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Chemistry 600 - Organic Chemistry The Sharpless Reactions

The document summarizes three Sharpless reactions: 1) The Sharpless asymmetric dihydroxylation reaction which uses a chiral ligand to catalyze the addition of osmium tetroxide to an alkene, producing a vicinal diol with high enantioselectivity and site selectivity. This makes it useful for the pharmaceutical industry. 2) The Sharpless oxyamination reaction which uses osmium catalysis to add a hydroxyl and amine group to a carbon-carbon double bond with enantioselectivity. This is important for the pharmaceutical industry. 3) The Sharpless epoxidation reaction uses titanium tetraisopropoxide and a chiral diethyl tartrate ligand to

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58 views

Chemistry 600 - Organic Chemistry The Sharpless Reactions

The document summarizes three Sharpless reactions: 1) The Sharpless asymmetric dihydroxylation reaction which uses a chiral ligand to catalyze the addition of osmium tetroxide to an alkene, producing a vicinal diol with high enantioselectivity and site selectivity. This makes it useful for the pharmaceutical industry. 2) The Sharpless oxyamination reaction which uses osmium catalysis to add a hydroxyl and amine group to a carbon-carbon double bond with enantioselectivity. This is important for the pharmaceutical industry. 3) The Sharpless epoxidation reaction uses titanium tetraisopropoxide and a chiral diethyl tartrate ligand to

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feng_ning_ding4153
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Chemistry 600 Organic Chemistry The Sharpless Reactions

David Ding

The Sharpless Asymmetric Dihydroxylation Reaction


Sharpless asymmetric dihydroxylation is the reaction of an alkene with osmium tetroxide in the presence of a chiral ligand to form a specific enantiomer of a vicinal diol. This enatioselectivity has been realized with many kinds of substituted alkenes. In addition, the reaction is highly site selective, with the hydroxylation occurring on the most electron rich double bond in the alkene, and this enatioselectivity and site selectivity make the reaction very useful to the pharmaceutical industry.

The chiral ligands used are typically (DHQD)2-Phal and (DHQ)2-Phal, which are quinine derivatives and stereoisomers. (DHQD)2-Phal:

(DHQ)2-Phal:

Osmium tetroxide is a good oxidizing agent due to the high oxidation number on Os, the highest known oxidation number on a transition metal. It is widely used to oxidize alkenes to form vicinal diols. Lewis bases will speed up the reaction due to the formation of OsO4L, which is more nucleophilic than osmium tetroxide and adds more readily to the alkene. The importance of the Sharpless reaction is that if the ligand is chiral, the dihydroxylation is enatioselective, which makes this reaction of great importance to the pharmaceutical industry, where the right enantiomer is key. The ferricyanide serves to replenish the osmium tetroxide by reacting with OsO2(OH)4 to reform osmium tetroxide. This step is important since osmium is rare and expensive, as well as highly toxic, so only a small amount of osmium tetroxide could be used. This step reduces the cost of the procedure one thousandfold, which allows industrial use of this reaction.

The Reaction Mechanism:

In the first step, the chiral ligand attacks the osmium in osmium tetroxide. Then, the osmium tetroxide adds to the alkene. There have been speculations on whether this addition occurs in one step, in which the oxygen on osmium tetroxide attacks one of the double bonded carbon and the pi electrons attacking another oxygen, or in two steps, in which the oxygen attacks the double bonded carbon and the pi electrons attacking the osmium, and then the pi electron in the bond between another oxygen and osmium attacks the carbon bonded to osmium, breaking that single bond. After this step, the ligand leaves, and two hydroxide ions attack osmium one at a time. The second hydroxide attack break the single bond between osmium and one of the oxygen atoms bonded to the substrate. The negatively charged oxygen on the substrate immediately deprotonates water as soon as it forms. Two more hydroxide attacks lead to the osmium compound detaching from the substrate, which has been converted to the vicinal diol. The ferricyanide then converts the OsO2(OH)4 back to osmium tetroxide.

Examples In this example, 1,6-dibromo 2,4-hexadiene is converted to an azasugar, which are important for the pharmaceutical industry. The first step of the reaction is asymmetric dihydroxlyation.

References http://en.wikipedia.org/wiki/Sharpless_asymmetric_dihydroxylation http://www.organic-chemistry.org/namedreactions/sharpless-dihydroxylation.shtm

The Sharpless Oxyamination Reaction

The Sharpless Oxyamination is the enantioselective addition of a hydroxyl group and an amine group to a carbon-carbon double bond using osmium as catalyst in the presence of a chiral ligand. The chiral ligand will transfer its chirality to the product, so that only one enantiomer will be formed. First, the catalyst reacts to form OsO3NR

Then, this catalyst attaches to the ligand. The oxygen attacks the carbon-carbon double bond, causing the pi electrons to attack the nitrogen, forming the intermediate shown.

The ligand will then leave, and nucleophilic attack on the osmium will regenerate the catalyst and force the oxygen and nitrogen to leave the osmium. This forms the product.

This reaction is useful because of its enantioselectivity and its regioselectivity. As a consequence, this reaction is important to the pharmaceutical industry.

References http://www.organic-chemistry.org/namedreactions/sharpless-aminohydroxylation.shtm

The Sharpless Epoxidation Reaction

The Sharpless Epoxidation is the formation of a specific enantiomer of an epoxide from an alkene with titanium tetraisopropoxide as catalyst, and the chirality of the product depends on the chirality of the diethyl tartrate. The oxidizing agent is tert-butyl hydroperoxide. The epoxide can be further converted to diols, aminoalcohols, and ethers, and the formation of this chiral epoxide is an important step in forming a specific enantiomer of the subsequent products. Epoxides can be formed by other means as well, such as with peroxyacids, but these methods do not produce enantiomerically pure products. The enantioselectivity of this reactions opens the door for synthesis of specific enantiomers for pharmaceutical purposes. The chiral ligand affects the product because the ligand determines which carbon the titanium catalyst attacks first, thus determining chirality.

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