Asymmetric dihydroxylation

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The asymmetric dihydroxylation is one of Barry Sharpless developed catalytic asymmetric oxidation of an olefin to a cis-vicinal diol . The high enantioselectivity of the reaction comes about through the use of a chiral ligand .

Reagents

(DHQ) 2 PHAL, the chiral ligand in the AD-Mix α.
(DHQD) 2 PHAL, the chiral ligand in AD-Mix β.

The reaction is carried out with a catalytic amount of osmium (VIII) oxide , which is usually added as an Os (VI) salt and in the course of the reaction from a cooxidant - K 3 Fe (CN) 6 or NMO - to Os (VIII) -Species is oxidized.

Dihydroquinine or dihydroquinidine derivatives are often added as chiral ligands, which are commercially available as AD mix . In addition to K 2 OsO 2 (OH) 4 , K 3 Fe (CN) 6 and K 2 CO 3, AD-Mix α contains the ligand (DHQ) 2 PHAL in catalytic amounts, while AD-Mix β as ligands (DHQD) 2 PHAL contains. A two-phase mixture - for example tert- butanol and water - is used as a solvent in order to prevent premature reoxidation of the cyclic osmate and the associated loss of enantioselectivity. In addition, methanesulfonamide is often used, which accelerates hydrolysis and acts as a phase transfer catalyst.

Attack directions of the respective AD mix.

The osmium (VIII) oxide is bound via a free electron pair in the sp 3 atom orbital of the nitrogen of a dihydroquinidine (see graphic), which accelerates the ligand and allows the entire reaction to proceed via the reaction path of the chiral complex . This in turn results in the high enantioselectivity. Due to the conformation of the ligand and the osmium (VIII) oxide bound to it, a “chiral pocket” is formed, similar to the active center of an enzyme, in which the olefin only orientates itself in a certain conformation.

Reaction mechanism

From the olefin and the osmium (VIII) oxide ligand complex, a [3 + 2] cycloaddition results in a five-membered cyclic intermediate that hydrolyzes and releases the diol . In addition, the reduced osmate is produced, which is reoxidized by the cooxidant added in excess of stoichiometry.

Reaction mechanism for asymmetric dihydroxylation. The cyclic addition takes place in the organic phase, while the reoxidation of the catalyst takes place in the aqueous phase.

Individual evidence

  1. ↑ Makoto Minato, Keiji Yamamoto and Jiro Tsuji : Osmium Tetraoxide Catalyzed Vicinal Hydroxylation of Higher Olefins by Using Hexacyanoferrate (III) Ion as a Cooxidant. In: The Journal of Organic Chemistry . Vol. 55, No. 2, 1990, pp. 766-768, doi: 10.1021 / jo00289a066 .
  2. ↑ Philippe Dupau, Robert Epple, Allen A. Thomas, Valery V. Fokin and K. Barry Sharpless: osmium-Catalyzed Dihydroxylation of olefin in Acidic Media: Old Process, New Tricks. In: Advanced Synthesis & Catalysis . Volume 344, No. 3-4, June 2002, pp. 421-433, ISSN  1615-4150 , doi : 10.1002 / 1615-4169 (200206) 344: 3/4 <421 :: AID-ADSC421> 3.0.CO; 2-F .
  3. ↑ Mikko H. Junttila and Osmo OE Hormi: Methanesulfonamide: A Cosolvent and a General Acid Catalyst in Sharpless Asymmetric Dihydroxylations. In: The Journal of Organic Chemistry. Volume 74, No. 8, 2009, pp. 3038-3047, doi: 10.1021 / jo8026998 .
  4. ^ EJ Corey , Mark C. Noe and Sepehr Sarshar: X-Ray Crystallographic Studies Provide Additional Evidence that an Enzyme-Like Binding Pocket is Crucial to the Enantioselective Dihydroxylation of Olefins by OsO 4 -bis -cinchona Alkaloid Complexes. In: Tetrahedron Letters . Volume 35, No. 18, May 2, 1994, pp. 2861-2864, doi: 10.1016 / S0040-4039 (00) 76644-5 .
  5. ↑ Hartmuth C. Kolb, Pher G. Andersson and K. Barry Sharpless: Toward an Understanding of the High Enantioselectivity in the osmium-Catalyzed Asymmetric Dihydroxylation (AD). 1. Kinetics. In: Journal of the American Chemical Society. Volume 116, No. 4, 1994, pp. 1278-1291, doi: 10.1021 / ja00083a014 .

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