Vicinal Dihydroxylation of Olefins

It has been known for decades that osmium tetroxide catalyzes the H2O2 oxidation of olefins to c -l,2-diols but the cost, toxicity and volatility of OSO4 have limited its use to the organic research laboratory. Industrial interest was aroused in the 1990 s by i) the invention of a system for vicinal hydro-xylation using an electrochemical device as the ultimate oxidant and ii) the discovery of conditions to carry out the reaction enantioselectively, mainly by Sharpless and his group. The reaction is currently carried out by Chirex to 

The chiral ligand used is based on a phthalazine (PHAL) modified by two dihydroquinidine (DHQD) substituents. Other asymmetric dihydroxylation reactions for the synthesis of pharmaceuticals have been developed at Chirex and Pharmacia/Upjohn. 

As shown, osmium tetroxide bearing the chiral ligand interacts with the olefin to give an Os(VI) ester, which upon hydrolysis releases the chiral diol. The actual oxidant is the metal itself that reduces from Os(VIII) to Os(VI). This reaction was known since the 1930 s and in this respeet it resembles the Wacker system where ethylene is oxidized to acetaldehyde with reduction of Pd(II) to 

The real challenge was the reoxidation of osmium to make the process catalytic. When the osmate ester is hydrolyzed at the organic aqueous interface, an osmate(VI) dianion (as a potassium salt) is released in the aqueous phase. Oxidation of osmate(VI) by potassium ferricyanide regenerates osmium tetr-oxide via an intermediate perosmate(VIII) anion. Loss of two hydroxide groups from the perosmate(VIII) ion gives osmium tetroxide, which then migrates back to the organic phase to restart the cycle. 

The new development is that electrochemical oxidation of ferrocyanide to ferricyanide can be coupled with asymmetric dihydroxylation to give a very efficient electrocatalytic process. The electrons necessary to the reoxidation of Fe(II) are provided by water that is reduced to OH and H2. Hydrogen gas, released at the cathode, is the only by-product of this process. This electrochemical device uses iron in catalytic amounts ( 0.15 equivalents per equivalent of olefin). 

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Fig. 4.31 Mechanism of osmium-catalyzed vicinal dihydroxylation of olefins.

This situation obtains for example in the asymmetric vicinal dihydroxylation of olefins (see Fig. 13) reported by Sharpless and coworkers [41]. Coordination of a (chiral) amine to the 0s04 catalyst affords a (chiral) catalyst with much higher activity. 

The osmium-catalyzed vicinal dihydroxylation of olefins with single oxygen donors, typically tert-butyl hydroperoxide or N -methylmorpholine-JV-oxide (NMO), has been known for three decades and forms the basis of the Sharpless asymmetric dihydroxylation of olefins. Recently, Sharpless and coworkers reported that particularly electron-deficient olefins are dihydroxylated more efficiently with NMO (Eq. 2) when the pH of... 

The cis dihydroxylation of olefins (10—>11, Scheme 2), one of organic chemistry s most venerable reactions, was first reported by Makowaka in 1908.9 It is also one of the most useful reactions, since it converts an olefin, itself a pivotal functional group, to a vicinal diol, another pivotal functional group present in many natural products and unnatural molecules. The original dihydroxyl-... 

Osmium-catalysed dihydroxylation of olefins is a powerful route towards enantioselective introduction of chiral centers into organic substrates [82]. Its importance is remarkable because of its common use in organic and natural product synthesis, due to its ability to introduce two vicinal functional groups into hydrocarbons with no functional groups [83]. Prof. Sharpless received the 2001 Nobel Prize in chemistry for his development of asymmetric catalytic oxidation reactions of alkenes, including his outstanding achievements in the osmium asymmetric dihydroxylation of olefins. 

In 1994, Hanessian and co-workers [50] reported the first examples of metal-free three-dimensional triple-stranded helicates through spontaneous self-assembly of chiral C2-symmetrical diols and chiral C2-symmetrical diamines. The initial observation resulted from the utilization of enantiopure C2-symmetrical vicinal trans-1,2-diaminocyclohexane [51,52] as ligands in the asymmetric dihydroxylations of olefins [53] and as reagents for asymmetric synthesis [54], When equimolar amounts of (5,5)-frfl x-l,2-diaminocyclohexane (28) and its (i ,i )-enantiomer (29) were individually mixed with (5,5)-frfl x-l,2-cyclohexanediol and heated in refluxing benzene, crystals of the respective supraminol complexes 28 30 and 29 30 were formed quantitatively (Scheme 12). This was the physical basis for the separation of racemic diols with tr[Pg.104]

Example 8.10. Osmium-tetroxide catalyzed asymmetric dihydroxylation of olefins. Substituted olefins such as styrene can be dihydroxylated to give vicinal diols ... 

The asymmetric dihydroxylation of olefins by 0s04 NR3 catalysts is an extremely useful reaction in organic synthesis. It is able to introduce two vicinal functional groups simultaneously on olefins not functionahsed. The apphca-tion of theoretical methods to study this reaction has proven to be critical in order to determine the reaction mechanism, and to identify the origin of the enantioselectivity. 

Moving forward from 59, six steps were required to convert this compound to 60. Vicinal dihydroxylation of the olefin was followed by oxidative cleavage of the intermediate diol using lead tetraacetate. Reductive amina-tion of the resulting aldehyde with methylamine, followed by acylation of the intermediate secondary amine gave the desired carbamate. Swern oxidation of the secondary alcohol, followed by enol ether formation gave 60. Elimination of -toluenesulfinic acid from 60 provided 61. Oxidation of this dienol ether to dienone 62 was followed by release of the secondary amine, followed by a conjugate addition reaction to establish the critical C-N bond. The remainder of the synthesis followed known chemistry. The mixture of enones 63 was converted to codeinone (35), codeine (3) and then morphine (1). 

The next task was to convert 42 to ketone 44. This transformation called for a regioselective hydration of the C13-C14 olefin. This was accomplished by vicinal dihydroxylation of the olelin, which was accompanied by formation of the y-lactone (rather that the d lactone). The preference for y-lactonization (which is most often the case in such simations) left the C14 hydroxyl group free for oxidation to ketone 43. Reductive cleavage of the a-C-O bond, and esterification of the resulting acid, gave 44 (see 99 to 100 in Alkaloids-12 for comparison). 

Treatment of 47 with alumina gave a separable 1 1 mixture of intramolecular aldol condensation products 48 and 49. The required isomer (48) was converted to the mesylate and dehydration afforded 50. Reduction of 50 from the convex face of the dithiaoctalone gave 51 after protection of the alcohol with a MOM group. Vicinal dihydroxylation of the olefin from the most accessible face, and acetonide formation, completed the synthesis of 38 (R=MOM). 

More recently Backvall and coworkers developed a novel and robust system for osmium-catalyzed asymmetric dihydroxylation of olefins by H2O2 with methyltrioxo-rhenium (MTO) as the electron transfer mediator [19]. Interestingly, here MTO catalyzes oxidation of the chiral ligand to its mono-N-oxide, which in turn reoxidizes Os to Os ". This system gives vicinal diols in good yields and high enantiomeric excess up to 99%. 

Amino-Hydroxylation. A related reaction to asymmetric dihydroxylation is the asymmetric amino-hydroxylation of olefins, forming v/c-ami noalcohols. The vic-hydroxyamino group is found in many biologically important molecules, such as the (3-amino acid 3.10 (the side-chain of taxol). In the mid-1970s, Sharpless76 reported that the trihydrate of N-chloro-p-toluenesulfonamide sodium salt (chloramine-T) reacts with olefins in the presence of a catalytic amount of osmium tetroxide to produce vicinal hydroxyl p-toluenesulfonamides (Eq. 3.16). Aminohydroxylation was also promoted by palladium.77... 

The epoxidation of olefins and the related vicinal dihydroxylation are reactions of great industrial importance. The use of commercially available 30% aq. H2O2 is obviously... 

The osmium-catalyzed dihydroxylation reaction, that is, the addition of osmium tetr-oxide to alkenes producing a vicinal diol, is one of the most selective and reliable of organic transformations. Work by Sharpless, Fokin, and coworkers has revealed that electron-deficient alkenes can be converted to the corresponding diols much more efficiently when the pH of the reaction medium is maintained on the acidic side [199]. One of the most useful additives in this context has proved to be citric acid (2 equivalents), which, in combination with 4-methylmorpholine N-oxide (NMO) as a reoxidant for osmium(VI) and potassium osmate [K20s02(0H)4] (0.2 mol%) as a stable, non-volatile substitute for osmium tetroxide, allows the conversion of many olefinic substrates to their corresponding diols at ambient temperatures. In specific cases, such as with extremely electron-deficient alkenes (Scheme 6.96), the reaction has to be carried out under microwave irradiation at 120 °C, to produce in the illustrated case an 81% isolated yield of the pure diol [199]. 

An interesting offshoot of the work on osmium-catalyzed dihydroxylations is vicinal hydroxyamination [24]. Here, imido analogs of OSO4 react with olefins to produce /5-aminoalcohols by a cw-addition process. The oxyamination reaction can be made catalytic in OSO4 by employing chloramine salts of arylsulfonamides (ArS02NClNa) or carbamates. 

Despite the dominance of dihydroxylation reactions employing Os(VlIl) for the production of vicinal diols, alternatives have been utilized in asymmetric syntheses. The best known of these is perhaps Woodward s modification [205] of the Prevost reaction [206]. This classic oxidation is known to generally yield anti-1,2-diacetates from olefinic substrates [207]. Woodward s key modification involves the inclusion of water in the reaction mixture. The intermediate iodo-acetate 303 undergoes hydrolytic cleavage... 

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