Brevianamide structure

An intramolecular cycloaddition also occurred with 3-ylidenepiperazine-2,5-diones such as 124 or 125, obtained by Wittig-Horner-Emmons reaction from phosphonate 121 and aldehydes 122 or 123, respectively. The products of the Diels-Alder reaction are the bridged bicyclo[2.2.2]diazaoctane rings 126 and 127 that have been found in biologically active secondary metabolite such as VM55599 and brevianamide A. The different type of structures employed in this case requires a chemoselective reaction in order to produce the expected products as single diastereoisomers after 20 days (Scheme 18) <2001JOC3984>. 

Penicillium brevi-compactum has yielded a group of neutral compounds which have been called the brevianamides. Brevianamides A and E have been examined in detail, and assigned structures on the bases of spectral measurements, some simple transformations and, most importantly, an intuitive combination of these data with the experimentally proven biogenetic precursor units. 

The structure (23) proposed for brevianamide A has been confirmed" crystal structure analysis of its 5-bromo-derivative (24). 

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. 

Non-terpenoid Alkaloids.— The structure (14) adduced for austamide, a metabolite from Aspergillus ustus, is based principally on a thorough n.m.r. analysis [see data on (14)]. Like the brevianamides it is made up of proline,... 

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). 

The most intriguing feature of the final assembly of brevianamides A and B is the mechanism of formation of the novel bicyclo [2.2.2] ring system common to this family of metabolites. Porter and Sammes [14] were the first to suggest the involvement of an intramolecular Diels-Alder reaction for the formation of this ring system and drew the structure shown in Fig. 2 to illustrate this provocative idea. 

These experiments clearly indicate that the C5 units in paraherquamide A are introduced in stereofacially distinct manners. Since it has been established that prenylation of the indole moiety in the biosynthesis of the structurally related brevianamides occurs in an analogous fashion to that postulated for paraherquamide A [19], the prenyl transferase that installs this C5 unit must display DMAPP to the 2-position of the indole in a n-facially indiscriminate manner. 

The authors speculate about the incorporation of the reverse prenyl unit in this and related molecules such as echinulin, lanosulin, oxaline, austamide, and the brevianamides and infer the rearrangement of the N-prenyl to the reverse 2-prenyl structure as shown in Scheme 22. These workers investigated the involvement of the 2-position of the indole by deuterium labeling using an auxotrophic mutant strain of Penicillium roqueforti that was apparently deficient in anthranilate synthetase. 

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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