Other Diketopiperazines Derived from Tryptophan

Few fungal metabolites consist of a diketopiperazine ring derived from tryptophan and an amino acid other than alanine and proline. Those known in Aspergillus species include ditryptophenaline and D-valyl-L-tryptophan anhydride. 

Ditryptophenaline (56), mp 204-205°C, was isolated from the mycelium of Asp. flavus during the investigation for food-borne mycotoxin by Biichi and coworkers (104). The chemical formula, C42H4QNg04, is assigned on the basis of the high-resolution mass spectrum (m/z 692.3095), and the NMR spectrum indicates a dimeric structure. It possesses a diketopiperazine ring derived from tryptophan and phenylalanine and has UV absorptions at 244 and 303 nm. The chemical structure was determined by single-crystal X-ray experiments. Later, Hino and co- 

D-Valyl-L-tryptophan anhydride (57) was isolated by Stipanovic et al. (106) from cultures of Asp. chevalieri (Margin) Thom and Church together with pre-echinulin (MICAT). The rhombic crystals change to long needles between 235 and 255°C, and 57 melts at 277-279°C. High-resolution mass measurement 

A weakly neurotoxic metabolite, neoxaline (58) 107), mp 202°C (dec.), —16.3° (CHCI3), is described here even though it does not possess a diketopiperazine system in the molecule. It was isolated from cultures of Asp. japonicus (yield, 230 mg/18 liters) (see this treatise, Vol. 22 (1984), p. 317) 108). Its physicochemical properties are very similar to oxaline (59), isolated from Pen. oxalicum, and the unique structure was determined by correlation with oxaline (709). The efficient conversion of roquefortine (60) to oxaline (24.3%) is known (770), and neoxaline is probably also biosynthesized from 60, which has been isolated from Pen. roquefortii 111) as a tremorgenic toxin and has a tryptophan-histidine-derived diketopiperazine system in the molecule. 

---

The authors started their synthesis with the preparation of diketopiperazine 672 from the commercially available D-tryptophan derivative 670 and known N-Chz-protected A-methyl-D-serine (671) (430). Tetracyclic derivative 673 was available through a stereoselective bromocyclization reaction with NBS. Treatment of 673 with more NBS and the radical initiator V-70 led to a two-fold bromination at the diketopiperazine ring ( 674). Hydrolysis with water afforded diol 675 as a major diastereomer in a mediocre yield with three other stereoisomers as side products. 

---