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Sharpless Asymmetric Dihydroxylation
Introduction, History, and Overview
The Sharpless Asymmetric Dihydroxylation Reaction can be employed to
enantioselectively convert numerous substituted olefins into asymmetric alcohols, which can
subsequently be utilized in the synthesis of a variety of biologically active and medically
important products. I chose to study this reaction because of its importance in the process of
producing antitumor drugs such as Taxol and Cryptophycin 52, an antitubulin molecule effective
in the treatment of tumors resistant to Taxol and similar pharmaceuticals. I have always been
interested in and am still considering a career in pediatric oncology; the discovery and synthesis
of these drugs is not only fascinating, but also incredibly important to the treatment of deadly
cancers and the ability to give an individual the chance to enjoy the life that, without the
development of crucial drugs, they would not have had. 1
The Sharpless Asymmetric Dihydroxylation (AD) Reaction bears the name of K. Barry
Sharpless (1941-), a chemist at the Scripps Institute, who received the Nobel Prize in Chemistry
in 2001 along with William Knowles and Ryojo Noyori for their contributions to chirally
catalyzed reactions. The AD Reaction was preceded by and shares various similarities with
Sharpless’s Asymmetric Epoxidation Reaction; Sharpless and associates have since begun to
refine another asymmetric reaction, the Asymmetric Aminohydroxylation.2,3
The (AD) Reaction can be carried out under stoichiometric or catalytic conditions; the
osmium-catalyzed dihydroxylation scheme is discussed, as it provides a relatively simple and
more cost-effective method for producing a higher enantiomeric excess of the desired
asymmetric product. The catalytic AD Reaction is now conducted in a bi-phase mixture to
prevent the initiation of a second catalytic cycle and a resultant lower ee when a cooxidant such
as N-methylmorpholine N-oxide (NMO) is utilized in a homogenous mixture. For optimum
results, K2OsO2(OH)4 is used as the source of OsO4, K3Fe(CN)6 is added as the cooxidant, and
other compounds such as K2CO3 or MeSO2NH2 are included in commercially available “ADmixes” to increase the reaction rate. A chiral ligand is necessary for an efficient AD reaction.
Through the many years of development of the AD reaction, a variety of chiral ligands have been
tested and evaluated; with the exception of pyridines, various quinuclidine derivatives, cinchona
alkaloids, chiral diamines, monodentate, CLB, PHN, and MEQ ligands have proved reasonably
successful in the AD reaction but have all been largely eclipsed by the ability of dimeric PHAL
and PYR ligands to direct the enantioselective dihydroxylation process. 2, 4, 5
The enantioselectivity of this reaction in general and as facilitated by different ligands
has been studied in great detail, and a mnemonic device has been proposed that can be applied to
many, although not all, substituted olefins. Assuming an olefin structure that aligns with the
assigned quadrants in the mnemonic, DHQD based ligands will selectively attack the  face,
while DHQ based ligands will attack the  face. Further study has led to the conclusion that
matching the O9 substitutent of the chincona alkaloid with the structure of the olefin can greatly
vary the reaction rate, and DHQD and DHQ based ligands can allow for transition state
stabilization of olefins with an aromatic substitutent that occupies the chiral binding pocket; this
interaction is utilized in the AD step of the synthesis of Cryptophycin 52. Numerous variations,
exceptions, and applications have been and continue to be discovered in the mechanics of this
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reaction, yet after many years of research and experiments, three main ligands (PHAL, PYR, and
IND) have been proposed to effect the asymmetric dihydroxylation of each of the six olefin
classes in a satisfactory enantiomeric excess. 2, 4
Generic Reaction 6
Specific Example
Crucial Step in Synthesis of Cryptophycin 52 7
304 mg, 0.34 mmol
AD conditions: 7
1) Add K2OSO2(OH)4 (2.5 mg, 0.0067 mmol), (DHQD)2PHAL (5.2 mg, 0.0067 mmol),
K3Fe(CN)6 (333 mg, 1.01 mmol), K2CO3 (93 mg, 0.67 mmol),
MeSO2NH2 (32 mg, 0.34 mmol)
2) Add 0.615 mL t-BuOH, 0.615 mL H2O, rapidly stir at room temperature for 20.5 hrs
3) Add 304 mg Na2SO3, stir 25 min
4) Dilute with 3 mL H2O, wash with ethyl acetate
5) Dry organic extracts with Na2SO4, filter, concentrate in vacuo
6) Chromatography (34 g of flash SiO2) eluting with ethyl acetate-hexanes (1:1, then 2:1)
Review Articles
Trindade, A. F., Gois, P. M., Afonso, C. A. Chem Rev. 2009, 109, 418.
Kolb, H. C., VanNieuwenhze, M. S., Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
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Mechanism 4
References
(1) Al-awar, R. S.; Corbett, T. H.; Ray, J. E.; Polin, L.; Kennedy, J. H.; Wagner, M. M.;
Williams, D. C. Mol. Cancer Ther. 2004, 3, 1061
(2) Clayden, J.; Greeves, N.; Warren, S.; Wothers, P. Organic Chemistry; Oxford University
Press: New York, 2001; pp 1239-1243.
(3) Nobelprize.org. The Nobel Prize in Chemistry 2001.
http://nobelprize.org/nobel_prizes/chemistry/laureates/2001/ (accessed April 8, 2011).
(4) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
(5) HJRHEE’s Lab. Sharpless Asymmetric Dihydroxylation Reaction.
http://www.hrhee-hanyang.net/board_file_img/Sharpless-AD.pdf (accessed April 3,
2011).
(6) Ahrgren, L.; Sutin, L. Org. Process Res. Dev. 1997, 1, 425.
(7) Liang, J.; Moher, E. D.; Moore, R. E.; Hoard, D. W. J. Org. Chem. 2000, 65, 3143.