N-h insertion reactions of Boc-amino acid amides: solution- and solid-phase synthesis of pyrazinones and pyrazines

A series of alpha-diazo-beta-ketoesters were reacted with Boc amino acid amides in the presence of rhodium octanoate catalyst. The resulting N-H insertion products were treated with acid, providing the 1,4-azine intermediates, which were oxidized by air to form the corresponding pyrazine-6-one products. The pyrazine-6-ones were further derivatized by N-alkylation or by conversion to the arylpyrazines using sequential bromination and Suzuki coupling reactions. [reaction: see text]     

Reaktionen des 2,2-Dimethylcyclohexadienons, 2. Mitt.: Umsetzung mit Phenylmagnesiumbromid

Zusammenfassung Es wird gezeigt, daß 2,2-Dimethylcyclohexadienon (I) in gleicher Weise wie die o-Chinolacetate mit Phenylmagnesiumbromid unter praktisch ausschließlicher 1,4-Addition reagiert. Das Reaktionsprodukt ist das 2,2-Dimethyl-5-phenylcyclohexen-(3)-on-(1) (IIc). Es ergibt sich also der erwartete Unterschied von I gegen die o-Chinolacetate, da bei diesen, verbunden mit der 1,4-Addition der Grignardverbindung, Essigsäureabspaltung zum aromatischen System zurückführt.1. Mitt.:F. Wessely, H. Budzikiewicz undH. Janda, Mh. Chem.91, 456 (1960).     

Catalysis of the photo-Fries reaction: antibody-mediated stabilization of high energy states

A conformationally constrained hapten is presented that is capable of catalyzing the first antibody-mediated photo-Fries rearrangement. In this reaction, absorption of light energy by a diphenyl ether substrate results in homolytic C-O bond cleavage followed by recombination to yield biphenyl-derived products. The most proficient antibody studied converts 4-phenoxyaniline 15 into 2-hydroxy-5-aminobiphenyl 16 under high-intensity irradiation at a rate of 8.6 microM/min. These results support a recent hypothesis stating that immunization with conformationally constrained haptens provides higher titers for the acquisition of simple binding antibodies; however, in this case, conformational constraint does not ensure the development of more efficient catalysts. Using the obtained antibodies, the presence of products resulting from escape of free radicals from the solvent cage can be suppressed, altering the excited state energy surface such that free radicals are funneled into the formation of the desired biphenyl product. However, studies also show the inactivation of the antibodies as a result of photodecay of the biphenyl product. Using an isocyanate scavenging resin, the photodecay product could be removed and the inactivation of the antibody drastically reduced. Furthermore, despite the observed photodecay, turnover of the antibody was present; this represents the first case in which true turnover of a photochemical reaction using a catalytic antibody could be observed.     

Polytetrahydrofuran cross-linked polystyrene resins for solid-phase organic synthesis

Currently, divinylbenzene cross-linked polystyrene (DVB-PS) is the polymer of choice for use in solid-phase organic synthesis (SPOS). While much research has been directed toward the optimization of linker groups for the attachment of compounds to the polymer, the development of new polymers themselves has been relatively neglected. In an attempt to overcome the shortcomings of DVB-PS and to develop new polymers with optimum properties for use in organic synthesis, we have prepared a series of polystyrene polymers that incorporate flexible polytetrahydrofuran (PTHF) based cross-linkers. The objective of incorporating PTHF into the polymers was to slightly increase the overall polarity of the polymer and thus render the resins more organic solvent-like. Since the degree to which a resin swells in and absorbs a particular solvent correlates to how well substrates attached to the polymer are solvated, we compared the swelling of our new resins to commercially available DVB-PS resins. In all cases, we found that our resins swelled to a much greater extent than do DVB-PS resins, and their use should therefore allow for SPOS reaction conditions that more closely mimic homogeneous solution-phase conditions. It was also found that the PTHF chain length of the cross-linker does not affect the level of swelling since all of our cross-linkers afford resins with comparable levels of increased swelling. Furthermore, we have examined the utility of our resins in directed ortho-metalation reactions and found that the increased swelling of our resins allows for isolation of reaction products in yields comparable to what is achieved using standard solution-phase conditions.     

Solution- and soluble-polymer supported asymmetric syntheses of six-membered ring prostanoids

An asymmetric synthesis of prostanoids containing a six-membered ring core structure (11a-homoprostaglandins), both in solution and using non-cross-linked polystyrene (NCPS) as a soluble support, was developed. Target molecule 1 was generated in a convergent fashion using a three-component coupling strategy, wherein chiral enone (R)-2 was the precursor of the central ring and the cuprate 3 and triflate 4 were used to introduce the side chains. The chiral center of (R)-2 directed the facial selectivity of the conjugate addition reaction which then dictated the stereochemical outcome of the subsequent alpha alkylation. Attachment of a six-membered ring scaffold to NCPS facilitated purification without compromising synthetic yields, still allowed 1H-NMR analysis of the intermediates in the synthesis, and provided an avenue for the construction of six-membered ring prostanoid libraries.     

Asymmetrical linear structures including three-electron hemibonds or other interactions in the (ABA)-type triatomic cations: Ne3+, (He-Ne-He)+, (Ar-Ne-Ar)+, (Ar-O-Ar)+, (He-O-He)+, and (Ar-He-Ar)+

By the counterpoise geometry optimization at the level of CCSD(T)aug-cc-pVDZ, the asymmetrical linear structures with all the real frequencies were obtained for the triatomic cations of (ABA)+ type: Ne3+, (He-Ne-He)+, (Ar-Ne-Ar)+, (Ar-He-Ar)+, (He-O-He)+, and (Ar-O-Ar)+. The validity of this optimization method is confirmed by comparing with the method of the potential-energy surface for the calculations of Ne3+ and (He-Ne-He)+. Using the molecular-orbital theory, it is found that the interaction within the triatomic cations is dominated by the contribution from the first two atoms while the contribution from the third atom is small. This result is justified as a direct consequence of forming an asymmetrical linear structure. Specifically, four types of interaction within the triatomic cations are identified: three-electron sigma-type hemibond, three-electron pi-type hemibond, two-electron sigma bond, and the attraction between cation and atoms. For Ne3+, (He-Ne-He)+, and (He-O-He)+ clusters, it is shown that the electron correlation effect supports the asymmetry.     

Suspension ring-opening metathesis polymerization: the preparation of norbornene-based resins for application in organic synthesis

A series of norbornene-based resin beads were obtained by aqueous suspension ring-opening metathesis polymerization (ROMP) and used as polymeric supports for organic synthesis. These resins were prepared from norbornene, norborn-2-ene-5-methanol, and cross-linkers such as bis(norborn-2-ene-5-methoxy)alkanes, di(norborn-2-ene-5-methyl)ether, and 1,3-di(norborn-2-ene-5-methoxy)benzene. The resulting unsaturated ROMP (U-ROMP) resins containing olefin repeat units were chemically modified using hydrogenation, hydrofluorination, chlorination, and bromination reactions to produce saturated ROMP resins with different chemical and physical properties. The hydrogenated ROMP (H-ROMP) resin was found to be highly resistant to acidic, basic, Lewis acid, and Birch reduction conditions and was assessed as a polymeric support in a series of solid-phase synthetic applications. The H-ROMP resin was found to have superior performance compared to polystyrene-divinylbenzene (PS-DVB) copolymers in aromatic nitration and acylation reactions. In a conventional five-step solid-phase synthesis of a hydantoin, similar results were obtained for both the H-ROMP and PS-DVB resins. The U-ROMP resin was also shown to be effective in the solid-phase syntheses of benzimidazoles and benzimidazolones.     

Aqueous aldol catalysis by a nicotine metabolite

Nornicotine, an endogenous tobacco alkaloid and minor nicotine metabolite, can catalyze aldol reactions at physiological pH. Catalysis appears to be due to a covalent enamine mechanism, an unprecedented reaction with small organic molecule catalysts in aqueous buffer. Kinetic parameters for nornicotine as well as other related alkaloids were measured and demonstrate that both the pyrrolidine and pyridine rings are critical for optimal catalysis. Substrate compatibility of this catalyst and its implications in vivo are discussed.     

A blue fluorescent antibody-cofactor sensor for mercury

[reaction: see text] A chemically programmed antibody sensor, consisting of a stilbenyl boronic acid cofactor and monoclonal antibody EP2-19G2, provides a new method of mercury detection. The fluorescent antibody sensor generates an intense powder blue fluorescence when bound to the stilbenyl boronic acid cofactor; however, it is quenched in the presence of Hg(2+) ions. The EP2-19G2-cofactor biosensor provides micromolar sensitivity and selectivity toward Hg(2+) ions over a wide range of metal ions in aqueous solution.     

Preparation and reactivity of the new cyclopentadienyl-bridged complex (Me2SiCH2CH2SiMe2)(C5H4Fe(CO)2)2

A new metal-metal bonded binuclear iron system [Me₂SiCH₂CH₂SiMe₂][η⁵-C₅H₄Fe(CO)₂]₂ (2) has been prepared by treating two equivalents of NaCp with one equivalent of ClSi(Me)₂CH₂CH₂SiClMe₂ obtaining the intermediate (C₅H₅)Si(Me)₂CH₂CH₂Si(Me)₂(C₅H₅) which then is directly allowed to react with Fe(CO)₅ given 2 in 30% yield. From this cyclopentadienyldisilyl linked system three new binuclear irom complexes are formed. Treatment of 2 with Na/Hg in THF produced the dianion [Me₂SiCH₂CH₂SiMe₂][η⁵-C₅H₄Fe(CO)₂^?]₂ which is quenched with CH₃I giving [Me₂SiCH₂CH₂SiMe₂][η⁵-C₄H₄Fe(CO)₂CH₃]₂ (4) in 76% yield. Complex 2 is oxidized with 1.2 equivalent of I₂ to give [Me₂SiCH₂CH₂SiMe₂][η⁵-C₅H₄Fe(CO)₂I]₂ (5) in 85% yield. Photolysis of 5 (1 equiv.) and PPh₃ (3 equiv.) results in the formation of the bis-substituted compound [Me₂SiCH₂CH₂SiMe₂][η⁵-C₅H₄Fe(CO)(PPh₃)I]₂ (6). These four new binuclear iron complexes are characterized by ¹H, ¹³C, and ³¹P NMR and IR spectroscopy.