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Book: Logic of Organic Synthesis (Rao)

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  • The job of a synthetic chemist is akin to that of an architect. While the architect could actually see the building he is constructing, a molecular architect called chemist is handicapped by the fact that the molecule he is synthesizing is too small to be seen. With such a limitation, how does he ‘see’ the developing structure? For this purpose, a chemist makes use of spectroscopic tools. How does he cut, tailor and glue the components on a molecule that he cannot see? For this purpose chemists have developed molecular level tools called Reagents and Reactions. How does he clean the debris and produce pure molecules? This feat is achieved by crystallization, distillation and extensive use of Chromatography techniques. A mastery over several such techniques enables the molecular architect (popularly known as organic chemist) to achieve the challenging task of synthesizing the myriade of molecular structures encountered in Natural Products Chemistry, Drug Chemistry and modern Molecular Materials. In this task, organic chemists are further guided by several ‘thumb rules’ that chemists have evolved over the past two centuries.

    • 1: Synthesis of Organic Molecules
      The Art of synthesis is as old as Organic chemistry itself. Natural product chemistry is firmly rooted in the science of degrading a molecule to known smaller molecules using known chemical reactions and conforming the assigned structure by chemical synthesis from small, well known molecules using well established synthetic chemistry techniques.
    • 2: Rules and Guidelines Governing Organic Synthesis
      There are a few rules that provide guidelines for planning strategies in organic synthesis. These rules and guidelines have come from the keen observations of chemists after looking into several examples from their own research and other published work in the literature. These observations are to be treated as thumb-rules to be applied with caution. They may not be applicable for all situations. Nonetheless, they serve as guidelines to avoid pit-falls in planning.
    • 3: Criteria for Selection of the Synthetic Route
      Once a Target Molecule is chosen for synthesis, one could sit down and device several routes for its synthesis. On what criteria do you select a Target and how do you arrive at a synthetic route? The answer depends on the overall goal of your project.
    • 4: The Logic of Synthesis
      A sound knowledge of mechanistic organic chemistry, detailed information on the art and science of functional group transformations, bond formation and cleavage reactions, mastery over separation and purification techniques and a sound knowledge of spectroscopic analysis are all essential basics for the synthesis of molecules. A synthetic chemist should also be aware of developments in synthetic strategies generated over the years for different groups of compounds.
    • 5: Strategies in Disparlure Synthesis
      he gypsy moth (Porthytria dispar) is a serious pest of the forests. In 1976 B.A. Bierl, (Science, 170,88 (1970)) isolated the sex pheromone from extracts of 78,000 tips of the last two abdominal segments of female moths. The precursor molecule – the cis-olefin was also isolated from the same source.
    • 6: Strategies in (-)-Menthol Synthesis
      (-)-Menthol is amongst the most important perfume / flavor chemical, extensively used in pharmaceuticals, cosmetics, toothpastes, chewing gums and toiletries. Out a the estimated total production of about 20,000 m.tons, natural menthol accounts to about 13 m.tons, the rest coming from synthetic sources. The natural source - oil of Mentha Arvensis - being erratic due to dependence on monsoon, the demand for synthetic menthol is on the increase.
    • 7: Strategies in Longfolene Synthesis
      The synthesis of Longifolene has held the fascination of synthetic organic chemists for several decades. Since the compound was available in a pure form from natural sources in sufficient quantities, the fascination was purely academic. During structure elucidation studies, it was observed that this bridged structure underwent a host of migration reactions. These rearrangements were of interest both from theoretical and practical points of view.
    • 8: Strategies in Cedrene Synthesis
      Cedrene represents a very complex tricyclic sesquiterpene. Such complexity called for ingenious approaches for the total synthesis of the ring system. There are several syntheses reported for this ring system.
    • 9: Strategies in Reserpine Synthesis
      The structure of Reserpine was solved by 1953. R.B. Woodward’s group reported the first synthesis of Reserpine in 1956 (J. Am. Chem. Soc., 78, 2023, 2657 (1956); Tetrahedron, 2, 1 (1958)). His scholarly analysis clearly displayed aspects of retroanalysis, which was just evolving at that time. This synthesis commands admiration for the way he used conformational analysis and stereoelectronic effects to precisely develop the stereopoints in this exceedingly complex problem for that time.
    • 10: Strategies in Prostaglandins Synthesis
      Chemical Synthesis of Prostaglandins witnessed phenomenal activity during the 1960’s and 70’s. During this period, organic chemistry saw intensive development in ‘disconnection’ and ‘Logic’ as primary tools for synthesis. This period also saw development of several new reagents for stereoselective synthesis. The complexity of the structure of PG skeleton posed a great challenge for synthesis.
    • 11: Strategies in Steroids Synthesis
      Students should also become familiar with another convention followed by chemists to categorize synthetic schemes, originally evolved for steroids. Similar descriptions are also found in alkaloid chemistry. ‘An AB→ABC→ABCD Approach’ would mean that a naphthalene skeleton (either aromatic or suitable perhydro- skeleton) is chosen as SM. The C ring is then constructed on the AB rings. The D ring is then formed by ring closure.
    • 12: Woodward’s Synthesis of Chlorophyll
      The synthesis of Chlorophyll ‘a’ by R. B. Woodward1 is acclaimed was an outstanding achievement in organic synthesis and ranks amongst the shinning gems in synthesis. The preliminary analysis for the synthesis, the persistent planned attach on this complex, delicate chemistry by his school and the logic of the famous Woodwardian approach are all good lessons for any discerning student of Organic Synthesis.
    • 13: Synthesis of Vitamin B₁₂
      The total synthesis of Vitamin B₁₂ was accomplished in 1973 by a grand collaboration between R. B. Woodward’s group at Harvard University (USA) and A. Eschenmoser’s group, Swiss Federal Institute of Technology (ETH), Zürich, Switzerland. It took about twelve years and more than two dozen senior scientists to complete this gigantic task. The achievement is variously eulogized by organic chemists – monumental achievement in the annals of organic synthetic chemists.
    • 14: Green Chemistry - Protection-Free Organic Synthesis
      The hectic pace of developments in industrial chemistry has taken place at the cost of environment that is so vital for survival of life on earth. The onus of development of new molecules rests on us (chemists) and therefore the onus of responsible development is once again on our shoulders. Clean Chemistry (meaning Green Chemistry) depends on several factors – clean starting materials, clean reagents, clean solvents, clean product, clean energy and (not the least) clean processes.