Asymmetric epoxidation electrophilic reactions

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. 

The Sharpless asymmetric epoxidation (sec. 3.4.D.i) exploits this chelation effect because its selectivity arises from coordination of the allylic alcohol to a titanium complex in the presence of a chiral agent. The most effective additive was a tartaric acid ester (tartrate), and its presence led to high enantioselectivity in the epoxidation.23 An example is the conversion of allylic alcohol 40 to epoxy-alcohol 41, in Miyashita s synthesis of the Cg-Ci5 segment of (-t-)-discodermolide.24 in this reaction, the tartrate, the alkenyl alcohol, and the peroxide bind to titanium and provide facial selectivity for the transfer of oxygen from the peroxide to the alkene. Binding of the allylic alcohol to the metal is important for delivery of the electrophilic oxygen and... 

Chiral nonracemic a-hydoxylated ketones are commonly accessed by asymmetric epoxidation or dihydroxylation of enol ethers and this methodology is discussed in the relevant sections of this book. Another general method for the enantioselective a-oxygenation of ketones and aldehydes is by reaction of an electrophilic source of oxygen with chiral nonracemic enamines or enolates or in the presence of Lewis acids. 

In addition to the great advances in asymmetric epoxidation techniques using electrophilic oxidants, there have been significant developments toward the catalytic nucleophific epoxidation of electron-deficient olefins. In 1980, Julia and co-workers reported on the first highly enantioselec-tive epoxidation (in >90% ee) of chalcones catalyzed by polyamino acids (Scheme 35.22). Typically, the reaction was carried out under mild conditions in a triphasic system (toluene, water, and polymer catalyst) using hydrogen peroxide as an oxidant. A relatively large quantity of the polymer was required for the reaction (typically 0.4 g of polymer to 0.5 g of substrate), but the polymer could be recovered and reused after the application. 

Both the oxygen atoms of the hydroperoxide anion interact with the highly electrophilic metal ion. This weakens the 0-0 bond and facilitates transfer of the non-carbon-bonded oxygen atom to the alkene in a concerted manner. As we will see in Section 8.5.3, this general mechanism with some modifications also operates in asymmetric epoxidation reactions, where organic hydroperoxides are used. 

Olefins have a rich history in organic chemistry and consequently there is a vast array of transformations available to this fundamental functional group. This chapter discusses the classic methods for stereoselective oxidations of olefins, spanning the range from diastereoselective [16-18] and enantioselec-tive [19-29] formation of epoxides to their asymmetric ring-opening reactions [30-33], stereoselective formation of aziridines [34—37], iodolactoniza-tions and other olefin cyclizations induced by electrophiles [38, 39], dihy-droxylations [40-49], and aminohydroxylations [47, 50] (Figure 9.1). 

In the present study the dimer (salen)CoAlX3 showed enhanced activity and enantioselectivity. The catalyst can be synthesized easily by readily commercially available precatalyst Co(salen) in both enantiomeric forms. Potentially, the catalyst may be used on an industrial scale and could be recycled. Currently we are looking for the applicability of the catalyst to asymmetric reaction of terminal and meso epoxides with other nucleophiles and related electrophile-nucleophile reactions. 

In most allylation reactions, only a catalytic amount of CuCN-2LiCl is required [41]. Use of the chiral ferrocenylamine 104 as a catalyst makes enables asymmetric allylation of diorganozinc reagents to be effected with allylic chlorides (Scheme 2.36) [78]. Related electrophiles such as propargylic bromides [79] and unsaturated epoxides [80] also undergo SN2 -substitution reactions (Scheme 2.37). 

This procedure was extended to a method for asymmetric synthesis of optically active epoxides starting from optically active sulfoxides. As the oxiranyUithium 131 reacts with the acidic hydrogen of the n-butyl aryl sulfoxide, the introduction of electrophiles to the reaction mixture was problematic. Therefore, the reaction was performed by addition of 1 equivalent of f-C4H9Li at — 100°C to 130 and the sulfoxide-lithium exchange reaction was found to be extremely rapid (within a few seconds at this temperature). Moreover, as f-butyl aryl sulfoxide 138 has now no more acidic hydrogen, the addition of several electrophiles leads to functionalized epoxides 139 (equation 48). ... 

Reviews have featured epoxidation, cyclopropanation, aziridination, olefination, and rearrangement reactions of asymmetric ylides 66 non-phosphorus stabilized carbanions in alkene synthesis 67 phosphorus ylides and related compounds 68 the Wittig reaction 69,70 and [2,3]-Wittig rearrangement of a-phosphonylated sulfonium and ammonium ylides.71 Reactions of carbanions with electrophilic reagents, including alkylation and Wittig-Homer olefination reactions, have been discussed with reference to Hammett per correlations.72... 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

The diols (97) from asymmetric dil droxylation are easily converted to cyclic sii e esters (98) and thence to cyclic sulfate esters (99).This two-step process, reaction of the diol (97) with thionyl chloride followed by ruthenium tetroxide catalyzed oxidation, can be done in one pot if desired and transforms the relatively unreactive diol into an epoxide mimic, ue. the 1,2-cyclic sulfate (99), which is an excellent electrophile. A survey of reactions shows that cyclic sulfates can be opened by hydride, azide, fluoride, thiocyanide, carboxylate and nitrate ions. Benzylmagnesium chloride and thie anion of dimethyl malonate can also be used to open the cyclic sulfates. Opening by a nucleophile leads to formation of an intermediate 3-sidfate aiuon (100) which is easily hydrolyzed to a -hydroxy compound (101). Conditions for cat ytic acid hydrolysis have been developed that allow for selective removal of the sulfate ester in the presence of other acid sensitive groups such as acetals, ketals and silyl ethers. 

A number of useful enantioselective syntheses can be performed by attaching a chiral auxihary group to the selenium atom of an appropriate reagent. Examples of such chiral auxiliaries include (49-53). Most of the asymmetric selenium reactions reported to date have involved inter- or intramolecular electrophilic additions to alkenes (i.e. enantioselective variations of processes such as shown in equations (23) and (15), respectively) but others include the desymmefrization of epoxides by ringopening with chiral selenolates, asymmetric selenoxide eliminations to afford chiral allenes or cyclohexenes, and the enantioselective formation of allylic alcohols by [2,3]sigmafropic rearrangement of allylic selenoxides or related species. 

---