The major objective of this proposal is the implementation of new methodology for stereocontrolled synthesis of subunits found in the exceedingly important macrolide antibiotics tylosin and magnamycin B. Alongside the development of these routes we also intend to produce subunits for ionophore antibiotics, in particular ionomycin, and we propose to synthesize the Lycopodium alkaloid luciduline. These targets are chosen to illustrate the applicability of new methodology developed in our laboratory for stereospecific introduction of substituents onto six- and seven-membered carbocyclic rings which utilizes the powerful directing effect of a transition metal moiety attached to the ring. This approach promises to be sufficiently flexible to allow the synthesis of analogs of the natural products, thereby making a potential contribution to disease control. The approach to tylosin and magnamycin B which is to be followed uses entirely new synthetic principles. Thus, synthesis of a key 5, 7-disubstituted cycloheptadiene is a stereospecific manner is effected by means of a cycloheptadiene iron complex, representing an entirely unprecedented method for the stereospecific functionalisation of the seven-membered ring. Subsequent elaboration of the product cycloheptadiene will be investigated using a regio- and stereospecific lactonisation method recently developed on related cyclohexadienylacetic acids in our laboratories. The use of cycloheptadienyl iron complexes is also of considerable value for preparation of analogs of the naturally occurring macrolides, since there is considerable flexibility concerning the nature of substituents which are introduced, thereby giving methods for variation of substitution pattern. Synthesis of radiolabeled, carbon 13- and deuterium-labeled compounds can also be accomplished, and these would be extremely useful for in vitro and in vivo studies of mode of action and metabolism.
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| Lee, Seung Jae; McCormick, Michael S; Lippard, Stephen J et al. (2013) Control of substrate access to the active site in methane monooxygenase. Nature 494:380-4 |
