Dihydroxylation

Dihydroxylation is the process by which an alkene is converted into a vicinal diol. Although there are many routes to accomplish this oxidation, the most common and direct processes use a high-oxidation-state transition metal (typically osmium or manganese). The metal is often used as a catalyst, with some other stoichiometric oxidant present. In addition, other transition metals and non-transition metal methods have been developed and used to catalyze the reaction.

Osmium tetroxide (OsO₄) is a popular oxidant used in the dihydroxylation of alkenes because of its reliability and efficiency with producing syn-diols. Since it is expensive and toxic, catalytic amounts of OsO₄ are used in conjunction with a stoichiometric oxidizing agent. The Milas hydroxylation, Upjohn dihydroxylation, and Sharpless asymmetric dihydroxylation reactions all use osmium as the catalyst as well as varying secondary oxidizing agents.

The Milas dihydroxylation was introduced in 1930, and uses hydrogen peroxide as the stoichiometric oxidizing agent. Although the method can produce diols, overoxidation to the dicarbonyl compound has led to difficulties isolating the vicinal diol. Therefore, the Milas protocol has been replaced by the Upjohn and Sharpless asymmetric dihydroxylation.

Upjohn dihydroxylation was reported in 1973 and uses OsO₄ as the active catalyst in the dihydroxylation procedure. It also employs N-Methylmorpholine N-oxide (NMO) as the stoichiometric oxidant to regenerate the osmium catalyst, allowing for catalytic amounts of osmium to be used. The Upjohn protocol yields high conversions to the vicinal diol and tolerates many substrates. However, the protocol cannot dihydroxylate tetrasubstituted alkenes. The Upjohn conditions can be used for synthesizing anti-diols from allylic alcohols, as demonstrated by Kishi and coworkers.

The Sharpless asymmetric dihydroxylation was developed by K. Barry Sharpless to use catalytic amounts of OsO₄ along with the stoichiometric oxidant K₃[Fe(CN)₆]. The reaction is performed in the presence of a chiral auxiliary. The selection of dihydroquinidine (DHQD) or dihydroquinine (DHQ) as a chiral auxiliary dictates the facial selectivity of the olefin, since the absolute configuration of the ligands are opposite. The catalyst, oxidant, and chiral auxiliary can be purchased premixed for selective dihydroxylation. AD-mix-α contains the chiral auxiliary (DHQ)₂PHAL, which positions OsO₄ on the alpha-face of the olefin; AD-mix-β contains (DHQD)₂PHAL and delivers hydroxyl groups to the beta-face. The Sharpless asymmetric dihydroxylation has a large scope for substrate selectivity by changing the chiral auxiliary class.

The synthesis of highly substituted and stereospecific sugars has been achieved by Sharpless-based methods. Kakelokelose is one specific example.

In the dihydroxylation mechanism, a ligand first coordinates to the metal catalyst (depicted as osmium), which dictates the chiral selectivity of the olefin. The alkene then coordinates to the metal through a (3+2) cycloaddition, and the ligand dissociates from the metal catalyst. Hydrolysis of the olefin then yields the vicinal diol, and oxidation of the catalyst by a stoichiometric oxidant regenerates the metal catalyst to repeat the cycle. The concentration of the olefin is crucial to the enantiomeric excess of the diol since higher concentrations of the alkene can associate with the other catalytic site to produce the other enantiomer.

As mentioned above, the ability to synthesize anti-diols from allylic alcohols can be achieved with the use of NMO as a stoichiometric oxidant. The use of tetramethylenediamine (TMEDA) as a ligand produced syn-diols with a favorable diastereomeric ratio compared to Kishi’s protocol; however, stoichiometric osmium is employed. Syn-selectivity is due to the hydrogen bond donor ability of the allylic alcohol and the acceptor ability of the diamine. This has since been applied to homoallylic systems.