Osmylation dihydroxylation

The interest in asymmetric synthesis that began at the end of the 1970s did not ignore the dihydroxylation reaction. The stoichiometric osmylation had always been more reliable than the catalytic version, and it was clear that this should be the appropriate starting point. Criegee had shown that amines, pyridine in particular, accelerated the rate of the stoichiometric dihydroxylation, so it was understandable that the first attempt at nonenzymatic asymmetric dihydroxylation was to utilize a chiral, enantiomerically pure pyridine and determine if this induced asymmetry in the diol. This principle was verified by Sharpless (Scheme 7).20 The pyridine 25, derived from menthol, induced ee s of 3-18% in the dihydroxylation of /rcms-stilbene (23). Nonetheless, the ee s were too low and clearly had to be improved. 

The history of asymmetric dihydroxylation51 dates back 1912 when Hoffmann showed, for the first time, that osmium tetroxide could be used catalytically in the presence of a secondary oxygen donor such as sodium or potassium chlorate for the cA-dihydroxylation of olefins.52 About 30 years later, Criegee et al.53 discovered a dramatic rate enhancement in the osmylation of alkene induced by tertiary amines, and this finding paved the way for asymmetric dihydroxylation of olefins. 

Asymmetric osmylation of alkenes.3 In the presence of 1 equiv. each of 1 and 0s04, alkenes undergo highly enantioselective ris-dihydroxylation. Highest enantiofacial selectivity (90-99%) is shown in osmylation of trans-di- and trisub-... 

Dihydroxylation. The key step in the synthesis of a natural mycotoxin from the dehydropentacyclic precursor 1 requires dihydroxylation of the nuclear double bond. Direct osmylation with catalytic 0s04 and N-methylmorpholine N-oxide... 

Directed osmylation.J One step in a synthesis of the carbonucleoside aris-teromycin (3) required dihydroxylation of the intermediate 1, in which a (nitro-phenylsulfonyl)methyl group is used as a carboxy equivalent. The desired diol (2)... 

Asymmetric catalytic osmylation.s Chiral cinchona bases are known to effect asymmetric dihydroxylation with 0s04 as a stoichiometric reagent (10, 291). Significant but opposite stereoselectivity is shown by esters of dihydroquinine (1) and of dihydroquinidine (2), even though these bases are diastereomers rather than enantiomers. 

Regio- and stereoselective dihydroxylation of dienes functionalized at the allylic position with a benzene sulfone group has been reported42. Osmylation of dienic sulfones 33, a potential key synthon for forskolin, occurred exclusively on the A6-7 double bound and preferentially from the a-face of the traws-fused bicyclic molecule, presumably due to a combination of steric and electronic factors (equation 25). While the reaction of diene sulfones proceeded sluggishly under catalytic conditions, treatment of 33a with a stoichiometric amount of OSO4 resulted in quantitative yield of diastereomeric diols 34a and 35 in a 9 1 ratio, respectively. Protecting the hydroxy group of the dienol as its t-butyldimethylsilyl ether (33b) affords diol 34b exclusively. 

Salinosporamide synthesis 196 Sharpless asymmetric dihydroxylation (see also Osmylation) 84,89, 141, 189 Sharpless asymmetric epoxidation 32,141 Silane, allylic synthesis 43 Sonogashira coupling (see Pd)... 

Dihydroxylation of ally lie (3 -hydroxy sulfoxides.3 Osmylation of chiral allylic P-hydroxy sulfoxides results mainly in anti, syn-trihydroxy sulfones. 

When the secondary reaction cycle shown in Scheme 6D.3 was discovered, it became clear that an increase in the rate of hydrolysis of trioxogly colate 10 should reduce the role played by this cycle. The addition of nucleophiles such as acetate (tetraethylammonium acetate is used) to osmylations is known to facilitate hydrolysis of osmate esters. Addition of acetate ion to catalytic ADs by using NMO as cooxidant was found to improve the enantiomeric purity for some diols, presumably as a result of accelerated osmate ester hydrolysis [16]. The subsequent change to potassium ferricyanide as cooxidant appears to result in nearly complete avoidance of the secondary cycle (see Section 4.4.2.2.), but the turnover rate of the new catalytic cycle may still depend on the rate of hydrolysis of the osmate ester 9. The addition of a sulfonamide (usually methanesulfonamide) has been found to enhance the rate of hydrolysis for osmate esters derived from 1,2-disubstituted and trisubstituted olefins [29]. However, for reasons that are not yet understood, addition of a sulfon-amide to the catalytic AD of terminal olefins (i.e., monosubstituted and 1,1-disubstituted olefins) actually slows the overall rate of the reaction. Therefore, when called for, the sulfonamide is added to the reaction at the rate of one equivalent per equivalent of olefin. This enhancement in rate of osmate hydrolysis allows most sluggish dihydroxylation reactions to be mn at 0°C rather than at room temperature [29]. 

Other comparisons of diastereoselective osmylations in the absence and in the presence of chiral ligands have been reported. A study of the dihydroxylation of unsaturated side chains... 

Corey also pointed out that 16 reflects the transition-state of an enzyme-substrate complex. Its formation was later supported by the observation of Michaelis-Menten-type kinetics in dihydroxylation reactions and in competitive inhibition studies [37], This kinetic behavior was held responsible for the non-linearity in the Eyring diagrams, which would otherwise be inconsistent with a concerted mechanism. Contrary, Sharpless stated that the observed Michaelis-Menten behavior in the catalytic AD would result from a step other than osmylation. Kinetic studies on the stoichiometric AD of styrene under conditions that replicate the organic phase of the catalytic AD had revealed that the rate expression was clearly first-order in substrate over a wide range of concentrations [38],... 

Dihydroxylation of allylic silanes. Osmylation [0s04,(CH3)3N0] of allylic... 

Asymmetric dihydroxylation of alkenes (14, 235-239). Further study1 of this reaction reveals that the optical yields of products can be markedly improved by slow addition (5-26 hours) of the alkene to the catalyst in acetone-water at 0° with stirring. The enantioselectivity can also be increased by addition of tetraethylam-monium acetate, which facilitates hydrolysis of osmate esters. The report suggests that the first product (1) of osmylation can undergo a second osmylation to provide 2, with reverse enantioselectivity of the first osmylation. 

Dihydroxylation of alkenes. C6H5B(OH)2 is useful for capture of the diols formed on osmylation with 0s04 and N-methylmorpholine N-oxide, particularly unstable or water-soluble diols. Osmylation with the borane can also be conducted in a nonaqueous medium with enhanced rates.1... 

The asymmetric cis dihydroxylation of alkenes covalently bound to chiral fragments, which can be cleaved after the osmylation step, has been the subject of several reports2-5. The subsequent removal of the chiral auxiliary can be effected by various methods and allows the preparation of enantiomerically pure hydroxylated compounds. 

The cix dihydroxylation of 2-methyl-2-butenoic acid esters of terpenic derivatives takes place with diastereomeric ratios of up to 84 16. In all the examples shown, the stoichiometric osmylation occurs with a better selectivity than the catalyzed version. Reductive treatment of the protected diols allows cleavage of the auxiliary and its quantitative recovery2. 

Z)-l,2-disubstituted alkenes proved to be the most difficult class. In fact, they are not osmylated efficiently with the all purpose ligands 1F/2 F. Further studies, however, led to the discovery of the indolinyl ligands 11/21 that allowed cis dihydroxylation of these alkenes in up to 80% eel0. It should be kept in mind, however, that in the case of 1,1-disubstituted alkenes and of (Z)-l,2-disubstituted alkenes, a lowering of difference in steric requirement between the two vicinal substituents inevitably means a drop in the 7t-face discrimination since the two enantiotopic alkene 7t-faces lend to become quasi-homotopic . 

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. 

The osmylation of alkenes incorporated into rigid frameworks reveals that reagent approach is usually determined by steric factors. However, in some cases, the dihydroxylation is apparently directed by a functional group which is located close by. 

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. 

In the concluding steps, manipulation of the furan ring of 89 gave 90 as a mixture of positional isomers. These were collectively converted to the unsaturated diol 91. The last crucial step, installation of two hydroxyl groups on the double bond, was achieved using a standard osmylation reaction [84]. In a second approach for the same step, the Sharpless asymmetric dihydroxylation of 91 was used and yielded one diastereoisomer 92 almost exclusively [85]. This second approach concluded with the synthesis of a lactone containing all correct stereocenters of the squalestatin core with the exception of that at C6. 

In general, dihydroxylations are carried out in mixtures of aqueous and organic solvents, although catalytic osmylations have been performed under virtually anhydrous conditions in toluene [21] or dichloromethane [22]. In combination with water, organic solvents such as acetone, r-butanol, methyl /-butyl ether, and others are employed. 

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