DOCSLIB.ORG

Olefin Synthesis Handout

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Olefin Synthesis Handout Olefin Synthesis Chem 6352 Jeremy May -Plethora of references in the literature on olefin synthesis: see Larock 2nd ed. p. 215-562 -These can be catagorized by reaction type: -Or categorized by the olefinic product: Elimination Reactions - Larock p. 251-315 Terminal Olefins (see other handout) X Y reagent R R R R R R R R R R Wittig-type Reactions - Larock p. 327-350 1,2-Disubstituted Olefins R R'' R R'' R R O + R3P R R R' R''' R' R''' E Z Metathesis Reactions - Grubbs group Tri & Tetrasubstituted olefins (see other handout) R' R R R R Catalyst + R R' R R R R Note: these are much more difficult because of E/Z issues! 1,2-Disubstituted Olefins •Z-olefins -From Acetylenes: by reduction R R R R I Lindar's Catalyst, H2 Pd/BaSO4, Quinoline (partially poisons catalyst) II Diimide reduction H N N H III CO Cr CO , H2 (JOC 1985, 30, 1147) CO IV Hydroboration/Acidic Quench R R R R HBR2 AcOH R R H BR2 H H -From Rings: OMe CO Me O3, NaBH4 2 OH -From Wittig Reaction: O R' H R R PPh PPh3 3 R R' preparation of ylide: Δ R PPh X base 3 R R X + PPh3 PPh3 Polar Solvent alkyl halide (THF, acetone, H H EtOH, MeCN) pKa ~22 O- mechanism of the Wittig reaction: + Chem. Rev. 1989, 863 S - JACS 1989, 6861 Vedejs Base: nBuLi, LDA, KHMDS, NaHMDS, LiHMDS, tBuOK, , etc. JACS 1981, 2823 (DMSO, NaH) Antiperiplanar R R R R R' C H C H Ph3P Ph3P O H Ph3P H R Ph P R' R' O 3 H O O H H H Kinetic Reaction Preference Betaine Ph Ph R R H Ph P H + Ph3P O R' O R' H H Oxaphosphetaine -Salt Effect: Li O Activation of the carbonyl by a Lewis acidic salt can increase the reaction rate and lower the selectivity. Also, it leads to a more open transition state (ie. there are fewer steric effects). R H -To counter the effect: N Additives: HMPA, TMEDA → these break up and sequester lithium ions N Li N Freeze/filter salts: becomes difficult preparatively. N -Examples: (Stork TL 1989, 30, 2173) O H + Ph P Very useful for Stille/Heck reactions. 3 R I We will see this again later! R H I + + I I PPh3 base -Phosphine effect: Synlett 1990, 605 Ar O Ph P + + Ar Z form is slightly favored 3 R Ar R H R H Z E Ar O + + Ar Z:E = 96:4 P R Ar R H R H 3 Z E O MeO -The Reaction of Lactols: (Corey, JACS 1969, 91, 5675) OH CO H HO O 2 Ph3P CO H I 2 DMSO NaH THPO OTHP THPO OTHP The Schlosser Modification of the Wittig: reversal of selectivity for non-stabilized ylides. ACIEE 1966, 5, 126 O Synth. 1971, 29 Liebigs Ann. 1967, 708, 35 1) R +PPh PhLi R R' H 3 PPh3 R' - R Br 2) PhLi (-70 → -30 °C) 3) MeOH or tBuOH (-30 °C) warming (-30 °C) + H H Ph-Li+ H R' H H R' R R' R R' H + - + - + - + - (MeOH) + - + - Li O PPh3 Br Li O PPh3 Br Li O PPh3 Br W. S. Johnson, Progesterone Synth. JACS 1971, 93, 4332 O O 1) O O PPh 3 o H 97:3 trans:cis 2) PhLi, then MeOH, O O -30 °C O O More Z-olefin formation: -Carbometallation: R R'' R R'' R E R'' M + M R' E R' R' -Copper/Magnesium: H 1) CuBr•DMS R H + Et2O, -20 °C There will be more examples with the R Li trisubstituted olefin section. 2) E E H H O O E=I2, , H H -Zirconium/Aluminum: Me AlMe2 Me I Me3Al I2 R H or Cp2ZrCl2 R E R TL 1981,22,315 TL 1986,27,4351 Org. Rxn. Vol. 41 (Lipschutz) -Hydrometallation/Halogenation: R H Br Et3SiH 2 R H R Br PtCl2 H SiEt Hydrosilylation Br2 Br Br H Br Br R H SiEt3 H R R H SiEt Br 3 H Br H SiEt3 Further reaction of the vinyl bromide: Pd mediated R R' reactions R Br R Me Me2CuLi "Gilman Reagent" R Note: treatment with I2 gives I . -Hydroboration/Alkyl transfer: R H R R' I2 R H + R'2 BH NaOH H BR'2 H H I2 Note: One R' group will be wasted! I I R R' R H H H H BR' 2 B OH R' HO HO I I R H R H OH H B H B OH R' R' R' R' •E-olefins: 1,2-disubstituted olefins continued From Olefins: Olefin Metathesis Grubbs Acc. Chem. Res. 2000, 34, 18 Schrock JACS 990, 112, 3875 N N PCy3 Cl i-Pr i-Pr Cl N Ru Ru Ph Cl Ph Cl Ph Mo PCy CH3C(CF3)2O CH3 PCy3 3 CH3 CH3C(CF3)2O Diene Metathesis Reactions Terminal Olefin Intermolecular Reactions X X n X ROM R R' R' R - RCM 4 C H 2 ADMET 2 H C 4 - R 1 CM R2 X R1 X ROMP - C2H4 n R2 n -Mechanism of Olefin Metathesis: R1 R R [M] [M] R1 R1 + R2 R2 R2 R [M] R [M] R [M] = Metal Alkylidene R1 R1 R2 R2 R [M] [M] + R1 R2 R1 R2 R1 Typically a thermodynamic equilibrium process. The reaction produces a new carbon-carbon double bond. Examples: Ring closing for meduim reings: Furstner JOC 1996, 61, 8746 O ClMg HO HO Mixture of diastereomers Dactylol Macrocycle formation: Cross Metathesis: Meyers ACIEE 2000, 9, 1664 Grubbs ACIEE 2002, 41, 3174 H Ar Me Ar Substituted O R styrenes O H O H H N S H CHO CHO Unsaturated H R O N aldehydes O NH H H R H H Si(OR') Vinyl 3 Si(OR')3 OH OH R silanes Griseoviridin H H B(OR')2 B(OR') Vinyl R 2 boronates H Olefin Categorizing for Selective Cross Metathesis N N PCy3 Cl i-Pr i-Pr Cl N Ru Ru Ph Cl Ph Cl Ph Mo Olefin type CH3C(CF3)2O CH3 PCy3 PCy3 CH3 1 2 CH3C(CF3)2O 3 Term inal olefins, 1° allylic alcohols, esters Terminal olefin Type 1 Allylboronate esters, Allylic halides Allylsilanes Terminal olefins Styrenes (no large ortho substit.) 1° allylic alcohols, ethers, esters (fast Allylsilanes homodimerization) Allyl phosphonates, phosphine oxides, Allylboronate esters sulfides, protected am ines Allylhalides Styrenes (large ortho substit.) Acrylate esters, amides, acids, Styrene aldehydes, and vinylketones 2° allylic alcohols Styrene Type 2 2 o allylic alcohols Vinyl dioxolanes (slow Unprotected 3° allylic alcohols Allylstannanes homodimerization) Vinyl epoxides Vinyl boronates Perfluorinated alkane olefins 1,1-Disubstituted olefins Vinylphosphonates Tertiary allylamines Type 3 Phenyl Vinyl Sulfone Vinylsiloxanes o Acrylonitrile (no homodimerization) 4 allylic carbons (all alkyl substituents) 3o allylic alcohols (protected) 1,1-disubstituted olefins Type 4 Vinyl nitro olefins Disubstit. α,β-unsaturated carbonyls 1,1-disubstituted olefins 4o allylic carbon containing olefins Trisubstituted allylic alcohols (protected) (spectators to CM) Perfluorinated alkane olefins 3o allylam ines (protected) From Acetylenes: Li, NH 3(l) R R R R H LAH R H2O R R OH dioxane OH 100 °C Al → O From Aldehydes: JACS 1978, 100, 1942 Wittig Reaction: Modifications to give E-selectivity Corey Ch. 11 - Prostanoids Ch. 12 - Leukotrienes & Eicosanoids -Internal basic group promotes E-selectivity Nicolaou ACIEE 1991, 30, 1100 O CO2Me CO2Me H PhMe + HMPA -78 → -10 °C HO Ph3P Li O -Electron Withdrawing Group (EWG) on Wittig Reagent: EWG H Consider the mechanism: PPh3 Normally Kinetic Ph3P R' H R' Z-olefin O H R R equilibration Stabilization of this anion by EWG as R' will favor the Ph P R' R' ultimate thermodynamic 3 H H product. R' Ph3P E-olefin O H O H R R R Vedejs Examples: JOC 1984, 49, 210 Synth. 1988, 911 Corey and Lazerwith O H H CN H R' JACS 1998, 12777 H or PPh OR PPh 2 PPh3 Me 2 PPh3 also: Phosphine oxides: S. Warren JCSPT1 1985, 2307 (Horner) 10% NaOH O 1)BuLi R Br Ph3P R R' Ph P R H2O 2) O Ph R' H + 100 °C -Horner-Emmons-Wadsworth Modification Arbuzov Rxn: O R Br O P(OR)3 O Br RO P CO2R OR RO P CO2R RO RO Phosphonate HEW Rxn: O RO OR O RO OR CO R O O P CO R 2 O R H, base 2 P H H O OR + RO P CO2R H RO P RO O RO O M O H R equilibrium R R Also: O O THF O O + P -78 → 0 °C P RO CH RO R RO 2 RO R 96% RO see Nicolaou amphotericin synthesis in Classics of Total Synthesis (many other examples). -Still Modification of the HEW reaction: TL 1983, 24, 4405 O O O R H OR Z-selective enoate synthesis P CO2Me F3CH2CO KHMDS 2 18-crown-6 R THF >95% >50:1 M O O RO P irreversible, and a late transition state RO OR O M M O O R H O O O O fast H P OCH2CF3 R OCH CF R OR R OR 2 3 RO C H P OCH CF P OCH CF 2 O 2 3 O 2 3 OCH2CF3 OCH2CF3 syn-aldol product RO RO P O P O RO R RO R O O H H O M O M H H OR OR Transition state that leads to the syn-aldol stereochemistry. -Takai Reaction: JACS 1986, 108, 6048 JACS 1987, 109, 951 H CHI (Iodoform) 3 I many uses R R O CrCl2 THF/dioxane 4:1 >20:1 stereoselectivity Nicolaou - Rapamycin Synthesis CrII I proposed active H intermediate CrII Also: R 1) I2 R' N R 2) CrCl2, Zn, DMF H NH2 95:5 E/Z 3) O R' H II R I CrCl2 R Cr H I H CrII -Julia Olefination: Phosphorus & Sulfur 1985, 24, 97 JCSPK1 1978, 834 Bull.
Load more

Recommended publications
  • Supporting Information a Convenient Chromatography-Free Method For
    Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012 Supporting Information A Convenient Chromatography-Free Method for the Purification of Alkenes Produced in the Wittig Reaction Peter A. Byrne, Kamalraj V. Rajendran, Jimmy Muldoon and Declan G. Gilheany Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland 1. General Experimental 2 2. Synthesis of phosphonium salts 4 3. Procedures for Wittig reactions & phosphine oxide removal 11 4. Characterisation of purified alkenes 15 5. Reduction of phosphine chalcogenides 34 6. Synthesis & isolation of neomenthyl chloride and reduction of phosphine oxide-by-product 37 7. NMR spectra of phosphonium salts 42 8. NMR spectra of purified alkenes and regenerated phosphines from Wittig reactions 56 9. NMR spectra of phosphines produced by reduction of phosphine chalcogenides 85 10. NMR spectra of purified products from Appel-type reactions 90 11. References 91 1 Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012 1. General Experimental All chemicals were supplied by Aldrich, with the exception of Zeoprep silica, 2- methylbenzaldehyde ( o-tolualdehyde, Fluka), ( tert -butoxycarbonylmethyl)- -1 triphenylphosphonium bromide (Fluka), 1 mol L LiAlH 4 in THF (Acros Organics) and Merck standardised alumina 90. All chemicals were used without further purification except diethyl ether, toluene, and THF, which were processed through an Innovative Technology Inc. Pure Solv-400-3-MD solvent purification (Grubbs still) system and stored in Strauss flasks under a nitrogen atmosphere, and ethyl acetate and dichloromethane, which were degassed by passing a stream of dry nitrogen gas (oxygen- free) through the solvent for one hour for the purposes of work-ups in phosphine syntheses.
    [Show full text]
  • 19.13 the Wittig Alkene Synthesis 933
    19_BRCLoudon_pgs5-0.qxd 12/9/08 11:41 AM Page 933 19.13 THE WITTIG ALKENE SYNTHESIS 933 PROBLEMS 19.32 Draw the structures of all aldehydes or ketones that could in principle give the following product after application of either the Wolff–Kishner or Clemmensen reduction. H3C CH2CH(CH3)2 L L 19.33 Outline a synthesis of 1,4-dimethoxy-2-propylbenzene from hydroquinone (p-hydroxyphenol) and any other reagents. 19.13 THE WITTIG ALKENE SYNTHESIS Our tour through aldehyde and ketone chemistry started with simple additions; then addition followed by substitution (acetal formation); then additions followed by elimination (imine and enamine formation). Another addition–elimination reaction, called the Wittig alkene synthe- sis, is an important method for preparing alkenes from aldehydes and ketones. An example of the Wittig alkene synthesis is the preparation of methylenecyclohexane from cyclohexanone. 1 1 A | A | O CH_ 2 PPh3 CH2 Ph3P O _ (19.70) 1 + 3 anL ylid + L 1 3 triphenylphosphine cyclohexanone methylenecyclohexane oxide The Wittig synthesis is especially important because it gives alkenes in which the position of the double bond is unambiguous; in other words, the Wittig synthesis is completely regios- elective.Itcanbeusedforthepreparationofalkenesthatwouldbedifficulttoprepareby other reactions. For example, methylenecyclohexane, which is readily prepared by the Wittig synthesis (Eq. 19.70), cannot be prepared by dehydration of 1-methylcyclohexanol; 1- methylcyclohexene is obtained instead, because alcohol dehydration gives the alkene iso- mer(s) in which the double bond has the greatest number of alkyl substituents (Sec. 10.1). OH " H2SO4 " CH3 H2O CH3 L + 1-methylcyclohexene H2SO4 (19.71) A CH2 (little or none formed) methylenecyclohexane The nucleophile in the Wittig alkene synthesis is a type of ylid.
    [Show full text]
  • Appendix I: Named Reactions Single-Bond Forming Reactions Co
    Appendix I: Named Reactions 235 / 335 432 / 533 synthesis / / synthesis Covered in Covered Featured in problem set problem Single-bond forming reactions Grignard reaction various Radical couplings hirstutene Conjugate addition / Michael reaction strychnine Stork enamine additions Aldol-type reactions (incl. Mukaiyama aldol) various (aldol / Claisen / Knoevenagel / Mannich / Henry etc.) Asymmetric aldol reactions: Evans / Carreira etc. saframycin A Organocatalytic asymmetric aldol saframycin A Pseudoephedrine glycinamide alkylation saframycin A Prins reaction Prins-pinacol reaction problem set # 2 Morita-Baylis-Hillman reaction McMurry condensation Gabriel synthesis problem set #3 Double-bond forming reactions Wittig reaction prostaglandin Horner-Wadsworth-Emmons reaction prostaglandin Still-Gennari olefination general discussion Julia olefination and heteroaryl variants within the Corey-Winter olefination prostaglandin Peterson olefination synthesis Barton extrusion reaction Tebbe olefination / other methylene-forming reactions tetrodotoxin hirstutene / Selenoxide elimination tetrodotoxin Burgess dehydration problem set # 3 Electrocyclic reactions and related transformations Diels-Alder reaction problem set # 1 Asymmetric Diels-Alder reaction prostaglandin Ene reaction problem set # 3 1,3-dipolar cycloadditions various [2,3] sigmatropic rearrangement various Cope rearrangement periplanone Claisen rearrangement hirstutene Oxidations – Also See Handout # 1 Swern-type oxidations (Swern / Moffatt / Parikh-Doering etc. N1999A2 Jones oxidation
    [Show full text]
  • Elimination Reactions Are Described
    Introduction In this module, different types of elimination reactions are described. From a practical standpoint, elimination reactions widely used for the generation of double and triple bonds in compounds from a saturated precursor molecule. The presence of a good leaving group is a prerequisite in most elimination reactions. Traditional classification of elimination reactions, in terms of the molecularity of the reaction is employed. How the changes in the nature of the substrate as well as reaction conditions affect the mechanism of elimination are subsequently discussed. The stereochemical requirements for elimination in a given substrate and its consequence in the product stereochemistry is emphasized. ELIMINATION REACTIONS Objective and Outline beta-eliminations E1, E2 and E1cB mechanisms Stereochemical considerations of these reactions Examples of E1, E2 and E1cB reactions Alpha eliminations and generation of carbene I. Basics Elimination reactions involve the loss of fragments or groups from a molecule to generate multiple bonds. A generalized equation is shown below for 1,2-elimination wherein the X and Y from two adjacent carbon atoms are removed, elimination C C C C -XY X Y Three major types of elimination reactions are: α-elimination: two atoms or groups are removed from the same atom. It is also known as 1,1-elimination. H R R C X C + HX R Both H and X are removed from carbon atom here R Carbene β-elimination: loss of atoms or groups on adjacent atoms. It is also H H known as 1,2- elimination. R C C R R HC CH R X H γ-elimination: loss of atoms or groups from the 1st and 3rd positions as shown below.
    [Show full text]
  • Studies in Directed Catalytic Asymmetric Hydroboration of 1,2-Disubstituted Unsaturated Amide
    University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Student Research Projects, Dissertations, and Chemistry, Department of Theses - Chemistry Department Summer 7-2017 STUDIES IN DIRECTED CATALYTIC ASYMMETRIC HYDROBORATION OF 1,2-DISUBSTITUTED UNSATURATED AMIDE Shuyang Zhang University of Nebraska - Lincoln, [email protected] Follow this and additional works at: http://digitalcommons.unl.edu/chemistrydiss Part of the Organic Chemistry Commons Zhang, Shuyang, "STUDIES IN DIRECTED CATALYTIC ASYMMETRIC HYDROBORATION OF 1,2-DISUBSTITUTED UNSATURATED AMIDE" (2017). Student Research Projects, Dissertations, and Theses - Chemistry Department. 85. http://digitalcommons.unl.edu/chemistrydiss/85 This Article is brought to you for free and open access by the Chemistry, Department of at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Student Research Projects, Dissertations, and Theses - Chemistry Department by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. STUDIES IN DIRECTED CATALYTIC ASYMMETRIC HYDROBORATION OF 1,2- DISUBSTITUTED UNSATURATED AMIDE by Shuyang Zhang A THESIS Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Master of Science Major: Chemistry Under the Supervision of Professor James M. Takacs Lincoln, Nebraska July 2017 DIRECTED CATALYTIC ASYMMETRIC HYDROBORATION OF 1,2- DISUBSTITUTED ALKENES Shuyang Zhang, M.S. University of Nebraska 2017 Advisor: Professor James M. Takacs The Rh-catalyzed, substrate directed catalytic asymmetric hydroboration of γ,δ-unsaturated amides provides a direct route to enantioenriched acyclic secondary γ- borylated carbonyl derivatives with high regio- and enantioselectivity. The catalytic condition optimization and substrate scope study is discussed, including the effects in catalytical asymmetric hydroboration on pre-installed chiral γ,δ-unsaturated amides.
    [Show full text]
  • The Wittig Reaction
    UC Berkeley College of Chemistry Chemistry 112B Organic Chemistry The Wittig Reaction Author: Jonathan Melville Graduate Student Instructor: Rebecca Triano March 13, 2014 1 Introduction The Wittig reaction, discovered in 1954 by Georg Wittig, is one of the most common tech- niques used for the stereoselective preparation of alkenes. Broadly speaking, the reaction allows for the formation of an alkene product and a triphenylphosphine oxide side product from the reaction of an aldehyde or ketone and a \Wittig reagent" (a triphenylphospho- nium ylide). In our experiment, we formed methyl (2E)-3-(2-nitrophenyl)acrylate and triphenylphosphine oxide from the reaction of 2-nitrobenzaldehyde and methyl (triph- enylphosphoranylidene) acetate. The key step of the mechanism of the ylide reaction is the nucleophilic addition of the ylide to the electrophilic carbonyl group, forming a 4-membered ring that dissociates into the product molecules. The stereoselectivity of the reaction is predicated on the stability of triphenylphosphonium ylide, which determines which of two ring intermediates form: the sterically-unfavored cis intermediate that forms via a fast yet reversible process, or the slow, irreversible trans intermediate. Because ylides contain (by definition) adjacent positive and negative charges (a positive on the phosphonium, and a negative on the carbon adjacent to the residue), R groups that can better stabilize the adjacent negative charge produce more stable ylides. We can thus classify three distinct levels of stabiliza- tion of the ylide by its residue: neutral substituents that do not stabilize negative charge (like alkyl groups or hydrogens) produce an unstabilized ylide that preferentially forms cis product, whereas electron-withdrawing residues (like nitro or ester groups) stabilize the charge and preferentially form trans product, while \semi-stabilized" substituents (generally aromatic rings) produce a mixture of the two.
    [Show full text]
  • Tandem-, Domino- and One-Pot Reactions Involving Wittig- And
    DOI: 10.5772/intechopen.70364 Provisional chapter Chapter 1 Tandem-, Domino- and One-Pot Reactions Involving Wittig- and Horner-Wadsworth-Emmons Olefination Tandem-, Domino- and One-Pot Reactions Involving Wittig- and Horner-Wadsworth-Emmons Olefination Fatima Merza, Ahmed Taha and Thies Thiemann Fatima Merza, Ahmed Taha and Thies Thiemann Additional information is available at the end of the chapter Additional information is available at the end of the chapter http://dx.doi.org/10.5772/intechopen.70364 Abstract The Wittig olefination utilizing phosphoranes and the related Horner-Wadsworth- Emmons (HWE) reaction using phosphonates transform aldehydes and ketones into substituted alkenes. Because of the versatility of the reactions and the compatibility of many functional groups towards the transformations, both Wittig olefination and HWE reactions are a mainstay in the arsenal of organic synthesis. Here, an overview is given on Wittig- and Horner-Wadsworth-Emmons (HWE) reactions run in combination with other transformations in one-pot procedures. The focus lies on one-pot oxidation Wittig/HWE protocols, Wittig/HWE olefinations run in concert with metal catalyzed cross-coupling reactions, Domino Wittig/HWE—cycloaddition and Wittig-Michael transformations. Keywords: Wittig olefination, one-pot reactions, Domino reactions, tandem reactions, Horner-Wadsworth-Emmons olefination 1. Introduction The Wittig olefination utilizing phosphoranes and the related Horner-Wadsworth-Emmons (HWE) reaction using phosphonates transform aldehydes and ketones into substituted alkenes. Because of the versatility of the reactions and the compatibility of many functional groups in the transformations, both Wittig olefination and HWE reactions are a mainstay in the arsenal of organic synthesis. The mechanism of the Wittig olefination has been the subject of intense debate [1].
    [Show full text]
  • Investigation of Factors Influencing the Stereochemistry of the Wittig Reaction
    THE INVESTIGATION OF FACTORS INFLUENCING THE STEREOCHEMISTRY OF THE WITTIG REACTION By JEROME THOMAS KRESSE A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA December, 1965 ACKNOWLEDGMENTS The author wishes to express his appreciation to his research director, Dr. George B. Butler, for his guidance and encouragement during the execution of this work. The author also expresses his gratitude to his fellow graduate students and associates for their helpful suggestions and criticisms. Particular thanks are due Mrs. Frances Kost and Mrs. Thyra Johnston for their conscientious typing of this dissertation. The author also thanks his wife for her patience, encouragement and under- standing. Without her cooperation this work would not have been possible. The financial support of the Petroleum Research Fund is also gratefully acknowledged. TABLE OF CONTENTS PAGE ACKNOWLEDGMENTS ii LIST OF TABLES v LIST OF FIGURES vi CHAPTER I INTRODUCTION 1 Historical Background 1 Stereochemistry 9 Statement of the Problem 19 Method of Attack 20 H DISCUSSION AND RESULTS 22 Solvents 22 Temperature Effects 27 Reaction Times 33 Concentration Effects 34 Substituent Effects 37 Anion Effects 49 1, 4 -Addition and Isomerization 51 TABLE OF CONTEXTS (Continued) CHAPTER PAGE EI EXPERIMENTAL 54 Equipment and Data 54 Source and Purification of Materials 54 Solvents 55 Aldehydes " 57 Miscellaneous Chemicals 57 Preparation and Purification of Phosphonium
    [Show full text]
  • Application of Complex Aldol Reactions to the Total Synthesis of Phorboxazole B
    J. Am. Chem. Soc. 2000, 122, 10033-10046 10033 Application of Complex Aldol Reactions to the Total Synthesis of Phorboxazole B David A. Evans,* Duke M. Fitch,1 Thomas E. Smith, and Victor J. Cee Contribution from the Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138 ReceiVed June 29, 2000 Abstract: The synthesis of phorboxazole B has been accomplished in 27 linear steps and an overall yield of 12.6%. The absolute stereochemistry of the C4-C12,C33-C38, and C13-C19 fragments was established utilizing catalytic asymmetric aldol methodology, while the absolute stereochemistry of the C20-C32 fragment was derived from an auxiliary-based asymmetric aldol reaction. All remaining chirality was incorporated through internal asymmetric induction, with the exception of the C43 stereocenter which was derived from (R)-trityl glycidol. Key fragment couplings include a stereoselective double stereodifferentiating aldol reaction, a metalated oxazole alkylation, an oxazole-stabilized Wittig olefination, and a chelation-controlled addition of the fully elaborated alkenyl metal side chain. Introduction and HT29 (3.31 × 10-10 M), as well as leukemia CCRF-CBM (2.45 × 10-10 M), prostate cancer PC-3 (3.54 × 10-10 M), and Phorboxazoles A (1)andB(2) are marine natural products breast cancer MCF7 cell lines (5.62 × 10-10 M).2b In addition isolated from a recently discovered species of Indian Ocean to this impressive anticancer activity, phorboxazoles A and B sponge (genus Phorbas sp.) near Muiron Island, Western also exhibit potent in vitro antifungal activity against Candida Australia.2 These substances are representative of a new class albicans and Saccharomyces carlsbergensis at 0.1 µg/disk in of macrolides differing only in their C hydroxyl-bearing 13 the agar disk diffusion assay.2a stereocenters.
    [Show full text]
  • 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.
    [Show full text]
  • Olefination Reactions Lecture Notes OTBS OPMB O
    Olefination Reactions Lecture Notes OTBS OPMB O Key Reviews: O Me O Me XX Wittig Reaction K. C. Nicolaou and co-workers, Ann. 1997, 1283. Horner-Wadsworth-Emmons and Tebbe Olefinations S. E. Kelly, Comprehensive Org. Synth. 1991, Vol. 1, 729. Peterson Olefination D. J. Ager, Synthesis 1984, 384. Julia (Julia-Lythgoe) Olefination B. M. Trost, Bull. Chem. Soc. Jpn. 1988, 61, 107. Wittig Olefination: Background and Principles R1 n-BuLi, Ph P 3 O X LDA, R R1 LiHMDS PPh + 1 3 X Ph3P + R1 Ph3P pKa = 18-20 ylide when R = alkyl, H Ph Ph Ph Ph Ph R1 P Ph P -[Ph3P=O] O R1 O R strong bond 1 formation drives reaction oxaphosphatane betaine G. Wittig and G. Schollkopf, Chem. Ber. 1954, 87, 1318. Wittig Olefination: Background and Principles Stereoselectivity with non-stabilized ylides Me OMe Me Ph3P Ph3P Ph3P Me Ph3P Ph3P Not stable; must be made in situ and used immediately Wittig Olefination: Background and Principles Stereoselectivity with non-stabilized ylides Me OMe Me Ph3P Ph3P Ph3P Me Ph3P Ph3P Not stable; must be made in situ and used immediately Addition to carbonyl is an irreversible and concerted [2+2] cycloaddition such that the R groups on the aldehyde and the ylide are as far apart as possible PPh3 Ph3P O H H H O + Me Me Ph3P R O R H -[Ph3P=O] As the size of the R groups increases, selectivity for Z-alkene increases Me Nonpolar solvents favor initial addition Polar solvents favor the elimination Z-alkene Wittig Olefination: Background and Principles Stereoselectivity with stabilized ylides Me O O Ph P Ph3P 3 Ph3P Me OEt semistabilized Incredibly stable; not moisture sensitive, can be chromatographed Price for stability is lower reactivity: reacts well with aldehydes, slowly with ketones Wittig Olefination: Background and Principles Stereoselectivity with stabilized ylides Me O O Ph P Ph3P 3 Ph3P Me OEt semistabilized Incredibly stable; not moisture sensitive, can be chromatographed Price for stability is lower reactivity: reacts well with aldehydes, slowly with ketones Initial addition to carbonyl is reversible so the thermodynamic elimination product results.
    [Show full text]
  • University of California
    UC Riverside UC Riverside Electronic Theses and Dissertations Title Towards a Catalytic Asymmetric Cope Rearrangement and the Synthesis and Self-Assembly of Metal-Coordinated Hosts Permalink https://escholarship.org/uc/item/4gc654st Author Moehlig, Melissa Padilla Publication Date 2013 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA RIVERSIDE Towards a Catalytic Asymmetric Cope Rearrangement and the Synthesis and Self- Assembly of Metal-Coordinated Hosts A Dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Chemistry by Melissa Padilla Moehlig December 2013 Dissertation Committee: Dr. Richard J. Hooley, Chairperson Dr. Catharine H. Larsen Dr. Michael C. Pirrung Copyright by Melissa Padilla Moehlig 2013 The Dissertation of Melissa Padilla Moehlig is approved: Committee Chairperson University of California, Riverside ACKNOWLEDGEMENTS Graduate school has been one of the most rewarding and yet the most exhausting and stressful times of my life. It would not have survived without the help of several people. I would like to thank Dr. Courtney Meyet, Dr. Katherine Djernes, and Yoo-Jin Ghang for their friendship and all the laughs that were necessary to keep me sane. I would like to thank Michael Young, Hou Ung, and Jay-Ar Bendo for our morning coffee breaks, they were crucial to get my day started. I would like to thank Prof. Larsen for teaching me to be independent. I would like to thank Prof. Hooley for all his guidance over the past five years. You are truly a great mentor and I don’t think I would have survived graduate school without your help and advice.
    [Show full text]