Advanced Organic Synthesis Dr. A. G. Nikalje

9. Latent Polarity Think about some of the reactions we've looked at for carbonyl compounds: Let, 2/11-10-2010

Let, 2/11-10-2010

10. Latent polarity in bifunctional compounds Consider a 1,3-disubstituted molecule, e.g. Let, 2/11-10-2010

Let, 2/11-10-2010

Let, 2/11-10-2010

But what about 1,4-disubstitution? Let, 2/11-10-2010

Let, 2/11-10-2010

The German word UMPOLUNG, meaning polarity reversal is used to describe the situation where the polarity in a compound is deliberately changed to facilitate a particular reaction. example: Let, 2/11-10-2010

11. Strategy in retrosynthesis Consider different possibilities. Try a number of disconnections and FGI's. Try to keep the number of steps down, and stick to known & reliable reactions. In real life, a synthesis has to be economically viable. Whenever possible, go for a convergent route rather than a linear one, as this will lead to a higher overall yield Let, 2/11-10-2010

eg. Linear vs. convergent synthesis assume 80% yields (optimistic!) Let, 2/11-10-2010

Linear: Convergent: Let, 2/11-10-2010

12. Aim for the greatest simplification 1 12. Aim for the greatest simplification 1. make disconnections towards the middle of the molecule (this is more convergent anyway) 2. disconnect at branch points 3. use symmetry where possible eg. (towards the middle) Let, 2/11-10-2010

eg. (at branches) Let, 2/11-10-2010

eg. (look for symmetry) Let, 2/11-10-2010

better syntheses minimise the use of protecting groups. Alternatively, potentially reactive groups can be protected or masked so they don't react, eg. reduction of an ester in the presence of a ketone Note that protection strategy requires two extra steps (must be efficient); better syntheses minimise the use of protecting groups. Let, 2/11-10-2010

Sometimes it helps the retrosynthesis if you add a functional group to facilitate bond formation (Functional Group Addition, FGA). An example of this is acetoacetic ester synthesis: Thus: Let, 2/11-10-2010

The synthesis therefore is Let, 2/11-10-2010

13. Ring Closing Reactions Synthesis of carbocyclic molecules Same approach as to acyclic systems. The probability of reaction between two functional groups is higher if: a) reaction is intramolecular (faster reaction) b) the distance between the two groups is shorter e.g. Intramolecular alkylation: Let, 2/11-10-2010

e.g. Intramolecular alkylation: Let, 2/11-10-2010

Intramolecular acylation eg. the Dieckmann cyclisation; especially good for 5-membered rings: Let, 2/11-10-2010

Condensation: Let, 2/11-10-2010

similarly 14. Medium and Large Rings (8-11 membered and 12+) Intramolecular reaction is less favoured with bigger rings. Often, high-dilution conditions and slow addition can be used to suppress intermolecular reaction and hence promote ring closure. eg. similarly Let, 2/11-10-2010

eg 15. Cycloaddition reaction (Diels-Alder) Generic reaction (in retrosyntheic terms): eg Let, 2/11-10-2010

Unsymmetrical Diels-Alder reactions: Let, 2/11-10-2010

note that the 1,3-disubstituted product is the minor product in both cases Let, 2/11-10-2010

16. Disconnections & Functional Group Interconversion in Aromatic Systems Some reactions used in aliphatic systems don't apply for aromatic systems (SN1 and SN2 reactions, for example, are extremely unfavourable for ArX. eg. Let, 2/11-10-2010

In planning synthesis of polysubstituted aromatics, the order of reactions is important to ensure that the reagents are compatible and to take advantage of the directing effect of existing substituents: Let, 2/11-10-2010

Examples Let, 2/11-10-2010

17. Birch Reduction Partial reduction of aromatic systems by (usually) sodium in liquid ammonia. It's an example of dissolving metal reduction. Such methods used to be quite popular but most applications have been replace by modern hydride reagents. Dissolving metal reduction does still have it's uses thoughand the Birch reduction is one of them, . (also recall the specific reduction of alkynes totrans-alkenes). The typical conditions involve liquid ammonia (bp. −33 °C) and sodium metal,in the presence of a proton source (usually an alcohol, EtOH). Let, 2/11-10-2010

Let, 2/11-10-2010

18. Fusing Rings onto aromatic systems The classical Hayworth naphthalene synthesis. The fused aromatic system is formed by dehydration of a tetralin intermediate, which is prepared from an existing benzene ring and succinic anhydride. Let, 2/11-10-2010

Thus: Let, 2/11-10-2010

19. Blocking positions in aromatic rings Functional groups that are introduced reversibly, or can be easily cleaved under mild condtions, can be used to access otherwise hard-to-make compounds Let, 2/11-10-2010

You have to know the terminology of stereochemistry a) Chiral, achiral compounds. b) Stereogenic, nonstereogenic centers. c) Enantiomers, diastereomers. d) Prochiral, prostereogenic. e) Enantiotopic, diastereotopic atoms and faces. f) Ways of drawing stereochemistry. g) For two adjacent stereocenters, we can use i. (R) and (S) ii. For cyclic structures, cis and trans iii. threo and erythro (very old-fashioned) iv. syn and anti (for a chain drawn in zigzag fashion) v. like and unlike (only Europeans use this one) Let, 2/11-10-2010