Retrosynthetic analysis in organic synthesis

Retrosynthetic analysis, definition, importance, disconnection approach, one group two group disconnection logical and illogical disconnection approach compounds containing two nitrogen atom retrosynthetic analysis of camphor, cartisone, reserpine

1. Dr. R. VALLIAPPAN PROFESSOR DEPARTMENT OF CHEMISTRY ANNAMALAI UNIVERSITY ANNAMALAI NAGAR 608 002 Email: [email protected] V M.Sc., CHEMISTRY NINTH SEMESTER ICHT 91: SYNTHETIC ORGANIC CHEMISTRY

2. UNIT: V – RETROSYNTHETIC ANALYSIS 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 analysis ’ 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 strategy by Corey for the synthesis of the stereochemically complicated natural molecule – prostaglandin .

3. 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 . 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 Retrosynthetic analysis is the exact reverse ( antithetic) of a synthetic reaction . However , the first notable example of a product being transformed into its synthetic precursors was that of Robinson’s tropinone synthesis . starting materials for the synthesis. At each step, the availability of the intermediate is evaluated .

4. Tropinone was submitted to imaginary hydrolysis at the points indicated by the dotted lines below and resolved into succinaldehyde , methylamine and acetone . The precursors were identified from the starting material, and then a suitable path was devised to convert these starting materials into the target molecule using known reactions .

5. Terms and Definitions 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. .

6. 4. Retrosynthetic arrow: Disconnection is represented by a double line closed arrow which indicates the transformation of the molecule into its immediate precursor 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 .

7. The following reaction shows a concerted cycloaddition reaction, where the synthons are neutral fragments. 6 . Retron : Each reaction generates a characteristic structural element in the product, such as the enone resulting from aldol condensation. This substructure, called the retron , must be present in a target molecule to be able to apply the corresponding transformation to that target .

8. 7. Reagents: These are the actual source of the synthons. NO + 2 ≡ HNO 3 + H 2 SO 4 ; Br + ≡ Br 2 ; Cl + ≡ Cl 2 + AlCl 3 Alkyl ions – a) Alkyl cation ( carbenium ion)− H + - H 2 O i ) R − OH → R − O + H 2 → R + Alcohol AlCl 3 ii ) R − X → R + + X - A lCl 3 Alkyl halide b ) Alkyl anion (carbanion)− R −M → R - + M + organometallic compound carbanion

9. C) Acyl ions Acyl cations H + ( i) R−CO−CH 2 − X → R − CHOC + H 2 + HX ( X = Cl or Br) Acyl halide −¯ X Acyl cation H + ( ii) R − CO − CH = CH 2 → RCOC + H − CH 3 Enone Acyl cation b ) Acyl anion Removal of a proton from a methylene group adjacent to a electron withdrawing group . Base ( i ) R − COCH 3 → R − CO¯CH 2 methyl ketones − H + Base ( ii) RCH 2 − COOR → RC¯H − COOR − H + ( iii) RCH 2 − NO 2 → RC¯H − NO 2

10. D) Ethoxy anion E) Aldehyde carbonyl as a cation and anion The aldehyde carbonyl carbon is electron deficient and undergoes nucleophilic attack . The aldehyde carbonyl carbon can also undergo electrophilic attack when it is converted into an anion. The polarity of the electron – deficient aldehyde carbonyl carbon can be reversed and this is known as ‘ umpolung ’.

11. 8) Retrosynthetic tree It is a complex pattern of Retrosynthetic analysis of a molecule may lead to the possibility of identifying several different starting materials and several different routes to the synthesis of a molecule . several or all possible retrosynthesis of a single compound. Each structure derived from a disconnection becomes a TM itself for further analysis. The analysis can be repeated for each precursor, generating a second level of precursors. Each precursor generated is checked for its availability. Such repeated disconnections give an outline of the available routes for the TM, and this is known as the retrosynthetic tree (Figure 1). A retrosynthetic tree is a complex pattern with many branches which lead to different routes and different synthetic precursors . The synthetic tree is a graph of several synthetic routes to the TM which can be designed and evaluated, from which an efficient The synthetic plan is written by choosing an appropriate route according to the analysis and adding reagents and reaction conditions. The synthetic strategy was further simplified by the use of computers. Figure 1. Schematic depiction of a retrosynthetic tree .

12. Guidelines or Empirical Rules (Heuristics) to a Proper Disconnection 1) Disconnection should correspond to a known and reliable reaction . So , a thorough knowledge of reactions is necessary ( Figure 2). Figure 2. Route A is a good disconnection as acetylation of an amino group is a known reaction to get the N-acetyl group . Routes B and C route disconnections are improper as they do not lead to known reactions .

13. 2) Disconnect C–X bond These are the known reactions where alkyl halides are obtained by nucleophilic attack by a halide whereas the halogen is an electrophile in the preparation of arylhalides . 3 ) For compounds comprising of two parts joined by a heteroatom, dis connection is carried out next to the heteroatom. The molecule is disconnected in the middle for greater simplification. The aryloxyacetic acid can be readily obtained by reaction of a phenol and chloroacetic acid in presence of NaOH . So, the proper disconnection is at the ‘b’ site. The amide can be obtained from an acid chloride and an amine, so, the proper disconnection is at the a site.

14. 4) In open-chain compounds, the disconnection at the heteroatom is also based on the stability of the synthons . Both these disconnections are next to the heteroatom and also in the middle to give equal size synthons. But route ‘a’ is preferred as it gives a more stable secondary cation.

15. Functional Group Interconversion (FGI): FGI is substituting functional group for another when the disconnection of the group does not lead to a proper precursor. In the following reaction, disconnection is not possible because there is no corresponding reaction to introduce group X directly on the benzene ring. Hence, it has to be converted to group Y by FGI as group Y can be disconnected to give the appropriate starting materials . Aniline on bromination gives 2, 4, 6-tribromoaniline so the group interconversions has to be carried. Amino group is readily obtained by the reduction of nitro group. So, in the above reaction , the first step is the functional group interconversion followed by disconnection .

16. Aniline on bromination gives 2, 4, 6-tribromoaniline so the group interconversions has to be carried. Amino group is readily obtained by the reduction of nitro group. So, in the above reaction , the first step is the functional group interconversion followed by disconnection . Preparation of p- bromoaniline from aniline is shown below. The synthetic route for the target molecule is the exact reverse of these retro steps.

17. RETROSYNTHETIC ANALYSIS Retrosynthetic analysis is he process of problem solving technique for transforming the structure of a synthetic target molecule to a sequence of progressively materials along a pathway which ultimately leads to a simple or commercially available starting material for chemical synthesis Disconnection approach It is a good mechanism b) Greatest possible simplification c) Gives recognizable starting materials

18. ONE GROUP DISCONNECTION Disconnection of Alcohols Target molecule

19. one-group disconnection 1. Disconnection of alcohols Retrosynthetic route for target molecule (TM) Acetone + Sodium cyanide + Acid Here , cyanide is a good anion, and the cation is stabilized by a lone pair of electrons on oxygen. All simple alcohols can be disconnected in this way. The most stable anion of the substituent must be chosen first and disconnect to acarbonyl compound. Acetone reacts with sodium cyanide in acid medium yields the Target molecule 2-hydroxyl-2-cyano-propane

20. one-group disconnection 2 . Disconnection of Olefins Olefins can be made by the dehydration of alcohols. So the Functional Group interconversion (FGI) stage in designing the synthesis of olefins is to add water across the double bond

21. one-group disconnection 1. Disconnection of Ketones Retrosynthetic analysis for Target molecule – Ketone Even though not always in practice, in principle, retrosynthetic analysis of carbonyl compounds is made by disconnecting any bond next to an aromatic ring to an aliphatic side chain in the compound Synthesis of Target molecule – Ketone Friedel -Crafts reaction using acetyl chloride and aluminium chloride to attack the benzene ring yields the Target molecule 1-( 4-methoxyphenyl) ethanone

22. Two-group disconnection Logical and Illogical synthesis (OR) Rational and irrational Synthesis Rational Synthesis: The synthesis of compounds using logical disconnection is said to be rational synthesis Example: Synthesis of 1,3- and 1,5-bifunctional compounds Irrational Synthesis: The synthesis of compounds using illogical disconnection is said to be irrational synthesis Example: 1,2-, 1,4- and 1,6-bifunctional compounds

23. LOGICAL TWO GROUP DISCONNECTIONS 1,3-Dioxygenated skeletons a) -hydroxyl carbonyl compound Synthesis of Target molecule 2-ethyl-3-hydroxyhexanal Retrosynthetic analysis of 2-ethyl-3-hydroxyhexanal Disconnection gives an aldehyde and its enolate anion (B) same of (A) Butaraldehyde with Base gives the enolate anion (B) is an intermediate and the aldehyde (A) reacted gives the Target molecule 2-ethyl-3-hydroxyhexanal

24. 1,3-Dioxygenated compound: , -unsaturated carbonyl compound Retrosynthetic analysis of E-3-(4-nitrophenyl) acrylaldehyde

25. 1,3-Dicarbonyl compounds It belongs to logical one group disconnection. It is an example for rational synthesis (logical). Disconnection of the same bond gives a good synthesis of 1,3-dicarbonyl compounds Retrosynthetic analysis for Target molecule pentane-2,4-dione

26. 1,5-Dicarbonyl compounds It belongs to logical one group disconnection . It is an example for rational synthesis (logical). Disconnect the 1,5-dicarbonyl compound at either of the two middle bonds gives the unsaturated ketone Retrosynthetic analysis for Target molecule Nonane-3,7-dione Synthesis of Target molecule Nonane-3,7-dione

27. ILLOGICAL TWO GROUP DISCONNECTIONS 1,2-Dioxygenated skeletons a) - hydroxyl carbonyl compound The Illogical disconnection approach there should be no logic or reason for the disconnection approach that is why we call it as illogical disconnection or irrational method Logical one group disconnections have sensible synthons with anions or cations all stabilized by functional groups in the right positions. Here we given an example. The common reagent for the synthon –COOH is a simple one carbon anion namely cyanide ion, CN - which adds to ketone and whose adducts with Acetophenone could easily be converted into the Target molecule 2-hydroxyl-2-phenylpropanoic acid

28. ILLOGICAL TWO GROUP DISCONNECTIONS 1,2-Diol skeletons b) -hydroxyl compound Retrosynthetic analysis of 2,3-dimethyl butane-2,3-diol Disconnection of the diol by Functional Group interconversion gives an olefin, which can be disconnected by the Wittig method Propan-2-one on reaction with the ylide gives the olefin in the presence of base, which on hydroxylation in the presence of OsO 4 yields the 2,3-dimethyl butane-2,3-diol

29. ILLOGICAL TWO GROUP DISCONNECTIONS 1,2-Diol skeletons c) Illogical Electrophiles - Hydroxy carbonyl compounds and 1,2-diols uses Illogical nucleophiles and special methods to get round of making 1,2-deoxygenated compounds. Another approach is obviously to use an illogical electrophile and among the most important of these is  -halo carbonyl compound One can easily make a  - Halo carbonyl compounds from the carbonyl Compounds by halogenation of the enol. The Enol is nucleophilic at the  -carbon atom but the  - bromoketone is electrophilic at the  -carbon atom since By halogenation one can able to invert the natural polarity of the molecule

30. ILLOGICAL TWO GROUP DISCONNECTIONS 1,4-Dioxygenated pattern a) 1,4-dicarbonyl compounds The obvious disconnection on a 1,4-dicarbonyl compound gives a logical Nucleophilic synthon 9an enolae anion (A) but an illogical electrophilic synthon (B):. Also for (B), a derivative of a ketone in which the normal polarity is inverted is needed. For these things -halo carbonyl compound is ideal

31. ILLOGICAL TWO GROUP DISCONNECTIONS 1,4-Dioxygenated pattern b) - Hydroxy carbonyl compounds The -halo-carbonyl compounds are reagents for the synthon C + - C=O. At a lower oxidation level, epoxides are reagents for the synthons C + - C-OH as in their reaction with Grignard or Organolithium reagents. Here the enamine can be used to provide the enolate synthon

32. ILLOGICAL TWO GROUP DISCONNECTIONS 1,6-Dicarbonyl compounds It belongs to illogical disconnections. Here the disconnection must be done in such a way that it should links up the wo carbonyl groups . The following is the reaction with ozone or its equivalent Retrosynthetic Analysis of 6-oxo-6-phenylhexanoic acid synthesis of 6-oxo-6-phenylhexanoic acid

33. RETRO DIEL’S-ALDER REACTION Since cyclohexanones can also be made by the Diel’s -Alder reaction, a wide range of 1,6-dicarbonyl compounds must be accessed Retrosynthetic analysis of butane-1,2,3,4-tetracarboxylic acid

34. synthesis of butane-1,2,3,4-tetracarboxylic acid Reaction of buta-1,3-diene wih furan-2,5-dione yields 3a,4,78,7a-tetrahydroisobenzofuran-1,3-dione, which on treatment with hydrogen peroxide and ozone yields a dicarboxylic acid which in the presence of a base gives butane-1,2,3,4-tetracarboxylic acid

35. PERICYCLIC REACTIONS Retrosynthetic Analysis of the Target molecule Synthesis of Target molecule by Diel’s Alder reaction – by FGI method. Fumarate is used

36. Retrosynthesis of some Heterocycles containing two nitrogen atoms Retrosynthetic analysis of Target molecule 3-methyl-1H-pyrazol-5(4H)-one

37. Tips for Synthesis Based on Retrosynthetic Analysis An efficient synthesis should be planned based on the following conditions : • Advantages and disadvantages of the route. • Availability of the starting materials for each step. • Type of reactions: Less competent reactions should be involved in the synthesis. The reaction conditions should be simple and high yielding processes. They should work out on industrial scale . Yield at each step is to be considered . • Safety: Dangerous chemicals are best avoided when planning a synthesis as they require more expensive equipment to ensure safe handling and containment. More important is they pose more danger to the person handling them. This is an important consideration for large scale preparations . • Length and cost of each synthetic step: Minimum number of steps would save time. A convergent synthesis is preferred over the linear method. A lengthy scheme can be selected when the starting materials are inexpensive and readily available and easy experimental conditions are involved. Expensive starting materials are used when the number of steps are less . • Starting materials for industrial syntheses: Starting compounds of linear skeleton upto six carbon atoms with one functional group like – COOH, CHO, OH, X, NH2, etc., are commercially available . Small molecules like simple aromatic compounds , alkenes , monomers for plastics, etc., are commercially available .. Naturally occurring compounds like amino acids, simple sugars and other plant materials are preferred .