In Sharpless

Fig. 12.6. Conformational factors affecting syn and anti diastereoselectivity in Sharpless epoxidation. If substituent R4 > H, A1,3 strain favors the syn product. If R4 = H, the preferred transition structure leads to anti product. Reproduced from/. Org. Chem., 67, 1427 (2002), by permission of the American Chemical Society.

Figure 3.3 Rationale for predicting the enantiofacial selectivity in Sharpless s dihydroxylation.

In Sharpless epoxidation reactions, (Z)-substituted allylic alcohols react much more slowly than the corresponding (E )-substituted substrates, and sometimes the reaction is sensitive to the position of preexisting chirality in the selected substrate. For instance, in the presence of (+)-DET, chiral (E)-allylic alcohol 10 undergoes epoxidation in 15 hours to give product 11 as the major product with a diastereomeric ratio of >20 1. As for reaction with ( )-DET, 12 is then obtained, also with a diastereoselectivity of >20 1 (Scheme 4-4). 

The CaH2/Si02 System. Almost by chance, Zhou and colleagues found that the reaction time in Sharpless epoxidation could be reduced dramatically by adding a catalytic amount of calcium hydride and silica gel to the reaction system, although the mechanism is not yet clarified (Table 4 1).12... 

Diastereofacial selectivity in Sharpless epoxidation of 1-substituted allylic alcohols... 

One of the first attempts to extend polymer-assisted epoxidations to asymmetric variants were disclosed by Sherrington et al. The group employed chiral poly(tartrate ester) hgands in Sharpless epoxidations utilizing Ti(OiPr)4 and tBuOOH. However, yields and degree of stereoselection were only moderate [76]. In contrast to most concepts, Pu and coworkers applied chiral polymers, namely polymeric binaphthyl zinc to effect the asymmetric epoxidation of a,/9-unsaturated ketones in the presence of terPbutyl hydroperoxide (Scheme 4.11). 

The two enantiomeric forms of the diethyl tartrate ligand in Sharpless oxidation lead to epoxy alcohols 22 and 24. Which of the isomeric ligands is required for the present reaction ... 

Catalytic reactions in Sharpless epoxidation were achieved in 1986 by addition of molecular sieves, which suppress the formation of nonenantioselective complexes by moisture already present in the medium or produced during the reaction [33]. Similar problems needed to be solved in the asymmetric oxidation of sulfides because a decrease in the concentration of a... 

Figure 4.4 Dimerization effects in Sharpless asymmetric dihydroxylation.

Asymmetric dihydroxylation Sharpless developed a catalytic system (AD-mix- 3 or AD-mix-a) that incorporates a chiral ligand into the oxidizing mixture which can be used for the asymmetric dihydroxylation of alkenes. The chiral ligands used in Sharpless asymmetric dihydroxylation are quinoline alkaloids, usually dihydroquinidine (DHQD) or dihydroquinine (DHQ) linked by a variety of heterocyclic rings such as 1,4-phthalhydrazine (PHAL) or pyridazine (PYR) (see section 1.6, reference 32 of Chapter 1). 

FIGURE 13.4 Proposed intermediates and reaction steps in Sharpless mechanism. 

Despite the complexity of the active catalyst, the sense of asymmetric induction in Sharpless asymmetric epoxidation reactions can be rehably predicted using the model shown in Figure 4.2. In order for the model to predict the stereochemical outcome correctly, only two points need to be remembered. The allyhc hydroxy group resides in the bottom right corner and D-(-)-diethyl tartrate (which has the (S,S)-configuration) attacks from above the plane. 

The main drawback in Sharpless epoxidation is that the substrate must bear a functional group to achieve the precoordination required for high enantioselec-tivity (as in the case of allyl alcohol). This restriction is not applicable to the epoxidation of alkyl- and aryl-substituted olefins with manganese complexes of chiral Schiffs bases as catalysts. Very high enantioselectivities can be obtained in these reactions (Jacobsen, 1993). The most widely used catalysts that give high enantioselectivity are those derived from the Schiff bases of chiral diamines such as [SiS] and [RR] 1,2-diphenylethylenediamine and [SS] and [RR] cyclohexyl-1,2-diamine. An example is the synthesis of cromakalim. 

Finally, the asymmetric arylation of 60 has also been reported, although the yields and ees are more modest (Scheme 15).[ Hydrolysis of the product 61 conveniently gives the 1,3-diol 62, an intermediate in Sharpless s synthesis of fluoxetine.t ... 

In Sharpless epoxidation reactions, the activity and enantioselectivity of the catalysis are significantly influenced by several variants, (i) Ti(0 Pr)4 is usually the choice of the titanium precursor, although the use of the corresponding tert-butoxide... 

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