Synthesis, thermodynamically controlled

Entries 7, 8, and 10 describe so-called Idnetically controlled syntheses starting from activated substrates such as ethyl esters or lactose. In two reaction systems it was possible to demonstrate that ionic liquids can also be useful in a thermodynamically controlled synthesis starting with the single components (Entry 11) [39]. In both cases, as with the results presented in entry 6, the ionic liquids were used with addition of less than 1 % water, necessary to maintain the enzyme activity. The yields observed were similar or better than those obtained with conventional organic solvents. 

Eurlan RLE, Otto S, Sanders JKM. Supramolecular templating in thermodynamically controlled synthesis. Ptoc Natl Acad Sci USA 2002 99 4801-4804. 

Compared to thermodynamically controlled synthesis, the initial rates of kinetically controlled synthesis are usually faster and the conversion can be complete. 

Figure 12.2 Time courses of kinetically controlled and thermodynamically controlled synthesis. The dotted line represents the position of the thermodynamic equilibrium.

PGME ADCA Cephalexin Thermodynamically controlled synthesis 100 Very high substrate concentrations (>750mM) with PGME/ADCA = 3. 85... 

Scheme 12.3 Enzymatic production of pi-lactam antibiotics (cephalosporins and penicillins) via kinetically or thermodynamically controlled synthesis.

Fig. 18 Thermodynamically controlled synthesis of chiral host 34.127 Energy-minimized structures of 34 (MM2) are shown on the right. (For color version of this figure, the reader is referred to the web version of this book.)...

The thermodynamically controlled synthesis gives rise to another advantage of metal-directed assembly the capability to correct mistakes within the assembly until the final product is formed. The reversibility of M-L bond formation means that large assemblies and the individual components are in equilibrium until a stable product is formed. Many small assemblies form in the reaction mixture, some of which continue to grow towards the final product while others fall apart and their components are recycled. 

Enzymatic peptide synthesis can proceed by two mechanisms thermodynamic and kinetic control (Kumar and Bhalla 2005). The thermodynamically controlled synthesis of peptides (TCS) with proteases represents the reverse of the hydrolytic breakage of peptide bond catalyzed by those enzymes, as shown in the scheme (Jakubke et al. 1985) ... 

Nierstrasz VA, Schroen CGPH, Bosma R et al. (1999) Thermodynamically controlled synthesis of cefamandole. Biocatal Biotransform 17 209-223... 

Schroen CGP, Nierstrasz VA, Kroon PJ et aL (1999) Thermodynamically controlled synthesis of 13-lactam antibiotics. Equilibrium concentrations and side-chain properties. Enzyme Microb Technol 24 489-506... 

Industrial enzymes are usually hydrolases that catalyse hydrolysis or synthesis reactions in aqueous environments. For thermodynamically controlled hydrolysis reactions, the equilibria can - in principle - be shifted completely to the product-side by dilution (increasing entropy of product formation). Thermodynamically controlled synthesis reactions using the reverse action of hydrolases can be enhanced by using excess of the cheaper reactants. This does not lead to compact processes, and affects their economic feasibiUty in a negative maimer. Therefore, possibilities to selectively remove reaction products from each other or fi om the reactors during the reaction are very attractive. 

Diender MB, Straathof AJJ, van der Wielen LAM, Ras C, Heijnen JJ (1998) Feasibility of the thermodynamically controlled synthesis of amoxicillin. J Mol Catalysis B Enzymatic 5 249-253... 

Thermodynamic control in organic synthesis is very familiar, for example, in the synthesis of esters, acetals, or imines. Specific product formation can be favored by shifting the equilibrium position, through the removal or addition of water, the choice of solvent, the use of excess reagents, or by controlling the temperature and pressure of the reaction. Templates may be used in thermodynamically controlled synthesis to guide the system towards the production of a desired product that fits the template. 

The success of chemoenz)nnatic peptide synthesis is critically dependent on the availability of effective peptide coupling and modification enzymes, both in the case of kinetically controlled synthesis with an activated acyl donor and in tire case of thermodynamically controlled synthesis starting with free amino acids or peptides. If the coupling reaction case is kinetically controlled, critical properties are a high synthesis/hydrolysis... 

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