Asymmetric Dihydroxylation (AD)

Reaction Scheme:

The Asymmetric Dihydroxylation involves the conversion of a substituted alkene to a diol. Osmium tetroxide is used as a catalyst and one of the various cinchona ligands is used to enantioselectively deliver the the oxygens to the olefin.

Facial Selectivity:

The facial selectivity is easy to predict using a simple mnemonic shown graphically below.

Catalytic Cycle:

The catalytic cycle is shown below. It is important to notice that the second catalytic cycle is racemic, thus a higher turnover rate is critical to avoiding this second cycle. When the AD reaction is run in two phases, using potassium iron(III) hexacyanide, this second cycle is virtually eliminated.

The AD mixes:

As the various substrated all require similar reaction conditions, it has been possible to premix all the reactants, and they are commercially available. AD-mix-alpha contains the ligand (DHQ)2PHAL and AD-mix-beta contains the ligand (DHDQ)2PHAL. The current recommended contents in 1 kilgram of AD mix are as follows: 699.6g K3Fe(CN)6, 293.9g K2CO3, 5.52g (DHQ)2- or (DHDQ)2-PHAL, and 1.04g K2OsO2(OH)4. The standard procedure calls for 1.4g of this AD-mix per millimole of olefin.

An example procedure for the dihydroxylation of 1 mmol olefin:

A 25-ml round-bottomed flask equipped with a magnetic stirrer is charged with 5 ml of t-butyl alcohol, 5 ml water, and 1.4 g of AD-mix-alpha or beta. (Also added is 95 mg methane sulfonamide if the olefin 1,2 disubstituted, trisubstututed, or tetrasubstituted). The mixture is stirred at room temperature until all reagents dissolve. The reaction is cooled to 0 C (some of the inorganic salts may precipitate); in the case of sluggish alkenes, the reaction is left at room temperature.

One mmol olefin is added at once, and the heterogenous slurry is stirred until TLC or GC indicate reveal absence of starting material (ca. 6-24h). The reaction is quenched by addition of sodium sulfite (1.5g) and then stirred at room temperature for one hour.

The reaction mixture is then extracted several times with ethyl acetate or DCM. (When methane sulfonamide is used, the organic layer should be washed with 2N KOH). The organic layer is then dried and concentrated to give a mixture of crude diol and ligand, which is then purified by flash chromatography (silica gel, EtOAc/Hex; the ligand does not elute under these conditions) to give the pure diol.

(More comprehensive overview can be found in the review article below.)



For the original reference on catalytic AD:
Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968.

For the original reference on using a two phase system and K3Fe(CN)6 as the oxidant:
Kwong, H. L.; Sorato, C.; Ogino, Y.; Chen, H.; Sharpless, K. B. Tetrahedron Lett.1990, 31, 2999.

For the authoritative review see:
Kolb, H.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev.1994, 94, 2483-2547.

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