Quinine epoxide synthesis

Following Uskokovic s seminal quinine synthesis [40], Jacobsen has very recently reported the first catalytic asymmetric synthesis of quinine and quinidine. The stereospecific construction of the bicyclic framework, introducing the relative and absolute stereochemistry at the Cg- and expositions, was achieved by way of the enantiomerically enriched trans epoxide 87, prepared from olefin 86 by SAD (AD-mix (3) and subsequent one-pot cyclization of the corresponding diol [2b], The key intramolecular SN2 reaction between the Ni- and the Cg-positions was accomplished by removal of the benzyl carbamate with Et2AlCl/thioanisole and subsequent thermal cyclization to give the desired quinudidine skeleton (Scheme 8.22) [41],... 

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. 

Guanidines are useful nucleophiles in the intramolecular ring opening of epoxides <2003TL3075>. The intramolecular addition of an amide anion to an oxirane in a 6-o o-fashion formed 2-ketopiperazine derivatives <20040L4069>. This reaction type was also used in a recent quinine synthesis <2004TL3783>. 

Synthesis of Optically Active Epoxides. Alkaloids and alkaloid salts have been successfully used as catalysts for the asymmetric synthesis of epoxides. The use of chiral catalysts such as quinine or quinium benzylchloride (QUIBEC) have allowed access to optically active epoxides through a variety of reaction conditions, including oxidation using Hydrogen Peroxide (eq 5), Darzens condensations (eq 6), epoxidation of ketones by Sodium Hypochlorite (eq 7), halohydrin ring closure (eq 8), and cyanide addition to a-halo ketones (eq 9). Although the relative stereochemistry of most of the products has not been determined, enan-tiomerically enriched materials have been isolated. A more recent example has been published in which optically active 2,3-epoxycyclohexanone has been synthesized by oxidation with t-Butyl Hydroperoxide in the presence of QUIBEC and the absolute stereochemistry of the product established (eq 10). ... 

The first racemic synthesis of fosfomycin is based on the epoxidation of ( ) (Z)-l-propenylphosphonic acid (Scheme 4.24). The reaction was effectively achieved using an excess of H2O2 (30% solution) at 60°C in the presence of Na2WO4 as catalyst (2%) at pH 5.5. The (Z)-l-prope-nylphosphonic acid was prepared by stereospecific hydrogenation, with Lindlar catalyst, of dibutyl 1-propynylphosphonate into dibutyl (Z)-l -propenylphosphonate, followed by hydrolysis of the ester functions with concentrated HCl. The resolution of the racemic ( ) (Z)-l,2-epoxypropylphosphonic acid to fosfomycin was accomplished by way of optically active amines, a-phenylethylamine, or quinine. ... 

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