SUPPLEMENTARY SUBJECT
AROMATIC & HETEROCYCLIC PHARMACEUTICAL CHEMISTRY

Dr S. Conway, Prof. S G Davies, Prof. B G Davis, Dr A.J. Russell, Prof. C.J. Schofield and Dr M. Willis

Aromatic and heterocyclic chemistry is a very large and important branch of chemistry with which those students who enter the chemical industry are almost certainly going to intimately involved. Mechanistic rationales for the synthetic basis of aromatic chemistry that is practised today will be presented; more descriptive organic chemistry than would be reasonable in a main lecture course will be given. The relationship of reactions in aromatic chemistry to those of aliphatic chemistry will be emphasised. This is an area that provides a substantial part of the profits of the pharmaceutical industry, the syntheses of some of the past and potential blockbusters will be exemplified.

The main organic chemistry lecture course at present has 12 lectures on aromatic chemistry as the basic core is expected to be known by all students. The supplementary subject will be complementary to the main course and will have minimal overlap. The course will be given by Dr. S. Conway, Prof. S G Davies, Prof. B G Davis, Dr. A.J. Russell, Prof. C.J. Schofield and Dr. M. Willis. Although a list of books for further reading will be provided, it is intended that the lectures and problem classes will self contained and provide all the material necessary.

The course will consist of 5 modules each having lectures and ONE CLASS of problems. The first three modules will be lectured in Michaelmas Term. There will then be three classes on the last session of the Michaelmas and the first two of the Hilary Term; this will allow you to go through most of the problems over the Christmas vacation The problems for each class will be provided at least two lectures before the class; attempts at the problems together with attendance at the classes to go through answers is strongly recommended. No other work will be required nor teaching provided. The course this year will be very similar to last year except there will be some treatment of nucleoside chemistry in module 3. There will be few handouts.

Brief descriptions of the modules:

Module 1 Heterocyclic Synthesis I - Michaelmas Term
Objectives of the course. Range of 5 ring heterocycles: synthesis of 1,4-dicarbonyls in many different guises. Cheap natural sources. Fused systems and in particular indole.

Module 2 Heterocyclic Synthesis II - Michaelmas Term
Range of 6 ring heterocycles: 1,5-dicarbonyls by aldol, base-catalysed dehydration and Michael reactions. Synthesis of frameworks with more than one heteroelement towards purines and pyrimidines.

Module 3 Reactions of Heterocycles - Michaelmas Term
Some aspects of nucleoside chemistry.
C=C versus C=O frameworks. Electrophilic attack easy on pyrroles and pyridines (at nitrogen). Dichotomies of electrophilic substitution mechanisms. Mannich and Vilsmeier in aromatic and aliphatic systems. Decarboxylation and other ipso substitutions. Easy attack by nucleophiles - sometimes by electrophilic catalysis. Ring opening reactions. Difference from benzene.

Module 1 Class Heterocyclic Synthesis I Problems - Michaelmas Term
Module 2 Class Heterocyclic Reaction Problems - Hilary Term
Module 3 Class Heterocyclic Synthesis II Problems - Hilary Term

Module 4 Benzenoid Chemistry - Hilary Term
Comparison with heterocyclic reactions. Reactions of benzenoid systems: electrophilic aromatic substitution; early and late transition states; reactivity-selectivity in electrophilic and oxidative attack; electrophilic reactivity; ipso attack - mechanistic dichotomies; kinetics versus thermodynamics; nucleophilic substitution; SNAr, SRN1, benzyne mechanisms; applications in synthesis. Synthesis of di- and tri- substituted benzenoid systems. Oxidation and reduction - of rings and side chains - sequential reactions - when they work and when they don't. Aromatic rearrangements. Arene metallations.

Module 4 Benzenoid Chemistry Class - Hilary Term

Module 5 Pharmaceutical Chemicals - Hilary Term
Basic principles of medicinal chemistry and terminology. Enzyme inhibition. Neurotransmitters, receptor action and agonism / antagonism. Examples of modern blockbuster drugs with billion dollar annual sales- mode of action and synthesis. Chemotherapeutic approaches to the treatment of stomach ulcers, pain, nausea associated with chemotherapy, erectile disfunction, fungal infection, and HIV / viral infection.

Module 5 Pharmaceutical Chemicals Problems Class - Hilary Term

Books:

1. D T Davies OCP no 2 Aromatic Heterocyclic chemistry
2. M Sainsbury OCP no 4 Aromatic Chemistry
3. Graham L Patrick, An Introduction to Medicinal Chemistry 1995, OUP
4. John Saunders Top drugs; top synthetic routes (2000) OCP no 90
5. FD King Medicinal Chemistry: Principles and Practice Royal Soc of Chemistry (1994),
6. Murder, Magic and Medicine John Mann (1992) OUP ISBN 0-19-855854-6 - readable.

Examination
The course examination, which will take place at the end of the Hilary Term, will have substantial choice although candidates are expected to attend all the modules; the exam will last three hours and you will be expected to answer five out of eight questions. The questions may require knowledge of more than one of the modules.

Feedback
Comments and feedback from participants will be welcomed by any of the organisers of the course. This is the second year of the course and there have been some minor changes on the basis of comments received about the course. Please contact us by e.mail or by coming to see any of us in our lab offices.