Publications by authors named "Mark Seierstad"

24 Publications

  • Page 1 of 1

Heteroarylureas with fused bicyclic diamine cores as inhibitors of fatty acid amide hydrolase.

Bioorg Med Chem Lett 2020 10 9;30(20):127463. Epub 2020 Aug 9.

Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of mechanism-based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with fused bicyclic diamine cores is described. In contrast to compounds built around a piperazine core, most of the fused bicyclic diamine bearing analogs prepared exhibited greater potency against rFAAH than the human enzyme. Several compounds equipotent against both species were identified and profiled in vivo.
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http://dx.doi.org/10.1016/j.bmcl.2020.127463DOI Listing
October 2020

Discovery of a Gut-Restricted JAK Inhibitor for the Treatment of Inflammatory Bowel Disease.

J Med Chem 2020 03 16;63(6):2915-2929. Epub 2020 Mar 16.

Janssen Research and Development, 3210 Merryfield Row, San Diego, California 92121, United States.

To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01439DOI Listing
March 2020

Discovery of Imidazo[1,2-]pyrazines and Pyrazolo[1,5-]pyrimidines as TARP γ-8 Selective AMPAR Negative Modulators.

ACS Med Chem Lett 2019 Mar 26;10(3):267-272. Epub 2018 Dec 26.

Janssen Research & Development L.L.C., 3210 Merryfield Row, San Diego, California 92121 United States.

This report discloses the discovery and characterization of imidazo[1,2-]pyrazines and pyrazolo[1,5-]pyrimidines as selective negative modulators of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) associated with transmembrane AMPAR regulatory protein γ-8. Imidazopyrazine was initially identified as a promising γ-8 selective high-throughput screening hit, and subsequent structure-activity relationship optimization yielded subnanomolar, brain penetrant leads. Replacement of the imidazopyrazine core with an isosteric pyrazolopyrimidine scaffold improved microsomal stability and efflux liabilities to provide , JNJ-61432059. Following oral administration, exhibited time- and dose-dependent AMPAR/γ-8 receptor occupancy in mouse hippocampus, which resulted in robust seizure protection in corneal kindling and pentylenetetrazole (PTZ) anticonvulsant models.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421542PMC
March 2019

Predicting the Binding of Fatty Acid Amide Hydrolase Inhibitors by Free Energy Perturbation.

J Chem Theory Comput 2018 Nov 23;14(11):5815-5822. Epub 2018 Oct 23.

Janssen Research and Development , 3210 Merryfield Row , San Diego , California 92121 , United States.

Since a goal of most drug discovery projects in either academia or industry is to design molecules that selectively bind to the desired protein, determination of protein-ligand binding free energies is of utmost importance in computer aided drug design. With the help of significant improvements in computer power, enhanced sampling techniques and accuracy of force fields, FEP (free energy perturbation) is becoming an important tool to estimate binding free energies in many drug discovery projects both retrospectively and prospectively. We have evaluated the ability of Schrödinger's FEP+ to predict relative binding free energies of a congeneric series of noncovalent fatty acid amide hydrolase (FAAH) inhibitors using an in-house crystal structure. This study shows that although an impressively accurate correlation can be obtained with experimental ICs considering small perturbations on the deeper side of the pocket, the same was not observed with small perturbations on the relatively more open-ended and solvent-accessible side of the pocket. To understand these observations, we thoroughly investigated several key factors including the sampling of asymmetrically substituted rings, different perturbation maps, impact of simultaneous perturbations at two different ends of the ligand, and selecting the perturbations in a "chemically sensible" way.
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http://dx.doi.org/10.1021/acs.jctc.8b00672DOI Listing
November 2018

Lead Optimization of 5-Aryl Benzimidazolone- and Oxindole-Based AMPA Receptor Modulators Selective for TARP γ-8.

ACS Med Chem Lett 2018 Aug 13;9(8):821-826. Epub 2018 Jul 13.

Janssen Research & Development L.L.C., 3210 Merryfield Row, San Diego, California 92121, United States.

Glutamate mediates fast excitatory neurotransmission via ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The trafficking and gating properties of AMPA receptors (AMPARs) can be amplified by transmembrane AMPAR regulatory proteins (TARPs), which are often expressed in localized brain regions. Herein, we describe the discovery, lead optimization, and preclinical characterization of 5-arylbenzimidazolone and oxindole-based negative modulators of AMPARs associated with TARP γ-8, the primary TARP found in hippocampus. High-throughput screen lead was optimized for potency and brain penetration to provide benzimidazolone , JNJ-55511118.1 Replacement of the benzimidazolone core in with an oxindole mitigated reactive metabolite formation and led to the identification of (GluA1/γ-8 pIC = 9.7). Following oral dosing in rats, demonstrated robust target engagement in hippocampus as assessed by autoradiography (ED = 0.6 mg/kg, plasma EC = 9 ng/mL).
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http://dx.doi.org/10.1021/acsmedchemlett.8b00215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088354PMC
August 2018

Getting a Handle on Neuropharmacology by Targeting Receptor-Associated Proteins.

Neuron 2017 Dec;96(5):989-1001

Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA. Electronic address:

Targeted therapy for neuropsychiatric disorders requires selective modulation of dysfunctional neuronal pathways. Receptors relevant to CNS disorders typically have associated proteins discretely expressed in specific neuronal pathways; these accessory proteins provide a new dimension for drug discovery. Recent studies show that targeting a TARP auxiliary subunit of AMPA receptors selectively modulates neuronal excitability in specific forebrain pathways relevant to epilepsy. Other medicinally important ion channels, gated by glutamate, γ-aminobutyric acid (GABA), and acetylcholine, also have associated proteins, which may be druggable. This emerging pharmacology of receptor-associated proteins provides a new approach for improving drug efficacy while mitigating side effects.
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http://dx.doi.org/10.1016/j.neuron.2017.10.001DOI Listing
December 2017

The SAR of brain penetration for a series of heteroaryl urea FAAH inhibitors.

Bioorg Med Chem Lett 2016 07 5;26(13):3109-3114. Epub 2016 May 5.

Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.

The SAR of brain penetration for a series of heteroaryl piperazinyl- and piperadinyl-urea fatty acid amide hydrolase (FAAH) inhibitors is described. Brain/plasma (B/P) ratios ranging from >4:1 to as low as 0.02:1 were obtained through relatively simple structural changes to various regions of the heteroaryl urea scaffold. It was not possible to predict the degree of central nervous system (CNS) penetration from the volumes of distribution (Vd) obtained from pharmacokinetic (PK) experiments as very high Vds did not correlate with high B/P ratios. Similarly, calculated topological polar surface areas (TPSAs) did not consistently correlate with the degree of brain penetration. The lowest B/P ratios were observed for those compounds that were significantly ionized at physiological pH. However, as this class of compounds inhibits the FAAH enzyme through covalent modification, low B/P ratios did not preclude effective central target engagement.
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http://dx.doi.org/10.1016/j.bmcl.2016.05.001DOI Listing
July 2016

Preclinical Characterization of the FAAH Inhibitor JNJ-42165279.

ACS Med Chem Lett 2015 Dec 2;6(12):1204-8. Epub 2015 Nov 2.

Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.

The pre-clinical characterization of the aryl piperazinyl urea inhibitor of fatty acid amide hydrolase (FAAH) JNJ-42165279 is described. JNJ-42165279 covalently inactivates the FAAH enzyme, but is highly selective with regard to other enzymes, ion channels, transporters, and receptors. JNJ-42165279 exhibited excellent ADME and pharmacodynamic properties as evidenced by its ability to block FAAH in the brain and periphery of rats and thereby cause an elevation of the concentrations of anandamide (AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA). The compound was also efficacious in the spinal nerve ligation (SNL) model of neuropathic pain. The combination of good physical, ADME, and PD properties of JNJ-42165279 supported it entering the clinical portfolio.
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http://dx.doi.org/10.1021/acsmedchemlett.5b00353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677372PMC
December 2015

1-Aryl-2-((6-aryl)pyrimidin-4-yl)amino)ethanols as competitive inhibitors of fatty acid amide hydrolase.

Bioorg Med Chem Lett 2014 Mar 31;24(5):1280-4. Epub 2014 Jan 31.

Janssen Pharmaceutical Companies of Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, United States.

A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibitors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have excellent pharmacokinetic properties, demonstrated robust central target engagement, and was efficacious in a rat model of neuropathic pain.
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http://dx.doi.org/10.1016/j.bmcl.2014.01.064DOI Listing
March 2014

Heteroarylureas with spirocyclic diamine cores as inhibitors of fatty acid amide hydrolase.

Bioorg Med Chem Lett 2014 Feb 6;24(3):737-41. Epub 2014 Jan 6.

Janssen Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of mechanism based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with spirocyclic diamine cores is described. A potent member of this class, (37), was found to inhibit FAAH centrally, elevate the brain levels of three fatty acid ethanolamides [FAAs: anandamide (AEA), oleoyl ethanolamide (OEA) and palmitoyl ethanolamide (PEA)], and was moderately efficacious in a rat model of neuropathic pain.
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http://dx.doi.org/10.1016/j.bmcl.2013.12.113DOI Listing
February 2014

Heteroaryl urea inhibitors of fatty acid amide hydrolase: structure-mutagenicity relationships for arylamine metabolites.

Bioorg Med Chem Lett 2012 Dec 22;22(24):7357-62. Epub 2012 Oct 22.

Janssen Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.

The structure-activity relationships for a series of heteroaryl urea inhibitors of fatty acid amide hydrolase (FAAH) are described. Members of this class of inhibitors have been shown to inactivate FAAH by covalent modification of an active site serine with subsequent release of an aromatic amine from the urea electrophile. Systematic Ames II testing guided the optimization of urea substituents by defining the structure-mutagenicity relationships for the released aromatic amine metabolites. Potent FAAH inhibitors were identified having heteroaryl amine leaving groups that were non-mutagenic in the Ames II assay.
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http://dx.doi.org/10.1016/j.bmcl.2012.10.076DOI Listing
December 2012

Aryl Piperazinyl Ureas as Inhibitors of Fatty Acid Amide Hydrolase (FAAH) in Rat, Dog, and Primate.

ACS Med Chem Lett 2012 Oct 22;3(10):823-7. Epub 2012 Aug 22.

Janssen Pharmaceutical Research and Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

A series of aryl piperazinyl ureas that act as covalent inhibitors of fatty acid amide hydrolase (FAAH) is described. A potent and selective (does not inhibit FAAH-2) member of this class, JNJ-40355003, was found to elevate the plasma levels of three fatty acid amides: anandamide, oleoyl ethanolamide, and palmitoyl ethanolamide, in the rat, dog, and cynomolgous monkey. The elevation of the levels of these lipids in the plasma of monkeys suggests that FAAH-2 may not play a significant role in regulating plasma levels of fatty acid ethanolamides in primates.
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http://dx.doi.org/10.1021/ml300186gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025847PMC
October 2012

Library enhancement through the wisdom of crowds.

J Chem Inf Model 2011 Dec 14;51(12):3275-86. Epub 2011 Nov 14.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

We present a novel approach for enhancing the diversity of a chemical library rooted on the theory of the wisdom of crowds. Our approach was motivated by a desire to tap into the collective experience of our global medicinal chemistry community and involved four basic steps: (1) Candidate compounds for acquisition were screened using various structural and property filters in order to eliminate clearly nondrug-like matter. (2) The remaining compounds were clustered together with our in-house collection using a novel fingerprint-based clustering algorithm that emphasizes common substructures and works with millions of molecules. (3) Clusters populated exclusively by external compounds were identified as "diversity holes," and representative members of these clusters were presented to our global medicinal chemistry community, who were asked to specify which ones they liked, disliked, or were indifferent to using a simple point-and-click interface. (4) The resulting votes were used to rank the clusters from most to least desirable, and to prioritize which ones should be targeted for acquisition. Analysis of the voting results reveals interesting voter behaviors and distinct preferences for certain molecular property ranges that are fully consistent with lead-like profiles established through systematic analysis of large historical databases.
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http://dx.doi.org/10.1021/ci200446yDOI Listing
December 2011

The discovery and synthesis of JNJ 31020028, a small molecule antagonist of the Neuropeptide Y Y₂ receptor.

Bioorg Med Chem Lett 2011 Sep 18;21(18):5552-6. Epub 2011 Jul 18.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of small molecules based on a chemotype identified from our compound collection were synthesized and tested for binding affinity (IC(50)) at the human Neuropeptide Y Y(2) receptor (NPY Y(2)). Six of the 23 analogs tested possessed an NPY Y(2) IC(50) ≤ 15 nM. One member of this series, JNJ 31020028, is a selective, high affinity, receptor antagonist existing as a racemic mixture. As such a synthetic route to the desired enantiomer was designed starting from commercially available (S)-(+)-mandelic acid.
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http://dx.doi.org/10.1016/j.bmcl.2011.06.136DOI Listing
September 2011

Discovery and development of fatty acid amide hydrolase (FAAH) inhibitors.

J Med Chem 2008 Dec;51(23):7327-43

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

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http://dx.doi.org/10.1021/jm800311kDOI Listing
December 2008

Thiadiazolopiperazinyl ureas as inhibitors of fatty acid amide hydrolase.

Bioorg Med Chem Lett 2008 Sep 25;18(17):4838-43. Epub 2008 Jul 25.

Johnson & Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of thiadiazolopiperazinyl aryl urea fatty acid amide hydrolase (FAAH) inhibitors is described. The molecules were found to inhibit the enzyme by acting as mechanism-based substrates, forming a covalent bond with Ser241. SAR and PK properties are presented.
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http://dx.doi.org/10.1016/j.bmcl.2008.07.081DOI Listing
September 2008

Novel ketooxazole based inhibitors of fatty acid amide hydrolase (FAAH).

Bioorg Med Chem Lett 2008 Mar 30;18(6):2109-13. Epub 2008 Jan 30.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Efforts to improve the properties of the well studied ketooxazole FAAH inhibitor OL-135 resulted in the discovery of a novel propylpiperidine series of FAAH inhibitors that has a modular design and superior properties to OL-135. The efficacy of one of these compounds was demonstrated in a rat spinal nerve ligation model of neuropathic pain in rats.
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http://dx.doi.org/10.1016/j.bmcl.2008.01.091DOI Listing
March 2008

R3(BDelta23 27)R/I5 chimeric peptide, a selective antagonist for GPCR135 and GPCR142 over relaxin receptor LGR7: in vitro and in vivo characterization.

J Biol Chem 2007 Aug 2;282(35):25425-35. Epub 2007 Jul 2.

Johnson & Johnson Pharmaceutical Research and Development, LLC, San Diego, California 92121, USA.

Both relaxin-3 and its receptor (GPCR135) are expressed predominantly in brain regions known to play important roles in processing sensory signals. Recent studies have shown that relaxin-3 is involved in the regulation of stress and feeding behaviors. The mechanisms underlying the involvement of relaxin-3/GPCR135 in the regulation of stress, feeding, and other potential functions remain to be studied. Because relaxin-3 also activates the relaxin receptor (LGR7), which is also expressed in the brain, selective GPCR135 agonists and antagonists are crucial to the study of the physiological functions of relaxin-3 and GPCR135 in vivo. Previously, we reported the creation of a selective GPCR135 agonist (a chimeric relaxin-3/INSL5 peptide designated R3/I5). In this report, we describe the creation of a high affinity antagonist for GPCR135 and GPCR142 over LGR7. This GPCR135 antagonist, R3(BDelta23-27)R/I5, consists of the relaxin-3 B-chain with a replacement of Gly23 to Arg, a truncation at the C terminus (Gly24-Trp27 deleted), and the A-chain of INSL5. In vitro pharmacological studies showed that R3(BDelta23-27)R/I5 binds to human GPCR135 (IC50=0.67 nM) and GPCR142 (IC50=2.29 nM) with high affinity and is a potent functional GPCR135 antagonist (pA2=9.15) but is not a human LGR7 ligand. Furthermore, R3(BDelta23-27)R/I5 had a similar binding profile at the rat GPCR135 receptor (IC50=0.25 nM, pA2=9.6) and lacked affinity for the rat LGR7 receptor. When administered to rats intracerebroventricularly, R3(BDelta23-27)R/I5 blocked food intake induced by the GPCR135 selective agonist R3/I5. Thus, R3(BDelta23-27)R/I5 should prove a useful tool for the further delineation of the functions of the relaxin-3/GPCR135 system.
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http://dx.doi.org/10.1074/jbc.M701416200DOI Listing
August 2007

Dual serotonin transporter/histamine H3 ligands: Optimization of the H3 pharmacophore.

Bioorg Med Chem Lett 2007 Feb 2;17(3):702-6. Epub 2006 Nov 2.

Johnson & Johnson Pharmaceutical Research and Development LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of tetrahydroisoquinolines acting as dual histamine H3/serotonin transporter ligands is described. A highly regio-selective synthesis of the tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH3 was developed. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2006.10.089DOI Listing
February 2007

A QSAR model of HERG binding using a large, diverse, and internally consistent training set.

Chem Biol Drug Des 2006 Apr;67(4):284-96

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Over the past decade, the pharmaceutical industry has begun to address an addition to ADME/Tox profiling--the ability of a compound to bind to and inhibit the human ether-a-go-go-related gene (hERG)-encoded cardiac potassium channel. With the compilation of a large and diverse set of compounds measured in a single, consistent hERG channel inhibition assay, we recognized a unique opportunity to attempt to construct predictive QSAR models. Early efforts with classification models built from this training set were very encouraging. Here, we report a systematic evaluation of regression models based on neural network ensembles in conjunction with a variety of structure representations and feature selection algorithms. The combination of these modeling techniques (neural networks to capture non-linear relationships in the data, feature selection to prevent over-fitting, and aggregation to minimize model instability) was found to produce models with very good internal cross-validation statistics and good predictivity on external data.
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http://dx.doi.org/10.1111/j.1747-0285.2006.00379.xDOI Listing
April 2006

Experimental and theoretical characterization of the 3,5-didehydrobenzoate anion: a negatively charged meta-benzyne.

J Am Chem Soc 2003 Jan;125(1):131-40

Department of Chemistry, Purdue University, West Lafayette, IN 47907-1393, USA.

A negatively charged analogue of meta-benzyne, 3,5-didehydrobenzoate, was synthesized in a Fourier transform ion cyclotron resonance mass spectrometer, and its reactivity was compared to that of the same ion generated previously in a flowing afterglow apparatus and to its positively charged cousin, N-(3,5-didehydrophenyl)-3-fluoropyridinium. 3,5-Didehydrobenzoate was found to react as a nucleophile with electrophilic reagents. In contrast, N-(3,5-didehydrophenyl)-3-fluoropyridinium does not react with the same electrophilic reagents but reacts instead with nucleophilic reagents. Neither ion is able to abstract hydrogen atoms from typical hydrogen atom donors. The absence of any radical reactivity for these meta-benzynes is consistent with predictions that radical reactions of singlet biradicals should be hindered as compared to their monoradical counterparts. High-level calculations predict that the carboxylate moiety does not significantly perturb the singlet-triplet splitting of 3,5-didehydrobenzoate relative to the parent meta-benzyne.
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http://dx.doi.org/10.1021/ja021112oDOI Listing
January 2003

Design optimization of 1,3-diphospha-2,4-diboretane diradicals.

Angew Chem Int Ed Engl 2002 Oct;41(20):3894-6

Department of Chemistry and Supercomputing Institute, University of Minnesota, 207 Pleasant St. SE, Minneapolis, MN 55455-0431, USA.

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http://dx.doi.org/10.1002/1521-3773(20021018)41:20<3894::AID-ANIE3894>3.0.CO;2-ZDOI Listing
October 2002

Tandem Cycloaddition Chemistry of Nitroalkenes: Probing the Remarkable Stereochemical Influence of the Lewis Acid.

J Org Chem 1999 Mar;64(5):1610-1619

Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801.

The influence of several Lewis acids on the stereochemical course of the [4 + 2] cycloaddition of nitroalkene 1 and chiral, nonracemic propenyl ether 8 has been examined. All of the Lewis acids examined favored ul relative diastereoselection ("exo" approach); TiCl(4), TiBr(3)(Oi-Pr), SnCl(4), and ATPh were the most selective. Within the titanium-based Lewis acids, it was found that increasing the halide-to-alkoxide ratio increased the degree of ul (relative) selectivity, as did switching from chloride to bromide. The internal diastereoselectivity was also dependent on the Lewis acid; most titanium isopropoxide-halides (bromide and chloride) and SnCl(4) were highly selective for (1,3-lk) approach, with the selectivity increasing with increasing halide content. Two aluminum-based Lewis acids (MAPh and ATPh) were selective for the opposite sense of internal diastereoselection. The high lk (relative) diastereoselectivity observed only with TiCl(2)(Oi-Pr)(2) is proposed to arise either from Coulombic stabilization of an endo approach or precomplexation of the vinyl ether to the Lewis acid. The switch in internal diastereoselectivity seen in the exo manifold is thought to arise from subtle changes in the steric nature of the Lewis acid-nitroalkene complex.
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http://dx.doi.org/10.1021/jo9820869DOI Listing
March 1999

Tandem Cycloaddition Chemistry of Nitroalkenes: Preparative and Theoretical Studies on the Stereochemical Course of [3 + 2] Cycloaddition of Cyclic Nitronates.

J Org Chem 1999 Feb;64(3):884-901

Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, Illinois 61801.

Intermolecular [3 + 2] cycloadditions between two cyclic nitronates and a series of dipolarophiles are examined. High facial selectivity is observed in all cases and is analyzed with the aid of ab initio transition structure calculations. Monosubstituted dipolarophiles reacted with exclusive regiocontrol. Disubstituted dipolarophiles reacted with varying degrees of regiocontrol, which was dependent on the substituent. A theoretical approach for predicting regioselectivity is discussed. Exo selectivity was generally favored due to steric effects, and was especially high with cis-disubstituted dipolarophiles.
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http://dx.doi.org/10.1021/jo9818374DOI Listing
February 1999