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2.
Org Lett ; 19(5): 1052-1055, 2017 03 03.
Article in English | MEDLINE | ID: mdl-28253632

ABSTRACT

A nickel(0)-catalyzed method for the synthesis of quinazolinediones from isatoic anhydrides and isocyanates is described. High-throughput ligand screening revealed that XANTPHOS was the optimal ligand for this transformation. Subsequent optimization studies, supported by kinetic analysis, significantly expanded the reaction scope. The reaction exhibits a case of substrate inhibition kinetics with respect to the isocyanate. Preliminary results on an asymmetric synthesis of atropisomeric quinazolinediones are reported.

3.
J Am Chem Soc ; 137(41): 13272-81, 2015 Oct 21.
Article in English | MEDLINE | ID: mdl-26461028

ABSTRACT

Kinetic, spectroscopic, crystallographic, and computational studies probing a Pd-catalyzed C-H arylation reaction reveal that mono-oxidation of the bis-phosphine ligand is critical for the formation of the active catalyst. The bis-phosphine mono-oxide is shown to be a hemilabile, bidentate ligand for palladium. Isolation of the oxidative addition adduct, with structural elucidation by X-ray analysis, showed that the mono-oxide was catalytically competent, giving the same reaction rate in the productive reaction as the Pd(II)/xantphos precursor. A dual role for the carboxylate base in both catalyst activation and reaction turnover was demonstrated, along with the inhibiting effect of excess phosphine ligand. The generality of the role of phosphine mono-oxide complexes in Pd-catalyzed coupling processes is discussed.


Subject(s)
Palladium/chemistry , Phosphines/chemistry , Xanthenes/chemistry , Catalysis , Crystallography, X-Ray , Kinetics , Magnetic Resonance Spectroscopy , Oxidation-Reduction
4.
J Pharm Sci ; 101(9): 3124-33, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22262489

ABSTRACT

The stability of a 1,2,4-oxadiazole derivative, BMS-708163, A, was studied in the cosolvent mixture of acetonitrile-water at various pH values, in the solid state and in the presence of various excipients. The objective of this study was to develop a deep understanding of the stability of compound A based on its degradation kinetics and mechanism to enable design of a robust drug product. A series of isotopically (13) C- and (15) N-labeled compounds were synthesized and their degradation was studied by liquid chromatography-mass spectrometry and nuclear magnetic resonance to prove the degradation mechanism. Compound A exhibited maximum stability at a pH range of 3-5. In forced degradation studies, higher or lower pH resulted in an increase in degradation rate. At low pH, the N-4 atom on the 1,2,4-oxadiazole ring is protonated, followed by nucleophilic attack on the activated methine carbon to cause ring opening to form aryl nitrile degradation product, compound B. At high pH, the nucleophilic attack occurs on the methine carbon to generate an anion on N-4. Subsequent proton capture from a proton donor, such as ambient water, facilitates ring opening to generate compound B. In the absence of a proton donor, such as in dry acetonitrile, anion on N-4 will go back to compound A. Therefore, compound A is stable in absence of proton donor. This study defines the package condition and microenvironmental pH under which compound A can be formulated into a stable product.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/chemistry , Oxadiazoles/chemistry , Sulfonamides/chemistry , Acetonitriles/chemistry , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Chromatography, Reverse-Phase , Drug Stability , Excipients/chemistry , Hydrogen-Ion Concentration , Kinetics , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Chemical , Solvents/chemistry , Technology, Pharmaceutical/methods , Temperature , Water/chemistry
5.
Tetrahedron ; 67(27-28): 5069-5078, 2011 Jul 08.
Article in English | MEDLINE | ID: mdl-21811346

ABSTRACT

The design, synthesis and biological evaluation of a new phorboxazole analogue, comprising an acetal replacement for the C-ring tetrahdropyran of the natural product and carrying a potency-enhancing C(45-46) vinyl chloride side chain, is described. In addition, the synthesis of (+)-hemi-phorboxazole A and a series of related hemi-phorboxazole A analogues has been achieved. The new acetal ring replacement analogue displayed activity comparable to that of the parent natural product against HCT-116 (colon) cells (IC(50) 2.25 ng/mL). Equally important, the phorboxazole analogue and two related hemiphorboxazole A congeners exhibited significant antifungal activity when assayed against pathogenic Candida albicans strains.

6.
J Org Chem ; 74(3): 1381-4, 2009 Feb 06.
Article in English | MEDLINE | ID: mdl-19178357

ABSTRACT

A ligand-free Suzuki-Miyaura reaction for the cross-coupling of aryl and heteroaryl bromides with aryl and heteroarylboronic acids has been developed utilizing catalytic polyethylene glycol 2000 (PEG 2000). This preparatively convenient system afforded the corresponding cross-coupled products in good to excellent isolated yields after a simple aqueous workup. Transmission electron microscopy (TEM) analysis of the Pd-PEG 2000 catalyst system revealed in situ-generated palladium nanoparticles after only 1 min of reaction.


Subject(s)
Biphenyl Compounds/chemical synthesis , Boronic Acids/chemistry , Bromobenzenes/chemistry , Polyethylene Glycols/chemistry , Biphenyl Compounds/chemistry , Catalysis , Ligands , Palladium/chemistry
7.
Acc Chem Res ; 41(5): 675-87, 2008 May.
Article in English | MEDLINE | ID: mdl-18489082

ABSTRACT

The frequent low abundance of architecturally complex natural products possessing significant bioregulatory properties mandates the development of rapid, efficient, and stereocontrolled synthetic tactics, not only to provide access to the biologically rare target but also to enable elaboration of analogues for the development of new therapeutic agents with improved activities and/or pharmacokinetic properties. In this Account, the genesis and evolution of the Petasis-Ferrier union/rearrangement tactic, in the context of natural product total syntheses, is described. The reaction sequence comprises a powerful tactic for the construction of the 2,6- cis-substituted tetrahydropyran ring system, a ubiquitous structural element often found in complex natural products possessing significant bioactivities. The three-step sequence, developed in our laboratory, extends two independent methods introduced by Ferrier and Petasis and now comprises: condensation between a chiral, nonracemic beta-hydroxy acid and an aldehyde to furnish a dioxanone; carbonyl olefination; and Lewis-acid-induced rearrangement of the resultant enol acetal to generate the 2,6- cis-substituted tetrahydropyranone system in a highly stereocontrolled fashion. To demonstrate the envisioned versatility and robustness of the Petasis-Ferrier union/rearrangement tactic in complex molecule synthesis, we exploited the method as the cornerstone in our now successful total syntheses of (+)-phorboxazole A, (+)-zampanolide, (+)-dactylolide, (+)-spongistatins 1 and 2, (-)-kendomycin, (-)-clavosolide A, and most recently, (-)-okilactomycin. Although each target comprises a number of synthetic challenges, this Account focuses on the motivation, excitement, and frustrations associated with the evolution and implementation of the Petasis-Ferrier union/rearrangement tactic. For example, during our (+)-phorboxazole A endeavor, we recognized and exploited the inherent pseudo symmetry of the 2,6- cis-substituted tetrahydropyranone product to overcome the inherent chelation bias of an adjacent oxazolidine ring during the Lewis-acid-promoted rearrangement. In addition, we discovered that a more concentrated solution of Cp2TiMe2 (0.7 versus 0.5 M in THF) with the addition of ethyl pivalate dramatically improves the yield in the Petasis-Tebbe olefination. During the (+)-zampanolide and (+)-dactylolide programs, we observed that the addition of trifluoromethanesulfonic acid (TfOH), especially on a preparative scale, was crucial to the efficiency of the initial condensation/union reaction, while our efforts toward (-)-kendomycin led to the improved implementation of a modified Kurihara condensation of the beta-hydroxy acid and aldehyde involving i-PrOTMS and TMSOTf. Finally, the successful deployment of the Petasis-Ferrier tactic in our synthesis of (-)-clavosolide A validated the viability of this tactic with a system possessing the highly acid-labile cyclopropylcarbinyl moiety, while the challenges en route to (-)-okilactomycin demonstrated that a neighboring alkene functionality can participate in an intramolecular Prins cyclization during the TMSOTf-promoted union process, unless suitably protected.


Subject(s)
Biological Products/chemical synthesis , Pyrans/chemistry , Biological Products/chemistry , Drug Design , Molecular Structure , Stereoisomerism
8.
J Org Chem ; 73(4): 1192-200, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-18215058

ABSTRACT

A highly convergent second-generation synthesis of (+)-phorboxazole A has been achieved. Highlights of the synthetic approach include improved Petasis-Ferrier union/rearrangement conditions on a scale to assemble multigram quantities of the C(11-15) and C(22-26) cis-tetrahydropyrans inscribed with the phorboxazole architecture, a convenient method to prepare E- and Z-vinyl bromides from TMS-protected alkynes utilizing radical isomerization of Z-vinylsilanes, and a convergent late-stage Stille union to couple a fully elaborated C(1-28) macrocyclic iodide with a C(29-46) oxazole stannane side chain to establish the complete phorboxazole skeleton. The synthesis, achieved with a longest linear sequence of 24 steps, proceeded in 4.6% overall yield.


Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Oxazoles/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Magnetic Resonance Spectroscopy , Oxazoles/chemistry , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Infrared
9.
J Org Chem ; 73(4): 1201-8, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-18215059

ABSTRACT

Highly convergent syntheses of eight phorboxazole congeners and their evaluation against a diverse panel of human solid tumor cancer cell lines have been achieved. Specifically, the C(45-46) alkyne, alkene, and alkane phorboxazole A analogues [(+)-4-(+)-6] were constructed and found to display single digit nanomolar cell growth inhibitory activities in a series of human cancer cell lines. The structurally simplified C(11-15)-acetal congener (+)-20Z also proved potent albeit reduced (cf. 34.6 nM) when evaluated against the same cell line panel. Importantly, (+)-C(46)-chlorophorboxazole A (3) displayed picomolar (pM) inhibitory activity in several cell lines.


Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacology , Oxazoles/chemical synthesis , Oxazoles/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Spectrophotometry, Infrared
10.
Bioorg Med Chem Lett ; 16(23): 6102-6, 2006 Dec 01.
Article in English | MEDLINE | ID: mdl-16971122

ABSTRACT

Inhibition of the p38 map kinase pathway has been shown to be beneficial in the treatment of inflammatory diseases. The first class of potent p38 kinase inhibitors was the pyridinylimidazole compounds from SKB. Since then several pyridinylimidazole-based compounds have been shown to inhibit activated p38 kinase in vitro and in vivo. We have developed a novel series of pyridinylimidazole-based compounds, which potently inhibit the p38 pathway by binding to unactivated p38 kinase and only weakly inhibiting activated p38 kinase activity in vitro.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/toxicity , Esters/chemistry , Mice , Molecular Structure , Piperazine , Piperazines/chemistry , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/metabolism
11.
Org Lett ; 8(4): 797-9, 2006 Feb 16.
Article in English | MEDLINE | ID: mdl-16468770

ABSTRACT

[structure: see text] We disclose here the design, synthesis, and biological evaluation of simplified Z- and E-C(2-3) alkynyl phorboxazole C(11-15) acetals (+)-7Z and (+)-7E, wherein the Z-isomer proved to be a potent nanomolar cytotoxic agent. Reevaluation of (+)-C(45-46) E-chloroalkenyl phorboxazole A (6) confirms subnanomolar activity across a broad panel of human cancer cell lines.


Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Oxazoles/chemical synthesis , Cell Line, Tumor , Drug Screening Assays, Antitumor , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Molecular Structure , Oxazoles/chemistry , Oxazoles/pharmacology , Stereoisomerism
12.
Org Lett ; 7(20): 4399-402, 2005 Sep 29.
Article in English | MEDLINE | ID: mdl-16178543

ABSTRACT

[structure: see text] A second generation total synthesis of the potent antitumor agent (+)-phorboxazole A (1) has been achieved. The cornerstone of this approach comprises a more convergent strategy, involving late-stage Stille union of a fully elaborated C(1-28) macrocycle with a C(29-46) side chain. The second generation synthesis entails the longest linear sequence of 24 steps, with an overall yield of 4.2%.


Subject(s)
Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Oxazoles/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Molecular Structure , Oxazoles/chemistry
13.
Org Lett ; 7(20): 4403-6, 2005 Sep 29.
Article in English | MEDLINE | ID: mdl-16178544

ABSTRACT

[structure: see text] Effective, scalable total syntheses and biological evaluation of six phorboxazole A analogues (1-6) have been achieved. Importantly, the C(45-46)-saturated, C(45-46)-alkenyl, and the C(45-46)-E-chloroalkenyl congeners (4, 5, and 6, respectively) reveal low nanomolar tumor cell growth inhibitory activity (GI50's) similar to or, in some cell lines, greater than that of the phorboxazoles across a diverse panel of human cancer cell lines.


Subject(s)
Carbon/chemistry , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/toxicity , Oxazoles/chemical synthesis , Oxazoles/toxicity , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Heterocyclic Compounds, 4 or More Rings/chemistry , Humans , Molecular Structure , Oxazoles/chemistry , Structure-Activity Relationship
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