- A Direct Synthesis of Highly Substituted π-Rich Aromatic Heterocycles from Oxetanes
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The ubiquitous use of π-rich five-membered heterocycles has driven the development of new methods for their synthesis for more than a century. Here, we disclose a general and reliable reaction manifold for the construction of highly substituted heterocycles through a facile Lewis-acid-catalyzed oxetane rearrangement. Notably, this methodology employs a keto-oxetane motif as a 1,4-dicarbonyl surrogate, which can be synthesized using robust alkylation or alkenylation reactions, and thus obviates the need to access 1,4-dicarbonyl compounds via umpoled starting materials. We harnessed this reactivity to generate a broad range of substituted furans and pyrroles, and extended this methodology to produce benzo-fused versions thereof.
- White, Alexander R.,Kozlowski, Ryan A.,Tsai, Shiou-Chuan,Vanderwal, Christopher D.
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- An Oxetane-Based Polyketide Surrogate to Probe Substrate Binding in a Polyketide Synthase
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Polyketides are a large class of bioactive natural products with a wide range of structures and functions. Polyketides are biosynthesized by large, multidomain enzyme complexes termed polyketide synthases (PKSs). One of the primary challenges when studying PKSs is the high reactivity of their poly-β-ketone substrates. This has hampered structural and mechanistic characterization of PKS-polyketide complexes, and, as a result, little is known about how PKSs position the unstable substrates for proper catalysis while displaying high levels of regio- and stereospecificity. As a first step toward a general plan to use oxetanes as carbonyl isosteres to broadly interrogate PKS chemistry, we describe the development and application of an oxetane-based PKS substrate mimic. This enabled the first structural determination of the acyl-enzyme intermediate of a ketosynthase (KS) in complex with an inert extender unit mimic. The crystal structure, in combination with molecular dynamics simulations, led to a proposed mechanism for the unique activity of DpsC, the priming ketosynthase for daunorubicin biosynthesis. The successful application of an oxetane-based polyketide mimic suggests that this novel class of probes could have wide-ranging applications to the greater biosynthetic community interested in the mechanistic enzymology of iterative PKSs.
- Ellis, Bryan D.,Milligan, Jacob C.,White, Alexander R.,Duong, Vy,Altman, Pilar X.,Mohammed, Lina Y.,Crump, Matthew P.,Crosby, John,Luo, Ray,Vanderwal, Christopher D.,Tsai, Shiou-Chuan
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- Synthesis of oxetane/azetidine containing spirocycles
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Oxetane-benzopyran spirocycles were synthesised via a palladium catalysed cyclisation-cross coupling cascade reaction whilst oxetane/azetidine-pyrrolidino isoindolone spirocycles were synthesised via a silver catalysed 1,3-dipolar cycloaddition reaction f
- Hamill, Rosalie,Jones, Benjamin,Pask, Christopher M.,Sridharan, Visuvanathar
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supporting information
p. 1126 - 1129
(2019/03/26)
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- Furo-3-carboxamide derivatives and methods of use
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Compounds of formula (I) and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein R1, Z1, Z2, and n are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by Tropomysin receptor kinases (Trk). Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.
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Page/Page column 101; 102; 104
(2017/10/24)
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- FURO-3-CARBOXAMIDE DERIVATIVES AND METHODS OF USE
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Compounds of formula (I) and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein R1, Z1, Z2, and n are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by Tropomysin receptor kinases (Trk). Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.
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Paragraph 0620; 0630
(2015/08/04)
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- D3 AND 5-HT2A RECEPTOR MODULATORS
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The present invention provides compounds of the general formula (I) wherein X, n and R1 are as described herein, as well as pharmaceutically acceptable salts and esters thereof, methods for their manufacture, pharmaceutical compositions contain
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Page/Page column 49
(2010/04/23)
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