Glenn C Micalizio

Dartmouth College, Hanover, NH, United States

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Publications (66)465.07 Total impact

  • Xiayun Cheng, Glenn C Micalizio
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    ABSTRACT: In efforts directed toward the synthesis of seco-prezizaane sesquiterpenoids, a stereoselective annulation reaction has been developed between 4-hydroxy-1,6-enynes and TMS-alkynes that delivers cross-conjugated triene-containing hydroindanes. Contrary to previous reports, enyne substrates bearing two propargylic ethers enable the presumed organometallic intermediate to be trapped by double elimination. The tendency of products from this annulation to undergo Diels-Alder-based dimerization was harnessed to accomplish a two-step complexity-generating sequence en route to densely functionalized carbo- and heteorocyclic systems.
    Organic letters. 09/2014;
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    ABSTRACT: Angularly substituted trans-fused hydroindanes are now accessible by direct and convergent union of TMS-alkynes with simple 4-hydroxy-1,6-enynes by a process that forges three C-C bonds, one C-H bond, and two new stereocenters. The annulation is proposed to proceed by initial formation of a Ti-alkyne complex (with a TMS-alkyne), followed by regioselective alkox-ide-directed coupling with an enyne (by alkyne-alkyne coupling), stereoselective intramolecular cycloaddition, elimination of phe-noxide, 1,3-metallotropic shift, and stereoselective protonation of the penultimate allylic organometallic intermediate. A variety of examples are given that demonstrate the compatibility of this reaction with substrates bearing aromatic and aliphatic substitu-ents, and an empirical model is presented to accompany the stere-ochemical observations made.
    Journal of the American Chemical Society 05/2014; · 10.68 Impact Factor
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    ABSTRACT: A synthesis of C11-desmethoxy soraphen A1α is described that proceeds in just 14 steps from readily available starting materials. This natural product analog was identified as a target of interest in a program aimed at identifying novel natural product-inspired inhibitors of acetyl-CoA carboxylase (ACC) as potential anticancer therapeutics. While describing the most efficient synthesis of a soraphen A1α analog (total syntheses of the natural product have been reported that proceed in 25 to ≥40 linear steps), we also present data supporting the conclusion that C11-heteroatom functionality is a beneficial but unnecessary structural characteristic of soraphen A1α analogs for inhibiting ACC.
    ACS Medicinal Chemistry Letters 12/2013; 4(12):1244-1248. · 3.31 Impact Factor
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    ABSTRACT: Almost half of prescription medications are metabolized by cytochrome P450 3A4 and 3A5. CYP3A4 and 3A5 have significant substrate overlap and there is currently no way to selectively monitor the activity of these two enzymes individually, which has led to the erroneous habit of attributing the cumulative activity to CYP3A4. While CYP3A4 expression is ubiquitous, CYP3A5 expression is polymorphic, leading to individuals with large differences in CYP3A5 expression levels which have been shown to alter the pharmacokinetics of drugs in patients. We report the first highly selective CYP3A5 substrate, T-5, capable of determining CYP3A5 activity in biological samples containing both enzymes. Oxidation of T-5 by CYP3A5 yields an N-oxide metabolite that is over 100-fold selective over CYP3A4. Formation of T-5 N-oxide highly correlates with CYP3A5 genotype and CYP3A5 expression levels in human liver microsomes and human hepatocytes.
    Drug metabolism and disposition: the biological fate of chemicals 12/2013; · 3.74 Impact Factor
  • Dexi Yang, Glenn C Micalizio
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    ABSTRACT: Azatitanacyclopropanes (titanaziridines) are shown to be stereochemically labile under reaction conditions for reductive cross-coupling. This fundamental property has been employed to realize highly selective asymmetric coupling reactions with allylic alcohols that proceed by dynamic kinetic resolution.
    Chemical Communications 08/2013; · 6.38 Impact Factor
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    ABSTRACT: Screening of bead-based split and pool combinatorial chemistry libraries is a powerful approach to aid the discovery of new chemical compounds able to interact with, and modulate the activities of, protein targets of interest. Split and pool synthesis provides for large and well diversified chemical libraries, in this case comprised of oligomers generated from a well-defined starting set. At the end of the synthesis, each bead in the library displays many copies of a unique oligomer sequence. Because the sequence of the oligomer is not known at the time of screening, methods for decoding of the sequence of each screening "hit" are essential. Here we describe an electron-transfer dissociation (ETD) based tandem mass spectrometry approach for the decoding of mass-encoded split and pool libraries. We demonstrate that the newly described "chiral oligomers of pentenoic amides (COPAs)" yield non-sequence-specific product ions upon collisional activated dissociation; however, complete sequence information can be obtained with ETD. To aid in the decoding of libraries from MS and MS/MS data, we have incorporated (79)Br/(81)Br isotope "tags" to differentiate N- and C-terminal product ions. In addition, we have created "Hit-Find," a software program that allows users to generate libraries in silico. The user can then search all possible members of the chemical library for those that fall within a user-defined mass error.
    Journal of the American Society for Mass Spectrometry 05/2013; · 3.59 Impact Factor
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    ABSTRACT: We report a concise and convergent laboratory synthesis of the rare marine natural product lehualide B that has led to the discovery that (1) this compound has low nanomolar activity against human multiple myeloma cells and (2) the anticancer effects of lehualide B and its analogues are selective (i.e., they are approximately 2-3 orders of magnitude less toxic to human breast cancer cells). Synthetic lehualide B is shown to be an effective inhibitor of complex I of the mitochondrial electron transport chain, with potency similar to that observed for the terrestrial natural products piericidin A1 and rotenone, an observation that led to the discovery that piericidin A1 is also selectively cytotoxic toward human multiple myeloma cells. Interestingly, synthetic derivatives of lehualide B that resemble verticipyrone (an established complex I inhibitor composed of a γ-pyrone and a simple monounsaturated hydrophobic chain) lack the potent antimyeloma activity of the natural product. Finally, the synthesis and evaluation of a collection of lehualide-inspired analogues led to the elucidation of structure-activity relationships for this rare natural product that established important roles for the substituted γ-pyrone headgroup and the skipped polyene side chain.
    ACS Chemical Biology 04/2013; · 5.44 Impact Factor
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    ABSTRACT: One is not like the other: The title approach proceeds by stepwise coupling of three relatively simple substrates. Three natural product-inspired agents are described, one of which has natural product-like toxicity for HeLa and MCF7 cells. It is isoform-selective, thus targeting Hsp90α/β over Grp94, and adopts a conformation similar to that of geldanamcyin when complexed with Hsp90.
    Angewandte Chemie International Edition 04/2013; · 11.34 Impact Factor
  • Valer Jeso, Glenn C Micalizio
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    ABSTRACT: A boron complex catalyses the addition of allyl groups -- hydrocarbon motifs -- to 'activated imines' in a relay-like process, generating synthetically useful compounds as single mirror-image isomers. See Letter p.216
    Nature 02/2013; 494(7436):179-81. · 38.60 Impact Factor
  • Ozora Kubo, Daniel P Canterbury, Glenn C Micalizio
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    ABSTRACT: Synthesis of the C1-C26 hexacyclic subunit of pectenotoxin-2 (PTX-2) is described that features a stereoselective annulation to generate the C-ring by triple asymmetric Nozaki-Hiyama-Kishi coupling followed by oxidative cyclization. Preparation of the C1-C14 AB spriroketal-containing subunit employs a recently developed metallacycle-mediated reductive cross-coupling between a TMS-alkyne and a terminal alkene.
    Organic Letters 10/2012; · 6.14 Impact Factor
  • Dexi Yang, Glenn C Micalizio
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    ABSTRACT: An asymmetric synthesis of alkaloid (-)-205B, a tricyclic member of the architecturally diverse family of natural products isolated from the skin of neotropical poison frogs, is described that proceeds through two recently developed stereoselective synthetic methods: (1) Ti-mediated allylic alcohol-imine reductive cross-coupling and (2) intramolecular [3+2] cycloaddition of a glyoxylate-based homoallylic nitrone. The utility of this latter cycloaddition process for the assembly of the stereochemically dense piperidine core of 205B is noteworthy, as this method enables direct [3+2] cycloaddition of an intermediate homoallylic (E)-nitrone via a pathway that is stereochemically unscathed by competitive [3,3]-sigmatropic rearrangement processes. Overall, the synthesis is asymmetric, concise, and highly stereoselective-features which point to the potential future utility of these chemical methods in natural product synthesis and medicinal chemistry.
    Journal of the American Chemical Society 09/2012; 134(37):15237-40. · 10.68 Impact Factor
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    Peter S Diez, Glenn C Micalizio
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    ABSTRACT: Metallacycle-mediated allylic alcohol-alkyne reductive cross-coupling is described as a convergent solution to the synthesis of deoxypropionates. This approach offers superior step-economy in comparison to available strategies based on multi-step iterative chain elongation. The technique is demonstrated in a concise synthesis of the C1-C11 subunit of borrelidin, and a total synthesis of (-)-vittatalactone.
    Angewandte Chemie International Edition 04/2012; 51(21):5152-6. · 11.34 Impact Factor
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    Stephen N Greszler, Holly A Reichard, Glenn C Micalizio
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    ABSTRACT: A convergent synthesis of highly substituted and stereodefined dihydroindanes is described from alkoxide-directed Ti-mediated cross-coupling of internal alkynes with substituted 4-hydroxy-1,6-enynes (substrates that derive from 2-directional functionalization of readily available epoxy alcohol derivatives). In addition to describing a new and highly stereoselective approach to bimolecular [2 + 2 + 2] annulation that delivers products not available with other methods in this area of chemical reactivity, evidence is provided to support annulation by way of regioselective alkyne-alkyne coupling, followed by metal-centered [4 + 2] rather than stepwise alkene insertion and reductive elimination. Overall, the reaction proceeds with exquisite stereochemical control and defines a convenient, convergent, and enantiospecific entry to fused carbocycles of great potential value in target-oriented synthesis and medicinal chemistry.
    Journal of the American Chemical Society 02/2012; 134(5):2766-74. · 10.68 Impact Factor
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    ABSTRACT: The discovery of new compounds for the pharmacological manipulation of protein function often embraces the screening of compound collections, and it is widely recognized that natural products offer beneficial characteristics as protein ligands. Much effort has therefore been focused on 'natural product-like' libraries, yet the synthesis and screening of such libraries is often limited by one or more of the following: modest library sizes and structural diversity, conformational heterogeneity and the costs associated with the substantial infrastructure of modern high-throughput screening centres. Here, we describe the design and execution of an approach to this broad problem by merging principles associated with biologically inspired oligomerization and the structure of polyketide-derived natural products. A novel class of chiral and conformationally constrained oligomers is described (termed 'chiral oligomers of pentenoic amides', COPA), which offers compatibility with split-and-pool methods and can be screened en masse in a batch mode. We demonstrate that a COPA library containing 160,000 compounds is a useful source of novel protein ligands by identifying a non-covalent synthetic ligand to the DNA-binding domain of the p53 transcription factor.
    Nature Chemistry 02/2012; 4(2):99-104. · 21.76 Impact Factor
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    Ming Z Chen, Glenn C Micalizio
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    ABSTRACT: A de novo synthesis of substituted pyridines is described that proceeds through nucleophilic addition of a dithiane anion to an α,β-unsaturated carbonyl followed by metallacycle-mediated union of the resulting allylic alcohol with preformed trimethylsilane-imines (generated in situ by the low-temperature reaction of lithium hexamethyldisilazide with an aldehyde) and Ag(I)- or Hg(II)-mediated ring closure. The process is useful for the convergent assembly of di- through penta-substituted pyridines with complete regiochemical control.
    Journal of the American Chemical Society 11/2011; 134(2):1352-6. · 10.68 Impact Factor
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    ABSTRACT: A convergent synthesis of benzoquinone ansamycin analogs is described that proceeds by a sequence of metallacycle-mediated alkyne-alkyne coupling, followed by site- and stereoselective dihydroxylation and global carbamate formation. These studies have led to (1) validation of alkyne-alkyne coupling to produce geldanamycin analogs that lack the problematic quinone, (2) the discovery that C6-C7 bis-carbamate functionality is compatible with Hsp90 inhibition, and (3) the identification of 1 as a nonquinone geldanamycin-inspired paralog-selective Hsp90 inhibitor.
    Organic Letters 08/2011; 13(19):5108-11. · 6.14 Impact Factor
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    Dexi Yang, Glenn C Micalizio
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    ABSTRACT: A convergent and stereodivergent pathway to highly substituted 1-aza-7-oxabicyclo[2.2.1]heptanes is described. It begins with a coupling reaction involving allylic alcohol, aldehyde, and LiHMDS to produce stereodefined primary homoallylic amines. Subsequent N-oxidation and condensation with formaldehyde or glyoxylate defines a convenient entry to densely functionalized homoallylic nitrones whose intramolecular annulation can be controlled to deliver one of two distinct heterocyclic skeletons, each with ≥20:1 stereoselection. Control of the stereochemistry in these reactions results from both control of the nitrone geometry and selective partitioning of the reaction pathway between direct [3 + 2] cycloaddition and tandem [3,3] rearrangement/[3 + 2] cycloaddition.
    Journal of the American Chemical Society 06/2011; 133(24):9216-9. · 10.68 Impact Factor
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    ABSTRACT: Management of chronic pain continues to represent an area of great unmet biomedical need. Although opioid analgesics are typically embraced as the mainstay of pharmaceutical interventions in this area, they suffer from substantial liabilities that include addiction and tolerance, as well as depression of breathing, nausea and chronic constipation. Because of their suboptimal therapeutic profile, the search for non-opioid analgesics to replace these well-established therapeutics is an important pursuit. Conolidine is a rare C5-nor stemmadenine natural product recently isolated from the stem bark of Tabernaemontana divaricata (a tropical flowering plant used in traditional Chinese, Ayurvedic and Thai medicine). Although structurally related alkaloids have been described as opioid analgesics, no therapeutically relevant properties of conolidine have previously been reported. Here, we describe the first de novo synthetic pathway to this exceptionally rare C5-nor stemmadenine natural product, the first asymmetric synthesis of any member of this natural product class, and the discovery that (±)-, (+)- and (-)-conolidine are potent and efficacious non-opioid analgesics in an in vivo model of tonic and persistent pain.
    Nature Chemistry 06/2011; 3(6):449-53. · 21.76 Impact Factor
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    Daniel P Canterbury, Glenn C Micalizio
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    ABSTRACT: A convergent synthesis of the CDEF-tetracyclic region of pectenotoxin-2 (PTX-2) is described. The synthetic pathway derives from a head-to-tail union of 2 equiv of linalool to establish a stereodefined DEF-tricyclic aldehyde. Subsequent coupling with a "northern" fragment enolate, followed by a tandem Sharpless epoxidation/cyclization, delivers the C10-C26 polycyclic region of the natural product.
    Organic Letters 05/2011; 13(9):2384-7. · 6.14 Impact Factor
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    Dexi Yang, Justin K Belardi, Glenn C Micalizio
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    ABSTRACT: Regioselective titanium alkoxide-mediated reductive cross-coupling reactions of allylic alcohols with vinylsilanes and imines have previously been demonstrated to proceed with allylic transposition by formal metallo-[3,3]-rearrangement [thought to proceed by a sequence of: 1) directed carbometalation, and 2) syn-elimination]. While many examples have been described that support this reaction path, a collection of substrates have recently been identified that react by way of an alternative pathway, delivering a concise convergent route to coupled products bearing a quaternary center.
    Tetrahedron Letters 04/2011; 52(17):2144-2147. · 2.40 Impact Factor

Publication Stats

305 Citations
465.07 Total Impact Points

Institutions

  • 2013
    • Dartmouth College
      • Department of Chemistry
      Hanover, NH, United States
  • 2009–2013
    • The Scripps Research Institute
      • Department of Chemistry
      La Jolla, California, United States
  • 2005–2009
    • Yale University
      • Department of Chemistry
      New Haven, CT, United States
  • 2008
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States