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Practice Problems in Pericyclic Reactions.

The following are a set of practice problems in Pericyclic Mechanisms, prepared by Henry Rzepa for the for a second year course in Pericyclic Reactions at the Department of Chemistry, Imperial College. Each of these problems is intended to take between 1-3 hours to solve. They are NOT typical of examination questions! Please note also that the compound numbers are not consecutive between questions.

Qu 31. The dicyclopentacyclo-octenyl ring system is common to many natural products. A particularly efficient synthesis of one such system is shown in part below. The first stage involves photolysis of the two reactants shown (R=Me) to produce an intermediate W as a single regio- and stereoisomer. If R=H, a mixture of two regioisomers is produced. Subsequent thermolysis of W (R=Me) produces the final product Z, accompanied by an unexpected change in the stereochemistry at the C-8 carbon. This last observation implicates the intermediacy of X and Y. Discuss the following aspects of these reactions.

  1. Classify the mechanism of the reaction resulting in the formation of compound W. Pay particular attention to the stereochemistry of this product. (8 marks)
  2. Suggest a structure for the additional regioisomer formed when R=H and suggest a reason why this regioisomer is not formed when R=Me. (8 marks)
  3. What other stereoisomers possible for W are consistent with the mechanism you propose in 1 above? Suggest a reason why they are not formed (Hint: you might have to build models to answer this part, ideally using a modelling program). Are there yet more stereoisomers possible which would be inconsistent with the mechanism you propose? (9 marks)
  4. Classify the mechanism of the reaction resulting in the formation of the presumed intermediate X, paying particular attention to explaining its stereochemistry. (9 marks)
  5. On the basis of the mechanism you give in 4, can you suggest an isomer of X, which might also be possible? (Hint: consider the stereochemistry of the double bonds). (8 marks)
  6. Suggest a pericyclic mechanism which would involve the formation of another intermediate Y which might explain the inversion of stereochemistry at C-8, indicating your proposed structure of Y (Hint: rotation about single bonds in intermediate Y might be possible). (9 marks)
  7. What would be the consequence of applying the mechanism proposed for the formation of Y to the stereoisomer of X implied in 5? (9 marks)


Qu 32. The reaction sequences 1 - 4 shown below each involve pericyclic steps. Suggest a possible mechanism for each sequence, together with structures (discuss any stereo or regio-chemical features) for the various unidentified intermediates labelled [A] through to [J], indicate what type of pericyclic reaction, if any, is involved (including appropriate nomenclature), which electron counting rule (4n+2 or 4n) applies and whether the reaction will involve a Huckel or a Mobius transition state.

1. 200200.jpg
(10 marks)
2. 200201.jpg
(10 marks)
3. 200202.jpg (Hint: [D] is monocyclic and [E] is bicyclic).
(12 marks)
4. 200203.jpg

The last step from [J] is assumed to take place in the scrupulous absence of any traces of acid or base catalyst. What mechanism might prevail for this step if such catalysts were indeed present? (18 marks)


Qu 33. As part of a strategy for the synthesis of natural products such as the marine alkaloid hyellazole, the following annelation procedure was developed. Compound U was photolysed, resulting in loss of nitrogen and rearrangement to give a reactive intermediate V. This was treated with the alkyne shown under thermal conditions to give another transient intermediate W, which upon standing thermally rearranged via two more intermediates to the final product Z, the last being in equilibrium with Y. Propose structures for V, X and Y (12 marks) and mechanisms for their formation (13 marks). Include in your answer details of any pericyclic processes involved, including nomenclature and selection rules.


Qu 34. An elegant synthesis of the diterpenoid core of natural products such as tetrodecamycin or the antimalarial drug arteannuin is based on the following reaction. The starting material A is heated (actually as the oxy-anion to accelerate the reaction) to produce a transient intermediate B, which soon isomerises to C (hint: think keto-enol tautomerism for this last reaction). On further heating, C gives mostly isomer D, with traces of E. D in turn rearranges to a transient intermediate F, which again rapidly equilibrates with G (hint: more carbonyl chemistry). Compared with the reactant, G has two new chiral centres (marked with a *), which are formed with high stereospecificity and a third that is not (marked with a wavy bond). The trace isomer E instead gives the alternative diasteroisomer H. Identify the intermediates B, C and F (9 marks) and the pericyclic mechanisms involved in this sequence, including any nomenclature and selection rules you can readily assign (11 marks). Try to propose a model (5 marks) for showing how C can give both D and E (you do not have to explain why D predominates over E) and why D gives the stereochemistry shown in G, whilst E gives H (hint: think chair).


Qu 35. The following sequence is part of a biomimetic synthesis of propionate derived natural products. The tetraene ester is heated to give the tricyclic core B of the natural system, via a presumed intermediate A. Propose a structure for A (10 marks), mechanisms leading to it and B, including nomenclature (10 marks) and using your knowledge of the predicted stereochemistry of your mechanistic steps, predict the stereochemistry of the centre to which the ester group E is attached (5 marks).


Qu 36. The biomimetic synthesis of a potent microtubule-stabilizing agent involves the use of an acyclic precursor C to create the complex pentacyclic chemotherapeutic molecule F, forming seven new stereogenic centres in a fully diastereocontrolled fashion. The step C to D is a conventional macrocyclisation, whilst E to F is a simple lactonisation. Your task is the following;

  1. to propose a mechanism for the thermal transformation D to E (it may involve more than one step!). Include nomenclature of any mechanistic steps (13 marks),
  2. to deduce stereochemistry for the two stereogenic centres shown with a wavy line (2 marks).
  3. to identify the five other new stereogenic centres in E. (5 marks),
  4. if their stereochemistry is indicated in the diagram, to show it is consistent with the mechanism(s) you propose, giving your reasons (3 marks),
  5. if their stereochemistry is NOT indicated in the diagram above, to complete it (2 marks).


Qu 37. The following sequence of reactions starting from compound A (the four bonds marked with a b are in fact benzo derivatives of the alkene, not shown below to retain clarity in the diagram) and B was recently reported as the culmination of a "holy grail" target in chemistry. Reaction via intermediates C, D led to an isolable mixture of two isomers E (each showing the presence of six alkene C-H 1H resonances, as well as aromatic resonances resulting from the benzo groups), one of which was claimed to have a structure with an C2 axis of symmetry and the other a plane of symmetry. Further gentle irradiation led to an equilibrium mixture of five isomers of the [16] annulene F. One of these, after separation by HPLC, proved to be the long sought molecule (and also exhibited a C2 axis of symmetry). Suggest mechanisms for the various transformations, possible structures for the intermediates corresponding to C, E and (only one of) F, and include discussion of why a [16] annulene with a two-fold axis of symmetry might arouse such interest. (Hint: the stereochemistry of the intermediates may not always be unambiguous or necessarily follow selection rules, a point which you might wish to discuss).


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