Pathway optimization technique

The clinical demand for (—)-galanthamine together with the erosion of habitat of at least some of the source plants has created supply issues. As a result, new means of production of the alkaloid are being sought with in vitro cultivation and pathway optimization techniques (in which the biosynthetic pathway is tweaked ) being prominent among these. To date, no industrially applicable (cost-effective) chemical synthesis of compound 1... 

In Chap. 2, we have seen that the theoretical study of a molecular system is, in a vast majority of cases, separated in two steps. In a first step, the electronic structure of the system is studied by solving the electronic Schrodinger equation with fixed nuclei. This approach, combined with geometry optimization techniques, allows one to locate the important features of the various potential energy surfaces (PESs) of the electronic states of interest. In the context of photochemistry, as seen in Chap. 3, this approach allows one to characterize the various decay pathways of the molecule after photoexcitation. This information can then be used to interpret the various decay time constants obtained from time-resolved spectroscopic measurements. However, in most cases, including aniline studied in Chap. 3, various decay mechanisms are in competition, and it is often difficult to infer, from this static information, the relative importance of the various decay mechanisms. It is thus often necessary to study the dynamics of the nuclei in the manifold of the excited states of interest to obtain a deeper insight into the photophysics and photochemistry of the system of interest. 

Metabolic control analysis (MCA) assigns a flux control coefficient (FCC) to each step in the pathway and considers the sum of the coefficients. Competing pathway components may have negative FCCs. To measure FCCs, a variety of experimental techniques including radio isotopomers and pulse chase experiments are necessary in a tissue culture system. Perturbation of the system, for example, with over-expression of various genes can be applied iteratively to understand and optimize product accumulation. 

Another related technique is the use of critical pathways. A critical pathway or clinical care plan is a detailed plan of care for a specific diagnosis, disease, or procedure [27], It describes the use and timing of all the care activities to try to optimize cost-effectiveness and improve patient outcomes. Critical pathways are much more specific than practice guidelines, which means they tend to take much more effort to produce. However, their comprehensive nature can enhance communication and coordination by different practitioners who are providing care to a particular patient. While critical pathways have been accepted within hospitals, their adoption for ambulatory care has been mixed. 

There are many problems associated with carrying out asymmetric synthesis at scale. Many asymmetric transformations reported in the literature use the technique of low temperature to allow differentiation of the two possible diastereoisomeric reaction pathways. In some cases, the temperature requirements to see good asymmetric induction can be as low as -100°C. To obtain this temperature in a reactor is costly in terms of cooling and also presents problems associated with materials of construction and the removal of heat associated with the exotherm of the reaction itself. It is comforting to see that many asymmetric catalytic reactions do not require the use of low temperature. However, the small number of robust reactions often leads development chemists to resort to a few tried and tested approaches, namely chiral pool synthesis, use of a chiral auxiliary, or resolution. In addition, the scope and limitations associated with the use of a chiral catalyst often result in a less than optimal sequence either because the catalyst does not work well on the necessary substrate or the preparation of that substrate is long and costly. Thus, the availability of a number of different approaches helps to minimize these problems (Chapter 2). 

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