Cinchona epoxidation

A catalytic enantio- and diastereoselective dihydroxylation procedure without the assistance of a directing functional group (like the allylic alcohol group in the Sharpless epox-idation) has also been developed by K.B. Sharpless (E.N. Jacobsen, 1988 H.-L. Kwong, 1990 B.M. Kim, 1990 H. Waldmann, 1992). It uses osmium tetroxide as a catalytic oxidant (as little as 20 ppm to date) and two readily available cinchona alkaloid diastereomeis, namely the 4-chlorobenzoate esters or bulky aryl ethers of dihydroquinine and dihydroquinidine (cf. p. 290% as stereosteering reagents (structures of the Os complexes see R.M. Pearlstein, 1990). The transformation lacks the high asymmetric inductions of the Sharpless epoxidation, but it is broadly applicable and insensitive to air and water. Further improvements are to be expected. 

One of the most significant developmental advances in the Jacobsen-Katsuki epoxidation reaction was the discovery that certain additives can have a profound and often beneficial effect on the reaction. Katsuki first discovered that iV-oxides were particularly beneficial additives. Since then it has become clear that the addition of iV-oxides such as 4-phenylpyridine-iV-oxide (4-PPNO) often increases catalyst turnovers, improves enantioselectivity, diastereoselectivity, and epoxides yields. Other additives that have been found to be especially beneficial under certain conditions are imidazole and cinchona alkaloid derived salts vide infra). 

Another microwave-mediated intramolecular SN2 reaction forms one of the key steps in a recent catalytic asymmetric synthesis of the cinchona alkaloid quinine by Jacobsen and coworkers [209]. The strategy to construct the crucial quinudidine core of the natural product relies on an intramolecular SN2 reaction/epoxide ringopening (Scheme 6.103). After removal of the benzyl carbamate (Cbz) protecting group with diethylaluminum chloride/thioanisole, microwave heating of the acetonitrile solution at 200 °C for 2 min provided a 68% isolated yield of the natural product as the final transformation in a 16-step total synthesis. 

B. Lygo, P. G. Wainwright, Asymmetric Phase-Transfer Mediated Epoxidation of a,p-Unsaturated Ketones using Catalysts Derived from Cinchona Alkaloids , Tetrahedron Lett. 1998,39,1599-1602. 

Asymmetric dihydroxylation can be achieved using osmium tetroxide in conjunction with a chiral nitrogen ligand. " The very successful Sharpless procedure uses the natural cinchona alkaloids dihydroquinine (DHQ) and its diastereomer dihy-droquinidine (DHQD), as exemplified in the epoxidation of imni-stilbene... 

Epoxidations and Darzens Condensations The asymmetric catalytic epoxida-tion of a,p-unsaturated ketones using cinchona alkaloid-derived catalysts was introduced in the 19708. However, high levels of enantioselectivity were achieved only 20 years later, when Lygo, Arai, 2-t94 others P ... 

Darzens condensation using crown ethers and cinchona alkaloids-derived catalysts, respectively, obtaining epoxides with moderate enantioselectivity. 

Electron-deficient alkenes generally require the use of some other epoxidation procedure, owing to their low reactivity under electrophilic addition conditions. Within this categoiy, o,P-unsaturated ketones tend to be the substrates of interest, and basic oxygen transfer reagents are fiequently encountered, such as HjOj/NaOH, t-BuOOH/NaOH, and NaOCl. Much activity has centered around the modification of these traditional conditions to accommodate asymmetric induction. In this regard, variously substituted Cinchona alkaloids (e.g., 39 - 41) have received a fair amount of attention over the past year. 

While the oxygenation of alkenes represents the lion s share of methodology development, new and improved protocols for the [C=0 + C] approach to epoxides have also been reported. For example, the phase-transfer-catalyzed asymmetric Daizens reaction using the chiral Cinchona derivative 41 afforded spirocyclic epoxide 52 in good to excellent yields and fair to good ee s <99T6375>. 

The epoxidation of enones using chiral phase transfer catalysis (PTC) is an emerging technology that does not use transition metal catalysts. Lygo and To described the use of anthracenylmethyl derivatives of a cinchona alkaloid that are capable of catalyzing the epoxidation of enones with remarkable levels of asymmetric control and a one pot method for oxidation of the aUyl alcohol directly into... 

Promising examples of the catalytic asymmetric Darzens condensation, which yields an epoxide product via carbon-carbon and carbon-oxygen bond formation, have been reported recently by two groups (Scheme 10.11). Toke and co-workers used crown ether 24 in the reaction to form the a,P-unsaturated ketone 78 [38b] with 64% ee, whereas the Shioiri group used the cinchona-derived salt 3a [52], which resulted in 78 with 69% ee. The latter authors propose a catalytic cycle involving generation of a chiral enolate in situ from an achiral inorganic base... 

Lygo and Wainwright recently reported a detailed study of the asymmetric phase-transfer mediated epoxidation of a variety of acyclic a,P-unsaturated ketones of the chalcone type. The third-generation cinchona-derived quats (8c and 7c), related to those discussed earlier in the alkylation section and Scheme 10.4, gave the best inductions (89% ee, 88 to 89, Scheme 10.13 and 86% ee for the pseudoenantiomeric catalyst 7c to give, as product, the enantiomer of 89). 

Asymmetric Epoxidation with Polymeric Cinchona-PTCs 63... 

During the search for the optimal dimeric PTC for this epoxidation, the Park-Jew group found an interesting result, namely that the functional groups of 9-0 H and 6 -OMe in the cinchona unit, along with 2-F group in the phenyl linker, were critical factors for high enantioselectivity of the reaction (Scheme 4.16). 

Asymmetric epoxidation catalyzed by chiral phase-transfer catalysts is another reaction which has been extensively studied following an initial report by Wynberg [2,44]. Shioiri et al. further improved the enantioselective epoxidation of naphthoquinones under cinchona alkaloid-derived chiral phase-transfer catalysis [45],... 

Dehmlow and coworkers [17] compared the efficiency of monodeazadnchona alkaloid derivatives 14a-c in the enantioselective epoxidation of naphthoquinone 50 with that of cinchona alkaloid-derived chiral phase-transfer catalysts 15a-c (Table 7.7) (for comparison of the alkylation reaction, see Table 7.1). Interestingly, the non-natural cinchona alkaloid analogues 14a-c afforded better results than natural cinchona alkaloids 15a-c. The deazacinchonine derivatives 14a,b produced epoxidation product 51 in higher enantioselectivity than the related cinchona alkaloids 15a,b. Of note, catalyst 14c, which possessed a bulky 9-anthracenylmethyl substituent on the quaternary nitrogen, afforded the highest enantioselectivity (84% ee). 

Table 7.7 Asymmetric epoxidation using monodeazacinchona analogues 14a-c and natural cinchona alkaloids 15a-c.

Phase-transfer catalysis has been widely been used for asymmetric epoxidation of enones [100]. This catalytic reaction was pioneered by Wynberg et al., who used mainly the chiral and pseudo-enantiomeric quaternary ammonium salts 66 and 67, derived from the cinchona alkaloids quinine and quinidine, respectively [101-105],... 

Draw structures of ligands derived from the chiral framework of glucose, tartaric acid, binaphthol, and cinchona alkaloids that are used for efficient asymmetric hydrocyanation, epoxidation, hydroformylation, and alkene dihydroxylation reactions respectively. 

A number of chiral phase-transfer salts capable of catalyzing the epoxidation of electron-deficient alkenes have been developed. The molecular framework provided by the Cinchona alkaloids have appeared to be a useful starting... 

Asymmetric Weitz-Scheffer epoxidation is commonly used for the epoxidation of electron-poor alkenes. Cinchona-derived phase-transfer catalysts, initially used... 

Another important asymmetric epoxidation of a conjugated systems is the reaction of alkenes with polyleucine, DBU and urea H2O2, giving an epoxy-carbonyl compound with good enantioselectivity. The hydroperoxide anion epoxidation of conjugated carbonyl compounds with a polyamino acid, such as poly-L-alanine or poly-L-leucine is known as the Julia—Colonna epoxidation Epoxidation of conjugated ketones to give nonracemic epoxy-ketones was done with aq. NaOCl and a Cinchona alkaloid derivative as catalyst. A triphasic phase-transfer catalysis protocol has also been developed. p-Peptides have been used as catalysts in this reaction. ... 

The Sharpless asymmetric epoxidation of allyl alcohol gives the glycidol derivative 61 in 90% ee after in situ tosylation of 60 [63]. This process is working on a multiton-a-year scale (Arco Co., USA), facilitating the synthesis of a variety of /0-blockers. Asymmetric dihydroxylation of the allyl ether 63 catalyzed by a combined system of OSO4 and the cinchona alkaloid-based ligand 65 allows the commercial synthesis of the propranolol intermediate 64 in 91 % (Sepracor Co., USA) [64]. 

The enantioselective ring opening of epoxides with salen-Cr complexes yields intermediates for the manufacture of ( )-9-[2-(phosphonomethoxy)propyl]ade-nine [67] (a prophylactic against SIV infection). Os-catalyzed asymmetric amino-hydroxylation (ligand modified by cinchona alkaloids) leads to a-hydroxy-j6-phenylalanine, a derivative for the C13 chain of taxol [68]. 

A variation of the Sharpless asymmetric epoxidation is to employ chiral hydroperoxides. The chiral iminium salt 89 has moderate enantiocontrol for epoxidation. Quatemized cinchona alkaloids can serve as chiral catalyst and phase-transfer agents in epoxidation of enones with NaOCl. Enones are also epoxidized by oxygen in the presence of diethylzinc and A-methylpseudoephedrine, whereas IZj-enones are submitted to enantioselective epoxidation by t-BuOOH-O-PrO),Yb and the BINOL 90. 

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