I-N. EpoxidesI. Basic Principles1. High-Valent TM(d0) EpoxidationsMo, V, W (H2WO4), Ti, Al serve as catalysts with t-BuO2H or otherperoxides as stoichiometric oxidants. Toluene is a frequent solvent.Mo(CO)6 is the catalyst of choice for substrates lacking directing groups.mechanism:OOMLnO t-Busyn- epoxidationwith directing groups such as -OH: ca. 1000x faster than parent alkene, esp.with allylic and homoallylic OH, ester, etc.Dr. P. WipfPage 1 of 443/17/2008CO2MeTBHP, Mo(CO)666%CO2MeO94%+CO2MeO6%OHreagentOHO+OHOreagentMCPBAt-BuOOH/VO(acac)2t-BuOOH/Mo(CO)6t-BuOOH/Al(t-Bu)3ratio64 : 3629 : 7162 : 3864 : 36Dr. P. WipfPage 2 of 443/17/2008OHreagentOHO+OHOreagentMCPBAt-BuOOH/VO(acac)2t-BuOOH/Mo(CO)6ratio95 : 571 : 2984 : 16 OHreagentOHO+OHOreagentMCPBAt-BuOOH/VO(acac)2t-BuOOH/Mo(CO)6t-BuOOH/Al(t-Bu)3ratio95 : 586 : 1495 : 5100 : 0t-BuOOHVO(acac)2arylOHarylOHO(8 : 1) More detailed references:Oshima, THL 1980, 21, 1657,4843; Sharpless, THL 1979,20, 4733; Kishi JACS 1978,100, 2933.Dr. P. WipfPage 3 of 443/17/2008Zhang, W.; Yamamoto, H., "Vanadium-Catalyzed Asymmetric Epoxidation of HomoallylicAlcohols." J. Am. Chem. Soc. 2007, 129, 286-287.NNOPhPhOHOHOPhPhNNOCPh3OHOHOCPh3ROHRRRRROHRRROHOROHRROVO(O-i-Pr)3 or VO(acac)2 (1 mol%)ligand A (2 mol%)aqueous TBHP, CH2Cl2 or toluene-20 oC~0 oCVO(O-i-Pr)3 (1 mol%)ligand B (2 mol%)CHP, toluene, rtAB>95% eeCHP = cumene hydroperoxide~70% eeNNOCR3OHOHOCR3CR =with ligand C: >93% eeDr. P. WipfPage 4 of 443/17/2008The extent to which a hydroxyl group is involved in the epoxidationof cyclic alkenes and alkadienes is determined not only by its positionrelative to the double bond but also by the conformation of themolecule as a whole (Dryuk, V. G.; Kartsev, V. G., "Mechanism ofthe directing influence of functional groups and the geometry ofreactant molecules on peroxide epoxidation of alkenes." Russ. Chem.Rev. 1999, 68, 183-201):OHkrel 100OHkrel 2.1OHkrel 0.09OHkrel 19OHkrel 40Dr. P. WipfPage 5 of 443/17/20082. Sharpless Asymmetric Epoxidation (SAE)1980: Katsuki & Sharpless; Ti(IV)alkoxide, tartrate, t-BuOOH.References: Comprehensive Organic Synthesis 1991, vol. 7, chapter3.2; pp 389; Chem. Rev. 1991, 91, 437. Org. React. 1996, 48, 1-300."O" with D-(-)-DIPT (unnatural; 2S,3S)"O" with L-(+)-DIPT (natural; 2R,3R)CH2Cl2, -20 °Cepoxyalcohol70-90% yield>90% eeEtO2CCO2EtOHOHDETOHDr. P. WipfPage 6 of 443/17/2008mechanism: dimer is active species (Finn, M. G.; Sharpless, K. B.J. Am. Chem. Soc. 1991, 113, 112).• incompatible functional groups: amines, -CO2H, -SH, phenols,phosphines.TiORORO OOOEROTiOOOOtBuER3HRSRLEDr. P. WipfPage 7 of 443/17/2008Stoichiometry: 5% Ti / 6% tartrate to 10% Ti / 12% tartrate:PhOH3 Å MS, TBHPPhOHO5% / 6% ! 92% ee2% / 2.5% ! 69% eeDr. P. WipfPage 8 of 443/17/2008Masamune, S.; Sharpless, K. B. Tetrahedron 1990, 46, 245. Totalsynthesis of L-hexoses.Dr. P. WipfPage 9 of 443/17/2008Dr. P. WipfPage 10 of 443/17/2008Kinetic resolution of allylic alcohols (J. Am. Chem. Soc. 1981,103, 6237)."O" with (-)-DIPTD-(-)-DETOHHmismat chedOHHOslow1 : 1"O" with (-)-DIPTD-(-)-DETOHHmatchedOHHOfastif stopped at 50% conversion, this enantiomer is enrichedif stopped at 50% conversion, this diastereomer is enrichedDr. P. WipfPage 11 of 443/17/2008OHOHanti/syn 98 : 2anti/syn 38 : 62with (+)-DIPTkfast / kslow = 104 OHracemic1 mmol1.2 mmol DIPT,1 mmol Ti(O-i-Pr)4,0.6 mmol t-BuOOH,CH2Cl2, -20 °C, 15 hOH>96% ee,35-45%relative rates at 0 °C:DIPT74DET28DMT15bulkier esters improvekinetic resolutionDr. P. WipfPage 12 of 443/17/2008Especially interesting in this context is the potential of the Sharplessasymmetric epoxidation in bi-directional synthesis and for thedifferentiation of diastereotopic alkenes:OHdiastereotopic alkenesan achiral (prochiral) compoundSAEOHOOHOOHOOHO+ diepoxidesDr. P. WipfPage 13 of 443/17/2008Assuming that no significant bis-epoxidation has occurred after 3 h, theee of this reaction would be 84% forthe major product, and the de wouldbe 87% (anti/syn) for the reaction.OHwith (+)-DIPT:fast, 90% ee90OHO86%OHO+4%10slow,ca. 50% eeOHOfastOHOO+OHO2.5%7.5%OHOOfastslowOHOOslowOHOOenantiomers:ee 84%If we allow the reaction to proceed, the ee and de should increase!3 h @ -25°C ee 84% de 87%24 h @ -25 °C ee 93% de 92%140 h @ -25 °C ee >97% de >95%Dr. P. WipfPage 14 of 443/17/2008Schreiber, S. L. et al. J. Am. Chem. Soc. 1987, 109, 1525. Two-directional chain synthesis with end-group differentiation.For a general discussion of chain synthesis strategies, see: Poss, C. S.;Schreiber, S. L., "Two-directional chain synthesis and terminusdifferentiation." Acc. Chem. Res. 1994, 27, 9.Dr. P. WipfPage 15 of 443/17/2008Application in synthesis: Schreiber, S. L. et al. J. Org. Chem. 1989, 54, 15):Dr. P. WipfPage 16 of 443/17/2008Preparation of starting diepoxide:Leung, L. M. H.; Gibson, V.; Linclau, B., "Improved synthesis of enantiopure pseudo-C2-symmetric 1,4-bis-epoxide building blocks from arabitol." Tetrahedron: Asymmetry 2005, 16,2449-2453.Moffat reagent(J. Am. Chem. Soc.1973, 95, 4016):Dr. P. WipfPage 17 of 443/17/2008Related to Moffatt’s reagent is the use of Viehe’s reagent (Fraser-Reid, B.et al. Tetrahedron Lett. 1986, 27, 4697).Dr. P. WipfPage 18 of 443/17/20083. Jacobsen-Katsuki EpoxidationsJacobsen, JACS 1990, 112, 2801; JACS 1991, 113, 7063; Katsuki,THL 1990, 31, 7345. Based on Kochi’s achiral salen catalyst.Mcgarrigle, E. M.; Gilheany, D. G., "Chromium- and manganese-salen promoted epoxidation of alkenes." Chem. Rev. 2005, 105,1563-1602.PhH2O, CH2Cl284%, 92% eePhOH HO72%, 98% ee63%, 94% eeTMStrans, cis -epoxides (2 : 1), 23%trans: 46% eecis: 28% eeNMnNHHO OCl0.02 - 0.15 equivco-ox: NaOClMn(III)Dr. P. WipfPage 19 of 443/17/2008Application in process chemistry (THL 1995, 36, 3993):H2OJacobsen-Epox.O> 86% eeH2SO4, MeCN (Ritter reaction)ONHNHOHOMerck HIV protease inhibitorN+O-P3NOThe use of the co-catalyst P3NOallowed for a decreased charge of theMn salen catalyst in the Jacobsenepoxidation. P3NO stabilized thecatalyst, increased the rate, andtransported bulk oxidant HOCl into theorganic phase (JOC 1997, 62, 2222).Dr. P. WipfPage 20 of 443/17/2008Mechanistic considerations (Linker, T. Angew. Chem. Int. Ed. Engl. 1997, 36,2060).Preferred directions of attack of alkenes according to Jacobsen (a) and Katsuki(b):3 possible mechanisms regarding the oxygentransfer to the double bond:NMnNHHO OClRSRLRSRLab
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