Alkene substrates, asymmetric dihydroxylation

The final compound is a diol, so asymmetric dihydroxylation is a possible approach. The precursor is a rather unreactive alkene, but asymmetric dihydroxylation is a versatile reaction which can still perform well on challenging substrates. 

Another important reaction associated with the name of Sharpless is the so-called Sharpless dihydroxylation i.e. the asymmetric dihydroxylation of alkenes upon treatment with osmium tetroxide in the presence of a cinchona alkaloid, such as dihydroquinine, dihydroquinidine or derivatives thereof, as the chiral ligand. This reaction is of wide applicability for the enantioselective dihydroxylation of alkenes, since it does not require additional functional groups in the substrate molecule ... 

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. 

Figure 17.21 (part II) shows the 1 1 complex from (DHQD)2-PHAL and 0s04 together with the stereostructure, which is derived from the previous discussion, in the transition state of the asymmetric dihydroxylation. Here, the alkene nestles between the amine-complexed 0s04 on the one side and the methoxyquinoline residue on the other. The enantioselectivity of the dihydroxylation is the result of the alkene s preference to nestle in this niche with the orientation shown here. This orientation is characterized by the fact that no repulsion may occur between the alkene and the bottom of this niche, i.e., the central heterocycle of (DHQD)2-PHAL. This is the case if and only if the. s/r-bound hydrogen atom (as the smallest double bond substituent in the substrate) points in the direction of the central heterocycle. 

The essential components of the catalyst for the asymmetric dihydroxylation process are osmium tetroxide (OSO4) and an ester of one or the other of the pseudoenantiomeiic cinchona alkaloids dihydro-quinidine (DH( D) and dihydroquinine (DHQ). An amine oxide, generally N-methylmorpholine N-oxide, serves as the oxidant for foe reaction. When an alkenic substrate is added very slowly to a... 

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. 

Table 3.1 Alkene substrates for an asymmetric dihydroxylation reaction.0 6...

The cinchona alkaloids have opened up the field of asymmetric oxidations of alkenes without the need for a functional group within the substrate to form a complex with the metal. Current methodology is limited to osmium-based oxidations. The power of the asymmetric dihydroxylation reaction is exemplified by the thousands (literally) of examples for the use of this reaction to establish stereogenic centers in target molecule synthesis. The usefulness of the AD reaction is augmented by the bountiful chemistry of cyclic sulfates and sulfites derived from the resultant 1,2-diols. 

Many other dihydroquinidine derivatives have been assayed In the catalytic, asymmetric dihydroxylation reaction (ADH)4 g d the submitters have recently found that the benzoate and 2-naphthoate esters are slightly better for aryl-substituted alkenes while certain ethers are better for other substrates. However, since the level of asymmetric Induction Is already high, there is little advantage to be gained from their use in this case. 

A noted earlier, coordination of transition-metal ions to water-soluble polymers can allow for facile catalyst recovery, by ultrafiltration, from water-soluble substrates and/or products. For example, Han and Janda [22] used an osmium complex of the water-soluble polymeric chiral ligand 8 as a catalyst for the asymmetric dihydroxylation of alkenes in aqueous acetone (Eq. 5). However, they suggested that the catalyst should be recovered by precipitation with methylene chloride. Obviously the use of an ultrafiltration membrane for catalyst separation would be far more attractive. nu... 

The reason for this must come from the way in which the substrate interacts with the osmium-ligand complex. However, the detailed mechanism of the asymmetric dihydroxylation is stUl far from clear-cut. What is known is that the ligand forms some sort of chiral pocket, like an enzyme active site, with the osmium sitting at the bottom of it. Alkenes can only approach the osmium if they are correctly aligned in the chiral pocket, and steric hindrance forces the alignment shown in the scheme above. The analogy with an enzyme active... 

In summary, the asymmetric osmylation of alkenes catalyzed by derivatives of cinchona alkaloids represents a very elegant method which enables the enantioselective cis dihydroxylation of several types of alkenes in high enantiomeric excess and with predictable selectivities. The design of specific chiral ligands for substrates that still do not afford enantiomeric excesses over 90% would be desirable for the near future. 

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