Evans aldol reaction

What is Evans aldol reaction?

Evans et al. first reported the Evans aldol reaction in 1979. Evans aldol reaction is diastereoselective and involves the addition of the dibutylboryl enolate of chiral N-acyl-oxazolidone to aldehydes. The chiral auxiliary in this reaction facilitates the generation of the enolate from the acyl portion to take on different conformations, depending on the presence or absence of an oxophilic metal. This leads to the formation of chelated coordination between the metal cation and the oxygens of two carbonyl groups. The chiral N-acyl-oxazolidone is known as the Evans reagent.

Evans aldol reaction - general reaction scheme
Evans aldol reaction

R = i-Pr, Bn, etc. (see list of acronyms)

The Evans aldol reaction is an ideal method for controlling the vicinal syn stereogenic centers, particularly for the case of propionate. It has a high diastereoselectivity of > 140:1 to 500:13, regardless of the absolute configuration of α-branched aldehydes. This reaction has a broad tolerance for a wide range of aldehydes, including alkyl or aryl, hindered or unhindered. It has been effectively applied to the synthesis of many natural products, especially macrolides such as phyllanthocin, tautomycin, amphidinolide B1, tedanolide, (+)-rhizoxin D, altohyrtin A, salicylihalamides, bafilomycin A1, aplyronine A, etc.

Evans aldol reaction - general reaction scheme
Evans aldol reaction

The Evans aldol reaction has undergone extensive modification, including the application of Lewis acid, the replacement of oxazolidone with 3,4,5,6-tetrahydro-2H-1,3,4-oxadiazin-2-ones or thiazolidinethione, and the application of different chelating metals. Due to these modifications, this reaction is also referred to as the Evans asymmetric aldol reaction, Evans aldol condensation, Evans aldol methodology, Evans aldol process, Evans catalytic asymmetric aldol reaction, Evans syn-aldol addition, Evans-Tischenko reaction, and Tischenko-Evans reaction.

Evans aldol reaction - general reaction scheme
Evans aldol reaction

In the case of an aldol reaction in the presence of a Lewis acid, both “non-Evans” syn– and anti-aldol products can be generated, depending on the size of the applied Lewis acid or the experimental procedure. The non-Evans anti-aldol product predominates if a large Lewis acid is used, such as Et2AlCl or the formation of a reactive 2:1 complex via the slow addition of TiCl2. The non-Evans syn-aldol product will be formed favorably if a small Lewis acid such as SnCl4 is applied. Coupling with the original Evans condition, three out of four aldol products can be selectively produced. Although the diastereoselectivity is not perfect, a product with high enantiomeric purity can be easily purified through crystallization.

Furthermore, under the guidance of a chiral auxiliary group, the generated enolate can react with electrophiles to form α-alkylated ketones, which is known as Evans alkylation, such as in the preparation of discodermolide.

The utilization of the Evans aldol reaction is highly advantageous in producing compounds that possess distinct vicinal stereogenic centers.

References

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