Prostaglandins epoxidation

To control the stereochemistry of epoxidation at the 10,11-double bond in intermediates in prostaglandin synthesis, a bulky protective group was used for the C15-OH group. Epoxidation of the tribenzylsilyl ether yielded 88% a-oxide epoxidation of the tri-/ -xylylsilyl ether was less selective. ... 

Without question, the most significant advance in the use of sulfur-centered nucleophiles was made by Shibasaki, who discovered that 10 mol% of a novel gallium-lithium-bis(binaphthoxide) complex 5 could catalyze the addition of tert-butylthiol to various cyclic and acyclic meso-epoxides with excellent enantioselectiv-ities and in good yields (Scheme 7.11) [21], This work builds on Shibasaki s broader studies of heterobimetallic complexes, in which dual activation of both the electrophile and the nucleophile is invoked [22]. This method has been applied to an efficient asymmetric synthesis of the prostaglandin core through an oxidation/ elimination sequence (Scheme 7.12). 

Tumorigenicity of tetrahydroepoxides. As yet, only Ch H -epoxide has been directly demonstrated to be tumorigenic (18). However, indirect evidence has been found in the high tumorigenicity of 3,4-dihydro BA, 9,10-dihydro BeP and 3,4-dihydrobenz[c]acridine (19-21), each of which is a likely metabolic precursor of a bay-region H -epoxide. In the case of 9,10-dihydro BeP, cis- and trans-9,10-dihydroxy -9,10,11,12-tetrahydro BeP were identified as products of metabolism of 9,10-dihydro BeP (22), and are the expected products of hydration of the epoxide. Diols are also formed from 7,8-dihydro BaP upon metabolism with prostaglandin endoperoxide synthase (23) or with rat liver homogenates (24). 

Eicosanoid synthesis. Arachidonic acid is converted by cyclooxygenases into prostaglandins, and thromboxanes. Lipoxygenases convert arachidonic acid into HPETEs, which are then converted to lipoxins, leukotrienes, and 12-HETE (hydroxyeicosatetraenoic acid). Epoxygenases convert arachidonic acid into epoxides. 

In an approach to the prostaglandins [43], seco-solvolysis of an epoxycyclopropane serves to establish the oxy functionality in the cyclopentane subunit and an E double bond in the side-chain. Opening of the epoxide that triggers the sequence of events is directed by the cyclopropyl group (donor) and the cyano group (acceptor). 

The Sharpless epoxidation is sensitive to preexisting chirality in selected substrate positions, so epoxidation in the absence or presence of molecular sieves allows easy kinetic resolution of open-chain, flexible allylic alcohols (Scheme 26) (52, 61). The relative rates, kf/ks, range from 16 to 700. The lower side-chain units of prostaglandins can be prepared in high ee and in reasonable yields (62). A doubly allylic alcohol with a meso structure can be converted to highly enantiomerically pure monoepoxy alcohol by using double asymmetric induction in the kinetic resolution (Scheme 26) (63). A mathematical model has been proposed to estimate the degree of the selectivity enhancement. 

Selective polymerization, enantiomers, 185 Semico rrin-copper complexes, 199 Sharpless epoxidation, racemic alcohols, 45 Side-chain units, prostaglandins, 310 Sigmatropic reactions, 222 Silanes, oxidative addition, 126 Silica gel, 285, 352... 

Phase I reactions include microsomal monooxygenations, cytosolic and mitochondrial oxidations, co-oxidations in the prostaglandin synthetase reaction, reductions, hydrolyses, and epoxide hydration. All of these reactions, with the exception of reductions, introduce polar groups to the molecule that, in most cases, can be conjugated during phase II metabolism. The major phase I reactions are summarized in Table 7.1. 

During cooxidation, some substrates are activated to become more toxic than they were originally. In some cases substrate oxidation results in the production of free radicals, which may initiate lipid peroxidation or bind to cellular proteins or DNA. Another activation pathway involves the formation of a peroxyl radical from subsequent metabolism of prostaglandin G2. This reactive molecule can epoxidize many substates including polycyclic aromatic hydrocarbons, generally resulting in increasing toxicity of the respective substrates. 

Anandamide can be metabolized by cyclooxygenase-2 (COX-2), 12- and 15-lipoxygenase (LOX), and cytochrome P450 (CYP450) to generate prostaglandin ethanolamides (prostamides), hydroperoxide, hydroxide, and epoxide... 

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