Files in this item



application/pdfStang_Erik.pdf (7MB)
(no description provided)PDF


Title:C—H oxidation reactions in complex molecule synthesis: application and development
Author(s):Stang, Erik M.
Director of Research:White, Maria C.
Doctoral Committee Chair(s):White, Maria C.
Doctoral Committee Member(s):Denmark, Scott E.; Hergenrother, Paul J.; Nuzzo, Ralph G.
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):C–H Activation
6-Deoxyerythronolide B
Dehydrogenative Diels-Alder
Abstract:Among the frontier challenges in chemistry in the 21st century are the interconnected goals of increasing synthetic efficiency and diversity in the construction of complex molecules. Oxidation reactions of C–H bonds, particularly when applied at late-stages of complex molecule syntheses, hold special promise for achieving both these goals by minimizing the use of functional group manipulations typically required to synthesize these molecules. Traditionally, C–H oxidation reactions install oxidized functionality onto a preformed molecular skeleton, resulting in a local molecular change. However, the use of C–H activation chemistry to construct complex molecular scaffolds is a new area with tremendous potential in synthesis. This work showcases a late-stage C–H oxidation strategy in the total synthesis of 6-deoxyerythronolide B (6-dEB), the aglycone precursor to the erythromycin antibiotics. An advanced intermediate is cyclized to the 14-membered macrocyclic core of 6-dEB using a late-stage (step 19 of 22) C–H oxidative macrolactonization reaction that proceeds with high regio-, chemo-, and diastereoselectivity (>40:1). A chelate-controlled model for macrolactonization predicted the stereochemical outcome of C–O bond formation and guided the discovery of conditions for synthesizing the first diastereomeric 13-epi-6-dEB precursor. Overall, this C–H oxidation strategy affords a highly efficient and stereochemically versatile synthesis of the erythromycin core. Throughout the erythromycin’s rich synthetic history, no concept has been entrenched as deeply as the perceived need for biasing elements in order to effect 14-membered macrocyclization. This work showcases the cyclizations of completely unbiased 6-deoxyerythronolide B precursors, using either C–H oxidative or Yamaguchi macrolactonization reactions. Late-stage and stereodivergent C–H oxidation reactions enabled seco acid formation with both configurations at C13. Consequently, it is shown that both the natural and unnatural C13 configurations can be formed in the macrocyclization of the 6-dEB core in the absence of preorganizational elements. Overall these findings require revision of the 30-year-old dogma that preorganization is mandatory for achieving macrocyclization of the erythromycins. Sequential transformations in a single reaction have the potential to dramatically increase synthetic efficiency by rapidly building molecular complexity while lowering step count and intermediate isolations. Catalytic dehydrogenation reactions of hydrocarbons represent a powerful reaction class capable of activating an otherwise non-reactive substrate through sequential C–H bond activations. As a result, coupling a dehydrogenation transformation to a complexity generating reaction would lead to complex molecular architectures from topologically simple starting materials in a rapid fashion. We report a Pd(II)/bis-sulfoxide catalyzed dehydrogenative Diels-Alder reaction that converts simple terminal olefins into complex cyclohexenyl adducts in good yields and selectivities. Based on the high functional group tolerance, this method enables expedient access to a wide variety of biologically and medicinally relevant heterocycles, such as hydroisoindolines, cis-decalins, hydroisoquinolines, and isoindoloquinolines. Mechanistic studies indicate the reaction proceeds through a sequential allylic C–H cleavage and homoallylic β-hydride elimination to produce a mixture of E and Z terminal 1,3-dienes, which isomerize to the Diels-Alder capable (E)-isomer via Pd(II)-catalysis, followed by a thermal Diels-Alder cycloaddition.
Issue Date:2012-02-06
Rights Information:Copyright 2011 Erik M. Stang
Date Available in IDEALS:2012-02-06
Date Deposited:2011-12

This item appears in the following Collection(s)

Item Statistics