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Biomedical subjects

Michael G Organ

Publications and source records attributed to Michael G Organ.

At least 19 recordsLinked to original sources
PubMed2007

Biaryls made easy: PEPPSI and the Kumada-Tamao-Corriu reaction.

An easily employed, highly versatile Kumada-Tamao-Corriu (KTC) protocol utilizing the PEPPSI (Pyridine, Enhanced, Precatalyst, Preparation, Stabilization and Initiation) precatalysts 1 and 2 is detailed. The ease-of-use of these catalysts and the synthesis of a wide range of hindered biaryls, large coupling partners and drug-like heterocycles, in high yield, makes the PEPPSI-KTC protocol very attractive. The high reactivity of the PEPPSI system allowed a tetra-ortho-substituted heterocycle, 11 to be synthesized at room temperature for the first time using any protocol. The PEPPSI protocols also tolerated the Boc protecting group and phenols required no protection in modified conditions. A relatively large scale (10 g) reaction was also performed with no loss in performance. Furthermore, PEPPSI-IPr, 1, was compared to previously reported highly active phosphine ligands 42, 43, and 44 and was shown to result in significantly better yields under identical conditions. Finally, we demonstrated that the PEPPSI catalyst system is very adept at performing sequential KTC coupling reactions, analogous to multicomponent reactions, which allow complex polyaryl and polyheteroaryl architectures to be produced in one single operation.

Journal Article↗
PubMed2006

A 2.13 A structure of E. coli dihydrofolate reductase bound to a novel competitive inhibitor reveals a new binding surface involving the M20 loop region.

Dihydrofolate reductase (DHFR) is a vital metabolic enzyme and thus a clinically prominent target in the design of antimetabolites. In this work, we identify 1,4-bis-{[N-(1-imino-1-guanidino-methyl)]sulfanylmethyl}-3,6-dimethyl-benzene (compound 1) as the correct structure of the previously reported DHFR inhibitor 1,4-bis-{(iminothioureidomethyl)aminomethyl}-3,6-dimethyl-benzene (compound 2). The fact that compound 1 has an uncharacteristic structure for DHFR inhibitors, and an affinity (KI of 11.5 nM) comparable to potent inhibitors such as methotrexate and trimethoprim, made this inhibitor of interest for further analysis. We have conducted a characterization of the primary interactions of compound 1 and DHFR using a combination of X-ray structure and SAR analysis. The crystal structure of E. coli DHFR in complex with compound 1 and NADPH reveals that one portion of this inhibitor exploits a unique binding surface, the M20 loop. The importance of this interface was further confirmed by SAR analysis and additional structural characterization.

Binding Sites↗
PubMed2006

A user-friendly, all-purpose Pd-NHC (NHC=N-heterocyclic carbene) precatalyst for the negishi reaction: a step towards a universal cross-coupling catalyst.

We have developed the first user-friendly Negishi protocol capable of routinely cross-coupling all combinations of alkyl and aryl centers. The use of an easily synthesized, air stable, highly active, well-defined precatalyst PEPPSI-IPr (1; PEPPSI=pyridine-enhanced precatalyst preparation, stabilization and initiation; IPr=diisopropylphenylimidazolium derivative) substantially increases the scope, reliability, and ease-of-use of the Negishi reaction. All organohalides and routinely used pseudohalides were excellent coupling partners, with the use of chlorides, bromides, iodides, triflates, tosylates, and mesylates resulting in high yield of the coupled product. Furthermore, all reactions were performed by using general laboratory techniques, with no glove-box necessary as the precatalyst was weighed and stored in air. Utilization of this methodology allowed for the easy synthesis of an assortment of sterically encumbered biaryls and druglike heteroaromatics, demonstrating the value of the PEPPSI-IPr system. Furthermore, this is also the first time Pd-NHC (NHC=N-heterocyclic carbene) methodology has surpassed the related phosphine-ligated Negishi processes both in activity and use.

Journal Article↗
PubMed2006

Easily prepared air- and moisture-stable Pd-NHC (NHC=N-heterocyclic carbene) complexes: a reliable, user-friendly, highly active palladium precatalyst for the Suzuki-Miyaura reaction.

The synthesis of NHC-PdCl(2)-3-chloropyridine (NHC=N-heterocyclic carbene) complexes from readily available starting materials in air is described. The 2,6-diisopropylphenyl derivative was found to be highly catalytically active in alkyl-alkyl Suzuki and Negishi cross-coupling reactions. The synthesis, ease-of-use, and activity of this complex are substantial improvements over in situ catalyst generation and all current Pd-NHC complexes. The utilization of complex 4 led to the development of a reliable, easily employed Suzuki-Miyama protocol. Employing various reaction conditions allowed a large array of hindered biaryl and drug-like heteroaromatic compounds to be synthesized without difficulty.

Journal Article↗
PubMed2005

A microcapillary system for simultaneous, parallel microwave-assisted synthesis.

A continuous flow, microwave-assisted, parallel-capillary microreactor has been developed. Libraries of drug candidates were prepared on the milligram scale with this reactor by injecting plugs of reagents from separate syringes into common reaction capillaries, thereby producing discrete compounds in excellent yield and purity. Microwave irradiation provides the necessary energy that existing room-temperature microreactor technology lacks for higher activation barrier transformations, producing the required amounts of desired compounds in minutes or less.

Journal Article↗
PubMed2005

Room-temperature Negishi cross-coupling of unactivated alkyl bromides with alkyl organozinc reagents utilizing a Pd/N-heterocyclic carbene catalyst.

A high-yielding cross-coupling reaction of unactivated alkyl bromides possessing beta-hydrogens with alkylzinc halides utilizing a Pd/N-heterocyclic carbene (NHC) catalyst at room temperature is described. A variety of Pd sources, Pd2(dba)3, Pd(OAc)2, or PdBr2, with the commercially available ligand precursor 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IPr.HCl) successfully coupled 1-bromo-3-phenylpropane with n-butylzinc bromide in THF/NMP. An investigation of different NHC precursors showed that the bulky 2,6-diisopropylphenyl moiety was necessary to achieve high coupling yields (75-85%). The corresponding ethyl analogue was moderately active (11%). A range of unsymmetrical NHC precursors were prepared and evaluated. The ligand precursor containing one 2,6-diisopropylphenyl and one 2,6-diethylphenyl afforded the coupling product in 47% yield, clearly suggesting a direct relationship between the steric topography created by the flanking N-substituents and catalyst activity. Under optimal conditions, a number of alkyl bromides and alkylzinc halides possessing common functional groups (amide, nitrile, ester, acetal, and alkyne) were effectively coupled (61-92%). It is noteworthy that beta-substituted alkyl bromides and alkylzinc halides successfully underwent cross-coupling. Also, under these conditions alkyl chlorides were unaffected.

Journal Article↗
PubMed2005

The first Negishi cross-coupling reaction of two alkyl centers utilizing a Pd-N-heterocyclic carbene (NHC) catalyst.

The development of an NHC-based system capable of cross-coupling sp(3)-sp(3) centers in high yield has been a long-standing challenge. This communication describes the use of a Pd-NHC catalytic system that achieves room-temperature Negishi cross-couplings of unactivated, primary bromides and alkyl organozinc reagents with a variety of functionality. [reaction: see text]

Journal Article↗
PubMed2005

A microreactor for microwave-assisted capillary (continuous flow) organic synthesis.

A capillary-based flow system has been developed for conducting microscale organic synthesis with the aid of microwave irradiation. The capillary internal diameter investigated ranged from 200 to 1200 mum, while the flow rate was varied between 2 and 40 muL/min, which corresponds to the sample being irradiated approximately 4 min. Other parameters investigated include reaction concentration and power setting of the microwave. Excellent conversion was observed in a variety of cross coupling and ring-closing metathesis (RCM) reactions employing metal catalysts and in nucleophilic aromatic substitution and Wittig reactions that do not employ metals. Reactions that have solids in them do not seem to pose a significant concern for the method, such as blocked channels. It was shown that capillaries coated internally with thin films of Pd metal show tremendous rate accelerations and that the thin films themselves are capable of catalyzing Suzuki-Miyaura reactions with no exogenous catalyst added. Importantly, it has been demonstrated that reagents in separate syringes can be coinjected into the capillary, mix, and react with none of the laminar flow problems that plague microreactor (lab on a chip) technology. This paves the way to use microwave-assisted, flow capillary synthesis as a powerful and efficient means to replace "one-at-a-time" microwave synthesis to provide libraries of compounds in a scale suitable for biological screening purposes.

Journal Article↗
PubMed2005

Electronic nature of N-heterocyclic carbene ligands: effect on the Suzuki reaction.

Suzuki reactions of aryl chlorides and arylboronic acids with a range of electronically different N-heterocyclic carbene ligands derived from N,N-diadamantylbenzimidazolium salts are reported. Results indicate that an electron-rich NHC ligand enhances the rate of oxidative addition. However, reductive elimination is unchanged by the electronic nature of the supporting ligand and is primarily affected by the steric environment.

Journal Article↗
PubMed2004

Allylic ionization versus oxidative addition into vinyl C-X bonds by Pd with polyfunctional olefin templates.

The chemoselectivity of activation by a (PPh3)4Pd catalyst on a series of small, olefin-based compounds that were substituted with a variety of allylic and vinylic functional groups was studied. Of particular note, the allylic acetate of 1-acetoxy-2-bromo-2-propene (7) was selectively ionized by Pd in the presence of a malonate nucleophile, while oxidative addition of the C-Br bond to Pd occurred exclusively in the presence of a boronic acid nucleophile. When the acetate nucleophile was used, no ionization of the acetate leaving group occurred at all, which was proven by the use of deuterium-labeled substrates (e.g., 11). This report demonstrates that the nucleophile interacts in some way with Pd prior to catalyst activation of the substrate. Certainly in the case of the malonate nucleophile, this is without precedent and contradicts the central dogma of how these proposed catalytic cycles operate.

Journal Article↗
PubMed2004

Use of olefin templates in queued chemical transformations using late transition metal catalysis. Total synthesis of cis and trans bupleurynol via a single multireaction sequence.

1-Bromo-2-iodoethylene (9) was used as a central, pseudosymmetric building block for the fully convergent and modular synthesis of two related natural products, cis (1a) and trans (1b) bupleurynol. In doing so, a 9-step synthesis of 1a (reported previously) has been vastly truncated to one single operation by using queued cross-coupling reactions with Pd catalysis, negating the need for any protecting group chemistry.

Journal Article↗
PubMed2004

Metal-catalyzed coupling reactions on an olefin template: the total synthesis of (13E,15E,18Z,20Z)-1-hydroxypentacosa- 13,15,18,20-tetraen-11-yn-4-one 1-acetate.

The naturally occurring ant venom (13E,15E,18Z,20Z)-1-hydroxypentacosa-13,15,18,20-tetraen-11-yn-4-one 1-acetate was synthesized stereospecifically using a series of metal-mediated cross-coupling reactions. The use of the difunctional olefin template (E)-1-chloro-2-iodoethylene as the central, pseudosymmetrical building block facilitated a fully convergent and, thus, efficient strategy to prepare this polyunsaturated natural product.

Acetates↗
PubMed2003

The synthesis of deoxyfusapyrone. 2. Preparation of the bis-trisubstituted olefin fragment and its attachment to the pyrone moiety.

A convergent and modular synthesis has been devised to construct the eight diastereoisomers of deoxyfusapyrone (1). In this paper the synthesis of the complex polyene chain is reported as is its connection to the pyrone moiety that is in the middle of the structure of the final target molecule. This route has been fully worked out for one of the isomers and will now be applied in a parallel synthesis format to make all the stereoisomers of 1.

Alkenes↗
PubMed2003

On the regiochemistry of nucleophilic attack on 2-halo pi-allyl complexes. 4. The effect of silver acetate and nucleophile concentrations in competitive nucleophilic attack with malonate and phenoxide nucleophiles.

2,3-Dibromo-1-propene or its allyl carbonate analogue are ionized under Pd catalysis to generate the 2-bromo Pd-pi-allyl complex (triphenylphosphine ligand), which alkylates with malonate nucleophile at the terminal position. The presence of acetate ion in the reaction mixture results in some malonate attack being redirected to the central carbon. The acetate ion can come from the ionization of 1-acetoxy-2-bromo-2-propene or by the addition of silver acetate to the reaction mixture. The addition of phenoxide ion to the reaction also causes the same regiochemical phenomena, although harder anions such as methoxide exert no such effect.

Journal Article↗
PubMed2003

Combining the use of solid-supported transition metal catalysis with microwave irradiation in solution-phase parallel library synthesis.

Microwave heating methods have been combined with the use of solid-supported catalysts to produce small solution-phase libraries of medicinally-relevant compounds. Palladium supported on charcoal (Pd/C) has been used to produce libraries of pyrazole compounds for screening in COX II studies via Suzuki cross coupling reactions, while the same catalyst has been used also to produce styryl-based nAChR compounds using analogous chemistry. Although the reaction substrates are very different (aryl vs. vinyl), this catalyst system provided consistently good and reliable results. The use of a polystyrene-supported Ru catalyst for ring-closing metathesis (RCM) reactions was also evaluated to prepare benzolactam structures for evaluation as factor Xa inhibitors.

Catalysis↗
PubMed2002

A concise synthesis of silanediol-based transition-state isostere inhibitors of proteases.

[reaction: see text] An efficient synthesis of silanediol-based transition-state inhibitors of proteases is described. A new convergent synthesis has been optimized by using a two-step sequence of hydrosilylation followed by the addition of a silyllithio species to an imine. The method should be applicable to the synthesis of a wide variety of silanediol isosteres to probe the utility of this unique transition-state isostere.

Protease Inhibitors↗