Dihydroxylation

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Dihydroxylation is the process by which an alkene is converted into a vicinal diol. Although there are many routes to accomplish this oxidation, the most common and direct processes use a high-oxidation-state transition metal (typically osmium or manganese). The metal is often used as a catalyst, with some other stoichiometric oxidant present. [1] In addition, other transition metals and non-transition metal methods have been developed and used to catalyze the reaction.

Contents

Dihydroxylation.png

Mechanism

Mechanism for dihydroxylation using osmium tetroxide. Osmium Dihydroxylation Mechanism.png
Mechanism for dihydroxylation using osmium tetroxide.

In the dihydroxylation mechanism, a ligand first coordinates to the metal catalyst (depicted as osmium), which dictates the chiral selectivity of the olefin. The alkene then coordinates to the metal through a (3+2) cycloaddition, and the ligand dissociates from the metal catalyst. Hydrolysis of the olefin then yields the vicinal diol, and oxidation of the catalyst by a stoichiometric oxidant regenerates the metal catalyst to repeat the cycle. [2] The concentration of the olefin is crucial to the enantiomeric excess of the diol since higher concentrations of the alkene can associate with the other catalytic site to produce the other enantiomer. [3]

Osmium catalyzed reactions

Osmium tetroxide (OsO4) is a popular oxidant used in the dihydroxylation of alkenes because of its reliability and efficiency with producing syn-diols. Since it is expensive and toxic, catalytic amounts of OsO4 are used in conjunction with a stoichiometric oxidizing agent. [2] [3] The Milas hydroxylation, Upjohn dihydroxylation, and Sharpless asymmetric dihydroxylation reactions all use osmium as the catalyst as well as varying secondary oxidizing agents.

Milas

The Milas dihydroxylation was introduced in 1930, and uses hydrogen peroxide as the stoichiometric oxidizing agent. [4] Although the method can produce diols, overoxidation to the dicarbonyl compound has led to difficulties isolating the vicinal diol. [4] Therefore, the Milas protocol has been replaced by the Upjohn and Sharpless asymmetric dihydroxylation.

Upjohn

Upjohn dihydroxylation was reported in 1973 and uses OsO4 as the active catalyst in the dihydroxylation procedure. It also employs N-Methylmorpholine N-oxide (NMO) as the stoichiometric oxidant to regenerate the osmium catalyst, allowing for catalytic amounts of osmium to be used. [2] [5] The Upjohn protocol yields high conversions to the vicinal diol and tolerates many substrates. However, the protocol cannot dihydroxylate tetrasubstituted alkenes. [2] The Upjohn conditions can be used for synthesizing anti-diols from allylic alcohols, as demonstrated by Kishi and coworkers. [6]

Sharpless asymmetric

The Sharpless asymmetric dihydroxylation [7] was developed by K. Barry Sharpless to use catalytic amounts of OsO4 along with the stoichiometric oxidant K3[Fe(CN)6]. [1] [2] [8] The reaction is performed in the presence of a chiral auxiliary. The selection of dihydroquinidine (DHQD) or dihydroquinine (DHQ) as a chiral auxiliary dictates the facial selectivity of the olefin, since the absolute configuration of the ligands are opposite. [2] [8] [9] The catalyst, oxidant, and chiral auxiliary can be purchased premixed for selective dihydroxylation. AD-mix-α contains the chiral auxiliary (DHQ)2PHAL, which positions OsO4 on the alpha-face of the olefin; AD-mix-β contains (DHQD)2PHAL and delivers hydroxyl groups to the beta-face. [1] [10] The Sharpless asymmetric dihydroxylation has a large scope for substrate selectivity by changing the chiral auxiliary class. [8]

Mnemonic for the Sharpless asymmetric dihydroxylation. Sharpless Asymmetric Dihydroxylation Mnemonic.png
Mnemonic for the Sharpless asymmetric dihydroxylation.
TMEDA Transition State.png

Other variants

As mentioned above, the ability to synthesize anti-diols from allylic alcohols can be achieved with the use of NMO as a stoichiometric oxidant. [6] The use of tetramethylenediamine (TMEDA) as a ligand produced syn-diols with a favorable diastereomeric ratio compared to Kishi’s protocol; however, stoichiometric osmium is employed. Syn-selectivity is due to the hydrogen bond donor ability of the allylic alcohol and the acceptor ability of the diamine. [11] [12] [13] This has since been applied to homoallylic systems. [14] [15]

Other dihydroxylation methods

Since osmium tetroxide is expensive and toxic, other metals have been used to prepare vicinal diols from olefins. Another popular metal used in dihydroxylation is ruthenium. Although it is highly oxidative, ruthenium has been used because of its short reaction time and its cost-effectiveness. [16] Typically, the ruthenium tetroxide is created in situ from ruthenium trichloride, and a secondary oxidant NaIO4 is used to regenerate the catalyst. The turnover-limiting step of the reaction is the hydrolysis step; therefore, sulfuric acid is added to increase the rate of this step. [16] [17]

Manganese is also used in dihydroxylation and is often chosen when osmium tetroxide methods yield poor results. [17] Similar to ruthenium, the oxidation potential of manganese is high, leading to over-oxidation of substrates. Potassium permanganate is often used as the oxidant for dihydroxylation; however, due to its poor solubility in organic solvent, a phase-transfer catalyst (such as benzyltriethylammonium chloride, TEBACl) is also added to increase the number of substrates for dihydroxylation. [17] Mild conditions are required to avoid over-oxidation. In particular, a solution that is too warm, acidic, or concentrated will lead to cleavage of the glycol. [18]

Prévost and Woodward dihydroxylation

Scheme of the Prevost and Woodward Reactions. Prevost and Woodward Scheme.png
Scheme of the Prevost and Woodward Reactions.

Unlike the other methods described that use transition metals as catalyst, the Prévost and Woodward methods use iodine and a silver salt. However, the addition of water into the reaction directs the cis- and trans- addition of the hydroxyl groups. The Prévost reaction typically uses silver benzoate to produce trans-diols; the Woodward modification of the Prévost reaction uses silver acetate to produce cis-diols. In both the Prévost and Woodward reactions, iodine is first added to the alkene producing a cyclic iodinium ion. The anion from the corresponding silver salt is then added by nucleophilic substitution to the iodinium ion. [19]

The first step of the Prevost and Woodward hydroxylation methods. Prevost and Woodward First Steps.png
The first step of the Prevost and Woodward hydroxylation methods.

In the Prévost reaction, the iodinium ion undergoes nucleophilic attack by benzoate anion. The benzoate anion acts as a nucleophile again to displace iodide through a neighboring-group participation mechanism. A second benzoate anion reacts with the intermediate to produce the anti-substituted dibenzoate product, which can then undergo hydrolysis to yield trans-diols. [19]

The Prevost reaction mechanism. Prevost Reaction.png
The Prevost reaction mechanism.

The Woodward modification of the Prévost reaction yields cis-diols. Acetate anion reacts with the cyclic iodinium ion to yield an oxonium ion intermediate. This can then readily react with water to give the monoacetate, which can then be hydrolyzed to give a cis-diol [20]

The Woodward reaction mechanism. Woodward Reaction.png
The Woodward reaction mechanism.

To eliminate the need for silver salts, Sudalai and coworkers modified the Prévost-Woodward reaction; the reaction is catalyzed with LiBr, and uses NaIO4 and PhI(OAc)2 as oxidants. [21] LiBr reacts with NaIO4 and acetic acid to produce lithium acetate, which can then proceed through the reaction as previously mentioned. The protocol produced high dr for the corresponding diol, depending on the oxidant chosen.

The modification of the Prevost-Woodward reaction proposed by Sudalai. Prevost-Woodward Modification.png
The modification of the Prevost-Woodward reaction proposed by Sudalai.

Applications

The synthesis of highly substituted and stereospecific sugars is important since polysaccharides make up a large class of compounds found in nature. One specific example is in the biologically active molecule kakelokelose, which has been shown to have anti-HIV activity. [22] Research conducted by Harris et al. have worked on an enantiospecific synthesis of sugars pertaining to kakelokelose and other sugars, employing many different dihydroxylation reactions with osmium catalyst. Vinylfuran was reacted under Sharpless conditions with AD-mix-α to yield (R)-diol. Later, a resulting dihydropyran was reacted under Upjohn conditions to yield the resulting sugar, mannose (where R represents either H or a protecting group). [22]

Sugar synthesis.png

Additionally, talose and gulose were also synthesized from a different dihydropyran. Since the compound contains an allylic alcohol, Upjohn conditions and the Upjohn modification using TMEDA as the secondary oxidant to create the resulting sugars (where R represents either H or a protecting group). [22]

NMO vs TMEDA.png

Another application of dihydroxylation methods is in the synthesis of steroids. Brassinosteroids are a class of steroids shown to regulate plant growth and has been shown to have agricultural activity as an insecticide. This class of steroids contains the standard framework of steroids in addition to four vicinal diols that have their own stereochemistry. [23] Brosa installed the hydroxyl groups in the steroid using both Woodward conditions to yield a cis-diol to the A ring of the steroid. Then, the alkene chain on the D ring was dihydroxylated to yield the second cis-diol using OsO4 and NMO as the stoichiometric oxidant. [24]

Reactions showcasing dihydroxylation steps. Hydroxylation in the Synthesis of Brassinosteroid.png
Reactions showcasing dihydroxylation steps.

Related Research Articles

<span class="mw-page-title-main">Alkene</span> Hydrocarbon compound containing one or more C=C bonds

In organic chemistry, an alkene, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or in the terminal position. Terminal alkenes are also known as α-olefins.

<span class="mw-page-title-main">Osmium tetroxide</span> Chemical compound

Osmium tetroxide (also osmium(VIII) oxide) is the chemical compound with the formula OsO4. The compound is noteworthy for its many uses, despite its toxicity and the rarity of osmium. It also has a number of unusual properties, one being that the solid is volatile. The compound is colourless, but most samples appear yellow. This is most likely due to the presence of the impurity OsO2, which is yellow-brown in colour. In biology, its property of binding to lipids has made it a widely-used stain in electron microscopy.

<span class="mw-page-title-main">Sharpless epoxidation</span> Chemical reaction

The Sharpless epoxidation reaction is an enantioselective chemical reaction to prepare 2,3-epoxyalcohols from primary and secondary allylic alcohols. The oxidizing agent is tert-butyl hydroperoxide. The method relies on a catalyst formed from titanium tetra(isopropoxide) and diethyl tartrate.

Sharpless asymmetric dihydroxylation is the chemical reaction of an alkene with osmium tetroxide in the presence of a chiral quinine ligand to form a vicinal diol. The reaction has been applied to alkenes of virtually every substitution, often high enantioselectivities are realized, with the chiral outcome controlled by the choice of dihydroquinidine (DHQD) vs dihydroquinine (DHQ) as the ligand. Asymmetric dihydroxylation reactions are also highly site selective, providing products derived from reaction of the most electron-rich double bond in the substrate.

A diol is a chemical compound containing two hydroxyl groups. An aliphatic diol is also called a glycol. This pairing of functional groups is pervasive, and many subcategories have been identified.

<span class="mw-page-title-main">Wacker process</span> Chemical reaction

The Wacker process or the Hoechst-Wacker process refers to the oxidation of ethylene to acetaldehyde in the presence of palladium(II) chloride and copper(II) chloride as the catalyst. This chemical reaction was one of the first homogeneous catalysis with organopalladium chemistry applied on an industrial scale.

<span class="mw-page-title-main">AD-mix</span>

In organic chemistry, AD-mix is a commercially available mixture of reagents that acts as an asymmetric catalyst for various chemical reactions, including the Sharpless asymmetric dihydroxylation of alkenes. The two letters AD, stand for asymmetric dihydroxylation. The mix is available in two variations, "AD-mix α" and "AD-mix β" following ingredient lists published by Barry Sharpless.

(<i>E</i>)-Stilbene Chemical compound

(E)-Stilbene, commonly known as trans-stilbene, is an organic compound represented by the condensed structural formula C6H5CH=CHC6H5. Classified as a diarylethene, it features a central ethylene moiety with one phenyl group substituent on each end of the carbon–carbon double bond. It has an (E) stereochemistry, meaning that the phenyl groups are located on opposite sides of the double bond, the opposite of its geometric isomer, cis-stilbene. Trans-stilbene occurs as a white crystalline solid at room temperature and is highly soluble in organic solvents. It can be converted to cis-stilbene photochemically, and further reacted to produce phenanthrene.

<span class="mw-page-title-main">Tetrapropylammonium perruthenate</span> Chemical compound

Tetrapropylammonium perruthenate (TPAP or TPAPR) is the chemical compound described by the formula N(C3H7)4RuO4. Sometimes known as the Ley–Griffith reagent, this ruthenium compound is used as a reagent in organic synthesis. This salt consists of the tetrapropylammonium cation and the perruthenate anion, RuO−4.

N-Methylmorpholine N-oxide (more correctly 4-methylmorpholine 4-oxide), NMO or NMMO is an organic compound. This heterocyclic amine oxide and morpholine derivative is used in organic chemistry as a co-oxidant and sacrificial catalyst in oxidation reactions for instance in osmium tetroxide oxidations and the Sharpless asymmetric dihydroxylation or oxidations with TPAP. NMO is commercially supplied both as a monohydrate C5H11NO2·H2O and as the anhydrous compound. The monohydrate is used as a solvent for cellulose in the lyocell process to produce cellulose fibers.

<span class="mw-page-title-main">Jacobsen epoxidation</span>

The Jacobsen epoxidation, sometimes also referred to as Jacobsen-Katsuki epoxidation is a chemical reaction which allows enantioselective epoxidation of unfunctionalized alkyl- and aryl- substituted alkenes. It is complementary to the Sharpless epoxidation (used to form epoxides from the double bond in allylic alcohols). The Jacobsen epoxidation gains its stereoselectivity from a C2 symmetric manganese(III) salen-like ligand, which is used in catalytic amounts. The manganese atom transfers an oxygen atom from chlorine bleach or similar oxidant. The reaction takes its name from its inventor, Eric Jacobsen, with Tsutomu Katsuki sometimes being included. Chiral-directing catalysts are useful to organic chemists trying to control the stereochemistry of biologically active compounds and develop enantiopure drugs.

Ruthenium tetroxide is the inorganic compound with the formula RuO4. It is a yellow volatile solid that melts near room temperature. It has the odor of ozone. Samples are typically black due to impurities. The analogous OsO4 is more widely used and better known. It is also the anhydride of hyperruthenic acid (H2RuO5). One of the few solvents in which RuO4 forms stable solutions is CCl4.

The Sharpless oxyamination is the chemical reaction that converts an alkene to a vicinal amino alcohol. The reaction is related to the Sharpless dihydroxylation, which converts alkenes to vicinal diols. Vicinal amino-alcohols are important products in organic synthesis and recurring pharmacophores in drug discovery.

Asymmetric catalytic oxidation is a technique of oxidizing various substrates to give an enantio-enriched product using a catalyst. Typically, but not necessarily, asymmetry is induced by the chirality of the catalyst. Typically, but again not necessarily, the methodology applies to organic substrates. Functional groups that can be prochiral and readily susceptible to oxidation include certain alkenes and thioethers. Challenging but pervasive prochiral substrates are C-H bonds of alkanes. Instead of introducing oxygen, some catalysts, biological and otherwise, enantioselectively introduce halogens, another form of oxidation.

The Upjohn dihydroxylation is an organic reaction which converts an alkene to a cis vicinal diol. It was developed by V. VanRheenen, R. C. Kelly and D. Y. Cha of the Upjohn Company in 1976. It is a catalytic system using N-methylmorpholine N-oxide (NMO) as stoichiometric re-oxidant for the osmium tetroxide. It is superior to previous catalytic methods.

The Milas hydroxylation is an organic reaction converting an alkene to a vicinal diol, and was developed by Nicholas A. Milas in the 1930s. The cis-diol is formed by reaction of alkenes with hydrogen peroxide and either ultraviolet light or a catalytic osmium tetroxide, vanadium pentoxide, or chromium trioxide.

The Lemieux–Johnson or Malaprade–Lemieux–Johnson oxidation is a chemical reaction in which an olefin undergoes oxidative cleavage to form two aldehyde or ketone units. The reaction is named after its inventors, Raymond Urgel Lemieux and William Summer Johnson, who published it in 1956. The reaction proceeds in a two step manner, beginning with dihydroxylation of the alkene by osmium tetroxide, followed by a Malaprade reaction to cleave the diol using periodate. Excess periodate is used to regenerate the osmium tetroxide, allowing it to be used in catalytic amounts. The Lemieux–Johnson reaction ceases at the aldehyde stage of oxidation and therefore produces the same results as ozonolysis.

Alcohol oxidation is a collection of oxidation reactions in organic chemistry that convert alcohols to aldehydes, ketones, carboxylic acids, and esters where the carbon carries a higher oxidation state. The reaction mainly applies to primary and secondary alcohols. Secondary alcohols form ketones, while primary alcohols form aldehydes or carboxylic acids.

<span class="mw-page-title-main">Oxoammonium-catalyzed oxidation</span>

Oxoammonium-catalyzed oxidation reactions involve the conversion of organic substrates to more highly oxidized materials through the action of an N-oxoammonium species. Nitroxides may also be used in catalytic amounts in the presence of a stoichiometric amount of a terminal oxidant. Nitroxide radical species used are either 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) or derivatives thereof.

In chemistry, a reoxidant is a reagent that regenerates a catalyst by oxidation. In some cases they are used stoichiometrically, in other cases only small amounts are required.

References

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  3. 1 2 Kolbe, H.C.; VanNieuwanhze, M.S.; Sharpless, K.B. (1994). "Catalytic Asymmetric Dihydroxylation". Chem. Rev. 94 (8): 2483–2547. doi:10.1021/cr00032a009.
  4. 1 2 Milas, N.A.; Sussman, S. (1936). "The Hydroxylation of the Double Bond 1". J. Am. Chem. Soc. 58 (7): 1302–4. doi:10.1021/ja01298a065.
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  9. ↑ Carey, F.A.; Sundberg, R.J. (2007). Advanced Organic Chemistry Part A: Structure and Mechanisms. Springer. p. 202.
  10. ↑ Xu, D.X.; Crispino, G.A.; Sharpless, K.B. (1992). "Selective asymmetric dihydroxylation (AD) of dienes". J. Am. Chem. Soc. 114 (19): 7570–1. doi:10.1021/ja00045a043.
  11. ↑ Donohoe, T.J.; Blades, K.; Moore, P.R.; Waring, M.J.; Winter, J.J.G.; Helliwell, M.; Newcombe, N.J.; Stemp, G. (2002). "Directed dihydroxylation of cyclic allylic alcohols and trichloroacetamides using OsO4/TMEDA". J. Org. Chem. 67 (23): 7946–56. doi:10.1021/jo026161y. PMID   12423122.
  12. ↑ Donohoe, T.J.; Moore, P.R.; Waring, M.J.; Newcombe, Nicholas J. (1997). "The directed dihydroxylation of allylic alcohols". Tetrahedron Lett. 38 (28): 5027–30. doi:10.1016/s0040-4039(97)01061-7.
  13. ↑ Donohoe, T.J. (2002). "Development of the Directed Dihydroxylation Reaction". Synlett (8): 1223–32. doi:10.1055/s-2002-32947.
  14. ↑ Donohoe, Timothy J.; Mitchell, Lee; Waring, Michael J.; Helliwell, Madeleine; Bell, Andrew; Newcombe, Nicholas J. (2003-06-10). "Scope of the directed dihydroxylation: application to cyclic homoallylic alcohols and trihaloacetamides". Organic & Biomolecular Chemistry. 1 (12): 2173–2186. doi:10.1039/B303081D. ISSN   1477-0539. PMID   12945911.
  15. ↑ Donohoe, Timothy J; Mitchell, Lee; Waring, Michael J; Helliwell, Madeleine; Bell, Andrew; Newcombe, Nicholas J (2001-12-17). "Homoallylic alcohols and trichloroacetamides as hydrogen bond donors for directed dihydroxylation". Tetrahedron Letters. 42 (51): 8951–8954. doi: 10.1016/S0040-4039(01)01999-2 . ISSN   0040-4039.
  16. 1 2 Plietker, B.; Niggemann, M. (2003). "An improved protocol for the RuO4-catalyzed dihydroxylation of olefins". Org. Lett. 5 (18): 3353–6. doi:10.1021/ol035335a. PMID   12943425.
  17. 1 2 3 Bataille, C.J.R.; Donohoe, T.J. (2011). "Osmium-free direct syn-dihydroxylation of alkenes". Chem. Soc. Rev. 40 (1): 114–28. doi:10.1039/b923880h. PMID   21049111.
  18. ↑ Wade, L. G. (2013). Organic chemistry (8th ed.). Boston: Pearson. p. 367. ISBN   978-0-321-76841-4. OCLC   752068109.
  19. 1 2 Kurti, L.; Czako, B. (2005). Strategic Applications of Named Reactions in Organic Synthesis. Elsevier. pp. 360–1.
  20. ↑ Woodward, R.B.; Brutcher, Jr., F.V. (1958). "cis-Hydroxylation of a Synthetic Steroid Intermediate with Iodine, Silver Acetate and Wet Acetic Acid". J. Am. Chem. Soc. 80: 209–11. doi:10.1021/ja01534a053.
  21. ↑ Emmanuvel, L.; Shaikh, T.M.A.; Sudalai, A. (2005). "NaIO4/Li Br-mediated diastereoselective dihydroxylation of olefins: A catalytic approach to the Prevost-Woodward reaction". Org. Lett. 7 (22): 5071–4. doi:10.1021/ol052080n. PMID   16235960.
  22. 1 2 3 Harris, J.M.; Keranen, M.D.; O'Doherty, G.A. (1999). "Syntheses of D- and L-Mannose, Gulose, and Talose via Diastereoselective and Enantioselective Dihydroxylation Reactions". J. Org. Chem. 64 (9): 2982–3. doi:10.1021/jo990410. PMID   11674384.
  23. ↑ Bishop, G.; Koncz, Csaba (2002). "Brassinosteroids and Plant Steroid Hormone Signaling". The Plant Cell. 14 (Suppl): S97–110. doi:10.1105/tpc.001461. PMC   151250 . PMID   12045272.
  24. ↑ Brosa, C.; Nusimovich, S; Peracaula, R (1994). "Synthesis of new brassinosteroids with potential activity as antiecdysteroids". Steroids. 59 (8): 463–7. doi:10.1016/0039-128x(94)90058-2. PMID   7985206. S2CID   45409677.
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