Epoxides basic activation

Fish are extremely good biliary concentrators of drugs. Molecular weight and polarity concerns for biliary elimination are basically similar to mammals, but bile formation in fish is nearly 50 times slower than mammals. As a result, fish have the capacity to biotransform a variety of substrates, although the rates generally observed are lower than in many mammalian species. Sufficient evidence exists to indicate that glucuronyl transferase, sulfotransferase, glutathione-S-transferase, and epoxide hydrolase activities in fish are, at least qualitatively, similar to those found in mammals (23, 24). 

In each case, note that the attack of the nucleophile is from the opposite side to the bridging oxygen atom, and so the resultant addition of the two hydroxyl units is anti. Under basic conditions, the nucleophile is a hydroxide anion, and the resultant anion gains a proton from the solvent. Under acidic conditions, the epoxide is activated by protonation of the epoxide oxygen. This in turn makes the epoxide carbons more electrophilic and so more susceptible to attack by a nucleophile, namely in this case a water molecule. After the nucleophilic attack, the resultant adduct loses a proton to the solvent, and so yields the desired product. Overall, there has been an anti-addition of the symmetrical molecule H202. 

Jacobsen subsequently reported a practical and efficient method for promoting the highly enantioselective addition of TMSN3 to meso-epoxides (Scheme 7.3) [4]. The chiral (salen)Cl-Cl catalyst 2 is available commercially and is bench-stable. Other practical advantages of the system include the mild reaction conditions, tolerance of some Lewis basic functional groups, catalyst recyclability (up to 10 times at 1 mol% with no loss in activity or enantioselectivity), and amenability to use under solvent-free conditions. Song later demonstrated that the reaction could be performed in room temperature ionic liquids, such as l-butyl-3-methylimidazo-lium salts. Extraction of the product mixture with hexane allowed catalyst recycling and product isolation without recourse to distillation (Scheme 7.4) [5]. 

The pH-dependence of the inactivation rate indicated the participation of both a basic and an acidic group in the reaction with 40. The latter could be explained by the formation at the active site of the highly reactive epoxide 1,2-anhydroconduritol F (42) which is subsequently activated by the acidic... 

In practice, promising results have been obtained for several systems. For example, fair to good yields of epoxides are obtained when a two-phase system consisting of alkene and ethyl chloroformate is stirred with a buffered basic solution of hydrogen peroxide. The active oxidant is presumed to be O-ethyl peroxycarbonic acid.85... 

There are two catalytically active residues in pepsin Asp-32 and Asp-215. Their ionizations are seen in the pH-activity profile, which has an optimum at pH 2 to 3, and which depends upon the acidic form of a group of pKa 4.5 and the basic form of a group of pKa 1.1.160,161 The pKa values have been assigned from the reactions of irreversible inhibitors that are designed to react specifically with ionized or un-ionized carboxyl groups. Diazo compounds—such as A-diazoacetyl-L-phenylalanine methyl ester, which reacts with un-ionized carboxyls—react specifically with Asp-215 up to pH 5 or so (equation 16.28).162-164 Epoxides, which react specifically with ionized carboxyls, modify Asp-32 (equation 16.29). 

The publication (70) in 1976 of the preparation of optically active epoxyketones via asymmetric catalysis marked the start of an increasingly popular field of study. When chalcones were treated with 30% hydrogen peroxide under (basic) phase-transfer conditions and the benzylammonium salt of quinine was used as the phase-transfer catalyst, the epoxyketones were produced with e.e. s up to 55%. Up to that time no optically active chalcone epoxides were known, while the importance of epoxides (arene oxides) in metabolic processes had just been discovered (71). The nonasymmetric reaction itself, known as the Weitz-Scheffer reaction under homogeneous conditions, has been reviewed by Berti (70). 

In general, cydohexenones fail to give optically active products under phase-transfer, hydrogen peroxide, benzylquininium chloride, and basic reaction conditions (77). In fact, it appears that the starting material decomposes, since only water-soluble products are formed. Of several cydohexenones tried, only one, namely 4,4-diphenylcyclohexenone, furnished an optically active epoxide. 

Direct phase-transfer catalysed epoxidation of electron-deficient alkenes, such as chalcones, cycloalk-2-enones and benzoquinones with hydrogen peroxide or r-butyl peroxide under basic conditions (Section 10.7) has been extended by the use of quininium and quinidinium catalysts to produce optically active oxiranes [1 — 16] the alkaloid bases are less efficient than their salts as catalysts [e.g. 8]. In addition to N-benzylquininium chloride, the binaphthyl ephedrinium salt (16 in Scheme 12.5) and the bis-cinchonidinium system (Scheme 12.12) have been used [12, 17]. Generally, the more rigid quininium systems are more effective than the ephedrinium salts. 

Due to conjugation, epoxides are less basic than linear ethers or larger saturated oxaheterocycles. Also, ring strain and conjugation render the two adjacent C-atoms markedly electrophilic, resulting in the characteristic alkylating activity of epoxides [3],... 

Fig. 10.5. Catalytic models of epoxide hydrolase (modified from [59]). a) In an earlier model, a basic group in the enzyme activates a H20 molecule during nucleophilic attack on the epoxide, b) A more-elaborate model showing a carboxylate group in the catalytic site that carries out the nucleophilic attack on the substrate to form an ester intermediate. Only in the second step is the intermediate hydrolyzed by an activated H20 molecule, leading to enzyme reactivation and product liberation. 

Finally, one example of trityl salt analogues in the phase-transfer catalysis is presented. The highly stable triazatriangulenium cations 62 [161, 162] were jnst recently introduced to the phase-transfer chemistry [163], Persistent to strongly basic and nncleophilic conditions, these salts revealed efficient catalytic activity in addition reactions (Scheme 64). Modification of the alkyl side chains on nitrogen allowed matching the fair hydro/lipophilicity with the optimised conditions in the alkylation, epoxidation, aziridination and cyclopropanation reactions. The results are comparable to those of tetrabutylammonium salts and in some cases showed even a better outcome. 

Nucleophilic additiou is geuerally observed as the principal mode of action for poorly basic organolithium reageuts or activated epoxides. This reaction will be described in detail in Section IV. 

Thus, a synthetic source of promising allelochemicals is essential if we are to comprehensively study the agent s mode of activity and establish its basic structure-activity profile. The proposed work addresses this need. We will synthesize alleopathic natural products isolated from the sunflower (the heliannuols), and structurally related compounds, in optically pure form based on biomimetic phenol-epoxide cyclizations. The bioactivity of the targets and intermediates will be evaluated through laboratory tests on plant germination and growth. Bioassays will be performed on the synthetic intermediates to allow for the development of a preliminary structure-activity profile for these novel natural herbicides. 

Besides the chiral, secondary hydroperoxides employed by Adam and coworkers and the tertiary hydroperoxide used by Seebach, the optically active carbohydrate hydroperoxides 72, 93 and 94 have been tested by Taylor and coworkers in epoxidation reactions of the quinones 95 under basic conditions (Scheme 41). The yields of the corresponding epoxides 96 that were obtained with this type of oxidant varied from 33 to 83% and the enantioselectivities were moderate and in some cases good (23 to 82%), depending... 

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