Citrinin
Citrinin (116) (Fig. 3.1), first reported in 1931 following its isolation from Penicillium citrinum (67), was found to display a significant antibiotic activity against several Gram-positive bacteria in the 1940’s (68, 69). In the following decade (at the
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3.1
General
Citrinin (116) (Fig. 3.1), first reported in 1931 following its isolation from Penicillium citrinum (67), was found to display a significant antibiotic activity against several Grampositive bacteria in the 1940’s (68, 69). In the following decade (at the time of the widespread application of penicillin), there was a considerable interest in citrinin (116) and other antibacterials of fungal origin. Despite this, and its additional insecticidal properties (70), the investigation of 116 for either therapeutic or agrochemical application was abandoned due to its substantial toxicity (71), including nephrotoxicity (72). Both Whalley and co-workers and Cram published extensively on the stereochemistry of citrinin (116) in the 1940’s, particularly through the use of degradation studies (73, 74). Further stereochemical data were later provided from X-ray analysis (75). In particular, the (3R,4S)-configuration was determined by comparison of degradation products with compounds of known stereochemistry (76, 77). In addition to these degradation studies, a prominent product of degradation, “phenol B” (117) (Fig. 3.1), was utilized by several groups for enantioselective and racemic syntheses of the natural product (78, 79).
HO HO HO 2C
O
O
OH O
O
OH O
HO2C
117 ('phenol B')
OH 116 (citrinin)
O
O
O
O HO
OH
O
OHC OCHO OH
119 (citrinin H1)
120 (dicitrinin A)
118 (citrinin H2)
Fig. 3.1 Citrinin (116) and derivatives of interest S. Bra¨se et al., The Chemistry of Mycotoxins, Progress in the Chemistry of Organic Natural Products, Vol. 97, DOI 10.1007/978-3-7091-1312-7_3, # Springer-Verlag Wien 2013
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3 Citrinin
Citrinin (116) has an interesting structure: as a hydroquinone activated towards nucleophilic attack, and as a potential participant in redox processes, consistent with a variety of toxic effects in biological systems. Many derivatives of 116 were also isolated by various groups, including those reported by Curtis et al. in 1968 (80). Under certain conditions (aqueous decomposition with heating), a decarboxylated and ring-opened derivative, citrinin H2 (118), was isolated and shown to have greatly diminished cytotoxicity (81). Under similar conditions, the formation of a notably toxic derivative of citrinin (116), citrinin H1 (119) (Fig. 3.1), has been observed (82). In more recent times, a new dimeric species, dicitrinin A (120) has been identified by Capon et al. at the University of Queensland (83). This compound also occurred as an artifact, generated during handling and storage of biological extracts of the organism of origin.
3.2
Total Syntheses of Citrinin
The Barber and Staunton synthesis of ()-citrinin (rac-116) was reported in 1986 (84). This synthesis employed selective benzylic lithiation as a key transformation, and was followed shortly thereafter by an asymmetric variant to give access to (+)-citrinin (the unnatural stereoisomer of 116). The synthesis pathway started with the lithiation of ethylbenzene 121 at the benzylic position, followed by acylation of the toluat
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