Osmylation asymmetric 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 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. 

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)... 

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. 

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. 

Figure 8.4. Representative ligands used in stoichiometric, asymmetric dihydroxylation reactions, (a) Dihydroquinidine (DHQD) and (b) dihydroquinine (DHQ) are used for stoichiometric osmylation reactions when R = H effective dihydroxylation catalysts result from appropriate modifications at this position (e.g., see Figure 8.5 below). Also, (c) [69] and (d) [70] are examples of C2 symmetrical ligands used in stoichiometric reactions.

Osmylation occurs much more rapidly in the presence of amines than it does in their absence. The addition of a chiral amine like an 0-alkyl- or O-aryldihy-droquinine or -quinidine to a mixture of OSO4 and an alkene allows asymmetric dihydroxylation of prochiral alkenes. The chiral amine-0s04 complex adds preferentially to one face of the alkene over the other. 

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-... 

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. 

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. 

Asymmetric osmylation. Chiral ligands of /V,/V -dialkyl bispiperazines linked by two carbons (I, n = 2) can effect highly enantioselective dihydroxylation of trans-disubstituted alkenes. 

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