Perspective

The research described in this thesis, executed as part of the CatchBio program,1 _{focuses on}

developing novel catalytic methodologies for the conversion of renewables from biomass into fuels, chemicals and pharmaceuticals. Regarding chemicals from biomass, two strategies can be followed as is shown in Figure 7.1.2 _{A drop-in strategy relies heavily on existing}

infrastructure by generating common intermediates from biomass that can be directly fed into the fossil feedstock stream. In order to make this strategy interesting, a competitive process is required for the generation of the particular intermediate. As an alternative, an emerging strategy is possible, which is totally detached from the current chemical process chain and the renewables from biomass are therefore converted into new chemical targets. Thus, instead of aiming at known chemical targets from the fossil feedstock product stream, this strategy anticipates on finding new targets by efficiently using the functionalities that are contained in the renewables from biomass. Although the emerging strategy brings significant challenges, it may also offer great opportunities by giving access to new and unrevealed products. This is clearly illustrated by the exemplary case of PEF (polyethylene furanoate). PEF is a plant- based plastic derived from furandicarboxylic acid and can be directly utilized as a substituent for PET (polyethylene terephthalate). The Dutch company Avantium, which is world leading regarding PEF production and development, has recently closed a multimillion deal with several multinationals in order to make a leap towards commercial scale manufacturing of this novel plastic.3 _{PEF is therefore a typical example of a new innovative product that}

exploits the functionalities offered by the renewable resources from biomass.

Figure 7.1 Two strategies for the conversion of renewables from biomass into target chemicals.

As demonstrated by the previous example, the emerging strategy offers new opportunities for the chemical industry. However, this strategy is less conveniently applied to the pharmaceutical industry, primarily because Active Pharmaceutical Ingredients (API’s) are specifically designed to exhibit a desired activity and pharmacokinetic profile. Thus, the API’s are fixed and therefore the most obvious way to incorporate renewable resources from biomass is via the drop-in strategy. Albeit that this strategy is the most logical, it certainly has its limitations too. Registration and validation of API production processes are of utmost

importance to have the final products released to the market for human intake. By changing the starting material, the synthetic pathway of the API should often be revised, which is generally associated with costly registration and validation procedures to remain compliant. Notwithstanding these additional costs, changing to alternative starting materials often results in lower production costs and may therefore eventually turn out to be economically beneficial. The work that was described in Chapter 3 may contribute to the field by providing new synthetic methodologies for the preparation of enantiomerically pure piperidinone building bocks starting from renewables from biomass. The synthetic pathway to the targeted piperidinone building blocks might be competitive with the other more established routes to similar scaffolds.4 _{An application of these building blocks was provided in Chapter 6, where}

one of them has been successfully applied in a total synthesis of the natural product (−)- sedacryptine, underlining that they can indeed give access to more complex enantiomerically pure products.

As mentioned above, it is more straightforward to incorporate renewables from biomass via the drop-in strategy, however; the emerging strategy for generating novel pharmaceuticals might also be effective. Usually, the development of a drug commences by screening large compound libraries on their activity against the biological target of interest. By simply extending these libraries with compounds that are derived from biomass, the probability will increase that one of them will emerge as a potential lead compound and eventually may result in a commercial product. The furfural-derived scaffolds that were synthesized in Chapters 4 and 5 are certainly relevant for this purpose. Because their bicyclic frameworks resemble the structural skeleton of biologically active tropane alkaloids, it is anticipated that these scaffolds might also exhibit some form of biological activity.

The scaffolds that were synthesized in this thesis are all derived from furfural, and require multiple reaction steps involving reagents which are not derived from biomass. Therefore, new, preferably catalytic methodologies have to be developed in order to efficiently synthesize the targeted scaffolds without the need to rely on reagents derived from fossil feedstocks. For this reason, we initially investigated iron-based chiral Lewis acids for the activation of imines (see Chapter 1). However, to create asymmetric induction in reactions with imines by means of a chiral iron complex appeared more difficult than anticipated. These findings are in line with the rather limited number of reports on iron-based asymmetric imine activation that have been published since we abandoned this topic two years ago.5

The work described in this thesis only aims at reactions using furfural as a starting material, but there are of course many other renewables from biomass that may give access to pharmaceutically relevant building blocks as well.6 _{The current major renewable resource}

from biomass is lignocellulose, which is composed of lignin, cellulose and hemicellulose and is obtained from forestry remains and agricultural waste. Lignin, a polymeric network of phenols, is considered the most potential resource for aromatics from biomass.7 _However,

conversion of lignin into small molecules that could be used as starting material for the chemical industry remains difficult. On the other hand, the cellulosic and hemicellulosic

components of lignocellulose can be readily converted into platform chemicals (i.e. succinic acid and lactic acid) via chemical transformation or fermentation.6c _{Since oxygen is highly}

abundant in these platform chemicals, introduction of nitrogen, for example via the organocatalyzed Mannich reaction, may turn these chemicals into pharmaceutically relevant building blocks. As an example, ethyl levulinate (1), which is directly derived from the plant- based platform chemical levulinic acid, can be used for the asymmetric Mannich reaction with imine 2 (Scheme 7.1). An initial experiment showed that β-amino ketone 3 was successfully obtained in good yield and excellent ee. Subsequent cyclization under acidic conditions gave access to γ-lactam 4, which may be considered another potentially useful and synthetically versatile building block from biomass.

Scheme 7.1 Organocatalyzed Mannich reaction of ethyl levulinate 1 and subsequent lactamization of 3.