GAMBACORTA, GUIDO (2022) New Synthetic Routes for Natural and Synthetic Fragrance Ingredients. Doctoral thesis, Durham University.
|PDF (PhD thesis) - Accepted Version|
Research & development of alternative routes for fragrance ingredients currently produced by International Flavours & Fragrances Inc. (IFF) in Benicarlò, Spain is reported herein. Past and current industrial syntheses of these ingredients are initially summarised as well as their primary role in the industry. The research disclosed has focused on designing and developing sustainable and safe methods for their industrial preparation and, where possible, evaluation to/of continuous flow approaches.
The first target was the musky, earthy natural ingredient known as Veramoss. For this molecule, three alternative synthetic pathways were explored starting with cheap and widely available raw materials such as butanone, dimethyl malonate, methyl acetoacetate, methyl crotonate, and acetaldehyde. Despite being unable to achieve the final compound, the study enabled the development of a continuous-flow Knoevenagel reaction employing polymer-supported dimethylamine catalyst to obtain dimethyl ethylidene malonate in moderate yields (38%) as well as an interesting one-pot methodology for the preparation of 4-chlorohex-4-en-3-one from dimethyl oxalate and butanone in good yields (76%). These developed methodologies could become interesting starting points for future works. Along with route scouting, the main goal of the project was to propose an improved “green” alternative to the currently employed toxic elemental chlorine. To this aim, four main alternative chlorination processes were investigated, one of which proved to be the candidate of choice: trichloroisocyanuric acid (TCCA). An optimisation based on utilizing TCCA was carried out by employing one-factor-at-the-time (OFAT) and design of experiment (DoE) approaches. The optimised one-pot procedure was scaled up to multi-grams quantities allowing the isolation of Veramoss whose quality was validated for commercial purposes. Furthermore, the study also proposed a de novo procedure for the purification of discoloured Veramoss obtained from mischarge and side reactions during chlorination. The methodology based upon selective phenol-amine H-bonded complex formation allowed the recovery of purified white material in 60% overall yield, reducing waste and the need to dispose of discoloured batches.
The second target molecule was the newly established IFF compound Ambertonic™, a synthetic tricyclic musk odorant featuring a pyrimidine scaffold. The investigation focused on finding valuable alternative routes starting from a readily available intermediate: Cashmeran. Five viable methods were explored, however, only one allowed the ultimate cyclisation to occur. The effective strategy was then optimised for the preparation of the material. Hence, a two steps one-pot synthesis was developed to yield Ambertonic™ in good yield (53%). The methodology consists in the formylation of the dihydro-cashmeran material with subsequent pyrimidine formation inspire by a publication by Bredereck et al. The optimisation of both stages were initially found to be challenging presenting low yields, solid precipitation, and formation of impurities. Scouting different reaction conditions and parameters, the issues were tackled and eventually solved. Additionally, the first SCXRD structure and racemic resolution of the trans-isomer was carried out allowing us to gain a deeper understanding of the absolute configuration of the active odorant species.
The final target investigated was dehydroherbac, a key intermediate for the preparation of the fresh, green odorant known as Galbascone. Three synthetic routes were envisioned starting from different raw materials such as acrylonitrile, 4,4-dimethylcyclohexanone, 5-methyl-hexan-2-one, and 3-carene. Two of the proposed strategies aimed at preparing an enaminone intermediate which undergoes de-amination through selective enamine reduction and elimination. The latter procedure ultimately proved to be impracticable on the desired scaffold. Regardless of the outcomes, a continuous-flow photo-catalysed method for the preparation of a cyano-ketone was optimised to yield 630 mg h-1 of material in 63% isolated yield as a proof-of-concept study. Employing 3-carene as a precursor was also considered through catalytic hydrogenolysis and CH activation of a tertiary carbon. Such a strategy allowed access to three possible oxidative hydroxylation methods as described in the literature utilising dioxiranes, and peracids. Due to the lack of time, the investigation was not completed, however it has established a solid foundation for future work. The project also involved the optimisation of a previously designed route to Galbascone via a Henry-Nef reaction. Kinetic studies performed on the amine-catalysed Henry reaction enabled establishment of a better understanding of the latter and reduced the amount of nitroethane employed for the reaction.
In summary, potential preparative routes to the three fragrance ingredients were developed and optimised. The process utilised known chemistry which employs safe and cheap raw materials. Both the developed methodologies for Veramoss and Galbascone have also been considered for scale up at IFF in Benicarlò, achieving interesting manufacturing results.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Keywords:||Fragrance; Flavours; Organic Chemistry; Process Development; Flow Chemistry|
|Faculty and Department:||Faculty of Science > Chemistry, Department of|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||08 Dec 2022 11:18|