Organic Chemistry Portal
Reactions >> Name Reactions

Further Information

Related Reactions
Sharpless Dihydroxylation
Upjohn Dihydroxylation
Synthesis of 1,2-amino alcohols
Synthesis of amino acids

Sharpless Aminohydroxylation
Sharpless Oxyamination

The Sharpless Aminohydroxylation allows the syn-selective preparation of 1,2-amino alcohols by reaction of alkenes with salts of N-halosulfonamides, -amides and -carbamates using OsO4 as a catalyst. Enantioselectivity is achieved through the addition of dihydroquinine- and dihydroquinidine-derived chiral ligands.

Mechanism of the Sharpless Aminohydroxylation

The catalyst first forms a imidotriooxoosmium(VIII) species by oxidation of OsO3 with the deprotonated N-chloro amine derivative.

The Os(IV) species adds syn-specifically to the alkene - probably in a (3+2) cycloaddition. Another possible mechanism includes a (2+2) cycloaddition followed by a ring-expanding migration (see dihydroxylation). Although some theoretical calculations lend weight to the (3+2) mechanism, the bond-forming step needs further investigation. The ligand increases the rate of reaction, influences the regioselectivity of the addition and induces enantioselectivity.

The osmium(VI) azaglycolate is reoxidized by the N-chloroamide substrate and releases the product after hydrolysis, leading to the following catalytic cycle:

It is possible for the reoxidized metallacycle to undergo a second cycloaddition leading to an osmium(VI) bis(azaglycolate). This side reaction will in most cases decrease the enantioselectivity. Conducting the reaction in an aqueous medium under more dilute conditions favors the hydrolysis.

A key issue is the regioselectivity of the reaction. For some substrates, the selectivity is quite low, but can be influenced by the proper choice of N-haloamide and ligand. The commercially available chloramine-T [TsN(Na)Cl] remains the most widely used reagent, but methods have been developed for the synthesis of nitrogen sources such as N-bromoacetamide and CBz-N(Na)Cl that allow the use of a broader scope of precursors, even for large scale synthesis. These yield the corresponding aminoalcohol after deprotection. Even the ligand can influence the regioselectivity, as has been shown by Sharpless for cinnamates where the use of PHAL and AQN-derived ligands caused opposite regioselection without affecting the enantioselectivity.

The Sharpless Aminohydroxylation of higher substituted alkenes and the prediction of regioselectivity still need to be investigated further. Recent developments, including a broader selection of olefin substrates and nitrogen sources, can be found in a review by McLeod (J. Chem. Soc., Perkin Trans. 2002, 1, 2733. DOI)

Recent Literature

Primary Amides. A General Nitrogen Source for Catalytic Asymmetric Aminohydroxylation of Olefins
Z. P. Demko, M. Bartsch, K. B. Sharpless, Org. Lett., 2000, 2, 2221-2223.

Reversal of regioselection in the asymmetric aminohydroxylation of cinnamates
B. Tao, G. Schlingloff, K. B. Sharpless, Tetrahedron Lett., 1998, 39, 2507-2510.