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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 Strategies & Tactics
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
Linear Synthesis 2. Convergent Synthesis
3. Divergent Synthesis : medicinal, combinatorial chemistry Templates : a scaffold with several attachment points --- increases diversity
Tropinone Roboinson “Mannich reaction” Willstatter
Steroids biosynthesis Van Tamelen JACS, 1972, 94, 8229
Steroids W.S. Johnson JACS 1970, 92, 4461 JACS 1987, 109, 5852
Endiandric acids K. C. Nicolaou see classics in total synthesis
Alkaloid C.H. Heathcock see PNAS 1996, 63, 14323
Alkaloid C.H. Heathcock see PNAS 1996, 63, 14323
5. Symmetry Considered Synthesis G. Stork, JACS 1959, 81, 5516
Mc Murry coupling JACS, 1974, 96, 4708
Cf.) meso compound A.B. Smith, JACS, 2000, 122, 4984
Pseudo Symmetry or Hidden Symmetry O. Chapman JACS 1971, 93, 6696 Biomimetic(?) : M. Matsmoto, TL 1981, 22, 4437
JACS 1978, 100, 4208 AC, 1957, 69, 69
Assignment calycanthine
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
Synthetic Analysis 2. Process recognition ---- reaction recognition : “ disconnection approach” H+ Endo olefin is preferred
Synthetic Analysis 3. TOPOLOGICAL ANALYSIS : independent of reactions i) cyclopropane Translate to chemical analysis 예 )
ii) Cyclobutane Translate to chemical analysis
ii) Cyclopentane Translate to chemical analysis Pauson-Khand
ii) Cyclohexane 10 possible Translate to chemical analysis
ii) Cycloheptane 14 possible, only 3 considered Translate to chemical analysis unknown
ii) Cyclooctane Translate to chemical analysis Not good
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
Strategic bond : a bond being disconnected during retrosynthesis Science, 1985, 228, 408
Exceptions to the strategic bond analysis Strategic bond Non-Strategic bond Natural synthetic pathway
Exceptions to the strategic bond analysis has no strategic bond !?! Volhardt found a new reaction
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
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
Molecular Complexity & Synthetic Analysis N2j = 13 Another way to look at it. ---- “ bond connectivity “ N2j 3 Reflects Complexity of structures 4 6 5 12
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
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.
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