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Azulene-based Protecting Groups

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thesis
posted on 15.11.2021, 17:43 by Bevan, Thomas

Protecting groups form an indispensable part of modern organic synthetic chemistry. Besides the benefits of selectively passivating certain reactive functionalities, they often provide handling benefits – such as a decrease in the polarity of the compound that facilitates purification, an increase in the structural order of a compound that allows for easier crystallisation, and chromophores that enable easy visualisation on fluorescent TLC plates under UV light.  Coloured protecting groups offer additional advantages in synthetic chemistry. They expedite purification by allowing the material to be tracked visually. Phase separation and column chromatography are easier to perform, and reduce the need for the collection of large numbers of fractions, while small-scale loss of material (left behind on taps or in flasks during routine handling) and spillages are much more readily apparent. Despite these advantages, only a few coloured protecting groups have been reported in the literature.  The azulenes are a class of compounds with several attractive qualities that can be exploited for use as protecting groups. They are coloured, but not overwhelmingly so. The colour is tunable through placement of electron-donating or electron-withdrawing groups at positions on the ring system, which further allows for protection/deprotection reactions to be designed that incorporate a colour change. Azulene itself is both non-polar and structurally compact, unlike many other organic chromophores such as triarylmethane dyes and carotenoids. Furthermore, azulene’s ability to stabilise both positive and negative charges through resonance with tropylium and cyclopentadienide motifs allows for unusual chemistry, and therefore potentially orthogonal modes of deprotection.  Four protecting group candidates incorporating azulene were devised. The 1-azulenylmethylene amine 79 and the 1-azulenesulfonamide 82 protecting group candidates for amines had fatal flaws that were discovered early, such as a tendency to rapidly degrade in open air. The 1-azulenecarboxylate protecting group candidate 74 for alcohols showed some promise, with a high-yielding protection reaction, but none of the deprotection conditions that were developed were sufficiently mild to be usable in a late-stage deprotection strategy on a complex target molecule.  The final protecting group candidate, 6-(2-[oxycarbonyl]ethyl)azulene 89, can be used for the protection of carboxylic acids, amines and alcohols as esters, carbamates and carbonates, respectively. The substitution at the 6-position of azulene allows for deprotection through an E1cB mechanism with mild base, involving a cyclopentadienide-stabilised carbanion intermediate, in a similar fashion to the FMOC protecting group. Mild conditions for the protection of all three were found: for carboxylic acids Steglich esterification is employed, and for alcohols and amines coupling with CDI is used. A selection of mild protocols for deprotection were developed, using bases such as DBU or TBAF, or involving two-step activation-deprotection procedures.  Finally, the compatibility of the protecting group 89 (dubbed Azul) with common and representative procedures in synthetic chemistry was investigated, such as with bases and with reaction conditions such as oxidations, reductions, cross-couplings, etc. Orthogonality with other common protecting groups (such as TBS, MOM, FMOC) was also explored. Some incompatibilities were found with strongly acidic conditions, high-temperature Suzuki cross-coupling reactions and Swern oxidations, but otherwise the Azul protecting group shows promise as a protecting group that expedites total synthesis through its colourful properties.

History

Copyright Date

01/01/2016

Date of Award

01/01/2016

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Chemistry

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Doctoral

Degree Name

Doctor of Philosophy

ANZSRC Type Of Activity code

970103 Expanding Knowledge in the Chemical Sciences

Victoria University of Wellington Item Type

Awarded Doctoral Thesis

Language

en_NZ

Victoria University of Wellington School

School of Chemical and Physical Sciences

Advisors

Harvey, Joanne