Retrosynthesis

This file includes Retrosynthesis introduction, principles, disconnection approach, functional group interconversion and relevant examples

1. RETROSYNTHESIS INTRODUCTION PRESENTED BY: A.S MADHU PRASANTH I st M.PHARM DEPARTMENT OF PHARMACEUTICAL CHEMISTRY JSS COLLEGE OF PHARMACY, MYSORE

2. INTRODUCTION 1 TERMINOLOGIES 2 FUNCTIONAL GROUP INTERCONVERSION 4 DISCONNECTION 3 5 CONTENTS APPLICATIONS

3. INTRODUCTION Retrosynthesis is the process of working backward from the target molecule in order to device suitable synthetic route. OR The process of mentally breaking down a molecule into a starting material. OR It is the problem solving technique for transforming the structure of a synthetic target molecule to a sequence of progressively simple structure along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. Retrosynthesis is denoted by meaning could be made from. It is different from the synthesis in which the normal synthesis is a forward process, starting from precursors and ending to form the target organic compound, whereas in retrosynthesis is a reverse process, starting from the target organic compound and going back to its relevant precursors. Retrosynthesis is used to a) To plan the synthesis of that organic compound. b) To know is there any synthesis path to the target. c) To increase the yield of the compound by choosing another synthesis strategy. C A + B Here the C is the compound where it can be synthesized from the precursors A and B.

4. TERMINOLOGIES Target molecule (TM) : The molecule whose synthesis is being planned. Usually written TM and identified by the frame number. Disconnection : An imaginary bon cleavage corresponding to a reverse of a real reaction. Functional group inversion (FGI) : The process of converting one functional into another by substitution, addition, elimination, reduction or oxidation. Synthon : Idealized fragment with an associated polarity (represented by a + or - ) resulting from a disconnection, which stand for reagents we are going to use in the forward synthesis. Synthon cannot itself be used, often because it is too unstable. Reagent : A real chemical compound used as equivalent of a synthon. It is also called as synthetic equivalents. Synthesis tree : Set of all the possible disconnections and synthons leading from the target to the starting material of a synthesis.

5. Some Synthons and Synthetic Equivalents : Synthons are classified into donor or acceptor synthons. The negatively polarized synthon is called as donor synthon and it denoted by “ d ”. The positively polarized synthon is called as acceptor synthon and it is denoted by “ a ”. We can classify the synthons further according to where the functional group is in relation to the reactive site. Some examples of synthons are : This synthon is corresponds to an aldehyde, we can an a 1 synthon because it is an acceptor that carries a functional group on the same carbon as its reactive center. It is an d 2 synthon because it is a donor whose reacting site is in the 2-position relative to the carbonyl group.

6. Some other synthons are a 2 and a 3 synthons in which the a 2 synthon is equivalent to the epoxide. Some synthons and their synthetic equivalents used are Synthons Synthetic Equivalents

7. PRINCIPLES The basic principles involved in the retrosynthesis are disconnection and functional group interconversion. DISCONNECTION: It is an imaginary bond cleavage, corresponding to the reverse of a synthetic reaction. As a result of disconnection usually negative ion and positive ion are formed which are called as synthons. Disconnection is shown by a wavy line like . The hardest task in designing a retrosynthetic analysis is spotting where to make the disconnections, so there are some guidelines. GUIDELINE – 1 Disconnections must correspond to known, reliable reactions and it’s the most important thing to bear in mind when working out a retrosynthesis. When we disconnect the ether we chose next to the oxygen atom because we know about the synthesis of ether. We chose not to disconnect on the aryl side of the oxygen atom because we know no reliable reaction corresponding to nucleophilic attack of an alcohol on an unactivated aromatic ring. GUIDELINE – 2 For compound consisting of two parts joined by a heteroatom, disconnect next to the heteroatom. In all the retrosynthetic analyses if there is a heteroatom (N, O, S) joining the rest of the molecule together, so in each case have to make the disconnection next to the N, O, S. This guideline works for esters, amides, ethers, amines, acetals, sulfides, and so on because these compounds are often mad by a substitution reaction.

8. Guideline-1 Guideline-2

9. GUIDELINE - 3 Consider alternative disconnections and choose routes that avoid chemoselectivity problems – often this means disconnecting reactive groups first. Disconnection (e) requires alkylation of a compound that is itself an alkylating agent. Disconnection (f) is much more satisfactory, and leads to a compound that is easily disconnected to 4-hydroxyphenol (para-cresol) and 1,2-dibromoethane. Using this guideline, we can say that it’s best to disconnect the bromoethyl group (f) before the benzyl group because the bromoethyl group is more reactive and more likely to cause problems of chemoselectivity.

10. FUNCTIONAL GROUP INTERCONVERSIONS (FGI): It is the process of converting one functional group into another by substitution, addition, elimination, reduction or oxidation. The FGI is needed because when a target molecule containing more than one functional group, one functional group may interfere with desired reaction on second functional group during a synthesis. For convenience these functional groups are initially divided into three major classes depending upon their oxidation level.

11. Transformations of carboxylic acid derivatives Esters Acyl chloride Amides Transformations of aldehyde derivatives

12. ALKANES ALKYL HALIDES AMINES CARBOXYLIC ACIDS ETHERS ALCOHOLS ALKENES ALKYNES NITRILES CARBONYL COMPOUNDS ACYL DERIVATIVES Reduction Halogenation Oxidation Replacement of OH with X, amino Hydration Dehydration Oxidation Alkaline hydrolysis WES Grignard reagent Ammonia WES-Williamson Ether Synthesis FUNCTIONAL GROUP INTERCONVERSION

13. The antihypertensive drug ofornine contains and amide and amin e functional group and we need to decide which to disconnect first. If we disconnect the secondary amine first (b), we will have chemo selectivity problems constructing the amide in the presence of resulting NH 2 group. If we follow the disconnection (a), we will have the chemo selectivity problems because we have to construct an amine in the presence of acyl chloride. However, we shall want to make acyl chloride from carboxylic acid, which can then easily be disconnected to 2-aminobenzoic acid and 4-chloropyridine.

14. Synthesis of Ofornine :

15. Retrosynthesis of Paracetamol = = The p-aminophenol reacts with the acetic anhydride through the nucleophilic addition-elimination reaction. The NH 2 is a poor electrophile it usually acts as an nucleophile. Therefore an equivalent electrophile for NH 2 would be NO 2 which can then be reduced to NH 2 . The NO 2 reacts with phenol through the electrophilic substitution reaction.

16. Synthesis Of Paracetamol

17. REFERENCES Jonathan Clayden , Nick Greeves, Stuart Warren. Organic Chemistry. Second Edition. Oxford University Press. Stuart Warren, Paul Wyatt. Organic Synthesis: The Disconnection Approach. Second Edition. A. John Wiley and Sons, Ltd., Publication. Retrosynthesis, In Wikipedia. https://en.m.wikipedia.org/wiki/Retrosynthetic_analysis. Paracetamol, In https://chembam.com/resources-for-students/the-chemistry-of/retrosynthesis-paracetmol.

18. ANY QUESTIONS ?