Bodwell Group Research Interests
NOVEL AROMATICS - Nonplanar Aromatic Compounds, Cyclophanes and Molecular Switches
1. Pyrenophanes.

Work in this area relies on the valence isomerization / dehydrogenation (VID) reaction to construct molecules that contain nonplanar pyrene moieties. Our group has so far prepared a wide variety of [n](2,7)pyrenophanes 2 from the corresponding tethered [2.2]metacyclophanedienes 1. Future work in this area will be directed towards the chiral systems such as 3, in which the chirality is a consequence of the substitution pattern of the pyrene unit, and 4, which has stereogenic centres in the bridges. Such systems may exhibit intriguing chiroptical properties or serve as ligands.

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2. Aromatic Belts.

Aromatic belts have been challenging synthetic targets for at least three decades, but no such system has yet been reported. Having established that the VID reaction can lead to the formation of severely distorted pyrene units, our group is actively pursuing the synthesis of a series of "Vögtle Belts", e.g. 7, from the potential precursors 5 and 6. Not only do such belts manifest themselves in the equators of certain fullerenes, but they also constitute small slices of nanotubes.

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3. Buckybowls and Fullerene Isosteres.

The discovery of the fullerenes and the subsequent development of methods for their gram scale production initiated a surge in interest in nonplanar polycyclic aromatic hydrocarbons (Buckybowls). Our interest in this area is to use cyclophanes as precursors to Buckybowls. One approach involves the elaboration of [n](2,7)pyrenophanes 2, in which the nonplanarity of the pyrene system is enforced by the bridge, to produce inherently nonplanar polycyclic aromatic systems, e.g. 8. Another approach involves the use of fluorenophanes, e.g. 9, as a precursor to 10. Another project, not yet initiated, is aimed at the synthesis of the first azacorannulenes, e.g. 11, through the use of IEDDA chemistry (see below).

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4. Tethered [2.2]Metacyclophanes.

[2.2]Metacyclophane 12 normally prefer to exist in the anti conformation. Our group has been studying how the presence of a third bridge, a tether, can be used to balance the energies of the syn and anti conformations such that they can interconvert, i.e. 13. The end goal of this work is to develop molecular devices based on this interconversion. Recent work has been directed towards the incorporation of polyether tethers, such that the syn conformer may be capable of complexing a metal cation, but not the anti conformer.

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5. [n](2,7)Dihydropyrenophanes - Tethered [2.2]Metacyclophanediene Switches.

This project is aimed at the development of cyclophane-based photochromic switches. It is based on the valence isomerization between [2.2]metacyclophanedienes 14 and 10b,10c-dihydropyrenes 15. The equilibrium normally lies on the side of the highly coloured dihydropyrene, which means that the colour is difficult, if not impossible, to bleach. We have demonstrated that the incorporation of a bridge can serve to strain the dihydropyrene and thus favour the colourless cyclophanediene, e.g. 16. The search for a tether that will permit some interconversion to the coloured form, e.g. 17, but still result in complete bleaching is underway.

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6. Conformational Behaviour of Cyclophanes.

One of the longstanding reasons for interest in small cyclophanes is their conformational behaviour. Our work in this area has to do with the study of the effect of substituents on the conformational preferences of systems such as 18 and 19. In 18, electron donating substituents favour chair conformations and electron withdrawing groups favour boat confor-mations. Dipole effects appear to play an important role.

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7. Calix[n]pyrenes.

This project has yet to be initiated. In collaboration with Dr. Paris Georghiou, we plan to prepare calixarenes that contain pyrene or tetrahydropyrene units, i.e. 20. It is envisaged that the presence of large pyrene units will result in the formation of large molecular cavities. As such they may be able to serve as host for large guests such as the fullerenes C60 and C70. The incorporation of appropriate functional groups R may lead to the self assembly of dimeric and polymeric entities that will possess very large cavities or channels.

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8. Cyclophane-Based Supramolecular Assemblies.

This project is a spin-off of project 6 above. Cyclophane 21 can be prepared in three steps and its x-ray crystal structure shows that a hydrogen bonded dimer is present in the solid state. Future work will be aimed determining whether 21 and related compounds can act as supramolecular C-clamps that are capable of holding two other molecules in a face-to-face-orientation, i.e. 22.

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INVERSE ELECTRON DEMAND DIELS-ALDER CHEMISTRY - Methodology and Total Synthesis
1. New Electron Deficient Dienes and their IEDDA Reactions.

The focus of this project is the synthesis of 1,3-dienes bearing electron withdrawing groups (EWG) at the 1 and 3 positions and their application on the IEDDA reaction. Three series of compounds 23-25 have so far been prepared and these react with a variety of electron rich alkenes such as ketene acetals (26 from 23). The most reactive dienophiles are enamines, which undergo IEDDA-initiated domino reactions to afford new aromatic products such as 27 from 24 and 28 from 25. This methodology provides very rapid access to multifunctional small molecules, which are currently being tested as potential therapeutic agents.

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2. Natural Product Targets.

The application of the IEDDA-driven domino reaction for the synthesis of natural products is underway. We are close to completing a short synthesis of benzocoumarin 29, a natural product isolated form squirrel feces, which exhibits antibacterial activity. More ambitious targets are the defucogilvocarcins 30, which exhibit strong anticancer activity.

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3. Transannular IEDDA Reactions of Cyclophanes.

Nitrogen-containing benzenoid aromatics (azines) can serve as dienes in the IEDDA reaction. 1,2-Diazines (pyridazines) are notoriuosly unreactive dienes and indoles are not very reactive dienophiles. However, when suitably constrained as in cyclophane 31 (3 step synthesis), intramolecular IEDDA reaction can occur to afford, following expulsion of nitrogen, pentacyclic system 32, which is structurally related to a number of indole alkaloids such as strychnine 33. More recently, we have succeeded in preparing cyclophane 34 and this reacts to afford 35. This was converted in three synthetic operations to give 36, which constitutes a very concise formal total synthesis of (±)-strychnine 33. Future work in this area will focus on our own total synthesis of strychnine in both racemic and enantiomerically pure form. Other complex indole alkaloids should also be accessible by our "cyclophane route".

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