Looking for methods to generate protected vicinal α-amino-β-alcohols, it is difficult to miss the work of Prof. Barry Sharpless who won the Nobel Prize in 2001 “for his work on chirally catalysed oxidation reactions”.1
In 1998 Sharpless and Reddy reported the osmium catalysed asymmetric aminohydroxylation (AA) reaction, which provided either (R)- or (S)-α-aryl-N-Cbz- or N-Boc- protected (R)- or (S)-α-amino-β-alcohols (R)- or (S)-(2) from styrenes (1) (Scheme 1).2 The enantioselectivities were generally excellent and a subsequent oxidation step yielded the corresponding α-arylglycine derivatives (R)- or (S)-(4).
Scheme 1: Asymmetric aminohydroxylation (AA) reaction of substituted styrenes by Sharpless and Reddy
It was observed that the regioselectivity was highly dependent on the nature of the styrene (1) as well as the choice of ligand, solvent, and ligand-solvent combination. Phthalazine ligands such as (DHQ)2PHAL or (DHQD)2PHAL in n-PrOH strongly favoured the benzylic amine (R)- or (S)-(2) over the benzylic alcohol (R)- or (S)-(3) regioisomer.
Investigating the extensions of this methodology I found a paper reporting the conversion of α,β-unsaturated esters to the corresponding β-hydroxyamides.3 As an example, Sharpless et al reported a synthesis of protected (2R,3S)-3-phenylisoserine (2R,3S)-(6), a precursor for the side chains of the anticancer drugs Taxol and Taxotere (Scheme 2).4
Scheme 2: Synthesis of (2R,3S)-(6)
Another important discovery was that anthraquinone ligands (DHQ)2AQN and (DHQD)2AQN imposed a regioselectivity pattern different from that seen with their more commonly used PHAL analogs (Scheme 3).5
Scheme 3: Regioselectivity of asymmetric aminohydroxylation (AA) reaction
Sharpless reported that the substrate orientation within the binding pockets of these two different ligand classes is obviously altered in such a way that opposite regioselection results, but remarkably, without affecting the sense or the degree of the enantiofacial selectivity. Most importantly the major product was obtained in the ration of at least 4:1 over unwanted regioisomer.
Sharpless demonstrated that versatility and great control in this reaction outweigh the toxicity and costs of the reagents. Although osmium tetroxide is well known for causing severe damage to the eyes, potassium osmate is a commercially available stable solid, which is a lot easier and safer to handle than osmium tetroxide. While catalyst and chiral ligand cost around £100 per gram, the loading is minimal (~ 5 mol%).
This quickly has become one of my favourite reactions due to its reliability and practicality. However I do still remember the first time I had to use osmium tetroxide reagent as an undergraduate student, and my boss telling me: “Stop messing around, just do the reaction with your eyes closed!” Still not sure if he was joking…
Blog written by: Victor Zdorichenko
- Nobelprize.org. Nobel Media AB 2014. <http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2001/>
- Reddy, K. L.; Sharpless, K. B.; J. Am. Chem. Soc. 1998, 120, 1207–1217
- Demko, Z. P.; Bartsch, M.; Sharpless, K. B.; Org. Lett. 2000, 2, 2221–2223
- Bruncko, M.; Schlingloff, G.; Sharpless, K. B.; Angew. Chem. Int. Ed. Engl. 1997, 36, 1483–1486
- Tao, B.; Schlingloff, G.; Sharpless, K. B.; Tetrahedron Lett. 1998, 39, 2507-2510