Subject Chemistry Paper No and Title 14: Organic Chemistry IV (Advance Organic Synthesis and Supramolecular Chemistry and carbocyclic Module No and 4: Two group C-X disconnections Title Module Tag CHE_P14_M4
TABLE OF CONTENTS 1. Learning outcomes 2. Introduction 3. Type of two group disconnection 3.1. 1,2-Disconnection approach 3.2. 1,1-Disconnection approach 3.3. 1,3-Disconnection approach 4. Summary
1. Learning Outcomes After studying this module, you shall be able to Know about the basics of two-group C-X disconnection approach or retrosynthetic analysis. Understand the 1,2-disconnection approach Analyze the 1,1-disconnection approach Understand 1,3-Disconnection approach Design and write the synthetic steps based on two-group C-X disconnection approach for molecules 2. Introduction The two group disconnection is an approach to organic synthesis is retrosynthetic analysis. If target molecules possess two functional groups, then a two group disconnection approach between the functional group may be applied. This method of retrosynthetic analysis produces two possible synthons. The two group disconnection may be due to heterolytic cleavage or homolytic cleavage. Retro-aldol type transformation is an example of heterolytic two group disconnection (Figure 1) whereas retro-acyloin transformation is an example of homolytic two group disconnection (Figure 2). The two-group disconnections are also written in short form as dix.
Figure 1. Heterolytic Two group disconnection Figure 2. Homolytic Two group disconnection 3. Types of Two Group Disconnections 3.1 1,2-Disconnection approach This has been observed that the two-group disconnections are better than one-group disconnections. In the two-group C-X disconnections, the numbering starts from the carbon atom bearing the functional groups (Figure 3). By 1,2-disconnection approach we mean that the two functional groups being disconnected are at relative 1 and 2 positions. The short form of twogroup 1,2-disconnection approach is 1,2-diX. Hydroxyethers and amino alcohols are the best examples for 1,2-disconnection approach. Figure 4 shows a typical 1,2-disconnection approach for hydroxylether. The retrosynthesis of amino alcohols from amine and epoxide is another example of 1,2-disconnection approach (Figure 5). From the Figure 5, one can see that the epoxides along with amines can be used for the synthesis of amino alcohols.
Figure 3 Figure 4 Figure 5 Let us consider another example which utilizes 1,2-disconnection approach. A number of biologically active molecules possess 1,2-functional group. A number of drugs are amino alcohol derivatives. The molecule like fenyramidol or phenyramidol is a muscle relaxant and sold with the trade name of Cabral. The IUPAC name of the molecule is 1-phenyl-2-(pyridin-2-ylamino) ethanol. The disconnection approach or retrosynthetic analysis of this molecule follows the path of two-group disconnection and can be made from 2-amino pyridine and styrene oxide (Figure 6). The disconnection of phenyramidol (1) gave two molecules, 2-amino pyridine (3) and the synthon (2). The synthon (2) is obtained from the reagent styrene oxide (4). The synthesis of (1) has been achieved by the reaction of (3) and (4) in the presence of strong base like sodamide in liquid ammonia (Figure 7).
Figure 6 Figure 7 3.2. 1,1-Disconnection approach Here, 1,1 means, the same carbon atom holds two functional groups. The short form of two-group 1,1-disconnection approach is 1,1-diX. The best example is the disconnection approach for acetals which falls in this category of disconnection approach. For acetal, one can use one oxygen atom to help disconnect the other (Figure 8).
Figure 8 The important application of acetals in synthesis is as protecting groups for aldehydes and ketones. Another group of compounds include cyclic acetals. They are generally used for ketones. The disconnection is similar to that for acetals. The disconnection approach and synthetic pathways for compound (5) is given in Figure 9 and Figure 10 respectively. Figure 9
Figure 10 3.3. 1,3-Disconnection approach The 1,3-disconnection approach is applicable to 1,3-difunctionalized compounds. A number of biologically active molecules possess 1,3-functional group and this disconnection approach finds its applications in drug design and synthesis. From the Figure 11, one can see the 1,3-disconnection approach for the synthesis of 1,3-functionalized compounds. Figure 11
Compound (8) is an example of 1,3-functionalized molecule. The retrosynthetic analysis of (8) shows that it can be synthesized from the reagent, unsaturated carbonyl compound (10). The synthon for this disconnection approach is (9). This is a Michael reaction type and is applicable for all the carbonyl compounds and most of the nucleophiles. This type of retroanalysis is equally applicable for cyanides and nitrocompounds. Let us consider another example. 1,3-Aminoethers can easily be synthesized by taking the help of 1,3-disconnection approaches (Figure 12 and 13). Figure 12
Using the above disconnection approach, one can design the forward reaction as given below: Figure 13 4. Summary If target molecules possess two functional groups, then a two group disconnection approach between the functional group may be applied. The two group disconnection may be due to heterolytic cleavage or hemolytic cleavage. The two-group disconnections are better than one-group disconnections. Hydroxyethers and amino alcohols are the best examples for 1,2-disconnection approach. The molecule like phenyramidol follows the path of two-group disconnection and can be made from 2-amino pyridine and styrene oxide. The 1,3-disconnection approach is applicable to 1,3-difunctionalized compounds. 1,3-Aminoethers can easily be synthesized by taking the help of 1,3-disconnection approaches.