Aziridination agents

Cyclic voltammetry provided Yudin with information that oxidation of aminophthalimide at +1.8 V will provide an active nitrogen species capable of aziridinating both electron-rich and electron-poor olefins. The electron-rich olefin of the diene 33 was thus able to be selectively aziridinated to provide aziridine 34 (Equation 15) <2005JOC932>. Yudin found that addition of acetate anion was key in the aziridination process. Addition of acetate to the solution forms the A -acetoxyaminophthalimide, a compound previously prepared by oxidation of aminophthalimide with lead tetraacetate. The absence of acetate allows the aminophthalimide to dimerize, then oxidize further to lose nitrogen and provide phthalimide as the final product, without any reasonable concentration of aziridinating agent. 

Aziridines occur naturally in the form of mitomycins (Table 3), which have antibiotic activity (1,449). Mytomycin C is used clinically as one of the most effective agents in the chemotherapy of cancer (450). 

N- Aminoaziridines have been converted to alkenes by reaction with a variety of oxidizing agents (70JA1784). Usually, the deamination reaction is stereospecific. The oxidation of l-amino-2,3-diphenylaziridines with manganese dioxide, however, was not stereospecific. The trans compound gives entirely frans-stilbene, whereas the cfs-aziridine forms a mixture of 85% trans- and 15% c -aikene. cw-Stilbene is not isomerized to trans under the reaction conditions, and the results are explained in terms of an azamine intermediate which can isomerize through a tautomeric equilibrium. 

The antitumor activity displayed by the mitosanes and many synthetic aziridines stems from their ability to act as alkylating agents which chemically modify (crosslink) DNA. For this reason, a large number have been screened for antitumor activity, the mechanism of which has been the subject of considerable research effort <75CJC289l). An excellent account of the broad spectrum of biological properties of a multitude of compounds containing the aziridinyl moiety has been published [Pg.93]

Two-component waterborne urethane dispersions are similar to the one-component PUD s in that a polyurethane dispersion comprises one of the two components. The second component is usually a crosslinker from the following classes of materials (a) polyisocyanates, (b) aziridines, (c) polycarbodiimides, and (d) epoxies. Many of the crosslinkers are not inherently water-soluble or water-dispersible. Therefore, they must be modified with surface active agents themselves, so as to become emulsifiable in water. 

Iodine azide, on the other hand, forms pure adducts with A -, A - and A -steroids by a mechanism analogous to that proposed for iodine isocyanate additions. Reduction of such adducts can lead to aziridines. However, most reducing agents effect elimination of the elements of iodine azide from the /mwj -diaxial adducts of the A - and A -olefins rather than reduction of the azide function to the iodo amine. Thus, this sequence appears to be of little value for the synthesis of A-, B- or C-ring aziridines. It is worthy to note that based on experience with nonsteroidal systems the application of electrophilic reducing agents such as diborane or lithium aluminum hydride-aluminum chloride may yet prove effective for the desired reduction. Lithium aluminum hydride accomplishes aziridine formation from the A -adducts, Le., 16 -azido-17a-iodoandrostanes (97) in a one-step reaction. The scope of this addition has been considerably enhanced by the recent... 

Yet another nontricyclic antidepressant consists of a relatively simple morpholine derivative. Acylation of aziridine with p-chlorobenzoyl chloride gives the amide 130. This intermediate is. sufficiently reactive to undergo ring opening on treatment with morpholine. The product is the antidepressant agent moclobemide (131) 33J. 

Cancer chemothCTapeutic agents as a rule poorly penetrate the blood brain barrier. Brain tumors are thus not readily treatable by chemotherapy. Diaziquone (at one time known as AZQ) is an exception to this generalization. Treatment of chloranil (213) with the anion from urethane gives intermediate 214, probably by an addition elimination scheme. Displacement of the remaining halogen with aziridine yields diaziquone (215) [.55J. 

Asymmetric transfer hydrogenation reducing agents react with 2-aryl azirines to give aziridines in good yields but with moderate enantiomeric excesses (Scheme 4.42) [62],... 

Epoxides are found in thousands of biological molecules and constitute vital functional entities. They can impart localized structural rigidity, confer cytotoxicity through their role as alkylating agents, or act as reactive intermediates in complex synthetic sequences. The widespread occurrence of epoxides is contrasted by only a handful of aziridines that are known to date. In this chapter we would like to introduce the different mechanisms by which enzymes produce epoxides. 

The tightly bound chromophore could be extracted from the protein with methanol [186], and the major component of the extract was determined to have the enediyne structure 116 (Figure 11.21), related to chromophores of other chromoprotein antitumor agents such as neocarzinostatin. Additional minor components were extracted, variously containing an OH group instead of OMe attached to the enediyne core, with Cl instead of OMe when chloride was present in the buffer salt, or with OEt instead of OMe when ethanol was used for the extraction. Another byproduct was isolated in the form of structure 117, consistent with a facile cy-doaromatization reaction as observed for all other enediyne antibiotics. Surprisingly, 117 also displayed antibiotic and antitumor activity, perhaps due to alkylation of DNA or protein by the aziridine. The interpretation of these results was that 116 and the other enediyne byproducts were merely artifacts of the extraction procedure and that the true structure of the maduropeptin chromophore is the aziridine 118. 

Very reactive nitrogen mustards and aziridine-containing molecules are usually too toxic for general therapeutic use, but find use in neoplastic disease. Benzodepa (182) is such an agent. Treatment of ethyl carbamate with phosphorous pentachloride leads to cyanate 180 which readily adds benzyl alcohol to produce carbamate 181. Displacement of the active... 

Among the most active alkylating agents used against cancer are nitrosoureas and aziridines. 

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