Cyclization enzymatically controlled

The principle underlying the ring-closure reaction and the structure of 47 is reminiscent of the natural biosynthetic pathway for steroids.16 In the latter case 2n3-oxidosqualene cyclizes under enzymatic control to lanosLerof a tetracyclic precursor of cholesterol. 

If the C-15, C-16 bond is oxidatively cleaved, the secodine skeleton results (the proposed progenitor of the Aspidosperma and the iboga systems) through alternative Diels-Alder type cyclizations to afford tabersonine and catharanthine. The bisindole alkaloids of Catharanthus roseus reflect the union of vindoline and catharanthine to afford anhydrovinblastine modification affords the clinically significant alkaloids, vinblastine (VLB) and vincristine (VCR Fig. 39). The alkaloids, particularly VCR, are important as anticancer agents and have led to the development of the semisynthetic derivatives vindesine and vinorelbine (Fig. 40). Synthetic approaches are available to join the monomeric precursors. The enzymatically controlled sequence of reactions from tabersonine to vindoline has been elucidated. 

For the cyclization to occur, the a-region is essential for the enzyme cyclase. A second enzymatic control is involved in the /S-region for the double bond to orient properly on the incoming carbonium ion. The reaction is therefore believed to proceed nonstop until a tetracyclic system is obtained. The role of the squalene oxide cyclase is to maintain the carbon skeleton in place to maximize orbital overlap which allows generation of the ff-bonds in the sterol molecule. This is represented below ... 

It should be pointed out that 0H5in is involved in RNA recognition [21-26] and might also have an influence on the enzymatic inactivation of the antibiotics. Since cyclization of neomycin-B to give 2 or 3 required the removal of this OH group, the deoxy- derivatives 5 and 6 were also synthesized as controls, in order to isolate the effect of rigidification. 

Working on the hypothesis that the stereochemical course of squalene biocycliza-tion may be controlled, in part, by stereoelectronic factors rather than by enzymatic conformational influences, a strong asymmetric induction has been achieved in the cyclization of the dienic acetal (97) with SnCl in benzene. The epimeric mixture (98) was oxidized to the octalones (99a and b) which were then separated and their absolute configurations determined. The (stereoselective) yields resulting from the cyclization reaction were 8 and 92 % for (99a) and (99b) respectively. 

It is not known if the formation of the polyketide chain and its cyclization proceed successively or as one process. The incorporation of smaller ketide units or of partly cyclized, possible intermediates of anthraquinone biosynthesis, e.g., 21 or 22, has not yet been investigated successfully. Furthermore, no information is available on the mechanism of the conformationally controlled enzymatic cyclization of the polyketide chain to give either endocrocin (17) or emodin (19) via 15, or to give the benzochromone eleutherin (20) via 16. 

---