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Julia-Colonna Epoxidation

Overview The Julia-Colonna Epoxidation is a poly-leucine catalyzed nucleophilic enantioselective epoxidation of α,β-unsaturated ketones in a triphasic or biphasic system. The reaction was first developed by Sebastian Julia (lnstituto Qulmico de Sarria, Barcelona, Spain) in 1980 (published), and the first article was followed up in 1982 with further elaboration by both Julia and Stefano Colonna ( lstituto di Chimica Industriale dell'Universita, Milan, Italy.)1 In the original triphasic protocol, the α,β-unsaturated ketone substrate is soluble in the organic phase, generally toluene or carbon tetrachloride. The alkaline hydrogen peroxide oxidant in the aqueous phase, and the reaction occurs at the insoluble polymer layer at the interface of the two phases.1b For the alternative biphasic protocol, the α,β-unsaturated ketone substrate is dissolved in tetrahydrofuran (THF) along with the urea hydrogen peroxide oxidant and a tertiary amine base such as diazacycloundecane (DBU.) The immobilized polymer catalyst forms a paste.

Reaction Mechanism The Julia-Colonna Epoxidation is a poly-leucine catalyzed nucleophilic enantioselective epoxidation of α,β-unsaturated ketones in a triphasic or biphasic system. ￼ Mechanistic study indicates2: a 10-mer Leucine polypeptide is of sufficient length to provide significant enantioselectivity the stereochemistry of the N-terminal amino acids dictates the enantioselectivity, but the free amino-terminus is not necessary for enantioselective reaction. The enantioselective induction by the N-terminus is mediated by the presence of 5-15 amino acids near the C-terminus. The greatest enantioselectivity was observed when n=30 residues.1b The greatest enantioselectivity was observed for lower molecular weight polymers, presumably due to the greater number of N-termini available for a given mass used.3

Catalyst Poly-amino acid selection Enantioselectivity is maximized by poly-amino acid sequences containing the greatest alpha-helical content; these include poly-leucine and poly-alanine.1a Poly-L- and poly-D-amino acids are both available and cause the opposite stereoinduction.2 Generating the Catalyst Leucine-N-carboxyanhydride reacts with an initiator such as an amine, an alcohol or water1b ￼ Especially in biphasic systems, reaction time can be reduced and enantioselectivity increased by activating the catalyst with NaOH prior to reaction. In triphasic systems, the polymer catalyst must be soaked in the organic solvent and peroxide solution to generate a gel prior to reaction.4 In biphasic systems, the polymer may be immobilized and formed into a paste.4 The polymers may also be generated by solid-phase peptide synthesis, but care must be taken to avoid racemization. Treatment of the poly-leucine catalysts with TFA deactivates them, presumably by acid-catalyzed racemization. Catalyst Stereochemistry The active component of the catalyst assumes an α-helical structure, so consistent enantiomeric content must be consistent through this region to give appropriate handedness to the structure.3 Catalyst Recycling With aqueous conditions, the catalyst may be recycled, but resulting enantioselectivity decreases. Under non-aqueous conditions, the catalyst may be recycled with high ee for low reaction times. Rinsing with NaOH may regenerate the catalyst

Scope Chalcones α,β-unsaturated Ketones, Esters, and Amides Sulfones Substrates that are NOT suitable compounds sensitive to hydroxide4 compounds with acidic protons on the α or α’ positions4 electron rich olefins

Stereoselectivity Catalyst Structure Solvent Chiral Amplification by Scalemic Catalysts5 Variations Biphasic (Non-aqueous) Reaction Conditions6 Silica-grafted Catalysts7 Silica-grafted polyleucine has been shown to effectively catalyze epoxidation of α,β-unsaturated aromatic ketones. The silica graft allows for the catalyst to be easily recovered with only mild loss of activity. Monophasic Reaction Conditions with Soluble PEG-immobilized Catalysts3 A soluble initiator O,O′-bis(2-aminoethyl)polyethylene glycol (diaminoPEG) for poly-leucine assembly was selected to generate a THF-soluble triblock polymer. Phase-Transfer Co-Catalysis8 Addition of tetrabutylammonium bromide as a phase transfer catalyst dramatically increases the rate of reaction. The co-catalyst is presumed to increase the concentration of the peroxide oxidant in the organic phase. These conditions were developed for application to two phase systems but also function for three phase systems.9 Applications to Synthesis Total Synthesis of Diltiazem4 ￼ Total Synthesis of (+)-Clausenamide10 ￼ Total Synthesis of (+)-goniotriol 7, (+)-goniofufurone 8, (+)-8-acetylgoniotriol 9 and gonio-pypyrone 11 ￼

See Also http://www.organic-chemistry.org/Highlights/2004/22November.shtm

References 1.	(a) Juliá, S.; Masana, J.; Vega, J. C., - “Synthetic Enzymes”. Highly Stereoselective Epoxidation of Chalcone in a Triphasic Toluene-Water-Poly (S)-alanine System. 1980, - 19 (- 11), - 931; (b) Julia, S.; Guixer, J.; Masana, J.; Rocas, J.; Colonna, S.; Annuziata, R.; Molinari, H., Synthetic enzymes. Part 2. Catalytic asymmetric epoxidation by means of polyamino-acids in a triphase system. Journal of the Chemical Society, Perkin Transactions 1 1982, 1317-1324. 2.	Bentley, P. A.; Cappi, M. W.; Flood, R. W.; Roberts, S. M.; Smith, J. A., Towards a mechanistic insight into the Julia-Colonna asymmetric epoxidation of alpha, beta-unsaturated ketones using discrete lengths of poly-leucine. Tetrahedron Letters 1998, 39 (50), 9297-9300. 3.	Flood, R. W.; Geller, T. P.; Petty, S. A.; Roberts, S. M.; Skidmore, J.; Volk, M., Efficient asymmetric epoxidation of alpha,beta-unsaturated ketones using a soluble triblock polyethylene glycol-polyamino acid catalyst. Organic Letters 2001, 3 (5), 683-686. 4.	Adger, B. M.; Barkley, J. V.; Bergeron, S.; Cappi, M. W.; Flowerdew, B. E.; Jackson, M. P.; McCague, R.; Nugent, T. C.; Roberts, S. M., Improved procedure for Julia-Colonna asymmetric epoxidation of alpha,beta-unsaturated ketones: total synthesis of diltiazem and Taxol (TM) side-chain. Journal of the Chemical Society-Perkin Transactions 1 1997, (23), 3501-3507. 5.	Kelly, D. R.; Meek, A.; Roberts, S. M., Chiral amplification by polypeptides and its relevance to prebiotic catalysis. Chemical Communications 2004, (18), 2021-2022. 6.	Allen, J. V.; Bergeron, S.; Griffiths, M. J.; Mukherjee, S.; Roberts, S. M.; Williamson, N. M.; Wu, L. E., Julia-Colonna asymmetric epoxidation reactions under non-aqueous conditions: Rapid, highly regio- and stereo-selective transformations using a cheap, recyclable catalyst. Journal of the Chemical Society-Perkin Transactions 1 1998, (19), 3171-3179. 7.	Yi, H.; Zou, G.; Li, Q.; Chen, Q.; Tang, J.; He, M. Y., Asymmetric epoxidation of alpha,beta-unsaturated ketones catalyzed by silica-grafted poly-(L)-leucine catalysts. Tetrahedron Letters 2005, 46 (34), 5665-5668. 8.	Geller, T.; Gerlach, A.; Kruger, C. M.; Militzer, H. C., Novel conditions for the Julia-Colonna epoxidation reaction providing efficient access to chiral, nonracemic epoxides. Tetrahedron Letters 2004, 45 (26), 5065-5067. 9.	Lopez-Pedrosa, J. M.; Pitts, M. R.; Roberts, S. M.; Saminathan, S.; Whittall, J., Asymmetric epoxidation of some arylalkenyl sulfones using a modified Julia-Colonna procedure. Tetrahedron Letters 2004, 45 (26), 5073-5075. 10.	Cappi, M. W.; Chen, W. P.; Flood, R. W.; Liao, Y. W.; Roberts, S. M.; Skidmore, J.; Smith, J. A.; Williamson, N. M., New procedures for the Julia-Colonna asymmetric epoxidation: synthesis of (+)-clausenamide. Chemical Communications 1998, (10), 1159-1160. 11.	Chen, W. P.; Roberts, S. M., Julia-Colonna asymmetric epoxidation of furyl styryl ketone as a route to intermediates to naturally-occurring styryl lactones. Journal of the Chemical Society-Perkin Transactions 1 1999, (2), 103-105.