Die Iromycine und das Collinolacton: Synthese mikrobieller Naturstoffe aus Streptomyces sp.

Abstract

In this work the total synthesis of two natural products - iromycins A and collinolacton was studied. The total synthesis of iromycin A, a microbial metabolite combining a novel structure with an interesting biological activity as a NO synthase inhibitor, was accomplished using a flexible and highly convergent approach (13 steps). The ring fragment was 6-bromomethylpyrone which was obtained through alkylation and acylation of the respective β-ketoester and subsequent lactonization of the thus obtained β,δ-diketoester, followed by bromination of the 6-methyl group. Another molecular fragment, the unsaturated side chain, was prepared from a terminal alkyne, which was then carboaluminated to give the alkenyldimethylalane. The assembly of these two molecular fragments to produce a precursor of iromycin was thoroughly studied using nickel, palladium, and copper catalysts. The synthesis, however, only succeeded in presence of lithium alkenyltrialkylalanate, which was generated from nBuLi and Alan, while the transition metals tested did not successfully catalyse the reaction. Treatment of the coupled product with liquid ammoniak at 70 °C completed the total synthesis and gave the natural product iromycin A with a yield of 64% (18% overall yield over the nine steps).According the initial synthesis plan, the collinolacton molecule should be assembled in four key steps: enantioselectiv aldol reaction, diastereoselectiv Diels-Alder reaction, Oxy-Cope rearrangement and Baeyer-Villiger oxidation. In this work only the aldol reaction was studied as an initial key step of the total synthesis. Two chain fragments were synthesised as precursors. Hexadienaldehyde was used as the first chain fragment and acetal, silylenolether and hexenbromide were prepared as starting material for the second chain fragment depending on the method applied. The addition reactions were studied using bases, Lewis acids as well as zinc and SmI2. The base-catalysed aldol reaction of both chain fragments, ketoacetal and hexadienaldehyde, were conducted using LDA and produced a mixture of desired aldol addition product and the starting material ketoacetal. Incomplete formation of the aldol addition product was attributed to minor stability of hexadienaldehyde. All attempts to conduct the addition reaction using of zinc and SmI2 were unsuccessful. In addition, Mukaiyama aldol additionens of the silylenolether and the hexendienaldehyde were studied using Lewis acids in order to synthese the aldol product. Coupling of the fragments using TiCl4 and ZnCl2 led to complete decomposition of reactants. The reaction in presence of Yb(OTf)3 did not succeed as well, due to back-formation of the endion. The aldolreaction using TBAF, however, gave a mixture of desired aldol products (66%) and silylenolether. The most successful reaction was the Mukaiyama aldol addition carried out in presence of (±)-BINOL und Ti(O-iPr)4 as a chiral Lewis acid catalyst mixture, which gave desired aldol products as racemic mixture.