Epoxides enantioselective preparation

Jacobsen has utilized [(salen)Co]-catalyzed kinetic resolutions of tenninal epoxides to prepare N-nosyl aziridines with high levels of enantioselectivity [72], A range of racemic aryl and aliphatic epoxides are thus converted into aziridines in a four-step process, by sequential treatment with water (0.55 equivalents), Ns-NH-BOC, TFA, Ms20, and carbonate (Scheme 4.49). Despite the apparently lengthy procedure, overall yields of the product aziridines are excellent and only one chromatographic purification is required in the entire sequence. 

The mesoporous character of MCM-41 overcomes the size limitations imposed by the use of zeolites and it is possible to prepare the complex by refluxing the chiral ligand in the presence of Mn +-exchanged Al-MCM-41 [34-36]. However, this method only gives 10% of Mn in the form of the complex, as shown by elemental analysis, and good results are only possible due to the very low catalytic activity of the uncomplexed Mn sites. The immobihzed catalyst was used in the epoxidation of (Z)-stilbene with iodosylbenzene and this led to a mixture of cis (meso) and trans (chiral) epoxides. Enantioselectivity in the trans epoxides was up to 70%, which is close to the value obtained in solution (78% ee). However, this value was much lower when (E)-stilbene was used (25% ee). As occurred with other immobilized catalysts, reuse of the catalyst led to a significant loss in activity and, to a greater extent, in enantioselectivity. 

Last year, a short enantioselective total synthesis of herbarumin III (42) in 11% overall yield was published the approach applied uses Keck s asymmetric allylation and Sharpless epoxidation to build the key fragment. Esterification with 5-hexenoic acid and a RCM was used to yield 42. Finally, another asymmetric synthesis of herbarumin III (42) was carried out using (R)-cyclohexylidene glyceraldehyde as the chiral template. The key steps of the synthesis were the enantioselective preparation of the... 

Enantioselective preparation of nonfunctionalized oxiranes 92CRV873. Epoxidation induced by transition metal complexes with N-heterocycles as ligands 92YGK997. 

Asymmetric epoxidation The catalytic asymmetric epoxidation of alkenes has been the focus of many research efforts over the past two decades. The non-racemic epoxides are prepared either by enantioselective oxidation of a prochiral carbon-carbon double bond or by enantioselective alkylidenation of a prochiral C=0 bond (e.g. via a ylide, carbene or the Darzen reaction). The Sharpless asymmetric epoxidation (SAE) requires allylic alcohols. The Jacobsen epoxidation (using manganese-salen complex and NaOCl) works well with ds-alkenes and dioxirane method is good for some trans-alkenes (see Chapter 1, section 1.5.3). 

Epoxides are key chiral synthetic intermediates and their enantioselective preparation by oxidation of achiral alkenes is a key reaction in many synthetic strategies. Sharpless asymmetric epoxidation is suitable for most allylic alcohols [26, 27], but few general procedures exist for unfunctionalized olefins. Jacobsen s manganese salen-mediated epoxidation is suitable for and gives good selectivities with Z-olefins (85 to 90% ee) [28]. The enzyme chloroperoxidase... 

As in the asymmetric epoxidation reaction, the development of such a powerful tool for the enantioselective preparation of diols spurred its application to a very wide variety of synthetic problems and the invention of new methods of manipulating the diol products [64], A few examples confer some of the flavor of this work. 

For the enantioselective preparations of chiral synthons, the most interesting oxidations are the hydroxylations of unactivated saturated carbons or carbon-carbon double bonds in alkene and arene systems, together with the oxidative transformations of various chemical functions. Of special interest is the enzymatic generation of enantiopure epoxides. This can be achieved by epoxidation of double bonds with cytochrome P450 mono-oxygenases, w-hydroxylases, or biotransformation with whole micro-organisms. Alternative approaches include the microbial reduction of a-haloketones, or the use of haloperoxi-dases and halohydrine epoxidases [128]. The enantioselective hydrolysis of several types of epoxides can be achieved with epoxide hydrolases (a relatively new class of enzymes). These enzymes give access to enantiopure epoxides and chiral diols by enantioselective hydrolysis of racemic epoxides or by stereoselective hydrolysis of meso-epoxides [128,129]. 

Asymmetric phase-transfer catalyzed cascades initiated by the conjugate addition of heteronucleophiles has been employed for the enantioselective preparation of epoxides and aziridines using a suitable oxygen- or nitrogen-based nucleophile incorporating an appropriate leaving group ready to... 

For some years, we have been investigating the Pd-catalyzed rearrangement of chiral silylated vinyl epoxides. Depending on the substituents attached to the silyl group and the ligands borne by the palladium, a very fast, totally stereoselective 1,2-carbon to carbon transfer of the silyl group was observed. AppUcation to the enantioselective preparation of a,)8-unsaturated lactones has been developed (Scheme 4). 

Introduction to Ethers Nomenclature of Ethers Structure and Properties of Ethers Crown Ethers Preparation of Ethers Reactions of Ethers Nomenclature of Epoxides Preparation of Epoxides Enantioselective Epoxidation Ring-Opening Reactions of Epoxides Thiols and Sulfides... 

Several new developments in enantioselective C-O ring construction have been applied in the s mtheses of natural products. To achieve control, the oxygenated quaternary center of dysiherbaine 9 must be established under kinetic conditions. One approach would be Sj 2 opening, but this would require displacement at a fully-substituted center. Susumi Hatakeyama of Nagasaki University has shown (Chem. Commun. 2007, 4158) that the epoxide 6, prepared by the Sharpless procedure, undergoes just such an opening under mild acid catalysis. 

Silyl ethers serve as preeursors of nucleophiles and liberate a nucleophilic alkoxide by desilylation with a chloride anion generated from CCI4 under the reaction conditions described before[124]. Rapid intramolecular stereoselective reaction of an alcohol with a vinyloxirane has been observed in dichloro-methane when an alkoxide is generated by desilylation of the silyl ether 340 with TBAF. The cis- and tru/u-pyranopyran systems 341 and 342 can be prepared selectively from the trans- and c/.y-epoxides 340, respectively. The reaction is applicable to the preparation of 1,2-diol systems[209]. The method is useful for the enantioselective synthesis of the AB ring fragment of gambier-toxin[210]. Similarly, tributyltin alkoxides as nucleophiles are used for the preparation of allyl alkyl ethers[211]. 

Since cbiral sulfur ylides racemize rapidly, they are generally prepared in situ from chiral sulfides and halides. The first example of asymmetric epoxidation was reported in 1989, using camphor-derived chiral sulfonium ylides with moderate yields and ee (< 41%) Since then, much effort has been made in tbe asymmetric epoxidation using sucb a strategy without a significant breakthrough. In one example, the reaction between benzaldehyde and benzyl bromide in the presence of one equivalent of camphor-derived sulfide 47 furnished epoxide 48 in high diastereoselectivity (trans cis = 96 4) with moderate enantioselectivity in the case of the trans isomer (56% ee). ... 

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

Desymmetrization of meso-bis-allylic alcohols is an effective method for the preparation of chiral functionalized intermediates from meso-substrates. Schreiber et al has shown that divinyl carbonyl 58 is epoxidized in good enantioselectivity. However, because the product epoxy alcohols 59 and 60 also contain a reactive allylic alcohol that are diastereomeric in nature, a second epoxidation would occur at different rates and thus affect the observed ee for the first AE reaction and the overall de. Indeed, the major diastereomeric product epoxide 59 resulting from the first AE is less reactive in the second epoxidation. Thus, high de is easily obtainable since the second epoxidation removes the minor diastereomer. 

Metzner et al. also prepared the selenium analogue 17 of their C2 symmetric chiral sulfide and tested it in epoxidation reactions (Scheme 1.6) [8]. Although good enantioselectivities were observed, and a catalytic reaction was possible without the use of iodide salts, the low diastereoselectivities obtained prevent it from being synthetically useful. 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

The first enantioselective synthesis of cis- and trans- 3-hydroxyflavanones is based on the Lewis-acid-catalysed reaction of phenylmethanethiol with chalcone epoxides <96CC2747>. Further support for the intermediacy of epoxides in the Algar-Flynn-Oyamada flavone synthesis has been provided by the isolation of epoxides in the corresponding preparation of 3-hydroxy-2-phenylquinol-4-ones <96JCS(P2)269>. 

Very few examples have been described for the non-covalent immobilization of chiral porphyrin complexes (Fig. 26). In the first case, the porphyrin-dichlororutheninm complex was encapsulated in silica, which was prepared around the complex by a sol-gel method [78], in an attempt to prevent deactivation observed in solution in the epoxidation of different alkenes with 2,6-dichloropyridine N-oxide. In fact, the heterogeneous catalyst is much more active, with TON up to 10 800 in the case of styrene compared to a maximum of 2190 in solution. Enantioselectivities were about the same imder both sets of conditions, with values aroimd 70% ee. 

The asymmetric ring opening (ARO) of racemic terminal epoxides with H2O via hydrolytic kinetic resolution provides an efficient synthetic route to prepare optically pure terminal epoxides. The dimeric type chiral Co(salen)AlX3 complex has great potential to catalyze HKR of terminal epoxides in a highly reactive and enantioselective manner in comparison to their monomeric analogy. 

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