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Organic Synthesis: Total Synthesis of Target Molecules

Organic Synthesis: Total Synthesis of Target Molecules. Strategies & Tactics. Classification of Organic Synthesis. Linear Synthesis : tedious, inefficient but could be simple ex.) DNA, Peptide Synthesizer.

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Organic Synthesis: Total Synthesis of Target Molecules

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  1. Organic Synthesis: Total Synthesis of Target Molecules Strategies & Tactics

  2. Classification of Organic Synthesis • Linear Synthesis : tedious, inefficient but could be simple • ex.) DNA, Peptide Synthesizer 2. Convergent Synthesis -- economic, time saving 3. Divergent Synthesis -- SAR, Combichem. 4. Biosynthesis driven Synthesis -- biomimetic synthesis 5. Symmetry considered synthesis -- simplification 6. Systematic Synthetic analysis and design

  3. Linear Synthesis 2. Convergent Synthesis

  4. 3. Divergent Synthesis : medicinal, combinatorial chemistry Templates : a scaffold with several attachment points --- increases diversity

  5. 4. Biomimetic Synthesis

  6. Tropinone Roboinson “Mannich reaction” Willstatter

  7. Steroids biosynthesis Van Tamelen JACS, 1972, 94, 8229

  8. Steroids W.S. Johnson JACS 1970, 92, 4461 JACS 1987, 109, 5852

  9. Endiandric acids K. C. Nicolaou see classics in total synthesis

  10. Alkaloid C.H. Heathcock see PNAS 1996, 63, 14323

  11. Alkaloid C.H. Heathcock see PNAS 1996, 63, 14323

  12. 5. Symmetry Considered Synthesis G. Stork, JACS 1959, 81, 5516

  13. Mc Murry coupling JACS, 1974, 96, 4708

  14. ACIE, 2001, 40, 761

  15. Cf.) meso compound A.B. Smith, JACS, 2000, 122, 4984

  16. Pseudo Symmetry or Hidden Symmetry O. Chapman JACS 1971, 93, 6696 Biomimetic(?) : M. Matsmoto, TL 1981, 22, 4437

  17. JCS CC, 1985, 48

  18. JACS 1978, 100, 4208 AC, 1957, 69, 69

  19. Assignment calycanthine

  20. Assignment

  21. Synthetic Analysis 1. Substructure correlation to starting material • Protein ----- amino acids • oligosaccharide ----- carbohydrates • Organics ----- Terpene • indole • arene Chiral pool Stereo centers in Target See “ Total synthesis of natural product: “chiron” approach by S. Hanessian “Enantioselective synthesis : natural products from chiral terpene by T. L. Ho

  22. JACS, 1978, 100, 8272

  23. JACS, 1985, 107, 7771

  24. Chiral Terpenes

  25. Synthetic Analysis 2. Process recognition ---- reaction recognition : “ disconnection approach” H+ Endo olefin is preferred

  26. Synthetic Analysis 3. TOPOLOGICAL ANALYSIS : independent of reactions i) cyclopropane Translate to chemical analysis 예 )

  27. ii) Cyclobutane Translate to chemical analysis

  28. ii) Cyclopentane Translate to chemical analysis Pauson-Khand

  29. ii) Cyclohexane 10 possible Translate to chemical analysis

  30. ii) Cycloheptane 14 possible, only 3 considered Translate to chemical analysis unknown

  31. ii) Cyclooctane Translate to chemical analysis Not good

  32. Strategies of Retrosynthetic Analysis • Transform based approach : disconnection approach – need knowledge of rxn. • Structure goal strategy : requires high imagination • Topological strategy : simple rules to disconnect – no need to know rxn. • Stereochemical strategy : linear compounds Ultimate Goal --- Computer Aided Synthetic Design

  33. Strategic bond : a bond being disconnected during retrosynthesis Science, 1985, 228, 408

  34. To achieve maximum simplification ---

  35. Exceptions to the strategic bond analysis Strategic bond Non-Strategic bond Natural synthetic pathway

  36. Exceptions to the strategic bond analysis has no strategic bond !?! Volhardt found a new reaction

  37. Molecular Complexity & Synthetic Analysis Based on Molecular complexity index : S. Bertz JACS, 1981, 103, 3599 Basic Idea S P Low complexity High complexity Intermediates should stay close to S Rule of maximum simplicity Definition CT = C(n) + C(E) C : complexity of a molecule CT : total complexity C(n) : skeletal complexity – pure complexity C(E) : elelmental complexity -- chemistry

  38. Molecular Complexity & Synthetic Analysis a) Skeletal complexity ** Graph theory : index of complexity of skeleta Define Nij : # ofdistinct ways in which skeleton i can be cut out of skeleton j : N23 = 3 : N24 = 4 : N34 = 4 i.e. N2j : # ofways to cut propane out of a skeleton

  39. Molecular Complexity & Synthetic Analysis N2j = 13 Another way to look at it. ---- “ bond connectivity “ N2j 3 Reflects Complexity of structures 4 6 5 12

  40. Molecular Complexity & Synthetic Analysis For multiple bonds N2j 1 3 3 1 9 In another sense Molecular connectivity : M Bond connectivity : M’ = B(M) ~ N2j

  41. Molecular Complexity & Synthetic Analysis Definition h : # of connections i.e. h =N2j Now we need to consider chirality & stereochemistry Symmetry ------ equivalent class Borrow idea from information theory Information content : ni : # of points in ith set of equivalent points, n =Sni Relative complexity of a graph.

  42. Molecular Complexity & Synthetic Analysis problem h : # of connections i.e. h =N2j When everything is equivalent , I = 0 New definition of skeletal complexity : C(n) = 2nlog2n – Snilog2ni examples

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