Osmium Tetroxide-N-Methylmorpholine N-Oxide1

(OsO4)

[20816-12-0]  · O4Os  · Osmium Tetroxide-N-Methylmorpholine N-Oxide  · (MW 254.20) (NMO)

[7529-22-8]  · C5H11NO2  · Osmium Tetroxide-N-Methylmorpholine N-Oxide  · (MW 117.17)

(cis dihydroxylation of alkenes; osmylation; asymmetric dihydroxylation of alkenes; oxidations of enol ethers, sulfides)

Physical Data: NMO monohydrate: mp 75-76 °C; 60 wt % aqueous solution: bp 118.5 °C, mp -20 °C, d 1.13 g cm-3. See also Osmium Tetroxide.

Solubility: NMO: sol water, acetone, t-butyl alcohol, THF.

Form Supplied in: NMO: as monohydrate or 60 wt % aqueous solution.

Handling, Storage, and Precautions: NMO is irritating to eyes, respiratory system, and skin. Store refrigerated. Use in a fume hood. See also Osmium Tetroxide.

Dihydroxylation of Alkenes.

The use of an amine N-oxide such as N-Methylmorpholine N-Oxide as cooxidant for osmium tetroxide-catalyzed cis dihydroxylation has become the standard method for the preparation of cis-1,2-diols because of the higher yield of diol product and less byproduct formation compared with oxidations carried out with Hydrogen Peroxide, metal chlorates, and t-Butyl Hydroperoxide.1 Other alkylamine N-oxides such as Trimethylamine N-Oxide have also been used in the catalytic cis dihydroxylation. NMO (as monohydrate and 60 wt % aq solution) is commercially available and readily prepared or regenerated by treatment of N-methylmorpholine (NMM) with H2O2. Normally, aqueous acetone or aqueous t-BuOH is used in the catalytic cis dihydroxylation with OsO4-NMO. Workup involves reduction by sodium sulfite or sodium bisulfite and extraction with ethyl acetate. A detailed procedure for the preparation of NMO (eq 1) and dihydroxylation of cyclohexene with OsO4-NMO (eq 2) has been published.2 Functional groups such as alcohols, esters, lactones, carboxylic acids, ketones, and electron-poor alkenes such as a,b-unsaturated ketones are not affected. For unstable or water-soluble diols, the osmylation can be performed in the presence of Dihydroxy(phenyl)borane and the product is isolated as the borate ester (eq 3).3

The OsO4-NMO system works well with mono- and disubstituted alkenes. Bases such as Pyridine accelerate the cis dihydroxylation in the OsO4-amine N-oxide system, especially for hindered alkenes.4,5 For example, the a-pinene derivative nopol is hydroxylated in low yield by the Osmium Tetroxide-t-Butyl Hydroperoxide system; however, it is hydroxylated in 62% yield with OsO4-Me3NO in the presence of pyridine in aqueous t-BuOH. Other hindered alkenes are also oxidized by this system in 78-93% yield. By switching the solvent to aqueous acetone, the OsO4-Me3NO-pyridine system has been used for the cis dihydroxylation of an intermediate for the preparation of an HMG-CoA reductase inhibitor on a 20-kg scale with 95% diastereoselectivity in 78% yield (eq 4).6

Diastereoselective Osmylation.

Diastereoselective dihydroxylations with OsO4-NMO have been extensively studied (see also Osmium Tetroxide). In general, in the osmylation of acyclic alkenes containing an allylic, oxygen-bearing stereocenter, the relative configuration between the pre-existing hydroxyl or alkoxyl group and the adjacent newly formed hydroxyl group in the major diastereomer is erythro (anti).7 Taking advantage of the high diastereoselectivity in the osmylation reaction, the OsO4-NMO or OsO4-Me3NO system has been used in many stereoselective organic syntheses. One example is the synthesis of octoses based on the catalytic osmylation of allylic alcohols with OsO4-NMO (eq 5).8

Opposite selectivity has been observed in the dihydroxylation of a cyclopentene derivative for the synthesis of carbonucleoside aristeromycin (eq 6).9 Dihydroxylation of (1) with alkaline permanganate proceeds from the less hindered side to give the desired diol, which is then converted to aristeromycin (2). However, dihydroxylation of (1) with OsO4-NMO proceeds from the more hindered side to give the cis-diol, which is subsequently transformed to lyxo-aristeromycin (3). This surprising stereoselectivity is attributed to the complexation of osmium tetroxide with the nitro group, resulting in a nitro-directed osmylation from the more hindered side.

Asymmetric Dihydroxylation (AD).

AD of alkenes with OsO4-NMO is usually performed in aqueous acetone in the presence of dihydroquinidine (DHQD) or dihydroquinine (DHQ) derived chiral ligands such as dihydroquinidine p-chlorobenzoate (DHQD-CLB) or dihydroquinine p-chlorobenzoate (DHQ-CLB) (eq 7) (see also Osmium Tetroxide-Potassium Ferricyanide).10

For example, using OsO4-NMO in the presence of the DHQD-CLB ligand, trans-stilbene is converted to (R,R)-stilbenediol in 88% ee, which is further enriched by recrystallization to >99% ee.11 This method has also been used for the preparation of optically pure (2S,3R)-methyl 2,3-dihydroxyphenylpropionate, useful for the synthesis of the taxol sidechain.12 A catalytic cycle of AD with OsO4-NMO has been proposed.13 The presence of a second catalytic cycle results in a reduced ee for some alkenes in comparison with the ee obtained under stoichiometric conditions, due to the slow hydrolysis of the intermediate osmate ester. Although addition of base such as tetraethylammonium acetate accelerates the hydrolysis of the osmate ester, thereby diminishing the second cycle, the best solution is to add the alkene slowly to prevent the build-up of the osmate ester. In this manner, many alkenes have been dihydroxylated to the corresponding diols in ee close to those obtained under stoichiometric conditions.14

Since the AD with OsO4-K3Fe(CN)6 suppresses the second cycle in the aqueous t-BuOH solvent system, the OsO4-NMO system has been largely superseded by the OsO4-K3Fe(CN)6 system in catalytic AD. However, by employing the most effective ligands such as (DHQD)2-PHAL or (DHQ)2-PHAL and using the slow-addition technique, higher enantioselectivity in the AD with OsO4-NMO can be expected.

Other Oxidations.

Vinylsilanes are converted to silyl enol ethers with retention of the double bond configuration by dihydroxylation with OsO4-Me3NO followed by an anti b-elimination with Sodium Hydride (eqs 8 and 9).15 a-Keto acylsilanes are prepared in over 40% overall yields from (Z)-vinylsilanes by dihydroxylation with OsO4-NMO followed by oxidation with Dimethyl Sulfoxide-Oxalyl Chloride (eq 10).16

Enol ethers are transformed to a-hydroxy ketones with OsO4-NMO (eq 11).17 In the presence of a chiral ligand, optically active a-hydroxy ketones are obtained (also see Osmium Tetroxide-Potassium Ferricyanide).14 Although OsO4 does not normally oxidize organic sulfides, the OsO4-NMO system can oxidize sulfides to sulfones in good yields (eq 12).18


1. (a) Schröder, M. CRV 1980, 80, 187. (b) Singh, H. S. In Organic Syntheses by Oxidation with Metal Compounds, Mijs, W. J.; De Jonge, C. R. H. I., Eds.; Plenum: New York, 1986; Chapter 12. (c) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, Ojima, I., Ed.; VCH: New York, 1993. (d) Lohray, B. B. TA 1992, 3, 1317.
2. (a) VanRheenen, V.; Cha, D. Y.; Hartley, W. M. OSC 1988, 6, 342. (b) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. TL 1976, 1973.
3. Iwasawa, N.; Kato, T.; Narasaka, K. CL 1988, 1721.
4. Larsen, S. D.; Monti, S. A. JACS 1977, 99, 8015.
5. Ray, R.; Matteson, D. S. TL 1980, 21, 449.
6. Decamp, A. E.; Mills, S. G.; Kawaguchi, A. T.; Desmond, R.; Reamer, R. A.; DiMichele, L.; Volante, R. P. JOC 1991, 56, 3564.
7. (a) Cha, J. K.; Christ, W. J.; Kishi, Y. T 1984, 40, 2247. (b) Cha, J. K.; Christ, W. J.; Kishi, Y. TL 1983, 24, 3943 and 3947.
8. (a) Brimacombe, J. S.; Hanna, R.; Kabir, A. K. M. S.; Bennett, F.; Taylor, I. D. JCS(P1) 1986, 815. (b) Brimacombe, J. S.; Hanna, R.; Kabir, A. K. M. S. JCS(P1) 1986, 823.
9. Trost, B. M.; Kuo, G.-H.; Benneche, T. JACS 1988, 110, 621.
10. Jacobsen, E. N.; Markó, I.; Mungall, W. S.; Schröder, G.; Sharpless, K. B. JACS 1988, 110, 1968.
11. McKee, B. H.; Gilheany, D. G.; Sharpless, K. B. OS 1992, 70, 47.
12. (a) Fleming, P. R.; Sharpless, K. B. JOC 1991, 56, 2869. (b) Denis, J.-N.; Correa, A.; Greene, A. E. JOC 1990, 55, 1957.
13. Wai, J. S. M.; Markó, I.; Svendsen, J. S.; Finn, M. G.; Jacobsen, E. N.; Sharpless, K. B. JACS 1989, 111, 1123.
14. Lohray, B. B.; Kalantar, T. H.; Kim, B. M.; Park, C. Y.; Shibata, T.; Wai, J. S. M.; Sharpless, K. B. TL 1989, 30, 2041.
15. Hudrlik, P. F.; Hudrlik, A. M.; Kulkarni, A. K. JACS 1985, 107, 4260.
16. Page, P. C. B.; Rosenthal, S. TL 1986, 27, 2527.
17. McCormick, J. P.; Tomasik, W.; Johnson, M. W. TL 1981, 22, 607.
18. (a) Kaldor, S. W.; Hammond, M. TL 1991, 32, 5043. (b) Priebe, W.; Grynkiewicz, G. TL 1991, 32, 7353.

Yun Gao

Sepracor, Marlborough, MA, USA



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