Glenn C Micalizio

Dartmouth College, Hanover, New Hampshire, United States

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Publications (87)630.67 Total impact

  • Xiayun Cheng · Glenn C Micalizio
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    ABSTRACT: An asymmetric approach to the synthesis of neurotrophic seco-prezizaane sesquiterpenes is described that is based on strategic application of a hydroxyl-directed metallacycle-mediated [2+2+2] annulation and an intramolecular radical cyclization cascade. Targets prepared are among the most potent members of the natural product class and include (1R,10S)-2-oxo-3,4-dehydroneomajucin, (2S)-hydroxy-3,4-dehydroneomajucin and (-)-jiadifenin. In addition to representing the first application of the alkoxide-directed metallacycle-mediated hydrindane-forming annulation reaction in natural product synthesis and the first total synthesis of (2S)-hydroxy-3,4-dehydroneomajucin, these pursuits have resulted in the elucidation of a complex radical cascade process for installation of the C5 quaternary center common to the natural product class.
    No preview · Article · Jan 2016 · Journal of the American Chemical Society
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    Full-text · Dataset · Dec 2015
  • Wan Shin Kim · Claudio Aquino · Haruki Mizoguchi · Glenn C. Micalizio
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    ABSTRACT: Termination of the Ti(OiPr)4-promoted [2 + 2 + 2] cycloaddition reaction of internal alkynes and enynes of type (II) with LiOOtBu is examined to yield angularly substituted hydrindanes (III).
    No preview · Article · Oct 2015 · ChemInform
  • Wan Shin Kim · Claudio Aquino · Haruki Mizoguchi · Glenn C. Micalizio
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    ABSTRACT: LiOOt-Bu is an effective oxidant for converting the penultimate organometallic intermediate generated in a titanium alkoxide-mediated [2+2+2] reaction cascade to an allylic alcohol. Oxidation of the presumed allylic titanium species is highly regioselective, providing direct access to substituted hydrindanes containing a primary allylic alcohol. In addition to demonstrating the feasibility of this oxidation process, we document the ability to convert the primary allylic alcohol products to angularly substituted cis-fused hydrindanes.
    No preview · Article · Jun 2015 · Tetrahedron Letters
  • Haruki Mizoguchi · Glenn C Micalizio
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    ABSTRACT: Bridged bicyclic metallacyclopentenes generated from the [4+2] cycloaddition of metallacyclopentadienes with alkenes have been proposed as reactive intermediates in the course of [2+2+2] annulation reactions. Recently a collection of alkoxide-directed Ti-mediated [2+2+2] annulation reactions have been discovered for the synthesis of densely functionalized hydrindanes, where the bridged bicyclic metallacyclopentenes from intramolecular [4+2] were treated as fleeting intermediates en route to cyclohexadiene products by formal cheletropic extrusion of Ti(Oi-Pr)2. In studies aimed at understanding the course of these organometallic cascade reactions it was later discovered that these bridged bicyclic intermediates can be trapped by various elimination processes. Here, we have realized metallacycle-mediated annulation reactions for the assembly of angularly substituted decalins - structural motifs that are ubiquitous in natural products and molecules of pharmaceutical relevance. In addition to defining the basic annulation reaction we have discovered a surprising stability associated with the complex organometallic intermediates generated in the course of this coupling process and document here the ability to control the fate of this species. Ligand-induced cheletropic extrusion of the titanium center delivers cyclohexadiene-containing products, while several distinct protonation events have been identified to realize polycyclic products that contain three new stereocenters (one of which is the angular quaternary center that is a hallmark of alkoxide-directed titanium-mediated [2+2+2] annulation reactions). Examples of this metallacycle-mediated annulation reaction are provided to demonstrate that a range of stereodefined fused bicyclo[4.4.0]-decanes are accessible, including those that contain aromatic and aliphatic substituents, and an empirical model is presented to accompany the observations made.
    No preview · Article · May 2015 · Journal of the American Chemical Society
  • Glenn C Micalizio · Sarah B Hale
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    ABSTRACT: Convergent C–C bond-forming reactions define the fabric of organic synthesis and, when applied in complex molecule synthesis, can have a profound impact on efficiency by decreasing the longest linear sequence of transformations required to convert simple starting materials to complex targets. Despite their well-appreciated strategic significance, campaigns in natural product synthesis typically embrace only a small suite of reactivity to achieve such bond construction (i.e., nucleophilic addition to polarized π-bonds, nucleophilic substitution, cycloaddition, and metal-catalyzed “cross-coupling”), therefore limiting the sites at which convergent coupling chemistry can be strategically employed. In our opinion, it is far too often that triumphs in the field are defined by chemical sequences that do not address the challenges associated with discovery, development, and production of natural product-inspired agents. We speculated that advancing an area of chemical reactivity not represented in the few well-established strategies for convergent C–C bond formation may lead to powerful new retrosynthetic relationships that could simplify approaches to the syntheses of a variety of different classes of natural products.
    No preview · Article · Feb 2015 · Accounts of Chemical Research
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    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.
    Preview · Article · Sep 2014 · Organic Letters
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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.
    Preview · Article · May 2014 · Journal of the American Chemical Society
  • G.C. Micalizio
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    ABSTRACT: A review of recent advances in early transition metal metallacycle-mediated coupling of C. C π-bonds is presented. Discussion is focused on bond-forming processes stemming from a sequence of metal-. π complex formation followed by carbometalation of a second π-system and spans developments in intra- and intermolecular chemistry. The purpose of this review is to provide the reader with a glimpse of the growing power that this mode of chemical reactivity has in organic synthesis and, as such, contains relevant examples showcasing the utility of the reactions presented to address challenging problems in chemical synthesis, including applications in the context of acyclic stereocontrol, fatty acid, carbocycle, and heterocycle synthesis. Overall, the reader is expected to gain an appreciation of the present scope and limitations of early transition metal metallacycle-mediated bond construction in organic synthesis.
    No preview · Article · Feb 2014
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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.
    No preview · Article · Dec 2013 · ACS Medicinal Chemistry Letters
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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.
    Full-text · Article · Dec 2013 · Drug metabolism and disposition: the biological fate of chemicals
  • 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.
    No preview · Article · Aug 2013 · Chemical Communications
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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.
    No preview · Article · May 2013 · Journal of the American Society for Mass Spectrometry
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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.
    No preview · Article · Apr 2013 · Angewandte Chemie International Edition
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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.
    No preview · Article · Apr 2013 · ACS Chemical Biology
  • 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
    No preview · Article · Feb 2013 · Nature
  • 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.
    No preview · Article · Oct 2012 · Organic Letters
  • 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.
    No preview · Article · Sep 2012 · Journal of the American Chemical Society
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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.
    Preview · Article · May 2012 · Angewandte Chemie International Edition
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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.
    Preview · Article · Feb 2012 · Journal of the American Chemical Society

Publication Stats

1k Citations
630.67 Total Impact Points

Institutions

  • 2014-2016
    • Dartmouth College
      • Department of Chemistry
      Hanover, New Hampshire, United States
  • 2009-2013
    • The Scripps Research Institute
      • Department of Chemistry
      لا هویا, California, United States
  • 2002-2010
    • Harvard University
      • Department of Chemistry and Chemical Biology
      Cambridge, Massachusetts, United States
  • 2000-2010
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2005-2009
    • Yale University
      • Department of Chemistry
      New Haven, Connecticut, United States
  • 1999-2001
    • University of Michigan
      • Department of Chemistry
      Ann Arbor, Michigan, United States