Enantioselective epoxidation Subject

Optically active epoxides are important building blocks in asymmetric synthesis of natural products and biologically active compounds. Therefore, enantio-selective epoxidation of olefins has been a subject of intensive research in the last years. The Sharpless [56] and Jacobsen [129] epoxidations are, to date, the most efficient metal-catalyzed asymmetric oxidation of olefins with broad synthetic scope. Oxidative enzymes have also been successfully utilized for the synthesis of optically active epoxides. Among the peroxidases, only CPO accepts a broad spectrum of olefinic substrates for enantioselective epoxidation (Eq. 6), as shown in Table 8. 

The catalytic asymmetric epoxidation of electron-deficient olefins, particularly a,P-unsaturated ketones, has been the subject of numerous investigations, and as a result a number of useful methodologies have been elaborated [44], Among these, the method utilizing chiral phase-transfer catalysis occupies a unique position in terms of its practical advantages. Moreover, it also allows the highly enantioselective epoxidation of trans-a,P-unsaturated ketones, particularly chalcone. 

Biological enzymes are well known to carry out epoxidation. For example, MMO is an efficient and selective catalyst for epoxidation of small terminal olefins such as ethylene, propylene, and 1-butene [246,247]. Lipases have been used to generate peroxoacids which in turn are used for epoxidation reactions [248,249]. The subject has been reviewed [250]. Biocatalytic systems are of interest not only because they can carry out enantioselective epoxidation of substrates, but also because they offer the exciting possibility of being engineered for specific transformations of nonnatural reagents. 

The design of viable, highly enantioselective epoxidation catalysts based on porphyrin ligands is confronted by the inherent difficulty associated with inducing dissymmetry from remote parts of an sp -hybridized coordination sphere, and the relative difficulties in constructing the chiral porphyrin rings. As research in this field has been the subject of an insightful review [90], only more recent developments will be covered here. 

Davies and Reider (1996) have given some details of the HIV protease inhibitor CRDCIVAN (INDINAVIR) for which (lS,2R)-c -amino indanol is required. Indene is epoxidized enantioselectively, using the lacobsen strategy (SS-salen Mn catalyst, aqueous NaOH and PiNO), to (lS,2/ )-indene oxide in a two-phase system, in which the OH concentration is controlled. Indene oxide was subjected to the Ritter reaction with MeCN, in the presence of oleum, and subsequent hydrolysis and crystallization in the presence of tartaric acid gives the desired amino indanol. 

Several other allylic alcohols with primary C-2 substituents have been epoxidized with very good results (entries 7-10, 14). Epoxy alcohols have been obtained with 95-96% ee and, when the catalytic version of the reaction is used, as in entry 10, the yield is excellent. When the C-2 substituent is more highly branched, as in entries 11-13, there may be some interference with high enantiofacial selectivity by the bulky group, because the enantioselectivity in two cases (entries 11 and 12) is 86%. Another example that supports this possibility of steric interference to selective epoxidation is summarized in Eq. 6A.3a [39]. In this case the optically active allylic alcohol 12, (3/ )-3,7-dimethyl-2-methylene-6-penten-l-ol, was subjected to epoxidation with both antipodes of the Ti-tartrate catalyst. With (+)-DIPT, enantiofacial selectivity was 96 4... 

Research by M. Majewski et al. showed that the enantioselective ring opening of tropinone allowed for a novel way to synthesize tropane alkaloids such as physoperuvine. The treatment of tropinone with a chiral lithium amide base resulted in an enantioslective deprotonation, which resulted in the facile opening of the five-membered ring to give a substituted cycloheptenone. This enone was subjected to the Wharton transposition by first epoxidation under basic conditions followed by addition of anhydrous hydrazine in MeOH in the presence of catalytic amounts of glacial acetic acid. 

The first reports of a reaction of an amine with an aldehyde by Schiff [584] led to the establishment of a large class of ligands called Schiff bases. Among the most important of the Schiff bases are the tetradentate salen ligands (N,N -bis(salicy-laldehydo)ethylenediamine), which were studied extensively by Kochi and coworkers, who observed their high potential in chemoselective catalytic epoxidation reactions [585]. The best known method to epoxidize unfunctionalized olefins enantioselectively is the Jacobsen-Katsuki epoxidation reported independently by these researchers in 1990 [220,221]. In this method [515,586-589], optically active Mn salen) compounds are used as catalysts, with usually PhlO or NaOCl as the terminal oxygen sources, and with a O=Mn (salen) species as the active [590,591] oxidant [586-594]. Despite the undisputed synthetic value of this method, the mechanism by which the reaction occurs is still the subject of considerable research [514,586,591]. The subject has been covered in a recent extensive review [595], which also discusses the less-studied Cr (salen) complexes, which can display different, and thus useful selectivity [596]. Computational and H NMR studies have related observed epoxide enantioselectivities... 

Three-membered heterocycles are invested with a speeial allure that is derived from their apparent simplicity and spartan architecture. Yet these systems are multifaceted, and the literature continues to provide evidence of their diversity, both in terms of preparative routes and subsequent transformations. These smallest of heterocycles also exhibit a synthetically very useful balance between stability and reactivity. Thus, they are often employed as versatile and selective intermediates. With the potential to introduce two adjacent chiral centers with high atom economy, this methodology rightly deserves a place of prominence in synthetic organic chemistry. The utility of epoxides, for example, in the enantioselective synthesis of oxygen-substituted quaternary carbon centers has been the subject of a recent review <04COC 149>. 

An alternative and more ingenious method gave all the stereochemical information required.13 The racemic dienol 94 was subjected to Sharpless asymmetric epoxidation (chapter 25), 15 This is another kinetic resolution run to about 50% completion. Using an excess of di-isopropyl tartrate (DIPT, 1.5 equivalents) one enantiomer of the alcohol (R)-94 remained (72% ee) and one enantiomer of one diastereoisomer of the epoxide 95 (>95% ee) was formed. Once again the unreacted starting material 94 has a lower ee than the enantioselectively formed product 95. 

When racemic secondary allylic alcohols 3.17 are subjected to standard Sharpless epoxidation conditions, kinetic resolution takes place [127], By choosing (RJi)- or (5,5)-tartrate, either enantiomer of the epoxyalcohol can be obtained with a maximum yield of 50%, alongside the unreacted allylic alcohol. The ratio of epoxidation rates of the enantiomeric allylic alcohols is usually high enough to obtain both the epoxyalcohol and the unreacted allylic alcohols in high enantiomeric excesses. In some cases, the use of dicyclohexyl- instead of diisopropyl tartrate improves the enantioselectivity. Homoallylic alcohols are also epoxidized, but the selectivities are significantly lower [808]. 

Recently, exceptional progress has been made in the development of chiral ketones (via dioxirane intermediates) based on asymmetric epoxidations (Eq. 3.10). Although the first such type of asymmetric epoxidation was carried out by Curci in 1984, it is only in the last decade that excellent enantioselectivity of such epoxidations has been achieved. Two of the most prevalent workers in the area are Shi " (by using chiral sugar-based ketone, 3.4) and Yang (chiral binapthalene derivative, 3.5). Often, these reactions are performed by using Oxone in an aqueous environment. Many other chiral ketones have also been developed and these methods have been used in various syntheses. This subject has been reviewed by many authors. ... 

The oxidative functionalization of olefins mediated by transition metal oxides leads to a variety of products including epoxides, 1,2-diols, 1,2-aminoalcohols, and 1,2-diamines [1]. Also the formation of tetrahydrofurans (THF) from 1,5-dienes has been observed, and enantioselective versions of the different reactions have been developed. Although a lot of experimental data has been available, the reaction mechanisms have been a subject of controversial discussion. Especially, osmium (VIII) complexes play an important role there, as the proposal of a stepwise mechanism [2] for the dihydroxylation (DH) of olefins by osmium tetroxide (OSO4) had started an intense discussion about the mechanism [2—11],... 

Another modification of Route B requires enantioselective reduction of ketones (E)-27 or stereoselective carbon-carbon bond formation at C-1 of (E)-27 (R = H) with appropriate organometallic species in the presence of chiral additives, both of which successfully supply the optically active (E)-26. The resulting chiral allylic alcohols (E)-26 are subjected to hydrogen bond-directed epoxidation with mCPBA, leading to the diastereoselective formation of syn-epoxy alcohols. In conplementary fashion, antz-selective epoxidation is possible using the Sharpless protocol. ... 

I have made a conscious effort to include some of the more modern synthetic approaches—particularly those leading to enantioselective syntheses such as Sharpless dihy-droxylation and epoxidation. Later chapters deal with the biological, environmental, industrial, and forensic aspects of the subject. 

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