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Pyrrole as a scaffold for the synthesis of complex molecules

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Olivier, WJ ORCID: 0000-0002-8838-9609 2021 , 'Pyrrole as a scaffold for the synthesis of complex molecules', PhD thesis, University of Tasmania.

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Abstract

A new, Brønsted-acid-mediated method for the efficient conjugate addition of pyrroles bearing N-tethered α,β-unsaturated esters (1, 2) and ketones (6) has been developed. This study highlighted significant differences in reactivity dependent on the identity of the Michael acceptor. Specifically, α,β-unsaturated ketone 6 cyclised under mildly acidic conditions, through exposure to silica gel, while esters 1 and 2 were unreactive under these conditions. However, treatment of these ester substrates with stronger acids promoted cyclisation, with methanesulfonic acid providing optimal results. This annulation methodology was applied to facilitate racemic total syntheses of the indolizidine alkaloids tashiromine (8) and indolizidine 209I (9). The former was synthesised in only five steps from commercially available starting material 5.
[Chemical diagram from thesis abstract in the PDF not included here].
A number of more complex polycyclic alkaloids, belonging to the Stemona alkaloid class, have also been accessed. Specifically, the first total syntheses of sessilifoliamides B (10) and D (12) and the second synthesis of sessilifoliamide C (11) were achieved from a simple pyrrole starting material. The bicyclic lactam core was obtained on a gram-scale, with a methanesulfonic-acid-mediated cyclisation of ester 2 and an efficient oxidative dearomatisation/hydrogenation strategy constituting the key transformations in the synthetic sequence. Overall, sessilifoliamide C (and its C-11 epimer) were synthesised in 24% yield over 11 steps, in addition to sessilifoliamide B and D which were accessed in 13 and 17 steps, respectively.
[Chemical diagram from thesis abstract in the PDF not included here].
The total syntheses of the tetracyclic pyrrole natural product dehydrostenine A (13) along with the structure originally assigned to dehydrostenine B (14), were also completed from a pyrrole starting material in 10 and 11 steps, respectively. The core tetracyclic structure of these compounds (i.e., heterocycle 16) was constructed via a Brønsted-acid-promoted conjugate addition of a pyrroloazepine bearing a pendant α,β-unsaturated lactone (i.e., lactone 15). Significantly, the results of this study along with analysis of complementary reported synthetic studies, reveal that the structures assigned to dehydrostenines A and B in the original isolation work were incorrect and, thus, revisions to the structures of these natural products have been proposed.
[Chemical diagram from thesis abstract in the PDF not included here].
Finally, a number of unexpected results obtained during these studies employing intramolecular conjugate additions of pyrroles to construct the bicyclic or tetracyclic architecture of these Stemona alkaloids, were investigated and rationalised by employing experiment and density functional theory.

Item Type: Thesis - PhD
Authors/Creators:Olivier, WJ
Keywords: Pyrrole, cyclisation, Michael addition, sessilifoliamide, dehydrostenine, stemona, alkaloid, conjugate addition
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Copyright 2021 the author

Additional Information:

Chapter 1 includes the following published article: Olivier, W. J., Smith, J. A., Bissember, A. C., 2018. Methods for the synthesis of annulated pyrroles via cyclisation strategies, Organic & biomolecular chemistry, 16(8), 1216–1226.

Chapter 2 includes the following published article: Olivier, W. J., Gardiner, M. G., Bissember, A. C., Smith, J. A., 2018. Brønsted acid-mediated annulations of pyrroles featuring N-tethered α,β-unsaturated ketones and esters: Total syntheses of (±)-tashiromine and (±)-indolizidine 209I, Tetrahedron, 74(38), 5436–5441.

Chapter 3 includes a published article which is reprinted with permission from: Olivier, W. J., Bissember, A. C., Smith, J. A., 2021, Unified total syntheses of (±)-sessilifoliamides B, C, and D., Organic letters, 23(9), 3437-3441. Copyright 2021 American Chemical Society.

Chapter 5 includes a published article which is reprinted with permission from: Olivier, W. J., BabaAhmadi, R., Lucas, N. T., Ariafard, A., Bissember, A. C., Smith, J. A., 2021. Exploring cyclization strategies to access Stemona alkaloids:
subtle effects influencing reactivity in intramolecular Michael additions, Organic letters, 23(21), 8494–8498. Copyright 2021 American Chemical Society.

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