Diastereoselective aldol
Evans aldol reaction
How the Evans aldol reaction works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: N-acyl oxazolidinone, Bu₂BOTf, iPr₂NEt; then aldehyde; then LiOOH or H₂O₂ for cleavage. Conditions: CH₂Cl₂, –78 °C → 0 °C. Bonds formed: C–C (aldol), new syn-stereocentres; bonds broken: α C–H; C=O π. Stereochemistry: Z-enolate → syn aldol; auxiliary sets absolute configuration. Rate and selectivity: Enolisation fast at –78 °C; aldol step via closed chair TS.
At a glance
Step 1: Z-boron enolate
A chiral oxazolidinone auxiliary is attached to the substrate as an imide; a boron reagent and mild base form a Z-enolate with a fixed, predictable geometry set sterically, through a chair-like enolization transition state that minimizes strain.
Step 2: Zimmerman–Traxler chair TS
This enolate attacks an aldehyde through a rigid, non-chelated Zimmerman-Traxler six-membered transition state — boron can't accommodate a second donor from the auxiliary's carbonyl, so that carbonyl rotates away and the chiral auxiliary instead blocks one face of approach sterically.
Step 3: syn-Aldol adduct, auxiliary removed
The result is an aldol product formed with excellent control over both the relative (syn/anti) and absolute stereochemistry — the auxiliary is later cleaved off, its whole job having been to enforce facial selectivity during just this one bond-forming step.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- Me
- Methyl. –CH₃.
- Bu
- Butyl. –(CH₂)₃CH₃.
- OTf
- Triflate. Trifluoromethanesulfonate – among the best leaving groups.
- DCM
- Dichloromethane. Common non-polar-ish solvent for reactions that need no nucleophilic or protic solvent.
- DIPEA
- N,N-Diisopropylethylamine (Hünig’s base). Hindered, non-nucleophilic amine base.
- H2O2
- Hydrogen peroxide. Oxidant; its anion HOO⁻ is an excellent nucleophile.
- TS
- Transition state. The highest-energy point on the pathway between two minima; it cannot be isolated.
How it compares with related reactions
| Evans aldol reaction | Claisen-Schmidt condensation | Mukaiyama aldol reaction | |
|---|---|---|---|
| Reagents | N-acyl oxazolidinone, Bu₂BOTf, iPr₂NEt; then aldehyde; then LiOOH or H₂O₂ for cleavage | Methyl ketone (ArCOCH₃), ArCHO (no α-H), NaOH or KOH | Silyl enol ether, aldehyde, TiCl₄ (or BF₃·OEt₂, Sc(OTf)₃) |
| Conditions | CH₂Cl₂, –78 °C → 0 °C | EtOH/H₂O, 0–25 °C | CH₂Cl₂, –78 °C; aqueous work-up |
| Stereochemistry | Z-enolate → syn aldol; auxiliary sets absolute configuration | E-chalcone (thermodynamic) | Open TS; syn/anti set by enol geometry and Lewis acid; chiral LAs give ee |
| Rate / selectivity | Enolisation fast at –78 °C; aldol step via closed chair TS | Aldol addition reversible; E1cB dehydration drives it forward | Lewis-acid activation of the aldehyde is essential |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the Evans aldol reaction?
N-acyl oxazolidinone, Bu₂BOTf, iPr₂NEt; then aldehyde; then LiOOH or H₂O₂ for cleavage. Conditions: CH₂Cl₂, –78 °C → 0 °C.
Which bonds are formed and which are broken?
Formed: C–C (aldol), new syn-stereocentres. Broken: α C–H; C=O π.
What is the stereochemical outcome?
Z-enolate → syn aldol; auxiliary sets absolute configuration
What controls the rate or the selectivity?
Enolisation fast at –78 °C; aldol step via closed chair TS
Study guides that help with this reaction
- Carbonyl chemistry: addition, acyl substitution and enolates
- SN1, SN2, E1 or E2? How to decide which mechanism wins
- Nucleophiles, electrophiles and leaving groups: what makes a reaction go