What Is Evans Aldol Addition Reaction?
Aldol addition reaction originally refers to the self-addition reaction of aldehyde or ketone under acid or base catalysis, and the product is β-hydroxycarbonyl compound. Aldol addition between different aldehydes (ketones) is called cross (mixed) aldol addition. Under certain conditions, the aldol addition product will be further dehydrated to form α, β-enal (ketone). The conversion from aldehydes or ketones to α, β-alkenals (ketones) is called aldol condensation reaction. Nowadays, the reaction of carbonyl compounds with aldehydes or ketones is generally called aldol addition (condensation) reaction.
Under general acid and base catalyzed conditions, cross-aldol addition reactions have problems with chemical selectivity, regioselectivity and stereoselectivity, and will produce a mixture of multiple regioisomers and stereoisomers. The use of preformed enol anions is the primary method for performing regioselective aldol reactions. The earliest established and most widely used asymmetric aldol addition is the method developed by Evans based on the chiral auxiliary group N-acyloxazolone (Evans aldol addition).
The main stereoisomer formed by the Evans aldol addition reaction catalyzed by boron trifluoromethanesulfonate is called the Evans-syn product. By choosing different chiral auxiliary groups and reaction conditions (Lewis acid), different stereoisomers can be obtained.
Fig 1. Evans aldol reaction and its mechanism. [1]
Stereoselectivity of Evans Aldol Addition
In the kinetic aldol addition reaction, the addition of 2-enolate and aldehydes mainly produces syn products, and the addition of E-enolate and aldehydes mainly produces anti products. Evans aldol addition is under kinetically controlled conditions and only produces Z-enolate, so it mainly produces syn products. The reaction transition state can be represented by the Zimmerman-Traxler model. The high selectivity of the reaction comes from the six-membered ring chair transition state formed by the complexation of boron atoms with two oxygen atoms. Due to the mutual repulsion of dipoles, the dipoles of the oxazolidinone carbonyl group and the enolate carbon-oxygen bond should be in opposite orientations in the stable transition state. At the same time, the Evans syn product obtained by aldehyde attacking from the less sterically hindered Re plane (B) is mainly the Evans syn product. product, when the aldehyde attacks from the sterically hindered Si surface (D), a secondary non-Evans syn product is generated.
Fig 2. Schematic diagram of the stereoselectivity of the Evans aldol reaction.
Application Examples of Evans Aldol Reaction
- Example 1: Since chiral β-hydroxycarbonyl compounds and their reduced form 1,3-diol fragments are widely present in complex natural products, Evans aldol addition and its improved forms have been widely used in the total synthesis of complex natural products. From the retrosynthetic analysis of natural product FD-891, we can see the importance of Evans aldol addition and its improved method in the synthesis of natural products.
- Example 2: Zhu et al. detailed the utilization of the Evans aldol reaction in the complete synthesis of hapalosin 50, a 12-membered cyclic depsipeptide known for its mild cytotoxic properties and improved multidrug resistance compared to verapamil, particularly in enhancing taxol accumulation in SKVLB1 cells. The process involved the synthesis of the intermediate b-hydroxy acid 54 from L-valine, where a successful aldol reaction between n-octanaldehyde 51 and chiral imide 21 resulted in the formation of syn-aldol 52 with high yield and diastereoselectivity. Following the introduction of the TBS protecting group, the chiral auxiliary was removed using LiOH from 53.
Fig 3. Synthetic examples via Evans aldol reaction.
Related Products
References
- Evans, D. A., et al. Journal of the American Chemical Society, 1981, 103(11), 3099-3111.
- Crimmins, Michael T., et al. Journal of the American Chemical Society, 2006, 128(10), 3128-3129.
- Heravi, Majid M., et al. Tetrahedron: Asymmetry, 2013, 24(19), 1149-1188.
