GENERAL ARTICLE Retrosynthetic Analysis* Art of Planning Organic Synthesis Bharati V Badami Organic synthesis is a creative science involving the construc- tion of molecules via chemical processes. Organic synthesis has the ability to produce new materials continuously, hence, bestow us with. The invention, discovery and development of new synthetic reactions, reagents and catalysts are collec- tively referred to as synthetic technology/methodology or meth- od-oriented synthesis. E J Corey formalized the concept of Bharati V Badami was a ‘retrosynthetic analysis’ for the total synthesis of a large num- Professor of Organic ber of naturally occurring and bioactive molecules. Chemistry Karnatak University, Dharwad. Her research interests are 1. Introduction synthesis, reactions and synthetic utility of sydnones. She is currently working on electrochemical and The social impact of organic synthesis can be understood when insecticidal/antifungal we recount its applications in everyday life – food, medicine, activities for some of these clothes, fuels, polymers, dyes, paints, cosmetics, perfumes, engi- compounds. neering and high technology materials and many more. The vir- tually unlimited kingdom of chemicals of unimaginable sizes and shapes is due to the creativity and brilliance of synthetic chemists. The most important frontiers of chemistry today are related to the synthesis and development of advanced materials with de- sired properties. Every few years, the discovery of a new mate- rial/molecule with unusual properties triggers chemical research in a big way. Hence, synthesis remains a major activity of chem- istry. Keywords Retrosynthesis, synthetic plan- ning, transformation, retrosyn- From a historical perspective, the science of organic synthesis thetic tree. *DOI: https://doi.org/10.1007/s12045-019-0877-2 RESONANCE | October 2019 1071 GENERAL ARTICLE saw its dawn in the 19th century, when its beginning was marked by the synthesis of urea by the German chemist Friedrich Wöhler in 1828. There is no record of the Landmark achievements in organic synthesis were made by R thought processes which B Woodward who is recognized as the greatest synthetic organic led to the realization of chemist and is known as the ‘Father of organic synthesis’. The un- successful synthesis of complex molecules. The precedented and brilliant contributions by R B Woodward sharply synthetic routes were defined the synthetic field and set the pace for what was to come developed by selecting during the 2nd half of the 20th century. The glorious Woodward an appropriate era (1950–1960) will remain a turning point for the art and sci- commercially available starting material, ence of chemical synthesis. structurally resembling Milestones such as the total synthesis of quinine, cholesterol, cor- the desired molecule and building the other parts tisone, reserpine, chlorophyll, cephalosporin, vitamin B12 and of the molecule. strychnine were achieved by the brilliance of the synthetic chemists of that era. Woodward was awarded the Nobel Prize in 1965 for his ideas on the art of synthesis for the landmark synthesis of strychnine. The total synthesis of vitamin B12 completed in 1973, stands as a major achievement in organic synthesis. Along with these, the synthesis of penicillinV by Sheehan is historical. However, synthetic planning was not formulated on a systematic footing. The early design of synthetic routes for a vast number of simple and complex molecules was largely an intuitive operation. There is no record of the thought processes which led to the re- alization of successful synthesis of complex molecules. The syn- thetic routes were developed by selecting an appropriate com- mercially available starting material, structurally resembling the desired molecule and building the other parts of the molecule. But the difficulty in recognizing the available starting materials for many complex molecules called for a more systematic method for recognizing simpler molecules from which the required prod- uct could be obtained. The earlier strategy of Woodward et.al. was transformed by an- other great synthetic chemist E J Corey of Harvard University, who developed the theory and methodology of organic synthesis. 1072 RESONANCE | October 2019 GENERAL ARTICLE According to Corey, the synthetic planning should start with the final product, and one could work backwards towards the simple starting materials. Corey coined the term ‘retrosynthetic anal- ysis’ for this methodology in 1957. It is a process of working backwards from the target molecule in order to devise a suitable synthetic route. These imaginary backward reactions are known as ‘antithetical reactions.’ One noteworthy example is the application of retrosynthetic strat- egy by Corey for the synthesis of the stereochemically compli- cated natural molecule – prostaglandin. 2. Retrosynthetic Analysis The advent of retrosynthetic analysis constituted a major advance in the strategic planning of total synthesis of natural and complex compounds. Retrosynthetic analysis is a problem-solving technique for the synthesis of complex molecules. It is the art of planning organic synthesis by transforming the structure of the desired molecule to simple commercially available starting materials for its synthesis. E J Corey was awarded the Nobel Prize in 1990 for develop- ing newer synthetic methodologies leading to efficient synthetic routes, newer reactions and newer reagents which simplified the synthesis of prostaglandins and other complex molecules. Transformation of a molecule to its synthetic precursor is done by the imaginary disconnection of its bonds to progressively simple structures along a pathway which ultimately leads to simple or commercially available starting materials for the synthesis. At Retrosynthetic analysis each step, the availability of the intermediate is evaluated. is the exact reverse (antithetic) of a synthetic Retrosynthetic analysis is the exact reverse (antithetic) of a syn- reaction. However, the thetic reaction. However, the first notable example of a product first notable example of being transformed into its synthetic precursors was that of Robin- a product being transformed into its son’s tropinone synthesis. synthetic precursors was Tropinone was submitted to imaginary hydrolysis at the points that of Robinson’s tropinone synthesis. RESONANCE | October 2019 1073 GENERAL ARTICLE indicated by the dotted lines below and resolved into succinalde- hyde, methylamine and acetone. The precursors were identified from the starting material, and then a suitable path was devised to convert these starting mate- rials into the target molecule using known reactions. 2.1 Terms and Definitions 1. Target molecule (TM): The molecule to be synthesized. 2. Retrosynthetic analysis: The process of imaginary break down of a molecule into progressively simpler starting materials. The reactions are viewed in the retrosynthetic direction i.e., starting with the product and going back to the reactants along a pathway that is reverse of a synthetic direction. 3. Disconnection: Imaginary bond cleavage corresponding to the reverse of a forward reaction leading to the immediate precursor. This is also known as transformation and is indicated by a wavy line. 4. Retrosynthetic arrow: Disconnection is represented by a dou- ble line closed arrow which indicates the transformation of the molecule into its immediate precursor. 1074 RESONANCE | October 2019 GENERAL ARTICLE 5. Synthons: Synthons are the imaginary fragments obtained by disconnection. The concept of bond polarity with the fragments is of prime importance during disconnection. Synthons are not real compounds but are idealized ionic or neutral fragments, and they are not reagents. The following reaction shows a concerted cycloaddition reaction, where the synthons are neutral fragments. 6. Retron: Each reaction generates a characteristic structural ele- ment in the product, such as the enone resulting from aldol con- densation. This substructure, called the retron, must be present in a target molecule to be able to apply the corresponding trans- formation to that target. 7. Reagents: These are the actual source of the synthons. + ≡ + + ≡ + ≡ + NO2 HNO3 H2SO4;Br Br2;Cl Cl2 AlCl3 RESONANCE | October 2019 1075 GENERAL ARTICLE B) Alkyl ions – a) Alkyl cation (carbenium ion)− + − H + H2O + i) R − OH −→ R − O H2 −→ R Alcohol Alcl3 + ii) R − X −→ R + XAlCl¯ 3 Alkyl halide b) Alkyl anion (carbanion)− + R − M −→ R¯ + M organometallic compound carbanion C) Acyl ions a) Acyl cations + H + (i) R − CO − CH2 − X −→ R − CHO C H2 + HX (X = Cl or Br) Acyl halide −X¯ Acyl cation + H + (ii) R − CO − CH = CH2 −→ RCOC H − CH3 Enone Acyl cation b) Acyl anion Removal of a proton from a methylene group adjacent to a electron- withdrawing group. (i) − −→Base − ¯ R COCH3 + R COCH2 methyl keystones −H Base (ii) RCH2 − COOR −→ RCH¯ − COOR −H+ Base (iii) RCH2 − NO2 −→ RCH¯ − NO2 −H+ D) Ethoxy anion E) Aldehyde carbonyl as a cation and anion The aldehyde carbonyl carbon is electron deficient and undergoes nucleophilic attack. 1076 RESONANCE | October 2019 GENERAL ARTICLE The aldehyde carbonyl carbon can also undergo electrophilic at- tack when it is converted into an anion. The polarity of the elec- tron – deficient aldehyde carbonyl carbon can be reversed and this is known as ‘umpolung’. 8) Retrosynthetic tree It is a complex pattern of several or all possible retrosynthesis of a Retrosynthetic analysis single compound. Retrosynthetic analysis of a molecule may lead of a molecule may lead