Organic Chemistry

Coursework Task

Part 1
You are a member of a drug discovery team working on the development of a new orally administered β-blocker for the treatment of abnormal heart rhythms. Your team have developed three lead compounds (A, B and C) which are found to have similar levels of potency.

Compound A
Compound B Compound C.

You have been asked to report your current findings to a review panel that will make a decision on which compound(s) should continue into biological testing and which compound(s) should be terminated. In order to help you, the review panel have returned the following questions;

A) i) The panel would like to know whether the new compounds are likely to be suitable for oral administration. In order to establish this you may want to consider if these compounds meet Lipinski’s “rule of 5” and Veber’s rules.
(9 marks)

ii) In addation, the panel would like to know two assays which could be used to assess the compounds permeability. Brielfy exaplain each.
(6 marks)

B) The panel would like to know whether the compounds are likely to show any toxicity.

i) Identify possible structural alerts (ie fragments which may result in toxicity) present in compounds A, B and C which may lead to toxic side effects. For the structural alerts you have identified suggest possible isoterer which would lead to a reduction in toxicity.
(9 marks)

ii) Indicate a total of FIVE possible metabolites which maybe observed in Compounds A, B or C. These should include a mixture of phase 1 and phase 2 metabolism products. For each, highlight if the metabolite is likly to result in increased toxicty or aid in excreation.
(10 mark)

C) In your assessments, you have used a number of chemoinformatics approaches to generate predictions of toxicity.

i) Some panel members are questioning these methods and the panel would like to know the advantages and disadvantages of using chemoinformatics.
(8 marks)

ii) In order to run your compounds though such software, state the SMILES notations for TWO of your compounds.
(6 marks)

D) Based on all of the above, indicate to the panel if each compound should progress into biological testing or should be terminated. Provide justification for all recommendations.
(12 marks)

PART 1 – TOTAL 60 MARKS
Part 2
Your team have experience in the synthesis of a related β-blocker, compound D. The panel have asked for you to present information on your synthesis of compound D. The route your team has developed involves six chemical steps, shown below;

A) Explain the reaction occurring in Step 1.

Your answer should include details related to pKa, any by-products formed during the reaction, weather the reaction is likely to proceed via an SN1 or SN2 mechanism. You are also asked to draw a detailed “curly arrow” mechanism for this step.
(10 marks)

B) Compound E has the molecular formula of C11H11FO4 and has the indicated key spectroscopic data.

i) Identify the structure of Compound E, providing a justification for your structure.
(5 marks)

ii) Provide the reagents required to achieve Steps 3 and 4, and provide a “curly arrow” mechanism for each step.
(15 marks)

C) Explain the reaction occurring in Step 5, the conversion of the acetal to a ketone.
Your answer should include, a detailed “curly arrow” mechanism for this step, including all tetrahedral intermediates and reference to any equilibrium or steps required to achieve a high yield of ketone formation.
(15 marks)

D) Provide two possible reagents which could accomplish Step 6. Indicate the most appropriate reagent and justify your choice.
(5 marks)

E) Calculate the expected amount (mass and mmols) of Compound D synthesised according to the Scheme.
(5 marks)
PART 2 – TOTAL 55 MARKS