Epimerizable substrates

Researchers found electron-rich iV-vinyl and iV-aryl amides proceeded to afford the corresponding pyrimidine derivatives at the ambient temperature however, less reactive substrates required heating for reactions to proceed. The use of epimerizable substrates provided the corresponding pyrimidine derivatives without any loss in optical activity. 

When the substrate is readily epimerizable, as with 3, the problem is even easier. Xumu Zhang of Pennsylvania State University reports (J. Am. Chem. Soc. 2004,126, 1626) the development of a chiral Ru complex (derived from C,-Tunephos) that selectively hydrogenates one of the two interconverting enantiomers of 3, delivering 4 with high enantioselectivity and diastereoselectivity. 

Thus, the need has arisen for larger amounts of unnatural amino acids—those that contain unusual side chains or are in the D-series. Because a-amino acids contain an epimerizable center, D-amino acids are usually accessible through epimerization of the natural isomer, followed by a resolution. Of course, the racemic mixture can also be accessed by synthesis. Because resolution can be either wasteful—if the undesired isomer is discarded—or clumsy—when the other isomer is recycled through an epimerization protocol—many large-scale methods now rely on a dynamic resolution, where all of the starting material is converted to the desired isomer (vide infra, Chapters 6 and 7). With the advent of asymmetric reactions that can be performed at large scale, a substrate can now be converted to the required stereoisomer without the need for any extra steps associated with a resolution approach. 

Dynamic kinetic resolution can occur for oc-substituted P-keto esters with epimerizable substituents provided that racemization of the antipodes 33 and 34 is rapid with respect to the Ru(BINAP)-catalyzed reduction, thereby potentially allowing the formation of a single diastereoisomer (Scheme 9). Deuterium labeling experiments have confirmed the rapid equilibrium of epimers at C-2 [36], Generally, the configuration of C-3 is governed by the chirality of BINAP, whereas the configuration at C-2 is substrate specific. 

However, this facile epimerization phenomenon was viewed as an opportunity, rather than a liability, to dramatically refine the oxazinone route. Within our process research group, it is commonplace to consider a crystallization-driven racemization resolution protocol whenever an epimerizable stereocenter exists in a molecule. Such an approach towards diastereomerically pure substrates simply relies on differences in the solubility of the diastereomeric products and on the ability of the undefined stereocenter to epimerize under the conditions used in the crystallization. In fact, these processes can effectively rival catalytic asymmetric synthesis and the literature is replete with recent examples of resolution/racemization approaches to chiral molecules. ... 

Weaker bases have been employed to reduce or even avoid the epimeiization of the stereocenter adjacent to the aldehyde group of the substrate in the HWE reaction. For example, Myers etal. have found that lithium 1,1,1,3,3,3-hexafluoroisopropoxide (LiHFI) promotes the HWE olefination of epimerizable aldehydes with dimethyl-phosphonoacetates to afford the desired alkenes with little or no epimerizatiOTi and with high E selectivity [168]. 

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