Stereoselectivity chemistry is a very important subject in the development of organic synthesis. Over the years, relative stereoselectivity (e.g. geometric isomerism) has made nearly perfect progress. However, absolute stereoselectivity, such as optical isomerism, did not make a breakthrough until the early 1980s. There are many types of chiral auxiliaries, among which oxazolidinone and sulfonamides are the most widely used ones. The oxazolidinone chiral auxiliary was first developed by Evans, so it is called Evans' chiral auxiliary. It is widely used in asymmetric syntheses, such as asymmetric alkylation reaction, Aldol condensation reaction, Diels-Alder reaction, and 1,3-dipolar cycloaddition reaction. This reagent is characterized by:
It is worth mentioning that many oxazolidinone reagents have been commercialized and two enantiomers are now available:
In Evans' method, the oxazolidinone chiral agent starts from the formation of a carbonyl imide compound. The open-chain imide acts with the base to form an enolate (Li, Na), which is then chelated by the metal to form a ring system. The stereoselectivity of the reaction is achieved by the induction of the chiral center in the system. The details are as follows: Firstly, acyl chloride (Fig. 1) or acid anhydride is added to the lithium oxazolidone to generate imide, which has a high yield.
The alkylation of chiral N-acyl oxazolidinone with alkyl halides is then accomplished through the participation of a chelate of (Z)-lithium amidoenol (Fig. 2).
For the base, NaHMDS and LiHMDS are good choices. For reactions involving benzyl oxygen methyl electrophiles, the enolates of titanium show more advantages over the corresponding lithium enolates both in terms of yield and diastereoselectivity of alkylation reactions (Fig. 3). However, their homologues of p-Methoxybenzyl (PMB)-protected B-hydroxyl adjuncts cannot be synthesized in this way. In other respects, the reaction methodology involving titanium is a strong complement to the corresponding reactions involving SN1 electrophiles such as lithium and sodium enolates. It is worth mentioning that in the presence of esters, amides can be selectively enolized according to the above methods (Fig. 3).
The acylation of these enolates provides a direct pathway for the synthesis of β-dicarbonyl system. Typically, the diastereoselectivity of acylation is greater than 95% and the yield is between 83-95%. If valine derivatives are used as auxiliaries, the selectivity is slightly higher (Fig. 4). The induction is consistent with chelation through (Z)-lithium enol. After conventional operation, the newly formed chiral center configuration is maintained.
The 1,3-dicarbonyl substrate is a useful class of substances. Another method for synthesizing this compound is the acylation of the enolate ester. Enolates of titanium can be used effectively for such reactions (Fig. 5).
The imide enolate of titanium is a very good nucleophile for the Michael addition reaction. Ethylene ketone, methyl, acrylonitrile, and tert-butyl acrylate react as Michael receptors with good diastereoselectivity (Fig. 6). The transfer of chirality of enolates can be predicted by the (Z)-enols of chelates. For unsaturated esters and nitriles with lower reactivity, the enolates produced from TiCl3(O-i-Pr) have a higher yield but slightly lower selectivity. β-substituted and α, β-unsaturated ketones cannot undergo this reaction because they have no induction effect in the pro-chiral center. In addition, unsaturated ester compounds with substituents are not good Michael receptors under these conditions.
Various imide enol lithiums can also be used as nucleophiles to undergo Michael addition with 3-trifluoro methacrylate, mainly to form trans isomers (Fig. 7).
Sodium enolate reacts with Davis oxazine reagent to produce hydroxylation products with the same inductance as alkylation products (Fig. 8). When molybdenum (VI) diperoxy (pyridine) (hexamethylphosphotriamine) (MoOPH) is used, the reaction has high diastereoselectivity, but very low yield.
Amination can occur in the presence of di-tert-butyl azodicarboxylate (DBAD). Despite the high yield and diastereoselectivity of this method (Fig. 9), harsh reaction conditions are required in the transformation of products, thus limiting its application in synthesis.
As one of the synthesis methods of α-amino acids, hydroxylation has been replaced in most cases by direct enol azide reactions (Fig. 10), and these compounds can be chemically modified to produce N-protected α-amino acid derivatives under mild conditions. Under optimal conditions, the yield is 74% to 91% and the selectivity is 91:9 ~ >99:1. Selective enolization of imines can also occur in the presence of tert-butyl esters that can be enolized and suitably protected amino groups. Using palladium on carbon and hydrogen, or tin dichloride, the azide portion can undergo hydrogenation to form an amine.
Chiral auxiliary can be used in an even wider range of fields, including halogenation of enolates, Aldol reactions, Diels-Alder reactions, conjugate addition reactions, oxazolidinone-substituted carbanion reactions, and chiral ligand reactions. It's now a common method used to control asymmetric synthesis. BOC Sciences is a leading supplier of chiral auxiliaries, which are used in a variety of chemical synthesis applications. We offer a wide range of chiral auxiliaries including chiral ligands, chiral catalysts, chiral reagents, and chiral building blocks. These products are manufactured under strict quality control standards, ensuring high purity, consistency, and reliability.
Please click here to learn more about chiral technical support.
Suitable for your research and production needs. BOC Sciences provides the most comprehensive products and services. 24 hours customer support!
