Sharpless aminohydroxylation

What is Sharpless aminohydroxylation?

The first report of this reaction was by Sharpless (Nobel Prize in Chemistry 2022) et al. in 1975, and it involves a set of procedures for converting olefins to α-amino alcohols, where nitrogen is attached to a less-substituted carbon using a tert-alkyl imido osmium compound, sulfonamide, amide, carbamate, or aminoheterocycle as the nitrogen source. This transformation is commonly referred to as the Sharpless aminohydroxylation, Sharpless asymmetric aminohydroxylation, or Sharpless oxyamination, depending on the specific protocol used.

Sharpless aminohydroxylation - general reaction scheme
Sharpless aminohydroxylation
  • R1, R2 = H, alkyl, aryl
  • R3 = t-Bu, 1-adamantyl
  • R4 = Et, t-Bu, Bn
  • R5, R3 = Ts, COOR4 (see list of acronyms)

The procedure utilizing carbamate as the nitrogen source is also called the catalytic asymmetric Sharpless carbamate aminohydroxylation.

All of these protocols are stereospecific, producing syn-α-amino alcohols via a cis-addition. However, the enantioselectivity and regioselectivity of the reaction depend on the nature of the substrates, ligand, reaction solvent, temperature, and pH of the reaction solution.

The presence of cinchona alkaloid ligands can also result in the formation of a single enantiomer of the amino alcohol. This reaction is typically conducted in methylene chloride, and a coordinating solvent such as THF or pyridine can increase the ratio of amino alcohol to diol. Pyridine is particularly effective because it enhances the addition of imido to olefin. Temperature and the geometry of the olefinic substrate also play important roles in determining the reaction outcome. A trans-olefin reacts approximately 4.9 times faster than its cis-isomer, and a higher temperature generates more diol.

The optimal method for removing the tert-alkyl group from the nitrogen atom of an amino alcohol is through LiAlH4 reduction, provided that no other LiAlH4-sensitive functional groups are present in the molecule. Otherwise, bisulfite reduction is a viable option. However, this earlier version of aminohydroxylation has a drawback due to the requirement of a stoichiometric amount of reagent and the difficulty of removing the nitrogen-protecting group. To overcome the need for a stoichiometric amount of tert-alkyl amido osmium compound, chloramines-T (chloro tosylamide) can be used to generate the imido osmium species in situ.

In addition, hydroxy sulfonamide can be transformed into amino alcohol in liquid ammonia by sodium reduction. However, the presence of chloride can inhibit this aminohydroxylation, which can be resolved by adding silver nitrate to remove chloride and improve both the reaction rate and yield for the aminohydroxylation of monosubstituted and sym-disubstituted olefins. However, silver ion has an adverse effect on the aminohydroxylation of asymmetrically substituted and trisubstituted olefins. To address this issue, a phase transfer catalyst has been applied.

The protocol that uses N-chlorosodiocarbamates as the nitrogen source in the presence of silver nitrate offers better regioselectivity for the aminohydroxylation of a terminal olefin in acetonitrile than chloramines-T, but it is less effective for the aminohydroxylation of trisubstituted olefins. It is worth noting that the N-chlorosodiocarbamate protocol is more effective for electron-deficient olefins, where mercury (II) salt can enhance the reactivity of carbamate for monosubstituted and disubstituted olefins. In particular, the formula of ROC(O)NClNa/Hg(NO2)2/Et4NOAc (1.5 / 0.75 / 1.0) is an effective reagent for the aminohydroxylation of trisubstituted olefins.

Overall, both protocols are less regioselective than the initial one with a stoichiometric amount of osmium reagent. More recent developments in aminohydroxylation employ the use of N-bromo-N-lithio salt of primary carboxamides (butyramide and acetamide) as the nitrogen source, with the concentration of the reagent being of utmost importance.


New reaction. Stereospecific vicinal oxyamination of olefins by alkyl imido osmium compounds
K. Barry Sharpless, Donald W. Patrick, Larry K. Truesdale, and Scott A. Biller
Journal of the American Chemical Society 1975 97 (8), 2305-2307
DOI: 10.1021/ja00841a071