Subject Chemistry

Paper No and Title 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No and 8: Stereo and regioselectivity in retrosynthesis Title Module Tag CHE_P14_M8

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 8: Stereo and regioselectivity in retrosynthesis

TABLE OF CONTENTS

1. Learning Outcomes 2. Introduction 3. Chemoselectivity 4. Regioselectivity 5. Stereoselectivity 6. Summary

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 8: Stereo and regioselectivity in retrosynthesis

1. Learning Outcomes

After studying this module, you shall be able to

 Understand the types of selectivity.  Explain chemoselectivity in retroanalysis  Understand the stereoselectivity in retroanalysis  Design the synthesis of chiral and achiral molecules

2. Introduction

The plants, animals or microorganisms produce a number of chiral and achiral complicated structures. Some of the groups of compounds include antibiotics, alkaloids, chlorophyll, steroids, biopolymers, carbohydrates, fats, vitamins, dyes etc. The chemist determines the structures of these compounds and try to synthesize them using disconnection approaches. The synthesis of these compounds becomes important due to their wide applications. Synthesis from simple starting materials with predictable regioselectivity and stereochemistry requires the utility of retrosynthetic analysis.

There are three types of selectivity possible for any synthesis: (i) Chemoselectivity is deciding which group reacts. (ii) Regioselectivity is where the reaction takes place in that group. (iii) Stereoselectivity is how the group reacts with respect to the stereochemistry of the product. Selectivity can be attained by selecting appropriate starting materials, reagents, solvents, reaction conditions and most importantly protecting and deprotecting methods.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 8: Stereo and regioselectivity in retrosynthesis

A protecting group or protective group is entered into a molecule through chemical modification of a functional group for obtaining the chemoselectivity in a chemical reaction. It plays an important role in multistep organic synthesis. Some of the common protecting groups are listed in table 1.

S. No. Functional group Protection group

1 Alcohol protecting group Ester; Ether; Ether silyl

2 Amine protecting group Substituted amine; Amide; Carbamate; Sulphonamide

3 Carboxylic acid Ester, Ester silyl; Oxazoline protecting group

Functions of protection group a. Through the protection of sensitive functional groups it becomes possible to make reagents that would otherwise be unstable. b. Protection allows us to overcome simple problems of chemoselectivity. c. The other important function of protecting groups is to stop a reagent from attacking itself. A more detail about protection and deprotection is given in module 9. The following sections will discuss the role of stereochemistry in retrosynthetic analysis.

3. Chemoselectivity

Chemoselectivity plays important role in organic synthesis. This is helpful in those molecules which possess more than one functional group. The selective reactivity of one functional group in the presence of others is controlled by chemoselectivity. The chemoselectivity is supported by protection and deprotection. Following examples will explain the chemoselectivity in organic reactions. CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 8: Stereo and regioselectivity in retrosynthesis

Selective Reduction: The selection of proper reagent plays important role in chemoselectivity. The selective reduction of either the double bond or the carbonyl group in cyclopent-2-enone (1) is reagent specific. For the chemoselective reduction of CC bond over CO bond is performed by catalytic hydrogenation (Figure 1). Hence, the reaction of cyclopent-2-

enone (1) with hydrogen in the presence of palladium (H2/Pd) gives cyclopentanone (2).

Figure 1

The reduction of CO bond over CC bond is performed by reducing agent sodium borohydride (Figure 2). The reaction of cyclopent-2-enone (1) with sodium borohydride

(NaBH4) gives cyclopent-2-enol (3). In this case, only the carbonyl group (>C=O) is selectively reduced to hydroxyl group (-OH). Whereas, in the former case (figure 1) the double bond is selectively reduced to single bond.

Figure 2 CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 8: Stereo and regioselectivity in retrosynthesis

Another example of chemoselectivity is the chemoselective reduction of ,  unsaturated esters in presence of alkenes. The reduction of the compound 4 with magnesium (Mg) in the presence of methanol reduced the double bond present at the position of the unsaturated esters giving the product 5 (Figure 3).

Figure 3

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 8: Stereo and regioselectivity in retrosynthesis

4. Regioselectivity

Regioselectivity gives preference for bond making at a particular place when there is possibility of bond formations at other possible positions also. In other words, there is a preference of one reactive site with respect to other reactive site. The best example to explain this is Markovnikov and anti- Markovnikov addition reactions. The reaction of hydrobromic acid (HBr) with styrene (vinylbenzene, 6) gives 1- bromoethylbenzene (8) through Markovnikov addition (Figure 4). The same reaction, if performed in the presence of peracids undergoes Anti-Markovnikov addition to give 2- bromoethylbenzene (7) (Figure 4). These information of regioselectivity is important for the retrosynthetic analysis.

Figure 4 Birch reduction is another important example of regioselectivity. In this reduction method, aromatic rings undergo a 1,4-reduction to provide unconjugated cyclohexadienes. This reaction is performed by sodium or lithium metal in liquid ammonia and in the presence of an alcohol. Here, the site of reduction is dependent upon the type of substitution present in the aromatic ring. Without any substitution in the aromatic ring, the reduction of simple benzene (9) gives cyclohexadiene (10) (Figure 5).

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 8: Stereo and regioselectivity in retrosynthesis

Figure 5 Figures 6 and 7 shows the regioselectivity in Birch reduction when electron donating

(-OCH3) (Figure 6) and electron withdrawing (-COOH) (Figure 7) groups are attached. The preference is based on the mechanism of the reaction where the radical-anion is protonated initially determines the structure of the product. While performing the retrosynthetic analysis, these preferences play important role in the synthetic design of any molecule(s).

Figure 6

Figure 7 CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 8: Stereo and regioselectivity in retrosynthesis

5. Stereoselectivity

Stereoselectivity is the preferential formation of one stereoisomer in a chemical reaction. This can be further classified into: . Enantioselective reactions . Diastereoselective reactions . Stereospecific reactions . Stereoselective reactions

Enantioselective reactions: The stereoselective reactions where a reactant gives enantiomeric products or enantiomers in unequal amounts are called enantioselective reactions. Diastereoselective reactions: The stereoselective reactions where a reactant gives diastereomer products or diastereomers in unequal amounts are called diastereoselective reactions. Stereospecific reactions: Those stereospecific reactions where the stereochemistry of the starting material determines the stereochemistry of the product are called stereospecific

reactions. For example, SN2 reactions. Stereoselective reactions: The stereospecific reaction where one stereoisomer of a product is formed preferentially over another is known as stereoselective reaction. In the stereoselective reaction of alkene with m-CPBA, the two epoxides formed in different amounts (Figure 8).

Figure 8 CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 8: Stereo and regioselectivity in retrosynthesis

6. Summary

. Retrosynthetic analysis provides important inputs for synthesis from simple starting materials with predictable regioselectivity and stereochemistry. . There are three types of selectivity possible for any synthesis; chemoselectivity, regioselectivity and stereoselectivity. . Chemoselectivity refers to selective reactivity of one functional group in the presence of others. . The selection of proper reagent plays important role in chemoselectivity. . Regioselectivity gives preference for bond making at a particular place when there is possibility of bond formations at other possible positions also. . Markovnikov and anti- Markovnikov addition reactions are examples of regioselective reactions. . Birch reduction is another example of regioselective reaction. . Stereoselectivity is the preferential formation of one stereoisomer in a chemical reaction.

CHEMISTRY Paper No. 14: Organic Chemistry –IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic rings) Module No. 8: Stereo and regioselectivity in retrosynthesis