Aerothionin structure

Thompson et al. have investigated the ecological role of the brominated isoxazoline alkaloids, aerothionin (Structure 2.84) and homoaerothionin (Structure 2.89), in Californian specimens of A. fistularis.134 139 The alkaloids caused behavioral modification in marine invertebrates, were toxic to dorid nudibranchs other than one specialized feeder, inhibited the settlement and/or metamorphosis of invertebrate larvae, and were strongly antimicrobial and cytotoxic. Sponges exuded significantly more of these two alkaloids when wounded,155 and, consistent with their defensive role, the metabolites were found to be localized in spherulous cells close to the aquiferous exhalant canals.156... 

The Mexican sponge Aplysina gerardogreeni contains calafianin (2106) (1880) (structure revised and confirmed by total synthesis, (1881-1883)), the known aerothionin, and the new phenylacetic acid 2107 (1880). These studies confirm that calafianin (2106) and aerothionin have the same absolute configuration (1883). Whereas aerothionin displays antibacterial activity against Mycobacterium tuberculosis, calafianin does not (1884). The Brazilian sponge Aplysina caissara contains the new caissarines A (2108) and B (2109) (1885). 

Aerothionin, a tetrabromo derivative, has been isolated from sponges Aplysina aerophoba and Verongia thiona the proposed structure is 24 (46). The oxime 25 was formed by treatment of aerothionin with dilute alkali. The relative positions of the aromatic substituents in 25 were established by cleavage in hot 6 N HC1 to give 26 and a lactone subsequently converted by methylation to 27. The tetramethyl derivative of 25 was hydrolyzed to form... 

Ten years later the same aerothionin was isolated from a different sponge. X-Ray structure determination in addition to CD data were employed to assign its absolute configuration (47). 

The planar structure, except the geometry of a C8 double bond, was initially proposed shown in Fig. (9) by the detailed analysis of ID and 2D NMR (COSY, HMQC and HNBC) data and by comparison of its and NMR spectra with those of structurally related compounds such as aerothionin (18), purealin (19) and others [30-41]. Although the DQF-COSY spectrum of 17 showed few H- H correlations, the HMBC spectrum was very useful for elucidating the planar structure of 17. The geometiy of C8 double bond was elucidated by a NOESY H7 /NH correlation to be trnas. The relative stereochemistry of 17 was clarified by... 

Kigoshi and co-workers recently isolated zamamistatin (17) from a sponge Pseudoceratina sp. [42]. In the spectral analysis of 17, they found tW the chemical shift of C6 (5ce 74.3) and C7 (8c 26.7) in 17 were different from those (See 91.5 and 8cy 40.2) of aerothionin (18), which let them reconsider its structure, Fig. (12). Considering the molecular formula of 17, they proposed a structure possessing a dihydro-1,2-oxazine ring for 17. To confirm this, they prepared dihydro-1,2-oxazine derivatives, 17a and 17b, Scheme (6) [42-45] and compared the CNMR data for 17 with those of 17a, 17b and the known 17c [45]. The CNMR data of synthetic 17a and 17b were similar to those of zamamistatin (17) rather than aerothionin-related compounds, Fig (12). Base on these observations it was concluded that the structure of zamamistatin should be revised to an endo-type dimmer. 

Bromo-Olefins from Verongia Sponges.—Full details have been published on the structural elucidation of the bromo-compounds Aeroplysinin-1, Aerothionin, and Homoaerothionin isolated from Verongia sponges. In addition, a new bromo-compound, designated Aeroplysinin-2, has been isolated from the same source, which has added further sustenance to biosynthesis commentary among this closely related group of compounds. 

Structurally related to aerothionin and homoaerothionin, caissarine B (76), recently isolated from the Brazilian sponge Aplysina caissara, is the only bromo-tyrosine-derived alkaloid bearing a l,7-diamino-3-hydroxyheptane chain, a diamine moiety that has no precedent among natural products (66). 

The two more complex brominated metabolites (7 and 8) obtained from V. aerophoba were also isolated by Moody and Thomson from V. thiona and accordingly named aerothionin and homoaerothionin. Structural elucidation of these two spirocyclohexadienylisoxazoles was the result of a collaborative effort between the Laboratories in Aberdeen (Scotland) and Naples (Italy) (82). 

Aerothionin (7), the major component in both species (10% of dry V. aerophoba), C24H26Br4N40s, is optically active, [a]o + 252°, and shows max 284 nm (cisoid diene, cf aeroplysinin-1). The symmetrical structure is reflected in the simplicity of the n.m.r. spectrum, which shows singlets for olefinic, CHOH (singlet after D2O exchange) and methoxy-protons at 5 6.50, 4.18 and 3.72. An isolated methylene group in an asymmetric environment is indicated by an AB quartet with line positions at 6 3.84 and 3.14 (J 18 Hz) p. p. m. A C4 saturated chain is suggested by a methylene multiplet at 5 3.34 coupled to another methylene multiplet at 6 1.60. Mild basic treatment of aerothionin converts it quantitatively into the isomeric... 

Bearing in mind the structure and properties of aeroplysinin-1 (4), a co-metabolite in V. aerophoba, it was clear that aerothionin must have structure (7). Its rearrangement to the phenol (12) is straightforward (Chart 2, arrows). 

The very closely-related homoaerothionin was found in smaller quantity in both V. aerophoba and V. thiona. Its structure (8) was established by analogy with that of aerothionin 80). A full account of the work on both aerothionin and homoaerothionin, which includes discussions of the mass spectra of the parent compounds and their derivatives, has been published 143). The structure of aerothionin has now been confirmed by X-ray analysis, which also revealed the relative stereochemistry (O —H and O —N trans) 62a). The spiro systems in (7) and (8) could arise in various ways including nucleophilic attack by an oxime function on an arene oxide (15). Following suggestions that nitriles may be derived in vivo from a-aminoacids by way of a-keto- and a-oximinoacids 174), we... 

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