Model asymmetric epoxidation

Asymmetric epoxidation, dihydroxylation, aminohydroxylation, and aziridination reactions have been reviewed.62 The use of the Sharpless asymmetric epoxidation method for the desymmetrization of mesa compounds has been reviewed.63 The conformational flexibility of nine-membered ring allylic alcohols results in transepoxide stereochemistry from syn epoxidation using VO(acac)2-hydroperoxide systems in which the hydroxyl group still controls the facial stereoselectivity.64 The stereoselectivity of side-chain epoxidation of a series of 22-hydroxy-A23-sterols with C(19) side-chains incorporating allylic alcohols has been investigated, using m-CPBA or /-BuOOH in the presence of VO(acac)2 or Mo(CO)6-65 The erythro-threo distributions of the products were determined and the effect of substituents on the three positions of the double bond (gem to the OH or cis or trans at the remote carbon) partially rationalized by molecular modelling. 

The first example of a catalytic enantioselective epoxidation by cyclohexanone monooxygenase was shown with a fosfomycin-related model compound [75]. The efficient asymmetric epoxidation of styrene to (S)-styrene oxide by recombinant styrene monooxygenase has been achieved by increasing biocatalyst concentrations and reducing the exposure time of the biocatalyst to the product [76]. 

The allylic alcohol binds to the remaining axial coordination site where stereochemical and stereoelec-tronic effects dictate the conformation shown in Figure 5. The structural model of catalyst, oxidant and substrate shown in Figure 5 illustrates a detailed version of the formalized rule presented in Figure 1. Ideally, all the observed stereochemistry of epoxy alcohol and kinetic resolution products can be rationalized according to the conq>atibility of their binding with the stereochemistry and stereoelectronic requirements imposed by this site. A transition state model for the asymmetric epoxidation complex has been calculated by a frontier orbital preach and is consistent with the formulation portrayed in Figure... 

With compound 64 available, vanadyl acetylacetonate catalyzed epoxidation [44] accompanied by simultaneous cyclization, afforded the corresponding tetrahydrofuran and its diastereomer in a 4 1 ratio (Scheme 12). Ring expansion of the corresponding mesylate 65 with silver (I) carbonate afforded compound 66 in a 42% yield for the two steps [45]. Extension of the side chain in six steps, followed by an asymmetric epoxidation, gave product 67 stereoselectively. The cyclization of 67 with titanium tetraisopropoxide in a manner consistent with model studies [27d], afforded bicyclic ether 68 in 65% yield. Transformation to the epoxide under standard conditions afforded fragment 69 ready to be coupled with the D-ring side chain. 

Given the difficulties encountered in the epoxidation of frans-olefins by Mn(salen) complexes, it is intriguing that a wide range of trisubstituted olefins are outstanding substrates for asymmetric epoxidation (Scheme 7) [62,76]. The absolute stereochemistry of the epoxide products is inverted at the benzylic carbon when compared with the sense of induction seen with cfs-disubstituted olefins. A qualitative transition state model has been suggested wherein the trisubstituted substrate reacts with the metal-oxo complex via a skewed side-on approach (Fig. 12). The distortion of trisubstituted olefins from planarity resulting from Aj 2 or Aj 3 interactions may be critical in this context. 

Manganese and iron porphyrins substituted by chiral atropisomeric groups are models for cytochrome P-450 and several of such catalysts have been recommended by Groves, Kodadek, Mansuy and their coworkers in asymmetric epoxi-dations of olefins with hypochlorites or ArlO [957, 970], Recently, asymmetric epoxidation of 2-mtrostyrene has been accomplished with 89% enantiomeric excess, but this result lacks generality. A preliminary report on the use of threitol-strapped manganese poiphyrins in enantioselective epoxidations of unfunctionalized aryl substituted olefins appeared in 1993 [971] enantiomeric excesses in the range of 80% were observed. 

The olefin epoxidation reaction has also been extensively studied with model metalloporphyrin systems. The epoxidation of olefins by Fe" porphyrin/PhIO systems generally proceeds by a stereo-retention pathway (Table VIII) (10, I20a,c). Asymmetric epoxidations of prochiral olefins have also been demon-... 

The first use of a chiral porphyrin to carry out asymmetric epoxidation was reported in 1983, giving 50% ee with jn-chlorostyrene . The ee was improved to 70% for epoxidation of cis-3-methylstyrene with the use of a very robust chiral vaulted binaphthyl porphyrin 16 (Figure 1.15) . More significantly, this catalyst afforded the first case of catal5rtic asyitunetric hydroxylation by a model system, giving a 70% ee for hydroxylation of ethylbenzene and related hydrocarbons . 

The previous section described metal catalyzed epoxidation of allylic alcohols by alkyl hydroperoxides, and 193 was proposed as a model to predict the diastereoselectivity of these reactions,. In the cases presented, the reaction was diastereoselective but not enantioselective (sec. 1.4.F) and those epoxidation reactions generated racemic epoxides. To achieve asymmetric induction one must control both the relative orientation of the alkene relative to the peroxide and also the face of the substrate from which the electrophilic oxygen is delivered. Control of this type can be accomplished by providing a chiral ligand that will also coordinate to the metal catalyst, along with the peroxide and the alkene unit. There are two major asymmetric epoxidation reactions, one that can be applied only to allylic alcohols and is the prototype for asymmetric induction in these systems. The other is a procedure that can be applied to simple alkenes. Both procedures use a metal-catalyzed epoxidation that employs alkyl hydroperoxides, introduced in section 3.4.B.ii. 

When the previously cited transition structure 193 is applied to the asymmetric epoxidation of allylic alcohols, it must be modified to include binding of the peroxide, the allylic alcohol, and also the chiral tartrate. The metal in the new model is titanium rather than vanadium, and tetraisopropoxy titanium was found to react with 2 equivalents of diethyl tartrate to form a species such as 212, where OR = 0/-Pr and CO2R = CO2Et.3i7.3i8 The tartrate can bind to titanium from either the bottom or the top face.3i8 The nature of the... 

For allylic alcohols, use the Sharpless asymmetric epoxidation reaction. Reagents are t-BuOOH, Ti(Oi-Pr)4 and (-l-)-diethyl (or di-isopropyl) tartrate. Note that the (-1-)-enantiomer of the ligand is required for the formation of the epoxide 6 (place the alcohol in the lower right using the model given in Scheme 5.55). 

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 target molecule must first be rotated to fit the Sharpless asymmetric epoxidation model (need to have allylic alcohol group in bottom right position). The retrosynthesis of the epoxide leads to an alkene with the stereochemistry shown. Since the oxidation has occurred at the top face, the (+) enantiomer of diethyl tartrate (DET) is required. Note that only the alkene with the aUyUc hydroxyl group is oxidized in the Sharpless epoxidation. 

Mechanisms of Asymmetric Epoxidation Reactions 558 Nature s Hydride Reducing Agent 566 The Captodative Effect 573 Stereoelectronics in an Acyl Transfer Model 579 The Swern Oxidation 580 Gas Phase Eliminations 588 Using the Curtin-Hammett Principle 593 Aconitase—An Enzyme that Catalyzes Dehydration and Rehydration 595... 

More recently, research concerning catalytic oxidation reactions has emerged on one side from bioinorganic chemistry with cytochrome P450 models and non-por-phyrinic methane mono-oxygenase models, and on the other side, from organic chemistry with asymmetric epoxidation and dihydroxylation. 

A further signiHcant advance in Nicolaou s work on brevetoxin synthesis comes with the synthesis of the FGHU framework of brevetoxin A from 2-deoxy-D-ribose, D-glucal, and the known mannose-derived C-glycoside (65), as outlined in Scheme 14, the other chiral centres in (66) being derived from asymmetric epoxidation. O in model work on brevetoxin... 

Extensive mechanistic studies have identified a bis-tita-nium complex [Ti(tartrate)(OR)2]2 as the active catalyst for asymmetric epoxidation of allylic alcohols by tertiary alkyl hydroperoxides, and they have suggested complex 3 as the transition state conformation (Figure 35.1). The proposed mechanism and transition state model allow for the prediction of stereochemical outcome. As depicted in Figure 35.2, the approach of the oxidant to the double bond occurs from the top face when d-(—)-DET or d-(-)-DIPT is used. When l-(+)-DET or l-(+)-DIPT is employed, the epoxide oxygen is added from the bottom face. ... 

Specifically, the reversal was found to occur with a molecular weight change of only 800. As the PEG chains did not affect the inherent chirality of the ligand, they proposed that the enantioreversal might occur as a result of coordination models. Further equilibrium measurements revealed that the predominant species in Ti/PEG-tartrate ester mixtures was a distinct 2 1 Ti-ligand complex, as opposed to the 2 2 Ti-ligand complex of traditional Sharp less asymmetric epoxidation. 

It should be noted that the sense of asymmetric induction in the lithiation/ rearrangement of aziridines 274, 276, and 279 by treatment with s-butyllithium/ (-)-sparteine is opposite to that observed for the corresponding epoxides (i.e. removal of the proton occurs at the (S)-stereocenter) [102], If one accepts the proposed model to explain the selective abstraction of the proton at the (R) -stereo-center of an epoxide (Figure 5.1), then, from the large difference in steric bulk (and Lewis basicity) between an oxygen atom and a tosyl-protected nitrogen atom, it is obvious that this model cannot be applied to the analogous aziridines. 

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