Juliá–Colonna epoxidation

The catalyst orients the reactants and, even more significantly, the peroxide enolate intermediate by a series of hydrogen bonding interactions with the four N-terminal amino groups in the poly-leucine α-helix.

While other models have been proposed,[9] computations by Kelly et al. have suggested that the NH-2, NH-3, and NH-4 form an isosceles triangle available for hydrogen bonding as an intermediate-stabilizing oxyanion hole.

[2] In triphasic systems, the polymer catalyst must be soaked in the organic solvent and peroxide solution to generate a gel prior to reaction.

While active catalysts have been generated from scalemic leucine, consistent enantiomeric content must be maintained through the N-terminal region to give appropriate handedness to the structure.

[4] The Juliá–Colonna epoxidation of electron-deficient olefins was originally demonstrated with chalcones, but it was soon extended to other systems with electron withdrawing moieties such as α,β-unsaturated ketones, esters, and amides.

[5][6] Chiral amino acids, including leucine, have been generated in electrical discharge experiments designed to mimic the prebiotic conditions on Earth, and they have been found in scalemic mixtures in meteorites.

[13] For the alternative biphasic protocol, the olefin substrate is dissolved in tetrahydrofuran (THF) along with the urea hydrogen peroxide (UHP) oxidant and a tertiary amine base such as 8-diazabicyclo[5.4.0]undec-7-ene (DBU.)

Utilization of this catalyst in homogeneous reaction conditions enabled marked extension of the methodology to α,β-unsaturated ketones, dienes, and bis-dienes.

The co-catalyst is presumed to increase the concentration of the peroxide oxidant in the organic phase enabling more efficient access to the reactive ternary complex.

[11] Adger et al. utilized the biphasic Juliá–Colonna epoxidation with immobilized poly-L-leucine (I-PLL) and urea hydrogen peroxide (UHP), and 8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the key step in the efficient synthesis of Diltiazem (Figure 6.)

[15] Chen et al. utilized the biphasic Juliá–Colonna Epoxidation protocol with urea hydrogen peroxide (UHP), poly-L-leucine (PLL), and 8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a key step in the synthesis of a family of styryl lactones isolated from Goniothalamus giganteus (Figure 8.)

General Juliá–Colonna Epoxidation
The Juliá–Colonna Epoxidation of a chalcone proceeds with poly-L-leucine and hydrogen peroxide in generic triphasic conditions. Image adapted from Juliá et al. [ 2 ]
Nucleophilic Epoxidation Mechanism
Figure 2: The generic mechanism for nucleophilic epoxidation of an electron-deficient olefin indicates that the reaction proceeds through a resonance stabilized peroxide enolate intermediate.
Poly-Leucine Synthesis
Figure 5: The original poly-leucine catalysts for the Juliá–Colonna Epoxidation were formed by reacting leucine-N-carboxyanhydrides with an initiator such as n -butylamine.
The Juliá–Colonna Epoxidation has been applied to the Total Synthesis of Diltiazem
Figure 6: The Juliá–Colonna Epoxidation has been applied to the Total Synthesis of Diltiazem. [ 11 ]
The Juliá–Colonna Epoxidation has been applied to the Total Synthesis of (+)-Clausenamide.
Figure 7: The Juliá–Colonna Epoxidation has been applied to the Total Synthesis of (+)-Clausenamide. [ 15 ]
The Juliá–Colonna Epoxidation has been applied to the Total Synthesis of (+)-goniotriol 7, (+)-goniofufurone 8, (+)-8-acetylgoniotriol 9 and gonio-pypyrone.
Figure 8: The Juliá–Colonna Epoxidation has been applied to the Total Synthesis of (+)-goniotriol 7, (+)-goniofufurone 8, (+)-8-acetylgoniotriol 9 and gonio-pypyrone. [ 16 ]