A5051093087- Synthetic Organic Chemistry Methods
- Chemical synthesis and alkaloids
- X-ray Diffraction in Crystallography
- Asymmetric Synthesis and Catalysis
- Crystallization and Solubility Studies
- Microbial Natural Products and Biosynthesis
- Cyclization and Aryne Chemistry
- Chemical Synthesis and Analysis
- Lung Cancer Treatments and Mutations
- Carbohydrate Chemistry and Synthesis
- Marine Sponges and Natural Products
- Lung Cancer Research Studies
- Cancer therapeutics and mechanisms
- Advanced Synthetic Organic Chemistry
- Cyclopropane Reaction Mechanisms
- Cytokine Signaling Pathways and Interactions
- Alkaloids: synthesis and pharmacology
- Phytochemical compounds biological activities
- Analytical Chemistry and Chromatography
- interferon and immune responses
- Cancer Treatment and Pharmacology
- Cellular transport and secretion
- Click Chemistry and Applications
- Epigenetics and DNA Methylation
- Asymmetric Hydrogenation and Catalysis
Harvard University
2012-2024
Harvard Stem Cell Institute
1999-2005
Howard Hughes Medical Institute
1998-2001
Yale University
1994-1997
Kettering University
1994-1996
Columbia University
1995-1996
Memorial Sloan Kettering Cancer Center
1996
University of Rochester
1993
Abstract Three generations of tyrosine kinase inhibitors (TKI) have been approved for anaplastic lymphoma (ALK) fusion–positive non–small cell lung cancer. However, none address the combined need broad resistance coverage, brain activity, and avoidance clinically dose-limiting TRK inhibition. NVL-655 is a rationally designed TKI with >50-fold selectivity ALK over 96% kinome tested. In vitro, inhibits diverse fusions, activating alterations, mutations, showing ≥100-fold improved...
The title compound has been synthesized as its racemate in 33 steps. An intramolecular Diels−Alder reaction (see Scheme 5, 24 → 25) was used to provide control over the eventual cis C4−C7 relationship. installation of another related ethynyl group at C2 arose from transformation 40 42 8) whose directionality is governed by a benzophenone ketal functioning temporary steric unit. Closure enediyne unit accomplished on trimethylsilylethoxycarbonyl (TEOC) protected dihydroquinoline derivative. It...
An enantioseletive, biomimetic synthesis of (-)-longithorone A has been achieved using an intermolecular/transannular Diels-Alder sequence which provides some support for the proposed biosynthesis. The cycloaddition precursors were two [12]-paracyclophanes that constructed with atropisomer control during ene-yne metathesis macrocyclizations.
This communication reports highly enantioselective and diastereoselective methyl malonic acid half thioester (MeMAHT) aldol reactions that are compatible with protic functional groups enolizable aldehydes, affording syn S-phenyl thiopropionates.
This manuscript describes an enantioselective synthesis of the naturally occurring inhibitor endothelial cell proliferation, cortistatin A. Key steps are a silicate-directed elimination/ring expansion reaction and highly diastereoselective aza-Prins cyclization with subsequent transannular etherification.
Cortistatin A (CA) is a highly selective inhibitor of the Mediator kinases CDK8 and CDK19. Using CA, we now report large-scale identification kinase substrates in human cells (HCT116). We identified over 16,000 quantified phosphosites including 78 high-confidence targets within 64 proteins, DNA-binding transcription factors proteins associated with chromatin, DNA repair, RNA polymerase II. Although RNA-seq data correlated targets, effects CA on gene expression were limited distinct from or...
This Article describes an enantioselective synthesis of cephalostatin 1. Key steps this are a unique methyl group selective allylic oxidation, directed C−H hydroxylation sterol at C12, Au(I)-catalyzed 5-endo-dig cyclization, and kinetic spiroketalization.
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTStereoselective Synthesis of over Two Million Compounds Having Structural Features Both Reminiscent Natural Products and Compatible with Miniaturized Cell-Based AssaysDerek S. Tan, Michael A. Foley, Matthew D. Shair, Stuart L. SchreiberView Author Information Department Chemistry & Chemical Biology Harvard Institute Cell Howard Hughes Medical University, 12 Oxford St. Cambridge, Massachusetts 02138 Cite this: J. Am. Chem. Soc. 1998, 120, 33,...
This report details our discovery of a new catalytic ester aldol reaction using malonic acid half thioesters (MAHTs) that directly affords β-hydroxythioesters. The is catalyzed by combination Cu(II) salt and an amine base, it can be performed under exceptionally mild conditions (23 °C, open to the air, wet solvent). Methyl afforded syn products with distereoselectivities greater than 6:1.
(−)-Shikimic acid, 3, was converted into both enantiomers of epoxycyclohexenol carboxylic 7, which were attached to a solid support via photocleavable linker. Tandem acylation−1,3-dipolar cycloaddition with nitrones 11a−g yielded tetracyclic templates 12a−g. After development several efficient coupling reactions iodobenzyl tetracycles 12b−d and completion extensive validation protocols, split-pool synthesis binary encoded library calculated contain 2.18 million polycyclic compounds. These...
Previously we developed a Cu(II)-catalyzed, enantioselective aldol reaction between malonic acid half thioesters (MAHTs) and aldehydes based on the biosynthesis of polyketides fatty acids in which MAHTs are decarboxylated enzymatically to afford ester enolates that condense with thioesters. We report evidence steric effects, kinetics, kinetic isotope crossover experiments support different mechanism for Cu(II)-catalyzed involving enolization by deprotonation, addition aldehyde,...
A modular, 18-step total synthesis of hyperforin is described. The natural product was quickly accessed using latent symmetry elements, whereby a group-selective, Lewis acid-catalyzed epoxide-opening cascade cyclization used to furnish the bicyclo[3.3.1]nonane core and set two key quaternary stereocenters.
The first total synthesis of the Lycopodium alkaloid (+)-fastigiatine has been accomplished in 15 steps and 30% overall yield from known compounds. Noteworthy transformations include a convergent fragment coupling via nucleophilic cyclopropane opening, highly diastereoselective formal [3 + 3]-cycloaddition, transannular Mannich reaction to construct core natural product.
Abstract ROS1 tyrosine kinase inhibitors (TKI) have been approved (crizotinib and entrectinib) or explored (lorlatinib, taletrectinib, repotrectinib) for the treatment of fusion–positive cancers, although none them simultaneously address need broad resistance coverage, avoidance clinically dose-limiting TRK inhibition, brain penetration. NVL-520 is a rationally designed macrocycle with >50-fold selectivity over 98% kinome tested. It active in vitro against diverse fusions mutations...
ADVERTISEMENT RETURN TO ISSUEPREVPerspectiveNEXTObservations in the Chemistry and Biology of Cyclic Enediyne Antibiotics: Total Syntheses Calicheamicin γ1I Dynemicin ASamuel J. Danishefsky Matthew D. ShairView Author Information Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute Cancer Research, 1275 York Avenue, Box 106, New York, 10021, Department Havemeyer Hall, Columbia University, 10027 Cite this: Org. Chem. 1996, 61, 1, 16–44Publication Date (Web):January 12,...
The synthesis and use of an alkylsilyl-tethered large (500-600 microm) polystyrene resin (1) are disclosed. An optimized Suzuki coupling bromine-functionalized a silicon-functionalized alkylborane generates the silicon-substituted 1 in scale (>100 g). Resin loading is accomplished by activation as silyl triflate, which can accommodate even sterically encumbered secondary alcohols phenols. Treatment with HF/pyridine for linker cleavage mild, efficient, amenable to automated, large-scale...
Anomeric O-alkylation/arylation is applied to the synthesis of 2-deoxy-β-glycosides. Treatment lactols with NaH in dioxane followed by addition electrophiles leads formation 2-deoxy-β-glycosides high yield and selectivity. The β-selectivity observed here demonstrates a powerful stereoelectronic effect for stereoselective acetals under kinetic control.
A unique subset of the Lycopodium alkaloid natural products share a 7-membered-ring substructure and may potentially arise from common biosynthetic precursor. To both explore exploit these structural relationships, we sought to develop unified biosynthetically inspired strategy efficiently access complex polycyclic alkaloids through use cascade sequence. In pursuit goals, first total synthesis (+)-fastigiatine (2) was accomplished via series reactions; describe herein full account our...