Retrosynthes analysis and disconnection approach

Retro synthesis Analysis and disconnection approach,
application of retro synthesis

1. retrosynthesis PRESENTED BY: PROTTAY DUTTA Roll no-MPH/10055/20 Mpharm (Pharmaceutical Chemistry dept.) Birla Institute of Technology, Mesra

2. Definition [2] Retrosynthetic (or antithetic) analysis is a problem solving technique for transforming the structure of a synthetic target molecule (TGT) to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. The transformation of a molecule to a synthetic precursor is accomplished by the application of a transform, the exact reverse of a synthetic reaction, to a TGT. Each structure derived antithetically from a target the itself becomes a TGT for a further analysis. Repetition of this process eventually produces a tree of intermediates having chemical structural as nodes and pathways from bottom to top corresponding to possible synthetic routes to the TGT.

3. reference https://www.ias.ac.in/article/fulltext/reso/024/10/1071-1086 https://www.slideshare.net/ShariqueKhan22/organic-retrosynthesis-by-professor-beubenz S Warren, Designing Organic Synthesis, Introduction to Synthon Approach, John Wiley & Sons, NY, 1978. E.J. Corey, J.Am.Soc . 98, 189, (1976). Lemke TL, Williams DA, Roche VF, Zito WS. Foye’s Principles of Medicinal Chemistry 6th ed. Lippincott Williams and Wilkins. 2010. p. 504

4. RETROSYNTHETIC ANALYSIS or RETROSYNTHESIS “The process of WORKING BACKWARD from the TM in order to devise suitable synthetic route” OR “The process of mentally breaking down a molecule into a starting material” OR “It is a problem solving technique for transforming the structure of a synthetic target molecule (TM) to a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis.” [2]

5. ARROW NOTATION [2] 1.Simple reaction arrow “ reacts to give” 2. Delocalisation arrow “two different ways to draw the same delocalised structures” 3.Equilibrium arrow ⇌ “two structures are interconverting ” 4. Curved arrow “motion of two electrons” ( Single Headed) 5. Fish-hook arrow “motion of one electron” 6. Curved arrow ( Double Headed)

6. Terminology [2] Target molecule (TM): the molecule to be synthesized Retrosynthetic analysis or retrosynthesis : the process of mentally breaking down a molecule into a starting material Disconnection : an imaginary bond cleavage corresponding to a reverse of a real reaction Functional Group Interconversion (FGI): the process of converting one functional group into another by substitution, addition, elimination, reduction, or oxidation Transform : the exact reverse of a synthetic reaction Retron : structural subunit on the target that enables a transform to operate Synthon : idealized fragment resulting from a disconnection, which is related to possible synthetic operations Umpolung : reversal of normal polarization of a molecule or synthon Reagent : a real chemical compound used as the equivalent of a synthon Synthesis tree : set of all the possible disconnections and synthons leading from the target to the starting materials of a synthesis

7. RETROSYNTHETIC ANALYSIS CAN BE DONE BY TWO METHODS : a) Disconnection b) Functional Group Interconversion (FGI) a) Disconnection It is a paper operation involving an imagined cleavage of a bond. As a result of disconnection usually negative ion and positive ion are formed which are called ‘SYNTHONS’ Disconnection is shown by a wavy line like ~ or VVVVVVVV

8. b) Functional Group Interconversion (FGI) : The process of writing one functional group for another to help synthetic planning is known as FGI. FGI can be done by, Addition Substitution Elimination Oxidation/Reduction Free Radical Reaction

9. DISCONNECTIONS [4] C-X disconnections If we need to make a C-X bond (where X is a heteroatom),a simple disconnections reveals a carbocationic synthon. We choose this polarity because X is almost invariably more electronegative than carbon. The C-X bond could exist in many different chemical environments which means there will be a correspondingly wide range of carbocationic synthons and synthetic equivalents.

10. The second of these examples is hugely important: these are acylation reactions The third of the C-X disconnections is an example of a two-group disconnection(like the Diels-Alder example)

11. C-C disconnections Alcohols - Alcohols are prime example of the need to disconnect right next to the hydroxyl functional group. A carbanion synthon and an α -hydroxyalkyl cation synthon. The synthetic equivalent of a carbanion synthon is almost invariably an organometallic compound.

12. Adding an organometallic compound to a carbonyl compound generates a new stereocentre and its non-trivial to control which enantiomer of the product is formed. If we disconnect one bond further away from the alcohol in the target we generate a ß-hydroxyalkyl cation synthon whose synthetic equivalent we ve seen in an epoxide.Epoxides are already chiral, so we have a single enantiomer of the epoxide, we form a single enantiomer of the product alcohol.

13. Carbonyl Compounds By direct analogy with the disconnection of alcohols,simple carbonyl compounds disconnect back to acyl cation synthons and carbanionic synthons.

14. Synthons [3] : 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.

15. The symbol signifies a reverse synthetic step and is called a transform. The main transforms are disconnections, or cleavage of C-C bonds, and functional group interconversions (FGI) Retrosynthetic analysis involves the disassembly of a TM into available starting materials by sequential disconnections and functional group interconversions(FGI).[4] Synthons are fragments resulting from disconnection of carbon-carbon bonds of the TM. The actual substrates used for the forward synthesis are the synthetic equivalents (SE)

16. Stereospecificity and stereoselectivity Diels-Alder reaction occurs in one step so that neither dienes nor dienophile has time to rotate and stereochemistry of each remains preserved in the product. Thus, with respect to the dienophile and the diene the addition is stereospecific and almost always. The Diels- Alder reaction is stereospecific. The cis dienophiles give the cis product and trans dienophile give trans product.

17. Application [3] Retrosynthetic analysis  is a technique for solving problems in the planning of  organic synthesis. This is achieved by transforming a target molecule into simpler precursor structures regardless of any potential reactivity/interaction with reagents. Each precursor material is examined using the same method. This procedure is repeated until simple or commercially available structures are reached. These simpler/commercially available compounds can be used to form a synthesis of the target molecule The power of retrosynthetic analysis becomes evident in the design of a synthesis. The goal of retrosynthetic analysis is structural simplification. Often, a synthesis will have more than one possible synthetic route.

18. Retrosynthesis is well suited for discovering different synthetic routes and comparing them in a logical and straightforward fashion A database may be consulted at each stage of the analysis, to determine whether a component already exists in the literature. In that case, no further exploration of that compound would be required. If that compound exists, it can be a jumping point for further steps developed to reach a synthesis.

19. Guidelines for choosing disconnections [2] 1.Synthesis backwards: The process of breaking down a target molecule into available starting materials by disconnection or FGI 2.Retrosynthetic arrow: A double line arrow used to indicate the reverse of a synthetic reaction. 3.Synthon: An idealized fragment (usually a cation or anion) resulting from a disconnection. 4. Synthetic equivalent: A real chemical 5.Disconnections must correspond to the reverse of real and workable reactions.

20. 6. For compounds consisting of two parts joined by a hetroatom , disconnect next to the hetro atom 7. Consider alternate disconnections and choose routes that avoid chemoselectivity problems. This can often be done by disconnecting more reactive groups first. 8. Evaluate all the possible advantages and disadvantages of each path- determine the most efficient route for synthesis. 9. Evaluation is based on specific restrictions and limitation of reactions in the sequence, the availability of materials and other factors. 10.In reality, it may be necessary to try several approaches in the laboratory in order to find the most efficient or successful route.

21. Thank you