Epoxides, biological formation

Since the seminal contributions by Nugent and RajanBabu the field of reductive C - C bond formation after epoxide opening via electron transfer has developed at a rapid pace. Novel catalytic methodology, enantio- and stereoselective synthesis and numerous applications in the preparation of biologically active substances and natural products have evolved. In brief, a large repertoire of useful and original reactions is available. These reactions are waiting to be applied in a complex context ... 

Although technical chlordane is a mixture of compounds, two metabolites — heptachlor epoxide and oxychlordane — can kill birds when administered through the diet (Blus et al. 1983). These two metabolites originate from biological and physical breakdown of chlordanes in the environment, or from metabolism after ingestion. Heptachlor can result from breakdown of cis- and trans-chlordane, eventually oxidizing to heptachlor epoxide oxychlordane can result from the breakdown of heptachlor, m-chlordane, tra .s-chlordane, or fram-nonachlor (Blus et al. 1983). Heptachlor epoxide has been identified in soil, crops, and aquatic biota, but its presence is usually associated with the use of heptachlor, not technical chlordane — which also contains some heptachlor (NRCC 1975). Various components in technical chlordane may inhibit the formation of heptachlor epoxide or accelerate the decomposition of the epoxide, but the actual mechanisms are unclear (NRCC 1975). 

Aldol reaction of keto-acid 21 with aldehyde 10 and esterification of the resulting acids with alcohol 22 led rapidly to cyclization precursor 23 and its 6S,7R-diastereomer (not shown). RCM using ruthenium initiator 3 (0.1 equiv) in dichloromethane (0.0015 M) at 25 °C afforded macrolactones 24a and 24b in a 1.2 1 ratio. Deprotection and epoxidation of the desired macrolactone, 24a, afforded epothilone A (4) via 25a (epothilone C) (Scheme 5). Varying a number of reaction parameters, such as solvent, temperature and concentration, failed to improve significantly the Z-selectivity of the RCM. However, in the context of the epothilone project, the formation of the E-isomer 24b could actually be viewed as beneficial since it allowed preparation of the epothilone A analog 26 for biological evaluation. 

In the pH range of 5 - 10, H20-catalyzed hydrolysis is the predominant mechanism (see Fig. 10.11, Pathway b), resulting in the formation of the (8R,9R)-dihydrodiol (10.133, Fig. 10.30). Thus, aflatoxin B1 exo-8,9-epoxide is possibly the most reactive oxirane of biological relevance. Such an extreme reactivity is mostly due to the electronic influence of 0(7), as also influenced by stereolectronic factors, i.e., the difference between the exo- and endo-epoxides. The structural and mechanistic analogies with the dihydro-diol epoxides of polycyclic aromatic hydrocarbons (Sect. 10.4.4) are worth noting. 

Squalene is an important biological precursor of many triterpenoids, one of which is cholesterol. The first step in the conversion of squalene to lanosterol is epoxidation of the 2,3-douhle bond of squalene. Acid-catalysed ring opening of the epoxide initiates a series of cyclizations, resulting in the formation of protesterol cation. Elimination of a C-9 proton leads to the 1,2-hydride and 1,2-methyl shifts, resulting in the formation of lanosterol, which in turn converted to cholesterol by enzymes in a series of 19 steps. 

Cerniglia, C. E. Gibson, D. T. (1980a). Fungal oxidation of benzo(a)pyrene and ( )-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene evidence for the formation of a benzo(a)pyrene 7,8-diol-9,10-epoxide. /oarW of Biological Chemistry, 255, 5159-63. 

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