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ERASMUS Intensive Program. SYNAPS: Synthesis and Retrosynthesis in the Chemistry of Natural Products July 2011 NATURAL PRODUCT CHEMISTRY Module 2 Retrosynthetic Approaches Towards the Synthesis of Natural Products DEPARTMENT OF CHEMISTRY UNIVERSITY OF CRETE.
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ERASMUS Intensive Program SYNAPS: Synthesis and Retrosynthesis in the Chemistry of Natural Products July 2011 NATURAL PRODUCT CHEMISTRY Module 2 Retrosynthetic Approaches Towards the Synthesis of Natural Products DEPARTMENT OF CHEMISTRY UNIVERSITY OF CRETE Lifelong Learning Program – Erasmus Hellenic National Agency LLP-Ι.Κ.Υ.
INTRODUCTIONBased on: S. Warren Organic Synthesis: The Disconnection Approach, Wiley: New York, 1982 • Chemists synthesize compounds in just about every organic chemistry laboratory in the world. • Industrial chemists synthesize pharmaceuticals, polymers (plastics), pesticides, dye stuffs, food colorings and flavorings, perfumes, detergents and disinfectants. • Research chemists synthesize natural products whose structure is uncertain, compounds for mechanistic investigations, possible intermediate in chemical and biological processes, thousands of potential drugs used in medical practice, and even compounds which might themselves be useful for organic syntheses. • Before and during these syntheses, groups of chemists sitting around blackboards or piles of paper plan the work they are about to undertake. Possible routes are drawn out, criticized, modified again when the behavior of the compounds in the flask turns out to be different from what was expected, until finally success is achieved. • The aim of this lecture is to show how this planning is done: to help you learn the disconnection or synthon approach to organic synthesis. • This approach is analytical: we start with the molecule we want to make (the target molecule) and break it down by a series of disconnection into possible starting materials.
Classifications in Synthetic Methodology Based on “Lecture Notes, Modern Organic Synthesis” by Dale L. Boger at The Scripps Research Institute, TSRI Press, La Jolla, CA, 1999
ROUTINE FOR DESIGNING A SYNTHESIS • ANALYSIS • Define the target molecule • Recognize the functional groups in the target molecule • Disconnect using as a guide methods corresponding to known reactions • Repeat the Retrosynthetic Analysis till you reach available starting materials • SYNTHESIS • Write down a synthetic scheme based in the Retrosynthetic Analysis adding reagents and reaction conditions. • If the synthesis fails, modify the synthetic scheme based on the failures/successes in the laboratory experiments.
SYNTHONS AND REAGENTS • During the retrosynthetic analysis of compound 2 the retrosynthetic cleavage (or disconnection) leads to a nucleophile(-) and an electrophile (+). The correct alternative, based in known chemical transformations, is in this case leading to 3 and 4. After the right choice has been made, the synthons may be converted retrosynthetically in to the corresponding reagents.
ONE GROUP DISCONNECTIONSBased on: S. Warren Organic Synthesis: The Disconnection Approach, Wiley: New York, 19821.1 Carbonyl derivatives R(C=O)X
TWO GROUP DISCONNECTIONS 2.3.2 a, b-Unsaturated Carbonyl Compounds (Aldol and Dehydration)
TWO GROUP DISCONNECTIONS 2.3.3. 1,3-Dicarbonyl Compounds (Claisen-Type Reactions)
TWO GROUP DISCONNECTIONS 2.4 1,4-Difunctionalized Compounds 2.4.1 2.4.1 1,4-Dicarbonyl Compounds (Enolates and a-Halocarbonyls)
TWO GROUP DISCONNECTIONS • 2.4.2 g-Hydroxy Carbonyl Compounds (Enolates and Epoxides)
TWO GROUP DISCONNECTIONS • 2.5 1,5-Difunctionalized Compounds • 2.5.1. 1,5-Dicarbonyl Compounds (Michael Reaction)
TWO GROUP DISCONNECTIONS • 2.6 1,6-Difunctionalized Compounds • 2.6.1. 1,6-Dicarbonyl Compounds (Ozonolysis of Cyclohexenes)
3. Regioselectivity • Mechanistic Principles • Michael products are the thermodynamic products since the more stable C=O bond is preserved and the weaker C=C bond reacts. • Direct addition is more easily reversed than the Michael addition. Therefore, the more stable the Nucleophile the more the Michael addition is favored. • Kinetically the C=O carbon is the hard site and the beta carbon is the soft one. Therefore, RLI, NH2-, RO-, H-, attack on the carbonyl and RMgBr, R3N, RS-, and stable carbanions tend to give the Michael type products.
4. Chemoselectivity Guideline 7: When the two groups are almost but not quite identical, avoid attempts to react only one of them.
