(+)-Zwittermicin A: Assignment of its Complete Configuration by Total Synthesis of the Enantiomer and Implication of D-Serine in its Biosynthesis

摘要

(+)-Zwittermicin A (1; Figure 1), a water-soluble natural antibiotic that was reported in 1994 and isolated from the fermentation of the soil-borne bacterium Bacillus cereus, shows significant activity against phytopathogenic fungi. Most importantly, 1 synergizes the bioactivity of the endotoxin produced by Bacillus thuringensis (BT), a "green" insecticide which is used globally for the protection of vegetable crops and for the eradication of gypsy moth from forest trees. BT toxin and related biocontrol agents are important commodities used in the fight against declining agricultural production and rising third world food shortages. The biosynthesis of the sugarlike natural product 1 is very unusual; the molecule does not derive from carbohydrate metabolism, as the structure may suggest, but instead arises from a non-ribosomal peptide synthetase/polyketide synthase (NRPS/PKS) pathway that starts with an activated serine unit (Ser; C13-C15, zwittermicin A numbering). Zwit-termicin A is the first polyketide described in which the two-carbon chain extensions occur by condensations of three-carbon units (and subsequent loss of CO2), derived from hydroxymalonate (HM; C7—C8), aminomalonate (AM; C9— C10), and the more common extender, malonate (C11— C12).