Editing Sharpless asymmetric dihydroxylation (section)

== Reaction mechanism ==
The reaction mechanism of the Sharpless dihydroxylation begins with the formation of the osmium tetroxide – ligand complex ('''2''').  A <nowiki>[3+2]</nowiki>-cycloaddition with the alkene ('''3''') gives the cyclic intermediate '''4'''.<ref>{{cite journal | last1 = Corey | first1 = E.J. | author-link = Elias James Corey | last2 = Noe | first2 = M. C. | last3 = Grogan | first3 = M. J. | year = 1996 | title =  Experimental test of the [3+2]- and [2+2]-cycloaddition pathways for the bis-cinchona alkaloid-OsO4 catalyzed dihydroxylation of olefins by means of kinetic isotope effects| journal = [[Tetrahedron Lett.]] | volume = 37 | issue = 28| pages = 4899–4902 | doi = 10.1016/0040-4039(96)01005-2 }}</ref><ref name="ReferenceA">{{cite journal | last1 = DelMonte | first1 = A. J. | author-link3 = Kendall Houk | author-link4 = K. Barry Sharpless | last2 = Haller | first2 = J. | last3 = Houk | first3 = K. N. | last4 = Sharpless | first4 = K. B. | last5 = Singleton | first5 = D. A. | last6 = Strassner | first6 = T. | last7 = Thomas | first7 = A. A. | year = 1997 | title =  Experimental and Theoretical Kinetic Isotope Effects for Asymmetric Dihydroxylation. Evidence Supporting a Rate-Limiting "(3 + 2)" Cycloaddition| journal = [[J. Am. Chem. Soc.]] | volume = 119 | issue = 41| pages = 9907–9908 | doi = 10.1021/ja971650e }}</ref>  Basic [[hydrolysis]] liberates the diol ('''5''') and the reduced osmate ('''6''').  Methanesulfonamide (CH<sub>3</sub>SO<sub>2</sub>NH<sub>2</sub>) has been identified as a catalyst to accelerate this step of the catalytic cycle and if frequently used as an additive to allow non-terminal alkene substrates to react efficiently at 0 °C.<ref name=":1" />  Finally, the [[stoichiometric]] oxidant regenerates the osmium tetroxide – ligand complex ('''2''').

[[Image:Sharpless Dihydroxylation Mechanism.png|600px|center|The reaction mechanism of the Sharpless dihydroxylation]]

The mechanism of the Sharpless asymmetric dihydroxylation has been extensively studied and a potential secondary catalytic cycle has been identified (see below).<ref>{{cite journal | last1 = Ogino | first1 = Y. | last2 = Chen | first2 = H. | last3 = Kwong | first3 = H.-L. | last4 = Sharpless | first4 = K. B. | year = 1991 | title =  On the timing of hydrolysis / reoxidation in the osmium-catalyzed asymmetric dihydroxylation of olefins using potassium ferricyanide as the reoxidant| journal = Tetrahedron Lett. | volume = 3 | issue = 2| pages = 3965–3968 | doi = 10.1016/0040-4039(91)80601-2 }}</ref><ref>{{cite journal | last1 = Wai | first1 = J. S. M. | last2 = Marko | first2 = I. | last3 = Svendsen | first3 = J. N. | last4 = Finn | first4 = M. G. | last5 = Jacobsen | first5 = E. N. | last6 = Sharpless | first6 =  K. Barry| year = 1989 | title =  A mechanistic insight leads to a greatly improved osmium-catalyzed asymmetric dihydroxylation process| journal = J. Am. Chem. Soc. | volume = 111 | issue = 3| page = 1123 | doi = 10.1021/ja00185a050 }}</ref> If the osmylate ester intermediate is oxidized before it dissociates, then an osmium(VIII)-diol complex is formed which may then dihydroxylate another alkene.<ref name="ReferenceB">Sundermeier, U., Dobler, C., Beller, M. Recent developments in the osmium-catalyzed dihydroxylation of olefins. Modern Oxidation Methods. 2004 WILEY-VCH Verlag GmbH & Co. KGaA,Weinheim. {{ISBN|3-527-30642-0}}</ref> Dihydroxylations resulting from this secondary pathway generally suffer lower enantioselectivities than those resulting from the primary pathway. A schematic showing this secondary catalytic pathway is shown below. This secondary pathway may be suppressed by using a higher molar concentration of ligand.

[[Image:Sharpless Asymmetric Dihydroxylation catalytic cycle.png|600px|center|Catalytic cycle of the Sharpless asymmetric dihydroxylation]]

===[2+2] vs [3+2] debate===
In his original report Sharpless suggested the reaction proceeded via a [[Cycloaddition|[2+2] cycloaddition]] of OsO<sub>4</sub> onto the alkene to give an osmaoxetane intermediate (see below).<ref>{{Cite journal|title = Asymmetric induction in the reaction of osmium tetroxide with olefins|date = June 1980|doi = 10.1021/ja00532a050|last = Hentges|first = Steven G.|last2 = Sharpless|first2 = K. Barry|journal = [[J. Am. Chem. Soc.]]|page = 4263|issue = 12|volume = 102}}
</ref> This intermediate would then undergo a [[Migratory insertion|1,1- migratory insertion]] to form an osmylate ester which after hydrolysis would give the corresponding diol. In 1989 E. J. Corey published a slightly different variant of this reaction and suggested that the reaction most likely proceeded via a [3+2] cycloaddition of OsO<sub>4</sub> with the alkene to directly generate the osmylate ester.<ref>{{Cite journal|title = Enantioselective vicinal hydroxylation of terminal and E-1,2-disubstituted olefins by a chiral complex of osmium tetroxide. An effective controller system and a rational mechanistic model|date = December 1989|last = Corey|first = E. J.|first2 = Paul|last2 = DaSilva Jardine|first3 = Scott|last3 = Virgil|first4 = Po Wai|last4 = Yuen|first5 = Richard D.|last5 = Connell|journal = [[J. Am. Chem. Soc.]]|volume = 111|issue = 26|page = 9243|doi = 10.1021/ja00208a025}}
</ref> Corey's suggestion was based on a previous computational study done by Jorgensen and Hoffmann which determined the [3+2] reaction pathway to be the lower energy pathway. In addition Corey reasoned that steric repulsions in the octahedral intermediate would disfavor the [2+2] pathway.

[[Image:Osmium tetroxide dihydroxylation proposed and correct mechanism.png|700px|center|Osmium tetroxide dihydroxylation proposed and correct mechanism]]

The next ten years saw numerous publications by both Corey and Sharpless, each supporting their own version of the mechanism. While these studies were not able to distinguish between the two proposed cyclization pathways, they were successful in shedding light on the mechanism in other ways. For example, Sharpless provided evidence for the reaction proceeding via a step-wise mechanism.<ref>Thomas, G.; Sharpless, K. B. ACIEE 1993, 32, 1329</ref> Additionally both Sharpless and Corey showed that the active catalyst possesses a U-shaped chiral binding pocket.<ref>{{Cite journal|title = Rigid and highly enantioselective catalyst for the dihydroxylation of olefins using osmium tetraoxide clarifies the origin of enantiospecificity|date = December 1993|last = Corey|first = E. J.|last2 = Noe|first2 = Mark C.|doi = 10.1021/ja00079a045|journal = [[J. Am. Chem. Soc.]]|page = 12579|issue = 115|volume = 26}}
</ref><ref>{{Cite journal|title = Toward an Understanding of the High Enantioselectivity in the Osmium-Catalyzed Asymmetric Dihydroxylation (AD). 1. Kinetics|date = February 1994|last = Kolb|first = H. C.|first2 = P. G.|last2 = Anderson|first3 = K. B.|last3 = Sharpless|journal = [[J. Am. Chem. Soc.]]|volume = 116|issue = 1278|pages = 1278|doi = 10.1021/ja00083a014}}
</ref><ref>{{Cite journal|title = X-ray crystallographic studies provide additional evidence that an enzyme-like binding pocket is crucial to the enantioselective dihydroxylation of olefins by OsO4-bis-cinchona alkaloid complexes|year = 1994|last = Corey|first = E. J.|first2 = Mark C.|last2 = Noe|first3 = Sepehr|last3 = Sarshar|journal = [[Tetrahedron Letters]]|volume = 35|issue = 18|page = 2861|doi=10.1016/s0040-4039(00)76644-5}}
</ref> Corey also showed that the catalyst obeys Michaelis-Menten kinetics and acts like an enzyme pocket with a pre-equilibrium.<ref name="J. Corey, M. C 1996">{{Cite journal|title = Kinetic Investigations Provide Additional Evidence That an Enzyme-like Binding Pocket Is Crucial for High Enantioselectivity in the Bis-Cinchona Alkaloid Catalyzed Asymmetric Dihydroxylation of Olefins|date = 17 January 1996|first = E. J.|last = Corey|first2 = M. C.|last2 = Noe|journal = [[J. Am. Chem. Soc.]]|volume = 118|issue = 2|page = 319|doi = 10.1021/ja952567z}}
</ref> In the February 1997 issue of the Journal of the American Chemical Society Sharpless published the results of a study (a Hammett analysis) which he claimed supported a [2+2] cyclization over a [3+2].<ref>{{Cite journal|title = Toward an Understanding of the High Enantioselectivity in the Osmium-Catalyzed Asymmetric Dihydroxylation. 4. Electronic Effects in Amine-Accelerated Osmylations|year = 1997|first = K. B.|last = Sharpless|journal = [[J. Am. Chem. Soc.]]|volume = 119|issue = 8|page = 1840|doi = 10.1021/ja961464t|last2 = Gypser|first2 = Andreas|last3 = Ho|first3 = Pui Tong|last4 = Kolb|first4 = Hartmuth C.|last5 = Kondo|first5 = Teruyuki|last6 = Kwong|first6 = Hoi-Lun|last7 = McGrath|first7 = Dominic V.|last8 = Rubin|first8 = A. Erik|last9 = Norrby|first9 = Per-Ola|last10 = Gable|first10 = Kevin P.|last11 = Sharpless|first11 = K. Barry}}</ref> In the October issue of the same year, however, Sharpless also published the results of another study conducted in collaboration with Ken Houk and Singleton which provided conclusive evidence for the [3+2] mechanism.<ref name="ReferenceA"/> Thus Sharpless was forced to concede the decade-long debate.

=== Catalyst structure ===
[[File:SAD active catalyst conformation.png|thumb|Allyl benzoate bound within the U-shaped binding pocket of the active [[dihydroquinidine]] catalyst, [[osmium tetroxide]] interacting with the ''Re'' face.]]
Crystallographic evidence has shown that the active catalyst possesses a pentacoordinate osmium species held in a U-shaped binding pocket. The nitrogenous ligand holds OsO<sub>4</sub> in a chiral environment making approach of one side of the olefin sterically hindered while the other is not.<ref name="J. Corey, M. C 1996"/>