SHARLEY, JAMES,STUART (2017) Improving the Synthesis of Fragrance Ingredients. Doctoral thesis, Durham University.
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Author-imposed embargo until 18 May 2020.
The synthesis of three fragrance ingredients currently manufactured at International Flavours and Fragrances (IFF), Benicarló, Spain are primarily investigated herein. After reviewing the literature surrounding each of these, efforts were made to improve upon their current synthesis through the development of new methodology. Assessments of the compatibility of the developed chemistry, as well as other industrially important transformations, with continuous flow processing were also made.
Hedione (methyl dihydrojasmonate) was the subject of the first of these three projects. Efforts were focused towards novel dehydrohedione (DHH) syntheses from Hedione. A new copper(II) bromide mediated oxidation was firstly developed that was shown to be capable of oxidising the Hedione enol-acetate to DHH in high yield. The methodology was also applied to a range of other substrates including to the synthesis of a phenol. A catalytic system was also developed and demonstrated on a model substrate derived from desoxyanisoin. A second novel DHH synthesis was achieved by direct Hedione oxidation via an α-chloro intermediate which underwent spontaneous elimination in methanol. Of the chlorinating agents used, sulfuryl chloride was found to be the best, giving DHH yields of 77%, an improvement upon the 71% yield associated with the currently used three-step process. The process was found to be easily scalable and its amenability to flow was demonstrated.
The second project involved an assessment of a Diels-Alder reaction currently used by IFF for the synthesis of Isofloriffone, a precursor to δ-Damascone. The reaction is currently catalysed using AlCl3 in high loading and an alternative catalytic system was sought. While none of the alternative methods employed gave yields that came close to those achieved with AlCl3, key factors influencing the yield were identified as the AlCl3 loading and the temperature, which must be kept low enough to prevent a runaway/diene polymerisation. The Lewis acid catalysed reaction, as it stands is not suited to flow, however, it is proposed that many thermal Diels-Alder processes in the flavour and fragrance industry would benefit from continuous flow manufacturing protocols.
The final project involved the synthesis of α-dehydroherbac, a precursor to a fragrance ingredient known as Galbascone. The current process used by IFF gives rise to a mixture of products and was poorly understood prior to this work. Following mechanistic studies, a proposed overall mechanistic pathway for the reaction was outlined that accounted for the products formed and their ratios. Following this, two novel routes towards the desired α-dehydroherbac isomer were investigated. The first of these failed to give the desired product but revealed unprecedented conjugate addition reactivity of a Wittig reagent. The second route developed made use of an irregular nitro-aldol reaction followed by a Nef reaction. High selectivity towards the desired isomer was successfully achieved through steric control of an imine intermediate. The resultant process, offered both an improved yield (51% vs 38% both over two steps) and selectivity (84% vs 50% isomeric purity) over the process used currently and was demonstrated for a range of substrates.
In summary, three new reactions were discovered; an irregular conjugate addition reaction of a Wittig reagent, a catalytic and non-catalytic CuBr2 mediated oxidation of ketones and enol acetates and a one-pot chlorination-elimination oxidation process which is well suited to flow and currently being trialled at pilot plant scale at IFF Benicarló. Key features of the Isofloriffone and α-dehydroherbac industrial processes were also established and a new process based on known chemistry was developed that resulted in higher yields and selectivities than the currently used α-dehydroherbac synthesis.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Keywords:||Flavours & Fragrances, Organic Synthesis, Flow Chemistry|
|Faculty and Department:||Faculty of Science > Chemistry, Department of|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||25 May 2017 09:58|