PLANNING OF ORGANIC SYNTHESISBy Bapu R. Thorat M.Sc. SET. NET Assit. Professor Dept of Chemistry & Dept of Biotechnology, Government of Maharashtra, Ismail Yusuf College of Arts, Science and Commerce, Jogeshwari (East), Mumbai - 60 Planning of organic synthesis The major goal of the organic synthesis is the construction of organic molecules (target molecule) and their synthesis by applying various synthetic strategies. The choice of target molecule is the starting of synthesis. Research Selection of Target molecule During the selection of target molecule, Scientist suggested that- what is most important is not a choice of a given target, but how the goal is going to be achieved is important. Why this molecule is choose as target or final molecule? How it can be synthesized? 1. Why this molecule was chosen as a target molecule? And 2. Where do I begin? How? Planning of organic synthesis The answer of the question (1) is 1. The need and interest of the synthetic chemist. 2. It may have challenging stereochemical problems or functional group combinations. 3. The molecule may possess unique chemical and or biological properties. 4. The challenging problem in the total synthesis of given target molecule provides many opportunities to find new reactions, process or strategies which may be of value to other reactions. 5. The learning opportunity. 6. More global and important regarding the destination and usefulness of pure science. 7. Does not immediate benefits to humanity, but in foreseable feature. Industrial application. 8. Necessary to eliminate toxic effect, explosive material, minimize the hazardous effect, etc Need and Interest Selection of target molecule Challenging Stereochemical & Functional gr. Combination Unique chemical & biological property Provides opportunities to find new reactions, process & strategies Learning opportunity Global & important in pure science To eliminate side effect Useful in feature & industrial applications Planning of organic synthesis • • • • • • The chemical reaction can be viewed in two directions – the synthetic direction corresponding to laboratory operations and the retrosynthesis (or antithetic). Retrosynthesis gives the answer of the second question- Where do I begin? These simple molecules are obtained by the degradation of the molecule which will be synthesized is called as retrosynthesis. It is a technique completely theoretical and used for solving problems in synthesis planning, especially those represented for complex problems. Required well trained eyes of professional to identify the fragment(s) present in the complex target molecule which is to be derived. Elias James Corey (Nobel Price in Chemistry 1990) N OH Where do I begin? HO T.M. O These simple molecules are obtained by the degradation of the molecule which will be synthesized. Retrosynthesis HO O O O Theoretical and used for solving problems in synthesis planning O Planning of organic synthesis The target molecule can be fragmented to by more than one way to gives simple starting molecule by starting disconnection from any site of the complex molecule. The starting molecule is- simple, small, easily available (fossile sources, nature, leaving organism), chief. This starting material was converted into product by applying your knowledge of reactions, reagents, synthetic and analytical methods. For transforming one to another intermediate, following parameters are considered i. The selection of chemical reaction for transforming one synthetic intermediate to next in the synthesis. ii. The selection of specific reagent. iii. The design of experiment. iv. Experimental conditions and analysis. O Ph O2N O O Target Molecule O Ph O2N OH O O Ph O2N O O2N O O TM H O O O2N H O OH O2N O OH H OH O2N H For all these stages- observations, discoveries (experimental results taken for references), inventions, and theorems are very important. Therefore someone can achieve their target in small period or even longer term basis. Ref: Elias James Corey brought a more formal approach to synthesis design based on retrosynthesis analysis for which he won the noble prize for chemistry in 1990. C2 H5 HO H C2 H5 H OH H H O The organic synthesis has been designed by the concept retro-synthesis. Retrosynthesis is used to developed synthetic route to a target molecule. Multistep synthesis of the complex target molecule from specified starting material becomes one of the most challenging problem. The design of the synthesis of simple molecule is very simple. E.g.- Synthesis of meso-3,4-hexanediol from 3-hexyne, most of students realized that alkyne was reduced to cis or trans-3hexene and then undergoes glycol formation. Therefore, there is more than one procedure for the synthesis of desired product. 3-Hexyne transH H CaC2 Na/liq.NH3 H3O+ 3-Hexyne m-CPBA H H O Lindlar cat. or 9-BBN/AcOH H3O+ C2H5 HO C2H5 H H OH cis- 1 OsO4 2 NaHCO3 Planning of Organic Synthesis Organic synthesis is the construction of a organic molecule via chemical processes or reaction. The synthesis of a organic molecule is difficult as compared to inorganic molecules in various aspects such as yield, purity, time etc. There are two areas of research in general of organic synthesis are- Total synthesis and methodology. Construction of carbon skeleton of target molecule Carried out the synthesis in minimum number of steps Construct the synthesis before carried out actual synthesis Introducing, removing & transforming functional groups Principles of Organic Synthesis Try to maintain stereochemistry of product of each step Functional group is less reactive, increase yield by using activating group To avoid side product or to protect the group use protecting groups Planning of Organic Synthesis Recovery or recycling of expensive reagents/ catalyst and less number of side products Starting compounds & reagents are cheaf & easily available. Principles of Organic Synthesis Used named reported reactions and reagents for the synthesis of new compounds because the yield, reaction conditions, by-products, reagents, etc are known. Functional groups are altered, without change the carbon skeleton of starting material or change both functional group and carbon skeleton or without affecting the functional group, carbon skeleton can be changed. OH Et H NH NH H Et H OH OH Et NH NH Et H OH (S,S) -isomer Tuberculostatic (R,R)-isomer Cause blindness Ethambutol OH OH OH OH HNCOCHCl2 HNCOCHCl2 O2N O2N (R,R)-isomer antibacterial Chloromycetin (S,S)-isomer inactive O S NH R O OH R CO2H HS H2N H S HS H2N Anti-arthritic Penicillamine Toxic CO2H H S - isomer, beta -blocker Propranalol OH R - isomer, Contraceptive NH Area of research in Organic Synthesis Total Synthesis Methodology A total synthesis is the complete chemical synthesis of complex organic molecules from simple, commercially available (petrochemical) or natural precursors. The choice of target molecule is the starting of synthesis. The target molecule can be synthesized in a series of steps which are performed one after another until the molecule is made is called as linear synthesis. It is applied for the synthesis of simple structure molecules. The chemical compounds made in each step are usually referred to as synthetic intermediate. For the synthesis of more complex molecules, convergent synthesis is often preferred. In this synthesis, several key intermediates are synthesized separately and then coupled together to give final product. The father of modern organic synthesis is regarded as Robert Burns Woodward who received Nobel Price for chemistry in 1965 for several brilliant examples of total synthesis such as synthesis of strychnine in 1954. Convergent synthesis Divergent synthesis Diversity oriented synthesis (DOS) Total synthesis Carbon-carbon bond formation Polar functions and Umpolung Cascade reaction sequences Multistep Transformation 1. Convergent synthesis In chemistry, a convergent synthesis is a strategy that aims to improve the efficiency of multi-step chemical synthesis. It is more convenient than the linear synthesis. Linear synthesis:- A 80% 80% 80% B 80% E D C 80% F Overall yield is 32.8% (3.1% if 50% each step) Convergent synthesis:- 80% A 80% U B 80% C 80% V W 80% F Overall yield is 51.2% (12.5% if 50% each step) 2. Divergent synthesis Divergent synthesis is a strategy with the aim to improve the efficiency of chemical synthesis. It is an alternative to convergent or linear synthesis. In one strategy, divergent synthesis aims to generate a library of chemical compounds by first reacting a molecule with a set of reactants. The next generation of compounds is generated by further reactions of another reagent with each compound in generation first. This methodology gives large number of new compounds. A generates A1, A2, A3, A4, A5, ……… in generation first. A1 generates A11, A12, A13, A14, A15, ……… in generation 2 and so on. In another strategy, divergent synthesis starts from a molecule as a central core from which generation of building blocks are added. e.g.:- Synthesis of dendrimers (in each generation new monomer reacts to the growing surface of the sphere). 3. Diversity oriented synthesis (DOS) DOS is a strategy for quick access to molecular libraries with an emphasis on skeleton diversity. In following example- A Petasis reaction product (1) is functionalized with propargyl bromide leading to starting compound (2) having five functional groups. This molecule can be subjected to whole set of reagents, each reaction yielding a unique skeleton already in generation one. Ph Ph During this synthesis, in a majority of reactions involving a functional group modifications, proceeding or following smaller number of carbon-carbon bond forming reactions because functional group chemistry consist of such a vast number of addition, elimination, substitution, rearrangement, free radical, pericyclic, redox, etc reactions. Ph N EtOOC N O COOEt N Ph OH Ph H Ph 3.81% OH OH 9.87% H 4.89% Ph Ph Ph COOEt HN N COOEt Br N EtOOC Ph Ph Ph OH OH OH H H 5.85% Ph Ph O O Ph N N O H Ph 8.88% H N EtOOC Ph OH COOEt O Ph 6.85% H O 7.85% During the synthesis, a stereochemistry of a product try to maintain along with regio- and stereo-control is important during this functional group modification. 4. Carbon-carbon bond formation Numbers of useful and well tested reactions are reported for the effective carbon-carbon bond formation, ideally in regio and stereospecific fashion. These reactions are relatively small as compared with the reactions used to modify the functional groups. Friedel-Craft alkylation and acylation. Robinson Annulation Addition of organometallic compounds to unsaturated compounds Diels-Alder cycloaddition C-C bond formation Wittig and other ylide reactions Alkylation of Acetylide anions Claisen, Aldol, Dickmann condensation, Reimer-Tiemann reaction, etc Alkylation of enolate anions 4. Carbon-carbon bond formation Coupling reactions carried out by using transition metal catalysts Addition of carbon radicals to multiple bonds C-C bond formation Photochemical cycloaddition and rearrangement reactions Reaction of transition metal alkylidene complexes e.g. Olefin metathesis In addition to development of these and other new reactions, many classic procedures have been modified and enhanced in scope byControl of regio and stereo-selectivity during the formation of reaction intermediates. Charge inversion in polar reactants, Umpolung. Applications of Tandem, Domino or Cascade reaction sequences. IF ONE CAN DO, I CAN ALSO DO, IF NONE CAN DO, I MUST DO……