1

ID. Miscellaneous Oxidation ReactionsBoger Notes: p. 41 - 86 (Chapter IV)Carey/Sundberg: B p. 786-820 (Chapter B 12.3 - 12.7)Problem of the Week: Provide a mechanism for this transformation:

I. Basic Principles

2. Bayer-Villiger OxidationsKetones react with peroxyacids or hydrogen peroxides to giveesters via a C→O rearrangement. Both acid- and base-catalyzedmechanisms have been proposed.

The migratory aptitudes are t-alkyl > cyclohexyl = 2°alkyl =benzyl = phenyl > vinylic > 1°alkyl >cyclopropyl > methyl.

P. Wipf - Chem 2320 1 2/13/2006

2

Baeyer-Villiger oxidations are highly stereoselective; migrationoccurs with retention of configuration. Recent work alsodemonstrates that alkoxyalkyl groups have an extremely highmigratory aptitude:

- Matsutani, H.; Ichikawa, S.; Yaruva, J.; Kusumoto, T.; Hiyama,T. J. Am. Chem. Soc. 1997, 119, 4541.

The bond antiperiplanar to the dissociating peroxide bond isalways the bond that migrates, even when electronicallydisfavored from doing so (Goodman, R. M.; Kishi, Y.,"Experimental support for the primary stereoelectronic effectgoverning Baeyer-Villiger oxidation and Criegee rearrangement."J. Am. Chem. Soc. 1998, 120, 9392).

P. Wipf - Chem 2320 2 2/13/2006

3

When an alkene and a carbonyl are present in the samemolecule, an increase in the acidity of the medium favors attackat the carbonyl. Acid-catalyzed side reactions can be suppressedby a phosphate buffer.

Jacobi, P. A.; Herradura, P., "Enantioselective syntheses of (+)-and (-)-blastmycinolactol." Tetrahedron Lett. 1997, 38, 6621-6624. Syn-selective Nicholas-Schreiber condensation. Themethyl ketone was unreactive to the usual reagents, includingMCPBA, AcOOH, CF3CO3H, and PhSe(O)OH/H2O2. The bestresults were obtained using bis(trimethylsilyl)peroxide [(TMSO)2],which was initially introduced by Noyori for the chemoselectiveoxidation of ketones in the presence of alkene double bonds.

P. Wipf - Chem 2320 3 2/13/2006

4

Aldehydes usually give acids, with the exception of electron-richaldehydes. Migration occurs with retention of configuration.

- Wipf, P.; Jung, J.-K. Angew. Chem. Int. Ed. Engl. 1997, 36, 764.(An example for a Dakin reaction)

3. DehydrogenationsCyclohexadienes: Corey, E. J.; Lazerwith, S. E., "A direct andefficient stereocontrolled synthetic route to the pseudopterosins,potent marine antiinflammatory agents." J. Am. Chem. Soc.1998, 120, 12777.

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

P. Wipf - Chem 2320 4 2/13/2006

5

Thiazolines: McDonald, L. A.; Foster, M. P.; Phillips, D. R.;Ireland, C. M.; Lee, A. Y.; Clardy, J. C. J. Org. Chem. 1992, 57,4616. Evans, D. L.; Minster, D. K.; Jordis, U.; Hecht, S. M.;Mazzu, A. L.; Meyers, A. I. J. Org. Chem. 1979, 44, 497.

Thiazolidines: Hamada, Y.; Shibata, M.; Sugiura, T.; Kato, S.;Shioiri, T. J. Org. Chem. 1987, 52, 1252.

P. Wipf - Chem 2320 5 2/13/2006

6

4. Oxidations of Organometallics

Hoffmann, R. W.; Hölzer, B.; Knopff,O.; Harms, K., "Asymmetric synthesisof a chiral secondary Grignardreagent." Angew. Chem. Int. Ed. 2000,39, 3072-3074.After a sulfoxide/magnesium exchangereaction, a carbenoid homologationreaction provides a chiral secondaryGrignard reagent that can be oxidizedenantioselectively.

5. Allylic OxidationsLimanto, J.; Snapper, M. L., "Sequential intramolecularcyclobutadiene cycloaddition ring-opening metathesis, and Coperearrangement: Total syntheses of (+)- and (-)-asteriscanolide."J. Am. Chem. Soc. 2000, 122, 8071-8072.

P. Wipf - Chem 2320 6 2/13/2006

7

6. Benzylic OxidationsNicolaou, K. C.; Baran, P. S.; Zhong, Y.-L., "Selectiveoxidation at carbon adjacent to aromatic systems withIBX." J. Am. Chem. Soc. 2001, 123, 3183-3185.

Stork, G.; Niu, D.; Fujimoto, A.; Koft, E. R.; Balkovec, J. M.; Tata,J. R.; Dake, G. R., "The first stereoselective total synthesis ofquinine." J. Am. Chem. Soc. 2001, 123, 3239-3242.

P. Wipf - Chem 2320 7 2/13/2006

8

7. OzonolysisAccording to the Criegee mechanism, 1,3-dipolar cycloadditiongives a 1,2,3-trioxolane product that rearranges to a 1,2,4trioxolane (the ozonide) by fragmentation into a ketone and acarbonyl oxide followed by a second dipolar addition. In addition tocatalytic hydrogenation, LAH, NaBH4, Zn/AcOH, and Me2S/MeOHcan be used to decompose the ozonide.1,3-Dipolarophiles, such as ketones, methyl formate, phenanthrene quinoneand methyl pyruvate have been employed to trap the carbonyl oxides to givetri- and tetra-substituted ozonides. The goal of these trapping experiments issimply to prepare the ozonides which are difficult to obtain by normalprocedures (Tetrahedron 1997, 53, 5217-5232).

Alkenes can usually be ozonized in the presence of alkynes (since ozone isan electrophilic reagent, it actually prefers alkenes). Non-compatiblefunctional groups are:

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

The nonoxidative decomposition of cyclohexene ozonide gives analdehyde-carboxylate.- Clause, R. E.; Schreiber, S. L. Org. Synth. 1985, 64, 150.

P. Wipf - Chem 2320 8 2/13/2006

9

-Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675.The ozonolysis of alkenes in methanolic NaOH or NaOMe withCH2Cl2 as a cosolvent leads directly to methyl esters.

-Pyridine serves to attenuate the reactivity of ozone towardelectron-rich functional groups such as a PMB-ether:-Schreiber, S. L. et al. J. Am. Chem. Soc. 1990, 112, 5583.

Travis, B. R.; Narayan, R. S.; Borhan, B., "Osmium tetroxide-promoted catalytic oxidative cleavage of olefins: An organometallicozonolysis." J. Am. Chem. Soc. 2002, 124, 3824-3825.

P. Wipf - Chem 2320 9 2/13/2006

10

8. High-Valent TM(0) EpoxidationsMo, 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.

P. Wipf - Chem 2320 10 2/13/2006

11

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

The extent to which a hydroxyl group is involved in theepoxidation of cyclic alkenes and alkadienes is determined notonly by its position relative to the double bond but also by theconformation of the molecule as a whole (Dryuk, V. G.; Kartsev,V. G., "Mechanism of the directing influence of functionalgroups and the geometry of reactant molecules on peroxideepoxidation of alkenes." Russ. Chem. Rev. 1999, 68, 183-201):

P. Wipf - Chem 2320 11 2/13/2006

12

9. Sharpless Asymmetric Epoxidations1980: Katsuki & Sharpless; Ti(IV)alkoxide, tartrate, t-BuOOH.References: Comprehensive Organic Synthesis 1991, vol. 7,chapter 3.2; pp 389; Chem. Rev. 1991, 91, 437. Org. React.1996, 48, 1-300.

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.

P. Wipf - Chem 2320 12 2/13/2006

13

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

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

P. Wipf - Chem 2320 13 2/13/2006

14

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

P. Wipf - Chem 2320 14 2/13/2006

15

Especially interesting in this context is the potential of theSharpless asymmetric epoxidation in bi-directional synthesis andfor the differentiation of diastereotopic alkenes:

P. Wipf - Chem 2320 15 2/13/2006

16

Assuming that no significant bis-epoxidation has occurred after 3 h, theee of this reaction would be 84% for themajor product, and the de would be87% (anti/syn) for the reaction.

Schreiber, S. L. et al. J. Am. Chem. Soc. 1987, 109, 1525. Two-directionalchain 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.

P. Wipf - Chem 2320 16 2/13/2006

17

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

How would you make this?

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: Asymmetry2005, 16, 2449-2453.

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

P. Wipf - Chem 2320 17 2/13/2006