Enantioselective dihydroxylations

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 ... 

Scheme 7. The first enantioselective dihydroxylation reactions (developed by Sharpless).

Fig. 12.1. Predictive model for enantioselective dihydroxylation by dimeric alkaloid catalysts. (DHQD)2 catalysts give (3-approach (DHQ)2 catalysts give ot-approach. Reproduced from J. Org. Chem., 57, 2768 (1992), by permission of the American Chemical Society.

Mono-, di-, and trisubstituted olefins undergo osmium-catalyzed enantioselective dihydroxylation in the presence of the (R)-proline-substituted hydroquinidine 3.9 to give diols in 67-95% yields and in 78-99% ee.75 Using potassium osmate(VI) as the catalyst and potassium carbonate as the base in a tm-butanol/water mixture as the solvent, olefins are dihydroxylated stereo- and enantioselectively in the presence of 3.9 and potassium ferricyanide with sodium chlorite as the stoichiometric oxidant the yields and enantiomeric excesses of the... 

Fig. 17. Chiral acetonide building blocks 36-39, protected 3rd-generation dendrimer 40 and deprotected 2nd-generation dendrimer 41, derived from enantioselectively dihydroxylated styrenes and cinnamic alcohols [74-76]...

DHQD-CL or DHQ-CL) was used as the chiral auxiliary.175,176 However, the enantioselectivity observed under catalytic conditions was inferior to that observed under stoichiometric conditions. The addition of triethylammonium acetate, which increases the rate of hydrolysis of the Osvm-glycolate intermediate, improved enantioselectivity. A further improvement in enantioselectivity was brought about by the slow addition of substrates (Scheme 44).177 These results indicated that the hydrolysis of the Osvm-glycolate intermediate (57) was slow under those conditions and (57) underwent low enantioselective dihydroxylation (second cycle). Thus, Sharpless et al. proposed a mechanism of the dihydroxylation including a second cycle (Scheme 45).177 Slow addition reduces the amount of unreacted olefin in the reaction medium and suppresses the... 

TABLE 4-14. Enantioselective Dihydroxylation of Olefins Using 0s04 92b R1 1.0s04,92b, -78 °C HO OH... 

Recently, effective chiral ligands for the enantioselective dihydroxylation of olefins have been intensively investigated. Among the reported asymmetric dihydroxylation systems, the superiority of an H20/f-Bu0H-K3Fe(CN)6/K2C03 system with chiral ligands, that is, dihydroquinidine (DHQD) and/or a dihydroquinine (DHQ) derivative, has been mentioned (see Sect. 15.2.4.7) [476]. 

New catalyst design further highlights the utility of the scaffold and functional moieties of the Cinchona alkaloids. his-Cinchona alkaloid derivative 43 was developed by Corey [49] for enantioselective dihydroxylation of olefins with OsO. The catalyst was later employed in the Strecker hydrocyanation of iV-allyl aldimines. The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would stabilize the aldimine already activated via hydrogen-bonding to the protonated quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an a-amino nitrile product (Scheme 10). 

Application of computaional methods to the enantioselective dihydroxylations of alkenes by osmium complexes have been reviewed with a special focus on methods used to study the origin of high enantioselectivity. The use of a vast number of computational techniques such as QM, MM, Q2MM, QM/MM, molecular dynamics, and genetic algorithms has been enumerated.98... 

Enantioselective dihydroxylation with OsO4.7 The (S,S)-diamine 6 [1,2-diphe-nyl-l,2-bis(2,4,6-trimethylbenzylamino)ethane] is prepared by reaction of (S,S)-1 with mesitylaldehyde followed by NaBH4 reduction. It markedly accelerates reac-... 

Petri, A., Pini, D. and Salvadori, P. Heterogeneous enantioselective dihydroxylation of aliphatic olefins - A comparison between different polymeric cinchona alkaloid derivatives, Tetrahedron Lett., 1995, 36, 1549-1552. 

CAimHPFf ] [CgQimHPFe] and others K2[0s02(0H)4] NMO K3[Fe(CN)6] k2co3 Enantioselective dihydroxylation of olefins with H20 and t-BuOH as co-solvents detailed study on reaction parameters product extracted with Et20 activity and selectivity stable for 9 runs, then considerable decrease osmium contamination in the product < 7 ppb. [64] [65]... 

C.CjimHPFe] 0s04 NMO Enantioselective dihydroxylation of olefins with H20 and t-butanol as co-solvents products extracted with Et20 addition of an amine ligand significantly improves catalyst retention catalyst recycled 5 times, activity decreases only slowly. [62]... 

QCjimJtPFe] CjimlfSbFs] 0s04 NMO Enantioselective dihydroxylation of aryl olefins with acetone-H20 as co-solvent 2.5-5 equivalents of chiral ligand added products extracted with Et20 catalyst reused four times, marked decrease in activity after the third run. [67]... 

QC mltPFs] K2[0s02(0H)4] NMO Enantioselective dihydroxylation of trans-stilbene with H20 and acetone as co-solvents and (DQ)2PHAL or (DFIQ)2PFIAL as ligand products extracted with diethyl ether. [68]... 

Salvador , P., Pini, D., Petri, A., Mandoli, A. Catalytic heterogeneous enantioselective dihydroxylation and epoxidation. Chiral Catalyst Immobilization and Recycling 2000, 235-259. 

Corey, E. J., Noe, M. C., Grogan, M. J. A mechanistically designed mono-cinchona alkaloid is an excellent catalyst for the enantioselective dihydroxylation of olefins. Tetrahedron Lett. 1994, 35, 6427-6430. 

An extended addition increases the effective mole ratio of reaction components, which can have a beneficial impact on reaction selectivity. This is particularly true for reactions using catalysts. In the dihydroxylations in Figure 8.7, olefin 13 was added over 6 hours in order to ensure high enantiomeric purity of the product [6], Excess olefin, which accumulates if the addition rate is faster than the reaction rate, is thought to coordinate with the catalyst in a fashion that leads to non-enantioselective dihydroxylation [6]. In the osmium-mediated dihydroxylation of... 

Osmium tetroxide is very expensive and very toxic which made using it quite unattractive. For a long time, many people who used osmium tetroxide to convert olefins to diols—and this was long before enantioselective dihydroxylations came on the scene—used the Upjohn procedure.20 This process used catalytic amounts of osmium tetroxide, NMO (/V-methylmorpholine /V-oxidc) 87 as the stoichiometric oxidant, and one solvent phase. The solvent was water, acetone and tert-butyl alcohol. The osmate ester 86 was hydrolysed under these conditions and the osmium (VI) species was reoxidised to 0s04 by NMO. 

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