Stoichiometric ADH

Figure 5.7 Calculated dependence of the weight-average degree of polymerization of molecules, (P)w, and hard clusters, (Pc)w, on conversion in a stoichiometric Adh) + B2(h) + B2(s) system (h - hard, s - soft). The system corresponds to a mixture of short and hard chains crosslinked with a tetrafunctional crosslinking agent...

Moreover, looking for more effective ligands, Sharpless and his group prepared and tested a number of cinchona alkaloid derivatives, first in the stoichiometric ADH process [33] and then in the catalytic process. They found that aryl ethers of dihydroquinidine, as 4a and 4b, are excellent ligands for ADH of dialkyl substituted olefins (Table 10.3). 

In the stoichiometric ADH of ( )-3-hexene the highest ee was achieved using the ligand 4b (88% ee). On the other hand, the catalytic process (Table 10.4, entries 1-3) was carried out by slow addition of ( )-3-hexene (1 equiv.) to a mixture of 4a (0.25 equiv.), A-methylmorpholine A-oxide (NMO, 1.5 equiv.) and OSO4 (0.004 equiv.) in acetone-water (10/1, v/v) at 0 °C, followed by working-up with Na2S205. Although the catalytic reaction was slow and required a slower addition... 

The stoichiometric ADH of olefins was performed by adding 1 equiv. of olefin to a 1 1 mixture of Os04 and 4a in dry toluene (O.IM in 4a), followed by reductive working-up with LAH to give the () ,) )-diol in 60-95% yield and good to excellent ee. 

Unlike the whole-cell system, enzymatic reductions require the addition of a hydride donating cofactor to regenerate the reduced form of the enzyme. Depending on the chosen ADH, the cofactor is usually NADH or NADPH, both of which are prohibitively expensive for use in stoichiometric quantities at scale. Given the criticality of cofactor cost, numerous methods of in situ cofactor regeneration, both chemical and biocatalytic, have been investigated. However, only biocatalytic regeneration has so far proven to be sufficiently selective to provide the cofactor total turnover numbers of at least 10 required in production. 

In fact, although good enantioselectivities in ADH of dialkyl substituted olefins could be previously obtained through the use of stoichiometric reagents at low temperature [34], the catalytic ADH developed by Sharpless is by far the best method that the synthetic organic chemist has presently at his hands. l... 

Only in the case of alcohol dehydrogenase (ADH)-catalyzed reactions, a substrate-coupled system can be applied, in which the enzyme that transforms the substrate of interest also regenerates the cofactor at the expense of a co-substrate to be used in at least stoichiometric amounts with respect to the substrate. 

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