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I-N. Epoxides

I. Basic Principles

1. High-Valent TM(d0) Epoxidations

Mo, V, W (H2WO4), Ti, Al serve as catalysts with t-BuO2H orother peroxides as stoichiometric oxidants. Toluene is afrequent solvent. Mo(CO)6 is the catalyst of choice forsubstrates lacking directing groups.

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More detailed references:Oshima, THL 1980, 21, 1657,4843; Sharpless, THL 1979,20, 4733; Kishi JACS 1978,100, 2933.

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The 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):

2. 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.

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mechanism: 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.

Stoichiometry: 5% Ti / 6% tartrate to 10% Ti / 12% tartrate:

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Masamune, S.; Sharpless, K. B. Tetrahedron 1990, 46, 245. Totalsynthesis of L-hexoses.

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Kinetic resolution of allylic alcohols (J. Am. Chem. Soc. 1981, 103,6237).

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Especially interesting in this context is the potential of the Sharplessasymmetric epoxidation in bi-directional synthesis and for thedifferentiation of diastereotopic alkenes:

Assuming 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.

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%

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Schreiber, 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.

Application in synthesis: Schreiber, S. L. et al. J. Org. Chem. 1989, 54, 15):

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Preparation 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):

Related to Moffatt’s reagent is the use of Viehe’s reagent (Fraser-Reid, B.et al. Tetrahedron Lett. 1986, 27, 4697).

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3. Jacobsen-Katsuki Epoxidations

Jacobsen, 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.

Application in process chemistry (THL 1995, 36, 3993):

The 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).

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Mechanistic 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:

Epoxidation of styrene derivatives leads to mixtures:

Radical clock experiments giveconflicting results:

There is clear evidence for theformation of radical intermediates,however, manganooxetanes, forwhich there is electrospray MSevidence, can also play a part inthe mechanism. The influence ofreaction conditions has to betaken into account.

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Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E. N.,"Mechanistic investigation leads to a synthetic improvement in thehydrolytic kinetic resolution of terminal epoxides (HKR)." J. Am. Chem.Soc. 2004, 126, 1360-1362.

The (salen)-Co(III) complex 1provides a general and effectivemethod for the preparation ofenantioenriched terminalepoxides. 1a is the mostcommonly used variant.

The catalyst shows a second-order dependence, and a cooperative bimetallicmechanism has been suggested:

Dominant catalytic cycle in HKR reactions (RDS = rate determining step):

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4. Peracid/Peroxide Epoxidations

Standard peracids are: MCPBA, CH3CO3H, MMP, CF3CO3H, 3,5-dinitroperbenzoic acid.

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Epoxidation under Payne conditions:

Bachmann, C.; Gesson, J.-P.; Renoux, B.; Tranoy, I. Tetrahedron Lett.1998, 39, 379.

With the less acidicMCPBA, epoxidationof allylic ethers isdirected by sterichindrance and is anti-selective.

Diastereomeric control in the epoxidation with peracids is quitegood, if appropriate directing groups are present, or if the substrateis sterically biased.

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Wipf, P.; Kim, Y.; Fritch, P. C. J. Org. Chem. 1993, 58, 7195.

Diastereocontrol in acyclic substrates:Kishi, Y. et al. Tetrahedron Lett. 1980, 21, 4229.

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mechanistic consideration of the relative stability of ground stateconformational isomers:

more calc.: Houk, K. N. J. Am. Chem. Soc. 1991, 113, 5006.

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Catalytic Asymmetric Epoxidation with Chiral Dioxiranes

Wang, Z.-Y.; Tu, Y.; Frohn, M.; Shi, Y. J. Org. Chem. 1997, 62,2328. Biphasic reactions, inexpensive oxidants; turnover and catalyticefficiency need to be improved for this chemistry to become a viablecompetitor to transition metal catalysts for asymmetric epoxidation.For recent progress, see: J. Org. Chem. 1997, 62, 8622.Shi, Y., "Organocatalytic asymmetric - epoxidation of olefins by chiralketones." Acc. Chem. Res. 2004, 37, 488-496.Yang, D., "Ketone-catalyzed asymmetric epoxidation reactions." Acc.Chem. Res. 2004, 37, 497-505.

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Epoxidation of enones: H2O2, t-BuO2H, cumene hydroperoxide

Ooi, T.; Ohara, D.; Tamura, M.; Maruoka, K., "Design of new chiralphase-transfer catalysts with dual functions for highly enantioselectiveepoxidation of α,β-unsaturated ketones." J. Am. Chem. Soc. 2004,126, 6844-6845.

Presently limited to aryl or t-Bu ketones

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Kakei, H.; Tsuji, R.; Ohshima, T.; Shibasaki, M., "Catalytic asymmetricepoxidation of α,β-unsaturated esters using an yttrium-biphenyldiolcomplex." J. Am. Chem. Soc. 2005, 127, 8962-8963.

5. Alternative Methods for Epoxide Formations

Epoxides from diols:

Martin, T.; Soler, M. A.; Betancort, J. M.; Martin, V. S. J. Org. Chem. 1997, 62,1570.

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Gardinier, K. M.; Leahy, J. W. J. Org. Chem. 1997, 62, 7098. Thebasic transesterification required with standard esters in the final stepof the Sharpless conversion of vicinal diols into epoxides (Kolb, H. C.;Sharpless, K. B. Tetrahedron 1992, 48, 10515) was incompatible withthe target molecule (cryptophycin).

Ireland, R. E.; Wipf, P.; Roper, T. D. J. Org. Chem. 1990, 55, 2284.

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Via halohydrins:

Cardillo-Epoxidation (TH 1990, 46, 3321):

Guo, J.; Duffy, K. J.; Stevens, K. L.; Dalko, P. I.; Roth, R. M.; Hayward,M. M.; Kishi, Y. Angew. Chem. Int. Ed. 1998, 37, 187.

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Arai, S.; Shioiri, T., "Catalytic asymmetric Darzens condensation underphase-transfer-catalyzed conditions." Tetrahedron Lett. 1998, 39, 2145.

Corey-Chaykovski Reaction: Aggarwal, V. K.; Ford, J. G.;Fonquerna, S.; Adams, H.; Jones, R. V. H.; Fieldhouse, R., "CatalyticAsymmetric Epoxidation of Aldehydes. Optimization, Mechanism, andDiscovery of Stereoelectronic Control Involving a Combination ofAnomeric and Cieplak Effects in Sulfur Ylide Epoxidations with Chiral1,3-Oxathianes." J. Am. Chem. Soc. 1998, 120, 8328-8339.

Aggarwal, V. K.; Winn, C. L., "Catalytic, asymmetric sulfur ylide-mediated epoxidation of carbonyl compounds: Scope, selectivity, andapplications in synthesis." Acc. Chem. Res. 2004, 37, 611-620.

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Review: Hanson, R. M. Chem. Rev. 1991, 91, 437.

6. Epoxide Opening Reactions

on rings: trans-diaxial opening is preferred (Fürst-Plattner rule):

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Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558; Wipf, P.; Lim, S.Chimia 1996, 50, 157.

Yamamoto, H. et al. J. Am. Chem. Soc. 1989, 111, 6431.

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