the strategic optimization of the co-catalytic system which enables higher yields and selectivity through the coupling of benzyl sulfonate esters with aryl halides. In this reaction, nickel reacts selectively with aryl halides through an oxidative addition step, while cobalt phthalocyanine generates radicals through an SN2 reaction with benzyl sulfonate esters, followed by homolysis. The extension of this method to coupling benzyl phosphonate esters and primary and secondary benzyl chlorides is also presented. Chapter 3 reports the quest for and ultimate discovery of a multimetallic catalyzed Csp²-Csp² coupling. Beginning with stoichiometric transmetalation studies for the coupling of aryl C-H bonds with aryl C-X bonds, the reaction of various metal aryl complexes based on iridium, ruthenium, copper, nickel, and palladium are described. While these reactions were ineffective in generating unsymmetrical biaryls, the catalytic combination of a nickel and palladium catalyst to couple aryl bromides with aryl trifluoromethanesulfonate esters for the design of a cross Ullman reaction was a success. This reaction provided access to a variety of unsymmetrical biaryls maintaining an equimolar catalyst loading of the two metals, and showed promise for later development of the formation of useful unsymmetrical bipyridines and dienes. The scope of this remarkable reaction, the origin of selectivity, and the enhancement in rate and selectivity by a KF additive is presented. Additionally, the optimization strategy towards coupling chlorobenzene and electron-rich aryl chlorides is communicated. Finally, this chapter includes the first attempted multimetallic catalyzed multicomponent reactions with the nickel and palladium as well as nickel and cobalt catalyzed systems, including carbonylation, and the difunctionalization of olefins and alkynes