24a synthesis


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24a synthesis

  1. 1. 24-24-11 Diels-Alder ReactionDiels-Alder Reaction Diels-Alder reaction:Diels-Alder reaction: A cycloaddition reaction of a conjugated diene and certain types of double and triple bonds. • dienophile:dienophile: Diene-loving. • Diels-Alder adduct:Diels-Alder adduct: The product of a Diels-Alder reaction. Diels-Alder adduct3-Buten-2-one (a dienophile) 1,3-Butadiene (a diene) + O O 3-Buten-2-one (a dienophile) 1,3-Butadiene (a diene) + O O
  2. 2. 24-24-22 Diels-Alder ReactionDiels-Alder Reaction • Alkynes also function as dienophiles. • Cycloaddition reaction:Cycloaddition reaction: A reaction in which two reactants add together in a single step to form a cyclic product. Diels-Alder adductDiethyl 2-butynedioate (a dienophile) + 1,3-butadiene (a diene) COOEt COOEt COOEt COOEt
  3. 3. 24-24-33 Diels-Alder ReactionDiels-Alder Reaction • We write a Diels-Alder reaction in the following way: • The special value of D-A reactions are that they: 1. form six-membered rings. 2. form two new C-C bonds at the same time. 3. are stereospecific and regioselective. Note the reaction of butadiene and ethylene gives only traces of cyclohexene. Diene Dieno- phile Adduct
  4. 4. 24-24-44 Diels-Alder ReactionDiels-Alder Reaction • The conformation of the diene must be s-cis. s-trans conformation (lower in energy) s-cis conformation (higher in energy)
  5. 5. 24-24-55 Diels-Alder Reaction Steric RestrictionsDiels-Alder Reaction Steric Restrictions • (2Z,4Z)-2,4-Hexadiene is unreactive in Diels- Alder reactions because nonbonded interactions prevent it from assuming the planar s-cis conformation. (2Z,4Z)-2,4-Hexadiene s-trans conformation (lower energy) s-cis conformation (higher energy) methyl groups forced closer than allowed by van der Waals radii
  6. 6. 24-24-66 Diels-Alder ReactionDiels-Alder Reaction • Reaction is facilitated by a combination of electron-withdrawing substituents on one reactant and electron-releasing substituents on the other. CyclohexeneEthylene1,3-Butadiene 200°C pressure 3-Buten-2-one 140°C + 1,3-Butadiene O O + 2,3-Dimethyl- 1,3-butadiene + 30°C 3-Buten-2-one O O
  7. 7. 24-24-77 Diels-Alder ReactionDiels-Alder Reaction Electron-Withdrawing Groups Electron-Releasing Groups -C N (cyano) - OR (ether) - OOCR (ester) - CHO (aldehyde, ketone) - COOH (carboxyl) - COOR (ester) - NO2 (nitro) - CH3, alkyl groups
  8. 8. 24-24-88 Diels-Alder ReactionDiels-Alder Reaction • The Diels-Alder reaction can be used to form bicyclic systems. + room temperature 170°C Diene Dienophile Dicyclopentadiene (endo form) H H
  9. 9. 24-24-99 Diels-Alder ReactionDiels-Alder Reaction • Exo and endo are relative to the double bond derived from the diene. the double bond derived from the diene endo (inside) exo (outside) relative to the double bond
  10. 10. 24-24-1010 Diels-Alder ReactionDiels-Alder Reaction • For a Diels-Alder reaction under kinetic control, endo orientation of the dienophile is favored. Methyl bicyclo[2.2.1]hept-5-en- endo-2-carboxylate (racemic) Methyl propenoate Cyclopentadiene + OCH3 O H COOCH3 COOCH3 redraw 1 2 3 45 6 7
  11. 11. 24-24-1111 Diels-Alder ReactionDiels-Alder Reaction • The configuration of the dienophile is retained. COOCH3 COOCH3 COOCH3 COOCH3 A cis dienophile) Dimethyl cis-4-cyclohexene- 1,2-dicarboxylate + COOCH3 H3 COOC COOCH3 COOCH3 A trans dienophile) Dimethyl trans-4-cyclohexene- 1,2-dicarboxylate (racemic) +
  12. 12. 24-24-1212 Diels-Alder ReactionDiels-Alder Reaction • The configuration of the diene is retained. CH3 CH3 CH3 O O O O O O O O O H3 C H3 C O O OH3C H3 C CH3 + + H H H H Check that this is endo.
  13. 13. 24-24-1313 Diels-Alder ReactionDiels-Alder Reaction Mechanism • No evidence for the participation of either radical of ionic intermediates. • Chemists propose that the Diels-Alder reaction is a concerted pericyclic reaction. Pericyclic reactionPericyclic reaction: A reaction that takes place in a single step, without intermediates, and involves a cyclic redistribution of bonding electrons. Concerted reaction: All bond making and bond breaking occurs simultaneously.
  14. 14. 24-24-1414 Diels-Alder ReactionDiels-Alder Reaction • Mechanism of the Diels-Alder reaction
  15. 15. 24-24-1515 Aromatic Transition StatesAromatic Transition States Hückel criteria for aromaticity:Hückel criteria for aromaticity: The presence of (4n + 2) pi electrons in a ring that is planar and fully conjugated. Just as aromaticity imparts a special stability to certain types of molecules and ions, the presence of (4n + 2) electrons in a cyclic transition state imparts a special stability to certain types of transition states. • Reactions involving 2, 6, 10, 14.... electrons in a cyclic transition state have especially low activation energies and take place particularly readily.
  16. 16. 24-24-1616 Aromatic Transition States,Aromatic Transition States, ExamplesExamples • Decarboxylation of β-keto acids and β- dicarboxylic acids. • Cope elimination of amine N-oxides. O O H O O H C O O O CO2+ enol of a ketone (A cyclic six-membered transition state) O heat + A cyclic six-membered transition state N,N-dimethyl- hydroxylamine C C H N CH3 CH3 N CH3 CH3 O HC C An alkene +
  17. 17. 24-24-1717 Aromatic Transition StatesAromatic Transition States • the Diels-Alder reaction • pyrolysis of esters (Problem 22.42) We now look at examples of two more reactions that proceed by aromatic transition states: • Claisen rearrangement. • Cope rearrangement. Diene Dieno- phile Adduct
  18. 18. 24-24-1818 Claisen RearrangementClaisen Rearrangement Claisen rearrangement:Claisen rearrangement: A thermal rearrangement of allyl phenyl ethers to 2- allylphenols. Allyl phenyl ether 200-250°C 2-Allylphenol O OH
  19. 19. 24-24-1919 Claisen RearrangementClaisen Rearrangement O Allyl phenyl ether heat OH o-Allylphenol O H A cyclohexadienone intermediate keto-enol tautomerism O Transition state
  20. 20. 24-24-2020 Cope RearrangementCope Rearrangement Cope rearrangement:Cope rearrangement: A thermal isomerization of 1,5-dienes. 3,3-Dimethyl- 1,5-hexadiene 2-Methyl-2,6- heptadiene heat
  21. 21. 24-24-2121 Cope RearrangementCope Rearrangement Example 24.8Example 24.8 Predict the product of these Cope rearrangements. (a) (b) 350°C OH H 320°C
  22. 22. 24-24-2222 Synthesis of Single EnantiomersSynthesis of Single Enantiomers • We have stressed throughout the text that the synthesis of chiral products from achiral starting materials and under achiral reaction conditions of necessity gives enantiomers as a racemic mixture. • Nature achieves the synthesis of single enantiomers by using enzymes, which create a chiral environment in which reaction takes place. • Enzymes show high enantiomeric and diastereomeric selectivity with the result that enzyme-catalyzed reactions invariably give only one of all possible stereoisomers.
  23. 23. 24-24-2323 Synthesis of Single EnantiomersSynthesis of Single Enantiomers How do chemists achieve the synthesis of single enantiomers? The most common method is to produce a racemic mixture and then resolve it. How? • the different physical properties of diastereomeric salts. • the use of enzymes as resolving agents. • chromatographic on a chiral substrate.
  24. 24. 24-24-2424 Synthesis of Single EnantiomersSynthesis of Single Enantiomers • In a second strategy, asymmetric inductionasymmetric induction, the achiral starting material is placed in a chiral environment by reacting it with a chiral auxiliarychiral auxiliary. Later it will be removed. • E. J. Corey used this chiral auxiliary to direct an asymmetric Diels-Alder reaction. • 8-Phenylmenthol was prepared from naturally occurring enantiomerically pure menthol. Me HO Me Me Me HO Me Me Ph 8-Phenylmenthol (an enantiomerically pure chiral auxillary) Menthol (enantiomerically pure) several steps
  25. 25. 24-24-2525 Synthesis of Single EnantiomersSynthesis of Single Enantiomers • The initial step in Corey’s prostaglandin synthesis was a Diels-Alder reaction. • By binding the achiral acrylate with enantiomerically pure 8-phenylmenthol, he thus placed the dienophile in a chiral environment. • The result is an enantioselective synthesis. OBn Me O Me Me Ph O ORO BnO RO O OBn + Diels-Alder + Enantiomerically pure 97% 3% 89% Achiral
  26. 26. 24-24-2626 Synthesis of Single EnantiomersSynthesis of Single Enantiomers • A third strategy is to begin a synthesis with an enantiomerically pure starting material. • Gilbert Stork began his prostaglandin synthesis with the naturally occurring, enantiomerically pure D-erythrose. • This four-carbon building block has the R configuration at each stereocenter. • With these two stereocenters thus established, he then used well understood reactions to synthesize his target molecule in enantiomerically pure form. HO H O OH OH D-Erythrose