Penicillium brevicompactum brevianamides from

The unique bicyclo[2,2,2]diazaoctane ring system constitutes one of the structural characteristics of brevianamides (Fig. (32)). Brevianamide A (144) was originally isolated from cultures of Penicillium brevicompactum by Birch and Wright in 1969 [98]. Brevianamide A (144) was also isolated from cultures of Penicillium viridicatum by Wilson and coworkers in 1973 [99]. Bird and coworkers observed that 144 is formed only after conidiation has begun in solid cultures of P. brevicompactum [100]. Birch and Russell isolated brevianamide B (145)... 

Brevianamide.—Echinulin (109) is elaborated in Aspergillus amstelodami along a pathway which includes (110) and (111). The structurally related metabolite, brevianamide A (112), isolated from Penicillium brevicompactum, appears to be derived in a similar way. Radioactive mevalonate, proline, and tryptophan gave labelled brevianamide A. Incorporation of cyclo-L-[methylene- C]-tryptophyl-L-[5- H]proline [as (113)] without change in isotope ratio indicated that this precursor was utilized intact for brevianamide A production. As further evidence of its role in brevianamide A biosynthesis (113) has been isolated from P. brevicompactum cultures. By analogy with echinulin biosynthesis, (114) could lie between (113) and brevianamide A (112). Its isolation" (from A. ustus) provides support for this suggestion. 

Following the original isolation, Birch and associates reported the isolation and structural elucidation of brevianamides B - F from Penicillium brevicompactum [8,9]. Brevianamide A is the major fluorescent metabolite produced by this fungus a minor metabolite named brevianamide B, that also exhibited the characteristic y>-indoxyl chromophore, was assigned a structure that was epi-meric to brevianamide A at the spiro-y>-indoxyl quaternary center. The structural assignment for brevianamide B was based primarily on the semi-synthetic conversion of natural (-I-)-brevianamide A into brevianamide B by borohydride reduction and acid dehydration to deoxybrevianamide A subsequent air oxidation provided (-)-brevianamide B [9] (Scheme 1). 

To demonstrate that brevianamide F was incorporated as an intact unit without any hydrolytic degradation and recombination of the constituent amino acids, 9/do-L-[metftjy/ene- C]-tryptophyl-L-[5- H]-proline was prepared ratio = 3.67 1) and fed in two batches of -100 mg to Penicillium brevicompactum. The brevianamide A isolated from these experiments had a ratio = 3.82 1 and 3.74 1 and total incorporations of 3.2% and 3.6%, respectively. The high specific incorporation of 14.0% confirms that brevianamide F is a biosynthetic precursor (Scheme 4). 

A similar pathway is deduced to lead to brevianamide A (7.55), in Penicillium brevicompactum, from tryptophan (7.25) and proline through the diketopiperazine (7.25), which has been isolated from P. brevicom-pactum. A further intermediate may be the Aspergillus ustus metabolite 7.29) (cf. echinulin biosynthesis) [15]. 

The assignment of the structures of the brevianamides A-E, five closely related diketopiperazine metabolites isolated from the mould Penicillium brevicompactum, was based partly on the results of biosynthetic studies and biogenetic considerations The presence of an indole unit and a diketopiperazine ring in the brevianamides suggested the possibility of the formation of these metabolites from L-tryptophan and L-proline (101) with the additional C5 unit in the molecules originating in mevalonate (102). Biosynthetic evidence to support this conclusion was obtained in the case of brevianamide A (105). Thus DL-3-[ CJ-tryptophan and L-U-[ C -proline were both readily incorporated into the... 

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