Chiral oxidants

Chiral chemical reagents can react with prochiral centers in achiral substances to give partially or completely enantiomerically pure product. An example of such processes is the preparation of enantiomerically enriched sulfoxides from achiral sulfides with the use of chiral oxidant. The reagent must preferential react with one of the two prochiral faces of the sulfide, that is, the enantiotopic electron pairs. 

While generation of a Mn(V)oxo salen intermediate 8 as the active chiral oxidant is widely accepted, how the subsequent C-C bond forming events occur is the subject of some debate. The observation of frans-epoxide products from cw-olefins, as well as the observation that conjugated olefins work best support a stepwise intermediate in which a conjugated radical or cation intermediate is generated. The radical intermediate 9 is most favored based on better Hammett correlations obtained with o vs. o . " In addition, it was recently demonstrated that ring opening of vinyl cyclopropane substrates produced products that can only be derived from radical intermediates and not cationic intermediates. ... 

Imamoto and Koto131 prepared some interesting chiral oxidants (104) by the reaction of iodosyl benzene with tartaric anhydride. Methyl p-tolyl sulfide (105) was oxidized by 104c to the sulfoxide in 80% yield with 40% e.e. Methyl p-tolyl, o-tolyl and o-anisyl sulfides (105-107) were oxidized by 104a to their sulfoxides with the enantiomeric purities shown. 

The well-known fact that enantiomers exhibit different reactivity towards chiral reagents has been used to obtain optically active sulphoxides in a process which is called kinetic resolution. Kinetic resolution of sulphoxides usually involves either oxidation to the corresponding sulphones or reduction to sulphides by means of proper chiral oxidizing or reducing agents. 

An attractive route to chiral sulfoxides is based on asymmetric oxidation of unsymmetrical sulfides by means of chiral oxidizing reagents. The first asymmetric oxidation of sulfides with optically active pera-cids (eq. [1]) has been independently described in 1960 by two groups headed by Montanan (36) in Italy and by Balenovic (37) in... 

The next group of [Ru(bpy)2L2] complexes to be considered involves pyridine-based ligands. The structural and spectroscopic properties of cM-[Ru(bpy)2(py)2] have been reported." Hydrolysis of ci5-[Ru(bpy)2(py)Cl] gives cw-[Ru(bpy)2(py)(H20)] with 80% retention of configuration. Retention of configuration also accompanies the oxidation of the latter to cis-[Ru(bpy)2(py)(0)] " ", racemization of which is slow the use of this Ru complex as a chiral oxidant has been examined." The kinetics of the comproportionation reaction between [Ru (bpy)2(py)(0)] " " and [Ru(bpy)2(py)(H20)] + in MeCN have been studied using stopped-fiow methods. The Ru product is unstable, and in MeCN solution undergoes disproportionation... 

Oxidation of chiral sulfonimines (R"S02N=CHAr)and chiral sulfamyl-imines (R RNS02N=CHAr)affords optically active 2-sulfonyloxaziridines and 2-sulfamyloxaziridines, respectively. These chiral, oxidizing reagents have been used in the asymmetric oxidation of sulfides to sulfoxides (15-68% ee), 11-13 selenides to selenoxides (8-9% ee] enolates to a-hydroxycarbonyl compounds (8-37% ee) and in the asymmetric epoxidation of alkenes (15-40% ee)... 

Because of the great synthetic utility, asymmetric versions of the epoxidation of allylic alcohols have been developed and will be discussed in the following. Two methods of asymmetric conduction of the reaction are known. The first one is the employment of chiral catalysts and the second possibility is the use of chiral oxidants, which will be presented separately. 

In 1967, Henbest et al. reported the first asymmetric epoxidation with an optically active peracid as the chiral oxidant [3], Since then, many optically active peracids have been used for this purpose but enantioselectivity remains low (<20% ee). This is probably because the substrate and the asymmetric center in the peracid are distant from each other in the transition state of the epoxidation as shown in Figure 6B.1 [4],... 

Chiral oxidants 49 are Dess-Martin periodinane analogues able to oxidize alcohols, and possessing a limited ability for the enantioselective oxidation of non-symmetric sulfides.113... 

It is important to underline in this introduction that the importance of oxaziridines as special oxidizing agents is expected to diminish in some fields due to the use of dioxiranes. Their importance, however, is indisputable since oxaziridines as chiral oxidizing agents201,202 offer greater possibilities than dioxiranes. 

In principle, oxidative kinetic resolution of racemic alcohols can be achieved by using chiral oxidation catalysts such as TEMPO derivatives or dioxiranes. The selectivity achieved by use of these methods is, however, less than that observed in acylation reactions (Section 12.1). 

Conventional methods for the production of R3HB by bioconversion include chiral oxidation of 1,3-butanediolby bacteria (19), microbialhydro-xylation of butyric acid, and microbial or enzymatic reduction of alkyl-3-ketobutyrate (20,21). However, all of these methods have the problem of low productivity and are therefore difficult to industrialize. 

ZEOLITE ENCAPSULATED CHIRAL OXIDATION CATALYSTS The issue of encapsulation of chiral complexes in zeolites and the retention of their... 

FIG. 10. Synthesis of chiral oxides by reaction of Grignard reagents with diastereo-merically pure menthyl phosphinates. Deoxygenation of chiral phosphine oxides gives chiral phosphines. 

Cyclohexyl selenides 162 can be prepared from the 4-substituted cyclohexanones via the selenoketals and upon oxidation with chiral oxidants, compounds 163 were obtained in high yields and with excellent stereoselectivities. Some representative examples are summarized in Table 5 and it is obvious that only the Davies oxidant 158 is leading to high enantiomeric excesses in the product 163 whereas under Sharpless oxidation conditions no selectivity is obtained. The titanium complex formed in the Sharpless oxidant may promote the racemization of the intermediate selenoxide by acting as a Lewis acid catalyst, while the aprotic nature of the Davies oxidant 158 slows down racemization dramatically. 

Further oxidation of sulfonimines 106 gave AAsulfonyloxaziridines 107, a versatile class of neutral, aprotic, chiral oxidizing reagents.72,73... 

Pentamethyleneoxaziridine (6) also acts as an aminating agent, giving quite good yield of aziridines (Scheme 2). > Remarkably, none of the corresponding epoxide was reported in this reaction. Cyclohexene yields instead the hydrazino alcohol (8), probably via the V-aminoaziridine (7). In view of the recent use of chiral oxaziridines for chiral oxidations, it will be interesting to see whether chiral aziridination is possible when chiral V-unsubstituted oxaziridines become available. ... 

Selenoxides derived from unsymmetrical selenides are chiral and stable toward pyramidal inversion at room or even higher temperatures. They are produced enantioselectively by the use of chiral oxidants such as the Sharpless reagent or camphor-derived oxaziridines or diastereoselectively with achiral oxidants when one of the selenide substituents is itself chiral (see Section 9). Racemic selenoxides have been resolved by chromatography over chiral adsorbents. Chiral selenoxides racemize readily in water, particularly under acid-catalyzed conditions, presumably via the intermediacy of achiral selenoxide hydrates (equation 2). 

In the case of alkenes with polar functional groups, two-site attachment of the substrate to a chiral oxidant is possible and has allowed spectacular enantioselection. Thus, both the hydroperoxide anion based epoxidation of a,/ -unsaturated carbonyls and the epoxidation of allylic alcohols by the titanium(IV)-based Sharpless method exhibit very high enantioselectivity on a wide variety of substrates. 

Thus, when cyclohexyl selenides 1, prepared from the corresponding 4-sub-stituted cyclohexanone via the selenoketals, were oxidized with various Davis and Sharpless oxidants, the chiral alkyl aryl 4-substituted cyclohexylidenemethyl ketones were obtained in excellent chemical yields with high enantiomeric excesses. Typical results are summarized in Table 4. In this asymmetric induction, of the substrate and the chiral oxidant employed were revealed to show a remarkable effect upon the enantioselectivity of the product. The use of a methyl moiety as instead of a phenyl moiety gave a higher ee value, probably due to the steric difference between the two groups bonded to the selenium atom of the substrate. The results indicate that the titanium complex of the Sharpless oxidant may promote the racemization of the chiral selenoxide intermediate by acting as a Lewis acid catalyst, whereas the racemization in the case of the Davis oxidant, which is aprotic in nature, is slow. 

K. Barry Sharpless shared the 2001 Nobel Prize in Chemistry for his work on chiral oxidation reactions. 

Sharpless reagent is the most popular of the chiral oxidants. It is a mixture of tetraisopropoxytitanium, diethyl (R,R)- or (5,5)-tartrate, water, and tert-butyl hydroperoxide in the molar ratio 1 2 1 1 [224],... 

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