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Structure and Reactivity Fall Semester 2008 Summary Prof. Jérôme Waser BCH 4306 021 693 93 88 [email protected] Assistant: Davinia Fernandez-Gonzalez BCH 4409 021 693 94 49 [email protected] Structure and Reactivity 2008, Summary page 1 Table of Content 1. Introduction and Literature 2. Conformational Analysis 2.1 Alkanes 2.2 Alkenes: Allylic Strain 2.3 Cyclohexane 2.4 Stereoelectronic Effects: HOMO-LUMO interactions 3. Alkenes 3.1 Synthesis of Alkenes 3.1.1 Elimination 3.1.2 From Acetylenes 3.1.3 Olefin Metathesis (see inorganic chemistry lectures) 3.1.4 From carbonyls 3.1.4.1 Aldol Condensation 3.1.4.2 Wittig and Variations 3.1.4.3 Julia and Variations 3.1.4.4 Peterson Olefination 3.2 Hydroboration of Alkenes 3.2.1 Important Boron Reagents and General Mechanism 3.2.2 Control of Diastereoselectivity 3.3 Alkene Oxidation 3.3.1 Epoxidation 3.3.1.1 Directed Epoxidation with m-CPBA 3.3.1.2 Directed Epoxidation with metal catalysts 3.3.1.3 Epoxide Opening and the Fürst-Plattner Rule 3.3.2 Dihydroxylation 4. Addition to Carbonyl 4.1 General Concepts and Models 4.2 Addition to Carbonyls not Following the Felkin Ahn Model 4.2.1 Chelate Control 4.2.2 Directed Reduction 4.2.3 Reagents Binding to Carbonyl during Addition 4.3 Allylation of Carbonyls 5. Enolate Generation and Reactivity 5.1 Selective Generation of Enolates 5.2 Chiral Auxiliary and Enolate Alkylation 5.2.1 General Concept 5.2.2 Evans Oxazolidinone Auxiliary 5.2.3 Other Auxiliaries 6. Aldol Reaction 6.1 Zimmermann-Traxler Transition State 6.2 Aldol Reactions using Evans' Auxiliary 6.3 Ketone (Paterson) Aldol 7. Reaction of Imines and Conjugated Systems 7.1 Chemistry of Imines 7.2 Chemistry of Enamine and Metalloenamine 7.3 Conjugate Addition and the Vinylogous Principle 8. Cross Coupling Reactions 8.1 Organometallic-RX Cross Coupling Structure and Reactivity 2008, Summary page 2 8.2 Heck Coupling 8.3 C-Heteroatom Coupling 9. Cycloadditions 9.1 Diels-Alder Cycloaddition 9.1.1 General Aspects 9.1.2 Diastereoselective Diels-Alder with Evans' Auxiliary 9.1.3 Special Diels-Alder Reactions 9.2 [3+2] Cycloaddition Reactions (1,3-Dipolar Cycloadditions) 10. Rearrangements 10.1 Rearrangements via Reactive Intermediates 10.1.1 Cationic Intermediates 10.1.2 Carbene and Nitrene Intermediates 10.2 [3,3] Sigmatropic Rearrangements 10.2.1 General Mechanism 10.2.2 Overman's Aza-Cope Mannich approach towards Strychnine Supplementary Material - Prerequired Knowledge (required for exam) - General Mechanism for Diels Alder Reaction (required for exam) - Polyketides and Drugs (not required for exam) Structure and Reactivity 2008, Summary page 3 Structure and Reactivity: Summary 1. Introduction and Literature Warning: This summary is meant as an help to check the note taken in the lecture and contains only the most important concepts and transition states, it cannot replace the blackboard notes! Important Supporting Material - Prerequired Knowledge Summary (necessary to solve exam problems!) repetition of easy concepts from bachelor - Evans CHEM 206 (on the internet via google) probably the best lecture on the net on advanced organic chemistry, contains most of the topics of this lecture and much more - Carey Sundberg: Advanced Organic Chemistry Part A and B Comprehensive books, focusing mostly on reactivity, but weaker on selectivity. - March's: Advanced Organic Chemistry Book good for consultation, not for learning - Kurti-Czako: Strategic Applications of Named Reactions in Organic Synthesis One of the best book for named reactions, very good to revise mechanism and scope of specific reactions 2. Conformational Analysis (Energy Values in Kcal/mol, M = Medium, L = Large) 2.1 Alkanes H H Butane CH3 H3C H H Sägebock Projection H CH H CH3 3 H3C H 1.4 H CH3 H H H 3 H 0.9 H C H H C H H3C H 3 H3C H 3 1 H H H H Gauche Interaction Newman Projection 1.4 0.9 H H3C 3 H H CH H H H3C H 3 H3C H H3C CH3 H3C H CH3 H H H H H H H H 1 Relative Energy 0 3.8 0.9 5 staggered eclipsed staggered eclipsed antiperiplanar anticlinal synclinal synperiplanar gauche conformer Structure and Reactivity 2008, Summary page 4 Structure and Reactivity 2008, Summary page 5 AValues R A value 2 gauche interactions (also called 1,3-diaxial interactions) H R CH3 1.7 H R CH2CH3 1.7 Raxial R equatorial CH(CH3)2 2.1 C(CH3)3 4.7 Avalue(R)=- G (axial-equatorial) CN 0.2 !!! A value are exact only for monosubstituted cyclohexanes!!! H C6 5 2.8 Important number to remember: Si(CH3)3 2.5 A Value CH3: 1.7 Kcal/mol OCH3 0.6 1.4 Kcal = 10:1 mixture 21 Kcal = thermal energy at room temperature Cl 0.6 2.4 Stereoelectronic Effects: HOMO-LUMO interactions Important Rules for HOMO-LUMO interactions 1) The nearest the energy of HOMO and LUMO, the strongest the interaction. 2) The absolute energy of orbitals is correlated to the electronegativity of the atoms/bonds 3) Stereoelectronics: a geometrical overlap of orbitals is necessary for interaction Important examples: Structural Anomeric Effect Enolate Formation R R1 H O n C-O O RO O C-H H H O O O A value: -0.6! R n H O O Axial is favored RO O RO *C=O R1 H R H C-H 1 C-H H C-O Hydrogen is acidic only to C=O! Microscopic Reversibility: nO Protonation from Enolate is to C=C! Anomeric Effect: In the axial position, a better stabilization with the more electronegative C-O is possible. Other examples seen in the lecture: Sn2 substitution, elimination, conformation of esters, stabilization of carbocations Structure and Reactivity 2008, Summary page 6 3. Alkenes 3.1 Synthesis of Alkenes 3.1.1 Elimination SCH3 X O S 150 °C 20 °C H O H Se Ph H OtBu E2, trans elimination Chugaev syn elimination Selenoxide syn elimination 3.1.2 From Acetylenes Pd/CaCO3 Lindlar cat. R1 R2 M R1 R2 R MH cross-coupling R2 R Li/NH3 M = B, Sn, Zr,... R1 Reduction Hydrometallation 3.1.3 Olefin Metathesis (see inorganic chemistry lectures) 3.1.4 From carbonyls 3.1.4.1 Aldol Condensation 3.1.4.2 Wittig and Variations Original Wittig O R1 cis for R = alkyl 1 or R PPh 1 R R trans for R = CO R' 3 R H R 2 phosphor ylide Mechanism R R = alkyl R R=Ester CO2Et CO2Et O H O H Ph H Ph H Ph Ph H P P H Ph Ph P 1 Ph Ph P 1 1 R 1 R Ph R Ph Ph R Ph H O H O Puckered PlanarPuckered Planar R CO2Et Ph P Ph P 3 cis trans 3 O O R1 R1 Two transition state are possible: puckered and planar. For alkyl groups, the reaction is controlled by sterics and the puckered TS is favored (less interactions with bulky Ph group). For esters, the reaction is controlled by electronics and the planar TS is favored (better Dipoles orientation). Structure and Reactivity 2008, Summary page 7 Schlosser Variation O PhLi, LiBr R1 R PPh + trans for R = alkyl 3 R1 H then H R Br Br Br R R R Li R Ph3P + Ph3P LiBr Ph3P PhLi Ph3P Ph3P H O Li R O trans 1 O O O 1 R 1 1 1 R Li R Li R Li R General problem with Wittig: Strong base is needed! It cannot be used for base-sensitive substrates. Milder Variations: Horner-Wadsworth-Emmons (HWE) O O O O Base P 1 EtO OEt R OEt EtO R1 H HWE is trans selective and weaker base can be used: very often used in total synthesis. Cis-selective variations: O O O O F CH CO P P 3 2 OEt PhO OEt F3CH2CO PhO Still-Gennari Ando 3.1.4.3 Julia and Variations Julia-Lythgoe O HO R1 1 1) BuLi, 1 AcO R R H Ac2O R SO2Ph 2) H O 2 R SO2Ph R SO2Ph Na, Hg 1 R1 AcO R 1 Na, Hg AcO R R R R Highly trans selective, but multi-steps Julia-Kocienski S 1steponly R S N Highly trans selective, milder than many Wittig methods O O Structure and Reactivity 2008, Summary page 8 3.1.4.4 Peterson Olefination 2 2 1 R 3Si O R 3Si O R base R R1 R R1 R 2 O SiR 3 trans 2 1) R1 H R 3Si OH R MgBr 1 2) H2O R R OH2 + 2 1 H ,H2O R 3Si R 1 R OH2 R R cis If high selectivity can be achieved in the first step, the Peterson protocol allows obtaining trans or cis olefins depending on the reaction conditions. 3.2 Hydroboration of Alkenes 3.2.1 Important Boron Reagents and General Mechanism H Me O O BH B Me 3 B H B H borane O Me O Me 9-BBN catechol borane pinacol borane 1 1 H O ,NaOH R R 1 1 2 2 1 R R 2BH BR 2 B OH OBR R R O R 2 H2O2,NaOH cross-coupling OH R Regioselectivity: H goes to more stabilized carbocation, because the mechanism is asynchronous: Partial positive charge H BH2 + tertiary carbocation > secondary carbocation > primary carbocation 3.2.2 Control of Diastereoselectivity Hydroboration with BH3: Minimize strongest Allylic strain, BH3 comes opposite from RL H H2B H2BH OH R R R H L 3 BH M H R3 H2O2 R R 3 H H L 3 R H R2 RM H R R3 M R2 2 R R RL M 2 RL A1,3 Minimized R H R3 R1 L R1 R R1 H O R R BH3 3 R BH2 2 2 R R L 3 R1 L L 3 H H R H H M H RM RM OH H RM HBH2 A1,2 Minimized Structure and Reactivity 2008, Summary page 9 Hydroboration with bulky boron reagents: Minimize reagent-substrate interactions H R1 HBR2 R1 BR H RM H R BR2 H O RL R3 2 3 R1 2 2 RL R3 R1 H RM H H R3 RM H R OH H RL M RL A1,2 not minimized RL R3 A minimized but R 1,2 1 H strong steric interaction with reagent! Reagent control is important! H RM HBR2 3.3 Alkene Oxidation 3.3.1 Epoxidation 3.3.1.1 Directed Epoxidation with m-CPBA Cl m-CPBA Cl OH directs m-CPBA O H O OH H O O H O O H H BH3 H O R1 H HO R1 H R2 R2 HO H R R2 1 H OH R2 H R1 A1,3 minimized OH OH Prediction easy for cyclic substrates: m-CPBA O Directed reactions often allows for good selectivity in organic chemistry! 3.3.1.2 Directed Epoxidation with metal catalysts General Mechanism HO R O O Lm-1M R O ROOH O MLn O Often used MLn: VO(acac)2,Ti(OR)4 LmM R HO O O O ROH ROOH Lm-1M O Structure and Reactivity 2008, Summary page 10 Catalytic Asymmetric Version: Sharpless Epoxidation i t conditions: 5 mol% Ti(O Pr)4,5mol%DET, BuOOH, molecular sieves, CH2Cl2,-20°C HO
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  • Bridging Mcmurry and Wittig in One-Pot

    Bridging Mcmurry and Wittig in One-Pot

    Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1755 Bridging McMurry and Wittig in One-Pot Olefins from Stereoselective, Reductive Couplings of Two Aldehydes via Phosphaalkenes JURI MAI ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6214 ISBN 978-91-513-0536-3 UPPSALA urn:nbn:se:uu:diva-368873 2019 Dissertation presented at Uppsala University to be publicly examined in Häggsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, Friday, 15 February 2019 at 10:15 for the degree of Doctor of Philosophy. The examination will be conducted in English. Faculty examiner: Professor Dr. Christian Müller (Freie Universität Berlin, Institute of Chemistry and Biochemistry). Abstract Mai, J. 2019. Bridging McMurry and Wittig in One-Pot. Olefins from Stereoselective, Reductive Couplings of Two Aldehydes via Phosphaalkenes. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1755. 112 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-0536-3. The formation of C=C bonds is of great importance for fundamental and industrial synthetic organic chemistry. There are many different methodologies for the construction of C=C bonds in the literature, but currently only the McMurry reaction allows the reductive coupling of two carbonyl compounds to form alkenes. This thesis contributes to the field of carbonyl olefinations and presents the development of a new synthetic protocol for a one-pot reductive coupling of two aldehydes to alkenes based on organophosphorus chemistry. The coupling reagent, a phosphanylphosphonate, reacts with an aldehyde to yield a phosphaalkene intermediate which upon activation with a base undergoes an olefination with a second aldehyde. A general overview of synthetic methods for carbonyl olefinations and the chemistry of phosphaalkenes is given in the background chapter.
  • Convergent Total Synthesis and Preliminary Biological Investigations

    Convergent Total Synthesis and Preliminary Biological Investigations

    Norrislide: Convergent Total Synthesis and Preliminary Biological Investigations Author: Krista Elizabeth Granger Persistent link: http://hdl.handle.net/2345/731 This work is posted on eScholarship@BC, Boston College University Libraries. Boston College Electronic Thesis or Dissertation, 2009 Copyright is held by the author, with all rights reserved, unless otherwise noted. Boston College The Graduate School of Arts and Sciences Department of Chemistry NORRISOLIDE: CONVERGENT TOTAL SYNTHESIS AND PRELIMINARY BIOLOGICAL INVESTIGATIONS a dissertation by KRISTA ELIZABETH GRANGER submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 2009 © copyright by KRISTA ELIZABETH GRANGER 2009 Norrisolide: Convergent Total Synthesis and Preliminary Biological Investigations Krista Elizabeth Granger Thesis Advisor: Professor Marc L. Snapper Abstract • Chapter 1: A review of Shapiro reactions as a coupling strategy in natural product total synthesis. The syntheses of lycoramine, galanthamine, yuehchukene analogues, ovalicin, studies toward the ingenol core, haemanthidine, pretazettine, tazettine, crinamine, Taxol, colombiasin A, elisapterosin B, the AB ring fragment of spongistatin 1 and 8-epipuupewhedione are discussed. Ar O S O nBuLi Li E+ E NH R' R' N R R R' R • Chapter 2: The convergent total synthesis of the marine natural product norrisolide is described. Both subunits, the hydrindane core and the norrisane side chain, are prepared in an asymmetric fashion through kinetic resolution and enantioselective cyclopropanation, respectively. A Shapiro reaction couples the two fragments and a Peterson olefination installs the 1,1-disubstituted olefin. O O MeO OTBS AcO MeO O O O O N Me Me Me MeO O O Me Li O OP H H Me Me Me Me norrisolide H Me Me • Chapter 3: Preliminary experiments to isolate the biological target of norrisolide through reductive alkylation and tritium labeling are investigated.