Cyclooctatetraene H was an exceedingly important molecule in the development of the theory of organi — Organic Chemistry Chemistry Question
Cyclooctatetraene
Cyclooctatetraene H was an exceedingly important molecule in the development of the theory of organic chemistry. It belongs to a class of compounds which, although they have alternating single and double bonds in a ring, do not benefit from the increase in stability that aromatic compounds such as benzene do. Cyclooctatetraene was first synthesised by Willstätter starting from the natural product pseudopelletierine A, according to the scheme below; in 1940 Reppe reported a one step synthesis of cyclooctatetraene from acetylene thus making this previously precious laboratory chemical into a commercially available material.
[VISUAL]
Pseudopelletierine A is a natural product found in the bark of the pomegranate. Biochemical labelling studies have shown that it is biosynthesised from lysine W, and ethanoate via ∆1–piperideine X, pelletierine Y and N-methylpelletierine Z.
Identify intermediates B, C, and D.
Model Answer
[VISUAL] (The structures of intermediates B, C, and D are shown in the solutions section: B is the alcohol derived from ketone reduction, C is the dehydrated bicyclic alkene, and D is the quaternary ammonium iodide salt formed by methylation with methyl iodide).
Suggest reagents for the conversion of D into E, E into F, F into G and G into cyclooctatetraene.
Model Answer
[VISUAL] (The reagents are shown in the solutions section: D to E: base (elimination), Ag2O was actually used; E to F: i) MeI, ii) Ag2O; F to G: i) Br2, ii) 2 Me2NH; G to H: i) MeI, ii) Ag2O).
The route by which pelletierine is formed from ∆1–piperideine and ethanoate was determined using 13C labelling studies. Four possible routes can be postulated:
[VISUAL]
To distinguish between the different biosynthetic routes two experiments were carried out. In the first experiment plants were fed a mixture of sodium ethanoate labelled with 13C at both carbon positions (sodium [1,2-13C2]ethanoate) and the unlabelled compound (a mixture was used to increase the probability that only a single labelled ethanoate molecule would be incorporated into each molecule of pelletierene).
Draw structures of pelletierine indicating the position at which 13C labels would appear in each of the biosynthetic routes. You may assume that in each case only one of the incorporated ethanoate molecules was 13C labelled.
Model Answer
The positions at which 13C labels would appear if each of the biosynthetic routes were followed are indicated with an asterisk:
[VISUAL]
Which biosynthetic routes can be distinguished in this experiment?
Model Answer
Routes I & III can be distinguished from II & IV in this experiment.
In a second experiment plants were fed a mixture of sodium 3-oxobutanoate labelled with 13C at all carbon positions (sodium [1,2,3,4-13C4]3-oxobutanoate) and the unlabelled compound.
Which biosynthetic routes can be distinguished in this experiment?
Model Answer
Routes I & II can be distinguished from III & IV in this experiment.
N-methylpelletierene was isolated from plants grown in each of the experiments and also from plants grown in presence of compounds with a natural abundance of 13C (the control experiment). The 13C NMR spectrum of each of the samples was recorded.
In N-methylpelletierene isolated from the control experiment atoms labelled j, k and l in the structure shown below [VISUAL] have 13C NMR chemical shifts of 31.0, 207.8 and 47.1 respectively. Each of these peaks is a singlet. These peaks also appear in the spectra of N-methylpelletierene isolated in experiments 1 and 2, however there are also the following additional peaks:
Experiment 1:
- 13C shift (ppm): 31.0 | Multiplicity: doublet | Coupling constant (Hz): 40.4 ± 1.8
- 13C shift (ppm): 207.8 | Multiplicity: doublet | Coupling constant (Hz): 39.5 ± 1.8
Experiment 2:
- 13C shift (ppm): 31.0 | Multiplicity: doublet of doublets | Coupling constant (Hz): 39.8 ± 1.8, 14.4 ± 1.8
- 13C shift (ppm): 47.1 | Multiplicity: doublet of doublets | Coupling constant (Hz): 39.4 ± 1.8, 13.7 ± 1.8
- 13C shift (ppm): 208.7 | Multiplicity: doublet of doublets | Coupling constant (Hz): 39.4 ± 1.8, 39.5 ± 1.8
Which route does the biosynthesis of pelletierene follow?
Model Answer
The additional peaks in the NMR spectra from experiments 1 and 2 arise from coupling between 13C nuclei. Experiment 1 shows that carbons k and j are 13C labelled, thus pelletierene must be synthesised via route I or route III. In experiment 2, a 13C label is seen at carbon j, k, and l showing that the biosynthesis proceeds via route I.