Organic Synthesis


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Organic Synthesis

  1. 1. Retrosynthetic Analysis of Organic Synthesis <ul><li>Introduction </li></ul><ul><li>Synthetic Methods </li></ul><ul><li>Total Synthesis by Retrosynthetic Analysis </li></ul>
  2. 2. <ul><li> Retrosynthetic (or antisynthetic) analysis is a problem-solving technique for transforming the structure of a synthetic target (TG) molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. The transformation of a molecule to a synthetic processor is accomplished by the application of a transform, the extract reverse of a synthetic reactions. </li></ul><ul><li>E. J. Corey, 1989 </li></ul>
  3. 3. Retrosynthetic analysis Disconnection of T.M. Intermediate Starting material Synthesis tree
  4. 4. 3.2 Common terms in retrosynthetic analysis <ul><li>FGI ( functional group interconversion) </li></ul><ul><li>disconnection : ~~~~ position ;  process </li></ul><ul><li>synthons: fragments from disconnection </li></ul><ul><li>synthetic equivalents: reagents as synthons </li></ul>
  5. 5. Factors in Design of Synthesis <ul><li>Cheapest starting material </li></ul><ul><li>Least number of steps </li></ul><ul><li>High Yield </li></ul><ul><li>In commercial syntheses, costs of starting materials and economy of operations play a dominant role, whereas in many syntheses carried out for research purposes, the dispatch with which a compound can be obtained is more important. </li></ul>
  6. 6. Reactions involved in Synthesis <ul><li>Skeleton construction- construction from smaller units called synthons </li></ul><ul><li>Functional alteration- interconversion of the functional groups on the skeleton . </li></ul>
  7. 7. Major Ionic Reactions for Carbon
  8. 8. Pericyclic Reactions <ul><li>Diels-Alder Reaction </li></ul><ul><li>[2+2] Cycloaddition Reaction </li></ul><ul><li>Cope and Claisen Rearrangements </li></ul>
  9. 9. Rearrangements Useful in Synthesis
  10. 10. Criteria for Evaluating Synthetic Methods <ul><li>Convergent Synthesis- two or more fragments of the molecule are assembled separately and are then brought together at a late stage in the synthesis </li></ul><ul><li>Linear Synthesis – the molecule is constructed in a stepwise fashion. </li></ul>
  11. 11. Key Points in Designing Synthesis <ul><li>The relationship between functional groups in a target molecule may reveal disconnections in the retrosynthetic analysis. </li></ul><ul><li>Other disconnections may be revealed by functional group interconversions. </li></ul><ul><li>The identification of particular rings may suggest specific strategies </li></ul><ul><li>A convergent synthesis has significant advantages over a linear synthesis. </li></ul>
  12. 12. Grignard and related organometallic reagents <ul><li>Grignard reagents (RMgX) </li></ul><ul><li>Organozinc reagents </li></ul><ul><li>Alkyl- and aryl-lithium compounds </li></ul><ul><li>Organocopper reagents </li></ul><ul><li>Organopalladium reagents </li></ul>
  13. 13. Organometallic and Ylide Methods of Carbon-Carbon Bond Formation
  14. 14. Stereochemistry of Grignard Addition
  15. 15. Orthometallation Cross Coupling (Suzuki Rxn 1,4-Addition
  16. 16. Acetylides and Nitriles
  17. 17. Wittig Reaction
  18. 18. Carbonyl Activation and Enolate Chemistry in Carbon-Carbon Bond Formation
  19. 20. Regiospecificity in Enol Ether Formation
  20. 21. Carbanion Generators
  21. 22. Alkylation of Carbanion CH 3 -OSO 2 F methyl fluorosulfonate oxirane (epoxide) CH 3 -OSO 2 O-CH 3 dimethyl sulfate (R-OTs) toluene-p-sulfonates (or tosylates) R-OSO 2 CH 3 (R-OMs) methanesulfnates (or mesylates) R-X alkyl halide Structure Alkylating agent
  22. 23. Enolate Anions in Carbonyl Addition Reactions <ul><li>Aldol Condensation-the electron-deficient carbon is an aldehyde or ketone and the product is a  -hydroxy ketone or an  ,  -unsaturated ketone </li></ul><ul><li>Claisen Condensation- the electron-deficient carbon is an ester carbon and the product is a 1,3-diketone or  -keto ester. </li></ul><ul><li>Michael Condensation (addition)- the electron-deficient carbon is the b-carbon of an  ,  -unsaturated ketone and the product is a 1,5-diketone. </li></ul>
  23. 24. Aldol Condensation
  24. 25. Claisen Condensation
  25. 26. Michael Addition
  26. 27. 4. Robinson annulation - a special class of Michael additions which lead to one six-membered ring fused to another
  27. 28. Functional Group Interconversion <ul><li>Dehydrogenation Rxn- Sulfur, Selenium, DDQ, Chloranil </li></ul><ul><li>Oxidation of Alcohols- Chromium (VI), Swern Oxidation, Dess-Martin periodinane oxidation </li></ul><ul><li>Oxidation of alkenes-Epoxidation, O3, OsO4 </li></ul><ul><li>Bayer-Villiger Oxidation </li></ul>
  28. 29. General Pattern of Reduction
  29. 30. Reductions with Hydride Reagents
  30. 31. Carbocations in Synthesis <ul><li>Friedel-Craft Alkylation, Acylation </li></ul><ul><li>Prins Reaction- alkene (aromatic) + H 2 CO, conc. HCl, ZnCl 2 </li></ul><ul><li>Mannich Reaction- H 2 CO, N(CH 3 ) 2 , Ketone ( generate  ,  -unsaturated ketone ) </li></ul>
  31. 32. Free Radical and Pericyclic Reactions <ul><li>Benzoyl peroxide, AIBN (azobisisobutyronitrile) – Polymerization </li></ul><ul><li>AIBN/Bu 3 SnH – cyclization reaction </li></ul><ul><li>Carbene Formation- CH 2 I 2 , Zn/Cu (Simon-Smith Rxn) </li></ul>
  32. 33. Alkene Metathesis <ul><li>Grubb’s Catalyst- using this catalyst, the reaction between two alkenes, a=b and c=d, the bonding partners are interchanged to give a=c and b=d. </li></ul>
  33. 34. Protection Groups <ul><li>1. Protection of alcohol </li></ul><ul><li>a. Methylethers (allyl ether, benzyl ether, triphenylmethyl ether, methoxymethyl ether </li></ul><ul><li>b. Silyl ethers (trimethyl silyl, triethylsilyl, TBDMS </li></ul><ul><li>c. Protection of Carboxylic Acids </li></ul><ul><li>2. Protection of Carboxylic Acids </li></ul><ul><li>2,2,2-trichloroethyl ester </li></ul><ul><li> -(trimethylsilyl)ethoxymethyl ester </li></ul><ul><li>3. Protection of Carbonyl Groups </li></ul><ul><li>Formation of 1,3-dioxolanes from ethane-1,2-diol (provide selectivity for compounds containing two carbonyl groups </li></ul><ul><li>Formation of thioacetals from ethane-1,2-dithioacetal (needs Hg or Cd salts) </li></ul><ul><li>Amino Groups </li></ul><ul><li>N-terminal – Cbz or Z (benzyloxycarbonyl), Boc (t-butoxycarbonyl) – stable to basic condition </li></ul><ul><li>9-fluorenylmethoxycarbonyl (Fmoc)- acid stable but base labile </li></ul><ul><li>C-terminal- activation with DCC (Dicyclohexylcarbodiimide </li></ul>
  34. 35. Retrosynthesis
  35. 36. Synthesis