Catalytic Asymmetric Epoxide Ring‐opening Chemistry

Nielsen, Lars Peter; Jacobsen, Eric N.

doi:10.1002/3527607862.ch7

Cited by 68 publications

(31 citation statements)

References 96 publications

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“…Epoxides are three-member strained rings leading in general or normally to electrophilic compounds with reactivity toward nucleophiles to give ␤ -substituted alcohols in a regio-and stereoselective way in S N 2 conditions (10)(11)(12). This reactivity makes chemicals bearing an epoxide group, such as benzo(a)pyrene diol epoxide or styrene oxide (SO), potent alkylating agents producing covalent adducts with proteins and nucleic acids, which contributes to their mutagenicity and carcinogenicity in mammals ( 13,14 ).…”

Section: Procedures For Comparing Epoxide Reactivity In Cell Culture Mmentioning

confidence: 99%

Surprising unreactivity of cholesterol-5,6-epoxides towards nucleophiles

Paillasse

Saffon

Gornitzka

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org thesis ( 2 ). We showed that ChEH was fully inhibited by therapeutic doses of AEBS ligands, including drugs belonging to different pharmacological classes and widely used nutritional compounds. These compounds include tamoxifen (tam), one of the main drugs used for the fi rstline and long-term hormone therapy of breast cancers; raloxifene, which has been approved for the prevention of osteoporosis ( 3 ); amiodarone, which is widely used for the prevention and the treatment of anti-arrhythmia ( 4 ); trifluoroperazine, an antipsychotic drug used for the treatment of schizophrenia ( 5 ); and the omega-3 fatty acid docosahexaenoic acid, which is widely proposed as dietary supplement with health benefi ts ( 2 ). Extensive knowledge of the mechanism of action of all these molecules is required to prevent toxicity to patients submitted to longterm treatment with such inhibitors of ChEH.AEBS/ChEH ligands, such as tam and raloxifene, were recently shown to induce cell differentiation and death of breast cancer cells through a mechanism involving sterol accumulation and autoxidation ( 6-8 ) leading to the production of 5,6-EC, suggesting that 5,6-EC accumulation is involved in their anticancer and chemopreventitive activity. This is contrary to the initial hypothesis that the biological function of ChEH was to detoxify 5,6-EC. This hypothesis emerged because it was initially postulated that 5,6-EC could, like other chemicals bearing epoxide groups, be potent alkylating substances and, hence, carcinogenic ( 9 ).Abstract We recently established that drugs used for the treatment and the prophylaxis of breast cancers, such as tamoxifen, were potent inhibitors of cholesterol-5,6-epoxide hydrolase (ChEH), which led to the accumulation of 5,6 ␣ -epoxy-cholesterol (5,6 ␣ -EC) and 5,6 ␤ -epoxy-cholesterol (5,6 ␤ -EC). This could be considered a paradox because epoxides are known as alkylating agents with putative carcinogenic properties. We report here that, as opposed to the carcinogen styrene-oxide, neither of the ECs reacted spontaneously with nucleophiles. Under catalytic conditions, 5,6 ␤ -EC remains unreactive whereas 5,6 ␣ -EC gives cholestan-3 ␤ ,5 ␣ -diol-6 ␤ -substituted compounds. These data showed that 5,6-ECs are stable epoxides and unreactive toward nucleophiles in the absence of a catalyst, which contrasts with the well-known reactivity of aromatic and aliphatic epoxides. These data rule out 5,6-EC acting as spontaneous alkylating agents. In addition, these data support the existence of a stereoselective metabolism of 5,6 ␣ -EC. Cholesterol-5,6-epoxide hydrolase (ChEH; EC 3.3.2.11) catalyzes the stereoselective hydration of cholesterol-5,6-epoxide diastereoisomers (5,6-EC: 5,6 ␣ -EC and 5,6 ␤ -EC) into cholestane-3 ␤ ,5 ␣ ,6 ␤ -triol (CT) ( 1 ). We recently reported the molecular identifi cation of this enzyme and established that ChEH activity was carried out by the microsomal antiestrogen binding site (AEBS), which consists of two subunits: the 3 ␤ -hydroxyste...

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Section: Procedures For Comparing Epoxide Reactivity In Cell Culture Mmentioning

confidence: 99%

Surprising unreactivity of cholesterol-5,6-epoxides towards nucleophiles

Paillasse

Saffon

Gornitzka

et al. 2012

Journal of Lipid Research

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“…The opening of epoxides with carbon nucleophiles is a useful transformation in organic synthesis because of the availability of epoxides and the versatility of the alcohol products. 1 The enantioselective opening of meso -epoxides forms two new, adjacent stereocenters, and highly selective catalysts have been reported for a variety of heteroatom nucleophiles, 1 , 2 carbon monoxide, 3 and cyanide. 1 , 4 In contrast, the enantioselective coupling of aryl and vinyl nucleophiles with meso -epoxides has proven to be more challenging.…”

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confidence: 99%

“… 1 The enantioselective opening of meso -epoxides forms two new, adjacent stereocenters, and highly selective catalysts have been reported for a variety of heteroatom nucleophiles, 1 , 2 carbon monoxide, 3 and cyanide. 1 , 4 In contrast, the enantioselective coupling of aryl and vinyl nucleophiles with meso -epoxides has proven to be more challenging. 5 , 6 The best results to date are with aryllithium reagents and stoichiometric 7 or catalytic 8 amounts of chiral ligands (Scheme 1 A).…”

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Enantioselective Cross-Coupling of meso-Epoxides with Aryl Halides

2015

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The first enantioselective cross-electrophile coupling of aryl bromides with meso-epoxides to form trans-β-arylcycloalkanols is presented. The reaction is catalyzed by a combination of (bpy)NiCl2 and a chiral titanocene under reducing conditions. Yields range from 57 to 99% with 78–95% enantiomeric excess. The 30 examples include a variety of functional groups (ether, ester, ketone, nitrile, ketal, trifluoromethyl, sulfonamide, sulfonate ester), both aryl and vinyl halides, and five- to seven-membered rings. The intermediacy of a carbon radical is strongly suggested by the conversion of cyclooctene monoxide to an aryl [3.3.0]bicyclooctanol.

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“…Although the opening of epoxides with heteroatom nucleophiles and stabilized or unstabilized carbon nucleophiles (most often cuprates) is well known, 1,2, 3 transition-metal catalyzed coupling of epoxides with less reactive nucleophiles or carbon electrophiles is rare, despite the obvious synthetic utility. 4 …”

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Nickel-Catalyzed Regiodivergent Opening of Epoxides with Aryl Halides: Co-Catalysis Controls Regioselectivity

2013

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Epoxides are versatile intermediates in organic synthesis, but have rarely been employed in cross-coupling reactions. We report that bipyridine-ligated nickel can mediate the addition of functionalized aryl halides, a vinyl halide, and a vinyl triflate to epoxides under reducing conditions. For terminal epoxides, the regioselectivity of the reaction depends upon the co-catalyst employed. Iodide co-catalysis results in opening at the less hindered position via an iodohydrin intermediate. Titanocene co-catalysis results in opening at the more hindered position, presumably via TiIII-mediated radical generation. 1,2-Disubstituted epoxides are opened under both conditions to form predominantly the trans product.

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Catalytic Asymmetric Epoxide Ring‐opening Chemistry

Cited by 68 publications

References 96 publications

Surprising unreactivity of cholesterol-5,6-epoxides towards nucleophiles

Surprising unreactivity of cholesterol-5,6-epoxides towards nucleophiles

Enantioselective Cross-Coupling of meso-Epoxides with Aryl Halides

Nickel-Catalyzed Regiodivergent Opening of Epoxides with Aryl Halides: Co-Catalysis Controls Regioselectivity

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