Brevianamide

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. 

Cyclopiazonic Acid.—Cyclopiazonic acid (115) is formed in Penicillium cyclopium from mevalonate, tryptophan, and an acetate-derived C4 unit [heavy bonding 

Ergot Alkaloids.—The elaboration of the tetracyclic ergoline skeleton, as represented by agroclavine (122), is more complex than cursory examination 

Schabort, International Symposium on the Control of the Human Environment, Abstract, p. 62, Johannesburg, 1969 quoted in ref. 118. 

In the conversion of chanoclavine-I (119) into elymoclavine (123) one of the C-17 hydrogens is lost. (The other appears at C-7 of elymoclavine as expec-ted.) This suggested that the aldehyde (124) might be an intermediate. This was strongly supported by the efficient incorporation of (124) into elymoclavine tritium label from C-17 in the precursor appeared at C-7 of the product OH 

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The reactivity of compound 113 toward reactive linear and cyclic dienophiles was reported in a study directed to find a model systems for the proposed [4+2] cycloaddition in the biosynthesis of the natural products brevianamides, paraherquamides, and marcfortines. With DMAD and diethyl azodicarboxylate the formation of 114 and 115 was almost quantitative after 48 h at 80 °C (Cbz = Carbobenzyloxygroup). When relatively unreactive dienophiles such as cyclopentene and cyclohexene were used, harsh reaction conditions and/or a Lewis acid catalyst are necessary for the formation of 116a and 116b (Scheme 16). In contrast, the analogous intramolecular reaction carried out on compound 117 takes place within a few hours at room temperature, even in the absence of a Lewis acid catalyst, to give 118 in 42% yield (Scheme 16) <2000T6345>. 

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>. 

Cox RJ, Williams RM, The paraherquamides, brevianamides and asperparaline Laboratory synthesis and biosynthesis. An interim report, Acc Chem Res 36 127-139,2003. 

The same strategy has been used by Williams (90JA808) in his synthesis of brevianamide B. The aldehyde (82), prepared enantioselectively from L-proline, was converted to the silyl ether. Acylation of this (BuLi, ClC02Me) gave the carbomethoxy derivative as a mixture of diastereo-mers, which was alkylated by gramine. As before, an enolate alkylation (Sn2 ) on an allyl chloride derived from the above gave the tricyclic compound, which could be transformed to brevianamide B (Scheme 24). 

As part of on going efforts of Williams and his coworkers [46] to elucidate the biosynthesis of the core bicyclo[2.2.2] ring system of the related alkaloids the brevianamides [51], they have applied methodology originally developed for the stereocontrolled total synthesis of (-)-brevianamide B [52] to complete the first stereocontrolled total synthesis of (+)-PHB. 

Mould Metabolites.—A second synthesis of deoxybrevianamide E has been reported 300 in essence, it is similar to the earlier synthesis,306 the major difference being simply the order in which the various stages are effected. Photochemical oxidation of deoxybrevianamide E (34a) provides the first satisfactory laboratory synthesis of brevianamide E (34b), which was obtained in 42% yield, together with its stereoisomer, the alternative cis-fused cyclization product. The stereochemistry depicted in (34b) rests on a comparison of the n.m.r. spectra of these two stereoisomers.300... 

Brevianamide A, an indole alkaloid from Penicillium, was isolated first and later its derivatives C and D were detected. In a simple experiment it could be demonstrated that C and D were formed when the fungus was grown in the light but were not found under light-exclusion conditions. This observation clearly indicates a... 

Fig. 26 Brevianamide A conversion into its isomers brevianamide C and D by exposure to light...

Details of Kametani s synthesis of deoxybrevianamide E and brevianamide E have been published.23... 

The semipinacolic rearrangement of 2-hydroxyimines has also been applied to the synthesis of 2-amino ketones which are not easily available by other methods (equation 43). ° An impressive example is the biomemetic formation of the spiroindoxyl brevianamide A (32 equation 44). ... 

Gliotoxiii.—In contrast to the recent report that the cyclic dipeptide (121) is not incorporated into gliotoxin (123) in Penicillium terlikowskii, it has recently been found that this cyclic dipeptide, with both constituent amino-acids labelled, is efficiently incorporated into gliotoxin (123) in Trichoderma viride and without alteration in isotope ratio. Thus, (123), like brevianamide A and echinulin, originates from a cyclic dipeptide. The difference in the two results could be due to the different organisms used in the two experiments, but is was suggested that the probable reason was associated with the large excess of (121) used in the first experiment. 

In connection with the synthesis of naturally occurring 3a-hydroxypyrroloindole derivatives, e.g. brevianamide E and sporidesmin A, it is of interest to note that the photosensitized oxidation of Nb-methyltryptamine with singlet oxygen affords the 4a-hydroxyoxazinoindole (8a) and the 3a-hydroxypyrroloindole (8b) via the 3a-hydroperoxy compound (8c) (Scheme 2). 

In the brevianamide series brevianamide A has been isolated from Penicillium... 

Synthesis and biosynthesis of paraherquamides, brevianamides, and asperpar-alines, bicyclo[2.2.2]diazaoctane derivatives 03ACR127. 

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