Alkenes, dihydroxylation, with

The first reaction, 8.30, is the classical alkene dihydroxylation with osmium tetroxide. In recent years the potential of this reaction has been vastly extended... 

Other Applications. Other (/ ,/ )-stilbenediamine derivatives have been used to direct the stereochemical course of alkene dihydroxylation (with stoichiometric quantities of Osmium Tetroxide and epoxidation of simple alkenes with Sodium Hypochlorite and manganese(III) complexes. ... 

Dihydroxylation.The conventional method of alkene dihydroxylation with OSO4 and Al-mcthylmorpholinc V-oxide (NMO) has been modified such that the latter reagent is replaced by substoichiometric A-methylmorpholine and 1.4 equiv of MCPBA. 

Dihydroxylation. Besides the enormously popular and effective cinchona alkaloid-based chiral auxiliaries several C2-symmetrical diamines (13), (14) and (15) have been developed to direct alkene dihydroxylation with OSO4. These efforts are probably overwhelmed by the Sharpless protocols because the approaches are not catalytic with respect to the most expensive and toxic reagent. 

Table 4. Calculated and experimental enantioselectivities in the asymmetric dihydroxylation with different alkenes and bases (adapted from Ref. 28).

It was of obvious interest to prepare the inhibitors 60 as their pure dia-stereoisomers, 66 and 67. Following on from our successful treatment of alkenyl D-glucosides under Sharpless asymmetric dihydroxylation conditions [21], we treated the alkenes 64 with the a-AD - and AD -mLxes - the results are summarized in Table 2. In no case did we ever obtain a satisfactory diastereo-isomeric excess of the diol 68 over the diol 69, or vice versa. A similar lack of stereoselectivity was also obtained with the triol 70 and the amine 71 [48]. 

Although a large number of asymmetric catalytic reactions with impressive catalytic activities and enantioselectivities have been reported, the mechanistic details at a molecular level have been firmly established for only a few. Asymmetric isomerization, hydrogenation, epoxidation, and alkene dihydroxylation are some of the reactions where the proposed catalytic cycles could be backed with kinetic, spectroscopic, and other evidence. In all these systems kinetic factors are responsible for the observed enantioselectivities. In other words, the rate of formation of one of the enantiomers of the organic product is much faster than that of its mirror image. 

Quite recently it was reported that in addition to hydrogen peroxide, periodate or hexacyanoferrat(III), molecular oxygen21,31-34 can be used to reoxidize these metal-oxo compounds. New chiral centers in the products can be created with high enantioselectivity in the dihydroxylation reactions of prochiral alkenes. The development of the catalytic asymmetric version of the alkene dihydroxylation was recognized by Sharpless receipt of the 2001 Nobel prize in Chemistry. 

The introduction of oxygen atoms into unsaturated organic molecules via dihydroxylation reactions leads to 1,2-diols. 1,2-Diols can be synthesized by the reaction of alkenes either with peracids via corresponding epoxides and subsequent hydrolysis or with OSO4, KMn04, RUO4 and Cr(VI) compounds. 

From the mechanism shown in Scheme 7.23, we would expect the dihydroxylation with syn-selectivity. The cyclic intermediate may be isolated in the osmium reaction, which is formed by the cycloaddition of OSO4 to the alkene. Since osmium tetroxide is highly toxic and very expensive, the reaction is performed using a catalytic amount of osmium tetroxide and an oxidizing agent such as TBHP, sodium chlorate, potassium ferricyanide or NMO, which regenerates osmium tetroxide. For example, Upjohn dihydroxylation allows the syn-selective preparation of 1,2-diols from alkenes by the use of catalytic amount of OSO4 and a stoichiometric amount of an oxidant such as NMO. 

Not unexpectedly, the enantioselectivity of the catalytic asymmetric dihydroxylation of alkenes is rather dependent on the substitution pattern of the starting alkene. (E)-, 2-Disubstituted, including a,/(-unsaturated esters, and trisubstituted alkenes are the most well behaved substrates and are dihydroxylated with ligands 1 f/2f in enantioselectivities usually exceeding 90% ee6a. 

From the synthetic point of view, satisfactory cis dihydroxylations with these reagents are best achieved with electron-poor alkenes such as oc,/ -unsaturated esters and lactones. Permanganate ion mediated dihydroxylations of chiral alkenes usually afford the same sense of diastereoselection as the osmylation reaction, a result suggesting comparable steric and electronic requirements in the corresponding transition states. 

The next stage is a standard dihydroxylation with OSO4. The two OH groups must be added in a cis fashion but why do they add to the top face of the alkene This is easier to see in a conformational drawing. The top face of the alkene is virtually unhindered whereas the bottom face... 

In addition to the 1,3-ally lie strain concept, Houk has employed a model for 7t-facial stereoselection of electrophilic additions to chiral alkenes, such as hydroboration, epoxidation, and dihydroxylation, with similar predictive success. ... 

Treatment of alkenes either with osmium tetroxide or with alkaline potassium permanganate results in 5yn-dihydroxylation of the double bond. 

Finally the remaining alkene is dihydroxylated with catalytic Os04and stoichiometric iV-methyl-morpholine (NMO) as oxidant to give the diol 56 that cyclises to the THF 57 stereospecifically. The aldehyde 58 was used to make (-)-dysiherbane. 

A good illustration of many aspects of this chemistry comes from Koreeda s synthesis of shikimic acid.22 The silyl diene 123 adds cleanly to methyl acrylate to give essentially one isomer of the adduct 124 (9 1). Dihydroxylation with catalytic 0s04 and the stoichiometric oxidant NMO (A-methylmorpholine-A-oxide) occurs on the opposite face to all three substituents. The alkene 124 is an allylic acetate but this group has no attractive interaction with the reagent. 

From the standpoint of general applicability, and scope the osmium-catalyzed asymmetric dihydroxylation of alkenes (Sharpless dihydroxylation) has reached a level of effectiveness which is unique among asymmetric catalytic methods . In the presence of an optimized catalyst ligand system nearly every class of olefin can be dihydroxylated with high enantioselectivities. 

The dihydroxylation reaction is very general, giving high yields of diol products from electron-rich or electron-poor alkenes. High levels of stereocontrol can often be obtained on dihydroxylation of alkenes bearing one or more chiral centre. The large steric requirements of the reagent normally dictates that dihydroxylation with osmium tetroxide takes place predominantly from the less-hindered side of the double bond. 

Accordingly, the synthesis of phthalide 44 began from methyl ketone 27 (Scheme 18). In order to avoid interference of the olefin moiety with haloge-nation of the aromatic ring, asymmetric dihydroxylation was conducted first. Treatment of alkene 27 with AD-mix a in tcrt-butanol/water (1 1) provided diol 27 in a pleasing 87% yield. Inspection of the and NMR spectra did not indicate the presence of a diastereomeric mixture. However, although alkene 27 is structurally well suited to the Sharpless mnemonic, we thought it... 

Of the quinuclidine-ligated transition metal catalyzed processes, the osmium-catalyzed asymmetric dihydroxylation of alkenes, developed by Sharpless, has had the greatest impact on synthetic chemistry (67). In a recent synthesis, 1,3-dienoates were dihydroxylated with high enantioselectivities in the presence of (DHQD)2PHAL (hydroquinidine 1,4-phthalazinediyl diether) (Fig. 19) (183). 

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