INTRODUCTION:

An analytical approach to Organic Synthesis in which the target molecule is broken into fragments through a series of logical disconnection to get the best plausible and likely starting materials (ie. synthons or building blocks) for the target molecule is called as Synthon approach.

Synthesis is the real test of the organic medicinal chemist to use and control organic reactions. In each case the starting material is converted to some desired compound, the target molecule through some key intermediate. Synthetic organic compounds are of wide and varied types. As far as the skeleton of carbon compounds are concerned, they may be small or large, simple or complex, straight or branched, cyclic or open, carbocyclic or heterocyclic, aromatic or non-aromatic carbon chains. The chain may bear one or more functional groups. So, to synthesize these varied compounds, appropriate starting materials are to be chosen. These starting materials are allowed to react and are converted finally to the required product called as the Target molecule.

Actually, a number of synthetic routes can be written for a given target molecule. But in actual synthesis, generally that route is selected which is economical, safe, and easy to carry out and produces maximum yield in a short reaction time¹.

What Is Synthon and Synthon Approach?

The process of going backwards and finding out starting materials and routes through which target molecule can be synthesized is called as Retrosynthetic Analysis. So, retrosynthetic analysis is a process of stepwise breaking down of target molecule to starting materials by disconnection of bonds and functional group interchange (FGI). Every disconnected part is an idealized fragment and is called as Synthon and the phenomenon is called as Synthon Approach.

Synthon are not easily available from bottle in the laboratory and synthon has its Synthetic equivalent. Synthetic equivalent are nothing but the chemicals we use to carry out the reaction¹.

Abbreviations Used In Synthon Approach

FGI: It represents functional group interchange or functional group interconversion.

FGE: It represents functional group equivalent or synthetic equivalent.

TM: It represents target molecule.

Symbols Used In Synthon Approach

Technical Terms Used in Synthon or Disconnection Approach

· Disconnection: The process of breaking down of bonds of target molecule to get possible starting materials is called as disconnection and the approach is called as disconnection approach.

· Functional Group Interchange: The process of conversion of one functional group into another so that disconnection becomes easy is known as functional group interchange.

· Synthon: Synthon is an idealized fragment obtained after disconnection. Synthon are usually ions.

· Synthetic Equivalent: Synthon cannot be straightway obtained from the bottle in the laboratory and hence its synthetic equivalent is used to run a reaction. So synthetic equivalent can be defined as a reagent carrying out function of a synthon which itself cannot be used because of its instability.

· Reagents: A compound that reacts to give an intermediate in the planned synthesis or to give a target molecule itself is called as reagent. The synthetic equivalent of a synthon is nothing but a reagent.

· Target Molecule: The molecule whose synthesis is being planned is known as target molecule.

· Analysis/Retrosynthetic Analysis: The process of breaking down of bonds in the target molecule to possible starting materials by disconnection and functional group interconversion (FGI)².

Basic Rules in Disconnection

1. Disconnection of bond should be done in such a way that stable ion fragments are obtained. Disconnection of only one bond should be done at a time. Usually, a heterolytic disconnection is done so that each disconnection generates two fragments, positive and negative fragments.

2. A bond carbon with a heteroatom (like N, O, or S) is always broken with electron pair being transferred to the heteroatom³.

3. The number of fragments generated from disconnection should be as small as possible and that must be available economically i.e. synthesis of target molecule should be carried out in as few steps as possible.

4. Examine the relationships between groups looking for the groups which directs to the original position.

5. Disconnection of the most electron-withdrawing group (added last) is done first because the electron-withdrawing group deactivates the ring and so it becomes difficult to add or substitute other groups¹.

6. Sometimes a disconnection carried out does not generate sufficiently stable fragments but using FGI or introducing additional electron-withdrawing groups and removing it after synthesis can give such fragments³.

7. When functional group interconversion (FGI) is needed during synthesis, other substituents should be added either before or after FGI as it may alter the directing effect of the group¹.

8. A dummy amino group is added to setup the required relationship and then amino group is removed by diazotization and reduction in case if there is a difficult task such as insertion of O, P-directing group meta to each other¹.

9. It is always good not to disconnect the substituents which are difficult to add but to use a starting material containing the substituents (such as –OH, -OR)¹.

10. Avoid sequencing, which may lead to unwanted reaction at other sites of the molecule. For example, nitration of benzaldehyde gives 50% m-nitrobenzaldehyde because nitric acid used for nitration oxidizes -CHO to –COOH i.e. to benzoic acid. So benzoic acid can be nitrated first and then subjected to reduction¹.

Protecting group allows us to overcome the problem of chemo-selectivity.

Protecting groups should have two important properties:

Ø It should be easy to introduce and easy to remove.

Ø It must be resistant to reagents which would attack the unprotected functional groups¹.

Routine for Designing Synthesis:

Here few steps are taking part, whose synthesis can be determined by using synthon approach are:

· Analysis: Before starting disconnection operation, one should examine the target molecule as a whole and recognize the functional groups in the target molecule and also positional relationship between them.

· Disconnect: After complete analysis of the target molecule, one should disconnect the bonds corresponding to the known and reliable reactions or FGI.

· Synthesis: One should write down the plan according to analysis, adding reagents and conditions. Then modify the plan according to unexpected failures or successes in the laboratory.

Some essential knowledge an organic chemist must have to design synthesis may include:

Ø An understanding of reaction mechanism.

Ø An appreciation that some compounds are readily available.

Ø A working knowledge of reliable mechanism.

Ø An understanding of stereochemistry⁴.

Eg. p-Methoxyacetophenone:-

Analysis:

Synthesis

Heterocyclic Rings System

Heterocyclic ring systems are a part of many drug molecules as a basic skeleton. Therefore, it is imperative we should deal with a few. Generally one performs retrosynthetic of heterocyclic rings using the criteria of “readily recognizable fragments”. E.g. NH₃, NH₂NH_2,NH₂OH, guanidine, urea, thiourea, H₂N-CH₂CH₂-NH₂are such readily recognizable fragment.

Eg: 2-aminopyrimidine

E.g.: Propranolol³

Some Examples of synthon approach in drug synthesis:

1. Alcindo A. dos Santos et al. introduced a synthon equivalent to a corboxymethyl anion to enones and nitroalkenes, through a 1,4-addition reaction of 2,4,4-trimethyl-2-oxazoline cyanocuprate, proved to be an interesting methodology for the synthesis of natural products such as (±)-methyl jasmonate and (±)-baclofen⁵.

2. YU Zhao-Lian et al. Synthesized Spiro-cyclopropane derivative using synthon approach strategy⁶.

3. Archan Dey et al. studied Crystal structure prediction of 2-amino-4-ethylphenol and 3-amino-2-napthol with the supramolecular synthon approach and compared this prediction with experimental structures⁷.

4. Marco Luparia have developed a rapid and flexible approach to 2,3-disubstituted cyclopentenols which are valuable intermediates in organic synthesis suitable for Claisen rearrangements, allylic couplings as well as simple hydrogenation of the double bond. Columbetdione was synthesized starting from an intermediate obtained using this new methodology⁸.

CONCLUSION:

· Synthon approach is a very useful analytical tool.

· One can easily determine different routes to synthesize the target molecule even if the target molecule has never been synthesized earlier.

· Also, it allows us to determine the most economical route for the synthesis.

· It is of most importance particularly when we think of synthesis of a new drug molecule obtained from natural resources like plants, animals etc.

· Synthon approach can provide a supply of useful compounds like Quinine, penicillin, vitamins, prostaglandins, and insect-attractants not available in adequate quantities from nature.

· It is expected that with advancement and development of our knowledge about newer molecules of interest, this approach will immensely help in solving many problems of future of organic / medicinal chemists.

REFERENCES:

1. Ghosh SK., Planning of synthesis, In Advanced General Organic Chemistry- a Modern Approach, New Central Book Agency Ltd., Kolkata, 2007; pp. 1197, 1198,1227,1228,1247.

2. Warren S., Introduction to disconnection, In Designing Organic Synthesis;- A programmed introduction to the Synthon Approach, John Wiley and Sons Ltd., 2002; pp. 8.

3. Clayden, Greeves, Warren and Wothers, Retrosynthetic analysis, In Organic Chemistry, Oxford University Press Inc., Newyork, 2001; pp. 773-778 .

4. Furniss BS., Hannaford AJ., Organic synthesis, In Vogel’s ‘Textbook of Practical Organic Chemistry’, Pearson Education Pvt. Ltd., Singapore, 2005; pp. 1-4,17-23.

5. Santos A. et. al., A New Approach to the Synthesis of (±)-Methyl Jasmonate and (±)-Baclofen via Conjugated Addition of Oxazoline Cyanocuprate to Michael Acceptors, J. Braz. Chem. Soc., 2001; 12: 673-679.

6. Zhao-Lian YU. et. al., An Efficient Approach to the Synthesis of Spiro-cyclopropane Derivatives Utilizing 4-Methoy-2-bromobutyrolactone, Chem. J. of Chinese Universities, 2005; 26: 860-864.

7. Dey A. et. al. Crystal structure prediction with the supramolecular synthon approach: Experimental structures of 2-amino-4-ethylphenol and 3-amino-2-naphthol and comparison with prediction, Cryst. Eng. Comm, 2006; 8: 751-755.

8. Luparia M., Total synthesis of columbetdione using a novel 1,2-bisanionic approach to 2,3-disubstituted cyclopentenols, Scientifica Acta, 2007; 1: 5-8.

Received on 15.05.2009 Modified on 09.07.2009

Asian J. Research Chem. 3(1):Jan.-Mar. 2010 page 1-4