Biosynthesis of the Cytochalasans. Biosynthetic studies on chaetoglobosin A and 19‐O‐acetylchaetoglobosin A

Abstract

Incorporation of [1‐13C]‐, [2‐13C]‐ and [1,2‐13C2]‐acetate, [1‐13C]‐propionate, [13C‐CH3]‐L‐methionine and [3‐14C]‐DL‐tryptophan into chaetoglobosin A (1) and 19‐O‐acetylchaetoglobosin A (2) by Chaetomium globosum demonstrated that the building blocks of 1 and 2 are 9 and 10 units of acetate/malonate respectively, 3 units of methionine and 1 unit of tryptophan. Propionate is incorporated indirectly after several biological transformations. Using [2‐13C, 2‐2H3]‐acetate as precursor, the starter unit of the polyketide‐chain was identified. Experiments which [13C, 2H3‐CH3‐L‐methionine demonstrated that the three C‐methylations occur with retention of all three H‐atoms of the methyl group. Incorporation experiments with various 14C‐ and 3H‐labelled tryphtophan samples and with [2‐2H]‐ and [2‐15N]‐L‐tryptophan showed that the amino acid is incorporated intact with retention of both the α‐H‐ and the α‐N‐atom. On the basis of these results a more detailed general scheme of the cytochalasan biogenesis is proposed.

Chemistry and Biology of Biosynthetic Diels–Alder Reactions

“…. [25,26] Biosynthetic Diels-Alder Reactions [30,31] propionate, [30,31] methionine, [31,32] phenylalanine, [33] and tryptophan [31] as biosynthetic precursors to the cytochalasans. The perhydroisoindole group of cytochalasin A (50) and B (51) is thought to arise through an endo-selective intramolecular Diels-Alder reaction (Scheme 11).…”

Phytotoxic chaetoglobosins are produced by the plant pathogen Calonectria morganii(anamorph Cylindrocladium scoparium).

“…Chaetoglobosins belong to cytochalasans, C18-polyketides well known for their multiple biological activities (Umeda et al, 1975) linked to an amino acid. In chaetoglobosins, the benzyl group of cytochalasans is replaced by a 3-indolyl group; i.e., chaetoglobosins are formed from a tryptophan unit instead of phenylalanine in other cytochalasans (Probst and Tamm, 1981). Chaetoglobosin A and some derivatives were originally isolated and structurally characterized from the ascomycete Chaetomium globosum (Sekita et al, 1973), a fungus that routinely occurs on rotting plant material.…”

“…We are currently looking for the distribution of chaetoglobosins and cyclic peptides in different isolates and for the genes encoding the respective polyketide synthases and nonribosomal peptide synthetases. Measured values are compared to data published by Probst and Tamm (1981). …”

“…3. The NMR data obtained for the larger toxic compound (19-O-acetylchaetoglobosin A) are given in Table 1 and compared to data taken from Probst and Tamm (1981).…”

First Stereoselective Synthesis of Penicillenol A1 via Novel O- to C-Acyl Rearrangement of O-Acyltetramic Acid

“…1 Penicillenol A 1 (1) has been identified as a potent cytotoxic agent (HL-60, IC 50 = 0.76 mM), displaying much higher activity than penicillenol A 2 (2). Although their planar structures and the absolute stereochemistry of the chiral center at C5 were elucidated by the analysis of NMR and CD spectra, absolute configurations of the C6 and C9 stereocenters remained unspecified.…”