Antifungal metabolites

An application of this strategy to the synthesis of the antifungal metabolite ( )-avenaciolide 182 is shown in Scheme 4183. The photoadduct in this case, 178, was hydrogenated and hydrolyzed to give 179. Reaction of 179 with vinylmagnesium bromide and subsequent manipulation afforded aldehyde 180, which could be transformed via ozonol-ysis, epimerization of the dialdehyde and acidification of the dialdehyde acetonide to protected bis(lactol) 181. Oxidation and methylenation then afforded the desired target 182. 

Brown AG Smale TC, King TJ, Hasenkamp R, Thompson RH. (1976) Crystal and molecular structure of compactin, a new antifungal metabolite from Penicillium Brevicompactum. J Chem Soc, Perkin Trans 1 1165-1170. 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

Indcio ML et ai, Antifungal metabolites from Colletotrichum gloeosporioides, an endophytic fungus in Cryptocarya mandioccana Nees (Lauraceae), Biochem Syst Ecol 54 822-824, 2006. 

Adeoye, A. O., Oguntimein, B. O., Clark, A. M. and Hufford, C. D. 1986. 3-Dimethylallylindole An antibacterial and antifungal metabolite from Monodora tenuifolia. Journal of Natural Products, 49 534-537. 

Fernandez, R. Dherbomez, M. Letoumeux, Y. Nabil, M. Verbist, J.F. Biard, J.F. (1999) Antifungal metabolites from the marine sponge Pachastrissa sp. new bengamides and bengazole da-ivatives. J. Nat. Prod., 62, 678-89. 

Assignment of the relative configuration of the Claisen rearrangement product rac-10 (p 425) by conversion to the antifungal metabolite avenaciolide (11) in its racemic form5,26S. 

Nuclear magnetic resonance (NMR) spectroscopy, with X-ray analysis, forms the basis for the determination of the structures of most of the compounds discussed in this chapter. H and 13C NMR played a key role in the revision of the structure of the antifungal metabolite strobilurin D 2, which was shown to contain a benzodioxepin moiety rather than epoxide <1999T10101>. 9-Methoxystrobilurin K was also shown to contain a 1,4-benzodioxepin <1997TL7465>. 

The ascidian Lissoclinum japonicum from Palau contained the antimicrobial and antifungal metabolites N,N-dimethyl-5-(methylthio)varacin and 3,4-dimethoxy-6-(2 -iV,./V-dimethylaminoethyl)-5-(methylthio)benzotrithiane, both of which were isolated as the trifluoroacetate salts <1994T12785>. They selectively inhibit protein kinase. Also, varacin and three new antimicrobial marine polysulfides, varacins A-C, were isolated from the Far Eastern ascidian Polycitor sp. <1995JNP254>, extracted from the New Zealand ascidian Lissoclinum notti <2002T9779>. 

Wicklow DT, Joshi BK, Gamble WR, Gloer JB, Dowd PF (1998) Antifungal Metabolites (Monorden, Monocillin IV, and Cerebrosides) from Humicola fuscoatra Traaen NRRL 22980, Mycoparasite of Aspergillus flavus Sclerotia. Appl Environ Microbiol 64 4482... 

Anke T, Besl H, Mocek U, Steglich W (1983) Antibiotics from Basidiomycetes. XIII Strobilurin C and Oudemansin B, Two New Antifungal Metabolites from Xerula Species (Agaricales). J Antibiot 36 661... 

The same research group reported a formal synthesis of avenaciolide, an antifungal metabolite (Scheme 3.27) [58], In this case, the oxetane (obtained in multigram quantities in high yields and with complete stereochemical control) was treated with hydrogen to give the saturated compound. The key step in this synthetic procedure is a reaction with ozone followed by a base-catalyzed epimerization with potassium carbonate and cyclization in acidic medium. 

An early stage in the synthesis of the antifungal metabolite FR-900848 exploited a double Simmons-Smith cyclopropanation directed by two di-isopropyl tartrate acetals [Scheme 2.42] 9192 The diastereoselectivity of the reaction can be attributed to intramolecular delivery of a zinc carbenoid co-ordinated to one of the ester carbonyls and an oxygen of the dioxolane ring.93 Note the use of the Noyori protocol (see above) for the bis-dioxolanation of the highly reactive mu-conaldehyde ... 

Trost et al. have exploited the Cp2TiCl-promoted 6-exo cyclization of 10 to 13 for the first enantioselective biomimetic total synthesis of the antifungal metabolite (-)-siccanin (15) (Scheme 21) [109]. These authors also observed a minor amount (20%) of by-product 14, presumably derived from the radical intermediate 12 by a process reminiscent of the Sr2 reaction described by Gansauer s group [66]. They took advantage of 14 for the preparation of (-)-5-epz-siccanin (16) (Scheme 21) [109]. 

Mycosubtilins were isolated by Peypoux et al. in 1976 as antifungal metabolites from B. subtil is. The constituent amino acids of mycosubtilin D are the same as those of iturin A, but the peptide sequences differ(Fig. 

The Patemo-Buchl reaction of furan and various aldehydes was shown to be a highly stereoselective photochemical version of the aldol reaction by S.L. Schreiber and co-workers in which the furan serves as an enolate equivalent. This strategy was applied to the total synthesis of the antifungal metabolite (+)-avenaciolide. The photocycloaddition of nonanal with excess furan proceeded in nearly quantitative yield, and the two out of the three required stereocenters were created in a single step. The photocycloadduct was first hydrogenated then hydrolyzed under acidic conditions. 

Canadensolide (6.18) is an antifungal metabolite of Penicillium canadense that was reported in 1968. Its dilactone structure was established by a combination of spectroscopic and chemical methods. Thus the presence of the exocyclic methylene was suggested by the IR data and established by ozonolysis to give formaldehyde whilst the presence of the vicinal diol as part of the dilactone was indicated by the coupling pattern in the NMR spectrum and confirmed by hydrolysis and cleavage of the resultant diol with sodium periodate to give valeraldehyde (pentan-l-al). There is a similarity between these metabolites and avenaciolide (6.19), a metabolite of Aspergillus avenaceus. 

Various other functionalization procedures have been developed and all have been summarized in detail in a recent review10. Some representative examples should be mentioned synthesis of the antifungal metabolite ( )-avenaciolide (6)74, the mycotoxin asteltoxin (7)75,76 and the antileukemic cembranolide isolobophytolide (8)77. 

Antifungal metabolites (O-heterocycles) produced by micromycetes 00CLY21. 

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